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THE

american Journal of Pharmacy

PUBLISHED BY AUTHORITY OF THE

PHILADELPHIA COLLEGE OF PHARMACY

EDITED BY

HENRY KRAEMER

— *M jxxM^T

PUBLICATION COMMITTEE FOR 1914

SAMUEL P. SADTLER M. I. WILBERT

JOSEPH W. ENGLAND CHARLES H. LaWALL

JOSEPH P. REMINGTON JOHN K. THUM

AND THE EDITOR

VOLUME 86

PHILADELPHIA 1914

THE AMEEIOAN

JOURNAL OF PHARMACY

JANUARY, 1Q14

THE ASSAY OF MERCURIC CHLORID TABLETS.

^^^_^B/Robert M. Chapin, Bureau of AmmaTlndustry, U. S. Department of Agriculture.

At the present time mercuric chlorid tablets, especially those prepared after the well-known Wilson formula, are very widely used, and are used moreover with implicit confidence in the accuracy of their declared content of mercuric chlorid under circumstances whic*h render such accuracy a matter of considerable importance to individual welfare and to the public health in general. There can be no question of the desirability of assay methods which shall be fairly accurate, yet simple and rapid enough to be freely used by manufacturers, pharmacists, hospitals, and sanitary officials at a minimum of expense and chemical equipment.

Several years ago Rupp 1 proposed a rapid method for the deter- mination of mercury in various compounds, involving the following steps : ( 1 ) Reduction to metallic mercury by formaldehyde in alkaline solution in presence of potassium iodid ; (2) solution of the precipi- tated mercury in excess of standard iodin solution after acidification with acetic acid ; and (3) titration of excess iodin by standard sodium thiosulphate. A modification of the method is now official in the German Pharmacopoeia for the assay of tablets composed of mer- curic and sodium chlorids.

In this country Smith 2 has thoroughly studied the Rupp method when applied to pure mercuric chlorid,. obtaining, when certain modi-

1 Rupp, E. Ueber die volumetrische Bestimmung des Quecksilbers. Be- richte der Deutschen Chemischcn Gesellschaft, Vol. 39, No. 14, pp. 3702-3704. Berlin, Nov. 10, 1906.

2 Smith, Carl E. Volumetric determination of mercury. American Journal of Pharmacy, Vol. 83, No. 7, pp. 311-315. Phila., July, 191 1.

(1)

2

Mercuric Chi or id Tablets.

f Am. Jour. Pharm. \ January, 1914.

fications were introduced, a recovery of 99.8 to 100.3 Per cent- of the mercuric chlorid employed. Smith's modifications involved (1) the use of a larger amount of substance and reagents to reduce experimental errors, (2) a longer time of action by formaldehyde to insure complete reduction to metallic mercury, and (3) a much less degree of acidification before addition of iodin, since large amounts of free acetic acid tend to produce low results. Smith states that similarly good quantitative results were obtained when the method was applied to mixtures of mercuric chlorid and ammonium chlorid colored with aniline dyes. That is, the modified method is implied to be applicable to commercial tablets prepared after Wilson's formula (mercuric chlorid, 7.3 grains; ammonium chlorid, 7.7 grains; coloring matter, q.s.).

In this laboratory Smith's statements and results were con- firmed on solutions of pure mercuric chlorid. Utter failure, however, followed attempts to apply his method either to commercial tablets or to similar laboratory mixtures of mercuric and ammonium chlorids. Abnormal precipitates appeared after addition of iodin, and results obtained were erratic and much too low. At the same time the method given in the German Pharmacopoeia, slightly modified, was found to work smoothly and quantitatively.

The addition of formaldehyde to a solution of ammonium salts produces hexamethylenamin, which is known to form difficultly solu- ble compounds with both iodin and mercuric salts.3 In Smith's modification, then, conditions appear to be such as to permit the formation and separation of hexamethylenamin compounds to the resultant vitiation of the process, while in the method of the German Pharmacopoeia the greater dilution at which the process is worked either inhibits the formation of such interfering substances, or, more probably, is sufficient to retain them in solution and hence in a harm- less condition. At all events, if, in addition to other minor modifi- cations later to be noted, a volume of 75 c.c. of water is added at the time the contents of the flask are acidified before the addition of iodin, no abnormalities appear in the working of Smith's process, and the results are equally accurate in the presence or absence of ammonium chlorid.

Inasmuch as the method finally chosen here as most satisfactory is

3 Cohn, G. Die Verbindung des Urotropins. Pharmazeutische Zentral- halle, Vol. 52, No. 44, pp. 1173-1179. Dresden, Nov. 2, 191 1.

Am. Jour, pharm. | Mercuric Chlorid Tablets.

January, 1914. j

3

somewhat different in details from either of the two modifications already noted, the points of difference and the reasons therefor will be discussed.

In the first place, while it is true that the use of large amounts of substance and reagents tends to reduce the relative magnitude of experimental errors, there is a point beyond which any slight possible gain in accuracy is attained only at the sacrifice of an unwarranted measure of simplicity, convenience, and rapidity. It is certainly open to question whether this point is not passed by Smith's modification with its considerable consumption of standardized solutions, espe- cially when the total volume of liquid worked with is increased by the 75 c.c. of water here found necessary to prevent interference by hexamethylenamin compounds. The writer therefore recommends the employment of 0.20 to 0.25 gram of mercuric chlorid for each test, and the addition of 25 c.c. of tenth-normal iodin.

Experiment 1. — To test the limits within which the results of parallel determinations may fall if the above proportions are used, a series of seven parallel tests were made on a solution of commercial tablets, using the equiva- lent of one-half tablet for each test. Aside from the use of volumetric apparatus which had passed the requirements of the Bureau of Standards, no precautions not employed in ordinary quantitative work in any laboratory were observed. The cubic centimetres of iodin solution (tenth-normal X 0.978) consumed in the solution of mercury were as follows: (1) 17.72; (2) 17.73; (3) 17.68; (4) 17.69; (5) 17.72; (6) 17.73; (7) 17-65; an extreme difference of 0.08 c.c. The average weight of mercuric chlorid per tablet was therefore found to be from 0.4677 to 0.4698, a difference of 0.45 per cent. The range of variation reported by Smith in a series of five tests by his method on pure mercuric chlorid was 0.5 per cent.

Secondly, the proportion of potassium iodid should be consider- ably increased over that employed by either Rupp or Smith in order to avoid the formation of mercurammonium compounds which result when caustic alkali in excess is added to a solution containing potas- sium mercuric iodid and ammonium salts, as in the well-known " Nessler test."

Thirdly, the presence of ammonium salts in one way or another operates to retard the reduction to metallic mercury so that it is not complete in 5 minutes though apparently so after 10 minutes.

Lastly, commercial formaldehyde solutions often contain foreign substances, some of which conceivably may consume iodin, and in fact such solutions have here been found which did possess this

4

Mercuric Chlorid Tablets. \ A™- Jour- ftj*-

l January, 1914.

power in slight but distinct degree. Hence a standard thiosulphate solution should be made the basal standard against which the iodin solution is standardized by running a blank assay with the other solutions and reagents intended for actual use.

The method finally chosen for tablets after Wilson's formula is as follows : Weigh 5 tablets, dissolve in water, dilute to 100 c.c, and pass through a dry filter, discarding the first 20 c.c. of filtrate. From the remainder pipette 10 c.c. (equivalent to one-half tablet) into a glass-stoppered 250 c.c. Erlenmeyer flask, add 2l/2 grams pure pow- dered potassium iodid, mix to entirely dissolve, and then wash down the sides of the flask with 20 c.c. of normal caustic alkali. Add exactly 3 c.c. of 37 per cent, formaldehyde solution, mix thoroughly, and let stand for at least ten minutes, swirling the flask occasionally. Then wash down the sides of the flask with a mixture of 5 c.c. of 36 per cent, acetic acid with 25 c.c. water; mix, and without delay run in from a burette 25 c.c. of tenth-normal iodin while constantly swirling the flask. Stopper the flask tightly, shake vigorously for three minutes, then after giving the contents a final swirling motion leave at rest for two minutes. If then no undis- solved mercury can be detected at the bottom the stopper is removed, rinsed, together with the neck of the flask, with a stream from a wash-bottle, and the excess iodin titrated with tenth-normal sodium thiosulphate, adding starch solution only when the iodin is nearly consumed.

Standardize the iodin solution by running a blank assay on 10 c.c. distilled water.

Subtract the volume of thiosulphate solution used in the assay from that used in the blank. The difference multiplied by the factor 0.0271 for strictly tenth-normal sodium thiosulphate will give the average weight of mercuric chlorid per tablet. For a direct check upon the value of the sodium thiosulphate solution run an assay on 10 c.c. of a 2.y2 per cent, solution of mercuric chlorid of known purity.

While mercuric chlorid is the important active ingredient of tab- lets made according to Wilson's formula, nevertheless ammonium chlorid is an essential part of the formula, added in order to render the tablets easily soluble and to inhibit the formation of insoluble, and hence inactive, compounds of mercury. An assay of such tablets

Am. jour, pharm. \ Mercuric Chlorid Tablets. 5

January, 1914. j ^

ought therefor to include an estimation of ammonium chlorid, espe- cially when a simple and convenient method is available.

The method for ammonium chlorid here adopted is an adaptation of the process of Ronchese,4 which is based on the reaction between formaldehyde and a neutral ammonium salt, whereby methylenamin, (CH2)fiN4, is formed, the acid originally contained in the ammo- nium salt being released and becoming titratable with standard caustic alkali and phenolphthalein. The strengths of reagents, etc., recommended by Wilkie 5 have been adopted.

Titration by standard alkali and phenolphthalein can not of course be conducted in presence of mercuric chlorid. This difficulty, however, is easily overcome by throwing the mercury into a complex ion through the addition of potassium iodid. The method is as fol- lows: Into each of two 150 c.c. Erlenmeyer flasks pipette 5 c.c. (one- fourth tablet) of the tablet solution previously prepared for the esti- mation of mercuric chlorid (5 tablets per 100 c.c.) and add to each flask 2 c.c. of a 20 per cent, solution of potassium iodid.

Dilute one volume of 37 per cent, formaldehyde solution with three volumes of water, measure 20 c.c. of the mixture into a small flask, add 0.5 c.c. of phenolphthalein indicator solution, neutralize with tenth-normal barium hydrate or caustic alkali, then flow the solution over the sides of one of the flasks (flask A) containing tablet solution, and mix well. To the other flask (flask B) containing tablet solution add about 65 c.c. water.

Now add to flask A 25 c.c. water and titrate with tenth-normal barium hydrate or tenth-normal caustic alkali free from carbon dioxid until, by using flask B as a standard for comparison, a color change is perceptible (titration A).

Add methyl red to flask B and titrate with either tenth-normal acid or alkali as needed (titration B).

To titration A add titration B if performed with acid, or subtract if performed with alkali. The resultant figure multiplied by the factor 0-.0214 for strictly tenth-normal alkali will give the average weight of ammonium chlorid per tablet.

4 Ronchese, A. Nouveau procede de dosage de rammoniaque. Journ. de Pharmacie et de Chimie, Vol. 25, No. 12, pp. 611-617. Paris, June 16, 1907.

5 Wilkie, John M. The Ronchese method of determining ammonia and its extension to the determination of the total acid content of organic am- monium salts and ammoniacal solutions. Journal of the Society of Chemical Industry, Vol. 29, No. 1, pp. 6-7. London, Jan. 15, 1910.

6 Mercuric Chlorid Tablets. {Aj^™£ PmT'

For a direct check upon the value of the tenth-normal alkali run an assay upon 5 c.c. of a 2]/2 per cent, solution of pure ammonium chlorid.

Solutions, reagents, and water used should be free from carbon dioxid.

Ordinarily titration B is very small, sometimes zero, but usually calling for the addition of a few drops of tenth-normal acid.

As respects the end points with the indicators it is only possible to state that up to the present time no blue or green tablets which have been received by the writer have presented the slightest difficulty. The characteristic colors of the indicators of course do not appear in the presence of other coloring matter, but the change of tint, if standards of comparison are used, is delicate and distinct. No red tablets have been received for examination.

The reliability of the method may be shown by noting a few results.

Experiment 2. — Four tests made on 5 c.c. of a solution of 2 grams each of commercial CP. chlorids of mercury and ammonium per 100 c.c. gave the following figures for titration A (titration B — O), made with barium hydrate solution (tenth-normal X 1.021) which had been standardized against a labora- tory stock solution of half-normal hydrochloric acid: (1) 18.24 c.c; (2) 18.26 c.c; (3) 18.29 cc-'> (4) 18.26 c.c; an extreme difference of 0.05 c.c. and a recovery of 99.6 to 99.9 per cent, of the ammonium chlorid employed.

Experiment 3. — Three titrations made on 5 c.c. of the solution of commer- cial tablets employed in Experiment 1 gave titration B as zero, and titration A as (1) 22.64 c.c; (2) 22.58 c.c; (3) 22.62 c.c; an extreme difference of 0.06 c.c

It appears, therefore, that assay methods are now available for accurately and conveniently estimating mercuric and ammonium chlorid in commercial tablets. Knowing the weight of tablets taken to prepare the stock solution for assay, estimation of coloring matter and " filler " is merely a matter of subtraction. Further possible tests, such as degree of solubility, amount of insoluble matter, and uniformity of weight of individual tablets, are a matter of discretion with the analyst and need no discussion.

A January m™' \ Resistance of Guinea Pigs to Poisonini

SEASONAL VARIATIONS IN THE RESISTANCE OF GUINEA PIGS TO POISONING BY OUABAIN AND BY liquid' PREPARATIONS OF DIGITALIS.

By C. C. Haskell, A.B, M.D.

In a previous paper 1 it has been shown that guinea pigs are more resistant to poisoning by ouabain during certain months of the year than at others. These results were confirmed in a general way by Vanderkleed and Pittenger 2 in a subsequent publication. It is of interest to compare the results secured in this laboratory with those reported by Vanderkleed and Pittenger.

I have used male pigs exclusively, and have been compelled to employ animals differing largely in weight; the majority, however, weighed 250 grams or more, so it seems best to compare my results with those obtained by Vanderkleed and Pittenger using " large males." In order to facilitate comparison, the average minimum lethal dose has been expressed in fractions of a gram per gram body weight and put in the following tabular form :

Table I.

Month.	Vanderkleed and Pittenger.	Haskell.
January	. 1912	.OOOOOO25	.OOOOOO52 +
February	1912	. OOOOOO30	.OOOOOO37
March.	. . 1912	.OOOOOO32	. OOOOOO36
April	1912	. OOOOOO33	. OOOOOO4O
May	1912	. OOOOOO33	. OOOOOO45
June	1912	. OOOOOO33	. OOOOOO4O
July	. .1911	. 0000002 I
August	1911	. 0000002 1	. OOOOOO29
September	. . 191 1	. 0000002 I	. OOOOOO30
October	1911	. 0000002 1	. OOOOOO36
November	1911	. OOOOOO24	. OOOOOO52
December	1911	.OOOOOO28	.OOOOOO52

It is readily seen that the same general conclusion is deducible from both series of tests : the resistance of the pigs is least during the hot summer months and greatest in the cooler weather. In August, there is a difference of 38 per cent, between the lethal dose required

1 Am. Jour. Pharm., Vol. 84, No. 6, p. 241, 1912.

2 Jour. Am. Ph. Assoc., Vol n, No. 5, P- 558, 1913-

8 Resistance of Guinea Pigs to Poisoning {^^"J

Pharm 1914.

in Indianapolis and that determined in Philadelphia ; and in January, the enormous preponderance of 108 per cent, is shown by the In- dianapolis lethal dose. Obviously, it is scarcely to be expected that we should secure very closely comparable results in assaying a galeni- cal if such divergence occurs in testing a " pure principle."

In endeavoring to account for this disagreement, the technic em- ployed should be closely scrutinized. It is a well-recognized fact that testing digitalis upon frogs requires the closest attention to details and necessitates the avoidance of any disturbing factors such as large variations in the weight of the animals and, especially, ex- tremes of temperature. From previous statements of those who have employed the guinea pig method, one is led to infer that such extreme caution is not necessary when this method is used, and the results of Vanderkleed and Pittenger seem to show that weight and age are factors of little moment.

In all of my experiments, a solution of ouabain, I to 10,000 in 25. per cent, alcohol, was used. Vanderkleed and Pittenger do not state whether alcohol was present in the solutions they employed, but its absence would explain the smaller dose determined by them as compared to the dose I found necessary in August, because alcohol exerts a similar antagonistic action toward the absorption of subcu- taneously-administered ouabain as it does toward digitalis adminis- tered in this way. Some other explanation, however, is necessary to account for the difference between the minimum lethal dose deter- mined in Indianapolis in January (.00000052 -(-) and that determined in Philadelphia for the same month (.00000025). The pigs used by Vanderkleed and Pittenger were kept in fairly warm quarters ; while our animals were subjected to considerable variations in temperature, the thermometer occasionally registering as low as 500 F. This, I believe, has an important bearing on the resistance of the guinea pigs and, together with the influence of the alcohol used in my experi- ments, may serve to explain the difference in the lethal dose as determined in the winter months.

Since this earlier report, the minimum lethal dose of ouabain in 25 per cent, alcohol has been determined upon guinea pigs in a number of different months and a comparison is of some interest. In Table II such a comparison is given.

These figures indicate that the temperature influences the powers of resistance. During the extremely cold winter of 1911-12 the

* January ^iST' } Resistance of Guinea Pigs to Poisoning. 9

dose for November, r^. fiber, and January was .00000052: while during the much milder winter of 191 2-1 3, the lethal dose was smaller. Where comparison is possible in other months, the differ- ence never amounts' to more than 15 per cent.

Table II.

Month.

January. . . February. .

March

April

May

June

July

August

September October. . . November. December.

IOII.

. 00000029 00000030 , 00000036 , 00000052 . 00000052

1912.

, 00000052 + .00000037 , 00000036 . 00000040 . 00000045 . 00000040

.00000036 . 00000042 . 00000040 . 00000045

00000040 00000042

.00000037 . 00000045

.00000025 .00000025

Seasonal variations in the resistance of test animals may be obviated by the use of a satisfactory standard, and Vanderkleed and Pittenger suggest the use of ouabain when galenicals of the " heart tonic " group are tested upon guinea pigs. The use of ouabain is justified, however, only when it has been shown that the variations in the resistance toward poisoning by ouabain parallels that toward poisoning by the galenicals under consideration. Opportunity has occurred to determine the minimum lethal dose of a small number of samples of tincture and fluid extract of digitalis at different seasons of the year. Some of the tinctures were made by the U.S. P. method and some were made with a menstruum containing 75 per cent, alco- hol. All of the fluid extracts were made with a menstruum contain- ing 70 per cent, or 80 per cent, alcohol.

In testing the tinctures, portions were evaporated to a semi- solid consistence upon the water-bath and the residue suspended in an amount of distilled water equal to the original volume of the portion taken for evaporation. The same procedure was followed with the fluid extracts, save that the volume of distilled water was five times that of the fluid extract taken. For reasons that will be apparent later; it is desirable that the preparations be divided into two groups ; one comprising preparations containing about 50 per

io Resistance of Guinea Pigs to Po«onitt^.jAJj™J llTI.™'

cent, alcohol ; the other comprising those containing from 70 to 80 per cent, alcohol.

The comparison of the lethal doses for two tinctures made with 50 per cent, alcohol and the lethal dose for ouabain during the same months is given in Table III. N

Table III.

	June, 1912.	Oct., 1912.	Dec, 1912.	Jan., 1913.	Aug., 1913.
Ouabain Tr. Digitalis U. S. P. 434900 Tr. Digitalis U. S. P. 457579	. OOOOOO4 .004	. OOOOOO42 .004	. OOOOOO45 .007 + .0075	. OOOOOO4 .OO65	.00000025 .OO42 .0052

So far as can be judged by this limited number of experiments, " seasonal " variations in the resistance of guinea pigs toward poison- ing by ouabain and by tinctures of digitalis made with 50 per cent, alcohol follow the same general curve. In January, 1913, the lethal dose for Tincture 434900 was .0065, while in July, 1913, it showed a decrease of 35.4 per cent.: the lethal dose of ouabain showed a decrease of 37.5 per cent, during the same time. In December, 1912, the dose of Tincture 457579 was .0075, while in July, 191 3, it was 30.6 per cent, less: the dose of ouabain suffered a decrease of 44 per cent.

In testing the preparations containing relatively high percentages of alcohol, entirely different results were obtained. These are so surprising that it was only after confirming them repeatedly that I could feel that they were not due to some error in testing. The tests were carried out in a manner exactly similar to those dealing with the tinctures just discussed and the difference in the behavior seems to depend upon an essential difference in the composition of prepara- tions made with 50 and 75 per cent, alcohol respectively.

From these results, it is evident that no seasonal variation has been observed in the resistance of guinea pigs to poisoning by fluid preparations of digitalis made by percolation of the leaf with men- strua containing 70 to 80 per cent, alcohol. Tinctures made with 75 per cent, alcohol differ in several important points from those made with 50 per cent, alcohol, but it seems almost incredible that the resistance of guinea pigs to poisoning by the two should follow

Am. Jour. Tharm. } January, 1914. j

M agma

B ism ut hi.

1 1

Table IV.

	Ouabain1	Tr. Digi- talis 471124	Tr. Digi- talis 46 10 1 1	Tr. Digi- talis 467056	Tr. Digi- talis2 24678	F. E. Digi- talis 461015	F. E. Digi- talis 1654092
Jan. 1912 1913 Feb. 1912 1913 Mar. 1912 1913 Apr. 1912 1913 May 1912 1913 June 1912 1913 July 1912 1913 Aug. 19 1 2 1913 Sept. 1912 1913 Oct. 1912 1913 Nov. 1912	52 40 37 42 36			.OO24	.0025 .0025
.OO27
40 37 45 45 40 25 29 25 42 40 45			.0030 .0025 .0025 .0025
			.00022	.OOO47
.0025	.0020	.OO23
			.OOO23	.OOO32
1913 Dec. 1912 1913		.0022

1 The figures in this column represent fractions of a gram to the eighth decimal

(.00000052).

