ISSN:
1573-904X
Keywords:
nuclear magnetic resonance spectroscopy
;
carbon-13 cross-polarization magic angle spinning spectroscopy
;
water
;
antibiotic
Source:
Springer Online Journal Archives 1860-2000
Topics:
Chemistry and Pharmacology
Notes:
Abstract Understanding how moisture interacts with a drug or formulation is a critical component of product development. This study demonstrates how water affects the 3′-gem-diol ↔ 3′-keto equilibrium in trospectomycin sulfate bulk drug and freeze-dried formulation, as probed by solid-state carbon-13 cross-polarization magic angle spinning (CP/MAS) and high-resolution nuclear magnetic resonance (NMR) spectroscopy. Drying the bulk drug or formulation to low water levels dehydrates trospectomycin sulfate from the diol to the keto form. Carbon-13 CP/MAS NMR spectroscopy measures the keto drug concentration in solid samples directly. The bulk drug, which contains approximately 16% water, is more than 90% in the 3′-diol form. Oven drying to 〈3% water converts approximately 75% of the drug to the 3′-keto form. The drug is formulated as a freeze-dried, sterile powder that can contain up to 12% water depending on the freeze-drying conditions. These studies show that the 3′-keto concentration rises uniformly (up to 75%) with decreasing residual water in the freeze-dried cake. The keto–diol equilibrium was also studied in solution by high-resolution carbon-13 NMR experiments, and it was found that raising the temperature or using dimethyl sulfoxide (DMSO) as a solvent also dehydrates the drug. For example, in aqueous solution at 25°C, nearly all (〉95%) of the drug is in the 3′-diol form. After equilibration at 60°C, however, the 3′-keto content increases to 7%, and in d 6-DMSO solvent at 25°C the drug is mostly (60%) in the 3′-keto form.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1023/A:1018925113721
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