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

Abstract

The initial drug release from an ASD was controlled by 1) the polymer release rate; 2) the strength of drug-polymer interaction, including the intrinsic interaction caused by the chemistry of the drug and the polymer (measured by the χ value), as well as that the apparent interaction caused by the drug-polymer ratio (measure by the extent of peak shift on spectroscopic analysis); and 3) the level of mixing homogeneity between the drug and polymer. In summary, the selection of polymer, drug-polymer ratio, and ASD processing conditions have profound impacts on the dissolution behavior of ASDs. Graphical Abstract Relationship between initial drug and polymer dissolution rates from amorphous solid dispersions with different mixing uniformity and drug-polymer interactions.

Moisture-Induced Amorphous Phase Separation of Amorphous Solid Dispersions: Molecular Mechanism, Microstructure, and Its Impact on Dissolution Performance

“…In an earlier study, we reported that intrinsic dissolution rate of ASDs was significantly different from that of physical blends, based on the comparisons of ketoconazole (KTZ) ASD systems using PVP, PVPVA, or HPMC-AS as the polymer carriers. 23 We attributed these findings to a nonuniform molecular distribution of drug and polymer in physical mixture and the overall interaction strength. 23 With the presence of homogeneous mixing and specific drugpolymer interaction, drug and polymer dissolved at approximately the same rate from ASDs, whereas a nonhomogeneous mixing state and insufficient drug-polymer interaction resulted in slower drug dissolution rate compared with polymer release rate.…”

“…23 We attributed these findings to a nonuniform molecular distribution of drug and polymer in physical mixture and the overall interaction strength. 23 With the presence of homogeneous mixing and specific drugpolymer interaction, drug and polymer dissolved at approximately the same rate from ASDs, whereas a nonhomogeneous mixing state and insufficient drug-polymer interaction resulted in slower drug dissolution rate compared with polymer release rate. 23 However, in the current BMS-817399/PVP-40/60 ASD, polymer release rate was about 3 times of the drug release rate (0.77 vs. 0.21 mg/cm 2 /min).…”

“…10,13 Drug-polymer interaction also plays an important role during the dissolution process of ASDs. 19,23,24 Therefore, the molecular interaction between BMS-817399 and PVP was firstly studied using FT-IR.…”

“…Previously, we compared the intrinsic dissolution performance of ASDs with good uniformity, and physical mixtures with the same overall drug content but mixed by ASDs with high and low drug loading (i.e., artificially prepared ASD systems with APS), and the results suggested that changes in the mixing state of ASDs could affect the dissolution behavior of ASDs to different extents, largely depending on the strength of drug-polymer interactions. 23 The artificially prepared ASDs with APS could certainly be very different in their microstructure and dissolution performance, compared with ASDs with moisture-induced APS, which are real-life scenarios. Therefore, in this study, we aim to (1) investigate the effect of moisture on the drug-polymer interaction and microstructure of a model ASD system based on BMS-817399, a lipophilic slow crystallizer, and PVP, a commonly used hydrophilic polymer; (2) to study the impact of APS on the intrinsic dissolution rate of both the drug and polymer from ASDs.…”

Mechanisms of increased bioavailability through amorphous solid dispersions: a review

“…In the literature, also the impact of drug-polymer interactions on the dissolution performance was investigated. A study by Chen et al (2016a) investigated the formulation factors that control drug and polymer dissolution rates by an example of ketoconazole ASDs of different polymers. Authors distinguished the systems' behavior according to the drugpolymer interaction, represented by Flory-Huggins interaction parameter.…”