2 Alcohol not removed from this tincture.

such different lines. A confirmation of these observations would cer- tainly suggest that careful pharmacological study of digitalis prepara- tions made with different menstrua would not entail a waste of time. From the Laboratory of Experimental Medicine, Eli Lilly and Company, Indianapolis, Aug. 26, 1913.

MAGMA BISMUTHI.

By S. Bertha Muller, P.D., Assistant Pharmacist at the German Hospital, Philadelphia.

In recent years Magma Bismuth has become quite popular, so much so that it was deemed advisable to make the preparation official.

With that end in view several formulas have been proposed and duly tried out, but in our experience have not proved generally satisfactory.

12

Magma Bismuthi.

IAm. Jour. Pharm. j January, 1914.

The formulas proposed direct ammonia water to be used to pre- cipitate the bismuth nitrate. This, in our experience, leads to con- siderable trouble trying- to wash the resulting Magma free from the excess of ammonia. It takes a great deal of water to do so and even if one has succeeded in getting the final washings to no longer react with phenolphthalein the Magma itself will always give a strong reaction. To reduce the amount of ammonia water leads to a reaction in the opposite direction, giving a decided acid reaction which causes the gradual solution of the bismuth hydroxide. Furthermore, when the Magma is poured on a strainer for the purpose of washing it, the surface of the Magma very soon develops a metallic coating which certainly points to a decomposition going on and may be due to exposure to air. Unfortunately this is the only way the Magma can be washed because distilled water has the property of causing the Magma to curdle into large flaky masses, taking up considerable water and holding it so that it is utterly impossible to get the Magma to settle in order to wash it by decantation, thus preventing undue exposure to air.

Attention should also be drawn to the fact that the amount of bismuth subnitrate used, results in too thick a Magma. Further- more, 80 grams of bismuth subnitrate cannot be satisfactorily dis- solved in 60 c.c. of nitric acid. It takes i c.c. of nitric acid for every gram of bismuth subnitrate to be dissolved.

However, with some modifications the proposed official formula will give satisfactory results. In the first place the amount of bismuth should be somewhat reduced, then ammonium carbonate should be substituted for ammonia water, and lastly, distilled water containing i-iooo sodium chloride should be used. By using am- monium carbonate the resulting Magma is not nearly so alkaline, it will not react with phenolphthalein but will and should react alkaline toward methyl orange. It therefore does not require nearly so much washing. It only needs to be washed until it is practically tasteless. The use of this small amount of sodium chloride in distilled water prevents the curdling of the Magma, and it therefore can readily be washed by decantation, no strainer being required. After sufficient washing it is allowed to settle to the required volume, which usually takes about a week.

Spigot water can also be used in place of distilled water if it has been previously boiled with i per cent, magnesium carbonate for

Aj;,mTry/i9i4m"} Books as a Source of Disease. 13

about 15 minutes, then cooled and filtered and 1-1000 sodium chloride added.

The following formula has been fairly satisfactory :

Bismuth Subnitrate 50.0

Nitric Acid 50.0

Ammonium Carbonate 80.0

Distilled water to make 1000.0

Dilute the nitric acid with an equal volume of water and dissolve the bismuth subnitrate in it, dilute further to 300 c.c. and filter through cotton.

Dissolve the ammonium carbonate in 3000 c.c. distilled water containing 1-1000 sodium chloride and filter.

Pour the acid solution slowly and with constant stirring into the alkaline solution. When the resulting precipitate has subsided, decant the supernatent liquor and wash by decantation until the Magma is practically tasteless, using distilled water containing 1-1000 sodium chloride. Then allow to settle to 1000 c.c.

When tested the Magma should react alkaline toward methyl orange.

BOOKS AS A SOURCE OF DISEASE.

By William R. Reinick.

I do not for a moment want anyone to think that I am endeavor- ing to prove that books, as fomites, are so dangerous that they should be shunned like the plague, but simply to show that books, especially when greasy or moist fingers are placed upon the pages and covers, are excellent hiding grounds for bacteria, both pathogenic and non-pathogenic, and that the same care should be used as in handling other objects of like character.

Is Such Transmission Possible?

As far as our exact knowledge of books and papers as a source of danger is concerned, we, at the present time, have very little evidence, but what we have proves beyond question, that disease may be contracted by this means. ( )n the other hand there are many reputable physicians who claim that transmission by this means is an impossibility, due to the fact that the organisms could not exist

14

Books as a Source of Disease.

< Am. Jour. Pharm. ( January, 1914.

for any length of time under such adverse conditions. A statement of this character is generally made by one who only has a superficial knowledge of the subject, especially in its biological aspect. The apparatus needed to properly conduct experiments upon bacteria is quite expensive, and generally, the young physician who has just graduated has the time and possesses the enthusiasm to undertake these researches, but not the capital, and then when he has the means, he has so many patients that he cannot spare the time.

Another trouble is the extreme difficulty which arises when one is prepared to study this subject. On account of the great surface covered by the pages of the books, it means a long and tedious series of experiments, and even then, on account of their being invisible to the eye, one is not sure that he has obtained every speck of life that may be on the paper.

The knowledge that we are now acquiring as to the great resist- ance of these small forms of life to adverse conditions of climate and atmosphere, their resistance to degrees of heat, their wonderful adaptability to rapid changes of environment, food, and their power to remain dormant for a period more or less unknown at the present day, their ability to form a protective coat, which prevents pene- tration when placed in material that would otherwise destroy them, all these points indicate that we may be on the wrong track in using the present means of eradication. And furthermore, in making our laboratory tests we are forced to isolate the colonies, giving conditions foreign to their natural state of existence, and also the difficulty in separating them into distinct species.

Newman states as follows : " A word may be said here respecting the much-discussed question of species of Bacteria. A species may be defined as ' a group of individuals,' which, however many characters they share with other individuals, agree in presenting one or more characters of a peculiar and hereditary kind with some cer- tain degree of distinctness. Now, as regards bacteria, there is no doubt that separate species occur and tend to remain as separate species. It is true, there are many variations, due in large measure to the medium in which the organisms are growing — variations of age, adaptation, nutrition, etc. — yet the different species tend to remain distinct. Involution forms occur frequently, and degenera- tion invariably modifies the normal appearance. But because of the occurrence of these, morphological and even pathological differences of environment and physical conditions must have marked effect

Am. Jour. Pharm. ) January, 1914. j

Books as a Source - of Disease.

15

upon such sensitive units of protoplasm as bacteria ; it has recently been proven that one great reason why modification occurs in pure artificial culture is that the species has been isolated from amongst its colleagues and doomed to a separate existence. One of the most abstruse problems in the immediate future of the science of bacteri- ology is to learn what intrinsic characters there are in species or individuals which act as a basis for the association of organisms for a specific purpose. Some bacteria appear to be unable to perform their regular function without the aid of others. An example of such association is well illustrated in the case of tetanus, for it has been shown that if the bacilli and spores of tetanus alone obtain en- trance to a wound, the disease may not follow the same course as when with the specific organism of lactic acid bacilli, or the common organisms of suppuration or putrefaction also gain entrance. Again, the virulence of other'bacteria is also increased by means of associa- tion. The bacilli coli is an example, for, in conjunction with other organisms, this bacilli, although normally present in health in the alimentary canal, is able to set up acute intestinal irritation, and various changes in the body of an inflammatory nature."

Among the higher forms of life we have, in a few hundred of years, recognized natural changes, or often brought the change about by artificial selection. Now if a change, quite noticeable, can be made during a period of years, in forms which do not produce more than one or two generations a year, what changes are able to take place, in forms capable of producing a new generation every twenty or thirty minutes, and these changes invisible to us?

Another source of failure to obtain positive results is due to the fact that conclusions are generally arrived at from twenty-four hour tests ; and, if there is no result within that period, the experi- ment is marked negative and the material destroyed.

Very little information of value, to help in deciding whether or not books act as carriers, was received from the various Boards of Health of the United States. A circular letter requesting a list of cases, the source of which was traced to books and papers, was sent to the Boards of Health of each State and forty-one cities. Answers were received from only ten States and nineteen cities, about 30 per cent, of the total number of letters sent.

With these replies no cases were given, although some of the officials stated it to be their belief that diseases were contracted through contact with books, while others ridiculed such a possibility.

16 Books as a Source of Disease. { ATanuiry 191T'

Quite a number of physicians have sent me histories of cases, which they have observed during their practice.

The medical and library periodicals are constantly printing notices about disease being contracted from books, and as in the case of the theory of insects transmitting disease germs, at first ridiculed, but now acknowledged to be true by the most skeptical, so are books now passing through the same criticism.

Diseases Claimed to Have Been Traced to Books.

Scarlet Fever. — Dr. J. Allen Palmer, of Erie, Kansas, notes a case of scarlatina developing in a girl, living in a town where there had been no cases of the disease for months, nor had she been exposed to personal contact. Investigation showed that the patient had received a letter a few days previous to the appearance of the rash, from a child living some sixty miles from her, who was just recovering from scarlatina. Another case of transmission was traced by Dr. Howard W. Lyon, of Chicago. In this instance a little girl living in Chicago contracted scarlatina from being allowed to handle a letter just received from a home in Minneapolis, where one of the family had the disease.

Dr. A. Maverick, of San Antonio, Texas, sent the following case : A boy convalescent from scarlet fever read a book from the public library and used as book-marks strips of skin peeled from his hands and feet. Unknown to the physician, the book was returned to the library by a servant of the household with no attempt at sterilization or even removing the pieces of skin. During the next month, two boys in different families who borrowed the book from the library, caught scarlet fever and one died from the disease.

Diphtheria. — Dr. Robert Britton, of Downsville, New York, writes of two cases in 1902, one of the patients dying, and as there were no cases of the disease in the neighborhood, the question arose where had the children contracted the infection. Questioning re- vealed, that on account of the weather and conditions of the road they did not attend school on March 27, but played in a house having a garret, in which were stored some old school books which had been taken from an old farm-house on this farm — in which in i860 had occurred six cases of diphtheria, four of which were fatal in forty-eight hours.

Small-pox. — Small-pox is one of the most contagious diseases, and few who are exposed escape infection. The contagion exists in

Am. jour, pharm. > Books as a Source af Disease. 17

January, 1(J14. J ' /

the pustules, in the fluid of the body, and apparently in the ex- halation from the lungsand skin. The dried scales thrown off during desquamation are the most important element in disseminating the malady, and is often communicated, through the medium of clothes, furniture, books, etc., which have come in contact with patients.

Dr. P. A. Jordan, of San Jose, California, states the following: A man, a great reader, continuously used books from a circulating library located in a neighboring town in which there was an epidemic of small-pox, and later developed a severe form of small-pox.

Blood-Poisoning. — Dr. Emericus Karacson, while making a trans- lation of a Turkish Manuscript, in one of the Mosques in Turkey, had his fingers soiled with some of the mould which covered the old musty tomes, and accidentally touched a cut on his face ; a few weeks later his face swelled up, causing him intense pain. A quick opera- tion relieved him of this and his face regained its normal size, and he soon resumed his work, apparently in perfect health. About a month later he was taken ill with fever and treated first for influenza, then for typhoid fever. His condition growing worse, a Hungarian physician was sent for, who diagnosed the case at once as blood- poisoning, caused no doubt by the fungi that had entered the patient's system through the abrasion on the face, and he died within a few days.

Venereal Diseases. — That the danger to man from what are called the " social evil " diseases, after exacting a cost in human life and physical disability beyond computation, and the necessity of using means which will prevent its spread, is now recognized, as seen by the numerous societies being formed to furnish speakers and publish literature upon the subject, thus forcing the public to face the question as it has never been done before.

A list of articles found to be carriers of the germs of gonorrhea, the one most likely to be contracted through contact, would include every article of domestic and public use, and even the hands of the unclean and ignorant may transfer the germs to the articles. A num- ber of cases have been traced to books.

Diseases, besides these mentioned, have been named as being transmitted by books, and there is no reason to doubt that the germs of other diseases found on fomites will also be found on books. The bacillus of anthrax, which occurs in cattle, must certainly be found on the leather bindings, as it is frequently transmitted through

?8

Books as a Source of Disease.

(Am. Jour. Pharm. \ January, 1914.

abrasions of the hands in cases of those who have the occasion to handle infected wools and hides.

Tuberculosis. — The number of bacilli in the sputum of a person suffering from tuberculosis is enormous. Nuttall estimated that a person moderately advanced in the disease, expectorated between two and four billions of bacilli every twenty-four hours. One having this disease does not at once become helpless, and in the meantime the patient generally spends a great deal of his spare time reading, and as this disease usually causes the one inflicted to cough a great deal, often involuntarily, it is but natural that particles of the sputum will be caught on the paper of the books, ready to be transmitted to another victim.

Dust. — I do not think that enough study has been given to the bacteria found in dust, as far as public institutions are concerned. Careful consideration of the examinations already made of dust from various sources, especially in the industrial trades during the past few years, will show at once that the health is often affected by the impurities found in the air inhaled, and that the purifying of this air is of greatest importance from a sanitary standpoint. Besides the danger from exposure to the so-called diseases, the germs of which are stated to be borne in the air, the pollution of the air by organic and inorganic dust is beyond a doubt the cause of a great deal of ill-health, and death.

An analysis made by Prof. Charles H. Lawall of dust collected by me at the State Library of Florida, at Tallahasse, off of books that had not been disturbed for many years, gave the following result:

" Ash (inorganic material, mainly sand), 54.90 per cent.

" Organic matter consists of much unidentifiable matter, in which, however, could be distinguished microscopically the following : wood fragments, cotton, linen, silk, wool (some of them dyed bright colors), hairs of various kinds, both plant and animal, starch grains, spore and an occasional yeast cell. No evidence was found of arsenic or mercury or other poisonous metals or their compounds, except what might be called a faint trace of arsenic, which was traced by a method so delicate as to detect arsenic in almost any substance from which it has not been specifically removed."

Dr. McFadden and Mr. Lunt seem to prove the paucity of bacteria in very dusty air. The evidence otherwise available is entirely conclusive that the risk to disease infection is much greater indoors than out in the open, where the germs are exposed to the

Am. Jour. Pharm. 1 Books dS d Source Off Disease. IQ

sunlight, which is a great factor in keeping the germs in an inactive state. ' j

But, besides the danger of infection from inhaling disease germs found in the dust, there is also to be considered that it is the cutting edges of the particles of dust, which when inhaled scratch or cut the delicate air passages leading to the lungs and also the lungs them- selves. The finer dust will not, perhaps, act as quickly as the coarser grains, but it means that the evil result will take a much longer time before making its appearance.

It is known that those who spend most of their time in outdoor occupations, generally have better health than those who are com- pelled to work in factories, offices, etc., and the first thought of sani- tary science to-day is the elimination of dust.

It is extremely difficult, in fact almost impossible, to trace many cases of infection on account of the long period between the first infection and the appearance of the disease in a form to demand medical attention.

Dr. Hugh H. Brown, of Washington, D. C, and an assistant, in 1907, moved a large number of books which had not been disturbed for quite some time. Within a few days both contracted severe colds, characterized by distinct bubbling, and a severe cough accompanied by a feeling of compression and pain in the chest, and an exceed- ingly profuse and purulent expectoration of a deep yellow color the consistency of thick cream. The cold lasted about two weeks.

Vitality of Bacteria. — Before considering the mode of overcom- ing these organisms, consideration should first be given to their power of resistance to disinfection, sterilization, etc.

Bacteria exist in nature in three states :

( 1) As adult or fully-developed and active microorganisms, with all the characteristics of parasites.

(2) As spores or reproductive cells endowed with latent life.

(3) As desiccated germs, whose vital principle had been sus- pended but not destroyed ; which, when placed in a moist and suitable environment, possess the power of resuscitation.

" The air germs," says Professor Tyndall, " differ much among themselves in their tendency to development ; there are some which are young and there are others which are old, some dry and some wet. The same water infected by those germs requires more or less time to develop bacterial activity. This explains the difference in the rapidity with which epidemic diseases act upon different persons.

20

Books as a Source of Disease.

/Am. Jour. Pharm. I January, 1914.

In certain cases the period of incubation, if it can be so called, is long-, in others it is short; the difference is the result of the different degrees of preparedness of the contagious matter, and I personally believe that the health of the person infected has most to do with the appearance or non-appearance of a disease."

The length of time that the different pathogenic bacteria can withstand drying varies greatly. Krausz placed bacteria from 48- hour old cultures in books and kept them in the dark at room tem- perature. He found that cholera lived only 40-95 days and tubercle bacilli 80-103 days. Other investigations confirm his results except in the cases of tuberculosis and diphtheria. Abel found that diph- theria bacilli retained their virulency on toys for six months and this is the length of time that Von Scham gives. Lion and Von Schab both say that tubercle bacilli withstand drying from six to nine months.

The number of bacteria that may be found on much-used books was investigated by Lion. A novel from a public library varied from 250 .bacteria per 100 square centimetres on the middle of a clean page to 1,250, 1,875, and 3,350 on the dirty edges. A college atlas showed from 650 to 1,075 Per 100 square centimetres; an anatomy book 2,275 to 3,700. The bindings were by far the richest in bacteria, yielding on an average of 7,550 per square centimetre.

As to the pathogenic bacteria that may occur on books, the follow- ing investigations are of great interest. Krausz inoculated seven guinea pigs with dirty pieces of paper from much-used books and they all died of peritonitis. The eighteen inoculated with pieces from clean books remained healthy. Du Cazal and Catrin found Staphy- lococcus pyogenes on an old book in a hospital. Most striking of all are Mitelescu's experiments. He took 60 much-used books that had been in a public library from six months to two years ; he cut out the dirtiest parts, soaked them in salt solution, centrifuged the liquid and inoculated guinea pigs with the sediment. Nineteen died of septicemia, and twelve of streptococcus infection. He repeated the experiment with thirty-seven books from three to six years old. Fourteen of the guinea pigs died of septicemia, and fifteen contracted tuberculosis. The damp dirt on the older books was a good medium for tubercle bacilli.

The following abstracts are taken from the report made to the Board of Trustees of the Chicago Public Library upon books in that

Aj»1mair,,Pi'il4m'J Boohs as a Source of Disease. 21

•

library by Dr. W. A. Kuflewski and are of value as showing the germs to be found on books long in use.

These books were selected by Mr. F. H. Hild, Librarian, and Dr. Reynolds, the object being to get the books that were most worn and most soiled, and the examination was made by Dr. Adolph Gehrmann, who reported as follows :

D 2017a From delivery station, 14 years.

19 Cultures from page 57, brown spot — negative.

Cultures from torn places on cover. <'

(A) Staphylococci and saprophytes.

(B) Negative.

C 7357 Delivery station, 20 years.

Cultures from title page — negative.

Cultures from title page — negative.

Cultures from page 19 — negative.

Cultures from page 19 — negative.

H 2455c Delivery station, 6 years.

Cultures from top of page 278 — negative. Cultures from leather back — Staphylococcus pyogenes albus. Cultures from bottom edge of pages — Staphylococcus pyogenes albus.

Cultures from top edge of pages — saprophytes and S. pyogenes.

F 8346c Circulating department, 2 years: Popular juvenile. Cultures from leather back — negative. Cultures from top of pages — negative. Cultures from page 190 — negative.

F 494aa Circulating department, 26 years : Popular fiction. Cultures from spot on page 25 — negative. Culture from leather back — negative. Cultures from bottom pages — negative.

RR 281 Buck's Cyclopaedia, 14 years : Reference book.

Cultures from leather back— 1 colony of Staphylococci. Cultures from edge of cover — 1 colony of Staphylococci. Cultures from dirty page — Staphylococci. Cultures from clean pages — Staphylococci.

Summary of Results. Negative results : 3 books — C 735 ; 58 346c ; and E 494aa.

Cultures from covers showing Staphylococci: 3 books — D 2017a, H 2455c, and

281. 1

Cultures from pages showing Staphylococci: 2 books — H 2455c and RR281.

I

22 Books as a Source of Disease. { A m™"

A series of cultures from the hands of two persons in the labora- tory were made in the same manner and these showed a few colonies of saprophytes and Staphylococci pyogenes albus. In a general way these cultures were similar to those giving positive results made from the books.

The method employed in making these cultures was to take a few drops of sterile bouillon and with a platinum wire rub it upon the place from which the inoculations were made and then transfer this loop of bouillon to the blood serum boxes used by the department for diagnosis of diphtheria. These were placed in an incubating oven for forty-eight hours. The resulting colonies were examined microscopically.

Control cultures were made on several boxes by first placing the drop of bouillon on the sterile slide and then transferring it to the blood serum media.

In none of the cultures were diphtheria bacilli found. The Staphylococcus pyogenes albus is one of the pus bacteria usually found upon the skin of most individuals. The saprophytes are accidental non-pathogenic bacteria from the air, and are of no consequence.

Dr. Kuflewski states that " after personal investigation and ex- amination of three sets of books taken at random from the shelves of the Chicago Public Library I am prepared to state that I found bacteria in large numbers in all the samples and that each book was more or less infected. These bacteria were in large numbers and were both pathogenic and non-pathogenic— the word pathogenic meaning ' disease-producing.' "

In many instances these bacteria do not harm, not even the pathogenic, because of the resistance of the tissue — being unimpaired — or because of the comparatively small numbers of bacteria which gain access to the tissues ; but under favorable circumstances, such as a simple exposure to cold and especially to bronchitis, which is so prevalent in Chicago, a little wound or an abrasion of the surface of the body, a little scratch of the mucous membrane or of the skin-, which as we all know is often treated as insignificant and is neglected, may be the means of introduction into the system of the most infectious disease germs. It is well known that a fresh wound absorbs bacteria and their toxins very rapidly.

I have had in my own experience a case in which I satisfactorily proved that a child contracted an infectious disease in the eye, from

Aja/wy ^914"'} Books as ct Source af Disease. 23

the page of a book. Prof. Dr. W. A. Evans, who is an authority, states the case of a person who was infected with typhoid germs from books, which case was established beyond question. I had another case two or three years ago ; a gentleman who was suffering from cancer in the roof of the mouth, in which the tongue and lips were also affected, was reading books from public libraries in this city for nearly two years and until I was called to treat him. He had been treated before by the " faith cures " and by the followers of Dowie. This patient was found expectorating minute pieces of his tongue and lips, which were a cancerous tissue, all over the pages of the book he read. That they were cancerous was not only proven by my own examination, but by that of Dr. LeCount, an eminent bacteriologist, who reported to me that the piece of tissue submitted was cancerous, containing' cancerous cells.

