Final form of thesis _Krystel Howard 2011.pdf (11.62 MB)
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Process-analytical technology investigation of the crystallization of pharmaceutical polymorphs, salts and hydrates

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posted on 29.01.2020, 16:13 authored by Krystel S. Howard
Pharmaceutical industries aim for continuous improvement in the manufacturing process of producing medicines. Demands on the pharmaceutical industries are to produce quality products in a quick and cost effective way. Designing a robust crystallization process so as to produce quality crystals with the desired polymorphic form, morphology, size and size distribution, will contribute towards meeting these demands. The Food and Drug Administration regulating body encourages the development of quality by design (QbD) approaches, involving the use of process analytical technology (PAT) for the design of the crystallization process. This method enables the design of the crystallization process to be more flexible in terms of variation in operating conditions and process parameters so long as the quality of the product is maintained. The aim of this thesis work is to use QbD approaches involving the use of PAT tools and solid state analytical (SSA) techniques to increase process knowledge and understanding, which is required for the robust design of crystallization processes. Discovery of all possible polymorphic forms of an active pharmaceutical ingredient (API) is important for the design of a robust crystallization process in which product quality is consistent during scale up and to prevent late stage failures. This thesis work shows the importance of using PAT tools and SSA techniques for monitoring polymorphic transformations and for the discovery of new polymorphic forms that have not yet been reported in the literature. A range of PAT tools including the FBRM, turbidity probe and ATR-UV/Vis spectrometer detected polymorphic transformations during both cooling and antisolvent crystallization experiments using the model system sodium benzoate in water and a propan-2-ol (IPA)/water mixture. Information obtained from a range of SSA techniques provided supporting evidence for the discovery of a new channel hydrate, channel solvate and an anhydrous form of sodium benzoate. The problem of crusting (solid depositing on vessel walls) occurring within crystallization vessels has been investigated with the use of a combination of PAT tools and SSA techniques. The FBRM and turbidity probe detected a change occurring during the cooling crystallization process of para-amino benzoic acid (ABA) in ethyl acetate. Repeats of the experiments using the ATR-UV/Vis confirmed that the change was due to crusting forming on vessel walls and not a polymorphic transformation. PAT tools also detected changes occurring during a pH controlled polymorphic cooling crystallization experiment (Chapter 9), which was subsequently confirmed by SSA methods to be due to the formation of a mixture of products and not a polymorphic transformation. This research work shows the importance of using a combination of PAT tools and SSA techniques for gaining a deeper understanding of the crystallization process and to prevent misinterpretation of results, saving both time and money. Also this research work highlights the need for improvement within industrial scale vessel design, such as vessels with variable jacket height, to prevent the problems of crusting. Robust MSZW measurements are obtained at laboratory scale using the model crystallization systems para and meta-ABA in water. PAT tools used include the FBRM and turbidity probe. The robust MSZW takes into consideration variation in process parameters including ramp rate, vessel size (1 mL and 1 L), agitator speed and type. This robust MSZW can be used for the design of scale up experiments (pilot plant and industrial scale), increasing the likelihood of producing a quality product. Nucleation orders used within crystallization models were determined from the MSZW measurements. Results showed that the nucleation order varied within different crystallization set-ups (vessel size and mixing conditions) using the model system meta-ABA in water. Therefore model-based design and scale-up of crystallization processes must be used carefully and more detailed mechanistic models, which take into consideration the effect of mixing need to be designed to improve the generality and applicability of crystallization models. pH controlled polymorphic crystallization experiments were performed using the model systems meta and para-ABA in ethanol and water. A combination of 5 PAT tools were used in a single vessel to monitor the cooling crystallization process. PAT tools used include FBRM, ATR-UV/Vis, PVM, pH and a temperature probe. Various parameters including mixing conditions, solvent, pH of solution, strength and type of acid were varied to investigate the best conditions to produce salts. Results showed that careful selection of design parameters and salt selection is important for producing quality crystals of the desired morphology so as to prevent problems in downstream processing.



  • Aeronautical, Automotive, Chemical and Materials Engineering


  • Chemical Engineering


Loughborough University

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© Krystel Howard

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A Doctoral Thesis. Submitted in partial fulfillment of the requirements for the award of Doctor of Philosophy of Loughborough University.

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Zoltan Nagy ; Basu Saha

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