Pharmaceutical Studies on Aromatic Azido Compounds

Student thesis: Doctoral ThesisDoctor of Philosophy


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.
Date of Award1986
Original languageEnglish


  • Pharmaceutical studies
  • aromatic azido compounds

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