Drug–Polymer–Water Interaction and Its Implication for the Dissolution Performance of Amorphous Solid Dispersions

Abstract

The in vitro dissolution mechanism of an amorphous solid dispersion (ASD) remains elusive and highly individualized, yet rational design of ASDs with optimal performance and prediction of their in vitro/in vivo performance are very much desirable in the pharmaceutical industry. To this end, we carried out comprehensive investigation of various ASD systems of griseofulvin, felodipine, and ketoconazole, in PVP-VA or HPMC-AS at different drug loading. Physiochemical properties and processes related to drug-polymer-water interaction, including the drug crystallization tendency in aqueous medium, drug-polymer interaction before and after moisture exposure, supersaturation of drug in the presence of polymer, polymer dissolution kinetics, etc., were characterized and correlated with the dissolution performance of ASDs at different dose and different drug/polymer ratio. It was observed that ketoconazole/HPMC-AS ASD outperformed all other ASDs in various dissolution conditions, which was attributed to the drug's low crystallization tendency, the strong ketoconazole/HPMC-AS interaction and the robustness of this interaction against water disruption, the dissolution rate and the availability of HPMC-AS in solution, and the ability of HPMC-AS in maintaining ketoconazole supersaturation. It was demonstrated that all these properties have implications for the dissolution performance of various ASD systems, and further quantification of them could be used as potential predictors for in vitro dissolution of ASDs. For all ASDs investigated, HPMC-AS systems performed better than, or at least comparably with, their PVP-VA counterparts, regardless of the drug loading or dose. This observation cannot be solely attributed to the ability of HPMC-AS in maintaining drug supersaturation. We also conclude that, for fast crystallizers without strong drug-polymer interaction, the only feasible option to improve dissolution might be to lower the dose and the drug loading in the ASD. In this study, we implemented an ASD/water Flory-Huggins parameter plot, which might assist in revealing the physical nature of the drug-polymer interaction. We also introduced supersaturation parameter and dissolution performance parameter as two quantitative measurements to compare the abilities of polymers in maintaining drug supersaturation, and the dissolution performance of various solid dispersions, respectively.

Initial Drug Dissolution from Amorphous Solid Dispersions Controlled by Polymer Dissolution and Drug-Polymer Interaction

“…Although the interaction strength between the polymer and drug molecules is chemistry dependent and should not change with the drug/polymer ratio, the Bapparent^strength of drug-polymer interaction, measured here by the extent of peak shift, increased when the numbers of interacting drug-polymer pairs increased. Similar complex formation mechanism was reported in the literature (23). In the 13 C NMR spectra of the KTZ/PVP-VA solutions (Fig.…”

“…KTZ concentration was measured by HPLC (LC-20AT, Shimadzu, Kyoto, Japan) with a UV spectrophotometer (SPD-M20A, Shimadzu, Kyoto, Japan), and the polymer concentration was measured by HPLC with an Evaporative Light Scattering Detector (ELSD) detector (380-LC, Agilent Technologies, USA). More detailed description of the ELSD method was reported earlier (23).…”

“…However, due to the limitation of sample preparation methods and analytical tools, either precise controlling of the mixing homogeneity between drug and polymer, or in-depth investigation of drug-polymer interaction at molecular level was not achievable at that time. We have previously demonstrated that the drug-polymer molecular interaction mechanism directly influence the hydrophobicity of ASD, the robustness of drug-polymer interaction against water disruption, and eventually, the overall dissolution performance of ASD (23). However, ASD dissolution is a complex process consisting of multiple steps and could be influenced by many formulation and experimental factors.…”

Effervescence Assisted Fusion Technique to Enhance the Solubility of Drugs

“…Chen et al prepared solid dispersions of griseofulvin, felodipine, and ketoconazole in PVP-VA or HPMC-AS. Because of low crystallization tendency and strong drug-carrier interaction, solid dispersion of ketoconazole in HPMC-AS outperformed all others (18). Solid dispersion of ketoconazole in nicotinamide improves its solubility and dissolution (19).…”

Commentary: Why Pharmaceutical Scientists in Early Drug Discovery Are Critical for Influencing the Design and Selection of Optimal Drug Candidates

“…However, the dissolution, supersaturation, and precipitation of enabled solids are more complex and the assessment tools are still evolving [40]. Consequently, judicious application of orthogonal dissolution screens and careful analysis and modeling of data can provide reasonably predictive results [41,42].…”