(M1230-12-72) Optimizing the Synthesis and Performance of Amorphous Drug-Polymer Salts through Acid-Base Reactions: an X-ray Photoelectron Spectroscopy Study

Purpose: New drug candidates are increasingly trending toward insolubility, creating a challenging bottleneck in the drug development pipeline. A common approach to combating low solubility of potential APIs is amorphization, but conventional methods of generating amorphous solid dispersions are often expensive or limited in their applicability to certain drug-polymer systems or storage environments. This study investigates a recently reported novel formulation technique and its ability to form strong drug-polymer interactions.

Methods: X-ray photoelectron spectroscopy was used to determine the extent of acid-base reaction in the amorphous drug-polymer salts studied by quantifying changes in binding energy resulting from protonation of drug molecules. These binding energy curves were Gaussian fitted to quantitatively determine the proportion of protonated drug molecules in each formulation studied.

Results: We tested the effect of varied drug loading and polymer molecular weight on the extent of reaction and observed that for all polymer molecular weights studied, an increase in drug loading leads to a corresponding decrease in % protonation. Similarly, for a given drug loading an increase in the molecular weight of the counterion also reduces the extent of reaction. We find 100% protonation of drug in is achieved in salts at 25% drug loading by weight, ranging to a minimum of 40% at the highest drug loading and polymer molecular weight studied.

Conclusion: We find that an increase in the drug loading by weight and in the polymer counterion both contribute to a decrease in the extent of acid-base reaction achievable. Given the known impact of drug-polymer interactions on drug product performance, this critical quality attribute was investigated for its dependence on the common synthetic parameters considered in amorphous drug formulation.

References: X. Yao, S. Kim, Y. Gui, Z. Chen, J. Yu, L. Yu, Journal of Pharmaceutical Sciences, 00 (2021) 1−8

Acknowledgments: We thank the Bill and Melinda Gates Foundation for financial support, and Niya Bowers, Paco Alvarez, and David Monteith for helpful discussions, BMS for supporting this work, and the NSF-supported University of Wisconsin Materials Research Science and Engineering Center (DMR-1720415) for partial support and the use of its characterization facility. We also thank the Zeeh Pharmaceutical Experiment Station and the Analytical Instrumentation Center in School of Pharmacy at University of Wisconsin-Madison for instrument support.