Preformulation studies with 1, 3-bis (2-chloroethyl)-1-nitrosourea (NSC 409962) Public Deposited

http://ir.library.oregonstate.edu/concern/graduate_thesis_or_dissertations/p8418r07n

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  • The stability of 1 3-bis(2-chloroethyl)-1-nitrosourea (NSC 409962)(BCNU) was investigated in several buffered aqueous media, in mixed solvent and in nonaqueous solvent systems, and in the presence of several electrolytes and nonelectrolytes. The degradation rate constant of BCNU in these systems was calculated from the parameters of the linear regression of the logarithm of BCNU remaining on time. The calculated degradation rate constants in buffered aqueous media were utilized to ascertain both the presence of a pH at which minimum degradation ocurred and the value of this minimum pH. The existence of specific base catalysis and absence of specific acid catalysis were observed. In addition, evidence for the presence of general acid catalysis and no evidence for general base catalysis were found. The apparent activation energies for BCNU degradation in the buffered aqueous media were calculated. An apparent relationship between pH and the activation energy was observed. This relationship was found to be log - linear with a positive slope. This relationship is probably due to the effect of the activation energy for the specific base catalytic rate constant on the apparent activation energy of degradation. The calculated degradation rate constants for BCNU in mixed and nonaqueous solvents revealed that the degradation rate constant decreases as the dielectric constant decreases. The activation energy for BCNU degradation in these solvents indicated the lack of a relationship between the apparent activation energy and macroscopic dielectric constant. From the studies in several electrolytes no consistent effect of ionic strength on BCNU stability could be observed. The degradation rate of BCNU in the presence of several nonelectrolyte compounds disclosed no effect either to enhance nor diminish the stability of BCNU when compared to unbuffered aqueous media. An effect on BCNU stability of a hydrophilic surfactant at several concentrations was not observable. On the other hand, in the presence of a comparatively hydrophobic surfactant, the degradation rate constant for BCNU was found to be about one half that in unbuffered aqueous media. This effect may be attributable to the stabilizing effect of the micelles formed by the surfactant in which BCNU is solubilized and protected against solvolysis. Several recommendations aimed toward the logical development of an optimum parenteral formulation for 1,3-bis(2- chloroethyl)-l-nitrosourea were made as well as the rationale supporting these suggestions.
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