Overt and hidden polymorphism in the binary system involving the Z- and E- isomers of broparestrol

Broparestrol has been used as a drug to treat acne in the form of a mixture of its two stereoisomers. Although it has been withdrawn from the market, the binary system is rich in polymorphism and understanding the phase behaviour of the binary system involving the E- and Z-isomers is challenging. Physical mixtures do not immediately give rise to equilibrium phase behaviour, whereas recrystallization often leads to metastable phases and the appearance of stable phases can take years. A new polymorph of E-broparestrol has been found crystallizing in a monoclinic unit cell, space group P2₁/c, with lattice parameters a = 5.6079(4) Å, b = 16.1206(10) Å, c = 20.250 (1) Å, β = 100.569(4)°, V_cell = 1799.6(2) ų, and Z = 4. This polymorph, I_E, is stable at high temperatures, whereas the published form, II_E, is stable at room temperature. In the case of Z-broparestrol polymorphism has been observed too; however, it has so far only occurred within the binary phase diagram, and it has not been possible to isolate the new polymorph of Z-broparestrol, II_Z. Through the phase behaviour in the binary system, it could be determined that the new Z polymorph, II_Z, behaves monotropically in relation to the known triclinic polymorph of the Z-isomer, I_Z. Nothing is known about its structure, and it is therefore not clear yet whether II_Z may possess a stable domain under pressure. A stable temperature-composition phase diagram of the binary system containing E- and Z-broparestrol is proposed.