STA Pharmaceutical, a WuXi AppTec company
Abstract: STA Pharmaceutical, a WuXi AppTec company, is a global leading small molecule pharmaceutical development and manufacturing capability and technology platform company serving the life science industry, with operations in China and the United States. As a premier Contract Development and Manufacturing Organization (CDMO), STA offers our worldwide partners efficient, flexible and high-quality solutions for small molecule Active Pharmaceutical Ingredients (APIs) and finished dosage forms. STA began offering Flow Chemistry (Continuous Processing) services in 2013 and rapidly expanded due to our client’s need. Flow chemistry is a solution to some ubiquitous manufacturing challenges experienced with batch processing including process safety issues, presence of unstable intermediates, extreme reaction conditions requirements, the need for short residence time, and engineering issues such as poor heat or mass transfer in multiple phase reactions.
Description: Large Scale Production of Pharmaceutical Intermediates Using Continuous Processing Technologies
Major drivers for developing flow processes include process safety issues, poor heat and mass transfer, presence of unstable intermediates, extreme reaction conditions, and the need for short residence time. Since 2015, STA Pharmaceutical, a WuXi AppTec company, has established a leading continuous processing technology platform to support process R&D and plant scale production of pharmaceutical intermediates. Selected reaction types included cryogenic and room temperature lithiations, deprotection, ozonolysis, oxidations, dehydrations, coupling, cyclization, amination, and azide chemistries. Special technologies were used to develop photo reactions, an explosive compound, Grignard reaction, and a high temperature-high pressure reaction. Flow steps also included unit operations such as phase separation, crystallization, filtration, and dissolution. The scale of the operations ranged from hundreds grams to hundreds of kilograms under GMP and non-GMP modes. A 5-step flow step including 2 chemical and 3 unit operation processing 160 kg of solids in two weeks were performed under GMP conditions. Presented here are case studies illustrating the key benefits of this technology platform.
Process Safety Case Study: Challenges encountered in a batch process included potential for explosion and decomposition of intermediates due to the long reaction time. We designed a continuous process using an ozonolysis in a bubble column to optimize the gas-sparger temperature and flow rate. Under continuous flow mode we were able to produce 70 kg of material in 10 days eliminating the safety concern and increasing the yield.
Immiscible Phases Reaction: Challenges encountered in a batch process with two immiscible phases were hard to scale and maintain purity. We optimized the reactor configuration and designed a continuous process with a plug flow reactor and internal mixers to improve mixing, solvent temperature, reactant ratio, and residence time parameters. We scaled up the flow process to deliver 457 kg material in 15 days.
Extreme Temperature Case Study: Challenges encountered during a batch process included heating the substrate and DPPE to 200 ÌŠC to generate an intermediate prior to an intermolecular cyclization Cadogan Cyclization reaction. We designed a flo
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Category: Drug Substance
Type: Small Molecules
Contact: Yu Lu ([email protected])