Quantitative crystallinity determinations for beta-lactam antibiotics by solution calorimetry: correlations with...

Area of Science:

• Pharmaceutical Sciences
• Physical Chemistry
• Materials Science

Background:

• Amorphous forms of drugs possess higher energy than crystalline forms.
• Solution calorimetry leverages this energy difference to assess physical form.
• Understanding drug crystallinity impacts stability and bioavailability.

Purpose of the Study:

• To evaluate the utility and validity of solution calorimetry for assessing drug crystallinity.
• To compare calorimetric crystallinity with X-ray diffraction and thermal decomposition data.
• To establish the correlation between calorimetric crystallinity and chemical stability for specific cephalosporin sodium salts.

Main Methods:

• Preparation and characterization of amorphous, partially crystalline, and crystalline forms of cephalothin sodium, cefazolin sodium, cefamandole nafate, and cefamandole sodium.
• Powder X-ray diffraction (PXRD) for structural analysis.
• Solution calorimetry to determine heat of solution and relative energy.
• Thermal decomposition rate analysis for cephalothin sodium.

Main Results:

• Good qualitative correlation observed between calorimetric and X-ray diffraction-derived crystallinity.
• Heat of solution provides a precise (+/- 1%) and unambiguous measure of relative crystallinity.
• Sample history influences the energy and structure of the amorphous state and crystalline polymorphs.
• Calorimetric crystallinity correlates well with chemical stability when appropriate standards are selected.

Conclusions:

• Solution calorimetry is a valid and precise method for quantifying relative drug crystallinity.
• The method's accuracy depends on the appropriate selection of amorphous and crystalline standards.
• Calorimetric assessment of crystallinity is a reliable predictor of chemical stability for cephalosporin sodium salts.