Enhancement of solubility and dissolution rate of atorvastatin calcium by co-crystallization

Purpose: To investigate the formation of atorvastatin calcium (AC) co-crystal to improve its solubility and dissolution rate.
Method: Co-crystallization of AC in equimolar ratio with isonicotinamide (INA) was carried out by slow solvent evaporation
method using methanol. The solid obtained was characterized by powder x-ray diffraction (PXRD), differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), and then further evaluated for solubility and dissolution.
Results: The PXRD pattern of ACINA showed new crystalline peaks at 2θ values of 8.2 and 18.3^o, indicating the presence of a new crystalline phase of ACINA co-crystal. The DSC thermogram of ACINA displayed a melting point at 201.7 ^oC which is higher than the melting points of AC (159.4 ^oC) and INA (158.0 ^oC). The FTIR spectra of AC in ACINA shifted the absorption peak from 3363 to 3280 cm^-1 and to 1216 to 1222 cm^-1. The absorption peak shift is presumably due to N-H and C-N groups of AC form the hydrogen bonding interaction with groups in INA molecule. The solubility of ACINA co-crystal in distilled water was 270.7 mg/L which is significantly higher (p < 0.05) than that of pure AC (140.9 mg/L). The dissolution rate of ACINA co-crystal was 2 - 3 times faster than that of pure AC.
Conclusion: AC and INA in equimolar ratio forms a co-crystal by slow solvent evaporation. ACINA cocrystal significantly increases in solubility with a dissolution rate 2 - 3 times faster than that of pure AC. The enhancement of aqueous solubility and dissolution rate of AC with co-crystallization may be a potential way to solving the bioavailability problem of AC.

Keywords
Atorvastatin calcium; Co-crystal; Isonicotinamide; Solubility; Dissolution rate