Investigation of the Crystallization of Phenytoin in Normal Saline

Abstract

A study was designed to determine if the admixture of phenytoin in normal saline would remain physically stable for a suitable period of time to allow for intravenous infusion. Five phenytoin concentrations (1.0 mg/ml, 2.5 mg/ml, 5.0 mg/ml, 7.5 mg/ml, and 10.0 mg/ml) were prepared in triplicate by adding a sufficient volume of normal saline to the appropriate volume of phenytoin sodium injection to produce a total volume of 100 ml. Aliquots of all solutions were withdrawn at zero, 1, 8, 16, and 24 hours. Solutions were filtered through a 0.22 micron millipore filter and the concentration of phenytoin and pH of each solution was determined. A significant concentration difference was not seen between zero time and 24 hours. The pH of the samples ranged from 9.75 to 11.00. While phenytoin sodium appears to be stable in the concentrations tested when sodium chloride 0.9% is the vehicle, several important factors must be considered and caution must be used if the admixture is administered intravenously.

A 5% Glucose Infusion Fluid Provokes Significant Precipitation of Phenytoin Sodium Injection via Interruption of the Cosolvent Effect of Propylene Glycol.

“…Although the exact pH value was not determined, because of its unstable pH, no precipitation was observed for at least 24 h in this admixture (data not shown). Many authors stated that phenytoin sodium injection in saline, but not in glucose infusion fluid, is stable for hours; 8,10,14,15,18) our results agree well with this contention.…”

“…[8][9][10][11]14,15) From investigation using a glucose infusion fluid admixture, 8) Pfeifle et al insisted on the existence of crucial factors that are not associated with pH reduction. Regarding other fluids, such as saline and lactated Ringer's injection, their enhancement effect on the precipitation of phenytoin is doubtful: the majority of authors rejected their ability to induce precipitation, 8,10,14,15,18) whereas some authors reported opposite results. 11,12) In this study, first we characterized the precipitation occurring after mixing phenytoin sodium injection with glucose infusion fluids.…”

“…The influence of various factors other than the final pH of the admixture has been investigated. These factors include dilution of the phenytoin solubilizing agent by infusion fluids, 9,10,14) particulate matter present in infusion fluids, 9) time delay from the dilution, 14,18) and solvent evaporation and absorption of carbon dioxide when the solution is exposed to air. 11,19) Despite the best endeavors to elucidate the precipitation of phenytoin, some of its aspects remain unclear.…”

Contribution of Glucose to Crystallization of Phenytoin in Injectable Dosage Form by Dilution with Infusion Fluids

“…On the other hand, there are many studies indicating that the admixture diluted with saline is stable for many hours. 11,12,14,17,18) We also observed no crystallization from the admixtures as long as the injection was diluted with saline or water. 19) In the previous study, we have investigated the crystallization that occurs upon mixing with glucose-containing infusion fluid.…”

“…The influence of various factors other than the final pH of the admixture has been investigated. These factors include dilution of the phenytoin solubilizing agent by infusion fluids, [11][12][13] particulate matter present in infusion fluids, 13) time delay from the dilution, 12,14) and solvent evaporation and absorption of carbon dioxide when the solution is exposed to air. 15,16) Despite the best endeavors, there are still some unknown factors associated with the crystallization from phenytoin sodium injection occurring after mixing with infusion fluids.…”