The formation of pharmaceutical salts is widely recognized as a tool to improve the solubility in water of many acidic or basic drugs. This is also the case of diclofenac, an important member of non steroidal anti-inflammatory drug class, whose low solubility in water suggested formulations in the form of sodium and potassium salt, for oral delivery, and of diethylamine and N-pyrrolidine ethanol salts for topical applications. To support the idea that solubility is still an intriguing problem for diclofenac there is the number of paper in the scientific literature concerning the preparation and the physico-chemical determinations of many new diclofenac salts. In this communication we present a study of the solid state of some diclofenac salts, as a starting point to discuss and interpret their solubility values and their behavior to the release from solid dosage forms. Diclofenac is poorly soluble in water since in the solid state it exists as dimmers, bound together with a network of hydrogen bonding, involving the carboxylic groups. This way the hydrophilic moieties are kept far from interaction with the dissolution medium by the hydrophobic portions of the molecule. These hydrogen bonds are destroyed by increasing pH or by the formation of a salt form. Salts of alkaline metals are hydrate, but usually marketed as de-hydrate form; these are not stable since recover their water crystallization molecules, if not adequately protected. Their solubility in water is not so high as that of other sodium or potassium NSAID salts, but their behavior in water solution suggests that the diclofenac anions self-aggregate forming micelle-like forming systems, but with limited solubilisation ability. Salts formed with hydroxy aliphatic amines, despite the hydrophilic contribution of increasing number of hydroxy groups do not form hydrate, when prepared from water and have limited solubility in water. The nature of their solid state explains this behavior, since these salts exist as ion-pairs, where hydroxy groups of each cation are strictly hydrogen bonded with the corresponding diclofenac anion: this structure in most cases originates high melting point and reduce solubility. Salts formed with volatile amine have a narrow range of stability with temperature and experiment dissociation even at low temperature, during drying process, that leaves the parent acidic diclofenac, while the low-boiling amine is lost as vapor. Finally the most interesting compound of this group is represented by diclofenac/N-pyrrolidine ethanol salt, which forms a polymorph hydrate and displays a complex behavior as a function of RU, temperature and pressure; moreover its aqueous solution display solubilisation ability towards hydrophobic substances above 35 mM. As a conclusion it can be suggested that pharmaceutical salts offer a chemical form suitable to improve solubility and dissolution rate, and thus availability of an active agent, provided that the structure of the solid state of the salts does not originate unforeseen adverse problems, such as in the case of the particular molecular structure of diclofenac and ensure sufficient stability for their handling.

Aspects of diclofenac salts affecting the release from solid dosage forms

FINI, ADAMO;
2004

Abstract

The formation of pharmaceutical salts is widely recognized as a tool to improve the solubility in water of many acidic or basic drugs. This is also the case of diclofenac, an important member of non steroidal anti-inflammatory drug class, whose low solubility in water suggested formulations in the form of sodium and potassium salt, for oral delivery, and of diethylamine and N-pyrrolidine ethanol salts for topical applications. To support the idea that solubility is still an intriguing problem for diclofenac there is the number of paper in the scientific literature concerning the preparation and the physico-chemical determinations of many new diclofenac salts. In this communication we present a study of the solid state of some diclofenac salts, as a starting point to discuss and interpret their solubility values and their behavior to the release from solid dosage forms. Diclofenac is poorly soluble in water since in the solid state it exists as dimmers, bound together with a network of hydrogen bonding, involving the carboxylic groups. This way the hydrophilic moieties are kept far from interaction with the dissolution medium by the hydrophobic portions of the molecule. These hydrogen bonds are destroyed by increasing pH or by the formation of a salt form. Salts of alkaline metals are hydrate, but usually marketed as de-hydrate form; these are not stable since recover their water crystallization molecules, if not adequately protected. Their solubility in water is not so high as that of other sodium or potassium NSAID salts, but their behavior in water solution suggests that the diclofenac anions self-aggregate forming micelle-like forming systems, but with limited solubilisation ability. Salts formed with hydroxy aliphatic amines, despite the hydrophilic contribution of increasing number of hydroxy groups do not form hydrate, when prepared from water and have limited solubility in water. The nature of their solid state explains this behavior, since these salts exist as ion-pairs, where hydroxy groups of each cation are strictly hydrogen bonded with the corresponding diclofenac anion: this structure in most cases originates high melting point and reduce solubility. Salts formed with volatile amine have a narrow range of stability with temperature and experiment dissociation even at low temperature, during drying process, that leaves the parent acidic diclofenac, while the low-boiling amine is lost as vapor. Finally the most interesting compound of this group is represented by diclofenac/N-pyrrolidine ethanol salt, which forms a polymorph hydrate and displays a complex behavior as a function of RU, temperature and pressure; moreover its aqueous solution display solubilisation ability towards hydrophobic substances above 35 mM. As a conclusion it can be suggested that pharmaceutical salts offer a chemical form suitable to improve solubility and dissolution rate, and thus availability of an active agent, provided that the structure of the solid state of the salts does not originate unforeseen adverse problems, such as in the case of the particular molecular structure of diclofenac and ensure sufficient stability for their handling.
2004
The midnight sun meeting on drug transport and drug delivery
19
19
A. Fini; G. Fazio; F. Rosetti
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/8307
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