* Standardized to contain at least 0.37% total alkaloids by titration.

SUMMARY OF CONCLUSIONS

As a result of a survey of the whole subject, the following suggestions are offered for consideration by an International Pharmacopoeia Committee :

1. The bark should be standardized for total alkaloids by titration, and the limits fixed for galenical preparations should be from 6 to 8 per cent. of total alkaloids by titration, bark of this strength being usually available. The International assay process recommended above should be adopted.

2. A liquid extract should be prepared by percolation with 70 per cent. alcohol, hydrochloric acid and glycerin being added to the concentrated extract to increase the solu

bility and prevent precipitation. The finished product should be standardized to contain 5 per cent. alkaloids by titration.

3. A simple tincture should be prepared, 1 in 5, with 70 per cent. alcohol, and standardized to contain 1

of alkaloids by titration.

per cent. 4. A compound tincture should be prepared from a formula either on the lines of the British Pharmacopoeia or with gentian root in place of serpentaria as adopted by several of the other pharmacopoeias. The adoption of 70 per cent. alcohol has proved satisfactory, and the use of the simple tincture in place of the bark would save the necessity of separate standardization for the compound tincture. 5. A solid extract prepared with alcohol (70 per cent.) and standardized to contain 10-12 per cent. total alkaloids by titration, could be adopted if thought desirable. 6. A wine prepared as at present official in the French Codex, but using the standardized fluid extract in place of the bark, might be included unless the paragraph (a), Article 2 of the International Agreement is considered to apply. This states that "No potent drug shall be directed to be prepared in the form of a medicinal wine."

In conclusion, I wish to record my thanks to Mr. V. Cofman and Mrs. Shaw for their valuable assistance in compiling the above tables, and to Mr. F. R. Bateson for his useful references.

The CHAIRMAN said that Mr. Lloyd Howard unfortunately had another engagement, and would certainly have liked to stay and take part in the discussion on the paper.

COMMENTS by MR. BERNARD F. HOWARD

While welcoming Mr. Bennett's very valuable contribution on methods of valuation of cinchona bark, it is perhaps necessary to point out that the quinine manufacturer's view is not necessarily quite identical with that of the druggist requiring bark for the manufacture of tinctures, extracts, etc. It has long been a matter of surprise that parcels of bark sold on the London market have been sold apparently to a great extent on appearance, and have fetched prices in no way compatible with their alkaloidal contents. No doubt Mr. Bennett's paper will go far to remedy this anomalous state of affairs, but bark intended for quinine manufacture has always been valued on its quinine content, determined by methods mutually satisfactory to the planter

or seller, and manufacturer or user: before such a method as suggested by Mr. Bennett could be adopted for this purpose, both parties would require to be satisfied that it would give them accurate results. Hitherto manufacturers have not been in favour of titration methods for the following reasons:(1) The total alkaloids titrated being a complicated mixture of various alkaloids in unknown proportions (and some of unknown molecular weight) it is necessary to adopt an arbitrary "average molecular weight," which must in any case be far from the truth. (2) The alkaloids are of such high molecular weight that quite a small error in titration makes a big error in the result. (3) Some of these alkaloidal salts, mainly those of cinchonine and the amorphous alkaloids, dissociate in varying degrees in hot and cold solution, and therefore give incorrect end-points. Even pure quinine salts are not free from this objection. (4) No indicators have sharp enough end-points to be practicable with the cinchona alkaloids. Even bromphenol-blue, which has been recommended as the ideal indicator from the hydrogen-iron standpoint, is not sensitive enough to give a definite end-point.

