(M1530-03-17) Impacts of Polymer Thermal Degradation on In Vitro Performance of Amorphous Solid Dispersions

Purpose: Hot melt extrusion (HME) is a desirable technique for generating ASDs due to its low cost, high throughput, small footprint, and its sustainability with no solvent waste.¹ One of the largest risks of HME is the thermal degradation of drugs and polymers. While drug degradation is a well-documented issue, polymer degradation pathways and changes to physiochemical properties are much less understood.^2,3 This study aimed to investigate how HPMCAS-M degradation from thermal processing impacts performance of drug product intermediates.

Methods: Thermo Fisher's Haake MiniLab 3 was used to process pure hydroxypropyl methylcellulose acetate succinate (HPMCAS) M grade, as well as pre-blended physical mixtures of 50/50 (w/w) ezetimibe/HPMCAS-M and 15/85 phenytoin/HPMCAS-M. Processing conditions were chosen to produce four levels of degradation by varying set temperature, RPM, and residence time. All ASDs appeared amorphous and single-phase by PXRD and DSC. Drug impurities were quantified via HPLC. Polymer degradation was also quantified via HPLC, by measuring free acetic and succinic acid groups cleaved from the polymer during processing. Performance of neat ASD powder was analyzed in a non-sink in vitro dissolution test using a Pion µDisso apparatus in phosphate buffer media (pH 6.50) with 0.5% FaSSIF powder. With the same apparatus and media, a sustainment study was performed via a solvent-shift assay, by pre-dissolving HPMCAS-M with varying levels of degradation, and dosing an organic solution of unprocessed ezetimibe.

Results: The amount of polymer degradation in ezetimibe ASDs, as measured by hydrolyzed acid content, varied by 2-fold across the four samples. Dissolution curves of 50/50 ezetimibe/HPMCAS-M ASDs with most polymer degradation showed a 2-fold increase in T_max vs. the least degraded sample (figure 1). Free acid content did not impact C_max in this system. Studies testing drug sustaining capability of pre-dissolved HPMCAS showed an approximate 30% decrease in sustainment time with the least degraded polymer and an 80% decrease in sustainment time with the most degraded polymer relative to the unprocessed polymer (figure 2). Dissolution curves of 15/85 phenytoin/HPMCAS-M ASDs showed the two less degraded ASDs had approximately 60% faster dissolution rates to reach 25% dose than the two more degraded ASDs (figure 3). C_max and T_max did not trend with polymer degradation.

Conclusion: In vitro dissolution testing showed polymer degradation impacted ASD performance. An increase in HPMCAS degradation resulted in a decreased dissolution rate of ezetimibe and phenytoin ASDs powders in a non-sink dissolution test. Further, an increase in polymer degradation decreased sustainment time of ezetimibe in a solvent-shift test. Higher measured concentrations of free acid indicate less succinoyl and acetyl substitutions compared to unprocessed polymer. Fewer succinoyl groups within HPMCAS reduce its hydrophilicity, in turn decreasing its solubility in aqueous medias. This could explain the slower dissolution rates observed. However, removing acetyl groups has the opposite effect, increasing the polymer's hydrophilicity for a faster dissolution rate but often reducing sustainment time. While further investigation is required to understand the implications and mechanisms of these performance differences, this work demonstrates the importance of determining the impacts of thermal processing on development of robust ASDs

References: (1) Lang, B.; McGinity, J. W.; Williams, R. O. Hot-Melt Extrusion – Basic Principles and Pharmaceutical Applications. Drug Development and Industrial Pharmacy 2014, 40 (9), 1133–1155. https://doi.org/10.3109/03639045.2013.838577.
(2) Auch, C.; Harms, M.; Mäder, K. How Changes in Molecular Weight and PDI of a Polymer in Amorphous Solid Dispersions Impact Dissolution Performance. International Journal of Pharmaceutics 2019, 556, 372–382. https://doi.org/10.1016/j.ijpharm.2018.12.012.
(3) Feng, X.; Vo, A.; Patil, H.; Tiwari, R. V.; Alshetaili, A. S.; Pimparade, M. B.; Repka, M. A. The Effects of Polymer Carrier, Hot Melt Extrusion Process and Downstream Processing Parameters on the Moisture Sorption Properties of Amorphous Solid Dispersions. J Pharm Pharmacol 2016, 68 (5), 692–704. https://doi.org/10.1111/jphp.12488.

Acknowledgments: The authors would like to acknowledge Deanna Mudie and Mike Morgen for their provided expertise and continued support. There are no conflicts of interest to declare.

Figure 1. Dissolution curves of 50/50 ezetimibe/HPMCAS-M (left) and impurities by API and polymer degradation by free acid content (right).



Figure 2. Sustainment study of pre-dissolved HPMCAS-M and dosed ezetimibe (left) and free acid content of processed polymer (right).



Figure 3. Dissolution curves of 15/85 phenytoin/HPMCAS-M (left) and impurities by API and polymer degradation by free acid content (right).