This thesis is concerned with a study of the stability of salbutamol sulphate in aqueous solution together with the effect on its stability, of syrup formulation excipients. The work necessitated the development of a stability indicating assay. This comprised a preliminairy separation on ion-exchange material followed by reversed-phase, ion-pair HPLC assay. A comparison of this technique with the BPC indoaniline colorimetric assay revealed that the latter method seriously overestimates the salbutamol content of degraded solutions. The degradation of salbutamol sulphate in aqueous solution was studied using pH-statting for pH control in order to avoid the use of buffer salts. The breakdown of the drug was shown to be oxygen sensitive and to increase with drug concentration. However ionic strength did not affect the rate of breakdown. The pH stability profile of the drug showed a region of minimum stability around pH 9 and maximum stability between pH 3 and pH 4. The slow rate of breakdown in this region precluded a detailed study, but it was shown that the degradation is not a simple acid or base catalysed reaction. Buffer salts were unpredictable in their effects, acetate stabilising the drug whilst phosphate accelerated the breakdown. The effect of sugars was studied at both pH 7.0 and pH 3.5. Glucose accelerated the degradation of salbutamol sulphate at pH 7.0 but sucrose had no effect, whilst at pH 3.5, glucose, fructose and sucrose increased the degradation rate to similar extents. This was ascribed to hydrolysis of sucrose at the more acidic pH, liberating the monosaccharides with a potentially "free" carbonyl group. Such a functional group is not available in sucrose because it is utilised in the glycosidic bond. Further studies to elucidate the nature of the interaction involved the use of glyceraldehyde, glyceric acid, 5-hydroxy-methylfurfural and polyhydric alcohols. Attempts were also made to isolate and identify the major breakdown products but since these were unstable definitive identification was not possible. However Figures 55 and 57 show possible structures of isolated compounds.
|Date of Award||1980|