Biomedical subjects
Publications and source records attributed to E Shotton.
Flupenthixol dihydrochloride in aqueous solution oxidized to trifluoromethylthioxanthone, ethanol, and piperazine via aldehydic and epoxidic intermediates in the presence of air. The formation rate of trifluoromethylthioxanthone increased with increases in pH and oxygen concentration. Buffer ions also affected the decomposition rate. Micelle formation by the drug markedly influenced its oxidation rate.
The degradation rate of amitriptyline hydrochloride in buffered aqueous solution containing various additives was determined. The oxidation was a free radical-mediated process, and the rate was accelerated by the presence of metal-ion contaminants. Glass ampuls, particularly amber ones, in which the solutions were stored were the major source of these contaminants. Edetate disodium stabilized the solution, but the primary antioxidants propyl gallate and hydroquinone were less effective. Sodium metabisulfite accelerated the decomposition, and it is postulated that there was direct attack by metabisulfite at the olefinic double bond in the drug molecule.
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Five materials were compared for their effectiveness as disintegrating agents: maize starch, sodium calcium alginate, alginic acid, microcrystalline cellulose, and a colloidal aluminum silicate. The effect of the proportion of the agent present and the position with respect to the granule, intra- and extragranular, was examined. The extragranular formulations disintegrated much more rapidly than the intragranular ones, but the latter gave a much finer dispersion of particles. A combination of intra- and extragranular disintegrating agents gave the best compromise; of those tested, the alginates appeared to effect the breakdown to the smallest particles when placed intragranularly. A method of assessing the effectiveness of disintegrating agents for uncoated tablets is suggested, but the resulting weight mean particle size is the more important criterion for tablets complying with a pharmacopoeial disintegration test. The porosity and crushing strength of tablets are useful as guides to disintegration only when a given formulation is used.
Stearic acid or hard paraffin added to crystals of paracetamol and phenacetin reduced capping of tablets prepared by direct compression but did not produce acceptable tablets because the inter-particular bonds were very weak. The pressure cycle that can be constructed form the measurement of the axial pressure and the corresponding die wall pressures offers information that is useful in the formulation of the tablets. The behaviour of paracetamol or phenacetin and their mixtures with gelatin hydrolysate or water or both shows a similarity to a Mohr body and it appears that the maximum die wall pressure is affected by the particle size of the material compressed and also by the additives present. Good transmission of radial force implies that the material can be initially consolidated, but alone it does not indicate that the tablet formed is physically stable. When the tablet formed remains coherent after the axial pressure is removed the residual die wall pressure remains high. Measurement of the residual die wall pressure might therefore be a useful indicator for identifying satisfactory formulations of substances that cap readily. Hydrolysed gelatin or water or both together produced paracetamol and phenacetin mixtures with satisfacotry compression characteristics.
Plain tablets of quinine dihydrochloride, quinine bisulphate and quinine sulphate was prepared using salts of similar particle size. Proprietary sugar-coated tablets showed protracted disintegration and dissolution using dialysis method with forced convection and sink conditions was as anticipated by the solubilities. In vivo availability studies indicated release from the plain tablets in the order dihydrochloride, bisulphate, sulphate. The sugar-coated tablets showed delayed release and corresponding low availability
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Plasma indomethacin levels have been compared in 10 subjects following 100 mg of indomethacin from two different formulations, with similar disintegration and dissolution profiles. In four of these ten subjects plasma indomethacin levels were estimated after pretreatment with, and concurrent administration of, a buffered aspirin. The percentage of protein binding of indomethacin in the presence of salicylate was also estimated. No significant differences between peak plasma indomethacin levels with or without buffered aspirin were detected, but the rate of indomethacin absorption as shown by plasma levels, was significantly increased by pretreatment with and concurrent administration of, buffered aspirin. This was associated with a marked increase in side effects.
The tranmission of force to the die wall was measured by a piezoelectric sensor, and the compression cycles of lactose granules of different shapes were compared. In addition, a nearly spherical fraction of spray-dried lactose was similarly compared with a crystalline sample. Better tablets were formed when the conversion of axial to radial pressure was high and the residual pressure on the die wall remained after removal of the top punch. With acetaminophen and phenacetin, the pressure on the die wall was low, as was the residual pressure, and capping occurred in both cases. With direct compression acetaminophen, higher die wall pressure was produced and capping did not occur. It is considered that these results can be explained by the ease with which the more nearly isodiametric particle can rearrange under pressure and by the elastic properties of the solid.
The decomposition of amitriptyline hydrochloride upon autoclaving in a buffered solution (pH 6.8) was investigated. Three major decomposition products [3-(propa-1,3-dienyl)-1,2:4,5-dibenzocyclohepta-1,4-diene, dibenzosuberone, and 3-(2-oxoethylidene)-1,2:4,5-dibenzocyclohepta-1,4-diene] were detected and identified by chromatographic and spectroscopic techniques. Evidence is presented that the latter two compounds are formed by further oxidation of 3-(propa-1,3-dienyl)-1,2:4,5-dibenzocyclohepta-1,4-diene, and a possible decomposition pathway is outlined.
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