Congruent Release of Drug and Polymer from Amorphous Solid Dispersions: Insights into the Role of Drug-Polymer Hydrogen Bonding, Surface Crystallization, and Glass Transition

Abstract

Drug loading is an important parameter known to impact the release rate of a poorly soluble drug from an amorphous solid dispersion (ASD). Recent studies have shown that small increases in drug loading can dramatically reduce the drug release rate from ASDs prepared with poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA). However, the link between drug physicochemical properties and the drug loading where the release is abruptly compromised is not well understood. This study probes the role of different factors on the relative dissolution rates of drug and polymer from PVPVA-based ASDs as a function of drug loading: (1) the impact of drug-polymer hydrogen bonding interactions on the initial dissolution rate of ASDs, investigated using two structural analogues, indomethacin (IND) and indomethacin methyl ester (INDester), (2) the influence of surface drug crystallization, observed for INDester ASDs, and (3) by changing temperature, the impact of the "wet" glass transition temperature (T g ). Scanning electron microscopy (SEM), with or without energy dispersive X-ray (EDX) analysis, Fourier transform infrared spectroscopy (FTIR), and powder X-ray diffraction (PXRD) were utilized to study the solid-state phase behavior and/or drug enrichment on the partially dissolved ASD tablet surfaces. Nanoparticle tracking analysis (NTA) was utilized to study the solution-state phase behavior. It was found that, contrary to expectations, ASDs with drug-polymer hydrogen bonding exhibited poorer initial release at moderate drug loadings (15−25%) as compared to the non-hydrogen bonding analogue ASDs. Surface crystallization led to the deterioration of dissolution performance. Lastly, T g relative to experimental temperatures also appeared to play a role in the observed dissolution behavior as a function of drug loading. These findings shed light on potential mechanisms governing ASD dissolution performance and will aid in the development of optimized ASD formulations with enhanced dissolution performance.

Exploring the Role of Surfactants in Enhancing Drug Release from Amorphous Solid Dispersions at Higher Drug Loadings

“…The limit of congruency (LoC), which is the drug loading boundary above which the dissolution mechanism switches from being congruent to incongruent, varies from one drug-PVPVA system to another; however, it typically occurs at <25% drug loading and often acts as a limiting factor in achieving reasonable dosage sizes, especially for high dose drugs. In order to develop strategies to overcome this limitation, researchers have pursued understanding of this sudden change in dissolution mechanism at the LoC, whereby changes in the ASD microstructure and homogeneity during hydration appear to be important to the generation of a drug-rich layer at the surface of the ASD, which in turn results in slow drug release [ 4 , 7 , 14 , 17 , 35 , 36 , 37 ]. Once the water enters the ASD, it acts as an anti-solvent for the drug, generating a thermodynamic driving force for phase separation.…”

“…Based on these microstructural changes and the release behavior observed for the 30% DL ASDs, we propose a release model as outlined in the schematic shown in Figure 14 . The model is an extension of our previous model proposed for binary ASD systems [ 17 ], and it works on the premise of the presence of a “transient gel layer” at the dissolving interface of the ASD tablets, which is a typical behavior for amorphous polymers [ 47 ]. The transient gel layer here refers to an interface between the dry ASD matrix and the aqueous phase, where the polymer chains are plasticized by solvent ingress.…”

“…The polymer-controlled dissolution advantage of ASDs as well as the resulting amorphous nanoparticles formation is typically only realized up to the limit of congruency (LoC, the highest drug loading up to which the drug and polymer release congruently, i.e., at the same rate), which often corresponds to a low drug loading limit, in particular in the case of polyvinylpyrrolidone/vinyl acetate-based ASDs [ 7 , 8 , 16 , 17 ]. In such cases, either the drug loading must be kept low, or formulation strategies need to be devised to improve the LoC.…”

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

“…The values of m 1 determined separately for aprotic (1)(2)(3)(4)(5)(6)(7)(8)(9) and protic (10-14) solvents, correlation coefficients and difference in the ground and excited state dipole moment (∆µ) obtained on the basis of McRae (MR), Bakhshiev (B), and Lippert and Mataga (LM) models are also summarized in Table 2.…”

“…Despite the great potential of modern pharmaceuticals, their low solubility results in poor oral bioavailability [2,3]. To overcome these limitations, polymeric drug carriers are used in which the poorly soluble active substance is dispersed [4][5][6][7]. As was shown, the polymer can decrease the drug crystallization ability due to polymer-drug interactions (such as hydrogen bonding) by reducing drug mobility and limiting drug-drug molecular interactions [8][9][10].…”