Crystallization has a significant impact on the properties of the active pharmaceutical ingredient (API) since it is the final step in the manufacturing of the drug substance and determines particle size distribution, purity, shape, and polymorphs. Many publications have focused on the implementation of Process Analytical Technology (PAT) tools for monitoring batch and continuous operation; however, a comprehensive method development and validation of Raman spectroscopy to monitor continuous crystallization has not been presented. This work demonstrates the development and validation of a method to monitor the solute concentration of Carbamazepine and quantifies the limit of detection for a metastable polymorphic form. The experiments were based on the cooling crystallization of Carbamazepine to produce the most stable form. The method was validated following the principles described in USP general chapter ⟨1225⟩ validation procedures for analytical methods. The results demonstrate the model can predict the solute concentration with a root-mean-square-error of prediction of 2.46 mg/mL. The repeatability and intermediate precision were evaluated, and the relative standard deviation is below 5%. The limit of detection for the metastable form was determined by monitoring the ratio of characteristic peaks when increasing the percentage of the metastable form in the total amount of crystals in the solution. A significant change in the peak ratio is observed when 22.9% of the crystals are of the metastable form. In addition, this PAT method was used to monitor a continuous run for 10 residence times, in which the system reached a controlled state of operation after six residence times.
Continuous protein crystallization is a cost-effective alternative to traditional chromatographic purification techniques. However, proteins characteristically have slow growth rates, requiring long crystallization times to generate particles large enough for efficient isolation. In this work, spherical crystallization using an emulsion solvent diffusion (ESD) based methodology is proposed to produce large lysozyme agglomerates in an oscillatory baffled crystallizer (OBC). Process sensitivity analysis was performed to investigate the effect of the process parameters on the product's crystal size distribution at two different scales. The concentration of ethanol in the bulk phase was found to have a significant effect on the crystallization kinetics, as its diffusivity drives supersaturation at the droplet interface. Although controlling supersaturation is important in determining product quality, maintaining droplet suspension near the injection site is critical for process longevity, as fouling is most likely to occur in this high supersaturation region. Similarly, in scaling this process, the ratio of droplet diameter to tube diameter plays a significant role in the formation of encrust. Increasing the size of the droplets, relative to the diameter of the system, increases the role of wall effects in distorting the final product quality. Overall, these tunable process parameters make the OBC an ideal platform for spherical protein crystallization.
Using process modeling to understand process dynamics and potentially explore the design space of a crystallization process is difficult because of its complex nature with many factors at play, such as initial concentration, supersaturation, seeding strategy, and flow pattern. In this work, a systematic approach is applied to sequentially estimate the growth and nucleation rate of the cooling crystallization of carbamazepine at various conditions in batch operation. Different formulations of the kinetic expressions are tested as a model discrimination exercise to obtain the best fit with the most confidence form. Then, based on the risk, determined by the purpose of the obtained model, verification and validation activities are applied. The model is verified and validated to predict concentration and D50 for a specific seeding strategy for crystallization mechanisms, including both nucleation and growth, are highly dependent on the seed PSD. A brief discussion is also given on the transferring of the batch-developed model to continuous operations in response to the growing interest in continuous crystallization development. It is found that the model can be transferred to continuous operations where the supersaturation and solid concentration are similar to those tested during batch experimentation. Because of the complex and interactive effects of supersaturation and solid conditions on crystallization kinetics, it is reasonable to conclude that in order to infer transferable crystallization kinetics, batch experimental conditions must be wide and similar enough to cover the potential continuous operating space.
Pharmaceutical crystallization affects the properties of APIs as it determines the purity and crystal size distribution, among other attributes. This work presents two CLD–CSD models, theoretical and empirical, for a model compound.
Precompetitive collaborations on new enabling technologies for research and development are becoming popular among pharmaceutical companies. The Enabling Technologies Consortium (ETC), a precompetitive collaboration of leading innovative pharmaceutical companies, identifies and executes projects, often with third-party collaborators, to develop new tools and technologies of mutual interest. Here, we report the results of one of the first ETC projects: the development of a user-friendly population balance model (PBM)-based crystallization simulator software. This project required the development of PBM software with integrated experimental data handling, kinetic parameter regression, interactive process simulation, visualization, and optimization capabilities incorporated in a computationally efficient and robust software platform. Inputs from a team of experienced scientists at 10 ETC member companies helped define a set of software features that guided a team of crystallization modelers to develop software incorporating these features. Communication, continuous testing, and feedback between the ETC and the academic team facilitated the software development. The product of this project, a software tool called CrySiV, an acronym for Crystallization Simulation and Visualization, is reported herein. Currently, CrySiV can be used for cooling, antisolvent, and combined cooling and antisolvent crystallization processes, with primary and secondary nucleation, growth, dissolution, agglomeration, and breakage of crystals. This paper describes the features and the numerical methods of the software and presents two case studies demonstrating its use for parameter estimation. In the first case study, a simulated data set is used to demonstrate the capabilities of the software to find kinetic parameters and its goodness of fit to a known solution. In the second case study, the kinetics of an antisolvent crystallization of indomethacin from a ternary solvent system are estimated, providing a practical example of the tool.
Fouling, encrustation, and lack of polymorphic form control are some of the major drawbacks of continuous oscillatory baffled crystallizers (COBCs), which can lead to clogging, undesired crystal form generation, and process failure. To counter these drawbacks, seeding with crystals is a methodology to not only control nucleation mechanism and crystal size distribution (CSD) but also provide polymorphic form control. Consistent manual preparation of seeds for continuous crystallization is labor-intensive and often economically infeasible. Furthermore, any fluctuations of seed quality can impact the startup dynamics. In this work, a proof-of-concept and the benefits of continuous in situ seed generation was demonstrated with an integration of a mixed suspension mixed product removal (MSMPR) crystallizer with a COBC via a continuous combined cooling antisolvent crystallization (CCAC). First, a CCAC solubility design space of metastable (form II) and stable forms (form I) of ortho-aminobenzoic acid was developed to identify operating regimes for selective polymorphic form generation. Second, the in situ form I seed generation experiments, with the COBC, prolonged steady-state generation of the crystal product for more than eight residence times. The crystal product generated from the combined system with segmented cooling had a higher mean size and narrower size distribution when compared to the product obtained from a single-stage MSMPR experiment. Polymorphic control coupled with continuous seed generation in the combined system generated a uniform crystal product with no seed wash out occurring. Lastly, the importance of the method of slurry transport for the combined system was highlighted in experiments utilizing mechanical pump transfer compared to gravimetric transfer. Overall, these proof-of-concept experiments demonstrated the feasibility and benefits of using the integrated MSMPR–COBC crystallization system, utilizing the MSMPR crystallizer for continuous in situ seed generation providing for the robust operation of the COBCs.
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