Molecular-Level Examination of Amorphous Solid Dispersion Dissolution

Abstract

Amorphous solid dispersions (ASDs) are commonly used to orally deliver small-molecule drugs that are poorly water-soluble. ASDs consist of drug molecules in the amorphous form which are dispersed in a hydrophilic polymer matrix. Producing a high-performance ASD is critical for effective drug delivery and depends on many factors such as solubility of the drug in the matrix and the rate of drug release in aqueous medium (dissolution), which is linked to bioperformance. Often, researchers perform a large number of design iterations to achieve this objective. A detailed molecular-level understanding of the mechanisms behind ASD dissolution behavior would aid in the screening, designing, and optimization of ASD formulations and would minimize the need for testing a wide variety of prototype formulations. Molecular dynamics and related types of simulations, which model the collective behavior of molecules in condensed phase systems, can provide unique insights into these mechanisms. To study the effectiveness of these simulation techniques in ASD formulation dissolution, we carried out dissipative particle dynamics simulations, which are particularly an efficient form of molecular dynamics calculations. We studied two stages of the dissolution process: the early-stage of the dissolution process, which focuses on the dissolution at the ASD/water interface, and the late-stage of the dissolution process, where significant drug release would have occurred and there would be a mixture of drug and polymer molecules in a predominantly aqueous environment. Experimentally, we used Fourier transform infrared spectroscopy to study the interactions between drugs, polymers, and water in the dry and wet states and the chromatographic technique to study the rate of drug and polymer release. Both experiments and simulations provided evidence of polymer microstructures and drug−polymer interactions as important factors for the dissolution behavior of the investigated ASDs, consistent with previous work by Pudlas et al. (Eur. J. Pharm. Sci. 2015, 67, 21−31). As experimental and simulation results are consistent and complementary, it is clear that there is significant potential for combined experimental and computational research for a detailed understanding of ASD formulations and, hence, formulation optimization.

Benchmarking the Solubility Enhancement and Storage Stability of Amorphous Drug–Polyelectrolyte Nanoplex against Co-Amorphous Formulation of the Same Drug

“…Nevertheless, to elucidate the exact mechanisms of how the different drug–excipient interactions and excipients’ physicochemical properties between the nanoplex and CAM systems affected their CIP dissolution profiles, a fundamental study at the molecular level would need to be carried out. This fundamental study, which was beyond the scope of the present work, was similar to how the exact interaction mechanisms between polymer stabilizers (e.g., HPMC, PVP) and drugs in ASD during dissolution are presently being actively investigated by both experimental and molecular dynamic simulation approaches [ 42 , 43 , 44 ].…”

Advances in the development of amorphous solid dispersions: The role of polymeric carriers

“…The ideal dissolution profile is that the drug and the polymer are released with the same normalized rate [201] . The polymer-drug interactions may affect their congruent release from the ASD [184 , [201] , [202] , [203] , [204] . The maximal drug loading at which congruent release occurs is defined as the LoC [201 , 204 , 205] .…”

Predicting Surface pH in Unbuffered Conditions for Acids, Bases, and Their Salts – A Review of Modeling Approaches and Their Performance

“…The previous section underlined the importance of phenomena at the solid/ liquid interface, which determine the actual surface pH and surface solubility and thus the driving force for dissolution. Because of the fundamental role played by molecular interactions, computational techniques like molecular dynamics (MD) simulations are increasingly being used in formulation development, 23 studies at the molecular level in different environments, 24 and in the context of this article, we discuss two recent publications which focus on surface pH and transport phenomena. Herzberg et al 25 adopted a combined experimental and computational approach to understand pH effects at solid− liquid interface for ibuprofen and carvedilol, chosen as reference acidic and basic compounds, respectively.…”