Progress of Pharmaceutical Continuous Crystallization

Continuous Crystallization Processes in Pharmaceutical Manufacturing: A Review

A review on possible mechanisms of sonocrystallisation in solution.

Progress to Date in the Design and Operation of Continuous Crystallization Processes for Pharmaceutical Applications

Crystallization is an effective, low-cost purification & formulation process widely applied to pharmaceuticals and fine chemicals. This review describes recent advances in research on lab-scale solution-based continuous crystallization, including (1) a 5-step general design procedure; (2) key design/operational parameters; (3) process intensification strategies; and (4) a case study. The continuous crystallizers reviewed include mixed-suspension mixed-product removal, fluidized beds, oscillatory baffled flow, and tubular laminar/segmented/slug-flow crystallizers. Their corresponding design and operational considerations are summarized in terms of general parameters (e.g., residence time), and crystallizer-specific parameters and strategies (e.g., mixing strategies). In-line nucleation and crystal modification methods are categorized, including use of micromixers, wet milling, ultrasonication, temperature cycling, and recycling selection (filtration, sedimentation). Throughout the article, links are drawn with extensive existing knowledge of batch crystallizers, to facilitate the understanding and design of continuous crystallizers.

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Designs of continuous-flow pharmaceutical crystallizers: developments and practice

The countercurrent liquid-liquid extraction is a crucial step in industrial process to purify and extract a compound of inter-ests for its impurities. This step requires generally challenging and time-consuming optimisation of numerous factors that affect the overall yield of extraction and the energy needed. The simulation of this process has been investigated in this pa-per using a Non-Random Two Liquid model implemented as a thermodynamic method in Aspen. The outcome of this model enables the evaluation of the partition coefficients of the different analytes of a mixtures at the different compart-ments of extraction platform. In addition, this steady-state model allows a more straightforward optimisation of the factors that drive the performance of extraction.

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Steady-State Simulation of the Counter Current Liquid-Liquid Ex-Traction: Trimetozine Synthesis as a Case Study

Why the considerations for Lamivudine? * Increasing numbers of HIV/AIDS infections on yearly basis (2.1 million new cases in 2015, UNAIDS) * Hepatitis B infections (257 million cases globally, WHO) * Currently FDA-approved antiretroviral therapy for the prevention and treatment of both viral infections (FDA). Key research considerations and interests To the best of our knowledge, no publication yet exists on continuous manufacturing of stable Lamivudine form 1. The key research question here is: * Translate current batch crystallisation into a continuous process? * Improve the downstream process-ability by modifying the particle properties? * Develop miniaturise platforms for accelerated process development?

Developing process understanding for continuous manufacturing of Lamivudine (Epivir®) Stable Form I

Establishment of a Continuous Sonocrystallization Process for Lactose in an Oscillatory Baffled Crystallizer

A thorough, systematic study into the effect that structurally related impurities have on both the process and product quality during the crystallization of an active pharmaceutical ingredient is presented. The presence of acetanilide and metacetamol influences the crystallization and product quality of paracetamol. Where high concentrations of either impurity were present in the crystallization feed, product recovery decreased by up to 15%. Acetanilide is included in the final product through adsorption onto the particle surface in concentrations up to 0.79 mol%, which can be reduced to acceptable levels through product reslurrying. The presence of metacetamol results in much higher concentrations—up to 6.78 mol% in the final product, of which approximately 1 mol% is incorporated into the crystal lattice, resulting in the perturbation of the unit-cell dimensions. The incidental crystallization and subsequent isolation of metastable Form II paracetamol increased product purity in the presence of a low metacetamol concentration. This metastable product converts to stable paracetamol Form I through reslurrying, offering an efficient metacetamol impurity rejection route. The morphology of the product is modified consistently by both impurities. An elongation of the normal prismatic shape is observed, which in the extreme case of high metacetamol contamination results in the isolation of fine, fragile needles. This problematic morphology is also improved by a reslurrying of the crystallization product to give a more equilateral shape. This systematic study of the influence of acetanilide and metacetamol on the crystallization of paracetamol builds a well-rounded picture of the concomitant impact of impurities on the principal quality attributes of a crystallization product.

Impact of Impurities on Crystallization and Product Quality: A Case Study with Paracetamol

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Papers

Steady-State Simulation of the Counter Current Liquid-Liquid Ex-Traction: Trimetozine Synthesis as a Case Study

Developing process understanding for continuous manufacturing of Lamivudine (Epivir®) Stable Form I

Establishment of a Continuous Sonocrystallization Process for Lactose in an Oscillatory Baffled Crystallizer

Impact of Impurities on Crystallization and Product Quality: A Case Study with Paracetamol