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.
In this work, the polymorphic transformation of a dimorphic model compound, ortho-aminobenzoic acid (OABA), is investigated using experimental characterization in combination with population balance modeling. A novel experimental design is proposed to estimate the crystallization kinetic parameters of the polymorphic system in a combined cooling and antisolvent crystallization (CCAC) process with a minimum number of experiments, which can reduce the resources and time required to obtain kinetic information, which is of great importance in the drug substance development stage. The modeling studies revealed that the growth rates of the two polymorphs depend on the solvent composition. At a particular temperature and supersaturation, the form I growth rate increased as the solvent content proportion increased, whereas the form II growth rate decreased as the solvent content increased. The identified kinetic parameters of the nucleation and growth rate expressions of the two polymorphs were validated for different solvent compositions and temperatures. The validated model was then used to perform in silico design of experiments to develop a design space that can be used to identify operating conditions to achieve the desired crystal size and polymorphic form.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.