Knowledge-based H-bond prediction to aid experimental polymorph screening

Abstract

With an ever increasing regulatory and financial emphasis on solid form screening in the pharmaceutical industry, a knowledge-based method has been developed to assess crystal stability based on hydrogen bonding. An application is illustrated for the polymorphic drug ritonavir (Norvir™). The method quickly suggests a real threat of polymorphism in this compound by quantifying the likelihood of competing H-bonds, and strongly supports the relative stability of form II over form I. For the first time, H-bond geometry data are also reported following structure redeterminations deposited recently in the Cambridge Structural Database. The method's speed and versatility are emphasized, facilitating future application in assisting solid form selection of a diverse range of compounds.