Measurement, modelling, and closed-loop control of crystal shape distribution: Literature review and future perspectives

Crystal morphology is known to be of great importance to the end-use properties of crystal products, and to affect down-stream processing such as filtration and drying. However, it has been previously regarded as too challenging to achieve automatic closed-loop control. Previous work has focused on controlling the crystal size distribution, where the size of a crystal is often defined as the diameter of a sphere that has the same volume as the crystal. This paper reviews the new advances in morphological population balance models for modelling and simulating the crystal shape distribution (CShD), measuring and estimating crystal facet growth kinetics, and two- and three-dimensional imaging for on-line characterisation of the crystal morphology and CShD. A framework is presented that integrates the various components to achieve the ultimate objective of model-based closed-loop control of the CShD. The knowledge gaps and challenges that require further research are also identified

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

Modelling and control of crystal purity, size and shape distributions in crystallization processes

Crystallization is a key unit operation used for obtaining purified products by many process industries. The key properties of the crystalline products, such as size and shape distribution, purity and polymorphic form are controlled by the crystallization process. All these properties impact significantly the downstream operations such as drying or filtration. Therefore, monitoring and controlling this process is fundamental to ensure the quality of the final product. Process analytical technology (PAT) brings numerous new methods and opportunities in the process analytics and real time process monitoring systems, which can be integrated into the control algorithm and provide high level optimal control strategies as well as deeper understanding of the process. Process monitoring helps develop mathematical models which can, in one hand, help in better understanding the processes and consecvently the development and application of advanced control methods in order to achieve better product quality. In this work, image processing and image analysis based direct nucleation control (IA-DNC) is developed in order to investigate the evolution of the crystal properties, such as crystal size, and crystal shape distribution. The IA-DNC approach is also compared to alternative DNC techniques, in which particle number were measured by Focused Beam Reflectance Measurement (FBRM) in order to control crystal size. A control approach is introduced that control the nucleation and disappearance of crystals during cooling and heating segments related to the changes of the number of counts (measured by Particle Vision Measurment, so called PVM or combination of FBRM and PVM). The approach was applied to investigate crystallization of compounds with different behavior: potassium dihydrogen phosphate (KDP) water, contaminated KDP -water and Ascorbic acid water systems. The results demonstrate the application of imaging technique for model-free feedback control for tailoring crystal product properties. The second main aim of the thesis is to investigate and control crystallization processes in impure media in the presence of multiple impurities, with an impact on the crystal shape via growth kinetics. The broad impact of the crystal growth modifiers (impurities) on the growth kinetics is observed in real time by using in situ video imaging probe and real-time image analysis. A morphological population balance model is developed, which incorporates a multi-site, competitive adsorption mechanism of the impurities on the crystal faces. The kinetic parameters of primary nucleation, growth and impurity adsorption for a model system of potassium dihydrogen phosphate crystallization in water in the presence of two impurities, were estimated and validated with experimental results. It was demonstrated that the model can be used to describe the dynamic evolution of crystal properties, such as size and aspect ratio during crystallization for different impurity profiles in the system. Manual, feedback and hybrid feedback-feedforward control techniques are developed and investigated numerically for continuous processes, while model-based and model-free control approach for crystal shape are developed for batch processes. The developed morphological population balance model is implemented and applied in the model-based control approaches, which are suitable to describe multicomponent adsorption processes and their influence on the crystal shape. Case studies show the effectiveness of crystal growth modifiers based shape control techniques. Comparison of different control approaches shows the effectiveness of the techniques. The third part of the thesis deals with purification of crystals when adsorption of impurities on crystal surfaces and its incorporation into crystals are considered. A purification method, called competitive purity control (CPC) is proposed and investigated. A morphological population balance model, including nucleation, growth and competitive impurity adsorption kinetics is developed to describe the case when multiple impurities can adsorb competitively on the crystal surface. The model is also combined with liquid phase chemical reaction model, in order to investigate the purity control case when an additive is introduced in the system that reacts with the impurity forming a non-adsorbing reaction product. Both competitive purity control approaches proposed: the adsorption based competitive purity control (A-CPC) and the reaction based competitive purity control (R-CPC); are investigated using detailed numerical simulations then compared with the alternative widely used purification method, called recrystallization. In the last contribution chapter, an integrated process optimization of a continuous chemical reactor and crystallizer is performed and studied numerically. The purpose of this study is to show the way in which the byproduct produced in the chemical reactor may affect the crystallization process and how its negative effect can be reduced by applying integrated process optimization. Sensitivity analysis of the system was performed by considering the flow rate and the concentration of substances in the input stream of the chemical reactor as manipulated process variables. Model based integrated process optimization and the sensitivity analysis in order to obtain improved quality product in terms of crystal size, shape and purity

