Problems in studying amine/diclofenac salts with thermal analysis

Aim The real usefulness of employing amines to prepare diclofenac salts for commercial formulations was discussed and caution was suggested in extending the choice to volatile bases to prepare pharmaceutical salts, since these compounds originate problems concerning the stability of the final salt, difficulties in assessing and describing the nature of the solid forms obtained. Methods Eight cyclic aliphatic amines, pyrrolidine (Py), piperidine (Pp), morpholine (M) and piperazine (Pz) and the N-hydroxyethyl (HE) analogues, were employed to prepare a salt with acidic diclofenac. To characterize these salts a variety of analytical techniques were necessary: thermal (DSC, TGA and HSM) and spectroscopic (FTIR, Raman 1H NMR, UV). Results The results show the thermal instability of these salts, demonstrated by the TG profile that indicates loss of weight during the melting corresponding to the base content inside the salt; as a consequence the thermal dissociation leaves the starting acidic diclofenac, whose melting endotherm in DSC thermogram can be erroneously attributed to the melting of the salt. On the contrary the formation of acidic diclofenac inside the molten mass of the salts was confirmed by the FTIR and Raman spectra in the case of the salts with M and HEM. The nature of the salt with Pz (1:1 or 1:2) and HEPy (anhydrous or hydrate polymorph), but not for the salt with HEPz and Py, depends on the polarity of the solvent used for the preparation of the salt. Incomplete de-hydration of the hydrate Py and Pz salts progressively modifies the thermogram profiles and can originate false information concerning the nature of the final forms. Melting of the salts with Pp, M and HEM could be demonstrated by HSM, but not with DSC. Only the salts with HEPz and HEPp display a simple and normal thermal behaviour. Conclusions The occurrence of many possible thermal events (de-hydration, melting, phase transition, decomposition) does not make it easy and straightforward to understand the nature of the solid state of the diclofenac salts with volatile amines, except by means of DSC, that proved to be a rather invasive technique, promoting a decomposition reaction during temperature scanning. In many instances, in-depth examination of the samples must be carried out by means of a variety of analytical techniques, especially when treatments have not yet been completed. For practical applications, it is important that the salts are prepared from purified reagents, since possible volatile impurities can affect the stability of the final product and make the interpretation of thermal analysis results difficult; in addition, the nature of the solvent used for the preparation of the salt also appears important for the final result. The salts prepared with the hydroxy bases of this series are more stable and present a simpler thermal behaviour than the samples obtained using unsubstituted bases. For the thermal stability, bases with a high boiling point must be preferred for preparing this type of salts. The solubility in water achieved with these salts is lower than that obtained with the simpler sodium salt; only in very few cases is solubility (slightly) higher.The difficulty of providing a description of these salts in a simple way originates doubts on the utility of a wide application of aliphatic amines to prepare pharmaceutical salts, whose solubility in water does not significantly differ from that of the common sodium diclofenac. References Fini A, Cavallari C, Bassini G, Ospitali F, Morigi R. Diclofenac salts, part 7: Are the pharmaceutical salts with aliphatic amines stable? J Pharm Sci. 2012 Jan 10.