Polymorphism among diclofenac salts with alkyl and alkylhydroxy amines studied by thermomicroscopy

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 (diEtA)and N-(2-hydroxyethly) pyrrolidine (HEPy) salt. However the behaviour of diETA and HEPy diclofenac salts 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 diclofenac salts in order to reveal the formation of hydrates and/or the presence of polymorphs. Most diclofenac salts so far studied form hydrates, with different degree of hydration: in the case of substituent carried by N atom lacking of hydroxy groups, the crystal lattice is also built with water molecules. The salts display progressive complexity as the substituent number increases: EtA salt melts during de-hydration; diEtA can be obtained as anhydrate, triEtA salt exists as (hydrate?) polymorphs. The presence of one hydroxy group is not enough to fulfill the demand of hydrogen bonds and stabilization of the lattice: an additional water molecule of crystallization is needed for the ethanolamine salt. Increase of hydroxy group number allows the formation of a close network of hydrogen bond between anion and cation in the salts: diethanolamine salt shows two different forms, but very similar, having melting point very close together. The presence of three hydroxy groups further eliminates every complexity: only one form could be found for the triethanolamine salt. The presence of a ring in the amine (pyrrolidine, piperidine, morpholine, piperazine) contributes to a more frequent occurrence of polymorphism among these last salts that can be put in evidence only by thermomicroscopy, while DSC thermograms appear to suggest the presence of only one crystalline form. Our 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 of ionization or formation of a salt, the proton of the carboxyl is lost and hydrogen bonds are offered or by the presence inside the crystal lattice of water molecules of crystallization or by the hydroxy groups carried by the amine. The crystal structure of many of diclofenac salts of this study has been described and confirmed, beside the electrostatic interaction typical of ionic compounds, also a rather constant presence of hydrogen bonding between hydroxy group of the cation and carboxylate of diclofenac anion that contributes to a build a close contiguity between ions in the crystal lattice.