5-Fluoro-3-[3-[4-(5-methoxy-4-pyrimidinyl)-1-piperazinyl]propyl]-1H-indole dihydrochloride (1) facilitates
5-HT neurotransmission and was an antidepressant drug candidate.
The
development of a safe, rugged process for the large-scale,
chromatography-free preparation of this compound is described. The main areas of optimization included a
Fischer
indole synthesis, preparation and chlorination of a monohydroxypyrimidine, and coupling of the resultant fragments to
prepare the drug substance.
In this study, we describe the use of an innovative imaging system to measure and control the effect of nozzle operating parameters on the characteristics of a spray. These characteristics, including spray pattern, droplet size distribution, and droplet velocity, define the quality of the spray. They can have significant impact on the efficiency of the pan coating process and the quality of the coat. Suspensions of different composition were used in this study, and the authors demonstrated that the spray characteristics can be controlled with this approach.The main conclusions from this study were:1. The AA/Spray (atomization air/spray rate) and AA/PA (atomization air/pattern air) mass flow ratios were the key parameters that affect spray characteristics. Although viscosity can impact the spray, there was minimal impact within the viscosity range tested in this study. 2. With proper selection of the AA/Spray and AA/PA mass flow ratios, it was possible to generate sprays with consistent spatial distributions of volume flux with minimal variations of mean droplet size over the range of coating suspensions and spray rates studied.Spray characterization can be a powerful tool for exploring and establishing the design space of nozzles operation in the pan coating process. When scaling or transferring a spray coating process, the focus should be on maintaining consistent spray qualities rather than limiting nozzle operating parameters to a range. This approach embraces the FDA concept of process analytical technology (PAT) and design space (FDA, Guidance for industry PAT-A framework for innovative pharmaceutical development, manufacturing, and quality assurance, 2004) for sciencebased operation flexibility.
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