H. Berry

THE PREPARATION OF COMPRESSED TABLETS: Part III.—A Study of the Value of Potato Starch and Alginic Acid as Disintegrating Agents

WHEN a drug intended for internal administration is, for convenienx. presented as a compressed tablet, it should be axiomatic that the process of tableting should not alter either the therapeutic action of the drug or the time in which this action is produced. In other words the same effect should be produced in the same time when a tablet is swallowed as when the drug is taken in powder or solution form. Any deviation from these criteria is a measure of the pharmaceutical skill used in formulating and producing the tablets. The disintegration time of tablets intended to be swallowed whole is therefore of great importance, and the British Pharmacopceia 1948 has specified a test in which this time should not exceed 15 minutes except in the cases of tablets of barbitone and phenobarbitone, when the time is extended to 30 minutes. The disintegration time is a function of (a) the formulation, cb) the degree of compression, (c) the speed of compression and (d) the type of coating used, if any. The degree of compression is important, particularly to the manufacturer, for a tablet must be produced which will be hard enough to withstand abrasion during handling, transport a d storage. Often, however, increase in the degree of compression causes an increase in the disintegration time, and a compromise has to be adopted. This compromise whereby the hardness is balanced against an optimum time of disintegration is referred to, in this paper, as the “optimum cumpression.” This investigation is concerned with (a) ascertaining the effects of variation in degree of compression on dmisintegration time, the other factors being constant, i.e., formulation, speed of compression and absence of coating; (b) studying the relative values of potato starch and alginic acid as disintegrating agents when the other factors are constant. i.e., compression ratio, speed of compression and absence of coating. It was hoped that, as a result of these investigations, it would be possible to recommend that the disintegration time for all uncoated tablets intended to be swallowed whole should be 15 minutes. In previous paperslJ in this series it has been shown that 5-gr. phenacetin tablets were one of the types of compressed tablets that ma)

THE ESTIMATION OF BACTERICIDAL ACTIVITY FROM EXTINCTION TIME DATA

1 A new method for the determination of extinction time data is described. 2 The method has been employed for the disinfection of Bact. coli by aqueous solutions of phenol over a range of concentrations and death times ranging from 2 to over 100 minutes. 3 The use of extensive replication, short sampling intervals, and constant sample volumes withdrawn immediately after inoculation of the bactericide are among the chief features of the technique. 4 Estimates of the mean extinction time obtained from the data are of reproducibility within limits sufficiently close to invalidate other extinction time methods, and are of comparable value with those obtained by the use of any other techniques. 5 The method has been satisfactorily applied to systems containing water‐insoluble phenols solubilised in solutions of soaps (Berry and Bean9) where clumping of the test organisms might completely invalidate other methods of estimation of bactericidal activity.

The Evaluation of the Bactericidal Activity of Ethylene Glycol and some of its Monoalkyl Ethers against Bacterium coli. Part X.

Conclusions: As with the results from the experiments at 20°C. (Part VI1), the analysis of variance indicates that there is a significant variation in regressions between the different compounds, i.e. each substance has its characteristic regression coefficient which differs significantly from the average of the series. The analysis also shows that the variations in the regressions between the concentrations of the substances are of the same order as the variation between the individual tests at a particular concentration. Hence the regressions of different concentrations of the same substance may be taken as parallel. Summary 1 The course of the disinfection (at 30°C.) between Bact. coli and several concentrations of ethylene glycol and the following ethers: monomethyl, monoethyl, monopropyl, monobutyl and monohexyl has been investigated. Several experiments were conducted at every concentration and probit-log.*** time regressions calculated for all experiments. 2 For every concentration of a substance the sum of squares for the common regression and for the variation in regression were calculated; the error mean square of the regression was also computed. 3 The data for every concentration of each compound have been pooled and a mean regression has been calculated for each compound. 4 The statistical data from all the calculations for the terms of the regressions for every concentration of the compounds (at 30°C.) have been massed and an analysis of variance carried out. 5 The probabilities for the differences between the mean squares of the items in the analysis of variance have been deduced by means of the z distribution. 6 No significant difference could be shown between the variation in regression between concentrations and between tests; these two errors have been pooled in order to establish the error mean square for all the estimations performed. 7 The probit-log. time regression coefficient for every compound has been compared with its standard error; in all cases the ratio was large, thereby indicating that b had been estimated satisfactorily.

Bactericidal activities of soap-phenol mixtures.