Improving continuous crystallisation using process analytical technologies: design of a novel periodic flow process

In this thesis novel configurations and operating strategies in the mixed suspension mixed product removal (MSMPR) crystalliser are investigated, aided by integrated process analytical technologies (PAT) and crystallisation informatics system (CryPRINS) tools. The MSMPR is an idealised crystalliser model that assumes: steady-state operation; well mixed suspension with no product classification, such that all volume elements contain a mixture of particles (small and large) and crystal size distribution (CSD) that is independent of location in the crystalliser and is identical of the product withdrawn; and uniform supersaturation thought, leading to constant nucleation and growth rates. Single-stage MSMPR designs with continuous recycle/recirculation and modified heat exchanger were investigated and found to minimise fouling, encrustation and transfer line blockages. In particular, a modified MSMPR with baffled heat exchanger was found to significantly reduce the temperature between incoming feed hot feed solution and the cooled crystalliser, leading to a significant reduction in fouling, encrustation and blockages. In addition, the concept of the periodic mixed suspension mixed product removal (PMSMPR) crystallisation process is demonstrated for the first time viz single- and multi-stage cascaded operations. This method of operation involves the periodic transfer of slurry (addition and withdrawal) at high flow rates from either a single stirred vessel or between a number of stirred vessels arranged in series. The PMSMPR is therefore characterised by periodic withdrawals of product slurry. Similar to the MSMPR, the product withdrawn from a PMSMPR has exactly the same composition as the vessel at the time of removal. The rapid withdrawal of slurry at high flow rates in PMSMPR operation leads to the prevention of particle sedimentation and blockage of transfer lines. The transfer of slurry (to/from) the PMSMPR is followed by a holding (or pause) period when no addition or withdrawal of slurry takes place. The holding period extends the mean residence time of the PMSMPR relative to a typical MSMPR, thereby increasing the yield and productivity of crystallisation as more time is allowed for consumption of available supersaturation viz crystal growth and nucleation. A state of controlled operation (SCO) in the periodic flow process, defined as a state of the system that maintains itself despite regular, but controlled disruptions was characterised using the PAT tools and CryPRINS within an intelligent decision support (IDS) framework. The crystallisation of paracetamol (PCM) from isopropyl alcohol (IPA) using different configurations of a single-stage continuous MSMPR crystalliser that incorporated continuous recycle and recirculation loop, and a novel design with baffled heat exchanger was investigated. Crystallisations of PCM-IPA carried out in the MSMPR without heat exchanger suffered from severe fouling, encrustation and blockage problems due to the high level of supersaturation (S = 1.39) in the crystalliser, which was required for the initial burst of nucleation to generate enough particles for later growth, as well as the large temperature difference between the incoming feed (45 oC) and the crystalliser (10 oC). Using the modified MSMPR design with baffled heat exchanger, the challenges of fouling, encrustation and blockage were significantly reduced due to the rapid lowering of the feed stream temperature prior to entering the crystalliser. In addition, the closed loop system led to conservation of material, which is a great benefit since large amounts of materials would otherwise be required if the MSMPR was operated with continuous product