Effect of Organic Acids on Molecular Mobility, Physical Stability, and Dissolution of Ternary Ketoconazole Spray-Dried Dispersions

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Abstract
In an earlier investigation, ketoconazole (KTZ) - organic acid coamorphous systems were prepared, wherein, in the solid-state, there was ionic and/or hydrogen bonding interactions between the drug and the acid (Fung et al, Mol. Pharmaceutics, 2018, 15 (5), 1862-1869). While the coamorphous systems accelerated KTZ dissolution, the organic acids were not effective in maintaining supersaturation and drug precipitation was observed. Ternary drug-polymer-acid amorphous solid dispersions (ASDs) were prepared with ketoconazole, polyvinylpyrrolidone (PVP) and each oxalic (OXA), tartaric (TAR), citric (CIT) or succinic (SUC) acid. Solid dispersions containing only PVP resulted in a moderate reduction in molecular mobility and minimal improvement in dissolution performance. The incorporation of acid in PVP-KTZ solid dispersion led to orders of magnitude increase in α-relaxation times and decreased the crystallization propensity. The ternary ASDs containing OXA, CIT and TAR systems were exceptionally stable while crystallization of cocrystal was observed in the SUC system. Moreover, the addition of acids also dramatically improved the dissolution performance of KTZ, a result attributed to KTZ-acid interactions.
Funding Information
  • Pharmaceutical Research and Manufacturers of America Foundation
  • University of Minnesota
  • William and Mildred Peters Endowment Fund

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