Thermodynamic Modeling of the Amorphous Solid Dispersion-Water Interfacial Layer and Its Impact on the Release Mechanism.

During the dissolution of amorphous solid dispersion (ASD) formulations, the gel layer that forms at the ASD/water interface strongly dictates the release of the active pharmaceutical ingredient (API) and, hence, the dissolution performance. Several studies have demonstrated that the switch of the gel layer from eroding to non-eroding behavior is API-specific and drug-load (DL)-dependent. This study systematically classifies the ASD release mechanisms and relates them to the phenomenon of the loss of release (LoR). The latter is thermodynamically explained and predicted via a modeled ternary phase diagram of API, polymer, and water, and is then used to describe the ASD/water interfacial layers (below and above the glass transition). To this end, the ternary phase behavior of the APIs, naproxen, and venetoclax with the polymer poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA64) and water was modeled using the perturbed-chain statistical associating fluid theory (PC-SAFT). The glass transition was modeled using the Gordon-Taylor equation. The DL-dependent LoR was found to be caused by API crystallization or liquid-liquid phase separation (LLPS) at the ASD/water interface. If crystallization occurs, it was found that API and polymer release was impeded above a threshold DL at which the APIs crystallized directly at the ASD interface. If LLPS occurs, an API-rich phase and a polymer-rich phase are formed. Above a threshold DL, the less mobile and hydrophobic API-rich phase accumulates at the interface which prevents API release. LLPS is further influenced by the composition and glass transition temperature of the evolving phases and was investigated at 37 °C and 50 °C regarding impact of temperature of. The modeling results and LoR predictions were experimentally validated by means of dissolution experiments, microscopy, Raman spectroscopy, and size exclusion chromatography. The experimental results were found to be in very good agreement with the predicted release mechanisms deduced from the phase diagrams. Thus, this thermodynamic modeling approach represents a powerful mechanistic tool that can be applied to classify and quantitatively predict the DL-dependent LoR release mechanism of PVPVA64-based ASDs in water.

Explaining the Release Mechanism of Ritonavir/PVPVA Amorphous Solid Dispersions.

In amorphous solid dispersions (ASDs), an active pharmaceutical ingredient (API) is dissolved on a molecular level in a polymeric matrix. The API is expected to be released from the ASD upon dissolution in aqueous media. However, a series of earlier works observed a drastic collapse of the API release for ASDs with high drug loads (DLs) compared to those with low DLs. This work provides a thermodynamic analysis of the release mechanism of ASDs composed of ritonavir (RIT) and poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA). The observed release behavior is, for the first time, explained based on the quantitative thermodynamic phase diagram predicted by PC-SAFT. Both liquid-liquid phase separation in the dissolution medium, as well as amorphous phase separation in the ASD, could be linked back to the same thermodynamic origin, whereas they had been understood as different phenomena so far in the literature. Furthermore, it is illustrated that upon release, independent of DL, both phenomena occur simultaneously for the investigated system. It could be shown that the non-congruent release of the drug and polymer is observed when amorphous phase separation within the ASD has taken place to some degree prior to dissolution. Nanodroplet formation in the dissolution medium could be explained as the liquid-liquid phase separation, as predicted by PC-SAFT.

A Hot-Melt Extrusion Risk Assessment Classification System for Amorphous Solid Dispersion Formulation Development.

Several literature publications have described the potential application of active pharmaceutical ingredient (API)-polymer phase diagrams to identify appropriate temperature ranges for processing amorphous solid dispersion (ASD) formulations via the hot-melt extrusion (HME) technique. However, systematic investigations and reliable applications of the phase diagram as a risk assessment tool for HME are non-existent. Accordingly, within AbbVie, an HME risk classification system (HCS) based on API-polymer phase diagrams has been developed as a material-sparing tool for the early risk assessment of especially high melting temperature APIs, which are typically considered unsuitable for HME. The essence of the HCS is to provide an API risk categorization framework for the development of ASDs via the HME process. The proposed classification system is based on the recognition that the manufacture of crystal-free ASD using the HME process fundamentally depends on the ability of the melt temperature to reach the API's thermodynamic solubility temperature or above. Furthermore, we explored the API-polymer phase diagram as a simple tool for process design space selection pertaining to API or polymer thermal degradation regions and glass transition temperature-related dissolution kinetics limitations. Application of the HCS was demonstrated via HME experiments with two high melting temperature APIs, sulfamerazine and telmisartan, with the polymers Copovidone and Soluplus. Analysis of the resulting ASDs in terms of the residual crystallinity and degradation showed excellent agreement with the preassigned HCS class. Within AbbVie, the HCS concept has been successfully applied to more than 60 different APIs over the last 8 years as a robust validated risk assessment and quality-by-design (QbD) tool for the development of HME ASDs.

Predicting process design spaces for spray drying amorphous solid dispersions.

