APPLICATION OF UF TECHNOLOGY TO LARGE-SCALE SYNTHESIS OF GT 267-004, A SEQUESTRANT FOR C. DIFFICILE TOXIN

Abstract

GT 267-004 is a nonabsorbed, nonantibiotic, high molecular weight anionic polymer that is undergoing clinical evaluation as a Clostridium difficile toxin sequestrant. The API is a mixed salt form that consists of approximately 30 to 50% potassium and 70 to 50% sodium as the counterions on the polymer.

The initial polymerization process results in an aqueous polymer solution with the polymer in the 100% sodium form. It also contains some oligomeric impurities. UF technology was applied in a novel way to convert the single-salt polymer to the mixed salt form and to simultaneously remove the oligomers below the required specification limits in a single-unit operation.

Experiments with a UF lab unit validated the concept of simultaneously performing ion exchange and purification. An appropriate amount of potassium chloride was added to the polymer solution to carry out the ion exchange considering the selectivity of the polymer for the potassium ion over the sodium ion. The resulting mixed salts in solution were removed using ultrafiltration membranes. The process produced the API in excellent purity.

The lab data were used to scale up the process to produce several hundred kg of the API. The engineering analysis of the large-scale UF operation was carried out to run the UF process in the cyclic mode and in the diafiltration mode. The UF operation was optimized with respect to time, water usage, operability, and the concentration of product solution required for the subsequent processing.

The optimized UF process was found to be a very cost-effective and time-efficient route to produce the new API.

Keywords:

• API synthesis
• Cyclic and diafiltration modes
• GT 267-004
• Ionic conversion
• Oligomer removal
• Pharmaceutical scale-up
• Ultrafiltration
• UF optimization

Acknowledgments

The author would like to acknowledge the GT267–004 project team for technical discussions and support.

Sincere appreciation and thanks are due to Dr. Amy Tapper for executing the initial lab experiments. The scientific and operations staff at Yonezawa Hamari Chemicals Limited is acknowledged for their diligent execution of lab experiments and production runs.

Thanks are due to the analytical research and development (ARD) department at Genzyme for excellent analytical support. The author would like to express sincere appreciation to Drs. David Davidson, Mukund Chorghade, and Caroline Kurtz for interesting discussions and constructive comments.

The author thanks the management at Genzyme Drug Discovery and Development for active support and encouragement.