Solubility Enhancement of Clozapine Through Co-Crystal Formation with Isonicotinamide

Abstract

Clozapine (CLO) is an effective atypical antipsychotic to control the symptoms of psychosis and schizophrenia. Clozapine has low solubility and high permeability, so it is classified as a class II in the biopharmaceutical classification system. The aim of this study was to improve the solubility and dissolution rate of clozapine by clozapine-isonicotinamide (CLO-INA) co-crystal formation. CLO-INA co-crystal was prepared by solvent-drop grinding (SDG) method using water as a solvent. Characterization of SDG result was conducted by powder X-ray diffraction (PXRD) and Fourier transform infrared (FTIR). Solubility test was performed in water at room temperature. The dissolution test was performed in 900 mL of pH 6.8 phosphate buffer solution, 50 rotation per minute of paddle rotation, and at 37±0.5 °C. The PXRD pattern of SDG result of CLO-INA has many different peaks from its parent components, and this may indicate the co-crystal formation. The solubility of the co-crystal clozapine was fifteen folds higher than pure clozapine. The dissolution rate of CLO-INA co-crystal increased in the first 10 minutes compared to pure clozapine. Percentage of clozapine dissolved after 10 minutes from CLO-INA co-crystal and pure CLO were 10.2 and 2.4%, respectively. CLO and INA can form co-crystal by SDG method that can improve the solubility and dissolution rate of clozapine.Keywords: Clozapine, Isonicotinamide, Co-crystal, Solubility, Dissolution

Multicomponent Crystals of Clozapine with Improved Solubility: A Combined Theoretical and Experimental Strategy on Coformer Screening and Structure–Property

“…Additionally, the three virtual screening results of CLZ and 46 coformers were examined by PXRD patterns obtained by solvent-assisted grinding and summarized in Tables S1 and S2 (the new form column). Compared with PXRD patterns of CLZ and coformer, 24 of the 46 powder patterns which were obtained from the liquid-assisted grinding experiments showed distinctly different peaks, confirming the formation of new solid phases (among them, multicomponent crystals of CLZ with 3,5-dinitrobenzoic acid, , salicylic acid, and isonicotinamide, CA, OXA, and tartaric acid have been reported in the literature).…”

“…12 Several reports were focused on CLZ solubility enhancement via forming salts, such as dibromo salts, 9 3,5dinitrobenzoic acid salts, 11,13,14 maleic acid (MA) salts, 11 and 2hydroxybenzoic acid salts. 11 Moreover, CLZ can also form cocrystal with isonicotinamide 15 and co-amorphousness 16 with citric acid (CA), oxalic acid (OXA), and tartaric acid (TA). The above contributions to CLZ solubility improvements were of great importance; however, the multicomponent crystals screening process were "trial-error method", much inefficient in the extreme and numerous experimental trials.…”

Solid state thermomechanical engineering of high-quality pharmaceutical salts via solvent free continuous processing

“…The loss of a broad band OH group indicated the formation of hydrogen bond in KTZ OA salt crystals. 26 CFX showed a characteristic absorption peak at 3040 cm −1 which can be assigned to C-H olefinic and aromatic chains, with 1614 cm −1 corresponding to keto (CvO) group. The carboxylic group CvOOH didn't appear in the IR spectra as CFX is a zwitterion.…”

Formulation and evaluation of orally disintegrating film (ODF) containing piperine-succinic acid cocrystal

“…Piperine is classified in BCS class II based on its characteristics in the Biopharmaceutical Classification System (BCS) classification, indicating that it has low solubility in water and high permeability (Oladimeji et al, 2018). Solubility is one of the essential physicochemical properties to predict the gastrointestinal absorption rate of active drug substances that will affect bioavailability (Alatas et al, 2019;Aungst et al, 2002).…”