ACCELERATING THE DEVELOPMENT OF SOLUBILITY-ENHANCED SOLID DISPERSIONS: USE OF MILLISCALE AND MATHEMATICAL PREDICTION OF DRUG-POLYMER MISCIBILITY

Abigail Garcia-Radilla, Mariana Ortiz-Reynoso*, Edna T. Alcantara-Fierro and Jonnathan G. Santillán-Benítez and Fernando Hernández-Martínez

ABSTRACT

Introduction: Most solid oral drugs currently in a developmental phase, have low solubility in aqueous systems. This reduces their pharmacological efficacy because drug absorption is slowed down. Solid dispersions are an option to improve both dissolution rate and apparent solubility of poorly soluble drugs. Aim: This work shows the effect of different drug-polymer proportions and a plasticizer in ternary solid dispersions at a milligram scale, on the drug dissolution rate, and evaluates its correlation to the calculated Flory-Huggins theoretical model. Methods: We evaluated the drug-polymer miscibility using the melting point depression method by the Flory-Huggins theory and the dissolution rate of ketoconazole in ternary solid dispersions manufactured by melting granulation. Results: All ternary solid dispersions decreased the enthalpy of fusion of the drug, however, only those made with PVP/VA 64 and HPMCAS HF improved the solubility kinetics at pH: 1.2 and 6.8 respectively. The proportions with the best results were 1:2 for HPMCAS HF (p = 0.0023) and 2:1 for PVP/VA (p = 0.0053) (drug:polymer). The Flory-Huggins parameter yielded a correlation with PVP/VA 64 and HPMCAS HF, but not with Soluplus®, indicating that the theoretical model needs to be improved to reflect this last case. Conclusion: The studies carried out in the present work are useful, practical and simple to improving the dissolution of poorly soluble drugs (KTZ), reducing costs and mitigating risks associated with the development of solid dispersions manufactured by fusion techniques.

Keywords: Solid dispersion, Drug-polymer miscibility, Melting process, Dissolution.