Route, Solid-State, and Impurity Optimization (Small-Molecule API)
Program Type: Small-molecule API
CMC Focus: Route optimization, solid-state control, impurity management
Overview
In a separate small-molecule program, Medicilon re-engineered the API synthetic route and solid form strategy to significantly improve manufacturability, safety, and analytical control. The work integrated process chemistry, solid-state science, and analytical development under a unified CMC framework.
Key Outcomes
- Route simplification and yield improvement:
Reduced steps to a key intermediate from 7 to 4, increasing yield from <5% to >20%, while eliminating a malodorous sulfur reagent and avoiding reliance on SFC chiral separation. - Robust solid-form selection:
Identified an optimal salt form through comparative XRPD and crystallization screening, followed by tailored crystallization methods to generate high-quality single crystals for structure confirmation and IP support. - Enhanced impurity and solvent control:
Reduced residual solvents using a toolbox of 20+ crystallization and drying strategies, and upgraded analytical methods to clearly resolve and control previously overlapping impurities.
Route/step and yield optimization:
- Improve efficiency
The liner sequence steps were reduced from 12 to 7, total yield was increased from <1% to >10%l, no silica gel column purtications were needed.
2. Reduce steps
Medicilon reduced the route to the key intermediate from seven to four steps and increased yield from less than 5 to over 20 by redesigning the CMC API process.
Solid State R&D Platform:
1.) Salt and Crystalline” (XRPD of HCl vs malic acid salt).
2.) Crystalline Form” (conventional vs novel crystallization methods to obtain single crystals).
Solvent residue and impurity control:
1.) Solvent Residue Removal: 20+ classic and self‑developed methods to reduce solvent residue
2.) API analytical methods
- Original analytical Method Spectrum:
Related impurities could not be completely separated
- Analytical Method Spectrum after optimization
Related impurities could be effectively separated
