Development of Continuous Additive-Controlled MSMPR Crystallization by DoE-Based Batch Experiments.

Area of Science:

• Chemical Engineering
• Crystallization Science
• Pharmaceutical Technology

Background:

• Additive-controlled crystallization enhances drug particle properties but its continuous adaptation is under-researched.
• Developing continuous crystallization methods is crucial for efficient pharmaceutical manufacturing.
• Famotidine (FMT) crystallization presents challenges in controlling polymorphism and particle properties.

Purpose of the Study:

• To develop a systematic methodology for continuous additive-controlled crystallization of famotidine (FMT).
• To investigate the impact of poly(vinylpyrrolidone) (PVP-K12) on FMT crystallization in a continuous MSMPR cascade.
• To optimize process parameters for enhanced product quality, yield, and productivity in continuous crystallization.

Main Methods:

• A 2^4-1 fractional factorial design was employed in batch mode to identify critical process parameters.
• Batch experiments were conducted to simulate single residence times for the continuous system.
• Continuous cooling crystallization experiments were performed with and without PVP-K12 additive.

Main Results:

• Residence time and polymer amount significantly impacted yield, polymorphism, crystal size, and flowability.
• Continuous crystallization without additive produced a mixture of FMT polymorphs (Form A and B) with 70.8% yield.
• Additive-controlled continuous crystallization yielded pure, homogeneous Form A FMT with excellent flowability and a 4-fold productivity increase.

Conclusions:

• A methodology for systematic development of continuous additive-controlled crystallization was established.
• PVP-K12 additive enables the production of pure, high-quality famotidine Form A in a continuous process.
• Continuous crystallization offers significant advantages in productivity and product consistency for pharmaceutical manufacturing.