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The present example illustrates the application of a consistent process development strategy to ascertain reproducible active pharmaceutical ingredient (API) polymorph manufacture. Key methodologies are illustrated using a Novartis API and carbamazepine as model substances. In the present example, the Novartis API was synthesized in the final chemical step by hydrolysis followed by acidification. The process was investigated in four steps: First, solid-liquid equilibrium studies were carried out in several solvents and yielded two polymorphs that were characterized by X-ray powder diffraction. Reliable solubility data and the transition temperature (45 °C) were extracted from these experiments as well. Second, based on the knowledge of the enantiotropic behavior of the system, a procedure was developed that crystallized the stable polymorphswhich was chosen for developments reproducibly by seeding at low supersaturation below 45 °C, followed by cooling at a moderate rate. The absence of metastability with respect to the undesired polymorphic form throughout the process was confirmed by applying ATR-FTIR. Third, reaction conditions were modified to obtain the API in solution at undersaturated conditions. Subsequently, the API could be crystallized in a controlled manner as described above. Fourth, filtration, washing, and drying conditions were investigated to avoid scale-up problems. Constant pressure filtration yielded low compressibility of the filter cake allowing a nutsche or centrifuge as appropriate equipment for isolation. On the basis of vacuum thermogravimetry, fast drying kinetics could be determined. Bench scale paddle dryer experiments illustrated an unacceptable increase of bulk density at permanent rotation. Therefore, intermittent rotation was successfully used at production scale. Thus, the presented process development strategy leads to a robust process scale-up from lab to pilot and production plant, yielding the desired product quality with respect to physical properties as well as chemical purity. Using solid-liquid equilibrium studies, the solubility and the transition temperature (79 °C) between forms I and III of carbamazepine could be determined in 2-propanol. These results correspond well with findings of other authors. On the basis of vacuum thermogravimetry, fast drying kinetics of 2-propanol from carbamezepine is illustrated. Near-complete drying can be achieved at any pressure below the solvent vapor pressure, which points to solvent free from interactions with the solid drug substance.

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This article gives an overview on the questions to be asked and the activities to be planned during the development of an API manufacturing process. First of all the API properties required for formulation such as purity, polymorphism and solvate formation, residual solvents, particle morphology and particle size distribution have to be defined. Then process parameters have to be evaluated that ensure that the drug substance with these properties can be produced on lab scale. The transfer to large-scale production is discussed with emphasis on scale-up effects, appropriate equipment, potential bottlenecks, and cost aspects. Finally practical hints are given as how to design an API crystallization and work-up process in a way that all given requirements for the APi are fulfilled and the process can be run reproducibly and cost-effective in production.