Active ingredients in most pharmaceutical products are complex organic molecules that require crystallization as a purification and isolation step that results in a pure product at a high process yield. Knowledge of the operating conditions required to obtain crystals with the desired crystal shape, polymorph, and morphology is critical during process development. This paper describes a two-stage mixed suspension mixed product removal (MSMPR) continuous reactive crystallization procedure developed for Aliskiren hemifumarate. This process was able to crystallize Aliskiren hemifumarate at both high purity (>99%) and high yield (>92%). A model of the crystallization was developed through the simultaneous solution of a population balance equation, kinetic expression for crystal growth and nucleation, and a mass balance. Experimental data were fit to the model to obtain kinetic parameters for crystal growth and nucleation. After including equilibrium distribution coefficient data, the model was used to optimize crystal purity and yield of the product by adjusting the operating temperature and residence time. This process has been integrated into an end-to-end continuous manufacturing system developed at MIT.

This paper describes a two-stage mixed-suspension, mixed-product removal (MSMPR) continuous crystallization developed for a pharmaceutical intermediate which uses anti-solvent and cooling to generate supersaturation. The results indicate that the stage in which anti-solvent is added has a significant influence on the final crystal properties, while purity and yield were nearly identical. The population balance model was employed to determine growth and nucleation kinetics through parameter estimation. With the incorporation of measured equilibrium distribution coefficients, the model was used to optimize crystal purity and yield of the product with respect to operating temperature and residence time.

If continuous processing is to be employed in pharmaceutical production, it is essential that continuous crystallization techniques can meet the purity and yield achievable in current batch crystallization processes. Recycling of mother liquor in steady state MSMPR crystallizations allows the yield in the equivalent equilibrium batch process to be met or exceeded. However, the extent to which yield can be increased is limited by the buildup of impurities within the system. In this study, an organic solvent nanofiltration membrane was used to preferentially concentrate an API (deferasirox, M.W. = 373 Da) and purge the limiting impurity 4-hydrazinobenzoic acid (MW = 152 Da) from the mother liquor recycle stream in a mixed solvent (THF:ethanol) antisolvent (water) system. Incorporation of the membrane recycle allowed yields of 98.0% and 98.7% to be achieved. This compares to the following: a control MSMPR run without a membrane (70.3%), an equivalent batch process (89.2%), and the current commercial batch process (92%). Comparable product impurity levels were measured for the following: the MSMPR membrane recycle experiments (0.15 ppm and 0.22 ppm), the MSMPR control (0.13 ppm), and batch (0.32 ppm) control experiments. All processes met the regulatory specifications of a maximum of 3 ppm of the impurity 4-hydrainobenzoic acid.

We investigated the effect of spherical agglomeration of heterogeneous crystalline substrates on the nucleation of acetaminophen (AAP). Optical and electron microscopy showed that the surface morphologies of single crystal triclinic lactose and D-mannitol differed significantly from their counterparts formed via spherical agglomeration. Spherical agglomerates of lactose were shown to enhance the nucleation rate of acetaminophen (AAP) by a factor of 11 compared to single crystal lactose; however, no such enhancement was observed for D-mannitol. X-ray powder diffraction identified the presence of new crystal faces of lactose present only in the spherical agglomerates However, D-mannitol did not show any significant change in crystal morphology. The new crystal faces of triclinic lactose were analyzed using geometric lattice matching software and molecular dynamics simulations to establish any new and significant epitaxial matches between lactose and AAP. A coincident lattice match and a large favorable energy interaction from hydrogen bonding were observed between the (141¯) and (001) crystal faces of lactose and AAP, respectively. The enhanced nucleation kinetics, X-ray data, and computational studies indicated that the spherical crystallization of lactose exposed the (141¯) face on the surface of the agglomerates, which subsequently enhanced the nucleation rate of AAP through geometric lattice matching and molecular functionality. This study highlights the importance of exploring different heterogeneous substrate morphologies for enhancing nucleation kinetics.