Of course I prohibited this person from reading any more books from the libraries, and told his wife to be very careful as the disease was contagious.

In my own experiments I had no difficulty in obtaining colonies from the pages and bindings of all of the books examined, and I also obtained cultures of various forms from dust many years old, which according to the text-books, should have been destroyed.

Flies. — These insects are now known to carry germs. In some cases as many as six million have been found on a single specimen. In very few cases are libraries protected by screens ; the fly just from a patient suffering from a contagious disease, or off the waste matter in a near-by cesspool, has easy access to the interior of the library, where, alighting upon a binding or page of an open book it proceeds to eject a number of germs with its excreta, or by rubbing its body with its forelegs, shakes large numbers orf, which find ready lodge- ment, especially if the spot where the rubbing takes place is greasy, as is generally the case where a book has been much used or circu- lated for quite a number of times.

People do not seem able to overcome the vulgar habit of moisten- ing the fingers in turning over the leaves of the books and again plac- ing the finger on the lips each time to remoisten, never considering that each time he is, perhaps, transferring germs to fertile soil for propagation, resulting in sickness later on, or in case of a patient already suffering from disease, especially tuberculosis, helping to inflict another victim with the disease. And we all know that sick

24

Books as a Source of Disease.

i Am. Jour. Pharm. \ January, 1914.

persons, especially in the convalescent stage, spend a great deal of their time in reading books and magazines.

Disinfection. — This process in killing germs in books, although recommended, especially by those who have the disinfectants and the apparatus for sale, may be dismissed as of very little use, on account of the impossibility of the gases penetrating into the interior of the volumes, and in no case, even if the entire surface is reached, will they remove all of the spores.

Sterilisation. — Both steam and hot air sterilization are of little value for books, because the first will cause the paper of the books to absorb the moisture, swell and deform the book, and while in the case of hot air sterilization, the heat would, by drying up all the moisture in the books, have the same effect, besides, in the case of books bound with leather, cause the leather to stretch and often break.

The heat also will absorb the moisture and the paper will become dry and brittle, lessening the life of the volume. At present I do not believe, that there is any method which may be depended upon to entirely eliminate the possibility of diseases being contracted through contact with fomites, such as books and the hundreds of other articles in daily use, constantly being transferred to a sick- room, returned and ready for another victim. I believe that some of the State Boards of Health are now beginning to recognize the futility of quarantining and disinfecting. Instead they are spending all their energies in improving sanitary conditions as to the necessity of cleanliness and the proper care of health. If a person using books or any other of the numerous articles named as conveying germs will use precautions as to the degree of cleanliness of the article they handle, and will take the proper care of their health, they need have no fear of contracting any disease by means of a book or any other article.

Suppose that a library did disinfect their books, what claim can they make that the book has no germs, after it has been placed on a shelf next to another book or been handled by a reader or one of the assistants. Dr. A. W. Doty, of New York City, states along the line of using disinfectants at intervals, " I know of nothing in public sanitation which is more farcical than the general or periodical dis- infection of books with gaseous disinfectants for the purpose of preventing infection. These agents have no penetration of any account, and I have little faith in them for this purpose. I believe

Am. Jour. Pharm. ) January, 1914. /

Ehrlich's Chemotherapy.

25

that the careful dusting of the books and an abundance of fresh air and proper ventilation in a library is all that need be done under ordinary conditions."

He here touches the remedy, cleanliness, in relation to the books, but the same care that should be given to keeping the books clean should also be insisted upon for the employees and readers of libraries and all places where dust may accumulate.

A visit to almost any library will generally show, by placing the hands in back of the books upon the shelves, that there is a great deal of dust lying there. Very few libraries, even those recently erected, have had the vacuum system, which seems to be almost perfected, installed. Instead of making the reader wash his or her hands before using a book, it is very difficult for one to obtain access to the lava- tory to wash his hands even if he so desires. In fact, there are some libraries which have no lavatories at all for the public.

Books are often placed on shelves in stacks, poorly ventilated and lighted. The results obtained in the library at Hawaii, whose books were constantly being destroyed by insects while stored in a dark, badly ventilated building, but was almost eliminated when transferred to a well-lighted and ventilated building, prove the value of pure air and sunlight. Not disinfectant plants, but sunlight, fresh air, the elimination of dust, and the proper cleanliness on the part of the employees and readers, is the way, not only to prevent books from becoming fomites, but also the people becoming carriers in this age of prevention.

EHRLICH'S CHEMOTHERAPY.1

How His Logical, Systematic Campaign Against Certain Diseases Has Demonstrated the Value of Scientific Methods in Therapeutical Problems.

By Henry P. Talbot.

Chemotherapy has been called " a new science.'' It should, rather, be regarded as the designation of a scientific field in which therapeutics and chemistry intermingle in the solution of problems involving the principles of both of the older sciences, much as do physics and chemistry in so-called " physical chemistry/' which is not, on that account, regarded as a " new " science.

1 Reprinted from Science Conspectus, March, 1913.

26

Ehrlich's Chemotherapy.

( Am. Jour. Pharm. I January, 1914.

Therapeutics is defined as that branch of medical science " which deals with the composition, application, and modes of operation of the remedies for disease." But it has now taken on a somewhat broader, though less exact, meaning, and is understood to include the general administration of medicine, questions of hygiene and dietetics, and much that has to do mainly with the general well- being of the individual. That chemistry must be, as it has been for centuries, inseparable from the study of therapeutics is obvious, and the advance from the simplicity of the theory of Geber, accord- ing to which the animal organism was made up of only " sulphur " and " mercury " to our still very imperfect knowledge of the com- plex changes of physiological processes is, indeed, remarkable. But modern medical and chemical science is not content with the mere alleviation of the ravages of existing disease, that is, with the modify- ing or assisting of functions temporarily disturbed, but has struck more directly at the root of the trouble by devising means actually to destroy the causative agents and thus arrest the disease, or to render the animal organism inhospitable to these causative agents, as, for example, through the anti-toxins and the methods of preventive medicine in general.

All this had been done even before the advent of chemotherapy. What, then, is new about this combination of scientific effort in two al- lied fields ? Essentially this : It is a logical, systematic campaign against diseases which are caused by the infection of the animal organism by parasites (i.e, bacteria or protozoa) by means of chemicals which have not been found by empirical and more or less haphazard methods, but have been synthesized and built up solely for the pur- pose in hand, and as the result of researches which have called for the highest type of accurate observation and analytical reasoning for their execution. In this way it has been found possible to devise means by which the animal organism can be sterilized with respect to the parasites in question, and the consequent symptoms of disease can be arrested.

The development of this field is due almost entirely to Professor Paul Ehrlich, of Frankfort, and his co-workers. Dr. Ehrlich was educated as a physician, but has now become also one of the most accomplished and able investigators in the field of synthetic organic chemistry. A conception of the significance of his work can, perhaps, be best obtained by noting important phases in its progressive de- velopment.

A January Pi9i4m* } Eltrlich's Chemotherapy. 27

More than thirty years ago Ehrlich began using coal-tar colors in his physiological studies, employing them as stains for preparations to be examined under the miscroscope. It is, of course, now com- monly known that certain dye-stuffs appear to have a selective affinity for certain tissues of the body, or for certain parasites when residing within it, and these stains are in every day use by the pathologist. But it was not so thirty years ago, and Ehrlich first found that a dye-stuff known as methylene-blue, and its congeners, were the only colors which would stain live nerve tissue, and drew from this the important inference, which is at the basis of chemo- therapy, that this was because of a particular receptivity for these dye-stuffs on the part of these tissues or parasites. It is easy to understand something of the importance of this use of these stains, or dyes, if it is recalled that the changes produced in the individual cells or tissues by drugs are not detectable even under the micro- scope in most cases, and that it is only through these stains that a knowledge of what has actually happened can be even approximately learned.

Ehrlich concluded from his observations that it was probable that, since these tissues and parasites possessed this receptivity for these specific bodies, there must be some definite effect produced as a re- sult of the combination, if combination it were, and proceeded to conduct investigations in this direction. After some time these researches were rewarded, and in 1890 Ehrlich and Lappmann pub- lished a paper on the pain-relieving properties of methylene-blue, and, later, Ehrlich and Guttmann found that the same dye was fatal to one type of the plasmodium, the parasite which causes malaria. As the latter field of investigation, that of the effect upon parasites, appeared very promising, they turned their attention to a particular class of parasites known as trypanosomes, because these could be more easily studied by the inoculation of mice.

The disease-producing parasites are sometimes of vegetable origin, as the bacteria, and sometimes of animal nature, as the pro- tozoa. The trypanosomes are worm-like bodies, somewhat larger than bacteria, belonging to the animal class, and the diseases which they produce prevail most generally in tropical countries. Of these diseases, surra, most generally known in India among cattle, dogs and camels; nagana (tsetse-fly disease), known in Africa among animals in general; and mal de cadaras, known in South America among horses, are typical, while man is also attacked by the sleeping

28 Ehrlich's Chemotherapy. { ^ January, wu™'

sickness in the tropics. The scourge of syphilis is produced by a parasite known as the spirochete, which is closely allied to the others named, although it is still undetermined whether its nature is animal or vegetable. As will be seen, this particular disease has been found to be one of the most amenable to treatment.

As a result of his researches, Ehrlich formulated a theory regard- ing the behavior of the cells of living tissue, or of parasites toward foreign bodies. He conceives them as made up of a central " dom- inant body," which throws out " sidechains," to which he later gave the name receptors. These are of variable character, some being nutrient receptors, and others chemo-receptors, that is, recep- tors or certain definite chemical elements or groups of elements, known in chemistry as radicals. In a crude sense, the receptors may be likened to locks, and the nutrient or chemical bodies as keys, each fitting a particular lock, as, for example, the dyestuff methy- lene-blue already mentioned. The combinations thus affected may be beneficial to the cell, as in the case of the nutrients, or they may result in the poisoning and death of the cell, as in the case of the methylene-blue when brought into contact with the type of Plas- modium referred to above, or quinine for plasmodia in general, a specific remedy for malaria discovered by empirical research.

Ehrlich and his co-workers, with extraordinary skill and industry, prepared several hundred dye-stuffs, studying the varying effects of alterations in chemical structure, each new compound having been logically selected as the result of laboratory tests of its parasiticidal efficiency. Of all these, very few finally withstood severe tests, pos- sibly not more than ten in all, but the fact was established that it was possible in certain cases to sterilize the animal organism with respect to parasites, by this means, without, at the same time, poisoning the animal itself. They were also able to establish certain principles as to the chemical structure of the dye-stuffs most likely to be effective. They encountered, however, many difficulties. A dye which would attack and destroy a given parasite in a particular animal would not always do so in another species. Symptoms of disease would some- times recur after varying intervals, and the parasites would then often exhibit peculiar resistance to further attack.

While these researches were still in progress, Uhlenmuth and Salmon published an account of instances of marked success in the destruction of the spirochete of syphilis, and the arrest of the disease, by the use of an arsenical compound known as atoxyl. Secondary

AjanuTryPih9i4m'} Ehrlich' s Chemotherapy. 29

and seriously harmful effects to the patients were, however, the consequence of this treatment, but the parasiticidal properties of this compound were so marked that Ehrlich turned his attention to it, in an attempt to so modify its effects upon the animal organism which was harboring the parasites, that its curative power might be made available.

The task was by no means a simple one. He first established the composition of the atoxyl as a para-amido-phenyl arsenic acid. The vast amount of work already done with the dye-stuff indicated certain lines of probable success, which, nevertheless, was only attained on the synthesis of the six hundred and sixth organic compound by Ehrlich and Kata, sometimes known as " 606," and now designated salvarsan. Chemically it is dioxy-diamido-arseno-benzol, in which arsenic is associated with structural groups akin to those found in the dye-stuffs. A later preparation " 914," known as neo-salvarsan, is said to be a combination of a salvarsan with sodium formaldehyde sulphoxalate, which is designed to overcome a certain difficulty in administration of the salvarsan, due to acidity of its solutions.

Ehrlich assumes that the parasite of syphilis, the spirochete, possesses among others, arsenio-receptors, and that through the combination with this arsenic compound the parasite is poisoned and dies. Ehrlich claims that in more than twelve thousand cases in which this drug has been administered by him, no single case of poisoning has resulted. The administration of the drug, which is intravenous, or intramuscular, requires, however, considerable skill and care. The treatment with salvarsan is often combined with that of mercury. There seems to be no doubt that this preparation exerts a specific and destructive action upon the spirochete, and has already resulted in the alleviation of an enormous amount of suf- fering (often hereditary and undeserved) from this dreadful scourge. It is still too early to make final statements as to the per- manence of the cures affected although there is much reason for hopefulness. It should, however, be noted that this chemothera- peutic treatment, unlike the anti-toxin treatment for certain other diseases, does not at all produce immunity from later infection from the same disease. Indeed, there is some evidence to show that cases of re-infection are distinctly harder to treat successfully than those of initial infection. The cure of advanced cases of the disease natu- rally, presents greater difficulties, because of secondary disturbances of the vital organs, but many of these have been materially alleviated.

30 Ehrlich's Chemotherapy. { Aj J^y', m™'

The progress made in the chemotherapeutic treatment of diseases produced by other trypanosomes, notably that of the " sleeping sick- ness," has been less marked up to the present. Something has been gained, but no specific drug comparable with salvarsan in its effi- ciency has yet been found.

It is, however, recorded that in Surinam a hospital was estab- lished to treat cases of another tropical disease known as the yaws. In the course of eight days three hundred and twenty-eight cases were admitted, and at the end of fourteen days the last patient was discharged, cured, and the hospital had to be closed.

In another field the work of Ehrlich has led to procedures which are of the greatest promise in the study of the processes involved in the progress of medical and physiological research, namely, so- called " vital staining." By means of the injection of dye-stuffs into living organisms, it is possible, because of the selective receptivity of certain tissues or parasites, for a particular color, to trace the movement of bacilli, and to watch the changes which they occasion in the living organism itself. The same procedure is employed in the study of healthy tissue.

To Ehrlich's clear, analytical mind, exceptional executive ability, fine technique, and extraordinary industry is due not only the pro- cedure by which certain particular diseases may be arrested, but a splendid example of logical attack upon other similar problems, which offers great promise for the future, even though, as in the case of the anti-toxins, one marked success may not be at once followed by others of equal moment. He has demonstrated, in a way which cannot be detailed in the scope of this article, that the test-tube ex- periments made in the laboratory with a particular drug upon a special parasite cannot be alone relied upon as an index of the effect upon it of the same drug when it is harbored by the living organism, since the action is essentially modified by that organism, and he has advanced theories which at least help in the understanding of the possible reasons for the variations in behavior thus observed. Even though Ehrlich's chemotherapy may not be, in an exact sense, a " new science," it must be acknowledged to be a most fruitful and helpful combination of the principles of two well-recognized and time- honored sciences for the benefit of mankind.

Am. Jour. Pharm. ) January, 1914. J

Oil of Sandalwood.

3i

OIL OF SANDALWOOD.1

By E. M. Holmes.

The gradual, but steady, increase in the price of sandalwood oil during the last few years has naturally given rise to enquiries concerning its cause. Neither the growing use of the oil for medicinal purposes, nor the large demand for the wood in India and China, can sufficiently account for it. There is, however, a possible cause that has apparently not received the attention it deserves from merchants in this country. During the last 30 years or more, Lantana and Casuarina plants have been introduced into sandalwood plantations with the idea of their shade helping the growth of the young sandal plants, and it appears that concurrently with a diseased state of the Lantana, the sandal plants have become affected with what is known as the spike disease.

A most interesting account of this disease is given by Mr. F. S. Mason in the Pharmaceutical Journal in 1903 (May 30th, p. 756), which gives an excellent idea of the character of the disease, and of the extent to which the plantations are affected. One remark in this paper is well worthy of notice, viz., that " within five years it has swept whole tracts of country, and unless some means can be devised to check its ravages, it is only a question of time for the plant to become very rare, if not extinct." So convinced was the Mysore Government of the importance of rinding a means to check the disease, that in 1907 the Maharajah of Mysore offered a prize of 10,000 rupees to anyone who could discover the cause of the disease, and devise a curative treatment for it. But although the offer remained open until 19 10 no one succeeded in winning the prize.

The cause of the disease was investigated on behalf of the Indian Government by Mr. Barber and Dr. Butler, and they came to the conclusion that it was not due to any animal or vegetable parasite, but was connected with the disc-like suckers at the ex- tremities of the roots of the sandalwood tree, by which it attaches itself to the roots of other plants and obtains nourishment from them (Indian Forester, xxxiii, 1907, p. 199). That no curative means of arresting the disease has yet been devised is evident from

^he Perfumery and Essential Oil Record, June, 1913, 161.

Oil of Sandalwood.

Am. Jour. Pharm. January, 1914.

a statement published last October in the same journal, to the effect that the disease still continues with dire results, and that in two districts alone some 70,000 sandal trees had to be uprooted.

In order to obtain an idea of the probable cause of this disease it is necessary to pay some attention to the life history of the plant, so far as this is known. As already mentioned, the sandal tree is a root parasite, obtaining its food by means of suckers, which it attaches to the roots of other trees. It has been ascertained by Rama Rao that there are at least 144 species of plants which the sandal tree attacks in this way, as proved by experiment with sandal- wood seedlings, and he gives a list of 252 plants which are found growing near or with the sandal tree, but are as yet not known to be utilized as a source of food by this tree. It does not appear to be equally nourished by all of its host plants, and the condition of the tree depends upon the vigorous and healthy state of its host. Thus it is known that a plant on which it will thrive in one district fails to keep it in a healthy state in another, where the conditions are unsuitable to the healthy growth of the host plant. This require- ment of the sandalwood tree is well shown by an observation recorded in the Indian Forester, (xxxl, p. 191), that when a trunk of Heptapleurum was cut down, the sandal plant attached to its roots began to wither, but when new shoots formed on it the sandal plant began to revive. The sandalwood tree sends out roots for 150 feet or more, and therefore requires a comparatively loose and well-drained soil which the roots can easily penetrate and spread in. In a natural state it flourishes at an altitude of 1500 to 4000 ft., the best yield of oil being obtained from trees growing between 2000 to 3500 ft., on loose volcanic soil mixed with rocks, and preferably ferruginous in character. It requires to be shaded by thickets above which it can form a head of leafy branches.

Although in rich soil it grows more luxuriantly, less scented wood is formed, although, as the tree furnishes more wood, the proportion is about the same. It is considered that the richness of the wood in oil depends more upon elevation and exposure, since, although the tree grows luxuriantly at 700 ft., the wood is said to be totally devoid of scent at that altitude (Indian Forester, xxvl, pp. 1-50, 1900).

The experiments made by Rama Rao indicate that the physical conditions of soil and drainage affect the development of the root- branching system. The soil needs to be well drained, as the seed

Am. Jour. Pharm. \ January, 1914. j

Oil of Sandalwood.

33

rots in soil where stagnant water is present, more readily than in most plants.

The seed of the sandalwood tree germinates freely in the thickets where the tree grows, within a month of being sown, although germination may occur any time during three months or longer, but if the seed germinates in open ground where it does not meet with other roots, the seedlings soon wither and die. The young plants for plantations must therefore be raised by planting them with other plants on whose roots the seedlings can feed as soon as they have exhausted the nourishment of their own seed lobes, which lasts for about two months. The seeds are therefore planted in short wide tile tubes resembling drain pipes, but shorter, so that the young seedlings can be planted out without disturbing their root attachments. This planting out is done when they are about 4 ins. high or rather more than a year old. If allowed to grow larger there is likely to be injury done to the roots in planting them out. After planting out, the seedlings require to be gently but copiously watered until well established.

Experiment has shown that the best plants to grow with the seedlings are Pongamia glabra, Gossypium arboreum, Albizzia, Leb- bek and Cleistanthus collinus.

The seedlings need protection from animals, as the foliage of the sandalwood plants proves very attractive to them. Cattle and goats will greedily eat the foliage whenever they see it, and deer will leap over the obstructing bushes to get at it, and hares will creep through the thicket to reach it.

As the seedlings in a wild state reach only a height of 3 ins. the first year, and 12 ins. the second year, they are easily destroyed. It is only in the fifth or sixth year they appear above the surround- ing bushes and form a leafy head. At this time the stem is about 1 in. in diameter.

It takes 18 to 25 years before the tree is fit to yield oil. With respect to the spike disease, the trees attacked by it present the appearance of being dead, but on careful examination many leaves are seen to be scattered over the tree at the end of the stiff branches, but they are very small, and form small terminal tufts, hence the name " Spike " disease. The shoots are found to be full of starch, indicating that the plant has not been able to utilize its stored-up nourishment. The disease is pronounced to be infectious, because

34

Oil of Sandalwood.

(Am. Jour. Pharm. \ January, 1914.

all sandal plants, in plantations where it occurs, have died, whilst solitary trees are still thriving.

From the above facts, recorded by various observers, it becomes evident that the sandalwood tree requires plenty of room so as to be able to select vigorous hosts to feed it; that it requires soil por- ous enough to enable its roots to spread readily, and that, therefore, if too closely planted, it may easily be starved, especially in hard or heavy soil. The fact that isolated trees thrive in a natural condition also indicates that the disease is one of mal-nutrition, whilst the presence of starch in the withered shoots indicates the absence of a suitable enzyme to transform it into soluble food.

Apparently no attempts have as yet been made to ascertain the chemical constituents that the tree contains, and therefore needs, although Peterson (Pharmaceutical Journal (3), xvl, page 575) found that Macassar sandalwood was rich in iron (7.5 pc) and contained traces of manganese. The latter metal is believed to be connected with the activity of enzymes, and it is possible that a deficiency of it in the soil may injuriously affect the growth. Re- search is also evidently necessary to ascertain if the tree selects one ingredient for its nourishment from one tree and other ingredients from other species, as it is well known that certain enzymes can split up other bodies than those on which they usually act.

There is evidently much to be done before the cause of the disease and the means to prevent it can be ascertained.