The following paper was read in abstract by the author. INTERNATIONAL STANDARDIZATION OF BELLADONNA AND ITS PREPARATIONS

WITH SOME NOTES ON OTHER SOLANACEOUS DRUGS

By A. J. JONES

INTRODUCTION

The object of this paper is to summarize the position of the above-mentioned drugs and their preparations as they occur in official medicine, and to give some idea of the stages of development through which they have passed. In addition, it is hoped to contribute some material for discussion in connection with the proposal to establish an international formulary, with unifica tion of standards. In reviewing these drugs one of the most noticeable things is the variation in pharmaceutical procedure to which they have been submitted in the production of galenicals. There is a moderately wide margin of difference in quantitative composition between individual plants of the same species, but, in a qualitative sense-which is the matter of chief concern in

66

medicine-all morphologically comparable parts are practically constant; when dissimilar parts are compared, however, important differences may be found. The question arises, therefore, as to why formulation has been so various. Is it quite immaterial, and merely a matter for pharmaceutical expediency or fashion, or does alteration tend to produce preparations differing from time to time in their total therapeutic activity? The original galenicals were made with the simple idea of extracting the 66 virtues of the drug from its inert parts. Later on these virtues assumed a definite shape, and were attributed to the active principles that could be isolated. Pharmaceutical procedure then became concerned with the extraction of alkaloid, and ignored other aspects of the case; the result being variation in both raw material and method of production. But we must not lose sight of the fact that knowledge of the alkaloidal constituent is only partial knowledge of the drug, and that it was the original preparation as a whole that proved its value and became an established therapeutic agent. At the present time we recognize that molecular associates, and the internal physical state of the medicament are factors of importance, and that in crude natural substances there is always the possibility of obscure but nevertheless actual causative agents being present in addition to those which are already known. As an example, there may be possible effects resulting from the degradation products of the plant material, and from bodies passing through the various stages of synthetic processes which escape definition in terms of alkaloid.

The knowledge of plant substances, from the point of view of galenical pharmacy, is not complete. There are undoubtedly bases and split products present in the drugs under consideration which have not yet been defined, and whose physiological effects are unknown. It is not necessarily the absolute effect of an isolated principle that gives the key to the behaviour of a drug. In this connection it is worth noting how limited is the employment of stramonium; and the persistent use that physicians make of hyoscyamus as distinct from belladonna, the clinical effects of which are asserted to be quite different. The alkaloids are quite similar in these drugs, therefore this difference must be due either to the relatively high dose of hyoscyamus extractive that is administered with the corresponding dose of alkaloid, or else there must be some unknown difference in the composition of this extractive. Choline has been reported in the roots of

belladonna and hyoscyamus, but choline and atropine are antagonistic in action. Tetramethyl-putrescine occurs in Hyoscyamus muticus,* but is pharmacologically inert. Pyridine and bases of the pyrrole and pyrrolidine nucleus, and diamines have also been found in belladonna leaves.† Umney and Benettare of opinion that hyoscyamus does not depend entirely for its activity upon the mydriatic alkaloids, and Professor Liebrich, who has studied the matter, thinks that the nonalkaloidal constituents are not pharmacologically negligible. A. B. Lyons holds that the presence in the mydriatic alkaloids of belladonna and allied drugs of several alkaloids differing materially in medicinal effects makes the results of assay comparative rather than absolute.

All this points to the desirability of considering the solanaceous drugs as entities in themselves and not as mere natural vehicles for the alkaloid hyoscyamine or atropine; for, whatever substances may be present, they all go together to give that balance of reactivity which is recognized as the characteristic behaviour of the plant substance. The argument to be deduced is that galenicals of indefinite natural bodies which have achieved a thoroughly established place in clinical medicine should not be interfered with in any matter that may be fundamental to their composition, whether by changing solvents or by alteration in chemical and physical treatment. Yet, on the other hand, if there is reliable evidence to show that the vogue of a drug is only due to custom or habit among prescribers, and if its value is strictly measured by a specific alkaloidal content, then there can be no imperative reason for standardizing methods of manufacture or even for restricting the drug used to a single variety, if other drugs yielding the same alkaloid or its near neighbour are available.

These points are most important, and demand full consideration before anything can be done in suggesting universal formulæ. They are important because allied drugs are to be found in different countries and in general commerce, and these find their way into preparations bearing other names, as adjunctives to

*The Simpler Natural Bases (Barger), pp. 55 and 129.

† Goris and Larsonneau, Y. B. J., 1922, p. 4, using 500 kils. of leaves for volatile bases.

Umney and Bennett, Y.B.P., 1909, 514.

MacEwan and Forrester, ibid.

A. B. Lyons, Proc. VII. Internat. Cong. App. Chem., Sec. viii., b. (1910).