Thermal study of polymorphism among diclofenac salts with alkyl and alkylhydroxy amines

Diclofenac has been studied with a variety of aliphatic amines with the aim of preparing salts with improved solubility: the solubility of diclofenac has in fact represented a problem since its appearance on the pharmaceutical market, and it is currently formulated mainly as sodium salt, but also as potassium, diethylamine and N-(2-hydroxyethly) pyrrolidine salt. Many diclofenac salts with a variety of amines were tested for solubility and the factors affecting their solubility were examined. However the behaviour of diclofenac salts with N-(2-hydroxyethyl) pyrrolidine and diethylamine that form hydrate and hydrate polymorphs of different degrees of hydration in the solid state; or in aqueous solution, where micelle-like aggregates form and the easiness of dehydration of some alkaline diclofenac salts suggested that complex behaviours could be common to most diclofenac salts. Moreover, the crystal characterisation of a number of diclofenac salts with amines indicated that formation of hydrate and polymorphs could be rather common among these compounds: this suggested the need for a serious examination of the nature of the solid state of new, but also of old and poorly described diclofenac salts in order to reveal the formation of hydrates and/or the presence of polymorphs, before starting solubility measurements and other pre-formulation tests, and define the stable form as a function of the experimental conditions or the most suitable for technological purposes (e.g. formulations). Experimental methods Diclofenac was a gift (IBSA, Lugano, Switzerland) of pharmaceutical grade. The following bases: monoethylamine (EtA), diethylamine (diEtA), triethylamine (triEtA); monoethanolamine (MEA), diethanolamine (DEA), triethanolamine (TEA), tris methylolamino methane (TRIS); N-ethyl monoethanolamine (EtMEA), N,N-diethyl monoethanolamine (diEtMEA), N-methyl monoethanolamine (MeMEA), N,N-dimethyl monoethanolamine (diMeMEA); N-ethyl diethanolamine (EtDEA) and N-methyl diethanolamine (MeDEA). Diclofenac salts – Salts were prepared separately dissolving equimolar amount of acidic diclofenac and the appropriate base in acetone and then mixing the two solutions. Products recovered by filtration were examined by DSC (Mettler Toledo 821e), TGA (TGA/SDTA851e/SF/1100) and HSM (hot stage apparatus Mettler-Toledo mounted on Nikon UN2-PSE100 light microscope). Linear bases used as salt forming agents start from diethylamine and carry progressive structural variants, such as increasing number of hydroxy groups (mono-, di- and tri-ethanolamine; TRIS); or combination of ethyl (ethyl, diethyl, triethylamine), methyl and ethyl and hydroxyethyl groups (methyl-, dimethyl-, ethyl-, diethyl-monoethanolamine; methyl-, ethyl-diethanolamine). DSC – Thermograms of all the salts examined are characterized at least by the presence of two endotherm peaks: one peak associated to melting below 200°C. A second endotherm, at higher temperature in the range 180-230°C, associated to the decomposition of the salt (see below) is typical of these salts with organic bases, since it lacks in thermograms of diclofenac salts with alkaline cations. TGA – All the salts are thermally instable and loose weight during and after melting: the weight loss is in most cases of the same order of magnitude of the base content into the salt and is due to thermal dissociation of the salt that leaves acidic diclofenac as residue: D-.NH+ ↔ DH + N↑. Structure of the diclofenac salts – All these results allow to interpret the role of different substituents present on the salt forming bases on the nature of the solid state of corresponding diclofenac salts. The molecule of diclofenac suggests the presence of different hydrogen bond-donor/acceptor groups: chlorine atoms, imino moiety, carboxyl group: the acidic molecule forms a dimer, where two carboxyl groups face together, while a chlorine atom is linked via hydrogen bond with the imino group. As a consequence o...