(302d) Complex Oiling-out Behavior with Stable and Metastable Liquid Phases: Implications for Pharmaceutical Development

Oiling out, or liquid-liquid phase separation (LLPS), is commonly observed during the crystallization development of pharmaceuticals. Oiling out is often undesired due to its detrimental impact on crystal morphology control and impurity ejection, excessively long process time, and difficulties in scaling up. Various strategies, such as supersaturation control, solvents switch, and seeding, are utilized to avoid oiling out during crystallization. However, the selection of strategies to avoid oiling out are often based on trial-and-error, and a comprehensive understanding on this phenomenon remains lacking. Therefore, in this study, we systematically assessed the oiling out behavior of a model drug procaine. It has a relatively low melting point (62°C)¹. Its simple polymorph landscape also enables crystalline solubility determination in different solvents. Ethanol and heptane were chosen as a solvent and antisolvent for procaine, respectively. The phase behavior of procaine in ethanol/heptane solvents was characterized as a function of solvent composition and temperatures.

The crystalline solubility of procaine was determined gravimetrically using the shake flask method, and oiling out limits were measured by antisolvent titration. Slurry experiments were also performed to identify different phase regions. For the procaine-heptane binary system, heating and cooling experiments were performed to identify oiling out limits. For systems showing multiple liquid phases, the composition of each phase was analyzed using gas chromatography-mass spectrometry (GC/MS) to construct phase boundaries and tie lines. Combining all data, binary and ternary diagrams of procaine were created at various temperatures.

In the procaine-heptane binary system, two types of LLPS, stable LLPS above the melting point of procaine in the procaine-rich phase, and metastable LLPS, were observed. Stable LLPS occurred upon heating, and is characterized by the formation of large oil droplets that coalesce with time to form a drug-rich layer immiscible with the solvent-rich phase on top (Figure 1A). Metastable LLPS was observed upon cooling, with the formation of a cloudy solution with small drug-rich droplets. Crystallization is not expected to occur in the stable LLPS region. In the metastable LLPS region, the drug is supersaturated and could crystallize from either liquid phase.

In a ternary system, the phase behavior became more complicated (Figure 1B). At temperatures below 55°C, solid-liquid equilibrium was observed in solvent mixtures containing 60% or more ethanol (v/v), whereas solid-liquid-liquid (SLL) equilibrium and LLPS occurred in solvents containing 40% or less ethanol. Five different regions, a homogeneous liquid phase region (L), three 2-phase regions (two solid-liquid SL and one liquid-liquid LL), and a 3-phase region (SLL), were observed. At 55°C, the two phases containing procaine solids disappeared, leaving only two regions: a homogeneous liquid phase and a liquid-liquid phase region. As temperature increased, regions containing procaine solids (SL and SLL) shrunk, whereas the liquid-liquid region expanded. The oiling out limits of procaine was dependent on both solvent composition and temperature, and stable LLPS was observed at all temperatures.

This study revealed the complexity of oiling out behavior, where stable LLPS may occur under normal crystallization temperatures in the presence of solvents. Such a comprehensive analysis will help improving the crystallization development process of different pharmaceuticals. Moreover, knowledge gained from this study will shed light on the development of amorphous formulations, where the formation of stable amorphous phases is highly desired.

References

(1) Alzghoul, A.; Alhalaweh, A.; Mahlin, D.; Bergstrom, C. A. Experimental and computational prediction of glass transition temperature of drugs. J Chem Inf Model 2014, 54 (12), 3396-3403. DOI: 10.1021/ci5004834 From NLM Medline.