<div> <p>Guided by the continuous manufacturing paradigm shift in the pharmaceutical industry, the proposed thesis focuses on the implementation of an integrated continuous crystallization platform, the oscillatory baffled crystallizer (OBC), with real time process monitoring. First, by defining an appropriate operating regime with residence time distribution (RTD) measurements, a system can be defined that allows for plug flow operation while also maintaining solid suspension in a two-phase system. The aim of modern crystallization processes, narrow crystal size distributions (CSDs), is a direct result of narrow RTDs. Using a USB microscope camera and principal component analysis (PCA) in pulse tracer experiments, a novel non-contact RTD measurement method was developed using methylene blue. After defining an operating region, this work focuses on a specific process intensification technique, namely spherical crystallization.</p> <p>Used mainly to tailor the size of a final dosage form, spherical crystallization removes the need for downstream size-control based unit operations (grinding, milling, and granulation), while maintaining drug efficacy by tailoring the size of the primary crystals in the agglomerate. The approach for generating spherical agglomerates is evaluated for both small and large molecules, as there are major distinctions in process kinetics and mechanisms. To monitor the spherical agglomeration process, a variety of Process Analytical Technology (PAT) tools were used and the data was implemented for scale-up applications.</p> <p>Lastly, a compartmental model was designed based on the experimental RTD data with the intention of predicting OBC mixing and scale-up dynamics. Together, with validation from both the DN6 and DN15 systems, a scale independent equation was developed to predict system dispersion at different mixing conditions. Although it accurately predicts the behavior of these two OBC systems, additional OBC systems of different scale, but similar geometry should be tested for validation purposes.</p> </div> <br>

L’un des nombreux défis pour l’industrie pharmaceutique est de développer des procédés compétitifs pour produire des principes actifs de hautes qualités à bas coût. Pour ce faire, plusieurs sociétés se tournent vers la chimie en flux continu et les avantages qu’elle présente comparé au batch traditionnel. C’est pourquoi ces travaux de thèse se centrent sur le développement d’un procédé continu allant des matières premières au principe actif. La première étape pour parvenir à ce but fut de collecter des données sur le procédé batch industriel actuel. Il se compose de trois étapes de réactions chimiques, une de séparation chromatographique et une étape de cristallisation. A partir de là, la chimie de chaque réaction a été adaptée pour profiter au mieux des avantages du flux continu. La dissipation de chaleur étant plus efficace qu’en batch il fut possible de développer une réaction exothermique sans solvant à haute température. Une étude cinétique a été réalisée afin de modéliser cette réaction. Ensuite, cet outil fut utilisé pour déterminer les conditions opératoires optimales théoriques de la réaction et en guider l’optimisation ainsi que la conception du futur réacteur. La deuxième partie de ce travail se focalise sur la cristallisation en continu du principe actif avec la technique des jets impactant. Il est nécessaire d’avoir un contrôle précis sur la distribution de taille de particules (DTP) et la morphologie des cristaux. En effet, le principe actif peut cristalliser sous deux formes compétitives : cristaux cubiques ou en forme d’aiguilles. Les cubes sont la forme désirée. La technique des jets impactant a été sélectionnée car c’est un procédé continu qui permet la génération de fines particules avec une DTP resserrée. La sursaturation est généralement crée en impactant un jet de solution de principe actif avec un jet d’anti-solvant. Ici, le solvant et l’anti-solvant sont les mêmes. Seule une large différence de température entre les deux jets génère la sursaturation. En testant différentes conditions opératoires, une « zone cubique » a été définie, où seuls des cristaux de forme désirée sont générés. Une fois la nucléation maîtrisée, le murissement et la séparation solide-liquide furent étudiés pour développer un procédé complet de cristallisation. En combinant les recherches sur le développement des réactions chimiques et l’étape de cristallisation, un procédé continu complet fut proposé et comparé au procédé batch actuel afin d’évaluer les bénéfices apportés par la transposition en flux continu à la production du principe actif. / One of the many challenges in the pharmaceutical industry is to develop competitive processes to generate high quality active pharmaceutical ingredient (API) at low cost. To achieve this goal, many companies are looking towards flow chemistry and the advantages it affords, compared to traditional batch production. It is why this PhD work is focused on developing a continuous process from the raw materials to the API. The first step to achieve this goal was to collect data on the actual industrial batch process. It is composed of five steps, three steps of chemical reactions, one chromatographic separation and a crystallization step. From this starting point, the chemistry of each reaction was adapted to better use the advantages of flow chemistry. Thus, as the heat recovery in a continuous reactor is more efficient than in batch, it was possible to develop an exothermal reaction in neat conditions and at high temperature. A kinetic study was undertaken to gather knowledge on the reaction and develop a reaction model. This tool was used to find theoretical optimal operating conditions (temperature, residence time…) to guide the optimisation of the reaction and to design the future industrial reactor. The second part of this work is focused on the continuous crystallization of the API using the two impinging jets technology. It is required to have a tight control upon the morphology of the crystals and the particle size distribution (CSD). Indeed, the targeted API may crystallize under two competitive forms: cubic and needle crystals. The cubic form is the desired one. The two impinging jets technique was selected, since it is a continuous process able to generate small particles with a narrow CSD. The supersaturation is traditionally generated by impacting a jet of API solution with an anti-solvent one. Here, the solvent and the antisolvent are identical and only a large temperature difference between both streams is used to create the supersaturation. By screening different operating conditions, a “cubic zone” could be defined. Within this zone, only the desired crystal form is generated. Once the nucleation was under control, crystal growth and solid-liquid separation were studied to develop a complete crystallization process. By combining the research on the development of the chemical reactions and the crystallization step a full continuous process was proposed and was compared to the current batch one in order to evaluate the benefits brought by the flow chemistry to the API production.

