The effects of polymorphism, particle size and compression pressure on the dissolution rate of phenylbutazone tablets.

The dissolution rate of phenylbutazone from tablets after disintegration has been used to determine whether the drug particles underwent crushing or bonding during compression. Two polymorphic forms of the drug were used and the predominant effect for high drug concentration (60%), during compression was dependent upon the original particle size of the drug and its polymorphic form. With a low drug concentration (10%) in the tablet, the diluent protected the drug particles from bonding together. The particle size change of the drug during compression was affected by the nature of the diluent present. Lactose had an abrasive action on Form A phenylbutazone compared with Avicel but had little effect on the more ductile Form B. When the contact time of compression was decreased from 29 to 0.26 s, the 6 microns particles of drug showed less bonding at the shorter time (faster rate of compression) but the effect observed with the larger particles was independent the compression rate.

Thermal behaviour and dissolution properties of phenylbutazone polymorphs.

Five different polymorphic forms of phenylbutazone were prepared and characterized by differential scanning calorimetry (D.S.C.). Rapid heating rates produced single endothermic peaks due to melting but slower heating rates resulted in interconversion of three of the polymorphs to the more stable form. Interconversion on grinding the polymorphs was also observed. From equilibrium solubility and intrinsic dissolution rates it was concluded that the dissolution process could be described by the Berthoud model. The effect of some tablet excipients on the dissolution process is briefly reported.

Investigations on the in vitro dose-related metabolism of indomethacin in four laboratory species.

The influence of dose on the in vitro metabolism of indomethacin has been investigated in four laboratory species (rat, rabbit, guinea pig, hamster). It was found that in the rat and guinea pig the ratio of deacylated to demethylated metabolites was dependent on the substrate concentration of indomethacin, whereas in the rabbit the ratio remained constant in the dosage range investigated (1-10 mumoles). No demethylated product was found in the hamster but a high level of activity of the deacylase enzyme was observed. These findings may help to explain species-dependent toxicity.

Comparison of the in vitro dissolution behaviour of various indomethacin formulations with their in vivo bioavailability.

The effects of the core toi colloid wall ratio and particle size of the core on the in vitro release of indomethacin microcapsules prepared by the gelatin-acacia complex coacervation process have been examined. All formulations showed a zero order release pattern after an initial burst phase. The release rate increased with increasing core to coat ratios and decreasing particle size of core material. In vivo plasma level studies showed no difference in bioavailability between different microcapsule formulations or a conventional indomethacin capsule. In vitro release studies on a commercially available sustained release formulation of indomethacin (Indocid R) were slower than any of the microcapsule formulations and exhibited a square root t dependence indicating a diffusion controlled process from a matrix formulation. In vivo studies show this formulation to have a longer smoother plasma concentration than the microcapsule formulation, and to avoid high initial peak values of drug. Thus from the in vitro studies a sustained release effect was not unexpected but the in vitro differences between the microcapsule products were not paralleled by the in vivo behaviour. These results illustrate some of the problems in extrapolation of in vitro dissolution data to the in vivo situation.

Influence of crystal form on tensile strength of compacts of pharmaceutical materials.

The tensile strengths of compacts of different crystal forms of aspirin, sulfathiazole, and barbital were determined with a modified tablet hardness tester. For each material, the tensile strength could be correlated with the amount of plastic flow and/or crushing undergone by each crystal form during compression.

The crystallization behaviour of sulphathiazole.

Previous investigations into the dissolution kinetics of sulphathiazole Form 1 have shown the process to be first order with respect to driving force. However, below 37 degrees first order kinetics did not apply, due to the surface reaction becoming the rate controlling factor. The present study examines the kinetics of crystallization over the temperature range 25 to 50 degrees. Crystallization is a process greatly dependent upon the high-entropy surface integration step which, unlike the dissolution process, is much more sensitive to crystal growth inhibitors. In the absence of inhibitors crystallization above 34 degrees follows first order kinetics but below 34 degrees the process changes to third order. Similar temperature effects on the dissolution of sulphathiazole have been previously reported.

The influence of crystal form on the radial stress transmission characteristics of pharmaceutical materials.

Various crystal forms of sulphathiazole, barbitone and aspirin were compressed in a single-punch tablet machine instrumented to monitor axially applied and radially transmitted forces, and upper punch movement. The changes in radial stress during the compression cycle depended upon the polymorphic form of the compressed material. The results were rationalized in terms of the degree of plastic flow/crushing that occurred with each material, and the degree to which the final compact underwent elastic compression. It is postulated that the reduction in the transition temperature of polymorphic forms of sulphathiazole and barbitone and the polymorphic transition of sulphathiazole Form II was due to the production of dislocations in the crystal and the crystals at crystal boundaries formed in the compressed materials.