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The design of pharmaceutical crystallization processes is a challenging engineering problem because of the specific and versatile quality requirements of the end-product, amplified by the tight regulatory standards. The current industrial standard for crystallization process design is based on the use of the quality-bydesign (QbD) framework, which relies on factorial design of experiments (DoE). Hence, QbD inherently generates a large number of resource-consuming open loop crystallization experiments. This is especially true when more complex operating conditions need to be designed, such as temperature cycles, which require a large number of decision variables in the DoE. In contrast, the recently proposed quality-by-control (QbC) approach relies on feedback control algorithms to directly achieve the desired product properties by manipulating the appropriate process conditions. The first aim of this work is to demonstrate the effectiveness of a model-free feedback control strategy, referred to as model-free (mf) QbC. Direct nucleation control (DNC) and supersaturation control (SSC) are applied as a part of the mfQbC approach, which, ideally, requires only two feedback control experiments to obtain a temperature profile that results in obtaining the desired product quality. Although mfQbC provides a rapid process design, it is often suboptimal. In addition, it is shown that the experimental data generated by mfQbC can be used for process model development and kinetic parameter estimation. The validated model enables optimization-based design using the model-based (mb) QbC framework. For this case study, a population balance (PB) based process model is developed, which involves primary and secondary nucleation, growth, and dissolution, as well as a novel formulation of agglomeration, and deagglomeration of crystals. In addition to taking into account the agglomeration, the number of agglomerates is also tracked as a balance between the agglomeration and deagglomeration events. The kinetic parameters are estimated using a novel objective function formulation relying on the minimization of the difference between the measured and simulated concentrations and crystal size distributions (CSDs) and the maximization of the correlation between the simulated crystal number density and measured crystal count data obtained from focused beam reflectance measurement (FBRM). The kinetic parameters are identified based on the experimental data generated from the mfQbC, which inherently reduced the experimental effort required for the model development. The temperature profile is optimized for the fine index and agglomeration degree minimization. The repeated open-loop implementation of mfQbC-and mbQbC-designed processes showed that the batch-to-batch variation is low and the product quality is high in both cases. The proposed general framework is illustrated for the systematic quick and optimal design of crystallization processes that require temperature cycles with a low number of experiments.

Concentration is often an important process parameter in pharmaceutical crystallization processes. In this work, an ultra-performance liquid chromatography (UPLC) system designed for process monitoring (Waters PATROL UPLC) was applied online as a process analytical technology tool for real-time multicomponent concentration monitoring in pharmaceutical crystallization. Three online UPLC-based applications were investigated: (1) solute concentration monitoring during crystallizations and associated solubility, dissolution, and degradation analyses, (2) quick calibration for UV/vis and Raman spectroscopy, and (3) real-time crystallization product purity monitoring.

Control of crystal size distribution (CSD) and shape is critical in the pharmaceutical industries for meeting tight critical quality attribute (CQA) requirements in the manufacturing of active pharmaceutical ingredients (APIs). In general, to increase the efficiency of downstream operations such as filtration and drying, and increase the flowability and manufacturability of powders, large crystals with a low aspect ratio (AR) are preferred. Large AR, needle-shaped crystals are very common in the pharmaceutical industries; consequently, to achieve desired manufacturability performance, a careful design of the crystallization processes is required. In this work, the systematic design of a crystallization process for an API (compound A) from Takeda Pharmaceuticals International Co. is demonstrated. The challenges related to the crystallization of compound A include that the process is nucleation dominated by slow growth rates, which necessitates intermittent internal fines removal via temperature cycling. Moreover, compound A tends to form high AR crystals, which can cause manufacturability problems. The aim of the crystallization design is to produce low AR (<3) and sufficiently large crystals with narrow distributions. Two methods were applied to reach these goals: (1) application of immersion milling to further control the shape and size of crystals and (2) application of temperature cycles to internally remove the fines. It is also demonstrated that these approaches can be implemented in an unseeded crystallization without compromising the product quality.