<p>  </p> <p>Crystallization is a purity and particle control unit operation commonly used in industries such as pharmaceuticals, agrochemicals, and energetics. Often, the active ingredient’s crystal mean size, polymorphic form, morphology, and distribution can impact the critical quality attributes of the final product. The active ingredient typically goes through a series of process development iterations to optimize and scale-up production to reach production scale. Guided by the FDA, the paradigm shift towards continuous processing and crystallization has shown benefits in introducing cheaper and greener technologies and relieving drawbacks of batch processing. To achieve successful batch scale-up or robust continuous crystallization design, process intensification of unit operations, crystallization techniques, and utilizing data driven approaches are effective in designing optimal process parameters and achieving target quality attributes. </p> <p>In this thesis, a collection or toolbox of various process intensification techniques was developed to aid in control, optimization, and digitalization of crystallization processes. The first technique involves developing a novel control algorithm to control agrochemical crystals of high aspect ratio to improve the efficiency of downstream processes (filtration, washing, and drying). The second technique involves the further improvement of the first technique through digitalization of the crystallization process to perform simulated optimization and obtain a more nominal operating profile while reducing material consumption and experimentation time. The third method involves developing a calibration procedure and framework for in-line video microscopy. After a quick calibration, the in-line video microscopy can provide accurate real-time measurements to allow for future control capabilities and improve data scarcity in crystallization processes. The last technique addresses the need for polymorphic control and process longevity for continuous tubular crystallizers. Through a sequential stirred tank and tubular crystallizer experimental setup, the control of polymorphism, particle mean size, and size distribution were characterized. Each part of this thesis highlights the importance and benefits of process intensification by creating a wholistic process intensification framework coupled with novel equipment, array of PAT tools, feedback control, and model-based digital design.</p>

<p>Crystallization is a key solid-liquid separation and purification technique used in pharmaceutical industry. Some of the critical quality attributes (CQAs) of a product from crystallization process include crystal size distribution (CSD), purity, polymorphic form, morphology, etc. Different size and polymorphs of a drug substance may have different dissolution profiles and different bioavailability, which can have adverse effect on human health. Therefore, it is important to design and control crystallization process to meet product CQAs. In recent years, drug substances are becoming more complex, often being heat sensitive, which may limit the temperature that can be used in the crystallization step. Consequently, the traditional cooling only crystallization may not be well suited to recover the high value drug substances. For these systems, antisolvent crystallization is typically employed to improve the yield. On the other hand, the solvent composition can significantly impact the polymorphic outcome. Therefore, designing combined cooling and antisolvent crystallization (CCAC) processes to solve the challenges of active pharmaceutical ingredient (API) crystallization in a highly regulated environment is a complex engineering problem. </p> <p>With rising energy costs and intense price competition from generic pharmaceutical companies, the pharmaceutical industry is looking for ways to reduce the cost of manufacturing via process intensification (PI). This thesis focuses on different PI techniques for CCAC of drug substances. Continuous or smart manufacturing is gaining popularity due to its potential to lower the cost of manufacturing while maintaining consistent quality. Continuous crystallization is an important link in the continuous manufacturing process. The first part of the thesis shows PI of a commercial drug substance, Atorvastatin calcium (ASC) for target polymorph development via continuous CCAC using an oscillatory baffled crystallizer (OBC). An existing batch CCAC process for ASC was compared with the continuous CCAC in OBC and it was found the continuous process 30-fold more productive compared to the batch process. An array of process analytical technology (PAT) tools was used in this work to assess key process parameters that affect the polymorphic outcome and CSD. The desired narrower CSD product was obtained in the OBC compared to that from a batch crystallizer.</p> <p>The next part of the thesis focused on model-based PI technique for efficient determination of crystallization kinetics of a polymorphic system in CCAC. A novel experimental design was proposed which significantly reduced the number of experiments required to determine crystallization kinetics in a CCAC process. The kinetic parameters were validated, and a validated polymorphic model was used to perform an in-silico design of experiment (DoE) to develop a design space that can be used to identify operating conditions to achieve a desired crystal size and polymorphic form. </p> <p>The final part of the thesis combines the experimental and model-based approach for designing a continuous CCAC process for ASC in a cascade of Coflore agitated cell reactor (ACR) and three-stage mixed suspension mixed product removal (MSMPR). A combined artificial neural network (ANN) and principal component analysis (PCA) method was used to calibrate an ultraviolet (UV) probe which was used to monitor ASC solute concentration in the cascade process. The crystallization kinetic parameters were estimated in ACR and MSMPR which was used to build a digital model of the cascade process. The digital model was then used to obtain a design space with different temperature profile in the three-stage MSMPR that yielded narrow CSD of ASC form I. Overall, this thesis demonstrates the benefits of applying PI in the CCAC of drug substances using a holistic approach including novel equipment, application of an array of PAT tools, and model-based digital design to achieve desired CQAs of the product.</p>