Amorphous solid dispersions (ASDs) are commonly manufactured using spray-drying processes. The product quality can be decisively influenced by the choice of process parameters. Following the quality-by-design approach, the identification of the spray-drying process design space is thus an integral task in drug product development. Aiming a solvent-free and homogeneous ASD, API crystallization and amorphous phase separation needs to be avoided during drying. This publication provides a predictive approach for determining spray-drying process conditions via considering thermodynamic driving forces for solvent drying as well as ASD-specific API/polymer/solvent interactions and glass transitions. The ternary API/polymer/solvent phase behavior was calculated using the Perturbed-Chain Statistical Associating Theory (PC-SAFT) and combined with mass and energy balances to find appropriate spray-drying conditions. A process design space was identified for the ASDs of ritonavir and naproxen with either poly(vinylpyrrolidone) or poly(vinylpyrrolidone-co-vinylacetate) spray dried from the solvents acetone, dichloromethane, or ethanol.

Solvent influence on the phase behavior and glass transition of Amorphous Solid Dispersions.

Understanding the long-term stability of amorphous solid dispersions (ASDs) is important for their successful approval for market. ASD stability does not only depend on the interplay between the active pharmaceutical ingredient (API) and the polymer in the final formulation but may already be disadvantageously influenced by process steps during the production (e.g. selection of inappropriate solvent for spray drying). Residual solvent can affect the API solubility in the polymer, molecular mobility (by influencing the glass-transition temperature) and induce liquid-liquid phase separation. Enhanced mobility in the ASD due to residual solvent can promote recrystallization in ASDs. The removal of residual solvent can be expensive, time-consuming, and usually requires secondary drying procedures to fulfil the regulatory requirements. The aim of this work is to predict the API solubility in polymer-solvent mixtures, solvent influence on the glass transition, and the occurrence of liquid-liquid phase separation of solvent-loaded ASDs using the thermodynamic model PC-SAFT and to experimentally validate these predictions. ASDs containing the APIs ritonavir or naproxen and the polymers poly(vinylpyrrolidone), poly (vinylpyrrolidone-co-vinyl acetate), or hydroxypropyl methylcellulose acetate succinate were spray-dried using the solvents acetone, ethanol, and dichloromethane. API solubility, sorption behavior, liquid-liquid phase separation and glass transition in the ternary API/polymer/solvent mixtures were predicted based on the binary phase behavior between API/solvent, API/polymer, and polymer/solvent and successfully validated experimentally using dynamic vapor sorption (DVS), and Raman spectroscopy. Thus, the presented methodology allows for an in-silico selection of appropriate solvent systems for solvent-based ASD preparation based on a limited amount of experimental data for binary systems only.

Thermodynamic Modeling of Solvent-Impact on Phase Separation in Amorphous Solid Dispersions during Drying.

Understanding and prevention of unwanted changes of a pharmaceutical formulation during the production process is part of the critical requirements for the successful approval of a new drug product. Polymer-based formulations, so-called amorphous solid dispersions (ASDs), are often produced via solvent-based processes. In such processes, active pharmaceutical ingredients (APIs) and polymers are first dissolved in a solvent or solvent mixture, then the solvent is evaporated, for example, via spray drying or rotary evaporation. During the drying step, unwanted liquid-liquid phase separation may occur, leading to polymer-rich and API-rich regions with crystallization potential, and thus, heterogeneities and a two-phasic system in the final ASD. Phase separation in ASDs may impact their bioperformance because of the locally higher degree of API supersaturation. Although it is known that the choice of the solvent plays an important role in the formation of heterogeneities, solvent-impact on ASD drying and eventual product quality is often neglected in the process design. This study aims to investigate for the first time the phase behavior and drying process of API/polymer/solvents systems from a thermodynamic perspective. Unwanted phase changes during the drying process of the ASD containing hydroxypropyl methylcellulose acetate succinate and naproxen prepared from acetone/water or ethanol/water solvent mixtures were predicted using the thermodynamic model PC-SAFT. The predicted phase behavior and drying curves were successfully validated by confocal Raman spectroscopy.

Phase behavior of pharmaceutically relevant polymer/solvent mixtures.

In the pharmaceutical industry, polymers are used as excipients for formulating poorly water-soluble active pharmaceutical ingredients (APIs) in so-called "amorphous solid dispersions" (ASDs). ASDs can be produced via solvent-based processes, where API and polymer are both dissolved in a solvent, followed by a solvent evaporation step (e.g. spray drying). Aiming at a homogeneous API/polymer formulation, phase separation of the components (API, polymer, solvent) during solvent evaporation must be avoided. The latter is often determined by the phase behavior of polymer/solvent mixtures used for ASD processing. Therefore, this work investigates the polymer-solvent interactions in these mixtures. Suitable polymer/solvent combinations investigated in this work comprise the pharmaceutically relevant polymers poly(vinylpyrrolidone) (PVP), poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA64), and hydroxyppropyl methylcellulose acetate succinate 126G (HPMCAS) as well as the solvents acetone, dichloromethane (DCM), ethanol, ethyl acetate, methanol, and water. Based on vapor-sorption experiments demixing of solvents and polymers were predicted using the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT). These were found to be correct for all investigated solvent/polymer mixtures. Acetone, DCM, ethanol, methanol, and water were found to be completely miscible with PVPVA64. DCM, ethanol, methanol, and water were found to be completely miscible with PVP K90, while none of the investigated solvents was appropriate for avoiding immiscibility with HPMCAS. In addition, the impact of temperature, polymer molecular weight, and solvent-mixture composition on miscibility was successfully predicted using PC-SAFT. Thus, the proposed methodology allows identifying suitable solvents or solvent mixtures relevant for solvent-based preparations of pharmaceutical ASD formulations with low experimental effort.