Stable-form screening: overcoming trace impurities that inhibit solution-mediated phase transformation to the stable polymorph of sulfamerazine.
Solution-mediated phase transformation (SMPT) has been used as a focused technique to rapidly identify the stable polymorph of a given substance. Despite ample precedence for acetonitrile being a good solvent for SMPT of sulfamerazine (SMZ), samples from specific lots of SMZ failed to convert from Form I to Form II after suspension for 2 weeks in acetonitrile. In these lots, an acetyl derivative of SMZ was identified and shown to impede transformation to the stable polymorph. The inhibitory effect of this impurity on polymorphic conversion was overcome with practical adjustments to experimental procedure, which hastened the kinetics of SMPT. The critical factors considered were (1) modifying the solvent to increase solubility, (2) minimizing the level of impurity in the slurries, (3) pre-treatment of the solid to quickly reach maximum supersaturation, and (4) temperatures that optimized kinetics as well as the free energy difference between enantiotropically related polymorphs.
Gong
Yuchuan
Y
Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Weaver-Densford Hall, 308 Harvard Street S.E., Minneapolis, Minnesota 55455-0343, USA. yuchuangong@gmail.com
Collman
Benjamin M
BM
Mehrens
Shawn M
SM
Lu
Enxian
E
Miller
Jonathan M
JM
Blackburn
Anthony
A
Grant
David J W
DJ
D000097:Acetonitriles / Q000737:chemistry; D000890:Anti-Infective Agents / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical; D003460:Crystallization; D004340:Drug Contamination; D004355:Drug Stability; D007700:Kinetics; D008956:Models, Chemical; D010316:Particle Size; D012995:Solubility; D012997:Solvents / Q000737:chemistry; D013416:Sulfamerazine / Q000737:chemistry*; D013499:Surface Properties; D013678:Technology, Pharmaceutical / Q000379:methods; D013696:Temperature
D000097:Acetonitriles; D000890:Anti-Infective Agents; D012997:Solvents; D013416:Sulfamerazine; C032159:acetonitrile