Pimozide and Adipic Acid: A New Multicomponent Crystalline Entity for Improved Pharmaceutical Behavior

Abstract

Pimozide is a first-generation antipsychotic used in the treatment of schizophrenia, Gilles de la Tourette syndrome, and other chronic psychoses. Its in vivo efficacy is limited by poor solubility and consequent poor bioavailability. Therefore, adipic acid was used as a coformer for the preparation of a binary product with improved pharmaceutical properties. The thermal behavior of the liquid-assisted grinding products of compositions included in the range 0.1 < XPMZ < 0.9 has been interpreted using a thermo-dynamic model according to which the two components originate a new crystalline entity in molar ratio pimozide:adipic acid 0.66:0.33, which forms an eutectic system with adipic acid. The model was confirmed using the quantitative analysis of the melting peaks and using the X-ray diffraction measurements from powders and single crystals. In particular, the latter have demonstrated that the new entity resulting from the pimozide:adipic acid 0.66:0.33 composition is actually salt [PMZH]2[adipate]. The crystalline product was characterized, from a pharmaceutical perspective, in terms of solubility and wettability (contact angle). Then, a tablet formulation was developed, and its dissolution behavior was compared to a commercial product considered as a reference. The new entity showed improved pharmaceutical properties in terms of solubility and wettability compared to the pure drug in both deionized water and bio-relevant fluids simulating oral administration in fed and fasted conditions. The tablets containing the new crystalline form can make this virtually insoluble drug available for absorption within minutes regardless of the variability in gastric conditions.