Enhancing crystalline properties of a cardiovascular active pharmaceutical ingredient using a process analytical...

Area of Science:

• Pharmaceutical Science
• Chemical Engineering
• Crystallization Technology

Background:

• Pharmaceutical regulatory bodies mandate minimal solvent in Active Pharmaceutical Ingredients (APIs).
• Larger, uniformly sized crystals with minimal agglomeration are crucial for efficient downstream processing and reduced solvent inclusion.
• Production of the anti-arrhythmic drug AZD7009 faces challenges with agglomeration and solvent inclusion during crystallization.

Purpose of the Study:

• To address and resolve issues of crystal agglomeration and solvent inclusion during pharmaceutical crystallization.
• To demonstrate the efficacy of the Automated Direct Nucleation Control (ADNC) approach for pharmaceutical crystallization.
• To optimize crystallization conditions for APIs prone to agglomeration and solvent entrapment.

Main Methods:

• Implementation of the model-free Automated Direct Nucleation Control (ADNC) approach.
• Utilizing temperature cycling with adaptive heating and cooling rates to maintain a constant particle count.
• Employing Process Analytical Technologies (PAT) such as Focused Beam Reflectance Measurement (FBRM) and ATR-UV-vis spectroscopy.

Main Results:

• The ADNC approach successfully mitigated crystal agglomeration and reduced solvent inclusion.
• Crystallization using ADNC yielded larger, more uniform crystals compared to linear cooling.
• Residual solvent trapped between crystals was effectively removed by the ADNC method.

Conclusions:

• The ADNC approach offers a robust solution for pharmaceutical crystallization challenges, particularly agglomeration and solvent inclusion.
• PAT tools are vital for designing optimal crystallization processes for pharmaceutical production.
• ADNC facilitates rapid crystallization development for challenging APIs, enhancing product quality and process efficiency.