THE modification of bactericidal activities of phenols when dissolved in varying concentrations of soaps has been the subject of several communications during the past few years. These reports differ in the postulated mode of action of the soap, and the experimental data are conflicting. The present investigations were undertaken in an attempt to relate the previous findings. Agar and Alexander1 and Alexander and Tomlinson2 measured the extinction times of Bacterium coli when exposed to phenol and chlorinated phenols dissolved in aqueous solutions of anionic and cationic surfaceactive agents. In all cases, the extinction times were minimal at the critical micellar concentration of the surface-active agent. When the phenol concentration was kept constant and the concentration of surfaceactive agent varied, extinction times rapidly increased at concentrations either below or in excess of the critical micellar concentration of the surface-active agent. The concentration exponent of the phenol-soap mixture was found to remain virtually constant and Alexander and Tomlinson were led to postulate that, as the soap concentration was increased beyond the critical concentration, the extinction times of the mixtures would increase until a toxic concentration of the surface-active agent was reached, the only activity remaining being due to the surfaceactive agent alone. Enhanced activity when the soap concentration was increased to the critical concentration was ascribed to the formation of an interfacial “complex” at the bacterium-water interface, the effect being similar to that observed by Alexander and Trim3 in the anthelmintic activity of hexylresorcinol-soap mixtures. At soap concentrations in excess of the critical, they considered, the phenol passed into the micelles. Reduction in bactericidal activity was therefore due to a phenol depletion of the aqueous phase. At very high concentrations of soap, nearly all of the phenol would be dissolved in the micellar phase and any activity of the mixture would then reside only in the activity of the soap itself. The studies undertaken by Bean and Berry415 employed two phenols of lower water solubility than those investigated by Alexander and his colleagues. They used only one soap, potassium laurate, and they used mixtures which contained not a constant phenol concentration, but a constant phenol/soap ratio. In agreement with the findings of Alexander and Tomlinson, Bean and Berry observed that increases in soap concentration up to the critical * This account formed part of a thesis submitted by one of us (B.A.W.) for the degree of Ph.D. in the University of London.

The structure and properties of aqueous solutions of soap.

THE sodium and potassium salts of the higher members of the homologous series of saturated fatty acids have different properties from those of the lower members. For example, there is no reason to suspect the existence of colloidal particles in solutions of sodium acetate, but it is impossible to deny their existence in solutions of sodium stearate or palmitatel. McBain and Taylor2 found that the equivalent conductivity curve of * potassium palmitate shows a pronounced minimum at 0.2N and a maximum at 0.5N. Such a phenomenon had not previously been met in aqueous solutions. Similar maxima and minima were found by McBain, Cornish and Bowden3 in the equivalent conductivity curves of sodium myristate and sodium laurate. An examination by McBain, Laing and Titley4 of the whole range of potassium soaps from the acetate to the stearate showed that the equivalent conductivityconcentration curves are smooth in form for the soaps below the laurate, whereas the laurate, myristate, palmitate and stearate all exhibit pronounced maxima and minima. showed that the equivalent conductivity of solutions of soap cannot be attributed to the presence of free hydroxyl ions produced by hydrolysis. The latter could only account for a few per cent. of the observed conductivity, which is nearly as great for solutions of ammonium soaps as it is for the corresponding potassium soaps’. The belief that hydrolysis could account for the conductivity was finally disposed of by Reychler8 who found that solutions of cetyltriethylammonium iodide behaved similarly.

STUDIES OF RICINOLEIC ACID AND A TURBIDIMETRIC METHOD OF EVALUATING THE BACTERICIDAL ACTION OF SOLUTIONS OF PHENOLS IN POTASSIUM RICINOLEATES: Part III—Reproducibility of Nephelometer Results

INTRODUCTION IN Part I1 of this series1 it was shown that further investigations were necessary before the nephelometer results could be used for evaluating the bactericidal action of a bactericide. The large daily variation noted in the earlier investigations was attributed to the treatment accorded the suspension of Bacterium coli after the initial standardisation of the suspension. This initial suspension was mixed with a solution of phenol and then sampled at predetermined time intervals, the samples were incubated for 5 hours and their turbidities were measured on the nephelometer. The assumption that equal nephelometer readings, in two different experiments, indicated an equal number of survivors in the samples appeared incorrect and so a technique was evolved in this part of the work to make this assumption unnecessary.

THE EFFECT OF TEMPERATURE ON BACTERIOSTASIS

INTRODUCTION THE earlier work on bacteriostasis has been reviewed by Marshall and Hrenoff’, who suggest that bacteriostasis can be represented by the horizontal line in Figure 1, which represents a growth rate of zero. These authors state that this is “a point of equilibrium virtually unattainable in fact,” and Rahn2 also states that “usually a certain amount of death accompanies antisepsis.” Marshall and Hrenoff define bacteriostasis as “A concept of those conditions which living bacteria. under the influence