This paper addresses the problem of using the methods of physicochemical analysis for selecting optimum drug compositions containing poorly soluble components. We have studied the antifungal antibiotic griseofulvin, which is practically insoluble in water, the saturated solution concentration being as low as 10 g/ml. At present, griseofulvin is manufactured in the form of a fine disperse powder with a particle size not exceeding 4 m [1]. In order to determine the influence of the physicochemical interaction between system components on the solubility of griseofulvin, we studied two systems: griseofulvin – aminocaproic acid and griseofulvin – lactose. Both aminocaproic acid and lactose are harmless in the amounts studied: the substances are biocompatible with tissues of the human organism and produce no toxic damage. Systems involving these compounds ensure a proper manifestation of the anticipated pharmacological effect of the parent drug component. Other requirements to the drug components include high water solubility, possibility of using thermoanalytical techniques, and the difference between the UV spectral characteristics of fillers and griseofulvin. An additional criterion in selecting the solubilizing component for compositions with griseofulvin was the change in the melting points of components of the equilibrium system. Using these data, it is possible to determine the composition of a system provided that the phase diagram is known. Now let us briefly characterize the physicochemical properties of the compounds studied. Aminocaproic acid. Colorless crystals or white powder, tasteless and odorless. Hygroscopic, readily soluble in water, slightly soluble in ethyl alcohol. Melting point, 202°C; the melting is accompanied by partial decomposition with the formation of caprolactam, whereby the mass exhibits vitrification. The compound exhibits no absorption features in the UV range. The amounts of aminocaproic acid used for increasing the bioaccessibility of griseofulvin in compositions produces no blood-coagulating effect [2, 3]. Lactose. White crystalline odorless powder, tasting slightly sweet. Readily soluble in water, this compound is widely employed as a supplementary component in pharmaceutical technology. Melting point, 202°C. On melting, lactose exhibits oxidation and polymerization. The compound exhibits no absorption features in the UV range [1 – 3]. Griseofulvin. An extremely fine disperse powder with a weak specific odor. Practically insoluble in water, slightly soluble in 95% ethyl alcohol, readily soluble in DMF and methylene chloride. Melting point, 218°C. The fungicidal concentration determined for a DMSO solution was 200 g:ml. The UV spectrum measured in the range from 230 to 310 nm exhibits absorption bands peaked at 245 and 300 nm [1 – 3].

Bioaccessibility of Griseofulvin in Binary Compositions

La dispersion moleculaire d’un principe actif (PA) dans un polymere est generalement utilisee pour accroitre a la fois la solubilite et la stabilite physique de sa forme amorphe. Cependant, ce type de formulation demande une parfaite connaissance de la solubilite du PA dans le polymere. Cependant, les methodes actuelles pour determiner les courbes de solubilite sont longues et fastidieuses a mettre en oeuvre. Dans cette these, nous presentons une methode originale pour determiner efficacement la solubilite des PA dans les polymeres. L’originalite de cette methode reside dans le fait que les etats d’equilibre satures sont ici atteints par demixtion d’une solution solide amorphe sursaturee en PA et non par la methode classique de dissolution du PA cristallin au sein du polymere amorphe. Les etats d’equilibre satures sont donc beaucoup plus rapides a atteindre en raison de la mobilite moleculaire accrue resultant de la forte plastification du polymere imposee par les conditions de sursaturation. Nous avons aussi teste la possibilite de predire les courbes de solubilite par des methodes numeriques ab-initio (par dynamique moleculaire et methodes quantiques). Les methodes experimentales et numeriques ont ete validees en etudiant des systemes polymere/PA dont les courbes de solubilite ont deja ete determinees par des methodes classiques. Les systemes etudies sont : PVPK12/indometacine, PVPK30/griseofulvine et β-cyclodextrine methylee/griseofulvine. Les techniques d’investigations utilisees sont esentiellement l’analyse enthalpique differentielle a balayage (DSC) et la diffraction des rayons X sur poudre (DRX).

Aurélien Mahieu

Papers

Nouvelles méthodes de détermination des diagrammes de solubilité polymère / principe actif