Active pharmaceutical ingredients process development

Muller, M., Schneeberger, R., Wieckhusen, D. and Cooper, M. Example of finishing technologies as key elements for successful active pharmaceutical ingredient process development. Org. Process Res. Dev. 8 376-380, 2004. 

These and other FDA policy decisions launched the pharmaceutical industry and academia into a new era of developing stereoselective processes for the manufacture of enantiopure active pharmaceutical ingredients (APIs). 

However, compared with the traditional analytical methods, the adoption of chromatographic methods represented a signihcant improvement in pharmaceutical analysis. This was because chromatographic methods had the advantages of method specihcity, the ability to separate and detect low-level impurities. Specihcity is especially important for methods intended for early-phase drug development when the chemical and physical properties of the active pharmaceutical ingredient (API) are not fully understood and the synthetic processes are not fully developed. Therefore the assurance of safety in clinical trials of an API relies heavily on the ability of analytical methods to detect and quantitate unknown impurities that may pose safety concerns. This task was not easily performed or simply could not be carried out by classic wet chemistry methods. Therefore, slowly, HPLC and GC established their places as the mainstream analytical methods in pharmaceutical analysis. 

Tao, J., Zhao, L. and Ran, N. (2007) Recent advances in developing chemoenzymatic processes for active pharmaceutical ingredients. Organic Process Research Development, 11, 259-267. 

This chapter provides an introduction to the pharmaceutical sector, and the business of developing new active pharmaceutical ingredients (API). Crystallization is the preferred method of isolating commercial API products because it offers a highly efficient means of purification. The crystallization process is also where the physical properties of the drug substance are defined. These properties can have a significant impact on the formulated product and process, and eventually on the drug release profile in the patient. 

The design of crystallization processes for the manufacture of Active Pharmaceutical Ingredients is a significant technical challenge to Process Research and Development groups throughout the Pharmaceutical and related industries. It requires an understanding of both the thermodynamic and kinetic aspects of crystallization, to ensure that the physical properties of the product will consistently meet specification. Failure to address these issues may lead to production problems associated with crystal size, shape and solubility, and to dissolution and bioavailability effects in the formulated product. 

Safety Production of the requisite drug molecule, called the active pharmaceutical ingredient (API) or bulk pharmaceutical chemical (BPC), may involve materials, solvents, or intermediates that are volatile, toxic, or even explosive. The development program has to determine the appropriate manufacturing processes to ensure that safety is not compromised and the API can be produced and purified to remove impurities and toxic residues. 

Expert systems for the design of the solvent mix should be further developed. In particular, proposals including the type of reaction working in a particular system should be included. The availability of larger and more reliable data sets would reduce the hurdles for applications. Especially for active pharmaceutical and agrochemical ingredient process developments, which have to be done within a short time frame. There is no time available to adapt new solvent systems. Therefore, sufficient data should be available to select a solvent mix within a few experiments. 

In the pharmaceutical industry, distributors fall under intense scrutiny, as critical players in the supply chain. From the early development of many drug products to production and commercialization, distributors are integral parts of the entire process— supplying equipment, active pharmaceutical ingredients (APIs), and excipients—the focus of this chapter. 

Sertraline is the active pharmaceutical ingredient (API) in Pfizer s antidepressant Zoloft [25]. The developed commercial process employs an SMB chromatographic resolution of tetralone (Scheme 13.10) in >99% ee followed by diastereoselective reductive amination to give 95% sertraline (cis-isomer) and 5% trans-isomer the (4R)-tetralone can be racemized with an alkoxide base [8]. Asymmetric processes to sertraline have been described [26]. Our studies started with the original patented process involving palladium-catalyzed reductive amination of a tetralone to give a mixture of 80% racemic-cis and 20% racemic-trans diastereomers [27]. The cis-diastereomer can be purified by selective crystallization from toluene followed by diastereomeric crystallization of the (lS,4S)-enantiomer using (R)-... 

The Novartis Process Chemistry group s preparation of discodermolide represents a landmark in the industrial synthesis of complex natural products and pharmaceutical development. Having taken the bold decision to pursue the clinical development of discodermolide under tight time constraints, they met the challenge of combining the approaches of Smith and Paterson and delivering sufficient quantities of active pharmaceutical ingredient to enable clinical trials. 

---