Regarding the subject from the commercial side, the possibility of other sources of sandalwood suggests itself. The world's supply of sandalwood oil is at the present time chiefly derived from the trees grown in Southern India, only a comparatively small quantity coming from the Islands of Timor and Sumba via Macassar. The yield from Mysore last year was 2469 tons of sandalwood, exclusive of chips and sawdust. The average price, including chips and saw- dust, was 471 rupees as against 461 rupees per ton during the previous decennial period.

The only other oil that at present competes with the East Indian sandalwood oil is that of Amyris balsamifera L., a tree belonging to the natural order Burseracese, the wood of which is imported from Venezuela, and is known in Europe as West Indian sandal- wood. It competes, however, only in medicinal use, not in per- fumery.

Of the 20 or more known species of Santalum, which are dis-

Am. Jour. Pharm. \ January, 1914. j

Oil of Sandalwood.

35

tributed over Asia, Australia, New Caledonia and Polynesia, several were rendered almost extinct by the ruthless destruction of the trees during the first half of the last century, and are not now available in quantity for commercial purposes. These include 5\ Freycinetianum, Gaud., of the Sandwich Islands, S. Hornet, Seem., of Eromanga, S. insular e, Bert., of the Marquesas and Do- ciety Islands, and 5\ Yasi, Seem., of the Tongo Islands, and 5. Aus- tro-Caledonicum, VieilL, of New Caledonia. The wood of these trees was chiefly collected for the Chinese market, and not for the distillation of oil. None of these trees, so far as is known, yields an oil equal in fragrance to that of 5". album.

A log of wood of Santalum Yasi from the Indian and Colonial Exhibition was distilled by Mr. C. Umney in 1886, and a sample of the oil sent to Messrs. Schimmel and Co., who considered it in- ferior both in perfume and therapeutical effect to that of Santalum album. The yield appeared to be 6y2 per cent., although the real percentage might have been less, as an unusual amount of water separated from the oil in the winter weather.

Of the trees yielding sandalwood in Australia, some of which were formerly classed in the genus Santalum, the oils are known only in a few cases. That of Fusanus spicatus R. Br. (formerly Santalum cygnorum) or West Australian sandalwood oil, is dis- tilled to some extent in West Australia, but is considered by Gildemeister and Hoffmann to have an unpleasant resinous odor, and not fit to be used as a substitute for East Indian sandalwood oil. It is, however, the nearest to the true sandalwood oil, and contains 75 per cent, of alcohols, which have, however, not been positively identified with santalol, but owing to the small yield of oil (2 per cent.) and the expense of labor in Australia, although the tree is fairly plentiful, it cannot compete with the Indian oil. That of F. acuminatus R. Br. (formerly Santalum Preissianum Miq.) known as South Australian sandalwood, yields a vivid cherry-red oil, from which crystals separate out on cooling. It has a different, somewhat rose-like odor, and a different composition and specific gravity to that of East Indian sandalwood. Exocarpus latifolius R. Br., a West Australian plant, may perhaps yield some of the West Australian sandalwood oil, but there is no evidence that it yields an oil resembling that of true sandalwood.

Several fragrant woods are known under the name of sandal- wood in other countries; the wood of Osyris tenuifolia, Engl., a

36

Oil of Sandalwood.

{Am. Jour. Pharm. January, 1914.

native of Kilmandscharo, in East Africa, has been imported into Germany under the name of East African sandalwood. The oil was described in 1908 as being bright brown in color with an odor intermediate between that of vetivert and gurjun balsam, but quite different from sandalwood (Pflanzenweldt Ost. Afrika C. 167, Schimmel's Report, November, 1908, p. 109).

The Madagascar " Sandalwood," of which the native name is apparently " Hasoranto," is exported from Tamatave in the North of Madagascar to Zanzibar, and thence to Bombay, where it is known as taggar wood, and is largely used as a cheap substitute for sandalwood for funeral pyres. The wood is of a dark brown color, and yields a dark-colored thick oil, with an odor slightly resembling sandalwood, but which for medicinal or perfumery purposes could by no means be used as a substitute for it. Its botanical source is unknown, but is supposed to be a Lauraceous tree.

New Zealand Sandalwood. — The wood of Olearia Traversii, F. Muell, was exhibited at the International Exhibition in 1886 under the name of bastard sandalwood. It belongs to the Family of Compositae, but nothing appears to be known of its oil.

Cochin China Sandalwood. — This is ascribed by Baillon to Epicharis Loureirii, Pierre, Fam. Melacese, but I have not seen a specimen.

Guiana Sandalwood. — The oil has already been described (P. & E. O. R., 191 1, p. 79). Dr. Giessler, of Leipzig, is of opinion that the oil is probably derived from three species of the genus Acrodiclidium, or Ocotea (Schimmel's Report, October, 191 1, p. 82). It does not resemble sandalwood oil in odor and is not known to do so therapeutically.

Ibean Sandalwood. — The wood of Brachylana Hutchinsii, Hutchinson (Family Composite), is known under this name. The tree grows near Nhairobi and in forests near the coast at an elevation of 5000 to 6000 feet. The timber is white, hard, easily worked, and scented when freshly cut, and is not subject to the attacks of white ants. The native name of the tree is " Muhugu." It does not appear to have been exported as yet, the tree being only described three years ago in the Kew Bulletin, 1910, p. 126. The plant is illustrated in the Icones Plantarum, 292a.

It is obvious, therefore, that at present there is no oil known that can altogether take the place of sandalwood oil, and until a

AjanJuTry,Pi9i4m*} Pa- State Pharmaceutical Association. 37

means of combating the spike disease has been discovered and the best method of cultivation of the tree has been ascertained, the price of sandalwood is likely to rise, especially since it takes from 18 to 25 years for the tree to arrive at maturity and to grow scented wood.

The chemical constitution of the oil does not hold out much hope that it will be an easy matter to produce it synthetically, for even if santalol can be produced from piperidine, there are evidently other constituents that go to form the odor of the oil, and unless these can be ascertained it is not likely to take the same place in perfumery or medicine as the oil distilled from Santalum album.

ABSTRACTS OF SOME PAPERS READ AT THE 1913 MEETING OF THE PENNSYLVANIA STATE PHARMACEUTICAL ASSOCIATION.

By John K. Thum, Ph.G., Philadelphia, Pa.

What is the Quality of Pancreatin on the Market?

By Charles H. La Wall.

An examination of some pancreiatin by the author disclosed the interesting fact that it was adulterated with powdered malt. Of course this raised the starch converting power, and, as the author states, as this test is the only one applied sometimes and as the general appearance of such a sophisticated sample is normal, a more than superficial examination of pancreiatin is necessary to insure good quality.

Sterilization in Pharmacy.

By A. Parker Hitchens, M.D.

The author in a very interesting and illuminative manner de- scribes the possible purposes of sterlization in pharmacy and gives in detail the various methods which have been found to* be of value.

Crotalin — Collection, Preservation, Chemistry and Action. By Walter Roth well.

Attenuated snake venom, obtained from Crotalus Horridus, commonly known as " rattlesnake," has obtained some vogue in recent years in the treatment of epilepsy. The author briefly de-

38 Pa, State Pharmaceutical Association. {AjanJu°a^; ^In-

scribes the method of obtaining the venom, its preservation, chemis- try, and action. It is given hypodermatically and its action is to increase the time of the coagulation of the blood.

The Detection of Cane Sugar in Honey.

By Charles LaWall, Ph.M.

The author concludes that it is impossible to detect added cane sugar in honey by means of a qualitative test ; being present normally in small amounts its quanitative determination is preferably accom- plished by means of the polariscope. Invert sugar is the kind usually added and dan be easily detected in honey that has never been heated.

Oregon and Canada Balsam of Fir.

By J. G. Roberts and M. M. Becker.

The writers state that because of the scarcity of Canada Balsam of Fir for the last year or two a suitable substitute is desirable. And as a substitute Oregon Balsam of Fir is offered to the trade. As is well known this product closely resembles Canada Balsam of Fir.

Finding that the literature on Oregon Balsam contained little information the authors obtained some balsam from a known source and endeavored to obtain data as to tests for identity and purity.

It differed in the main from Canada Balsam in viscosity, solu- bility in alcohol, and in response to the magnesium oxide test. The Oregon Balsam is thinner; it is completely soluble in alcohol in contradistinction to the official balsam which yields a turbid solu- tion. Canada Balsam when mixed with 20 per cent, of its weight of magnesium oxide previously moistened with water, becomes solid. The Oregon does not solidify even when mixed with 60 per cent, of its weight of magnesium oxide. It was also noticed that the Oregon Balsam does not dry as readily as the Canada Balsam, a quality which renders it inferior to the latter for microscopical work.

Socotrine Aloes.

By C. J. Denneby.

The author remarks that although the United States Pharma- copoeia definition of aloes is broad enough to allow recognition of all varieties of genuine aloes yet it neglects to describe some samples

Am. Jour. Pharm. \ January, 1914. /

Book Reviews.

39

as imported. It is often received in barrels in a pasty condition, containing nearly twice the amount of water permitted by the U. S. P. It is further remarked by the author that when in this condition the only recourse is rejection of the shipment as abnormal as to its physical appearance, or, it being satisfactory as to identity and purity, to dry so that sample is of proper U. S. P. quality. A tabulation of five samples is given ; all contained twice the quantity of water allowable ; they also failed to pass the alcohol test for limit of gums, dextrins and impurities. While Kraemer and others state that aloes should not yield more than 4 per cent, of ash all of these samples were slightly higher. As is well known and has been for some time, no aloes is obtained from Soeotra.

The Microscopic Examination of Ointments.

By Fritz Heidlberg and Chas. E. Vanderkleed.

The value of an ointment, the authors state, consists mainly in the fineness or subdivision of the active ingredient suspended in the vehicle. And to properly determine when the ointment has been manipulated long enough for the active ingredient to be uni- formly and evenly divided they advise the use of the microscope. They state that this is the only satisfactory way to tell whether uniform results have been obtained. They also give their technic for preparing slides for this purpose and illustrate by showing micro-pho'togriaphs of mercury ointments.

BOOK REVIEWS.

Digest of Comments on the Pharmacopoeia of the United States of America (8th Decennial Revision) and on the National Formulary (3RD Edition) for the Calendar Year Ending December 31, 191 i. By Murray Gait Motter and Martin I. Wilbert.

The foregoing title, known also as Bulletin No. 87, Hygienic Laboratory, needs little introduction to the progressive members of the pharmaceutical profession. It speaks for itself. It is suffi- cient to say that the literature covered in this review embraces matters that must, if thoroughly and painstakingly studied by the

40

Book Reviews.

( Am. Jour. Pharm. \ January, 1914.

two revision committees, result in the publication of a Pharmaco- poeia and National Formulary that will be regarded as authoritative and the last word in pharmaceutical matters.

References to the great mass of literature consulted is com- plete in every respect and comments relating to the legal status and development of pure food and drug laws, scope, analytical data, clinical tests, biologic products and vegetable drugs are abstracted with the main points of the papers brought out. This is as it should be, as it enables a worker to see at once if a reference is worth while consulting.

It is particularly gratifying to note that references of a practical nature in regard to pharmaceutical preparations and suggestions as to their improvement, both as to formula and method of prepara- tion, are much in evidence.

The " digest " also places at the disposal of the revision com- mittees references to all literature pertaining to international standards. Every decade brings us closer to a realization of the fact that the question of unification of pharmacopceial preparations is becoming a matter of supreme importance. Rapid means of travel and communication are largely responsible for this.

Foreign Pharmacopoeias always bring forth considerable comment and criticism from workers and experts from various parts of the globe and last year was no exception. The collaborators of the " Digest " make this fact plain in their references to literature that comments on the German, Russian, Italian, French, Swedish, Swiss, Austrian, Japanese, Dutch, and British Pharmacopoeias and the British Pharmaceutical Codex.

Part III of this Bulletin is devoted to a most comprehensive review of the literature relating to> comments on official articles 504 pages being required to show what has been said and done in this field of endeavor, and also illustrating what a tremendous amount of reading the preparation of this valuable government publication required for its completion.

John K. Thum.

The Propaganda for Reform in Proprietary Medicines. Reprinted from the Journal of the American Medical Association. Eighth Edition, 1913.

There are many people who take as gospel truth anything they see in print. There are a great many other people who, while they

Am. Jour. Pharm. ) January, 1914. J

Book Reviews.

41

know better than to do this, are unable to discriminate and so are almost as easily led as the others. Then there are many people afflicted with some ailment, or think that they are, who clutch, like a drowning man after a straw, any statement which seems to bear upon their case.

To satisfy the " needs " of people like these there is a host of firms who manufacture remedies for every conceivable trouble, and to eliminate the need of having a physician they include in their packages circulars which purport to give complete directions of use. So extraordinary are some of these statements that anyone even only very superficially acquainted with the facts would prick up his ears at hearing them. But not so with the gullible public. The more extreme the statement, the more absolute dependence they place on the product.

Truly, this proprietary medicine venture is no more than a psychological game between the manufacturer and the public, only the public is not aware that it is playing the game. Here are some of the psychological weapons the manufacturer has at his command :

1. As one bows down to a man who is well dressed and imposing in appearance, so one worships an ordinary drug or food (or even a worthless one) when it is clothed in a dignified name.

2. As the average illogical mind believes that what comes after must be due to what goes before, the deduction is easily made that if a person recovers after having made use of some remedy, the remedy deserves the credit. This is termed the post hoc, ergo propter hoc argument. The folly of course lies in the fact that in the great percentage of cases the patient would have recovered without any remedy.

Yes, the Propaganda for Reform in Proprietary Medicines, which is a bound volume of reprints, might well be called " A Study in the Psychology of Advertising Worthless Products." A former book of reprints entitled " Nostrums and Quackery " is relative especially to those nostrums which are exploited only — or chiefly — to the public. The volume under consideration, however, relates to those products which are exploited to the physician and includes also some of those in the other -volume where there seemed to be an " overlapping."

Some 120 proprietaries are considered, the schemes by which they are foisted upon the public through the medical profession are discussed with numerous reproductions of illustrations of advertise-

42

Book Reviews.

{Am. Jour. Pharm. January, 1914.

ments, and chemical formulas and therapeutic properties are given.

A striking feature is the prominence which must be taken by the products of large well-known manufacturing houses who are making a mighty good thing out of the credulity of the public with no regard to the ethics of the profession.

A. K. Lobeck.

ARBEITEN AUS DEM Ph ARM AZEUTISCHEN INSTITUT DER UnIVER-

sitat Berlin, by H. Thorns, v. 10, including the work of the year 191 2, Urban & Schwarzenberg, Berlin, Wien, 191 3, 220 pages, with two illustrations.

This volume like the ones preceding it reflects the work done in the Pharmaceutical Institute of the University of Berlin, by Prof. Thorns and his associates, and includes a total of 35 contributions, under five general headings: 1, Contributions from the division for the examination of drugs, specialties and secret remedies ; 2, reports on organic chemical work ; 3, microchemical work ; 4, reports from the division for the examination of foods and technical products of the Colonies ; 5, general discussion. The whole is followed by an index of four double column pages. The first section of the book includes a systematic review of the new remedies introduced during the year 191 2, and reports the analytical examination of a number of proprietary preparations. The phytochemical work reported in this volume includes observations on the production of menthol in Germany and in the German Colonies, and an examination of the seed of Strychnos kongofera for strychnine. Lenz discusses the pro- duction and use of microchemical reagents in a paper covering eight pages, and Thorns, in a very comprehensive paper, reviews the problems of pharmaceutical education in Germany and other European countries.

Altogether the volume is well up to the high standard that has been established by those preceding it and the renewed energy with which the work on so-called new remedies is being prosecuted bodes well for the general progress of pharmacy along satisfactory lines.

M. I. W.

ARBEITEN AUS DEM Ph ARM AZEUTISCHEN INSTITUT DER UNIVER-

sitat Berlin, herausgegeben von, Prof. Dr. H. Thorns.

This publication, the tenth annual volume, consisting of 220 pages, presents a record of the work accomplished during 1912 at

Am. Jour. Pharm. 1 January, 1914. j

Book Reviews

43

the Pharmaceutical Institute of the University of Berlin under the direction of Dr. H. Thorns, the Director.

It also gives evidence that the German pharmacist, acting through this pharmaceutical institute, is alive to the need of pro- tecting the medical profession and the public against fraud, secret medicines and mendacious advertising. Here, in our own country, the pharmacists have been so busy worrying about price protection on nostrums and telephone rates that the medical profession took the bull by the horns, so to speak, and through its national organization, the American Medical Association, organized a permanent com- mittee, and named it the Council on Pharmacy and Chemistry. What this council has done since its organization is known to a1l progressive pharmacists. And its efforts for better things are surely showing results. One has but to glance over the proceedings and reports of some of the medical and pharmaceutical societies to realize that we are at the dawn of a new era as to things pertaining to these two professions.

The investigations of the laboratory workers of this German institution covered a wide field in the domain of synthetic chemistry, particularly as regards the output of the dye houses of that country, specialties of all kinds, and secret remedies and nostrums of all kinds.

Under the classification of Analgesics, Antipyretics, and Anti- rheumatics, considerable attention is given to such chemicals as Melubrin, one of the more recent antipyretics, said to be useful in rheumatism and resembling in its effects the salicylates, chemically it is sodium-phenyl-dimethyl-pyrazolon-amido-methan-sulphonate ; Atophan, said to be useful as an antirheumatic in so far as it aids in the elimination of uric acid and chemically known as phenyl-quinolin- carboxylic acid ; Novatophan a modification of atophan and taste- less while the latter is bitter ; Aspirin Soluble which is the calcium salt of acetyl-salicylic acid ; Luminal, a sedative and hypnotic, the chemical name of which is phenylethylmalonylurea ; Brophenin, a combination of bromine with phenetidin and chemically known as bromisovalerylamino-acetate-p-phenetidin ; many others too numer- ous to mention are also considered.

Besides giving considerable space in this publication to the in- vestigation of products (Kolonialprodukte) from the German colonies, both as to their chemistry and pharmacognosy, there also appears an exposure of some of the nostrum emmenagogues found

44

Book Reviezvs.

i Am. Jour. Pharm. I January, 1914.

on the German market. One of these consisted of small quantities of oil of cinnamon and cloves in 12 per cent, of alcohol. For two ounces of this wonderful and efficient (?) preparation the modest sum of one dollar was asked. Another, called " Menstruationpulver " consisted of a very poor quality of powdered Roman Chamomile, and for the small (?) sum of seventy-five cents the buyer received a package containing 35 grammes.

An interesting report is given of an examination of a fixed oil sent to the Institute by a German missionary pastor from Venezuela. This oil is used by the Indians in the region of Orinoco as a remedy in the treatment of tuberculosis. The results are reported as good. This oil is yellow in color, slightly cloudy, and in odor and taste somewhat resembling olive oil ; at room temperature fluid ; on cool- ing there was separated a small mass of fatty acid which, on warm- ing, disappeared. At 120 C. the oil congealed to a soft butter-like mass. It was miscible in all proportions with ether, chloroform, petroleum benzine, benzol, and carbon disulphide and on the con- trary immiscible with absolute alcohol and glacial acetic acid. On the addition of HC1 and furfurol no red coloration appeared. The test for cotton-seed oil by the addition of sulphur and carbon disul- phide gave negative results. The constants were ascertained in the usual manner and found as follows :

Specific gravity at 150 C 0.9125

Acid number 4.46

Saponification value 200.45

Iodine value according to Hiibl after 2 hours 69.9

Iodine value according to Hiibl after 6 hours 71.0

Unsaponifiable constituents 0.48 per cent.

Refractometer number in a Zeiss butter-refractometer at 250 . 59-60

Optical rotation in 200 ccm.-tube o

The oil also gave the reaction for elaidin. Hehner's method for the separation of the fatty acids was used and the melting point of these was found to be 30.31 °, the congealing point 22 0 and the saponification value 195.5. The fatty acids also gave an iodine value of 75.25. After recrystallization from alcohol twice, the elaidic acid showed a melting-point of 51 °. Experiments on mice proved this Ceje-Ol, as it is termed, to be non-toxic. Whether it will be of any more value than other better-known fatty oils in the treatment of tuberculosis remains to be proven clinically.

Am. Jour. Pbarm. ) January, 1914. /

Book Reviews.

45

As one reads through this volume, depicting the work done at this institute, the impression is gained that the aim of the workers is the scientific one, the desire for the truth; the truth about those remedies for which there may be a legitimate use and which are more or less ethically introduced, and the exposure of those remedies which are secret in composition and for which extravagant claims are made. John K. Thum.

" A Hankbook of Useful Drugs." A selected list of important drugs suggested for the use of teachers of materia medica and therapeutics and to serve as a basis for the examinations by state medical examining and licensing boards. Prepared under the direc- tion and supervision of the Council on Pharmacy and Chemistry of the American Medical Association. Press of the American Medical Association, 535 North Dearborn Street, Chicago, 1913.

It does not require the gifts of a seer or the abilities of a prophet to venture the opinion that this rather diminutive volume of 167 pages is destined in the near future to have a decidedly far-reaching influence on the teaching and on the practice of therapeutics and, consequently, is designed to have an equally important bearing on the future development of pharmacy and the efficiency of pharma- cists generally.

Conscientious students of medical economics have long appre- ciated the waste of energy, money and even life resulting from the haphazard or ignorant misuse of drugs and medicines so general a decade or more since. Some nine years ago the Council on Phar- macy and Chemistry of the American Medical Association made its first onslaught on quacks and quackery in the medicine supply busi- ness and although the Council at that time had fair reason to be- lieve that it might be assisted in its efforts by at least the more progressive of professional pharmacists, this expected cooperation has not been forthcoming, in this country at least. Medical prac- titioners, largely through the American Medical Association, have been compelled to stand practically alone in their fight against the purely commercial spirit in the practice of pharmacy of to-day. The little book before us is the latest step in this warfare, representing as it does the fundamentally constructive work of the Council on Phar- macy and Chemistry, as the earlier work " Propaganda for Reform " represents the destructive work of the same body, and the now well- known book, " New and Non-official Remedies " represents a com- pilation of reasonably good material that is offered for future in-

46

Book Reviews.

f Am. Jour. Pharm. \ January, 1914.

elusion in the recognized materia medica of conservative medical practitioners.

