Polymorphism in diclofenac salts with hydroxy aliphatic amines

The term pharmaceutical salt is used to indicate salts of acidic or basic drugs independently of the nature of the counterion. The salt forming reaction is easy and quite simple, but does not lack of consequences: occurrence of hydrates is almost a rule and polymorphism is also quite frequent. In the case of hydrates, water molecules of crystallization can be more or less strongly bounded to the ions and when the salt is dehydrated also amorphisation can be originated. Formation of hydrates, polymorphism, amorphisation are physical aspects of the pharmaceutical salts that are important from a technological point of view, since affect solubility, dissolution rate and availability of the active agents. As a consequence each pharmaceutical salt must undergo to a careful study of preformulation in order to define the experimental conditions of its stability. This is also the case of diclofenac salts. Diclofenac is a potent anti-inflammatory drug with serious problems of solubility and is formulated on the pharmaceutical market as a salt: with sodium or potassium for oral administration, with diethylamine in an emulgel for topical application. Recently a salt with pyrrolidine ethanol was proposed for the preparation of a plaster for anti-inflammatory transdermal therapy: the physical and chemical characteristics of this salt suggested to extend the research also to other salts prepared with hydroxy alkyl amines, such as mono-, di- and tri-ethanolamines. These diclofenac salts are stabilized in the solid state by a number of hydrogen bonds, in such a way that anion and cation exist as ion pairs. These hydrogen bonds are given by the water molecules of crystallization or by the hydroxyl group of the cation. The salt with di-ethanolamine does not form hydrates: two hydroxyl groups on the cation are sufficient to fulfil the request of hydrogen bonds and to prevent the formation of hydrates, but not the formation of polymorphs: two forms of this salt exist having melting point little different each other. Three hydroxyl groups are more than sufficient to originate only one form, without polymorphism or formation of hydrates, as it was found in the case of the salt with tri-ethanolamine or the TRIS base. But when the cation possesses only one hydroxyl group, such as in the mono-ethanolamine salt, an additional water molecule of crystallization is needed to fulfil the request of hydrogen bonds of the diclofenac anion. The salt forms a monohydrate and when water is lost, the salt, no longer stabilized by the hydrogen bond, undergoes polymorph transition.