Example of Finishing Technologies as Key Elements for Successful Active Pharmaceutical Ingredient Process Development

Abstract

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.

Comparison Study of Different Spherical Crystallization Methods of Ambroxol Hydrochloride

“…Generally, crystallization is the last step of the production of solid form active pharmaceutical ingredients (APIs) and additives. The process of crystallization is suitable not only for purification, but also for achieving a proper crystal size and morphology . Particle surface, size, and distribution influence many properties of solid materials and are valuable indicators of quality.…”

“…The process of crystallization is suitable not only for purification, but also for achieving a proper crystal size and morphology. 1 Particle surface, size, and distribution influence many properties of solid materials and are valuable indicators of quality. The size and shape of the particles influence flow and compaction properties.…”

Process Development Strategy to Ascertain Reproducible API Polymorph Manufacture

“…However, robust scale-up of polymorph manufacture is still often treated as an art; little has been published so far to illustrate the application of a consistent process development strategy to ascertain reproducible API polymorph manufacture. In the present example, key elements of finishing technologies 1 are discussed and illustrated based on data from a development project of Novartis Pharma AG and based on studies with carbamazepine, a well-reported compound. Under finishing technologies, we understand the interrelated processes of crystallization-filtration-drying.…”

The capture and release of biomass in a high voidage fibrous microstructure: Mechanisms and shear stress levels

“…The filtration of particle suspensions through porous media is of interest in areas as diverse as pharmaceutical production [22], oil production from subsurface wells [16,33,37,19], ground water seepage [27,2,28] and purification of molten metals [1,38]. The principal objectives of these filtration operations are to remove particulates and/or to maximise filter runs by preventing clogging of the filter medium.…”