The object of this, the latest of the three books offered by the Council on Pharmacy and Chemistry of the American Medical Asso- ciation, is perhaps best shown by quoting rather liberally from the preface, not necessarily exactly but rather the purport of the state- ments made, so as to avoid occasional repetition :

" Many of the articles in the Pharmacopoeia and in the National Formulary are worthless or superfluous. The repeated efforts that have been made to eliminate at least the more useless of these articles have uniformly encountered the assertion that the articles objected to are used somewhere by some one, and that they should, therefore, be officially recognized and authoritatively defined.

" For a number of years men active in the work of the Council on Medical Education and in the Confederation of State Examining and Licensing Boards have been trying to restrict instruction and examination in materia medica to the more important drugs. These efforts apparently failed, so far as the Committee of Revision of the U. S. P. is concerned, but the suggestions have been taken up and elaborated by the Council on Pharmacy and Chemistry and the result is this volume on useful drugs.

" The book is offered as a fundamental list of drugs and prepara- tions with which all medical students and practitioners might be expected to be familiar, and to which, therefore, state examining and licensing boards might largely or entirely confine their examinations in materia medica. As it now stands, it embodies a total of about 455 headings including 265 titles of drugs and chemicals, 137 phar- maceutical preparations, 13 cross references and 40 general defi- nitions or descriptions of forms of medicines."

It is confidently predicted that an intelligent and critical use of these selected drugs will prove their general sufficiency, and show definitely that many drugs now discussed in text books and official- ized in pharmacopoeias, are, to say the least, superfluous. A careful study of this book is also well designed to demonstrate that many newly discovered or widely exploited proprietary preparations have no appreciable advantage over established drugs and preparations whose limitations and possible untoward results are generally well known.

Pharmacists and teachers of pharmacy should acquaint them- selves with the nature as well as the intent of the volume. The last word on a limited list of useful drugs has not as yet been said, but

Am. Jour. Pharm. \ January, 1914. /

Book Reviews.

47

the agitation will undoubtedly do much toward insuring a more uniform and better supply of recognized, standard drugs, by placing responsibility for the identity and purity of drugs and preparations on the dispensing pharmacist, where it rightly belongs. By ulti- mately restricting the number of drugs and preparations used it will be possible to provide adequate supervision of the medicines dis- pensed ; and thus the pharmacist will eventually come to occupy the place he rightly deserves as an important factor in safeguarding public health. M. I. W.

War Department: Office of the Surgeon General, Bulletin No. 3. Studies of Syphilis. By Charles F. Craig, Captain, Medical Corps, U. S. Army, and Henry J. Nichols, Captain, Medical Corps, U. S. Army, with introduction by Major Frederick F. Russell, Medical Corps, U. S. Army.

This Bulletin, published for the information of medical officers by authority of the act of Congress approved August 23, 191 2, and with the approval of the Secretary of War, is striking evidence of the fact that the wonderful advances made in the last decade for the diagnosis and treatment of syphilis are being made use of and appre- ciated by the medical men of the army. In no branch of medicine has more rapid progress been made. And, as pointed out in the introduction, " it is noteworthy that medicine is indebted to* lab- . oratory workers and research institutions, and not to the practical syphilographers, for this phenomenal progress."

Exclusive of the introduction the Bulletin consists of a series of seven papers commencing with a study of the Spirochceta pallida, its morphology and cultivation. Under the head of immunity the interesting statement is brought out that there is no true immunity following an infection from this parasite. A person once infected and cured can be reinfected. Opinions contrary to this were long held by the medical profession.

The diagnosis of syphilis by the complement fixation test, or Wassermann test, as it is more generally known, is gone into very fully. That this test has proven of great value in .the army for diagnosis and control over treatment is attested by the experience gained from the performance of 12,000 reactions.

Ehrlich's great discovery, salvarsan and neosalvarsan, naturally, have been used and the behavior of these arsenic combinations with the benzol ring, in the treatment of syphilis is very fully gone into. The superiority of these drugs over mercury as a specific is clearly

48

Book Reviews.

iAm. Jour. Pharm. January, 1914.

proven; yet, in the light of our present knowledge, the consensus of opinion is that a wise combination of mercury plus salvarsan or neosalvarsan intravenously procures the best results.

The work recorded in this Bulletin clearly emphasizes the fact that the Medical Corps of the Army, in its care of our fighting men, possesses unusual facilities for the scientific observation, study, and treatment of .this disease. John K. Thum.

Essentials of Prescription Writing. By Cary Eggleston, M.D., Instructor in Pharmacology, Cornell University Medical College, New York City. W. B. Saunders Company, Philadelphia and London.

Within the confines of this small volume which consists of only 115 pages, a medical student or graduate physician may find all the information necessary to equip himself in the principles of prescription writing, a branch of medicine in which most graduates in medicine find themselves utterly at sea when first starting prac- tice. Some overcome this handicap and some do not; to the latter we most heartily recommend this handy little book, although, as a matter of fact, it may be read with profit by all who practise medicine.

This book consists of ten chapters which embody the funda- mentals in a sequential manner ; the chapter devoted to Latin gram- mar is brief but thorough — the author has evidently learned the art of saying much in few words — while the suggestions offered as to flavoring, coloring, and vehicles (aqueous, hydro-alcoholic and alco- holic), if carefully studied and faithfully carried out by physicians, would soon result in diminishing, if not abolishing, the proprietary medicine evil. John K. Thum.

Genealogy of the Descendants of Thomas French, with Some Account of Colonial Manners and Doings, together with One Hundred and Fifty Picture Prints Compiled and Published by Howard Barclay French, of the Seventh Generation. Vol. II, Phila- delphia. Privately printed, 1913.

Oliver Wendell Holmes once wrote that " Philadelphia was the center of genealogy." With this new contribution which is now completed, Dr. Holmes' views are confirmed. A very extended re- view of the first volume was given in this Journal in June, 1909, p. 309. The work is handsomely gotten out and will stand as a monument to Mr. French.

THE AMERICAN

JOURNAL OF PHARMACY

This is an American plant, which has run wild all over India. It may easily be known by its glaucous, prickly, thistle-like leaves, bright yellow flowers, and milky juice. The latter is used as an application to ulcers and in combination with the juice of Aristo- lochia bracteata is given internally in syphilis and gonorrhoea. In the Concan the juice with milk is given in leprosy. The seeds and oil have been used by European physicians. The oil in doses from 30 to 60 drops is a valuable remedy in dysentery and other affections of the internal canal. Fluckiger found 4 to 5 gms. to have a mild purgative effect. An extract made from the whole plant has been found to have an aperient action and the milky juice to promote the healing of indolent ulcers.

The oil used for examination was obtained by pressing the crushed seeds in a screw press in the laboratory in presence of the author. The chances of adulteration were thus avoided.

Some of the crushed seeds were submitted to steam distillation; the distillate had a slight opalescence and a very pungent odor, but no oil came over.

47.1176 gms. of the crushed seeds were exhausted in a Soxhlet apparatus with petroleum ether, the latter evaporated off when 10.4966 gms. of a thin brown colored oil was left behind. Hence the percentage of oil is 22.3. According to Charbonnier the seeds contain 36 per cent, of oil.

The petroleum ether extract has a pale greenish-yellow color with a green fluorescence, if it be evaporated at the ordinary tem- perature, the oil left behind has an olive green color. If this be

THE OIL OF ARGEMOtf E MEXICAN A.

By Kshitibhushan Bhaduri, M.Sc^ OFFlC^-

FEBRUARY, 1914

Historical.

Experimental.

(49)

The Oil of Argemone Mexicana.

Am. Jour. Pharm. February, 1914..

either left exposed to the atmosphere or heated on the water bath it gradually acquires a rich brown color. If it be still further heated the color deepens and it diffuses a very intense odor, like that of the juice of the fresh plant.

The pressed oil was of a deep brown color, had a mild odor and was tasteless. The freshly obtained oil was very thin, but on keep- ing it gradually thickened. Crossley and Le Sueur (Journ. Soc. Chem. Ind.} 1898, 991) say the fresh oil is of orange color and has a slight but distinctive smell.

The mixed fatty acids had a paler color and were very thin.

The oil on keeping exposed to the atmosphere or on treatment with an oxidizing agent deposited a very small quantity of a red crystalline substance (M.P. 1720 C).

The oil gradually thickened with the lowering of temperature, until at 1 70 C. the clear liquid became turbid, the temperature re- mained constant for a little time at 160 C. Charbonnier's oil re- mained clear at — 8° C. and Fluckiger's oil at — 6° C.

The specific gravity was determined at two different temperatures, at 28 0 C. and at the boiling point of water. In the former case it was 0.91 17 and at the latter it was 0.9007. Charbonnier obtained a specific gravity of 0.920, Fluckiger 0.919 at 16.5 0 C. and Crossley and Le Sueur 0.9247-0.9259 at 1 5.50 C.

The refractive index obtained with a Pulfrich's refractometer was 430 34' at 32 0 C. or 1.46552. With a butyro refractometer Crossley and Le Sueur obtained at 400 C. a refractive index of 62.5.

The oil and absolute alcohol were miscible in any extent. For the determination of its solubility in dilute alcohol the following method was adopted. In a stoppered graduated tall cylinder a measured volume of oil was introduced, to this a known volume of alcohol was added and then water added drop by drop with con- tinuous shaking till a permanent turbidity was obtained. The total volume was read off and from this when the volume of oil and alcohol was subtracted the volume of water added was obtained.

Table of Solubility in Alcohol of Different Strength at 32°C.

Oil.

Water.

Alcohol.

10 10 IO IO II

22

28 24 24

9 15

12 20 32 42 42 45

AFeb£la^ VmT' } The Oil of Argemone Mexicana. 51

116.4 c.c. oi~ alcoholic potash (calculated) were required for

the saponification of 3.4828 gms. of oil; hence the saponification value is 185.5. The saponification obtained by Crossley and Le Sueur is 187.8-190.3.

The oil was acetylated by boiling with acetic anhydride and purified, then dried with anhydrous Sodium Sulphate. 3.23 gms. of

oil thus obtained required 122 c.c. (calculated) of potash for

complete saponification. The saponification value of the acetylated oil was 213.4 and deducting from this 185.5, the saponification value, we got 27.9 as the acetyl value.

The oil contained a large proportion of free fatty acid for which determination 3.5998 gms. of oil was dissolved in 50 c.c. of neutral- ized alcohol and a little phenolphthalein solution added and titrated

with -j^ alkali. It was found that 94.3 c.c. was necessary for

neutralization, hence the acid value is 146. Two specimens of oil were examined by Crossley and Lie Sueur who found 6.0 and 83.9 as the acid value.

In the aqueous solution left after the decomposition of the soap with an acid, the presence of the following fatty acids was proved (1) acetic acid proved by the Cacodyl test and (2) valeric acid by the formation of the ester.

In a weighed flask 2.3696 gms. of oil was taken and dissolved in 50 c.c. of chloroform, and Bromine gradually added till no further absorption took place. It was then evaporated off on the water bath and dried. The weight of the brominated oil now was 4.7912 or the increase in weight was 102.2 per cent. This is the bromine value.

The iodine value of the oil is 106.7. That obtained by Crossley and Le Sueur is 119,91-122.5.

2.7 gms. of oil was saponified, then decomposed with dilute

sulphuric acid and submitted to steam distillation. 0.33 c.c. ©f-^

alkali was required for neutralization of 100 c.c. distillate. There- fore the Reichert-Meisel value is 0.61.

From 1.8426 gms. of oil the author obtained 1.7295 gms. of a mixture of insoluble fatty acids and unsaponifiable matters. The Hehner's value is 94.02. The above authors obtained 95.07.

The glycerol was estimated by the Benedikt and Zsismondy process. This consists in oxidizing the glycerol to oxalic acid by

52 The Oil of Argemone Mexicana. {A^b^ary "191?"

potassium permanganate. From the amount of oxalic acid obtained the weight of glycerol was calculated. It was found to be 15.48 per cent.

6.1996 gms. of oil was saponified, alcohol evaporated off; it was then dissolved in water and extracted with ether. The ethereal extract on evaporation left behind .1418 gm. of residue or the oil contains 2.29 per cent, of unsaponifiable matter.

The elaidin produced by the oil was an orange-colored, dough-like mass. The reaction was very violent.

When sulphur chloride was added to a solution of equal volume of oil and carbon disulphide a violent reaction ensued, the whole mass frothing up; a very sticky mass was left behind.

When 10 gms. of sulphuric acid was added to 50 gms. of oil the rise of temperature was 65 0 C. The Maumene test was 65 0 C.

The rise in temperature on brominating 1 c.c. of oil was 16.5 0 C.

The oil gave no characteristic color reaction with sulphuric acid even when it was diluted with carbon disulphide. The color was blackish-brown in the former case and in the latter case light brown.

On shaking the oil with nitric acid it acquired a deep brown color and the acid a deep red color. On heating it a violent reaction ensued, a pale orange-colored scum was formed when the whole was allowed to stand over night.

For the determination of oxygen absorption power a quantity of lead was prepared by Livache's method ; about a gram of it was spread upon a watch glass and a weighed volume of the oil was spread on it by allowing it to drop on different places. This was weighed. The weights on each successive day were noted till there was no further increase in weight.

Gain in Weight of 1.3437 gms. of Oil.

Days.	Increase in weight.	Per cent, increase.
1st day.	O.269	2 .002
2nd day.	O. 107	O.8
3rd day.	O . OO84	O.6
5th day.	O.OI52	I . I
6th day,	O.OO59	O.44
8th day.	O . OO65	O.48
9th day.	O.OOI5	O. I
10th day.	No increase.

Total gain in weight till constant = 5.522.

AreWJuTy)7oi4m'} The 0il °f Argemone Mexicana. 53

39 c.c. of the oil was fractionally distilled at 15 mm. pressure when the following fractions were obtained.

Temperature.

2i5°-2i7°C.

2I7°-224° C. 224°-228° C.

228°-23I°C.

23i°-235° C.

Weight of fraction.

3-8i 9.08 9.24

6-45 2.79

Remarks.

Instantly solidified.

Solidified but contained some liquid.

Liquid, on prolonged keeping a few crystals

separated out. Pale brown liquid. Greenish liquid.

Examination of the Mixed Fatty Acids.

The specific gravity at 28 0 C. is 0.9065 and at the boiling point of water 0.8889.

2.0688 gms. required for saponification 90.4 c.c. of alkali.

The saponification value is 194.

0.40745 gms. of oil absorbed 0.6003 gms. of iodine from a solution of iodine and mercury bichloride in absolute alcohol. The iodine value hence is 147.4.

To find out the neutralization value, 3.6638 gms. of the mixture were diluted with 50 c.c. of neutralized alcohol, a drop of phenol- phthalein solution added and titrated with a normal solution of caustic potash. It was found 12.64 c-c- were necessary for this purpose. Hence it follows that 193.2 mgms. of KOH were necessary for the neutralization of one gram of the mixture. The mean molecular weight is found by dividing 56.1 by that found necessary for the neutralization of one gm. of oil.

Let M be the molecular weight and n the weight of KOH in gms.

n

now n = a X 0.0561 (a number of c.c.'s of riormal KOH).

^1__= jooo _ jooo > 8

a X 0.0561 a 3.45

3-33°3 gms. of oil gave 2.5847 gms. of liquid fatty acid by the lead-salt-ether process. Therefore, 77 per cent, of the total fatty acid was liquid fatty acid.

It was found that the oil did not contain any stearic acid.

The lactone value of the mixed fatty acid was the difference between the saponification and neutralization values, .8.

54 Assay Process for Quinine in Tablets. { A™eb/uary Pi9iF'

The titer test of temperature of turbidity of the mixed fatty acid is 22° C.

The mixed fatty acid contains 8.14 per cent, of lauric acid as was found by fractional distillation of the oil in vacuo.

Chemical Laboratory, Presedency College, Calcutta.

AN ASSAY PROCESS FOR QUININE IN TABLETS. By Sidney F. Fieselmann, Peoria, 111.

A rapid method for the quantitative estimation of quinine in tablets, containing no other chloroform soluble constituents, that are not expelled at a temperature of 1250 C, which has been successfully used by the author with accurate results, is the following :

Count out a sufficient number of tablets, so as to make the total number represent 10 grains of quinine or quinine salts, based on the quantity claimed on the label. If the quantity stated per tablet cannot be made to come out in a whole number of tablets, take the number of tablets, which contain about 10 grains and make the required correction. Weigh the tablets counted out accurately on an analytical balance. Multiply this weight by two and call it X grams. Then powder a sufficient amount of tablets and force all through a number sixty sieve. In case of coated tablets be careful not to loose any particle of the hard coating or parts of tablets during the process of powdering and sifting. Then mix thoroughly after this operation, so as to insure a uniform representative mixture. Weigh up X grams of this powder in a 100 c.c. Erlenmeyer flask, add 50 c.c. of chloroform, accurately measured, stopper and shake well. Now add 5 c.c. of ammonia water U. S. P., stopper well and shake thoroughly for 20 minutes. Let stand for about 12 hours in a cool place, with occasional shaking, and decant the chloroform into a separatory funnel, stopper well and allow to stand until separation takes place. Take a 5 cm. plain folded filter paper, on a small 60 0 glass funnel, moisten with a little chloroform, taking care not to have any chloroform drop into the measuring cylinder or any remaining in the tube of the funnel. Then withdraw enough of the chloroformic solution in the separating funnel and filter the same through the moistened filter paper into a 50 c.c. measuring cylinder until 25 c.c. are obtained.

^'bra^iy Pi9ai4m' } Assay Process for Quinine in Tablets. 55

If this 25 c.c. of filtrate is colorless or of a light straw color, transfer it to a tared beaker of 60-100 c.c. capacity, rinsing the cylinder with three portions of 10 c.c. of chloroform and adding the same to the chloroform solution in the tared beaker. Then evapo- rate the chloroform carefully on a water bath. If the filtrate is highly colored, from the coating, coloring matter, or resinous substances in the tablets, transfer the same into a clean separatory funnel, rinse out the cylinder as before, adding the same to the chloroform solution in the separatory funnel, and shake out with three portions of normal sulphuric acid, 15, 5, 5 c.c. respectively, each portion diluted with 5 c.c. of distilled water. Collect the combined acid aqueous solution in a clean separatory funnel, add a small piece of red litmus paper, make distinctly alkaline with ammonia water U. S. P. and shake out with three successive portions of 25, 15, and 15 c.c. of chloroform, collecting the same in a tared beaker. After the chloroform has evaporated, redissolve the residue in 5 or 10 c.c. of ether and let evaporate spontaneously.

Finally, place the tared beaker, containing the quinine residue in a drying oven and heat to a constant weight at 1250 C, cooling the tared beaker each time in a desiccator before weighing. It usually requires from one to three hours of heating until the weight is con- stant. The tared beaker should be chemically clean and heated for at least one half hour at 125 0 C. and cooled in a calcium chloride desiccator, before it is weighed and the chloroformic solution added.

If exactly 10 grains of quinine or the salts of quinine were taken as per label the residue should weigh the following :

For Quinine Alkaloid U. S. P. (Quinine + 3H00) 0.5553 Grams.

For Quinine Bisulphate U. S. P 0.3830 Grams.

For Quinine Hydrobromide U. S. P 0.4963 Grams.

For Quinine Hydrochloride U. S. P 0.5296 Grams.

For Quinine Salicylate U. S. P 0.4457 Grams.

For Quinine Sulphate U. S. P 0.4814 Grams.

Tablets containing substances like calcined magnesia as a drying agent, do not filter rapidly by the above method. The water in the ammonia water forms a gelatinous mass with the magnesia, which prevents rapid filtration and sometimes stops it altogether. In that case the following method is suggested. Measure out in a 50 c.c. measuring cylinder, 5 c.c. of spirit of ammonia U. S. P., add a sufficient quantity of chloroform to make exactly 50 c.c. Use

56

U. S. P. ipoo Menstrua.

{Am. Jour. Piiarm. February, 1914.

this as a menstruum and follow the other directions as given above omitting the ammonia water. This last method cannot always be used on account of the alcohol in the spirit of ammonia U. S. P., which dissolves more substances than the chloroform would alone and so the residue would not be pure quinine. On the other hand chloroform alone will not dissolve anything but the quinine of the substances usually found in quinine tablets.

In order to obtain sufficient chloroformic filtrate from tablets containing an unusual large quantity of other material and only a small amount of quinine, it may be necessary to increase the chloroformic menstruum from 50 c.c. to 100 c.c. or more, filtering off one half the quantity used, following the instructions given above.

Sutliff and Case Co., Peoria, 111.

U. S. P. 1900 MENSTRUA. By H. C. Hamilton.

It seems almost superfluous to call attention, at this late date, to certain points in the 8th Revision of the U. S. P. which need correc- tion in the forthcoming 9th Revision. Particularly does it seem unnecessary in view of the fact that the objectionable features to which this article alludes have been pointed out before and by several critics. The excuse for doing so, however, if any is necessary, is that the data here published may be of value to those who have under consideration for the 9th Revision of the Pharmacopoeia the menstrua for the extraction of the digitalis series of heart tonics. The menstrua to which we refer are for the preparation of : I. F. E. Digitalis ; II. F. E. Squill ; III. F. E. Convallaria.

I. The first two of these were referred to by Houghton and Hamilton 1 in the following words :

" 3. Fluidextract digitalis, U. S. P. 8th Rev., 48 per cent, alcohol.

" Average potency of eleven samples at time of manufacture 55 H. T. U. per c.c. Three and a half years later 35 H. T. U. Aver- age loss about 10 per cent, yearly.