removal. This design is great for research purposes, in particular, to investigate process design and optimisation. Continuous crystallisation of PCM in the presence of hydroxyl propyl methyl cellulose (HPMC) additive was investigated in the modified MSMPR design with heat exchanger. HPMC was found to improve the crystallisation performance, leading to complete avoidance of fouling, encrustation and blockages at a concentration of 0.05 wt%. However, the yield of crystallisation was significantly reduced (28.0 %) compared to a control experiment (98.8 %, biased due to fouling/encrustation) performed without additive addition. Regardless, the productivity of crystallisation was more than four times that achieved in batch linear cooling (LC) (0.62 0.86 g/L-min) and batch automated dynamic nucleation control (ADNC) (0.24 0.25 g/L-min) runs. Aspects of the periodic flow crystallisation of single- and multi-component (co-crystals) molecular systems have also been examined to demonstrate the concept of state of controlled operation . The single component systems studied were PCM and glycine (GLY), each representative of compounds with slow and fast growth kinetics, respectively. The co-crystal systems investigated were urea-barbituric acid (UBA) and p Toluenesulfonamide-Triphenylphosphine oxide (p-TSA-TPPO). UBA is a polymorphic co-crystal system with three known forms (I, II and III). Form I UBA was successfully isolated in a three-stage periodic flow PMSMPR crystalliser. This study demonstrates the capability of periodic flow crystallisation for isolation of a desired polymorph from a mixture. p-TSA-TPPO exists in two known stoichiometric co-crystal forms, 1:1 and 3:2 mole ratio p-TSA-TPPO, respectively. The two crystalline forms exhibit solution mediated transformation, which proves to be a difficulty for separation. For this study, the implementation of temperature cycles in batch and flow control in semi-batch and periodic PMSMPR crystallisers were investigated to isolate pure 1:1 and 3:2 p-TSA-TPPO, respectively. Different regions of the ternary diagram of p-TSA, TPPO and acetonitrile (MeCN) were investigated. The desired co-crystal form was isolated all crystallisation platforms investigated. However, greater consistency was observed in the semi-batch and PMSMPR operations respectively. Periodic flow crystallisation in PMSMPR is a promising alternative to conventional continuous MSMPR operation, affording greater degrees of freedom operation, slightly narrower RTD profiles, consistent product crystal quality (size, shape and distribution), longer mean residence times, higher yield and productivity and significant reduction in fouling, encrustation and transfer line blockages over prolonged operating periods. Furthermore, the PMSMPR is a versatile platform that can be used to investigate a range of different molecular systems. Relative to batch operation, the PMSMPR can operate close to equilibrium, however, this is dependent on the system kinetics. In addition, retrofitting of batch crystallisers to operate as PMSMPRS fairly simple and require only subtle changes to the existing design space. The integrated array of PAT sensors consisted of attenuated total reflectance ultra violet/visible spectroscopy (ATR-UV/vis), attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR), focused beam reflectance measurement (FBRM), particle vision microscopy (PVM) and Raman spectroscopy. The results from the studies reported here illustrate very well the use of PAT and information system tools together to determine when the continuous and periodic MSMPR operations reaches a steady-state or state of controlled operation (i.e. periodic steady-state). These tools provided a better understanding of the variables and operating procedures that influence the two types of operations

