Project Goal:

HPLC method development, process development, and synthesis of 10 g of a peptide drug conjugate for toxicology studies

Details:

Synthesis of this compound was previously performed by a well-known CRO in Switzerland with little success and only 12 mg of the compound was delivered to the client in poor purity.

Following these unsatisfactory results, client discussed the project with CalChem for a process R&D and preparation of 10 g of the compound for toxicology studies.

Outcome:

The process was a multi-component sequence involving synthesis of a linker, attachment of an API to the linker, and treatment of the conjugate molecule with a peptide in the final step.  The process required development of a robust HPLC method to precisely detect and monitor all the components of the reactions during the In-Process-Control (IPC) analyses.  A good HPLC method with a high degree of resolution was developed prior to the process development.  Consequently, route scouting was completed by screening different reaction conditions, evaluating all critical process parameters (CPPs), and developing a robust process suitable for large scale synthesis of the molecule and future cGMP production.  Finally, two Proof-of-Concept (POC) batches were performed and 10 g of the compound was delivered in >95% purity by eliminating a reverse-phase purification in the final step and replacing it with a slurry/trituration protocol.  Further process optimization in the second phase of the project is underway to increase the purity of the target molecule to >98% without reverse phase purification and smoothly transfer the process to a GMP facility for the production of the compound in Phase I clinical studies.