" A very important point should be noted in this connection ; namely, the menstruum adopted in the last U. S. P. for the prepara- tion of fluidextract digitalis is much less desirable than the U. S. P. 7th Revision in at least two respects. Repeated trials show that it is

Am. Jour. Pharm. ) February, 1914. j"

U. S. P. 1900 Menstrua.

57

almost impossible to get a finished product containing the full number of H. T. U. of the standard we had previously adopted, the average being as above stated, 55 H. T. U. per c.c, while with drug of the same quality when the 7th Revision menstruum is employed no diffi- culty is experienced. Owing to this it was decided to no longer attempt to assay physiologically the 8th Revision product and to take such statement referring to it off the label, but, in order to supply the medical profession with a full strength fluidextract of the drug, it was decided to prepare such with a menstruum containing a larger per cent, of alcohol which could be assayed and so labelled. In the second place the loss in potency of the 8th Revision is about 10 per cent, per year, while with the 7th Revision it is less than one-half as great, or about 4 per cent. The results coincide quite closely with those following the change made in the menstruum for the fluidextract of squill except that the loss in activity was greater in the latter drug, as pointed out by Houghton 2 three years ago. In this paper several methods of physiological assay showed very clearly that a serious mistake had been made in changing to acetic acid as a menstruum. The writers feel certain that any one who has tried the 8th Revision menstruum for fluidextract digitalis has found that it is much less satisfactory from a pharmaceutical point of view, to say nothing of the loss in potency."

To this we wish to add data since obtained on F. E. Digitalis as follows :

The above samples were prepared from one lot of drug, using 100 grams and extracting until exhausted.

Another small sample of drug carefully extracted by both methods and tested gave results as follows :

A sample of drug extracted with several strengths of alcohol gave the following results :

Menstruum. 50 per cent, alcohol . 80 per cent, alcohol

Per cent. Activity.

IOO

120

with 50 per cent, alcohol with 80 per cent, alcohol

no per cent, of standard. 140 per cent, of standard.

Menstruum.

Per cent. Activity.

94 per cent, alcohol 75 per cent, alcohol., 62.7 per cent, alcohol. 50 per cent, alcohol.

90 140 125

no

5«

U. S. P. ipoo Menstrua.

f Am. Jour. Pharm. \ February, 1914.

The following table shows the tests of commercial lots of F. E. Digitalis, U. S. P. 8th Rev. (a) before and (b) after an attempt to improve the quality by concentrating the extract.

Number.	Tested.	Per cent. Activity.
I (a)	8/4/9	8=?
i (b)	8/19/9	go
2 (a)	7/20/9	85
2 (b)	8/4/9	85
3 (a)	3/4/9	60
3 W	4/2/9	100
4 (a)	I/3I/8	80
4 (b)	2/8/8	80
5 W	5/23/7	75
5 (b)	6/1/7	83

Further data on 20 samples of the preparation show results of first tests ranging from 50 to 100 per cent, standard and averaging exactly 78 per cent.

The standard referred to is the average activity obtained from 12 lots of crude drug, botanically of first class quality, selected at random and extracted with 62.7 per cent, alcohol, the official men- struum of the U. S. P. 7th Revision. The activity was determined by the frog method described by Houghton 3 as a means of standard- izing the heart tonics of the digitalis series. In that article attention was called to the enormous variation in samples of the crude drug for sale on the open market.

The value of such a method is also shown when endeavoring to extract from active material all the therapeutically active sub- stances and to establish by experiments on other than the human subject the relative activity of extracts obtained by means of various menstrua.

The above results speak for themselves, but if additional authority is needed it should be sufficient to note that the menstrua for making tinctures and fluidextracts of digitalis in the official Pharmacopceise of the world, specify, almost without exception, a percentage of alcohol in excess of that official in the U. S. P. 8th Revision. The menstruum adopted in 1906 by the Brussels Conference is 70 per cent, alcohol and it is to be hoped that the Revision Committee will be influenced by this in adopting an official menstruum for the 9th Rev. of the U. S. P.

II. As noted before in the abstract from: the American Journal

Am. Jour. Pharm. \ February, 1914. /

U. S. P. 1900 Menstrua.

59

of Pharmacy 1 a mistake was certainly made in adopting for the preparation of F. E. Squill, U. S. P., 8th Rev., a menstruum com- posed of a 10 per cent, solution of Acetic Acid. This is so far from being ideal for extracting the active substances from Squill bulb that it is practically impossible to prepare an extract representing the activity of the crude drug.

Comparison of the activity of F. E. Squill, U. S. P., 1890 and 1900, was made by Houghton 4 as follows :

" Comparative Strength of Fluid Extract of Squill Prepared from the Same Lot of Drug According to the United States Pharmacopoeia of 1890 and 1900:

" 1 U.S. P., 1890, 140 per cent, as active as standard fluid extract.

" 2 U.S. P., 1890, 140 per cent, as active as standard fluid extract.

"3 U.S. P., 1900, 60 per cent, as active as standard fluid extract.

"4 U.S. P., 1900, 60 per cent, as active as standard fluid extract.

" It may be observed that activity of both products is high as com- pared with the results given in Table 2. This probably is due to the great care exercised completely to exhaust the drug and to the high quality of the drug.

" In order to meet any objections that might be offered against the results as shown by the special method of assay employed, the work was checked by experiments on dogs showing the comparative activity of the two products in producing changes in the blood-pres- sure, which is perhaps the most characteristic physiologic action of the members of the digitalis series/'

The results of the latter experiments are here recorded in tabular form for more convenient reference.

Experiment I.

F. E. Squill, U. S. P., 1890. F. E. Squill, U. S. P., 1900. Before After injection. injection. Before. After.

Pulse Rate 100 96 116 138

Blood-pressure 46 54 48 45

In this experiment 0.3 c.c. F. E. Squill, U. S. P., 1890, was injected at 10.45 A-M- in*0 the femoral vein of an anaesthetized dog. Then at 2.41 p.m., when the effect of the first injection had passed, the same amount of F. E. Squill, U. S. P., 1900, was injected.

In the second experiment the order of injection was reversed an- other dog being used for the test, and the same amount of each preparation injected.

6o

U. S. P. 1900 Menstrua.

f Am. Jour. Pharm. ( February, 1914.

Experiment II.

Pulse Rate . . . Blood-pressure

F. E. Squill, U. S. P. , 1900.

Before. After. . . . 102 I44

F. E. Squill, U. S. P. ,1890.

Before. After. IOO 94 52 50

47 46

Note. — In both cases the U. S. P., 1900, preparation increased the rate and lowered the pressure. This is directly opposite in effect from the characteristic action of the heart tonics in general and from that of the F. E. Squill, U. S. P., 1890, from the same drug.

In this case again a stronger alcohol is better. If the drug is finely ground and extracted with menstrua containing 60 per cent, or less of alcohol, it swells so that percolation is either entirely or almost prevented. It becomes necessary either to cut the bulb without grinding or toi mix with sawdust in order to have it sufficiently open to percolate properly. An additional objection is in the large amount of gummy, water-soluble extractive obtained with such menstrua. A fluid extract of better appearance, better keeping quality and con- taining practically all the available activity of the drug, can be obtained by the use of 80 per cent, alcohol. Repeated experiments have shown the excellence of this menstruum over that of the 7th or 8th Revisions of the U. S. P.

III. Fluid Extract Convallaria, U. S. P., 1900, is not so open to criticism as the others but the menstruum is not entirely satis- factory. There are certain advantages to be gained by using a stronger alcoholic menstruum than that prescribed in the 8th Revis- ion U. S. P. While these advantages are more apparent when experiments are conducted on a manufacturing scale than when small experimental lots of fluid extract are prepared, even in the latter case the advantages are very real.

Several experiments have been carried out, of which the following is used as an example :

A small lot of drug was divided into two portions, one of which was extracted as prescribed in the U. S. P. ; namely, with 62.7 per cent, alcohol, the other with 80 per cent, alcohol. These extracts were carefully concentrated to fluid extract volume and tested for activity by the method previously cited, with the following results :

Menstruum.

62 per cent, alcohol 80 per cent, alcohol

Per cent. Activity. IOO I20

VebiJuTiT,Pih9T4m' } Standardisation of Heart Tonics. 61

The advantages to be gained from using a stronger alcoholic men- struum for extracting cdnvallaria roots and rhizome are not merely the greater activity obtainable, but in the improved appearance of the extract and its greater stability. It contains less of the gummy extractives and more alcohol, both of which are desirable features, as they affect deterioration, while the 20 per cent, increase in activity from the use of 80 per cent, alcohol is no less desirable.

It is to be hoped that those in charge of revising the forthcoming U. S. Pharmacopoeia will consider these suggestions.

LITERATURE CITED.

1 American Journal of Pharmacy, October, 1909.

2 Jour. American Medical Ass'n., June 12, 1906.

3 Ibid., September 11, 1897.

4 Ibid. , May 12, 1906.

From the Research Laboratory of Parke, Davis & Co.,

Detroit, Michigan.

THE PHYSIOLOGICAL STANDARDIZATION OF THE HEART TONICS.*

By Professor William A. Pearson, of The Hahnemann Medical College

of Philadelphia.

" The Physiological Testing of the Heart Tonics," which is the subject assigned for my discussion, is a very inaccurate title.

A satisfactory definition of a tonic has never been given, much less, a heart tonic. The word physiological is not appropriate be- cause when any active drug is given the normal processes of the body are no longer physiological.

For these reasons, such a subject as " The Pharmacologic Stand- ardization of Drugs Having a Particular Action on the Heart " would be far more fitting.

Since Digitalis is the most important member of the group of drugs known as " heart tonics," a discussion of the methods of standardizing this drug will be first considered.

Medicinal Use and Therapeutic Action of Digitalis, It is well known that Digitalis has had a place in domestic and medicinal therapy for centuries, and many of you know that a Bir-

* A special lecture given at The Philadelphia College of Pharmacy, De- cember 8, 1913.

62 Standardisation of Heart Tonics. {^ebruar'y,^™'

mingham physician by the name of Withering,1 published in 1785 the first reliable observations of the medicinal properties of this drug. The diuretic properties of Digitalis were first observed, but after the middle of the last century its ability to< slow the heart so impressed the medical profession that Digitalis was, and is even to this day, often used indiscriminately for all conditions where the heart beat is irregular or rapid. It can now be demonstrated that Digitalis is only of particular value in a very limited number of diseases of the heart and mainly in auricular fibrillation.

So far as showing the rate of the heart beats is concerned, it may be laid down as a law, that Digitalis is far less effective when the rhythm of the heart is normal than when there is auricular fibrillation.2 Most authors state that digitalis causes constriction of the blood- vessels and consequently a rise in blood-pressure, yet I have not been able to demonstrate more than slight variations in blood-pressure in test animals, although various lots of tinctures, fluid extracts and proprietary preparations have been tried.

Mackenzie 3 has made numerous observations on various classes of patients and refutes the idea that the administration of Digitalis has a tendency to produce fatal syncope, provided the drug is stopped as soon as nausea and vomiting appear or when the heart rate falls below 50 per minute.

When the rhythm of the heart is normal the first symptom is loss of appetite, if drug is continued, vomiting, feeling of malaise, head- ache, and very little diarrhoea may be reported.

Famulener and Lyons 5 state that the digitalis glucosides act not only on the heart but directly on the central nervous system, first stimulating then depressing it. Cushny 6 states that " the chief thera- peutic use is to counteract certain changes in the circulation, which result in the blood accumulating in the veins in too large quantities while the arteries are less filled than usual. In cases of dilation of the heart with a weak and insufficient systole, its action is almost specific.

" In these cases the action is very simple — the increased ventricu- lar systole approaches the normal, the output of the heart is increased, and in some cases the dilation is diminished by the direct action of the drug. The effect is an increased velocity and pressure in the arteries and improved nutrition of the whole body."

There is no doubt that Digitalis relieves distress and dropsy and has been directly responsible for numerous cures, yet it is possible

AFebraairy ^iuET' } Standardization of Heart Tonics. 63

that these favorable results may be attributed to some other reason than its effect on the heart, per se.

It is needless to say that Digitalis has been given thousands of times when its use was not indicated and doubtless its failure to pro- duce favorable results under improper conditions has been responsible, more than once, for condemnation of the particular preparation of digitalis being used.4 It has been repeatedly stated that analogous preparations of digitalis made by various manufacturers differ mark- edly in strength, that digitalis preparations rapidly deteriorate and that only the leaves of the first year's plant are active. It is no doubt true that analogous digitalis preparations differ markedly in strength,7 but it is very doubtful if the usual galenical preparations deteriorate rapidly,8 or that only the leaves of the first year's plant are active.9

It is possible, but not at all probable, that only the digitalis plants which are in flower are physiologically active and this need not ex- clude the first year's plants as John A. Bornemann 10 has shown me a digitalis plant with plenty of flowers on it, although it was a plant of the first year's growth. Certain it is that the therapeutic action of digitalis as stated by various authors is sadly confusing and no doubt much of this confusion is due not alone to clinical reports where digitalis was not indicated, but to the pharmacologic variability of the preparations themselves.

Chemistry of Digitalis.

Almost every pharmaceutical chemist of note has tried to isolate, unchanged, the complex active principles that are present in digitalis. The great Schmiedeberg and Kiliani agreed that the four glucosides which they separated and called digitoxin, digitalin, digitalein and digitophyllin, possess a true digitalis action. They separated, in addi- tion, other glucosides such as digitonin, digitin and digitoflavin, but they considered these decomposition products. Several carbohy- drates which came from the decomposition of the glucosides, were also described.

When one looks up the vast literature on the chemistry of digitalis it is quite evident that different glucosides are sometimes given the same name by different authors and vice versa.

Recently Kraft 11 has contributed an admirable article on this subject and his work is now generally accepted. He claims that both Schmiedeberg and Kiliani worked with German digatalin, a commer- cial product made largely from digitalis seeds, hence their results are

64 Standardisation of Heart Tonics. {A^u°^^a-

not reliable for digitalis leaves. Kraft has isolated a new active glucoside which he calls Gitalin, which probably has the chemical formula C28H48O10. This glucoside is amorphous but forms a crystalline hydrate, C28H48O104H2O. Gitalin readily decomposes in any solvent except chloroform into anhydrogitalin C23H4609 which on hydrolysis, with a dilute acid in the presence of alcohol, changes to anhydrogitaligenin C22H3405 and a sugar which was found to be identical with Kiliani's digitoxose. Another new glucoside was also isolated. This he called Gitin, and it is inactive physiologically. It is crystalline and melts at 265 ° C. It is considered similar to, but not identical with, Kiliani's digitonin.

Digitoxin is often considered the chief active glucoside in digitalis and chemical determinations of this constituent have been frequently made in the hope of finding a relationship between the digitoxin con- tent and the therapeutic activity, but the results in almost every case have proved a failure.12 If the digitoxin from a given amount of drug is isolated it will be found that the total amount of digitoxin is very much less toxic than the amount of drug from which it was obtained, hence it seems absolutely necessary to resort to pharmaco- logical standardization if any definite idea of the therapeutic strength is desired.

Pharmacologic Standardization of Digitalis. At least three distinctly different pharmacologic methods have been proposed for the standardization of Digitalis — the frog method, the guinea pig method, and the cat method.

The Frog Method. The frog method was first proposed by Houghton in 1898. 13 He found that " fairly accurate data could be obtained from the appli- cation of a solution containing Strophanthin, Digitalin, etc., to the laid-bare frog's heart, by comparing the action of the drug thus tested with that of a sample of known strength." After much ex- perimental work this method was replaced by the use of a simpler one — namely, the determination of the minimum lethal dose for frogs under definite conditions. Although the original method as modified by Houghton gives quite satisfactory results, yet various workers have proposed certain changes in the conditions under which the test is to be made. For example, twelve hours was specified as being the length of time that observations should be made after injection of the

AFe'braa^y *m£' } Standardisation of Heart Tonics. 65

frogs. As this is usually inconvenient, these observations were made after one hour, two hours, six hours, or twenty-four hours. Some workers began to pith the frog at the end of one hour and make a direct examination of the condition of the heart, for it was found that sometimes frogs would be apparently normal yet their hearts had been stopped by the drug.

Dr. Hale 14 observed that more concordant results were obtained when the frogs were kept at the uniform temperature of 22 0 C. It would neither be interesting nor instructive to relate the various modi- fications that have been proposed for the Houghton method.

Edmunds and Hale,15 Edmunds and Cushny,16 and Focke 17 have specified various conditions under which the " frog test " is to be made, but none of these methods make any provision to1 standardise the frogs that are used.

It is known that variety, weight, sex, season, and temperature affect the resistance of frogs and hence it is possible to> obtain different results with different lots of frogs. In order to eliminate these factors of unknown significance in any particular case, Houghton and Hamilton have suggested that a standard be used in testing the resistance of every lot of frogs, at the time the test is made. Upon these data " The Heart Tonic Unit " 18 is computed in every case.

The standard they propose to use is crystalline Strophanthin which is prepared from an authentic specimen of the official drug, Strophanthus Komibe, and has been studied in detail by Braun and Closson.19 The outline of the present method as modified by Hough- ton is as follows :

Frogs should all be of same species, a convenient variety is the Rana Pipiens. They should all be of weights between 15 and 35 gm. and the weights should not vary more than 25 per cent, in any one assay. Before being used the frogs may be kept in any convenient place where the water can be frequently changed and kept at a tem- perature of about 220 C. During the test the frogs can advan- tageously be kept in wire cages with sheet iron bottoms, standing in trays of running water, but the depth of water in the cages should not exceed one-half an inch. Scales for weighing the frogs should be accurate within 0.5 gm. The necessary apparatus consists of volu- metric flasks, cylinders, graduated pipettes and a 1 c.c. pipette graduated in hundredths of a cubic centimetre and fitted with a hypo- dermic needle or drawn out into a fine point for injecting.

66 Standardisation of Heart Tonics. { February Pi9i™'

The solution to be injected should not contain more than 10 per cent, alcohol and the dilution should be made with physiological salt solution (0.85 per cent. NaCl).

The doses are calculated on the weight of the frog, i.e., the M. L. D. is the minimum lethal dose, per gram weight of frog. For example, when the frogs are of average resistance the M. L. D. of Strophanthin is 0.000,001 gm. per gram weight of frog, i.e., for a 30 gram frog the lethal dose of Strophanthin is .000,03 gm-> which should be so diluted that this amount is contained in approximately 0.5 c.c. Several series of tests are necessary to establish the activity of any sample of unknown strength and since the frogs vary in resistance among themselves and also because of conditions more or less beyond control, the standard Strophanthin must be tested at the same time. When the M. L. D. of sample and of standard are obtained the activity can readily be expressed in Heart Tonic Units (H. T. U.) by reference to a table.

In the method just given the observations are to be made at the end of twenty-four hours, hence the one-hour method has certain advantages when several series are desired on a single sample as soon as possible. When the one-hour method is used it is necessary to not consider all frogs that have not absorbed the dose injected.

The One-Hour Method.

" In this method the frogs are secured and kept in the manner already described, weighed, and such a dose is injected that the heart will be found in complete systolic contraction at the end of exactly sixty minutes. The drug, properly diluted so as to make a volume of 0.5 to 1 c.c, is injected into the anterior lymph sac by means of a glass pipette. Shortly before the hour is up the frog is pithed, tied to a frog board, and the heart is exposed in the usual manner. If the heart is still beating, the dose has been too small and must be increased in subsequent trials. In the first series doses are chosen with wide limits, which in a second and third series of animals are narrowed down until the smallest amount of the drug which will produce systolic standstill in one hour is found. Usually three series of frogs are sufficient to assay one preparation, but in case of any irregularity in the reaction of any of the frogs a fourth or even a fifth series may be necessary."

The method of Focke 17 is long and complicated and does not appear to have any advantage over the other frog methods that have been described.

Am. Jour. Pharm. ) February, 1914. j

Standardisation of Heart Tonics.

67

Guinea Pig Method.

Reed and Vanderkleed 20 first advocated the advantages of using the guinea pig as the test animal although Houghton 13 had pre- viously tried pigs but considered the frog test more reliable.

The closer biologic relation of the guinea pig to man appears to be one important reason for preferring guinea pigs. It is claimed 21 that " frogs not only show the pharmacological action of the drug under test, but they react with so near an approach to uniformity that the medicinal value of a tested specimen can be gauged by the deter- mination of the minimum fatal dose — for the slowing of the heart beat and the systolic emphasis produced by active heart tonics are directly proportioned to the quantity of the drug administered, and under progressive doses at last reach a point which is incompatible with life."

Details of Reed and Vanderkleed Method for Testing Digitalis and its Preparations.

If Digitalis leaves are to be tested a tincture is first prepared from the sample by the U. S. P. process.

An amount of any alcoholic preparation representing one-tenth of a gramme of Digitalis Leaves is placed in a very small watch glass and the excess of alcohol evaporated from it at room temperature by placing the vessel in a current of air. This residue is then care- fully washed into a Hitchen's syringe 22 with sufficient physiologi- cal salt solution to make the total volume two cubic centimetres.

The hypodermatic needle is previously sealed with sufficient petro- latum to prevent loss of this solution.

Two cubic centimetres of physiological salt solution is placed in the side-arm of the syringe and the needle inserted under the skin of a guinea pig weighing about 250 gm.

The solution of the drug is then injected and the last portions washed under the skin with the physiological salt solution which was placed in the side arm, without removing the needle.

Great precaution is taken to inject accurate amounts and always a total of four cubic centimetres of liquid (2 c.c. of solution of drug and 2 c.c. of physiological salt).

After the injection, the guinea pig is kept under close obser- vation and evidences and time of salivation, purgation and convul- sions noted. If the pig should not develop these symptoms and die within two hours, another pig is injected with a larger quantity of the drug.

68 Standardisation of Heart Tonics. {^Zy^oit

The tests are repeated until the amount of the drug is found which will produce the characteristic symptoms of Digitalis poisoning and kill a 250 gm. guinea pig in two hours.

Post-mortem examinations are always made to note the con- dition of the heart and dilation of the blood-vessels.

In testing solid preparations of Digitalis a weighed quantity of the preparation is shaken with a definite amount of physiological salt solution so that two> cubic centimetres of the liquid will represent one-tenth gramme of the drug. This method has been found quite satisfactory, but Pittinger 23 has found that more concordant results are obtained if the time of observation is extended from two hours to twenty-four hours. One disadvantage to the method is that the cost of the required pigs is usually greater than the frogs necessary for Houghton's method. This objection is largely overcome by manu- facturers of antitoxin who can use the pigs that have survived the antitoxin tests for digitalis tests. These pigs cannot again be used for testing serum on account of anaphylaxis, and by the time they have completely recovered from the antitoxin tests they may weigh much more than 250 gm., which is the weight specified. No pro- vision is made for the varying susceptibility of the pigs and it is doubtful if the pig test, as it is usually carried out, will give any more reliable results than a larger number of frogs that have been " stand- ardized " with crystalline strophanthin.

