Multi-stage screening of pharmaceutical cocrystals with hydroxybenzamide isomers: design and testing
According to drugs distribution in Biopharmaceutical Classification System only a small percentage of drug molecules are commercially applicable due to their low solubility and tissue permeability properties. Thus, to design and develop new ways of drugs delivery becomes an urgent task for modern pharmaceutical industry.
Nowadays cocrystallization is considered to be one of the most promising approaches to instant-soluble drugs obtaining. A cocrystal is a multi-component crystal formed by heterosyntons (stable non-valence intermolecular interactions), in which all constituents are solid under ambient conditions when used in their pure form. Cocrystals’ advantages compared to other pharmaceutical systems are as follows: a) relatively simple ‘green’ synthesis via cogrinding; b) a wide area of applications; c) thermodynamic stability of resulting products and d) the possibility to set physical properties by changing a conformer molecule.
Reliable methods of predicting the cocrystal formation still not existing, the main goal of the research undertaken was to design and test a novel multi¬stage cocrystal screening technique based on thermal and phase analysis of binary systems by means of differential scanning calorimetry, hot stage microscopy and saturation temperature method.
18 binary mixtures with 2, 3 and 4-hydroxybenzamide were chosen as model objects of the investigation. Four new cocrystals were discovered, namely [2-hydroxybenzamide + 4-acetamidobenzoic acid] (1:1), [3-hydroxybenzamide + 2-acetamidobenzoic acid] (2:1), [4-hydroxybenzamide + salicylic acid] (1:1) and [4-hydroxybenzamide + 2-acetamidobenzoic acid] (2:1). The solubility of the first cocrystal mentioned was proved to increase in pH 7.4 phosphate buffer solution in comparison with pure 2-hydroxybenzamide. Acknowledgement: Present work is supported by BioSol project (2010-1.1-234-069), Federal Special-Purpose Program of Science and Innovation Supporting (N 02.740.11.0857) and the Grant of the President of Russian Federation (МК-2309.2013.3).
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