Characterisation of paracetamol form III with rapid-heating DSC

Form III is the most unstable polymorph of paracetamol discovered and has not been fully characterized. Its instability in air means that it must be formed in situ in whichever instrument is used for analysis and even its melting point is the subject of discussion, because it undergoes a solid–solid conversion to form II when heated. The recent development of rapid-heat differential scanning calorimetry (RHDSC), which offers heating rates up to 2000 °C/min, provides a new opportunity to characterize unstable polymorphs because of the likelihood that form changes can be inhibited at higher heating rates. Hence the specific aim of this work was to use RHDSC to isolate and characterize paracetamol form III. Form III was prepared from the glass by holding isothermally at 113 °C for 2 min. Upon heating at slow scan rates (up to 300 °C min−1) a solid–solid transition to form II at ca. 120 °C was seen, followed by melting of form II at 156 °C. At heating rates of 400 °C min−1 and higher, the solid–solid transition was absent and two endotherms were observed; the form II melt at 156 °C and a new, lower temperature endotherm at 143 °C. We ascribe the transition at 143 °C to the melting of form III. The form II melt was present in all experiments, irrespective of heating rate; thus we presume the paracetamol crystallizes to a mixture of forms II and III during preparation, indicative again of the unstable nature of form III. Experiments conducted with a crystal growth modifier (hydroxypropylmethylcellulose, HPMC) showed that increasing the HPMC molecular mass, or increasing the HPMC:paracetamol ratio, resulted in a concomitant increase in the form III peak, relative to the form II peak, which supports the hypothesis that the sample coexisted in both forms prior to crystallization.