Title:
|
Aspects of chlorhexidine degradation
|
This thesis examines the factors affecting the stability of
chlorhexidine salts (principally gluconate) in dilute aqueous solution
(0.001 to O.05%w/v). Such studies are pertinent to the use of
chlorhexidine as a preservative in aqueous pharmaceutical products.
The introduction details the factors affecting the stability of
pharmaceuticals in solution. Published work on the physico-chemical
properties of chlorhexidine and structurally related compounds is then
reviewed together with methods available for the quantitative analysis
of chlorhexidine.
The experimental section describes the evaluation of a HPLC
stability indicating method for the quantitative determination of
chlorhexidine in terms of sensitivity, precision, reproducibility and
selectivity. Comparison is made between this method and the more
conventional colorimetric methods based on the Holbrook technique and
4-chloroaniline determination. The degradation kinetics of dilute
aqueous solutions of chlorhexidine gluconate have been examined by a
pH-stat.ting technique. Over the range pH 2 to 10, 0.002% w/v
chlorhexidine gluconate fohowed a pH of maximum stability around pH 5
(at 90°C) with regions uf specific acid/base catalysis presen~.
Modifications attributable to a water catalysed reaction (pH 3.5
to 6.5) and presence of unionised chlorhexidine base (pH> 8.5) were
also apparent. Concentration dependency was noted at both alkaline and
neutral pH. Linear Arrhenius relationships were observed producing
-1 apparent activation energies varying from 69.5 to 96.1 kJ.mol •Degradation rate dependence upon ionic strength was consistent with a
negative salt effect in alkaline solution. Variable effects on rate
were observed in the presence of buffers and with different types of
surfactant. Limited studies indicated chlorhexidine solutions are
photochemically stable at netural pH but are not amenable to
y-irradiation sterilisation. Quantitative analysis of 4-chloroaniline
has shown that this compound is not, as previous literature might
suggest, the major degradation product of chlorhexidine. HPLC
analysis indicates that up to six degradation products may occur.
In the discussion an interpretation of kinetic data is
presented. Qualitative information from chromatographic studies is
used to support a proposed degradation pathway for chlorhexidine.
Finally the kinetic data has been used to assess the stability of
chlorhexidine to heat sterilisation processes and on long term
storage.
|