Effect of API-Polymer Miscibility and Interaction on the Stabilization of Amorphous Solid Dispersion: A Molecular Simulation Study

Abstract

In this study, a molecular dynamics simulation technique was employed to predict miscibility and interaction of Active Pharmaceutical Ingredient (API) with polymer carriers in solid dispersion system based on Hansen solubility parameter and hydrogen bond formation, respectively. Several APIs with and without hydrogen bonding tendency were studied. The Hansen solubility parameters of APIs and polymers calculated by molecular dynamic simulation were similar to reported values in the literature. Our simulation results were able to determine the interactions between APIs and various polymers (ionic and nonionic) and also predict the hydrogen bond interaction energy and hydrogen bond lifetime. The simulation results were verified by preparing solid dispersions using hot melt extrusion. As predicted by our simulation, clear and colorless extrudates were obtained for ibuprofen/PVP-VA 64, ibuprofen/Eudragit EPO, and fenofibrate/PVP-VA 64, which confirmed the miscibility between APIs (ibuprofen, fenofibrate) and polymers. Stability studies confirmed the amorphous stabilization of ibuprofen/PVP-VA64 and ibuprofen/Eudragit EPO solid dispersions. However, recrystallization of fenofibrate was observed from fenofibrate/PVP-VA 64 due to the lack of molecular interactions between fenofibrate and PVP-VA 64 as predicted in our simulation. This suggests that miscibility alone cannot be used to predict the stability of amorphous dispersion but molecular interactions have to be considered. The simulation method used in this study could be a useful tool for the selection of polymer excipients to form stable amorphous solid dispersions with enhanced performance.

Personalised 3D Printed Medicines: Optimising Material Properties for Successful Passive Diffusion Loading of Filaments for Fused Deposition Modelling of Solid Dosage Forms

“…In order to investigate the diffusion kinetics of NDF from the solvent into the different filaments, the degree of miscibility between the drug and the solvent molecules and also between the solvent molecule and the filament were calculated. Several approaches, such as the Hansen Solubility theory, have been used in the past to estimate the degree of miscibility of different materials, for example, during co-crystal formation or amorphous solid dispersion development [21,22]. Typically, it is assumed that materials with similar cohesive energy density will be miscible with one another, and the total cohesive energy can be divided into the individual, so-called, Hansen Solubility Parameters (HSP): dispersion forces (δd), polar forces (δp) and hydrogen bonding forces (δh).…”

Myth or Truth: The Glass Forming Ability Class III Drugs Will Always Form Single-Phase Homogenous Amorphous Solid Dispersion Formulations

“…The above observations can also be explained in terms of potential API and polymer interaction in ASD. The presence of hydrogen bonding between API and polymer has a positive impact on the physical stability of the ASDs, as reported in a recent molecular simulation study on ibuprofen/PVPVA 64, ibuprofen/Eudragit, and fenofibrate/PVPVA 64 system [29]. In another study, it was observed that drug–polymer combinations capable of forming hydrogen bonding in the solution state leads to the formation of highly miscible amorphous solid dispersion and were more effective in preventing drug crystallization compared to the drug–polymer systems without such interactions [19].…”

Mimicking the Dissolution Mechanisms of pH‐Responsive Drug Release Formulations in Atomistic MD Simulations

“…Simulations in the eroding matrix case are performed in the NVT ensemble for varying number (4,8,12,16,20) of PAA20 molecules and 50 DOX molecules, using the same protocol as the first set of the swellable matrix case (prior to water removal) [10] with equilibration for 80 ns and production for 30 ns. Simulations for the non-swellable matrix case are performed similarly for varying number (10,20,30,40,50) of DOX molecules and 16 PAA20 molecules, with equilibration for 50 ns and production for 30 ns.…”

“…Thus, though they succeed in explaining the experimental results or an approximate extrapolation of findings to longer times, they have limited applicability for other chemistries. An upcoming approach is the use of atomistic simulations, which though limited in the capability to simulate realistic length and timescales, are able to predict behavior of systems prior‐to‐synthesis. Apart from the possibility of deriving model parameters for pharmacokinetic studies, their strength lies in their ability to decipher the molecular details of excipient–drug interactions and how they change during the lifecycle of excipient–drug formulation inside the human body.…”

“…See text for model parameters. Hydrogen bond counts are normalized by number of PAA20 molecules(16). The values in brackets indicate the standard deviation of the last digit in decimals.…”