Development of Ezogabine Co Crystal Formation: An Efficient Approach to Enhance Aqueous Solubility

Purpose: The bioavailability of a development candidate active pharmaceutical ingredient (API) was very low after oral dosing. In order to improve bioavailability, we sought to increase the dissolution rate of the solid form of the API. Methods: A crystal engineering approach was used to design, develop a co crystal of the API. Hydrogen bonding between the API and carboxylic acids were used as a coformer for associating multiple components in the solid state. A number of carboxylic acid guest molecules were tested for co crystal formation with the API. Results: A co crystal containing the API and p-Amino benzoic acid or Benzoic acid in a 1:5 or 1:3 molecular ratio was identified and the crystal structure is reported. Physical characterization of the co crystal showed that it is unique regarding thermal, spectroscopic, X-ray, and dissolution properties. The co crystal solid is nonhygroscopic, chemically and physically stable to thermal stress. Use of the co crystal increased the aqueous dissolution rate by 11 times as compared to the pure form of the drug. Conclusions: APIs that are non-ionizable or demonstrate poor salt forming ability traditionally present few opportunities for creating crystalline solid forms with desired physical properties. In this case, a co crystal of Ezogabine with p-Amino benzoic acid or Benzoic acid was observed and used to demonstrate an improvement in the solubility and micromeritics properties of the API.

Author(s): Vikas G. Rajurkar, Ajay L. Aucharmal and Sopan Dethe

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