NERDG 2026
Poster 27 Abstract
Impact of impurity and API properties on oiling-out behavior
Saurav Adhikari (1), Da Hye Yang (1), Francesco Ricci (2), Fredrik L. Nordstrom (2), Na Li (1, 3, 4)
(1) Department of Pharmaceutical Sciences, University of Connecticut (2) Material & Analytical Sciences, Boehringer-Ingelheim (3) Institute of Material Science, University of Connecticut, (4) Department of Chemical & Biomolecular Engineering, University of Connecticut
Presenting Author: Saurav Adhikari
Corresponding Author: Na Li
Abstract
Spontaneous liquid-liquid phase separation (LLPS), commonly referred to as oiling-out, presents significant challenges in pharmaceutical crystallization processes. While significant amount of impurities are often present in the crystallization stream, there is limited academic research regarding the impact of impurities on oiling out risks, as well as specific mechanisms driving this phenomenon. This study systematically evaluates how impurities influence both stable and metastable oiling out limit (OOL) using two model APIs with low and high melting points, procaine and BI-730357 respectively. A range of impurities pertinent to the drugs' synthetic pathways were included, alongside arbitrarily selected poorly soluble compounds representing impurities that have poor solubility in the antisolvent. Our results indicate that some impurities did not have any impact on OOL while others significantly lowered the OOL. For both stable and metastable oiling out, impurities that exhibit strong interactions with the API significantly lower the OOL in a concentration-dependent manner. These shifts are governed by the interplay between solute-solvent interactions (impurity solubility) and solute-solute interactions (impurity-API). Notably, in the context of metastable oiling-out, the extent of OOL suppression is primarily dominated by impurity’s solubility in the antisolvent. In presence of multiple impurities, the impurity with the strongest effect was found to dominate the overall OOL. Crucially, the presence of poorly soluble impurities can suppress the metastable OOL to levels below the drug's crystalline solubility, thereby making crystallization thermodynamically unfavorable. These findings establish the distinction between problematic and non-problematic impurities to help categorize them based on their oiling out risk potential, offering a framework for designing rational strategies to mitigate oiling-out during crystallization development.
Keywords
Liquid-liquid phase separation, oiling-out, impurities, crystallization
Poster 27 Abstract
Impact of impurity and API properties on oiling-out behavior
Saurav Adhikari (1), Da Hye Yang (1), Francesco Ricci (2), Fredrik L. Nordstrom (2), Na Li (1, 3, 4)
(1) Department of Pharmaceutical Sciences, University of Connecticut (2) Material & Analytical Sciences, Boehringer-Ingelheim (3) Institute of Material Science, University of Connecticut, (4) Department of Chemical & Biomolecular Engineering, University of Connecticut
Presenting Author: Saurav Adhikari
Corresponding Author: Na Li
Abstract
Spontaneous liquid-liquid phase separation (LLPS), commonly referred to as oiling-out, presents significant challenges in pharmaceutical crystallization processes. While significant amount of impurities are often present in the crystallization stream, there is limited academic research regarding the impact of impurities on oiling out risks, as well as specific mechanisms driving this phenomenon. This study systematically evaluates how impurities influence both stable and metastable oiling out limit (OOL) using two model APIs with low and high melting points, procaine and BI-730357 respectively. A range of impurities pertinent to the drugs' synthetic pathways were included, alongside arbitrarily selected poorly soluble compounds representing impurities that have poor solubility in the antisolvent. Our results indicate that some impurities did not have any impact on OOL while others significantly lowered the OOL. For both stable and metastable oiling out, impurities that exhibit strong interactions with the API significantly lower the OOL in a concentration-dependent manner. These shifts are governed by the interplay between solute-solvent interactions (impurity solubility) and solute-solute interactions (impurity-API). Notably, in the context of metastable oiling-out, the extent of OOL suppression is primarily dominated by impurity’s solubility in the antisolvent. In presence of multiple impurities, the impurity with the strongest effect was found to dominate the overall OOL. Crucially, the presence of poorly soluble impurities can suppress the metastable OOL to levels below the drug's crystalline solubility, thereby making crystallization thermodynamically unfavorable. These findings establish the distinction between problematic and non-problematic impurities to help categorize them based on their oiling out risk potential, offering a framework for designing rational strategies to mitigate oiling-out during crystallization development.
Keywords
Liquid-liquid phase separation, oiling-out, impurities, crystallization
