Analytical and Computational Methods for the Estimation of Drug-Polymer Solubility and Miscibility in Solid Dispersions Development

Abstract

The development of stable solid dispersion formulations that maintain desired improvement of drug dissolution rate during the entire shelf life requires the analysis of drug-polymer solubility and miscibility. Only if the drug concentration is below the solubility limit in the polymer, the physical stability of solid dispersions is guaranteed without risk for drug (re)crystallization. If the drug concentration is above the solubility, but below the miscibility limit, the system is stabilized through intimate drug-polymer mixing, with additional kinetic stabilization if stored sufficiently below the mixture glass transition temperature. Therefore, it is of particular importance to assess the drug-polymer solubility and miscibility, to select suitable formulation (a type of polymer and drug loading), manufacturing process, and storage conditions, with the aim to ensure physical stability during the product shelf life. Drug-polymer solubility and miscibility can be assessed using analytical methods, which can detect whether the system is single-phase or not. Thermodynamic modeling enables a mechanistic understanding of drug-polymer solubility and miscibility and identification of formulation compositions with the expected formation of the stable single-phase system. Advance molecular modeling and simulation techniques enable getting insight into interactions between the drug and polymer at the molecular level, which determine whether the single-phase system formation will occur or not.

Spray-Dried Amorphous Solid Dispersions of Atorvastatin Calcium for Improved Supersaturation and Oral Bioavailability

“…Carrier selection plays a significant role in the performance of amorphous SDs, because the molecular dispersion of drug in the carrier must involve significant miscibility, with strong drug–carrier interactions (e.g., hydrogen-bonding) for stability against recrystallization [36,37]. To derive the maximal advantage from an ASD system, the carrier’s miscibility with the drug should be investigated prior to formulation.…”

Structure and Glass Transition Temperature of Amorphous Dispersions of Model Pharmaceuticals with Nucleobases from Molecular Dynamics

“…As such amorphous phases are thermodynamically metastable and tend to crystallize, which diminishes the solubility again, artificial stabilization of amorphous API is often required to benefit from their higher solubility over a relevant time horizon [ 3 ]. Solid mixtures (dispersions) of API and polymers have been subject to extensive research recently [ 4 , 5 ]. Polymers are known to form amorphous solid phases rather than crystals, suggesting that this dispersion strategy should yield a long-term stability of amorphous API.…”

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

“…Therefore, in order to merely study the effect of the GFA class of API in the formation of single-phase homogeneous systems, it is very important to prepare the ASD, wherein drug loading is well above the maximum solubility limit. The maximum solubility of drug in the polymer is mostly observed to be less than 30%, when calculated by different analytical and computational methods [47,48]. For example, Knopp et al recently studied drug–polymer solubility of CLX-PVPVA, IND–PVPVA, and FLD-PVPVA ASDs along with other drug–polymer systems by different methods [47].…”