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.
Little has been published so far to emphasize the role of finishing technologies (crystallization, filtration, drying) as crucial elements for successful process development of active pharmaceutical ingredients (APIs). In the presented example high marketing forecasts stressed the objective for the process to be robust, simple, and tailor-made for high-volume production. The major hurdle was the purification of the reaction mixture of an intermediate containing inorganic salts, polymers, isomers, and colored byproducts that needed to be separated. Systematic application of finishing technologies paved the way to a commercial process. Removal of colored byproducts and isomers was found to be the most challenging task after separation of inorganic salts by quench and of polymers by charcoal treatment. The problem was resolved in three steps. First, solvent screening for the crystallization yielded toluene to be most efficient to separate colored byproducts. Second, solubility measurements of product and isomers provided an operating range of the process parameters for an economic crystallization at an unusually high concentration (60% w/w). Isomers could be separated since they remain soluble at endpoint temperature. To avoid the problem of wall crusts during scale-up, the metastable range was estimated experimentally. And third, near-infrared spectroscopy was implemented as an on-line measurement method for the product concentration in toluene to determine the endpoint of evaporation and thus to facilitate robustness and yield optimization. As further result of proper elaboration of crystallization conditions the crystals exhibited compact cubic morphology and large size. Consequently, filtration and washing of the wet product cake were efficient, and the drying process could be eliminated before continuing with the next synthesis step.
As a basic operation of mechanical process engineering, pressure filtration and its scale-up has been described in detail in the literature. But, the pharmaceutical development of active substances, in particular, calls for a scale-up of relatively small quantities to execute downstream processes in a lean and reliable manner. Therefore, development depends on conclusions from smaller filter equipment. In this study, results from laboratory nutsche filters with filter surface areas of 1.4 cm 2 and 9.6 cm 2 were compared with results from a 20 cm 2 nutsche. It has been shown that no reproducible and reliable data could be generated using the 1.4-cm 2 nutsche. While this was possible using the 9.6 cm 2 nutsche, the permeability was greater than with the recommended 20 cm 2 nutsche so that a correction factor has to be introduced.
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