Continuous crystallization of pharmaceutical compounds in mixed suspension mixed product removal systems
- 1Higher Vocational and Technical College, Wenshan University , , ,
Abstract
Background: Continuous pharmaceutical crystallization requires simultaneous control of supersaturation, particle attributes, polymorphic form, fouling, and downstream processability. Accordingly, single-stage and two-stage mixed-suspension mixed-product-removal (MSMPR) crystallization systems were developed and compared for the controlled production of the target crystalline polymorphs: paracetamol Form I and carbamazepine Form III.
Methods: Equilibrium solubility and metastable-zone limits were determined before continuous operation. Four critical process parameters, residence time, relative supersaturation, continuous seed loading, and power input per unit volume, were evaluated using independent four-factor Box–Behnken designs. Response-surface optimization, stagewise population-balance modeling, multimodal process analytical technology, and matched configuration comparisons were performed at equal total active volume and overall residence time.
Results: For both APIs, longer residence time increased median particle size toward the prespecified product-size ranges, narrowed particle-size distributions, and improved target-polymorph content, but reduced space-time yield. Higher supersaturation increased recovery and productivity for both APIs while broadening distributions and reducing polymorphic selectivity. Externally validated population-balance models achieved R2 values of 0.894–0.943 and normalized RMSE values of 1.8%–8.8%. Relative to single-stage operation, two-stage MSMPR increased D50 by 15.8% for paracetamol and 13.6% for carbamazepine, reduced PSD span by 14.6% and 16.9%, and decreased fouling by 42.4% and 45.8%, respectively. The larger, narrower particles were beneficial because filtration time declined by 26.3% for paracetamol and 34.4% for carbamazepine, while chemical purity and mass-balance closure were preserved.
Conclusion: At matched active volume and overall residence time, staged supersaturation generation suppressed fines, improved particle uniformity and morphology, and reduced fouling and filtration time without compromising chemical or solid-state quality. These results identify controlled supersaturation distribution, not additional crystallizer capacity, as the principal benefit of two-stage MSMPR operation for the two APIs studied.
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BibTeX
@article{tan2026continuous,
title = {{Continuous crystallization of pharmaceutical compounds in mixed suspension mixed product removal systems}},
author = {Funeng Tan},
journal = {Frontiers in chemistry},
year = {2026},
month = oct,
doi = {10.3389/fchem.2026.1947756},
url = {https://europepmc.org/article/PMC/PMC13721075},
note = {CC BY},
}
RIS
TY - JOUR
TI - Continuous crystallization of pharmaceutical compounds in mixed suspension mixed product removal systems
AU - Funeng Tan
PY - 2026
DA - 2026/10/16
JO - Frontiers in chemistry
DO - 10.3389/fchem.2026.1947756
UR - https://europepmc.org/article/PMC/PMC13721075
AB - Background: Continuous pharmaceutical crystallization requires simultaneous control of supersaturation, particle attributes, polymorphic form, fouling, and downstream processability. Accordingly, single-stage and two-stage mixed-suspension mixed-product-removal (MSMPR) crystallization systems were developed and compared for the controlled production of the target crystalline polymorphs: paracetamol Form I and carbamazepine Form III. Methods: Equilibrium solubility and metastable-zone limits were determined before continuous operation. Four critical process parameters, residence time, relative supersaturation, continuous seed loading, and power input per unit volume, were evaluated using independent four-factor Box–Behnken designs. Response-surface optimization, stagewise population-balance modeling, multimodal process analytical technology, and matched configuration comparisons were performed at equal total active volume and overall residence time. Results: For both APIs, longer residence time increased median particle size toward the prespecified product-size ranges, narrowed particle-size distributions, and improved target-polymorph content, but reduced space-time yield. Higher supersaturation increased recovery and productivity for both APIs while broadening distributions and reducing polymorphic selectivity. Externally validated population-balance models achieved R2 values of 0.894–0.943 and normalized RMSE values of 1.8%–8.8%. Relative to single-stage operation, two-stage MSMPR increased D50 by 15.8% for paracetamol and 13.6% for carbamazepine, reduced PSD span by 14.6% and 16.9%, and decreased fouling by 42.4% and 45.8%, respectively. The larger, narrower particles were beneficial because filtration time declined by 26.3% for paracetamol and 34.4% for carbamazepine, while chemical purity and mass-balance closure were preserved. Conclusion: At matched active volume and overall residence time, staged supersaturation generation suppressed fines, improved particle uniformity and morphology, and reduced fouling and filtration time without compromising chemical or solid-state quality. These results identify controlled supersaturation distribution, not additional crystallizer capacity, as the principal benefit of two-stage MSMPR operation for the two APIs studied.
SN - 2296-2646
ER -