Process Intensification through Spherical Crystallization: Novel Experimental and Modeling Approaches

Process intensification is defined as the use of innovative techniques and technologies to create sustainable solutions to industrial production difficulties. Continuous spherical crystallization is a process intensification technique that could resolve production issues for pharmaceutical and solids processing industries, consequently, allowing for the integration of upstream and downstream manufacturing units. Spherical crystallization is carried out through emulsion based crystallization and/or agglomeration in suspension of fine crystals to produce aggregates of improved bulk and micromeritic properties. The advantages of spherical crystallization include: (i) replacing downstream particle correction units (i.e., milling, granulation), (ii) providing control of crystalline properties by decoupling crystallization and agglomeration mechanisms, and (iii) reducing plant foot print and allowing for reconfigurable units. The overall aim of the thesis is to further develop the scientific understanding of spherical crystallization mechanisms and introduce a systematic approach for implementing continuous spherical crystallization as a smart manufacturing platform enabled by a quality-by-design framework. Experimentally, the thesis achieves: (i) better mechanistic understanding of spherical crystallization in semi-batch systems using process analytical technologies (PAT); and (ii) the assessment of the feasibility of continuous spherical crystallization in mixed suspension mixed product removal (MSMPR) and oscillatory flow baffled crystallizer (OFBC) systems. Computationally, a coupled population balance model is developed that leads to an optimization framework for bioavailability and manufacturability through spherical crystallization. Together the experimental and modeling approaches deliver a model-based framework for process intensification that can lead to adaptive manufacturing systems for high value-added particulate products

Combined wet milling crystallisation methods for particle engineering

Recent advances in pharmaceutical manufacturing for consistent supply of medicines with the required physical properties has emphasised the need for robust crystallisation processes which is a critical separation and purification technique. Mechanical milling is employed post crystallisation as an offline unit operation usually in a separate dry solids processing facility for adjusting the particle size and shape attributes of crystalline products for downstream processing. An emerging and increasingly applied technology is high shear wet milling in crystalline slurries for inline size and shape modification during particle formation. This potentially avoids the need for multiple crystallisation trials and offline milling saving time, costs and powder handling. Similarly, sonication is a powerful particle engineering tool through immersing ultrasound probes directly in solution. This PhD project is focused on the investigation and process integration of wet milling and indirect ultrasound for enhancing crystallisation processes and engineering particle attributes. The experimental study combined a cooling and isothermal crystallisation (seeded & unseeded) process with wet milling and indirect sonication. Results from the combined method provides the ability to modify and selectively achieve a range of product outcomes including particle sizes with tight spans, equant shapes and low surface energies as well as increased nucleation rates.;High shear from wet milling is also implemented as a seeding protocol configured to a mixed-suspension mixed-product removal continuous crystalliser which proved to be an adequate seed generation strategy.Deploying accurate quantitative analysis of size and shape attributes for solid particles is further explored. A multi-sensor measurement approach was employed using inline sensors, computational tools and offline techniques. The performance of these tools were vigorously tested for strengths and limitations which was proven to be beneficial for characterising the breakage of crystalline materials as well as overall process understanding and opportunities for process control.Recent advances in pharmaceutical manufacturing for consistent supply of medicines with the required physical properties has emphasised the need for robust crystallisation processes which is a critical separation and purification technique. Mechanical milling is employed post crystallisation as an offline unit operation usually in a separate dry solids processing facility for adjusting the particle size and shape attributes of crystalline products for downstream processing. An emerging and increasingly applied technology is high shear wet milling in crystalline slurries for inline size and shape modification during particle formation. This potentially avoids the need for multiple crystallisation trials and offline milling saving time, costs and powder handling. Similarly, sonication is a powerful particle engineering tool through immersing ultrasound probes directly in solution. This PhD project is focused on the investigation and process integration of wet milling and indirect ultrasound for enhancing crystallisation processes and engineering particle attributes. The experimental study combined a cooling and isothermal crystallisation (seeded & unseeded) process with wet milling and indirect sonication. Results from the combined method provides the ability to modify and selectively achieve a range of product outcomes including particle sizes with tight spans, equant shapes and low surface energies as well as increased nucleation rates.;High shear from wet milling is also implemented as a seeding protocol configured to a mixed-suspension mixed-product removal continuous crystalliser which proved to be an adequate seed generation strategy.Deploying accurate quantitative analysis of size and shape attributes for solid particles is further explored. A multi-sensor measurement approach was employed using inline sensors, computational tools and offline techniques. The performance of these tools were vigorously tested for strengths and limitations which was proven to be beneficial for characterising the breakage of crystalline materials as well as overall process understanding and opportunities for process control