The Cat Method of Hatcher and Brodie.24

This method is based upon the determination of the minimum lethal dose for cats. The cat is anaesthetized with ether and about one-half of the amount of the preparation being tested necessary to kill the animal is injected directly into the venous circulation. The originators of this test have found that if preparations of digitalis or other members of this series are injected until the cat dies, the results will usually be too high, hence, after twenty minutes a 1 to 100,000 solution of Merck's Ouabain is cautiously injected until the cat shows signs of dying, namely, rapid respiration, which soon becomes irregu- lar and is accompanied by convulsive movements. The Ouabain should be injected in such amounts that the cat should die ninety minutes after the beginning of the test.

The " cat unit " is the amount of crystalline Merck's Ouabain which is fatal within about ninety minutes to each kilogram body

Ve'braary,Pih9air4m'} Standardization of Heart Tonics. 69

weight of the cat. This amounts to 0.1 milligramme of the Ouabain and the number of " cat units " in one cubic centimetre of the prep- aration being tested is computed from the data obtained. Eckler 25 has reported serious disadvantages to this method, and it is doubtful if it will ever have the popular favor the other two methods enjoy.

Factors Relating to the Standardization of Digitalis.

It may easily be seen that the last word has not been said in regard to the standardization of Digitalis and this unsettled condition, in its standardization, is certain to prevail until the therapeutic uses and chemistry of the drug are agreed upon.

It is true that some fault can be found with the methods we have outlined and no doubt many factors will soon be eliminated.

At the present time, it is possible to determine by physiological tests with reasonable accuracy the variability of the crude drug, the stability of its preparations, and to prepare preparations of con- siderable uniformity.26

Other Heart Tonics.

What has been said in regard to the methods used for standard- izing Digitalis applies also to preparations of Strophanthus, Squill and Convallaria. Strophanthus seems to be more certain in its action than digitalis and can also be advantageously tested by the blood- pressure method upon dogs.

Cactus grandiHorus has long been used empirically with appa- rently favorable results, yet competent pharmacologists have reported that it has no action analogous to digitalis 27'28. Graeber 29 has recently reported the presence of both alkaloids and glucosides in this drug and publishes experiments on frogs which " indicate that Cactus grandiflorus actually is possessed of an action upon the heart such as belongs to the substances of the digitalis group." In all his frog experiments the frequency of the pulse was reduced and the systole strengthened.

Sparteine sulphate is considered a drug of mediocre importance as a " heart tonic," yet Pettey 30 considers that Sparteine is unappre- ciated because it is not given in sufficient doses. He recommends the use of 2 grain doses as a true and reliable heart tonic, an excellent non-irritating diuretic and states that this dose is entirely free from untoward or objectionable effects.

70 Standardisation of Heart Tonics. {A?eb™?S,Pi»i™'

Work of the Normal Heart. Few realize the vast amount of work performed each day by the heart of the normal adult. One-fifth the total muscular energy of the body is used in propelling the heart and about twelve tons of blood are pumped each day.

New Methods of Observing Conditions of the Heart. The electro-cardiographic method 31 has made possible not only the accurate diagnosis of diseases of the heart but also enables the physician to observe the effects of the medicine he has prescribed. The practice of medicine under these conditions has become scientific, not empiric, and if uniform preparations of the " heart tonics " can be supplied, the physician needs only to consider the idiosyncrasy of the patient.

Summary.

In presenting this subject I have attempted to dwell not alone on the methods used in standardizing the " heart tonics " but the various factors that must be considered in producing reliable and potent prep- arations. The clinical side of the problem must not be lost sight of, and when a preparation is made that will produce certain therapeutic results it is of vital importance to produce another lot having the same action. Uniformity is practically as important as potency. When a competent observer like Faught 32 says " Usual preparations are variable and cannot be depended upon unless coming from a reliable source. I have seen less effect follow the administration of 20 minims of a poor preparation than 5 minims of a good active one " it is time to improve conditions. Conditions can be improved by the adoption of pharmacological standards and methods for these drugs. At the present time the manufacturers who have wisely adopted physiological standardization of their products often have different standards while those that have not adopted physiological standards have no assurity that these important drugs are even active.

- BIBLIOGRAPHY.

1 Withering, " An Account of the Foxglove and Some of its Medicinal Uses."

2 Mackenzie, " Digitalis " Heart, volume 2, No. 4, page 279.

3 Mackenzie, " A Scheme for Investigating the Treatment on the Human

Heart " Heart, volume 2, page 9. * Berkeley, Merck's Archives, September, 1910, page 275.

5 Proceedings of American Pharmaceutical Association, 1902, page 415.

6 Cushny, " Pharmacology and Therapeutics."

Am. Jour. Pharm. ) February, 1914. j

Colloids and Crystals.

71

T Journal of Amer. Med. Assoc., September 13, 1913.

8 " Observations on the Keeping Properties of Digitalis and Some of Its Prep- arations," Hatcher and Eggleston. American Journal of Pharmacy, 1913, page 203.

9 Miller and Baker, 8th International Congress of Applied Chemistry.

10 Personal Communication.

11 Kraft, Arch, der Pharm., 1912.

V£ Edmunds and Hale, " The Physiological Standardization of Digitalis." 18 Houghton, Journal of American Medical Association, June 7-10, 1898. "Hale, The Physiological Standardization of Drugs, American Journal of Pharmacy, 191 1.

16 United States Hygienic Laboratory, Bulletin 48.

18 " Laboratory Guide in Experimental Pharmacology," Geo. Wahr, publisher.

17 Focke, Arch. d. Pharm., 1903, 241, page 678.

18 Hamilton, " The Heart Tonic Unit," American Journal of Pharmacy, 1912,

page 97.

19 Braun and Closson, " The Chemical Constitution of Crystalline Strophan-

thus," Jour, of Amer. Pharm. Assoc., 1913.

20 Reed and Vanderkled, American Journal of Pharmacy, 1908, page no.

21 " Standardization of Pharmaceutical and Biological Products," Parke, Davis

and Co.

22 Hitchens. Journal of Experimental Medicine, 1905.

23 Pittinger, 1912 Proceedings American Therapeutic Society.

34 Hatcher and Brodie, American Journal of Pharmacy, 1910, page 362.

25 Eckler, American Journal of Pharmacy, October, 191 1.

26 Hale, Factors Relating to the Standardization of Digitalis ; Proceedings of

American Pharmaceutical Association, 1909.

27 Hatcher and Bailey, Jour. Amer. Med. Assoc., 1907, page 1021.

28 Lyon and Quail, Jour. Amer. Med. Assoc., 1910, pages 455, 459, 508. 19 Graeber, Therapeutische Monatshefte, 1913, page 581.

30 Pettey, " The Therapeutic Virtues of Sparetine Sulphate." Clinical Medi-

cine, Sept., 1913.

31 Lewis, " Clinical Electrocardiography."

52 Faught, " Blood-Pressure from Clinical Standpoint," page 268.

COLLOIDS AND CRYSTALS, THE TWO WORLDS OF

MATTER*

By Robert H. Bradbury, Head of the Department of Science in the Southern High School, Philadelphia.

When a solid is brought into contact with a liquid the result depends upon the nature of both. There may be apparently an entire

* Presented at the meeting of the Section of Physics and Chemistry held Thursday, April 10, 1913, and reprinted from Jour. Franklin Institute, Sep- tember, 191 3.

72

Colloids and Crystals.

j Am. Jour. Pharm. ( February, 1914.

absence of interaction, as when rosin is shaken up with water or chalk with alcohol. Or, as when sugar is agitated with water, the solid may disappear, entering into solution in the liquid. The study of sugar solution shows quite clearly that the connection of the sugar molecules with each other has been completely destroyed. They are dispersed through the water very much as the molecules of a gas distribute themselves uniformly in a vacant space, and in both cases the permanence of the uniform dispersion is due to the incessant motion of the molecules. Were the molecules at rest, both the sugar and the gas would settle and form a layer on the bottom of the containing vessel.

However, the molecules of the sugar retain their structure intact, the action being limited to their dispersion. When salt, on the other hand, is dissolved in water, a further breakdown occurs, the molecule is separated and ions of sodium and of chlorine move about in the liquid. Both solutions freeze below o° C. and boil above ioo° C. The most important difference between them is that the salt solution conducts the electric current, while the sugar solution is as poor a conductor as water itself.

A fourth possibility presents itself when glue or gelatin is treated with water. The gelatin absorbs water, swells up and, under the influence of heat, dissolves, but the liquid freezes and boils at prac- tically the same temperatures as pure water. The study of the solu- tion shows that the dispersion is not molecular. The particles of gelatin in it are composed of variable and rather large numbers of molecules. A system like this gelatin solution which presents a case of very fine but not molecular subdivision is called a colloidal solution. There are certain solids such as gelatin and dextrin (with water), and rubber (with benzene and carbon disulphide), which, when they dissolve in liquids, are invariably dispersed in this way. Such solids may properly be referred to as colloids. They are all amorphous. Crystallized substances never yield colloidal solutions by mere spon- taneous solution in a liquid. They always produce molecular or ionic dispersions. However, the phenomenon of colloidal solution is perfectly general, and crystallized substances can also be obtained in this condition, but not by mere solution.

It is an interesting fact that a substance which yields a colloidal solution with one solvent may form an ordinary molecular solution with another. Soap is an example. Its concentrated solution in

Am. Jour. Pharm. ) February, 1914. J

Colloids and Crystals.

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water boils at about ioo°, freezes at about o°, and exhibits the be- havior of a colloidal solution in general. On the contrary, a soap solution in alcohol shows the normal change in freezing and boiling points corresponding to the molecular weight, and conducts itself in all respects like an ordinary molecular dispersion.

II.

Every one is familiar with the distinctions between solutions and suspensions. Suspensions are turbid in aspect, and the solid can be removed by letting it settle, or by nitration. Solutions are clear, dis- solved matter does not subside and is unaffected by filtering. Col- loidal solutions occupy an intermediate position.

Consider for a moment the effect of increasing subdivision on a suspension of finely-divided gold in water. So long as the diameter of the particles is much greater than a thousandth of a millimetre,1 the system will be turbid and the gold will settle rapidly. But the wave-length of visible light ranges between 0.4 \x and 0.7 /x, and when the particles become smaller than this they can no longer reflect light and the liquid will appear clear. At the same time there will be a rapid falling off in the speed of settling. Stokes has derived a formula for the velocity of subsidence, V , of small spheres of radius R and density ^ falling in a liquid of density S' and internal friction / under the force of gravity g:

Substituting the proper values for gold and water and assuming a radius of /x for the particles, the value for V is about 14 centi- metres per hour. This means, of course, that the system would be a coarse suspension and would clear up at once. But when R = 10 fx fx, V is only about a centimetre a month. This begins already to be fairly permanent. It must be remembered that the high density of gold (19.5) increases the rapidity of subsidence. If we make the calculation for S = 3, which is about the density of arsenious sulphide, V comes out only about a millimetre a month.

1 It is usual to employ the symbol v> (the Greek letter mu) for the thou- sandth of a millimetre. In the same way ix fx indicates the millionth of a millimetre.

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Colloids and Crystals.

Am. Jour. Pharm. February, 1914.

So much for calculation. Now what are the facts ? As a matter of fact, the dispersed substance in a colloidal solution does not settle at all, so long as the subdivision is maintained. Colloidal gold solu- tions have been preserved unchanged for years. I have a solution of arsenious sulphide which has remained apparently unchanged for three years and whose countless particles can readily be seen, engaged in their incessant Brownian movement, with an ordinary oil immer- sion lens. Whenever settling does occur, it is preceded by the aggregation of the particles into' larger particles, which finally attain a diameter of fx or over, and slowly subside.

Here, then, is an apparent discrepancy between Stokes' law and the facts. The law informs us that the speed of subsidence decreases rapidly with decreasing radius of the particles, but it does not lead us to expect the total absence of settling which presents itself when the average radius is 10 f- /* or thereabout.

The explanation, of course, is molecular motion, or, in other words, heat. The particles are battered, on all sides, by a hail-storm of molecular impacts. If the particle is large, the blows of the mole- cules of the solvent in different directions neutralize each other. But when the particle is not so very much larger than the molecules themselves a molecule striking, say on the left, will give the particle a very perceptible push toward the right, "just as a cork follows better than a large ship the motion of the waves of the sea." 2 As the dimensions of the particle approach the molecular dimensions it begins to behave like a molecule and is swept along in the endless molecular movement. The cause which prevents the particles in a colloidal solution from settling is in no way different from the cause which prevents the earth's atmosphere from subsiding to a snowy layer a few feet deep on the surface of the planet.

It is worth remembering, also, that the particles of the dispersed phase ordinarily possess an electric charge, which is usually negative. The effect of the repulsion of these similar charges would be to* pre- serve the distribution of the particles throughout the liquid. It is a fact that, when the charges are removed, the system becomes instable and subsidence — preceded by coalescence of the small particles — readily, but not necessarily, occurs.

2 Perrin.

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Colloids and Crystals.

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III.

On the subject of the classification of colloid systems we must be very brief. One proposal subdivides them into suspensoids, such as the sols 3 of gold and arsenious sulphide, in which the dispersed phase is solid, and emulsoids, in which the dispersed phase is liquid. This classification would appear to be an attempt to extend the familiar distinction between liquid and solid to a domain in which that distinction has little if any meaning. To assert that a thing is solid is to say that it has a definite shape, which it retains with some persistence. There is not the slightest reason to think that the particles in a gold sol are solid. It is usual to assume that they are spherical, but this is done merely because it is the simplest assumption to make. There are faint indications that they really have the form of leaflets or of little rods, but they appear in the ultra-microscope simply as brilliant dancing points, and in reality we know nothing whatever about their shape. In connection with this it is interesting to recall the fact that the formation of a crystal begins with the appearance of minute liquid spheres (globulites) ,4 which pass through several stages (margarites, longulites, etc.) before the crys- tal is formed. It seems possible that, under such enormous sub- division, cohesion retires into the background and surface tension assumes the chief role, so that the gold particles are rather to be compared to minute drops than to little crystals.

Enough has been said to make clear the uncertainty which attaches to the attempt to classify colloid solutions according to the state of aggregation of the particles. A better classification is into reversible and irreversible colloids, according to the way in which the dissolved substance behaves when separated from the solution. Thus, when a gelatin solution is evaporated until it " sets " it is only necessary to warm the jelly with water to obtain it again in colloid solution. Gelatin is a typical reversible colloid. But when the gold is caused to separate from a gold sol — which can easily be brought about by adding any electrolyte to the sol — the gold will not again enter into colloidal solution. Shaking or warming with water gives a mere

3 Thomas Graham introduced the term sol as an abbreviation for colloidal solution.

4 Fink, " PoggendorfFs Annalen," vol. 46, p. 258 (1839) ; Schmidt, " Liebig's Annalen der Chemie," vol. 53, p. 171 (1845); Frankenheim, " PoggendorfFs Annalen," vol. in, p. i (i860).

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I Am. Jour. Pharm. \ February, 1914.

suspension, which settles at once. Gold is an irreversible colloid. The distinction is fundamental. Many organic colloids are reversible, while it is rather the habit of the inorganic colloids to behave in the irreversible way.

IV.

In order to prepare a sol containing an irreversible colloid all that is necessary is to reduce the solid to extreme subdivision in a liquid in which it is insoluble. The electric arc furnishes a rapid and simple method.5 Two gold wires about 2 mm. thick are con- nected with a 220-volt circuit and brought together under distilled water. A no-volt circuit can be used, but more patience is required. Sols of platinum, silver, copper, and other metals can be made in the same way. By related electrical methods, using such liquids as pen- tane and anhydrous ether, Svedberg 6 obtained sols of all five of the alkali metals. The colors of the sols agreed with those of the vapors of the corresponding metals.

Chemical reduction of a salt of a metal furnishes another method which has been largely employed by Zsigmondy 7 and other investi- gators. For instance, a very dilute solution of auric chloride is mixed with such reducing agents as formaldehyde, hydroxylamine or an ethereal solution of phosphorus. The gold sols obtained in this way are usually red by transmitted light, the particles being bright green and very much smaller than in the sols obtained by the electrical method.

By various chemical methods, which lack of space forbids us .to discuss, sols of sulphides (CdS, As2S;!, Sb2S3, etc.) and oxides (Fe203, A120;!) can be obtained. The sol of aluminum oxide is im- portant on account of its connection with dyeing and mordanting. The formation of the blood-red sol of ferric oxide by adding a con- centrated solution of ferric chloride to about 50 volumes of boiling distilled water is a simple and beautiful lecture experiment.

In making colloidal solutions of salts, the essential thing is to mix dilute solutions of the precipitants, using a liquid in which the

5 Bredig, Zcitschrift fur angeivandte Chemie, 1898, p. 951. For a full account of Bredig's work with the platinum sol see Zcitschrift fur physikal- ischc Chcmic, vol. 31, pp. 258-353 (1899).

6 Bcrichtc dcr dcutschcn chcmischen Gcsellschaft, vol. 38, p. 3616 (1905).

7 See his monograph, " Zur Erkentniss der Kolloide " (Jena, 1905), which has been translated by Jerome Alexander.

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insolubility of the product is as complete as possible. Thus, in mixing very dilute solutions of sodium sulphate and barium chloride, a crys- talline precipitate is usually obtained. The reason is that barium sulphate possesses a very slight but real solubility in water. Hence the liquid in contact with the particles first formed contains enough barium sulphate to nourish their growth and allow them to develop to crystals. If alcohol is added to the sulphate, before the barium chloride is introduced, the solubility of the barium sulphate is greatly reduced, and it is obtained in colloidal solution without difficulty.

In the same way, if we mix water solutions of sodium hydroxide and of hydrochloric acid we obtain merely an ordinary solution of common salt. But if salt is produced by a reaction between organic compounds in a liquid in which the sodium chloride is insoluble, then a colloidal solution is obtained. For instance, when chlor-acetic ester interacts with sodio-malonic ester a grayish opalescent sol of sodium chloride in ethenyl tri-carboxylic ester results : CHX1 COOC2H5 -f- CHNa(COOC2H5)2 = CH2(COOC2B5) — CH(COOC2H,)2 + NaCl. At low temperatures, in such liquids as toluene and chloro- form, even ice has been obtained in colloidal solution.

V.

The most striking property of the reversible colloids is that they are able to communicate their reversibility to the irreversible ones. Thus, if a trace of gelatin is added to a gold solution, the gold becomes much more difficult to coagulate by electrolytes, and when coagulated it can be dispersed again by merely warming with water. This curious protective action is exerted, in greatly varying degree, by most reversible colloids. Direct study of the phenomenon with the ultra-microscope shows that the view frequently expressed that the gelatin envelops or forms a film around the gold particles is incorrect. What actually happens seems to be a direct combination between gelatin particles and gold particles, which then pass through the reversible changes together.

Protective colloids enjoy a wide practical application. In the manufacture of photographic films the gelatin retards the crystalliza- tion of the silver bromide. Ink often contains a colloid which pre- vents the pigment from settling. The lubricant " aqua dag " put in the market by the Acheson Company consists of finely-divided arti- ficial graphite, held up by a protective colloid. Clay is made plastic

78

Colloids and Crystals.

j Am. jour, Pharth. \ February, 1914.

for the potter by an empirical process which involves the action of protective colloids derived from decaying vegetable matter. The addition of gelatin in making ice cream depends upon its protective action in preventing the growth of ice crystals, which would make the product " gritty." Without doubt protective action plays an important role in the cleansing action of soap. This has been made clear by some recent experiments of Spring.8 Lampblack, freed from oil by long washing with alcohol, ether, and benzene, forms a rather stable suspension in water, but the lampblack is de- tained by a paper filter. If the filter is now reversed, so that the blackened surface is outward, and water poured through it, the lamp- black is not removed, but a dilute soap solution removes the coating and cleanses the filter at once. Finally, lampblack suspended — or col- loidally dissolved — in soap solution, passes through a filter unchanged. It is of much practical interest that there is a well-marked optimum in the concentration of the soap required to protect the lampblack. A one per cent, soap solution is the most efficient. In two per cent, soap solution lampblack sinks about as rapidly as in pure water.

VI.

We have already considered the probable actual condition of the particles in a colloidal solution and have concluded that, for the present, no very definite information is obtainable about the matter. We must now return, for a moment, to the subject in order to allude to the thesis so brilliantly advocated by van Weimarn, the Russian investigator, who holds that the particles are of necessity minute crystals and that there is, in fact, no such thing as amorphous matter. He even goes so far as to state that substances like air and water are in a " dynamic crypto-crystalline condition," though I have been unable to understand what he means by this statement.

Briefly, the evidence that van Weimarn adduces to the support of his hypothesis is :

(1) That colloid particles will grow to crystals if provided with the proper nourishment, namely, a dilute solution of the same substance.

(2) That colloid particles are capable, when introduced into

8 Kolloid Zeitschrift, vol. 4, p. 161 (1909); Kolloid Zeitschrift, vol. 6, pp. 11, 109, 164 (1910).

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a supersaturated solution of the same substance, of discharging the supersaturation and inducing the formation of crystals.

Those who desire to follow this matter further should read van Weimarn's little book, " Grundziige der Dispersoidchemie," after which they will find themselves very much interested, but somewhat unconvinced. Let me hasten to add that I have not the least desire to undervalue the brilliant experimental work of the Rus- sian chemist. It is, in fact, precisely by the conception of more or less daring hypotheses, and the working out of their consequences, that our science achieves its endless victory over the nescience about us.

VII.

