Die stabiliteit van parasetamol in vaste doseringsvorme

Abstract

The objectives of this investigation were to: i) develop a stability indicating method for paracetamol tablets; ii) formulate and prepare different paracetamol tablets and to compare the bioavailability and physicopharmaceutical properties of these tablets and presently registered tablets; iii) evaluate the stability of the above mentioned tablets and to come to a conclusion on the quality after a period of storage; iv) come to a conclusion on the stability differences between the formulae; v) evaluate the effect of e levated temperature and humidity conditions on the rate of degra= dation of paracetamol in solid dosage form. A review of the physicalcharacteristic~ pharma= cological activity, metabolism and excretion of 231 paracetamol is given. The effect of humidity, temperature, light and air oxidation on the stability of paracetamol is discussed. In humid surroundings the process of hydrolysis is taking place at an accelarated rate and this is catalized by elevated temperatures. The resulting degradation product, p-aminophenol and impurity, p-chloroacetani lide that may be present during the synthesis of paracetamol, are both toxic (Woodbury, 1975). The degradation of paracetamol is a process of the first order (Koshy & Lach, 1961). A review of the published methods for analysis of paracetamol as raw material, in phannaceutical preparations and in biological material, are given. The factors involved in the preparation of para= cetamol in solid dosage fonn as well as in the in vitro and in vivo evaluation of the tablets, are discussed. The experimental section of this investigation comprises the developing of a stability indicating method for the de termination of unchanged paracetamol and its degradation products, the formulation, preparation and evaluation of various tablet formulae and a stability study. Four methods of analysis have been investigated for use as a stability indicating method, namely gas chromatography, thin layer chromatography, ultraviolet spectrophotometry and colorimetry. A colorimetric-ultraviolet spectraphotometric method was developed and employed in the stability study. Seven tablet formulae were prepared and together with the two registered formulae subjected to physicopharmaceutical evaluation. The in vitro evaluation of the tablets was used to select three formulae, which together with the two registered formulae were subjected to in vivo evaluation. Variation in espesially rate of dissolution and disintegration time, became apparent during t he in vitro testing . No significant differences bet ween the formulae could be found with regard to the in vivo behaviour. A stability study was performed and tablets from each of the different formulations were subjected to conditions of constant elevated temperatures and relative humidities . Minimum and maximum relative

humidities of 54 , 4 and 81, 2% respectively and minimum and maximum temperatures of 50° and 70°c respectively, were kept. An initial assay was performed by making use of colorimetric-ultraviolet-spectrophotometric method and the determination repeated after periods of 1, 3 and 4 months. The following deductions could be made: the degradation of paracetamol in solid dosage form, when kept under conditions applied in this investigation, averages 15%; no significant differences could be detected regarding the stability data of the various formulae and the effect of elevated temperature and humidity , was accelarated rate of hydrolysis. The average half life for paracetamol in solid 0 dosage form was calculated as 3,8 years at 25 C and relative humidity of 81 , 2%.