A quaternary solid-form of ritonavir: an oxalate salt oxalic acid co-crystal acetone solvate

Abstract

Ritonavir has been reported in seven crystal forms notably form I, II, IIIb and IV, as well as a hydrate, an l-tyrosine co-crystal and a formamide solvate. A new form is reported here with a novel quaternary structure with ritonavir as an oxalate salt, oxalic acid co-crystal and acetone solvate in a 1 : 1 : 0.5 : 0.5 stoichiometry. The new oxalate salt form (CCDC deposition number 2009282), was co-crystallised with oxalic acid from a supersaturated acetone solution, and exhibits a polar monoclinic crystal structure with a blocky needle-like crystal habit. The molecular conformation of ritonavir for the new form shows significant differences with respect to the well-characterised form I, II and IIIb polymorphs. Its crystallography is characterised by a 2-fold screw axis along the b axis, in a structure that exhibits multiple hydrogen bonds formed between amide-ureido, oxalate-oxalic acid and amide-amide groups in a layered intermolecular packing structure. Intermolecular stacking of the benzene and thiazole rings takes place along the crystallographic a axis with the needle axis growth of the crystals being likely to be governed by these interactions. The oxalate salt form co-crystal is found to have the characteristic conformations of the N-methyl urea and carbamate groups being in a trans and trans conformation respectively, as is the case for the recently discovered form IIIb, but in distinct contrast to cis and trans for form I, and trans and cis for form II. This may suggest that a cis and cis conformation for another new form may be feasible. The recovery of the form IV crystals at the lower concentrations of oxalic acid is perhaps indicative of its close similarity with the new oxalate salt co-crystal solvate form presented here.