Understanding the phase behavior of active pharmaceutical ingredients is important for formulations of dosage forms and regulatory reasons. Nimesulide is an anti-inflammatory drug that is known to exhibit dimorphism. It is shown in the paper that form II is intrinsically monotropic in relation to form I. This result has been obtained by experimental means, involving high-pressure measurements. In addition, it has been shown that with very limited means and statistical melting data, the same conclusion can be obtained, demonstrating that in first instance topological high-pressure phase diagrams can be obtained without measuring any high-pressure data.

Understanding the polymorphic behavior of active pharmaceutical ingredients is important for formulation purposes and for regulatory reasons. Metacetamol is an isomer of paracetamol and it similarly exhibits polymorphism. In the present paper, it has been found that one of the polymorphs of metacetamol is only stable under increased pressure, which has led to the conclusion that metacetamol like paracetamol is a monotropic system under ordinary (= laboratory) conditions and that it becomes enantiotropic under pressure with the I-II-L triple point coordinates for metacetamol T I-II-L = 535±10 K and P I-II-L = 692±70 MPa. However, whereas for paracetamol the enantiotropy under pressure can be foreseen, because the metastable polymorph is denser, in the case of metacetamol this is not possible, as the metastable polymorph is less dense than the stable one. The existence of the stability domain for the less dense polymorph of metacetamol, can only be demonstrated by the construction of the topological phase diagram as presented in this paper. It is a delicate interplay between the specific volume differences and the enthalpy differences causing the stability domain of the less dense polymorph to be sandwiched between the denser polymorph and the liquid. It is a characteristic that metacetamol shares with bicalutamide and fluoxetine nitrate.