Determination of the binding constant between alprostadil and alpha-cyclodextrin by capillary electrophoresis: Implications for a freeze-dried formulation

Determination of the binding constant between alprostadil and alpha-cyclodextrin by capillary electrophoresis: Implications for a freeze-dried formulation
May 26, 2005
Benjamin R. Schipper 1, Tore Ramstad 2 *
1Kalamazoo College, Kalamazoo, Michigan
2Pharmaceutical Sciences, Pfizer Corp., Kalamazoo, Michigan
Journal of Pharmaceutical Sciences Volume 94, Issue 7 , Pages 1528 - 1537
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Abstract
The binding constant between alprostadil (PGE1) and -cyclodextrin (-CD) was determined at three temperatures by capillary electrophoresis. -CD is an excipient material in Caverject Dual Chamber Syringe (DCS), added to enhance stability. The binding constant was used to calculate the amount of PGE1 free upon reconstitution and injection, the latter of which is critical to product performance. Measurement was made in a pH 7.2 separation buffer to ensure a negative charge on PGE1. The concentration of PGE1 was fixed while the concentration of -CD was varied over a suitable range. As the amount of PGE1 bound to -CD increases, the weighted average of the resultant mobility decreases, thereby allowing a binding isotherm to be generated from which the stability constant was extracted via nonlinear regression analysis. A value of 708 ? 64 M-1 was obtained at 27?C, while at physiological temperature (37?C) the value was 537 ? 27 M-1. These results compare favorably to values previously obtained by NMR. Calculation of the percent PGE1 free upon reconstitution and injection show it to be near the desired outcome of 100%. Hence, we were able to conclude that the amount of free drug delivered by Caverject DCS is nominally the same as for Caverject S. Po., an earlier-developed product that contains no -CD. ? 2005 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 94:1528-1537, 2005