Control of crystalline particle properties by spray drying

Although spray drying has been common place in the pharmaceutical industry for decades, the integration of the technique into continuous manufacturing can offer an extensive array of particle engineering applications. Continuous manufacturing aims to deliver consistent and sustainable drug products of a better and higher quality. Spray drying is a continuous processing technique typically adopted for amorphous solid production. However, the unique conditions of the technique can also can be adapted and applied to crystallisation enabling particle property engineering. The semi-continuous lab-scale Büchi B-290 Mini spray dryer is widely available and has been previously studied extensively for particle engineering and as a development platform for applications including pulmonary drug delivery, sustained release formulations and amorphous solid dispersions.The focus of this work is to engineer and enhance particle properties through the use of the Büchi spray dryer. Particle formation has been investigated, with specific focus in terms of polymorph formation in carbamazepine, to develop a predictive model for crystallisability and for co-spray drying of metformin hydrochloride with mannitol and lactose. Particle formation has been described in terms of theoretical drying kinetics and combined with off line characterisation to determine size and form of product. The metastable polymorph, form IV, of carbamazepine was made reproducibly by spray drying with the combination of rapid evaporation and product isolation shown to be crucial to prevention of solution mediated transformation. The application of non-invasive Raman spectroscopy was also utilised to assess product form. A crystallisability predictive model based on a Random Forest method was successfully produced through combining molecular descriptors with published and experimental outcomes. The model provided up to 79 % accuracy in predicting whether an amorphous or crystalline product would be expected from rapid drying. This shows considerable utility in streamlining process development. Finally, co-spray drying in the Büchi system using a three-fluid nozzle was used to produce multicomponent composite particles comprising of two crystallite phases. The effect of process configuration and material properties on the resultant particles was assessed using particle sizing, SEM, XRPD and Raman mapping. The results were compared on the basis of theoretical drying kinetics to assess the ability to predict the resultant particle morphology. Four multicomponent composite particles were produced by co-spray drying from metformin hydrochloride (MF), mannitol and lactose. MF-mannitol composites produced three-phase physical mixtures with both components present on the particle surfaces. The particle surface compositions were contradictory to the expected particle outcomes from the drying parameters. MF-lactose composite particle also produce three-phase physical mixtures with a relatively equal distribution of components present on particle surface. This is consistent with the expected particle from the drying parameters. The different particle outcomes suggest that co-spray drying of miscible multicomponent feeds using the three-fluid nozzle is highly dependent on the drying parameters for each component due to equal mixing of the feed at atomisation of droplets.Although spray drying has been common place in the pharmaceutical industry for decades, the integration of the technique into continuous manufacturing can offer an extensive array of particle engineering applications. Continuous manufacturing aims to deliver consistent and sustainable drug products of a better and higher quality. Spray drying is a continuous processing technique typically adopted for amorphous solid production. However, the unique conditions of the technique can also can be adapted and applied to crystallisation enabling particle property engineering. The semi-continuous lab-scale Büchi B-290 Mini spray dryer is widely available and has been previously studied extensively for particle engineering and as a development platform for applications including pulmonary drug delivery, sustained release formulations and amorphous solid dispersions.The focus of this work is to engineer and enhance particle properties through the use of the Büchi spray dryer. Particle formation has been investigated, with specific focus in terms of polymorph formation in carbamazepine, to develop a predictive model for crystallisability and for co-spray drying of metformin hydrochloride with mannitol and lactose. Particle formation has been described in terms of theoretical drying kinetics and combined with off line characterisation to determine size and form of product. The metastable polymorph, form IV, of carbamazepine was made reproducibly by spray drying with the combination of rapid evaporation and product isolation shown to be crucial to prevention of solution mediated transformation. The application of non-invasive Raman spectroscopy was also utilised to assess product form. A crystallisability predictive model based on a Random Forest method was successfully produced through combining molecular descriptors with published and experimental outcomes. The model provided up to 79 % accuracy in predicting whether an amorphous or crystalline product would be expected from rapid drying. This shows considerable utility in streamlining process development. Finally, co-spray drying in the Büchi system using a three-fluid nozzle was used to produce multicomponent composite particles comprising of two crystallite phases. The effect of process configuration and material properties on the resultant particles was assessed using particle sizing, SEM, XRPD and Raman mapping. The results were compared on the basis of theoretical drying kinetics to assess the ability to predict the resultant particle morphology. Four multicomponent composite particles were produced by co-spray drying from metformin hydrochloride (MF), mannitol and lactose. MF-mannitol composites produced three-phase physical mixtures with both components present on the particle surfaces. The particle surface compositions were contradictory to the expected particle outcomes from the drying parameters. MF-lactose composite particle also produce three-phase physical mixtures with a relatively equal distribution of components present on particle surface. This is consistent with the expected particle from the drying parameters. The different particle outcomes suggest that co-spray drying of miscible multicomponent feeds using the three-fluid nozzle is highly dependent on the drying parameters for each component due to equal mixing of the feed at atomisation of droplets

