Purdue University Graduate School
FinalThesis_Final_2.pdf (6.88 MB)

Modernizing Drug Substance Manufacturing: Continuous Crystallization in Traditional And Innovative Platforms

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posted on 2019-10-16, 18:52 authored by Yiqing LiuYiqing Liu

Crystallization, the final isolation and purification step in many drug substance manufacturing processes, has substantial impact on downstream efficiency and possibly final drug product qualities. Currently, crystallization is largely carried out in batch which may suffers from batch-to-batch variations. Continuous crystallization is the missing key to end-to-end continuous manufacturing of oral solid dosage form pharmaceuticals. It is estimated that shifting from batch to continuous operations may help the pharmaceutical industry (1) reduce plant footprint, (2) decrease energy consumption and (3) spawn faster response to drug shortages. The overall aim of this thesis is to study and design continuous crystallization processes in both a traditional stirred tank crystallizer (STC) and a novel oscillatory baffle reactor (OBR). In the STC, the thesis aims to establish a systematic framework to model crystallization via a risk-based approach. This methodology considers the highly regulated nature of the pharmaceutical industry where an impactful model must be verified and validated carefully. The OBR on the other hand is a novel commercial platform in which continuous operations have never been established. Its performance was compared to the STC in terms of residence time distribution where OBR showed more uniform and consistent operation. A start-up study was then carried out to study different start-up strategies to examine their effects on process dynamics and steady state products. The last piece is to study the integration of continuous crystallization with continuous filtration which is not well studied in the current literature. A novel commercial continuous filtration unit, the continuous filtration carousel (CFC) was studied to construct a truly continuous drug substance separation step. The operating conditions were optimized based on filter capacity and filter efficiency studies with particles of different shapes. Continuous coupling of crystallization and CFC was successfully carried out based on the optimized conditions and a risk consideration discussion was given for process safety assessments.


Degree Type

  • Doctor of Philosophy


  • Chemical Engineering

Campus location

  • West Lafayette

Advisor/Supervisor/Committee Chair

Dr. Zoltan K. Nagy

Additional Committee Member 2

Dr. Gintaras V. Reklaitis

Additional Committee Member 3

Dr. Michael T. Harris

Additional Committee Member 4

Dr. Teresa M. Carvajal