Most drugs are formulated, when possible, as salts, for their better technological parameters, such as solubility, handling, stability, crystallinity, etc. However this modification of the chemical form, beside many advantages, originates in turn a series of problems, such as formation of hydrates, polimorphs, thermal instability, in the solid state; and/or hydrolysis, acid-base equilibrium, etc. in solution, which limit their applications. The choice of the optimum salt forming agent for a given molecule is a problem not yet solved and is left to the sensitivity of the experimenter, as well as well the selection of a salt to improve a given parameter. From this point of view sodium salt, for acidic drugs, and hydrochloride, for basic drugs, represent the first choice, even though in the pharmaceutical market, different salts are present and many of them without being approved by FDA. An increased number of aliphatic amines are used to form salt with NSAID, opening new applications (e.g. absorption of the active principle via ion-pairs) or troubles for the taste or volatility of the bases. The main advantage deriving from the formation of a salt is the improvement of the solubility in water: most of acidic drugs form a dimer in the solid state, where the carboxyl groups face together by hydrogen bonds, preventing thus the hydrophilic portion to interact with water. This structure is destroyed by an increase of pH or the formation of the ionic structure of a salt. Diffractometric examination of the salt crystals can highlight the intimate structure of the compound, useful to interpret its behavior. A salt, with respect to the acidic parent drug, offers a better solubility and dissolution rate, provided that this chemical form is prevented to come into contact with the acidic gastric environment after its oral administration. However even in the case of destruction of the salt form in acidic medium, the drug precipitates in particles of very small size, guaranteeing a prompt dissolution when pH turns favorable. Not always the use of hydroxy organic bases, as salt forming agents, improving hydrophilicity of the salt, improves its solubility, since the promotion of hydrogen bonds in the solid state between anion and cation represents an unforeseen increase of the melting point and therefore decrease of solubility of the salt. In some case a depressed solubility is looked for depressed by the formation of a salt with heavy metal cation (e.g. calcium) for stability problem or for a masked taste. Many salts form hydrates, including water molecules into the crystal lattice. Thermal and thermogravimetric analysis are necessary to evidence the stoichiometry of the salt. In these cases the question is: which is the most stable or useful form, the one hydrate or the other one de-hydrated on heating? Dehydration can be accompanied by the formation of amorphous structures or thermal instability. Storage in controlled relative humidity is necessary in each case. All the situations reported above, which are rather general for pharmaceutical salts, were found studying the properties of the salts of the non-steroidal anti-inflammatory drug diclofenac, and represent the results of our most recent research.
A .Fini, G.Fazio, F. Rosetti, L. Benetti (2004). Pharmaceutical Salts.
Pharmaceutical Salts
FINI, ADAMO;
2004
Abstract
Most drugs are formulated, when possible, as salts, for their better technological parameters, such as solubility, handling, stability, crystallinity, etc. However this modification of the chemical form, beside many advantages, originates in turn a series of problems, such as formation of hydrates, polimorphs, thermal instability, in the solid state; and/or hydrolysis, acid-base equilibrium, etc. in solution, which limit their applications. The choice of the optimum salt forming agent for a given molecule is a problem not yet solved and is left to the sensitivity of the experimenter, as well as well the selection of a salt to improve a given parameter. From this point of view sodium salt, for acidic drugs, and hydrochloride, for basic drugs, represent the first choice, even though in the pharmaceutical market, different salts are present and many of them without being approved by FDA. An increased number of aliphatic amines are used to form salt with NSAID, opening new applications (e.g. absorption of the active principle via ion-pairs) or troubles for the taste or volatility of the bases. The main advantage deriving from the formation of a salt is the improvement of the solubility in water: most of acidic drugs form a dimer in the solid state, where the carboxyl groups face together by hydrogen bonds, preventing thus the hydrophilic portion to interact with water. This structure is destroyed by an increase of pH or the formation of the ionic structure of a salt. Diffractometric examination of the salt crystals can highlight the intimate structure of the compound, useful to interpret its behavior. A salt, with respect to the acidic parent drug, offers a better solubility and dissolution rate, provided that this chemical form is prevented to come into contact with the acidic gastric environment after its oral administration. However even in the case of destruction of the salt form in acidic medium, the drug precipitates in particles of very small size, guaranteeing a prompt dissolution when pH turns favorable. Not always the use of hydroxy organic bases, as salt forming agents, improving hydrophilicity of the salt, improves its solubility, since the promotion of hydrogen bonds in the solid state between anion and cation represents an unforeseen increase of the melting point and therefore decrease of solubility of the salt. In some case a depressed solubility is looked for depressed by the formation of a salt with heavy metal cation (e.g. calcium) for stability problem or for a masked taste. Many salts form hydrates, including water molecules into the crystal lattice. Thermal and thermogravimetric analysis are necessary to evidence the stoichiometry of the salt. In these cases the question is: which is the most stable or useful form, the one hydrate or the other one de-hydrated on heating? Dehydration can be accompanied by the formation of amorphous structures or thermal instability. Storage in controlled relative humidity is necessary in each case. All the situations reported above, which are rather general for pharmaceutical salts, were found studying the properties of the salts of the non-steroidal anti-inflammatory drug diclofenac, and represent the results of our most recent research.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
