Theoretical Study On The Dissolution Process Of Theophylline Cocrystals

Theophylline can be used as a common drug for the treatment of respiratory diseases such as asthma and chronic obstructive pulmonary disease because it can relax bronchial muscles and increase myocardial contractility.However,its solubility is small and its ability to form monohydrate hinders its industrial production and clinical use.Therefore,in this paper we studied the physicochemical properties of theophylline solubility and dissolution rate from the perspective of cocrystal.We chose L-(+)-arginine,hydrochlorothiazide,benzoic acid,3-hydroxybenzoic acid(3-HBA),4-hydroxybenzoic acid(4-HBA)as cocrystal formers.The THP-3-HBA and THP-4-HBA with a stoichiometric ratio of active pharmaceutical ingredient to cocrystal formers of 1:1 were prepared and screened theophylline by reaction crystallization.The solubility of theophylline in methanol,ethanol,acetonitrile and other ten organic pure solvents,methanol-acetonitrile binary mixed solvent,and the solubility of THP-3-HBA,THP-4-HBA cocrystal in methanol,ethanol and other six pure solvents was determined by laser dynamic method.Then,the dissolution thermodynamics of theophylline and its cocrystals were analyzed.And the data were correlated by various solubility models.The phenomenon of increasing the solubility of cocrystals was explained by the lattice energy-solvation energy theory.The dissolution curves of theophylline and THP-3-HBA,THP-4-HBA cocrystal in four different pH dissolution media(water,simulated intestinal fluid,simulated duodenal fluid,simulated gastric fluid)were studied.In the simulated gastric juice,the THP-4-HBA cocrystal has a similar dissolution rate to theophylline.In other cases,the dissolution rate of the cocrystals is lower than that of theophylline;in the in vitro dissolution process,the cocrystals don't have "collapse"phenomenon,so that the dissolution curves don't have the"spring-parachute" trend;explain the mechanism of dissolution behavior of cocrystal according to molecule structure and solvation energy theory,and deduce that physical stability of two cocrystals better than active pharmaceutical ingredient.In this paper,the research on the dissolution process and mechanism of theophylline and its cocrystals provides the data and theoretical basis for the study of the dissolution properties of the drug cocrystal.