(M1430-12-81) Formulation, Optimization, and In Vitro Studies of Atorvastatin Calcium Cocrystals

Purpose: Oral drug delivery remains the most favorable route of administration for patients. However, the oral bioavailability of some drugs is often low and variable because of their limited solubilities. The present study aimed at the formulation and optimization of cocrystals of atorvastatin calcium (ATC) (Class II-BCS) with selected coformers; glucosamine (GluN), and nicotinamide (NIC) by solvent drop grinding (SDG) method to enhance its dissolution rate. The optimized formulations along with their respective physical mixtures (PMs), were further characterized by Fourier-transform infrared (FT-IR) spectroscopy, Differential scanning calorimetry (DSC), and Powder X-Ray Diffraction (PXRD).

Methods: GluN and NIC were tested as coformers in different ratios with the drug (1:1, 1:2, and 1:3), with and without Tween 80 (0%, 0.25%, or 0.5%) as emulsifying agent, using hydroacoholic mixtures with methanol, ethanol, or acetone. PVP K15 and PVP K30 were investigated as stabilizers for the cocrystals. Different cocrystal formulations equivalent to 10 mg ATC were tested for dissolution for 60 min. using USP apparatus II, with 500 ml of phosphate buffer pH 6 at 50 rpm and 37± 0.5˚C for 60 minutes. GluN coformer showed better results compared with NIC, so it was used for optimization study. A three factor three level Box-Behnken experimental design was utilized for optimization by taking the drug: coformer ratio (X1), the solvent used (X2), and the percent of Tween 80 (X3) as the independent variables; and the percent drug released in 30 min (Y1) as the dependent variable (Table. 1). The three levels of the three factors were shown in Table 2.

Results: Significant enhancement in the dissolution rate was observed in different cocrystals formulations in comparison with the raw drug and the corresponding PMs. The amount of ATC dissolved after 5 min from the raw ATC and the physical mixtures ranged between 36 and 41%, compared to 40 and 71% for the different tested cocrystals. The mathematical relationship obtained between X1-X3, and Y was: Y= 69.237 - 0.6575X1 - 0.83375X2 + 1.5288X3 - 1.2875X1X2 + 0.9275X1X3 - 1.37X2X3 + 7.2192X1² + 2.2967X2² + 3.3417X3². The theoretical (predicted) and the observed values of Y were in reasonably good agreement (Table. 3). The relationship between the dependent and independent variables was further elucidated using contour plots.

Conclusion: The formulation of ATC with GluN coformer yielded cocrystals with enhanced physicochemical properties and resulted in a high rate of drug dissolution amounting to above 70% after 5 min. The experimental design applied succeeded to get the optimized formulation and the predicted and observed values of dissolution rates were in reasonably good agreement

Acknowledgements: The authors are grateful to Research Sector, Kuwait University for funding the research project PP01/20. Special thanks to Mrs. Doha Nabeel and Mr. Saji Abraham for their technical support.
The authors have no conflict of interest with any information included in the submitted abstract.

Fig. 1: Variables in the Box-Behnken design

Fig. 2: The tested cocrystal formulations

Fig.3: Observed and predicted values for the response factor (Y)