Continuous crystallization of multicomponent materials

The challenges of developing continuous crystallization processes of multicomponent crystals are addressed within this thesis. Multicomponent crystals such as co-crystals and solid solutions, can be used to modify physical properties of active pharmaceuticals, agrochemicals and other materials. These can result in enhanced product properties such as higher solubility, faster dissolution, better stability or improved manufacturability in downstream processing through desirable morphology and better powder flowability. Continuous manufacturing is routinely used in many industries but is a new trend in the manufacture of pharmaceuticals driven by the potential to reduce plant footprint and intermediate inventory, improve yields, reduce lead time, implement real time monitoring and automation and make processes safer.Compared to crystallization of single component crystals, additional component and solid phases introduce additional complexity in the phase diagram. Co-crystal phase diagram measurement in a series of solvents can be very time consuming compared to a solubility curve of a single component. A semi-empirical approach of modeling phase diagrams as well as new methods of measuring phase diagrams of multicomponent materials are presented to accelerate the time to obtain a phase diagram compared to traditional approaches. Transitions from small scale batch crystallization to continuous crystallization is also demonstrated here for co-crystals and solid solutions with high selectivity and reproducibility with respect to the solid phase produced.The challenges of developing continuous crystallization processes of multicomponent crystals are addressed within this thesis. Multicomponent crystals such as co-crystals and solid solutions, can be used to modify physical properties of active pharmaceuticals, agrochemicals and other materials. These can result in enhanced product properties such as higher solubility, faster dissolution, better stability or improved manufacturability in downstream processing through desirable morphology and better powder flowability. Continuous manufacturing is routinely used in many industries but is a new trend in the manufacture of pharmaceuticals driven by the potential to reduce plant footprint and intermediate inventory, improve yields, reduce lead time, implement real time monitoring and automation and make processes safer.Compared to crystallization of single component crystals, additional component and solid phases introduce additional complexity in the phase diagram. Co-crystal phase diagram measurement in a series of solvents can be very time consuming compared to a solubility curve of a single component. A semi-empirical approach of modeling phase diagrams as well as new methods of measuring phase diagrams of multicomponent materials are presented to accelerate the time to obtain a phase diagram compared to traditional approaches. Transitions from small scale batch crystallization to continuous crystallization is also demonstrated here for co-crystals and solid solutions with high selectivity and reproducibility with respect to the solid phase produced

Effect of process conditions on particle size and shape in continuous antisolvent crystallisation of lovastatin

Lovastatin crystals often exhibit an undesirable needle-like morphology. Several studies have shown how a needle-like morphology can be modified in antisolvent crystallisation with the use of additives, but there is much less experimental work demonstrating crystal shape modification without the use of additives. In this study, a series of unseeded continuous antisolvent crystallisation experiments were conducted with the process conditions of supersaturation, total flow rate, and ultrasound level being varied to determine their effects on crystal size and shape. This experimental work involved identifying acetone/water as the most suitable solvent/antisolvent system, assessing lovastatin nucleation behaviour by means of induction time measurements, and then designing and implementing the continuous antisolvent crystallisation experiments. It was found that in order to produce the smallest and least needle-like particles, the maximum total flow rate and supersaturation had to be combined with the application of ultrasound. These results should aid development of pharmaceutical manufacturing processes where the ability to control particle size and shape would allow for optimisation of crystal isolation and more efficient downstream processing

Application of process analytical technology (PAT) tools for the better understanding and control of the crystallization of polymorphic and impure systems

This work presents a comprehensive study on the application of PAT tools to study, monitor and control polymorphism during batch cooling crystallization processes. For the first time, the same techniques were used to control and adjust polymorphic purity of the solid phase but also to investigate the relation between chemical equilibrium in solution and polymorphic outcome of cooling crystallization. Crystallization is an important unit operation used as separation and purification technique. It is widely employed in the pharmaceutical, chemical, agrochemical, food and cosmetics industries but also in the electronic, metallurgic and material industries. More than 90% of the APIs on the market are produced by crystallization, therefore, monitoring and control this process is fundamental to ensure the quality of the final product. The implementation of process analytical technology (PAT) tools during the development stage of APIs has largely helped in better understanding and optimizing both batch and, more recently, continuous crystallization. Polymorphism is the capacity of a compound to crystallize in more than one different crystalline structure, which can have different properties such as density, melting point, bioavailability and solubility. The choice of solvent, pH, kinetic conditions and presence of impurities has very strong effect on the polymorphic outcome of a cooling crystallization in solution. Understanding this phenomenon as well as being able to monitor and control it during industrial crystallization is one the biggest challenges for pharmaceutical industries

Process-analytical technology investigation of the crystallization of pharmaceutical polymorphs, salts and hydrates

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

Morphological population balance modelling of the effect of crystallisation environment on the evolution of crystal size and shape of para-aminobenzoic acid

A current morphological population balance (MPB) modelling methodology, which integrates crystal morphology, facet growth kinetics with multi-dimensional population balance, is overviewed and demonstrated, hence providing an attractive approach for modelling crystallisation processes. MPB modelling is applied to simulate the batch crystallisation of the alpha-form of para-aminobenzoic acid from ethanolic solutions as a function of the crystallisation environment including cooling rate, seeding temperature and seed conditions (loading, size and shape). The evolution of crystal shape/size and their distributions revealed that higher loading led to smaller and less needle-like crystals with similar yields, hence potentially being an important parameter for process control. Examination of the development of the fracture surface for broken seeds, mimicking the seed conditions after milling in practice in the simulated processes, demonstrated that these faces grew fast and then rapidly disappeared from the external crystal morphology. Restriction and challenges inherent in the current model are also highlighted