Polymer-Mediated Drug Supersaturation Controlled by Drug–Polymer Interactions Persisting in an Aqueous Environment

Abstract

We investigated the drug–polymer interactions in nonaqueous and aqueous environments between a poorly water-soluble drug, BAY1161909 (909), and two commonly used polymers in amorphous solid dispersions, i.e., PVP and HPMC-AS. In an nonaqueous state, with a drug–polymer Flory–Huggins interaction parameter, solution NMR and FT-IR results revealed that strong specific interactions existed between 909 and PVP, while not between 909 and HPMC-AS. After prolonged moisture exposure under 95% RH, 909/PVP intermolecular interaction no longer existed, while hydrophobic interaction between 909 and HPMC-AS occurred and persisted. In an aqueous supersaturation study of 909, codissolved PVP significantly outperformed predissolved PVP in maintaining 909 supersaturation. We hypothesized that the codissolved PVP formed a specific interaction with 909, and thus, it was able to prolong 909 supersaturation before disruption of the interaction in aqueous medium, while predissolved PVP formed hydrogen bonds with water, and thus, it was no longer able to form specific interactions with 909 to prolong its supersaturation. In contrast, HPMC-AS effectively mediated 909 supersaturation through hydrophobic interaction, which became pronounced in an aqueous environment and was independent of how HPMC-AS was added. This hypothesis was supported by dynamic light scattering analysis, wherein the formation of nanosized drug/polymer aggregations was found to be correlating with the supersaturation of 909. In summary, we concluded that polymer-mediated drug supersaturation was controlled by drug–polymer interactions persisting in an aqueous environment. Therefore, the physical nature of the drug–polymer interaction as well as the dissolution kinetic of the drug and polymer are all critically important to achieve an optimal ASD formulation design.

Impact of HPMCAS on the Dissolution Performance of Polyvinyl Alcohol Celecoxib Amorphous Solid Dispersions

“…It has been discussed that polymers exhibiting a high hydrophilicity tend to preferably interact with water, which is also highly hydrophilic rather than with the hydrophobic drug substance [38]. Chen et al emphasized that interactions between a highly hydrophilic polymer with a hydrophobic drug are "water-vulnerable", which means that the interactions between the polymer and the drug become weaker over time, while the interactions between the polymer and water become stronger [16]. This fact is perfectly in line with our data from the supersaturation assay, where the supersaturation in presence of PVA dramatically crashed after a certain amount of time.…”

“…Therefore it was shown that hydrogen bonds between drug and polymer are decisive in order to avoid AAPS upon contact with moisture [11,14,15]. On the other hand the presence of hydrogen bonds alone was often shown to be not sufficient to generate a satisfactory maintenance of the supersaturated state in solution upon dissolution of the ASD [16]. A few studies investigated ternary ASDs with a combination of hydrophilic and hydrophobic polymers and showed a benefit compared to the respective binary ASD formulation, by achieving optimized dissolution rate and supersaturation maintenance [17,18].…”

Influence of Particle Size and Drug Load on Amorphous Solid Dispersions Containing pH-Dependent Soluble Polymers and the Weak Base Ketoconazole

“…The shift of the glass transition temperatures towards lower temperatures and the occurrence of two distinct glass transition temperatures also indicated a formation of an AAPS and a disruption of interactions between drug and polymer. The lower glass transition temperature reflected the drug-rich phase and the higher one corresponded to the polymer-rich phase (46,47).…”

The Role of Hydrogen Bonding in Paracetamol–Solvent and Paracetamol–Hydrogel Matrix Interactions

“…The diffusion process of the release of the active substance from the matrix can be described by Korsmayer-Peppas equation [52,53] C D (t) = k r t n , (15) where k r is the rate of the release process and depends on the external conditions during the experiment, the glass transition temperature T g of polymer, and the hydrophilicity and structure of the matrix [54]. It is important to note that n indicates the dominant mechanism of the release process for cylindrical sample: 0.45 indicates Fickan diffusion (Case I), 0.85 is Case II (when domination of polymer stress relaxation process occurs), and 0.45 < n < 0.85 means anomalous diffusion (non-Fickan) [55,56].…”

“…Despite the growing interest in understanding drug-carrier interactions at a molecular level, prediction of the drug release kinetics remains challenging due to many interrelated physicochemical processes that occur simultaneously in the aqueous environment [14,15]. Therefore, studies on the interaction of active substances (drugs) and their carriers in hydrous medium are important as they provide the basic foundation for their application [16][17][18][19][20].…”