Industry Examines Approaches for Characterizing APIs

Accurate characterization of active pharmaceutical ingredients (APIs)is a critical part of the drug development process. The approaches usedto characterize APIs with respect to structure, identification ofimpurities, and the solid state were discussed by Andrew C. Kolbert,manager, molecular structure and spectroscopy, Cardinal Health (Dublin,OH, www.cardinal.com)at the PharmTech AnnualEvent, held in Somerset, New Jersey this week.

Industry guidance for detecting organic impurities in APIs is addressedin the International Conference on Harmonization of TechnicalRequirements for Registration of Pharmaceuticals for Human Use (Geneva,Switzerland, www.ich.org)Q3A Impurities in New Drug Substances(www.fda.gov/cber/gdlns/ichq3a.htm).

The analytical tools and methods used in detecting these impurities isan important consideration. "Roughly 50-75% of organic impurities canbe identified using an LC-MS [liquid chromatography-mass spectrometry]screen," explained Kolbert. "However, for those impurities that cannot,LC-NMR [liquid chromatography-nuclear magnetic resonance] may be used.Although LC-NMR may be difficult to use, it is particularly useful if adegradant is unstable. Other approaches include isolation and/ordirect synthesis based upon the best guess as to the structure."

Solid-state characterization also is critical because molecules cancrystallize in more than one form (polymorphs). "The form affectsdissolution properties, bioavailability, and stability," said Kolbert."FDA requires an understanding of the solid state, an indication of theform to be used, and retesting and reapproval if the form changes."

These forms may be characterized by several methods: differentialscanning calorimetry, X-ray diffraction, solid-state nuclear magneticresonance, Raman spectroscopy, and optical microscropy.

Kolbert also emphasized the value in obtaining proof-of-structure,validated analytical methods, detecting impurities, and characterizingthe solid-state early in the drug development process, ideally at thetime of submission of an investigational new drug application. "If youdelay proof-of-structure, methods validation, impurity identification,and solid state characterization until Phase III, you may impact theapproval timeline," he said.