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Addressing poor solubility and oiling-out tendencies of drug substances

By Dr. Lotfi Derdour, Ph.D.
Associate director, GlaxoSmithKline

In recent years, there has been a increase in challenges related to low solubility1 and propensity for oiling-out2 in active pharmaceutical ingredient development. From a manufacturing perspective, low solubility creates challenges to achieve clarifying filtration in the final particle forming step, an operation required to ensure removal of all foreign particulates prior to API particle isolation. On the other hand oiling-out or Liquid-Liquid Phase Separation (LLPS) are highly undesirable because they negatively impact the impurity purge, yield, and scalability. Low solubility and oiling-out challenges were found to correlate well with a steady increase in molecular weight, molecular rigidity and lipophilicity of developmental drugs1, 2. Molecular rigidity results in low ability of the molecular to adopt various conformations/geometries. This restriction, along with increased molecular weight results in a decrease of the probability of the molecule to be in a conformation favorable for self-assembly, which leads to a decrease of propensity for crystallization. On the other hand, the increase in molecular weight and lipophilicity results in kinetically favorable lipophilic inter-molecular interactions, which are weak in nature. These interactions typically result in the formation of liquid-like clusters of API, leading to LLPS. On the other hand, once attained, crystals of relatively rigid molecules may display poor solubility, which can be partly attributed to molecular rigidity. In solution, solvation may require the molecules to be in a different conformation than the one present in the crystalline network. High energy barriers of transition between conformers, typically involved in rigid molecules may prevent transition of the crystalline conformation to the solution conformation, leading to low solubility. In addition, crystals of relatively large molecules often exhibit a increased number of inter-molecular bonds per unit mole compared to smaller molecules, which may result in stronger crystalline phase leading to low solubility.
In this presentation, approaches to identify paths to first crystals of molecules prone to oiling-out are presented. These approaches are based on determining the LLPS boundaries or identifying a path that involves an intermediate state to avoid LLPS. In addition, the combined effects of impurities and molecular rigidity on the occurrence of oiling-out and preventing or stopping crystallization is described and simple methods to restart crystallization is presented3. Moreover, approaches to achieve full dissolution and clarifying filtration of poorly soluble ionizable drugs are presented. These approaches involve the formation of a soluble intermediate and recovery of the desired molecule post clarifying filtration. Finally, an approach to achieve clarifying filtration, which takes advantage of LLPS is presented.

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