Enhancing Crystallization Control with In-Line PAT for Scalable Manufacturing

Crystallization is a critical unit operation in the pharmaceutical industry, essential for the purification and isolation of active pharmaceutical ingredients (APIs). However, the process is often complicated by phenomena such as “oiling out”, also known as liquid–liquid phase separation (LLPS). Oiling out occurs when the solution’s supersaturation—the driving force for crystallization—is not properly controlled, resulting in the formation of a secondary, solute-rich liquid phase rather than direct nucleation of a solid crystalline phase. This secondary phase can entrap impurities, hinder crystal growth, and disrupt downstream operations like filtration and drying, ultimately impacting product purity, yield, and process scalability.

At Aragen, the Particle Science & Engineering team encountered significant oiling out during the scale-up of an evaporative crystallization process. The process involved distillation of aqueous solution containing target compound, followed by co-distillation with isopropanol (IPA) to reduce water content and induce crystallization. However, rapid removal of water during co-distillation led to uncontrolled desupersaturation, triggering oiling out. This manifested as the appearance of a cloudy, heterogeneous suspension—a metastable emulsion of solute-rich droplets—rather than the desired crystalline solid. The oiling out phase caused:

• Formation of lumpy, sticky material
• Agglomeration and scaling on reactor walls
• Impurity entrapment within the oily phase
• Filtration and isolation challenges, compromising product quality and process efficiency

To address the problem, the team employed Process Analytical Technology (PAT), specifically the Blaze Metrics probe, which enabled real-time, in-situ monitoring of the crystallization process via high dynamic range (HDR) imaging. This allowed for early detection and characterization of oiling out events, distinguishing between true solid–liquid suspensions and metastable liquid–liquid emulsions (Figure 1).

Key process modifications included:

• Controlled Evaporation Rate: The rate of water removal during co-distillation was reduced, maintaining a higher water content for
  longer to moderate the rise in supersaturation.
• Solvent Composition Management: The volume of IPA was adjusted to fine-tune the solubility profile and prevent the system from
  entering the metastable oiling out region of the phase diagram.
• Seeding Strategy: Once a clear solution was achieved, seeding with pre-formed crystals was performed to induce nucleation at
  controlled supersaturation levels, promoting uniform crystal growth and minimizing spontaneous, uncontrolled precipitation (Figure 2).
• Intermittent Solvent Addition: IPA was added incrementally with intermittent holds, allowing for gradual supersaturation and steady
  crystal growth, rather than abrupt phase transitions.

These interventions resulted in:

• Elimination of Oiling Out: Real-time imaging confirmed the absence of secondary liquid phases after process optimization.
• Improved Crystal Quality: The controlled process yielded crystals with uniform size distribution and reduced agglomeration (Figure 3).
• Enhanced Purity and Yield: By minimizing impurity entrapment in the oily phase, the final product met stringent pharmaceutical
  quality standards.
• Scalable Process: The optimized crystallization protocol was successfully implemented at manufacturing scale, demonstrating robust
  control over supersaturation and phase behavior.

This case study highlights the importance of thermodynamic and kinetic control in industrial crystallization, the utility of PAT tools for real-time process monitoring, and the value of tailored solvent and seeding strategies to prevent oiling out—a phenomenon increasingly recognized as a key challenge in pharmaceutical manufacturing.

At Aragen, we leverage particle science and advanced technologies to optimize your drug substance for stability, performance, and manufacturability—delivering tailored solutions from early research to commercial scale-up. We offer:

• Customized Particle Engineering: Optimize particle size, solubility, and polymorph stability to enhance drug performance.
• End-to-End Support: Guidance across all development stages, focusing on critical material attributes.
• Cutting-Edge Technologies: Real-time process monitoring and analytical tools for precise control.
• Regulatory Alignment: Compliance with global standards to streamline approvals and manufacturing.

Whether your goal is to optimize crystallization performance, solve complex scale-up issues, or reduce risk in manufacturing, Aragen brings the tools and expertise to get you there—faster and more reliably.