As part of the search for drugs with activity on the central nervous system (CNS) a fluoroaryl-amine was identified and developed by GlaxoSmithKline. The manufacturing process was developed and optimised by following a quality by design approach whereby a control strategy was developed, underpinned by process understanding and risk analysis, for enhanced level of quality assurance. A summary of the overall control strategy for this process includes different elements of control (Quality Process Parameters, control of the Quality Attributes of starting materials, intermediates, solvents, in-process controls). The drug substance Critical Quality Attributes (drug substance-CQAs) related to the genotoxin content, methyl methanesulfonate (methyl mesylate, MMS), ethyl methanesulfonate (ethyl mesylate, EMS) and isopropyl methanesulfonate (isopropyl mesylate, IMS) are identified and discussed in detail to show the process development studies carried out to ensure quality control for the final drug substance. The process understanding developed could allow for the elimination of testing of the genotoxic impurities in the final drug substance.

Casopitant was identified as a potent NK 1 antagonist by Glaxo-SmithKline (GSK). It was selected as part of a wide drug discovery programme within GSK for its potential activities on a number of therapeutic targets such as inflammatory bowel disease, overactive bladder, CNS disorders, and others. The mesylate salt of casopitant was selected for full development. The manufacturing process to casopitant mesylate was developed and optimised by following a Quality by Design approach, whereby a control strategy was developed, underpinned by process understanding and risk analysis, for an enhanced level of quality assurance. Quality process parameters and specifications levels for the Stages 2a, 2b, and 2c are the elements of the control strategy of the manufacturing process discussed in detail in this paper. The Design of Experiment approach has been extensively used to support the definition of the proven acceptable ranges for the process. The aim is to show the process development studies carried out to ensure quality control for the final drug substance.

The chemical method for the preparation of the intermediate 14 was assessed in order to ensure safe scale up on pilot plants. Previous experience on the same kind of reactions

GW597599 1 is a novel NK-1 antagonist currently under investigation for the treatment of central nervous system disorders and emesis. The initial chemical development synthetic route, derived from the one used by medicinal chemistry, involved several hazardous reagents, gave low yields and produced high levels of waste. Through a targeted process of research and development, application of novel techniques and extensive route scouting, a new synthetic route for GW597599 was developed. This paper reports the optimisation work of the third and last stage in the chemical synthesis of GW597599 and the development of a pilot-plant-suitable process for the manufacturing of optically pure arylpiperazine derivative 1. In particular, the process eliminated the use of triphosgene in the synthesis of an intermediate carbamoyl chloride, substantially enhancing safety, overall yield, and throughput.