We have seen that the wave-lengths of the visible radiations are comprised between 0.4 /x and 0.7 With objects much smaller, the ordinary microscopic method ceases to be applicable. Using ultra- violet radiation for illumination, quartz lenses in the microscope, and receiving the image with the photographic plate instead of the eye, it is possible to advance a step further in the domain of the infini- tesimal, but only a step, and there are obvious objections to the proceeding. Since some of the particles in colloidal solutions are only 0.006 ^ in diameter, we can never hope to see them as little bodies subtending a visual angle. The ultra-microscope — -the power- ful instrument of investigation to' which most of our knowledge of colloid systems is due — renounces this idea and makes the particles visible merely as glittering points on a black background. The sol is placed in a small rectangular glass trough and a horizontal beam of arc light or sunlight focussed in it. The microscope is placed vertically above the trough. It will at once be seen that there are two fundamental things about the instrument : to< provide intense illumina- tion, and to make sure that no light enters the microscope except the rays which emanate from the particles. The principle is simple, but the system of diaphragms and lenses needed to secure the second object makes the ultra-microscope an elaborate and expensive instru- ment in practice.

Cotton and Mouton 9 achieve the same end in a different way. The illumination (arc or sunlight) is thrown up from below by a paraboloid reflector so ground that all rays, except those diffracted

Compt. Rendus, vol. 136, p. 1657 (1903).

So

Colloids and Crystals.

{Am. Jour. Pharm. February, 1914.

by the particles, are totally reflected from the cover-glass over the sol. This instrument is simple, easily adjusted and cheap. It is made commercially by the firm of Zeiss. It would seem to be admirably adapted to school purposes. In fact, after a look into the ultra- microscope, the study of the molecular topics ceases to be drudgery and becomes a positive intellectual need.

VIII.

Even a brief glance at the subject of colloid systems must at least mention the classic work of Perrin 10 on the distribution of the par- ticles in suspensions of gamboge and mastic. He succeeded, by an ingenious and simple method, in preparing emulsions of gamboge in water in which the spherical yellow granules were all of the same diameter. If we consider a mass of such a liquid in a tube, it is clear that the granules, if at rest, would, since they are denser than water, all fall to the bottom. The fact that they remain suspended is due to their movement. In other words, the state of things is the same as in the earth's atmosphere, and just as the molecules are more crowded near the earth's surface, so the granules of gamboge must be more numerous near the bottom of the liquid than in the upper layers. Perrin verified this prediction by direct counting of the granules under the microscope. The barometric formula which describes the progressive rarefaction of air with increasing height also describes the distribution of the granules in Perrin's uniform emulsions. The only difference is that, while the aviator must ascend six kilometres in order to reach air half as dense as at sea level, the same effect is produced, in Perrin's emulsion, by an ascent of o.i millimetre.

That the mean energy of rotation of a molecule must be equal to its mean energy of translation is one of the chief propositions of the kinetic theory. Perrin has proved this by direct measurement of the rotation of granules under the microscope. For this purpose, large granules (15 /x) of mastic were employed. These are far too heavy to remain suspended in water, so a solution of urea was used. For- tunately, the granules contain little inclusions which make it possible to measure their rotation.

10 Annates de Chimie et de Physique, 3d series, vol. 18, p. 5 (1909). There is a German translation by Donau in Kolloidchemische Beihefte, vol. 1, p. 1 (1910). An English translation by Soddy has appeared in book form under the title " The Brownian Movement and Molecular Reality."

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81

These are only two> of many fundamental results contained in this wonderful memoir. Van't HofT extended the gas laws to solutions. Perrin has now proved them to be valid for systems in which the moving particles are visible realities. Let us end by quoting one of the sentences of his conclusion :

" ha decouverte de telles relations marque le point ou s'eUve, dans notre conscience scientiUque, la realite moleculaire sousjacente."

THE INFLUENCE OF HEAT AND CHEMICALS ON THE STARCH GRAIN.1 By Henry Kraemer.

In presenting some of the most recent observations on the starch grain, it may be well to consider for a moment the nature and origin of starch. In a way starch is one of the most remarkable substances produced by the plant. It is the first visible product formed by the chloroplastid, or chlorophyll bodies, from the inor- ganic substances, carbon dioxide and water. Inasmuch as sunlight seems to be necessary to bring about this transformation the process is looked upon as one which involves the converting of the sun's energy into vital energy.

The substance thus formed by the chloroplastid through the influence of sunlight, in the leaves and other green parts of plants, is known as " assimilation starch," and serves subsequently not only as a food for the plant itself but is also the source of the energy of the animal world. Assimilation starch is not stored in the cells where it is manufactured, but each night through the influence of the plant ferments the starch formed during the day is converted into a soluble form, and transported to various other parts of the plant. In some cases this soluble starch is tem- porarily stored in the cells of the pith, medullary rays, or bark, and has received the name of " depot starch." While some of the soluble carbohydrate is converted into fixed oils and other substances, a considerable portion of it is carried to some reserve organ, as a root, tuber, rhizome, or seed, and under the influ- ence of a plastid similar to the chloroplastid, converted into a stable form, known as reserve starch.

1 Reprinted from Original Communications, Eighth International Con- gress of Applied Chemistry. Vol. XVII — Page 31.

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Ihis is the product with which we are specially concerned in the present article. Hereto t ore, the minute study of the starch grain, particularly of its structure, has been of scientific interest only, but with the application of scientific methods in nearly every department of industry, it is coming to have a practical application.

The commercial reserve starches are derived from various plants, and not only enter largely into food products but are also used for a variety of technical purposes. The grains of the re- serve starches have a number of characteristic features. They vary in size, in shape, in internal structure, and also to a con- siderable extent in composition. The variation in composition is shown by the use of aniline stain and also by the use of iodine. By the treatment of starch with iodine solution, we may distinguish three kinds of reserve starch: (i) one which is colored deep blue, as potato and maranta; (2) one which is colored somewhat purplish, changing to cinnamon-brown, as corn and wheat; and (3) one which is colored brownish-red, as in the amylo-dextrin starches of comfrey and a few other plants.

The shape of the grains varies from polygonal to ellipsoidal, the shape being influenced by the number of grains in a cell. Under the micro-polariscope the grains are seen to be anisotropic, the polarization effects differing with the grains of the different classes. Polarizing effects are usually produced by crystals, but may be produced by substances in a condition of tension, as minute globules of glass. It should also be stated that cell walls have this same property of double refraction, and it is very likely that the sub- stances in the starch grains, as well as in the cell wall, are crystalloidal and arranged in spherite aggregates, resembling those of inulin, a product closely resembling starch.

The theories which have been advanced regarding the struc- ture of the starch grain, have been largely based on studies of the potato starch grain. It was originally thought to be in the nature of a globule filled with a fluid. Fritzche, Schleiden and others considered it to be made up of more or less concentric layers formed around a central or excentral point. While it may be true, as pointed out by Naegeli, that many of the reserve and glucose starch grains arise free in the cell, the view of Schimper that starch grains always develop within plastids, is generally accepted at the present time.

The internal structure of the starch grain is shown in several

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ways. When starch is treated with certain chemicals, or heated with water alone to a temperature of 6o° C, the grains show a series of successive changes. First, the lamellae or layers become more distinct, and the layers appear to be made up of parallel crystal-like particles, these latter being more numerous in suc- cessive alternate lamellae. Then as the grain swells clefts which radiate from the centre are formed. Later the centre of the grain becomes hollow, and when the grain has swollen to about four times its original size the outer membrane breaks and the con- tents are gradually dissolved.

Some striking effects are also produced when starch is carefully treated with aniline dyes. The point of origin of growth and the successive layers alternating with it take up the stains, thus again showing the distinct character of the two kinds of lamellae making up the grains. When plant material containing mucilage is treated with aniline stains, the stain is taken up only by the cells containing mucilage, and this indicates that the lamellae in a starch grain which take up the stains are composed chiefly of colloidal sub- stances. From these observations it is apparent that the grains of certain of the starches, as the potato, if not of all the lamellated starch grains, are made up of two kinds of lamellae, one rich in colloids and one rich in crystalloids. The presence of two kinds of lamellae, at least in certain of the starch grains, and their difference of composition are further shown by the use of a weak solution of iodine, the so-called crystalloidal layers or lamellae taking up the iodine and becoming blue.2

Recently I have been conducting some experiments to deter- mine further the effects of heat upon the structure of the starch grain. When starch alone is heated to between 45 ° and 500 C. from 15 to 30 minutes, the lamellae and the crystalloidal structure of the grains are brought out. The grain is so resistent that the inner structure does not appear to be lost until a temperature of over 1250 C. is attained. Between 1400 and 1600 C. the polarization effects of the grains become faint, except in the case of potato starch, which now in addition gives chromatic effects. At 2400 C. all of the grains are disintegrated except those of corn starch, the individual grains of which are of a brownish-yellow color and not perceptibly

2Kraemer, Bot. Gazette, Vol. XXXIV, Nov., 1902 ; Ibid., Vol. XL, Oct., 1905; reprinted in Amer. Jour. Pharm., Vol. 79, 1907, pp. 217-229; 412-418.

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{ Am. Jour. Pharm. V February, 1914.

swollen. Besides the entire mass is more or less granular, while in the case of the other starches examined the charred mass is in a puffed condition.

The effects produced when starch is heated in the presence of a fixed oil, as almond oil, are of special interest. The inner structure of the starch grain is not usually apparent when it is mounted in a fixed oil, unless the starch has been previously heated to a temperature of from 8o° to 1600 C. When, however, a mixture of starch and oil is heated as high as i8'o C. the grains still polarize light, which shows that the structure has not been altered. In other words the effects of heat on the grain are more or less neutralized by the presence of the oil. On heating the mixture up to 2500 C. most of the grains still show their individual character, but no longer polarize light. They are but slightly swollen, and in the case of cassava and corn starch a central differential area occupies from one-half to nine-tenths of the original area of the grain.

It may be worth while to state that when starch and water in the proportion of 2 gm. of the former to 100 c.c. of the latter, are heated together at a temperature of between 900 and ioo° C. in a steam sterilizer seven or eight hours a day for a long period, even extending to months, dextrinization of the starch does not take place, that is, the solution still gives a blue color with iodine. Even though the operation be conducted in an autoclave under a pressure of 20 pounds for about ten hours, dextrinization is not effected. If, however, 1 c.c. of N/HC1 be added to 100 c.c. of water and this heated for five hours with 1 gm. of starch, the resulting solution is colored red with iodine. When the amount of the acid is reduced to .2 c.c. and the mixture heated under a pressure up to 12 pounds for one hour, cassava, corn, maranta and potato starch solutions give a deep blue color with iodine, while a solution of wheat starch gives a deep purple color with iodine. If the heat be continued an hour longer, wheat starch gives a purplish-red color, cassava a deep wine color, maranta and potato a light purple, while corn still gives a blue reaction with iodine.

These observations may be summarized as follows : 1. The starch grain consists of two nearly related substances: (a) a colloidal or mucilage-like substance which takes up aniline

Am. Jour. Pharm. ) February, 1914. /

Book Reviews.

85

dyes, and (b) a crystalloidal or crystal-like material giving a blue color with iodine.

2. The starch grain is made up of concentric layers, one series of which contains a large proportion of crystalloids, while the alternate layers are composed mostly of colloids.

3. The polarization effects produced by starch are probably to be attributed to the crystalloidal character of the grains.

4. The starch grains retain their polarizing properties even when heated up to a temperature of 1800 C, which seems very remarkable indeed.

5. At the higher temperatures the potato starch grains give chromatic effects in addition, similar to those when a selenite plate is used.

6. While heating the starch grains in water rapidly changes the structure of the grain, it is only by the addition of chemicals or ferments that dextrinization is brought about.

BOOK REVIEWS.

Semi-Annual Report on Essential Oils, Synthetic Per- fumes, &c. Published by Schimmel & Co. (Fritzsche Brothers), Miltitz near Leipzig. London, New York. October, 1913.

In the introduction to this report an admirable resume is given of conditions, both favorable and adverse, which affected business in the last year and particularly as to commodities handled by this firm.

As is known to well-informed pharmacists, the practice of sophistication is found in many branches of business but in none so much as in the essential oil industry. In fact, one is almost led to believe that adulteration of oils and perfumes is an industry in itself. Upward movement of prices is the dominant cause for this, and, as is always the way, the forces of evil and dishonesty are up and doing, and " the practice of adulteration is assuming dimen- sions, and is pursued with refinements of ingenuity that baffle de- scription." So cleverly are adulterants selected and manipulated that the constants of an adulterated oil are kept within the right limits of value and only a most thorough examination will show the true state of affairs. Artificial esters play an important part in this nefarious work ; for instance, when added to oils such as lavender

86

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f Am. Jour. Pharm. \ February, 1914.

and bergamot, they give " to them the appearance of containing far more linalyl acetate than the oils possess in reality."

In this report the statement is made that there are firms who do not hesitate to offer such esters openly for purposes of adulteration. Furthermore, it is stated that one firm made such an offer to the Schimmel people in writing who publish this communication in the original language and a translation of which follows :

Gentlemen :

For some years past we have been in the habit of supplying to lavender growers a product called " Ether L."

The advantage of this article is that it simulates in a perfect manner essential oil of lavender, and we have judged it opportune to forward you to-day a sample of it by post. The price is 12.50 francs per kilo delivered at your works.

If this product should interest you by any chance, please let us know what quantities of it you would be able to use annually.

Hoping to hear from you we are, &c,

N. V. Polak & Schwarz's,

Essence Fabrieken, Zaandam ( Holland ) . P. S. — Our Ether L. is pure and contains 100 p. c< Subsequent examination of this product showed that instead of being 100 per cent, it revealed a percentage of 86. The presence of this ester in lavender oil would not prove difficult of detection.

The high price of menthol also proved a stimulus to those of dis- honest tendencies. Two samples examined showed 100 per cent, adulteration. Both were acetanilid, one scented with menthol and the other with peppermint oil. Under the name Mentholin there is being offered to the trade a substitute for menthol made by a firm in Prague which proved to be 80 per cent, acetanilid and oily menthol.

This report consists of 151 pages of interesting matter, the greater part of which is devoted to commercial notes and scientific information pertaining to essential oils ; practically every oil used in pharmacy and in the manufacture of perfumery is touched upon as to source of production, supply, and conditions, favorable and other- wise, which may have had some influence on quality or lack of quality.

Considerable attention is given to recent scientific research in

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the field of essential oils. Abstracts of reports on experimental cul- tivation of medicinal plants are given, a field of endeavor which must be nurtured if the supply of drugs is to keep pace with the demand.

Among the pages of this report are several excellent pictures illustrative of the essential oil industry. One is a particularly strik- ing view, in color, of the Miltitz rose-fields at harvest time.

After reading over this report and digesting the information given, one cannot help but feel that in the examination of an oil (say oil of rose) and in which the other constants are normal — a remarkably high ester value should be regarded with suspicion !

British Pharmaceutical Conference. A Presidential Survey 1863 to 1913. Being a sketch of the origin and progress •of the conference prepared on the occasion of the celebration of its jubilee in London, July 21 to 25, 1913. The Chemist and Druggist, 42 Cannon Street, London.

This handy little volume of 96 pages contains concise but inter- esting biographies of the various men who have been honored by the presidency of the British Pharmaceutical Conference.

In the fifty years of its existence the Conference has been guided by thirty-three presidents, all men of ability and some of rare scien- tific attainments. Among the list of names two stand out in bold relief — Hanbury and Attfield. These two names are probably more familiar to workers in pharmacy in this country than any other two from other lands. Hanbury won an enviable position in the world of science by his work as a pharmacognocist. He will also be remem- bered as the donor of the Hanbury Medal. This is only given to men who have done something and our own Professor Maisch was the first American to> receive this signal honor. And Attfield, we think few American students are unfamiliar with the book on chem- istry bearing that name, with its many chemical experiments which the student is advised to perform. He impressed on the student the fact that the way to study chemistry was to work at it.

John K. Thum.

Payne's Dictionary of Pharmacy. By George F. Payne, Ph.G., M.D., F.C.S. Published by G. F. Payne, Atlanta, Ga.

Lack of space forbids us to give the full title given by the author to this little handbook of pharmaceutical facts. For the same

88

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f Am. Jour. Pharm. \ February, 1914.

reason we are compelled to omit mention of the numerous offices and honors the distinguished writer has been honored with and which he mentions on page one. It suffices to say that he is " an active pharmacist for 51 years"; that the little volume is copy- righted, and all rights are reserved, whatever that may mean.

We have been rather hopeful that the day of cramming books was over, but this short-cut to the study of pharmacy and allied branches seems like evidence to the contrary.

The study of a science and art like pharmacy by the " absorp- tion " of isolated facts is a survival of the day when the unschooled errand boy of the retail drug store developed into a clerk and squeezed through a board of pharmacy examination by heroically attempting to memorize the dispensatory. In the past, board of pharmacy ex- aminations consisted very much of " catch " questions and a student expected them and prepared for them ; if he answered them correctly the board assumed that he was fit to practise pharmacy ; all of which was not conducive to the best interests of the public and cer- tainly lowered the level of the profession. Indeed, the inefficiency of many pharmacists, who must, because of such inefficiency, depend upon manufacturing houses for many pharmaceuticals that they should make themselves, can be traced to this method of education or lack of education in their chosen profession.

Happily, in the larger centres of our country there is beginning to manifest itself by the public a demand for a higher type of man for the professions, ours included. And this demand is being met and complied with by the better class of schools with more stringent requirements as to preliminary education and a broadening of the curriculum. This is as it should be, and in the evolution of things schools of other centres must do likewise or cease to exist.

John K. Thum.

Materia Medica, Pharmacology, Therapeutics, Prescrip- tion Writing, for Students and Practitioners. By Walter A. Bastedo, Associate in Pharmacology and Therapeutics at Columbia University, etc.

This book, which is from the press of the W. B. Saunders Co., is a medium 8vo. in size, of 602 pages, price $3.50 net. It is an ex- cellent specimen of the book-making art, the binding and paper being excellent, the type clear and distinct.

Am. Jour. Pharm. )

February, 1914. J

Book Reviews.

89

The work is original in many respects, not following the beaten path, and has in it much to commend.

It is divided into three parts, Part I being largely by way of in- troduction. Among some of the subjects considered in this divi- sion are : Pharmaceutical preparations ; Weights and measures ; Active principles ; The Pharmacopoeia ; Dosage, Administration of medicines, etc.

Part II treats of materia medica proper. Many of the classifi- cations are different from other books on this subject, one of them being Sweetening Agents, which includes saccharin, which he states " has been much employed in canning foods, as it is slightly antiseptic and obviates the use of the highly fermentable sugar." This seems to be flying directly in the face of Dr. Wiley. The Anti- Bitters are claimed to abolish the appreciation of bitter tastes ; these include yerba santa and gymnemic acid. The list of cathartics in- clude those which act by " selective affinity," as physostigmine, which stimulates the ends of the vagus nerves of the intestines. A new classification is given to the Antispasmodics, they being called the Antihysterics.

The classification of the Antipyretics is somewhat original. We have the analgesic antipyretics, such as antipyrin, the antimalarial antipyretics, such as cinchona ; and the antirheumatic antipyretics, such as salicylic acid.

The article on the thyroid gland is interesting and of value, a new classification being called the Antithyroid preparations, designed to overcome undue activity of the thyroid gland, the remedies included under this head being Beebe's serum; Antithyroidin (Moebius), and Thyroidectin. Antithyroidin is the blood serum obtained from sheep whose thyroid glands have been removed, at least six weeks before.

The therapeutic classification of the Disinfectants is also original and valuable. It includes I, The general disinfectants and deo- dorizers ; II, The preservatives ; III, Disinfectants for surgical sup- plies ; IV, Disinfectants for local use about the body ; V, Disinfect- ants to be given by the mouth. The important drugs of the materia medica are treated of at considerable length, digitalis having 42 pages assigned to it, and epinephrine (adrenalin) ten pages. In the article on digitalis, it is stated that " digitalis contains digitonin, a saponin body which foams with water and possesses the peculiar property of holding the otherwise insoluble active principles in solu- tion in water. It is on account of this that infusion of digitalis, an

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Book Reviews.

f Am. Jour. Pharm. [ February, 1914.

aqueous preparation, represents the activity of the drug." While this is somewhat different from what we have heretofore believed, it does not justify the making of the infusion from a fluidextract, as digitonin is not soluble in an alcoholic menstruum, and such an infu- sion would not contain any digitonin, and the glucosides insoluble in water would not therefore be held in solution.

The book is up-to-date in the introduction of new remedies, a few only being cited, such as Hormonal from the spleen of the rabbit, which is stated to be " of value in post-operative tympanites and obstinate chronic constipation." Oxyntin and Acidol are albu- minous forms of hydrochloric acid. The chapter on Hypnotics is of interest, especially the contrast between natural sleep and that in- duced by the aid of drugs.

" The article on tobacco will be read with interest, as the author seems to think " that the demand for tobacco is not so much the physiological demand of the body for its dose of nicotine, as it is the psychic demand for the satisfaction of a habit."

He thinks that pepsin " in almost all cases of digestive disturb- ance is a superfluous remedy," but that pancreatin is of greater value. In fact, he gives some remarkable instances of its effects in the case of arrested development, one of which was a boy who grew five inches in two years and gained twenty-two pounds. He is op- posed to the prescribing of mixtures of the digestive ferments to- gether, as frequently they destroy each other. Of aconite which has been the sheet anchor of Homeopathy for so many years, is asserted, " that in the light of recent research has doubtful thera- peutic value." Camphor cerate is not " camphor ice " as stated, the latter being the Compound cerate of the N. F. Jalap is said to contain 8 per cent, of resin, the amount should be given as 7 per cent. The doses as given in the work vary considerably from those of the pharmacopoeia. Under the head of reflex emetics, the dose of copper sulphate is stated as thirty grains, the pharmacopoeia gives it as four grains, that of tartar emetic as two grains, the official dose is y^t g. ; we have same unpleasant remembrances of the effects of a one-grain dose of tartar emetic. The dose of sparteine sulphate is given as one grain, which is probably nearer correct than the dose given in the Pharmacopoeia. The dose of all the mydriatic alkaloids (as atropine) and their salts is stated as the 1/150 grain, no varia- tion between them being given.

Apomorphine hydrochloride is cited as being the only central

rtSS,?™'} Philadelphia College of Pharmacy. 91

(systemic) emetic, other authorities include tartar emetic, senega and squill.

Part III is devoted to Prescription Writing, which the author states " is the dread of the young medical practitioner." This part, while brief, is quite practical, and may be of considerable value in starting the young practitioner aright, but what he should have to make him an expert in the art of prescription writing is a more ex-