Enhancement of the Solubility of Asenapine Maleate Through the Preparation of Co-Crystals

Abstract

Background: Asenapine maleate, an anti-schizophrenic drug, is a class II drug with low solubility and high permeability. This exerts a rate-limiting effect on drug bioavailability.

Objective: To improve the solubility/dissolution rate of asenapine maleate and hence the bioavailability using the co-crystal approach.

Methods: Co-crystals were prepared using the solvent evaporation method. Since the drug has Hbond acceptor count of 6, and H-bond donor count of 2, several co-formers (nicotinamide, urea, succinic, benzoic, and citric acid) were investigated in different ratios. The optimized co-crystals (drug-nicotinamide in a ratio of 1:3) were evaluated using PXRD, DSC, FTIR spectroscopy, and SEM. Additionally, in vitro dissolution and stability studies were conducted.

Results: Preparation of the co-crystals was successful except when citric and benzoic acids were used. PXRD patterns showed that the co-crystals were crystalline. FTIR spectroscopy confirmed the formation of H-bond between the drug and the co-former. DSC indicated a lower melting point than that of the components followed immediately by an exothermic peak, which confirmed the formation of co-crystals. SEM showed the formation of crystals with different size and habit. The dissolution of the drug from all the prepared co-crystals was almost similar and much enhanced compared to that of the unprocessed drug. The initial dissolution of the drug from the optimized batch was much faster than that from the other co-crystals and the physical mixture with the same ratio. The optimized batch exhibited long term stability.

Conclusion: Co-crystals with improved solubility/dissolution rate of asenapine maleate were prepared successfully and were expected to enhance the bioavailability of the drug.

Keywords: Asenapine maleate; bipolar disorders; co-crystals; co-formers; enhancement of the solubility; schizophrenia.