Process Development Strategy to Ascertain Reproducible API Polymorph Manufacture

Abstract

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.

Seed loading effects on the mean crystal size of acetylsalicylic acid in a continuous‐flow crystallization device

“…Different crystal modifications are likely to produce crystals of varying shapes [6,17] and solid materials with varying physical properties (melting point, density, hardness, solubility) [18][19][20]. Consequently, polymorphism directly affects downstream operations, handling of the bulk particles and the bioavailability of the drug substance [21,22]. This is also true for solvates, salts and amorphous solids [8].…”

Conformational Polymorphism of Tolbutamide: A Structural, Spectroscopic, and Thermodynamic Characterization of Burger’s Forms I–IV

“…4 Hence, characterization of all possible polymorphs and identifying the desired form to design a reliable process for its consistent production is critical for a successful drug development. [5][6][7] But, even after a thorough search, new polymorphs can suddenly appear or previously known polymorphs can disappear at any stage of the process development. [8][9][10][11] This inability to control the appearance of polymorphs clearly demonstrates the lack of understanding in this phenomenon.…”

Polymorphism and Solvatomorphism 2006

“…The development strategy used by Novartis to obtain reproducible polymorphic composition of drug substances was illustrated using carbamazepine as the example, and it was shown how physicochemical characterization methods were used to develop a simple robust process that could supply approximately 1000 kg of a stable polymorph for clinical trials and market introduction. 33 Other methods of initiating nucleation in crystallization processes have been studied with the aim of obtaining better control over the isolated product. A study has been reported where the effect of ultrasound irradiation on the polymorphic composition, particle size distribution, and heat transfer characteristics in the batch cooling crystallization of glycine was evaluated.…”