K. C. James

Biological half-lives of [4–14C]testosterone and some of its esters after injection into the rat

Biological half‐lives for 14C from labelled testosterone in muscle and whole body of rats have been measured after intramuscular injection of [4‐14C]testosterone and its lower esters (formate to valerate). A relation has been observed between ethyl oleate‐water distribution coefficients, biological half‐lives in the rat and “times of maximum effect” in the rat and fowl.

Drug migration into soft gelatin capsule shells and its effect on in-vitro availability.

Analysis of the shells and contents of soft gelatin capsules containing acetomenaphthone, ephedrine, 4−hydroxybenzoic acid or phenobarbitone, dissolved in isopropyl myristate, revealed that the percentage of solute taken up by the shells increased with increasing aqueous solubility of the substrate. Thus no acetomenaphthone, which has a negligible aqueous solubility, was found in the shells, in comparison with 92% of the 4‐hydroxybenzoic acid, which has a significant solubility in water. Uptake was not influenced by the solubility in isopropyl myristate. The effect of the oily solvent was studied using blends of 1‐octanol and isopropyl myristate in which either 4−hydroxybenzoic acid or phenobarbitone were dissolved. Solute release shows that both release and migration can be predicted from a knowledge of the aqueous solubility of the solute and its partition coefficient between water and the non‐polar solvent. Samples of capsules containing 4‐hydroxybenzoic acid in isopropyl myristate were withdrawn at various stages of the manufacturing process, and the distributions between shell and contents noted. Most of the transfer took place while the capsules were being dried in rotating basket driers, and at this point 67% of the acid had migrated. This increased to 92% during tray drying, and remained so for at least 6 months after manufacture.

The solubilities of the lower testosterone esters

The solubilities of the formate to valerate esters of testosterone have been determined in water and several organic solvents. The aqueous solubilities decrease logarithmically as the homologous series is ascended, but the acetate is less soluble than anticipated in the organic solvents. The variation in solubility from ester to ester can be predicted in the organic solvents from thermodynamic data, and is a reflection of the differences in melting point. The melting point differences are explained from the space group dimensions and the area of α to α face contact in the crystals.

Influence of solvent on the availability of testosterone propionate from oily, intramuscular injections in the rat

The suggestion that the biological response to an oily intramuscular injection of testosterone ester is regulated by rapid accumulation of the steroid in body fat, followed by a slow release, has been tested by comparing the release rates of 14C‐labelled testosterone propionate from different solvents following intramuscular injection into rats. Disappearance from the injection site was rectilinearly related to in‐vitro partition coefficients, but elimination of radioactivity in urine and faeces was significantly longer, and the same for all four solvents. Testosterone and testosterone propionate were found in equal concentration in body fat, 2 and 3 days after injection, but their concentrations were too low to form an effective depot. It is suggested that the delay in release, and the independence of the delay on the nature of the solvent is a consequence of biliary recycling of testosterone.

An investigation of the distribution coefficients of some androgen esters using paper chromatography

Rm values have been determined for four homologous series of androgen esters, using a Bush paper chromatography system, to assess the value of the ratio of the solubilities in the individual solvents (solubility ratio), as an estimate of distribution coefficient. The distribution coefficients were proportional to Rm values in all four series, and for three of these the proportionality constant was the same. Limitations in the use of RM values to predict biological effects have been pointed out.

The influence of viscosity on the migration of chloramphenicol and 4-hydroxybenzoic acid through glycerogelatin gels.

Migration of chloramphenicol and 4‐hydroxybenzoic acid from solutions in 1‐octanol into Glycerol Suppository Base, BP and soft gelatin capsule shells is reported. Rates of migration through the gels, quantified in terms of diffusion coefficients, are given. An electron spin resonance probing technique was used to determine the microscopic viscosity. The latter, rather than the bulk viscosity, was shown to be the major rheological influence on the rate of diffusion.

Inter-relationships between solubilities, distribution coefficients and melting points of some substituted benzoic and phenylacetic acids.

Ten 4‐hydroxy and 4‐alkoxy benzoic and phenylalkanoic acids have been investigated. Solubilities in aqueous buffer at pH 1·2 were determined, together with distribution coefficients between the buffer and either octanol or isopropyl myristate. When plotted against the total number of carbon atoms in the side chains, log octanol/water distribution coefficients gave two parallel straight lines, one for the substituted benzoic acids, and the other for the substituted phenylalkanoic acids. The slopes approximated to 0·5, the generally accepted value for methylene. Similar plots could be obtained with isopropyl myristate, provided the hydroxy acid results were ignored, and also when log aqueous solubilities were plotted against carbon number, although there was considerable scatter. The differences between the distribution coefficient results were explained in terms of solute‐solvent interactions, and the scatter attributed to variations in the heats of fusion of the solutes. Yalkowskys equation (1977), linking aqueous solubilities and melting points with distribution coefficients, was applied to the results, and found to be of limited predictive value.

An in vitro model for assessing drug availability from lipophilic vehicles.

An apparatus for studying the rate of release of a solute from a water‐immiscible solvent into an acidic, aqueous liquid, followed by permeation through a simulated lipid membrane, is described. The object was to imitate the absorption of a drug after oral administration in a soft gelatin capsule. Rate constants of transfer were determined for a series of substituted benzoic acids, using octanol and isopropyl myristate as solvents. The quantity of solute in the acidic phase did not correlate with the solvent‐water distribution coefficient, but was linearly related to the rate constant for transfer from solvent to water. A dynamic system was therefore postulated, rather than one in which the two phases are in equilibrium. In vivo studies on two of the solutes confirmed the in vitro observations. No simple relationship could be derived between blood concentrations and any in vitro parameter, but the rank order of magnitude of the blood concentrations fitted the postulated dynamic mechanism.

The effect of gelatin grade and concentration on the migration of solutes into and through glycerogelatin gels.

Abstract— The diffusion of 4‐hydroxybenzoic acid and phenobarbitone through glycerogelatin gels was found to be independent of the type of gelatin used. Three types of gelatin, two acid‐processed and one alkali‐processed were studied, and the bulk viscosities of gels prepared from them was seen to vary considerably. However, the microviscosities of the gels, as measured by ESR, showed no significant differences. Thus microviscosity was the factor governing diffusion. Gelatin concentration in aqueous solutions without glycerol influenced microviscosity and hence diffusion. This is believed to be caused by dissolution of water‐soluble fractions of the gelatin. Interstices in the gelatin matrix, though reduced in size when gelatin concentration is raised, are still too large to act as physical barriers to diffusing molecules. It is suggested that hydrated gelatin forms the matrix of glycerogelatin mixtures and that the interstitial fluid, through which migration occurs, consists almost entirely of glycerol and water.

An apparatus for investigating drug migration into gelatin capsule shells

Abstract An apparatus for the study of migration of a solute from its solution in a non-aqueous solvent into the walls of soft shell capsules is described. The solution is applied to the top of a glycerogelatin column contained in a truncated hypodermic syringe. After the required period of time, the column is extruded from the syringe, cut into slices, and each slice analysed. The reproducibility of the method was established by following the migration of 4-hydroxybenzoic acid from isopropyl myristate solution into glycerol suppository base, and the technique extended to soft and hard gelatin capsule bases. The influence of temperature indicated that Arrhenius type plots could be used for accelerated testing, and migration from 1-octanol, isopropyl myristate and blends of the two showed that the rate and extent of migration were dependent upon the partition coefficient.