The recrystallization and dissolution of acetylsalicylic acid (2011)

Observations that some samples of commercial acetylsalicylic acid had different dissolution rates were followed by reports that acetylsalicylic acid exists in more than one polymorphic form. The evidence for polymorphism has been questioned by a number of authors and the effects of such factors as crystal habit, particle size, crystal imperfection, the presence of salicylic acid and spherulites of acetylsalicylic acid have been discussed in an attempt to explain the anomalous behaviour. This work attempts to resolve the conflicting points of view. Acetylsalicylic acid was recrystallized from ethanol in a crystallizer which permitted control of the degree of supersaturation and, therefore, growth rate. In addition, a number of other recrystallization techniques and solvents were used to produce acetylsalicylic acid crystals with a wide variety of habits and varying amounts of salicylic acid. The crystals were compressed into discs both with and without prior size reduction and sieving. Intrinsic dissolution rates, measured using a rotating disc technique showed that the rates were independent of crystal growth rate, crystal size and habit, the content of salicylic acid (up to 3.8% w/w) and the presence of spherulites of acetylsalicylic acid. X-ray diffraction patterns revealed no differences between the various crystals and the original commercial material. Melting points, however, were dependent on the method of measurement and the crystal size and habit. Using the hot-stage method and heating at a rate of 0.2°per minute from a starting temperature of 2° below the approximate melting point (previously determined), acetylsalicylic acid melted, with decomposition, in the range of 128.3 to 132.7°, (excluding spherulites). When heating was started at 100° the melting range became very broad with small unaggregated particles starting to melt at temperatures between 103° and 112°. Analysis of the melt showed that the proportion of salicylic acid increased with decrease in particle size of the original acetylsalicylic acid crystals. Hence, the depression of the melting point of individual crystals is related to the increased susceptibility of small particles to thermal decomposition with the formation of salicylic acid. Evidence for the existence of metastable polymorphs of acetylsalicylic acid rests on the reported properties of needle-like crystals recrystallized from n-hexane and spherulites grown in thin films from saturated alcoholic solution. The needle-like crystals melted over the range 123.9° to 130.1° using a heating rate of 0.2° per minute from a starting temperature 2° below the approximate melting point. The wide melting range is probably due to decomposition of the fine needles and the formation of salicylic acid as discussed above. Spherulites of acetylsalicylic acid underwent a thermal transformation over the range 104° to 128° to form elongated prisms and a solution phase transformation into well defined prisms when in contact with a saturated solution of acetylsalicylic acid in various alcohols. The intrinsic dissolution rates of compressed discs prepared from the needle-like crystals and spherulites were the same as the other acetylsalicylic acid crystals. Moreover, X-ray diffraction patterns of the needle-like crystals, the spherulites and the crystals formed from the spherulites after thermal and solution phase transformation were identical with each other and the original aspirin. Hence, the needle-like crystals and spherulites are not metastable polymorphic forms of acetylsalicylic acid. It is suggested that both the thermal and solution phase transformation are growth processes.