Synthesis of Cocrystals of Betulin with Suberic Acid and Study of Their Properties

摘要

Betulin and its derivatives belonging to the series of lupane triterpenoids attract a great interest due to a wide spectrum of biological and pharmacological activity. However, poor solubility of triterpenoids in aqueous media reduces significantly their bioavailability. The production of cocrystals, that is, multicomponent crystal systems containing active pharmaceutical ingredients and nontoxic partner molecules in their structure, is used in pharmacy to change physical and chemical properties of the drugs, including dissolution rate and solubility. In this work, cocrystals of betulin with suberic acid were obtained by a mechanochemical processing when adding small amounts of organic solvents of different polarity: ethanol, acetone, ethyl acetate, chloroform, toluene, dioxane. The production of cocrystals was confirmed by the methods of X-ray phase analysis, IR spectroscopy, as well as the methods of thermal analysis. It was demonstrated that cocrystals of betulin with suberic acid contain water molecules in their structure, while anhydrous cocrystals can be obtained by heating the physical mixture of reagents until the acid melts. In comparison with data for cocrystals of betulin with adipic acid, the results of the experiments on the dissolution of cocrystals of betulin with suberic acid demonstrated that an increase in the length of aliphatic acid chain leads to a decrease in the rate of betulin release into the solution.