Reformulation of a new vancomycin analog: an example of the importance of buffer species and strength.
The purpose of this research was to use our previously validated dynamic injection apparatus as a rapid method for screening pH-adjusted formulations of a new vancomycin analog, Van-An, for their potential to precipitate upon dilution. In 1 vial, Van-An was reconstituted according to the manufacturer's instructions. In a separate vial, the Van-An formulation's existing phosphate buffer species was supplemented with acetate buffer, which has a pKa in the desired range: between the pH values of the formulation (pH 3.9) and blood (pH 7.4). The formulations were injected using the dynamic injection apparatus into a flowing stream of isotonic Sorensen's phosphate buffer at rates of 0.25, 0.5, 1, and 2 mL/min. The peaks obtained with the spectrophotometer were reproducible for each injection rate/formulation combination. For the phosphate-buffered formulation, the least amount of precipitation was obtained at the 0.25 mL/min injection rate. Acetate buffer was able to substantially reduce such precipitation, even at the highest injection rate. The opacity peaks for the formulation with the acetate addition were significantly smaller (P < .05) than those obtained for the unaltered formulation at all 4 injection rates. The results suggest that acetate is a better buffer species than phosphate for the pH range defined. Furthermore, we present evidence to support a generally applicable approach to screening new formulations of drug products that may be clinically useful for reducing the incidence of phlebitis in humans.
Johnson
Jennifer L H
JL
Pharmaceutical Science, College of Pharmacy, University of Arizona, 1703 E Mabel St, Tucson, AZ 85721, USA. jjohnson@imarx.com
Yalkowsky
Samuel H
SH
D002021:Buffers; D011232:Chemical Precipitation; D002626:Chemistry, Pharmaceutical; D006863:Hydrogen-Ion Concentration; D012995:Solubility; D013053:Spectrophotometry; D014640:Vancomycin / Q000008:administration & dosage / Q000031:analogs & derivatives*
D002021:Buffers; D014640:Vancomycin