MANUFACTURE OF INDIVIDUALIZED DOSING: DEVELOPMENT AND CONTROL OF A DROPWISE ADDITIVE MANUFACTURING PROCESS FOR MELT BASED PHARMACEUTICAL PRODUCTS

The improvements in healthcare systems and the advent of precision medicine initiative have created the need to develop more innovative manufacturing methods for the delivery of individualized dosing and personalized treatments. In recent years, the US Food and Drug Administration (FDA) introduced the Quality by Design (QbD) and Process Analytical Technology (PAT) guidelines to encourage innovation and efficiency in pharmaceutical development, manufacturing and quality assurance. As a result of emerging technologies and encouragement from the regulatory authorities, the pharmaceutical industry has begun to develop more efficient production systems with more intensive use of on-line measurement and sensing, real time quality control and process control tools, which offer the potential for reduced variability, increased flexibility and efficiency, and improved product quality

A Model-Centric Framework for Advanced Operation of Crystallization Processes

Crystallization is the main physical separation process in many chemical industries. It is an old unit operation which can separate solids of high purity from liquids, and is widely applied in the production of food, pharmaceuticals, and fine chemicals. While industries in crystallization operation quite rely on rule-of-thumb techniques to fulfill their requirement, the move towards a scientific- and technological- based approach is becoming more important as it provides a mechanism for driving crystallization processes optimally and in more depth without increasing costs. Optimal operation of industrial crystallizers is a prerequisite these days for achieving the stringent requirements of the consumer-driven manufacturing. To achieve this, a generic and flexible model centric framework is developed for the advanced operation of crystallization processes. The framework deploys the modern software environment combined with the design of a state-of-the-art 1-L crystallization laboratory facility. The emphasis is on developing an economically and practically feasible implementation which can be applied for the optimal operation of various crystallization systems by pharmaceutical industries. The key developments in the framework have occurred in three broad categories: i. Modeling: Using an advanced modeling tool is intended for accurate representation of the behavior of the physical system. This is the cornerstone of any simulation, optimization or model-based control approach. ii. Monitoring: Applying a novel image-based technique for online characterization of the particulate processes. This is a promising method for direct tracking of particle size and size distribution with high adaptability for real-time application iii. Control: Proposing numerous model-based strategies for advanced control of the crystallization system. These strategies enable us to investigate the role of model complexity on real-time control design. Furthermore, the effect of model imperfections, process uncertainty and decision variables on optimal operation of the process can be evaluated. Overall, results from this work presents a robust platform for further research in the area of crystal engineering. Most of the developments described will pave the way for future set of activities being targeted towards extending and adapting advanced modeling, monitoring and control concepts for different crystallization processes

Multi-impurity adsorption model for modeling crystal purity and shape evolution during crystallization processes in impure media

© 2015 American Chemical Society. The impurity effect on the crystal properties, such as particle size and shape distribution, is significant, having significant impact on the downstream processes as well as on the product effectiveness. Currently very few studies exist that provide a quantitative model to describe crystal purity resulting from crystallization processes in impure media, and none to take into account the simultaneous effect of multiple impurities. Hence, the understanding of the effect of multiple impurities on crystallization process is important in order to obtain the desired product properties. Batch crystallization of potassium dihydrogen phosphate from aqueous solution in the presence of impurities was investigated experimentally by using an online particle vision and measurement tool with real-time image analysis. A mathematical model to describe the crystal purity and aspect ratio is proposed based on a morphological population balance equation including primary nucleation, growth of characteristic faces and multisite, competitive adsorption of impurities. The model parameters were identified and validated using crystallization experiments in mixtures of two impurities with variable composition. The developed and validated model can be an efficient tool for the investigation of crystallization processes in impure media with multiple impurities. The model can also serve as an effective tool for process and product design or optimization

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