Pharmaceutical Studies on Aromatic Azido Compounds

Abstract

2,4-Diamino-5-(3-azido-4-chloropheny1 )-6-ethy] pyrimidine [mazidopyrimethamine, MZP] is a novel lipophilic antifolate and the first arylazide to be considered for clinical use. HPLC methods were developed for quantitative evaluation of MZP and its analogues. 13¢ NMR spectroscopy studies revealed that, at physiological pH, protonation of the 2,4-diaminopyrimidines occurred predominantly on the heterocyclic N-1; in MZP, the pKa of this nitrogen was found to 7.19. The Log P of MZP was determined fo be 2.81. MZP was found to have low aqueous solubility (22 ugm1-1) and henge the more water soluble MZP ethanesulphonate [MZPES] (17.6 mgm1-1 ) was chosen for formulation development. Thermal degradation of 10 mgm1-1 aqueous MZPES_ solutions followed first order kinetics and the activation energy was calculated to be 139.3 kJmo1-1. Heating a 10 mgm1-1 aqueous MZPES solution at 145°C for 2 hours resulted in a 28% yield of m-aminopyrimethamine [MAP] as the major product. Aqueous solutions of MZPES were stable for at least 21 months when stored at -10, 4 or 20°C; but at temperatures >100°C degradation of the compound occurred rapidly. Aqueous solutions of MZPES were shown to be photo-labile. The photolytic rate of MZPES, however, was slightly retarded in nitrogensaturated solution. The nature and ratio of the photoproducts of MZPES formed in aqueous solution varied according to whether the solution was saturated with air, oxygen or nitrogen. Several of these degradation products have been identified and reaction schemes have been proposed to account for their formation. Structures and derivations of the unidentified products have also been proposed. MZPES was formulated as a 10 mgm1 -1 aqueous solution (pH 4.10) and recommended to be diluted in 500 mls 5% Dextrose infusion prior to administration. MZPES was shown to be stable in 5% Dextrose solution for at least 80 hours. MZPES injections were prepared under aseptic conditions and sterilized by filtration. The injections were packed in opaque containers and stored at 4°C to maximise stability The clinical pharmacokinetics of MZPES exhibited a biphasic profile. The distribution and elimination half-lives of the drug were determined to be 0.35 + 0.22 and 37.42 + 17.11 hours respectively. The average volume of distribution of MZPES was found to be 145.6 + seco. L. No adverse haematological effects were observed to be associated with MZPES administration during the current study up to a dose of 250 mgm°. MZPES was shown to be less toxic than the prototype lipophilic antifolate metoprine.