Giuseppe Fazio

Solubility and solubilization properties of non-steroidal anti-inflammatory drugs

Abstract Ten non-steroidal anti-inflammatory drugs (NSAID) of the acetic and propionic classes were analyzed in the form of salts to disclose the solubilization property of their aqueous solutions toward a lipid probe (the azo-dye Orange OT). This property is related to the self-aggregation of the anions above a concentration value that differs for each drug: indomethacin and fenclofenac showed solubilization ability in the form of sodium salts in pure water (starting from 30 and 40 mM, respectively); these values decreased with increasing ionic strength. In the case of diclofenac it was necessary to use a salt prepared with an organic base, that displayed a solubility higher than that of the sodium salt, required to overcome the critical value (35 mM). Naproxen, sulindac, ketoprofen, indoprofen were used at high concentrations of their sodium salts (100–160 mM) and solubilize the dye in the presence of a high total ionic strength. Alclofenac did not display solubilization ability; fenbufen and ibuprofen were tested as salts of an organic base: results were not conclusive because the presence of the organic base in the salt form and in the solution, as added electrolyte for the ionic strength, affected the results of the solubilization tests. The results are briefly discussed in terms of hydrophilic/hydrophobic balance present on the anion of the NSAID examined, as evaluated by the fragment constant approach.

Formation of ion-pairs in aqueous solutions of diclofenac salts.

In this work we studied the ability of the diclofenac anion to form ion-pairs in aqueous solution in the presence of organic and inorganic cations: ion-pairs have a polarity and hydrophobicity more suitable to the partition than each ion considered separately and can be extracted by a lipid phase. The cations considered were those of the organic bases diethylamine, diethanolamine, pyrrolidine, N-(2-hydroxyethyl) pyrrolidine and N-(2-hydroxyethyl) piperidine; the inorganic cations studied were Li(+), Na(+), K(+), Rb(+), Cs(+). Related to each cation we determined the equilibrium constant (K(XD)) for the ion-pair formation with the diclofenac anion in aqueous solution and the water/n-octanol partition coefficient (P(XD)) for each type of ion-pair formed. Among the alkali metal cations, only Li(+) shows some interaction with the diclofenac anion, in agreement with its physiological behaviour of increasing clearance during the administration of diclofenac. The influence of the ionic radius and desolvation enthalpy of the alkali metal cations on the ion-pair formation and partition was briefly discussed. Organic cations promote the formation of ion-pairs with the diclofenac anion better than the inorganic ones, and improve the partition of the ion-pair according to their hydrophobicity. The values of the equilibrium parameters for the formation and partition of ion-pairs are not high enough to allow the direct detection of their presence in the aqueous solution. Their formation can be appreciated in the presence of a lipid phase that continuously extracts the ion-pair. Extraction constants (E(XD)=P(XD) times K(XD)) increase passing from inorga to organic cations. This study could help to clarify the mechanism of the percutaneous absorption of diclofenac in the form of a salt, a route where the formation of ion-pairs appears to play an important role.

Factors governing the dissolution of diclofenac salts

Abstract Some factors governing the dissolution for 30 diclofenac salts were examined. The salts were prepared using alkaline metal hydroxides or organic aliphatic bases having linear or cyclic structures and bearing alkyl or hydroxy groups. Each salt was tested by scanning electron microscopy and by calorimetry. The results of dissolution are reported in terms of dissolution efficacy, Ed, as a functio of the molecular (chemical structure of the bases), microscopic (morphology of crystals) and macroscopic (solubility of the salts) parameters. All the factors affect Ed by different amounts: in the case of alkaline metal and methyl amine salts, dissolution appears governed by atomic or molecular parameters (the atomic volume and the number of methyl groups carried by the nitrogen atom); the morphology of the dissolving particle dominates in the case of the association of elongated crystals. The hydroxy groups, when present in the cation, improve the solubility and Ed values only to a limited extent, due to the possibility of an internal hydrogen bond, which limit the occurrence of hydrophilicity towards the dissolution medium.

Interaction between indomethacin and heavy metal ions in aqueous solution

The interaction between indomethacin anions and heavy metal ions, such as cadmium, zinc and copper(II) ions, was studied in aqueous solution by polarographic techniques. Indomethacin anions form complexes with these heavy metal ions: the complex formed with cadmium ions is sparingly soluble, while more soluble and also stronger complexes are formed with zinc and copper(II). At high concentrations, where indomethacin anions undergo self-aggregation, these last compounds are solubilised. This property is briefly discussed and compared to that of bile salts. In the presence of calcium ions, indomethacin forms a poorly soluble salt and no evidence was detected for the formation of complex species.

Influence of crystallization solvent and dissolution behaviour for a diclofenac salt

Abstract 11 samples of diclofenac/ N -(2-hydroxyethyl)pyrrolidine salt obtained by crystallization from alcohol-type solvents or mixtures with triacetin were analyzed by scanning electron microscopy and differential scanning calorimetry. Few differences were found concerning the size parameters of particles obtained from different solvents, while the shape parameters displayed major differences depending on the crystallization solvent. Most of the samples showed simple thermograms while in the case of those obtained from isopropanol and 1,3-butanediol, the presence of the solvent inside the mass of the crystals was recorded. Dissolution profiles were found to be different for all the samples (due also to different sizes of the dissolving particles). An interesting linear relationship was found between the efficiency of dissolution and the shape factor of the dissolving particles, suggesting the relevant importance of shape irregularity in affecting dissolution rate differences.

Interaction of iron(II) with bile salts

Iron(II) ions react with small aggregates of cholate, glycocholate, chenodeoxycholate, and deoxycholate to form soluble and colloidal compounds. Taurocholate under conditions used does not react with the Fe2+ ion. Small aggregates of dihydroxy bile salts (predominating in the premicellar region, at concentrations of the bile salt above 1 mmol dm-3) have a larger affinity for Fe2+ compared to those formed from cholate anions. In their interactions with small aggregates of cholate anions, the Fe2+ ion shows an affinity comparable to that of Cu2+ and Cd2+ and somewhat larger than that of Zn2+. Small aggregates of cholate show a higher ability to mask Fe2+ than those of taurocholate and glycocholate. Interaction of glycocholic acid anions with Fe2+ ions is sufficient to prevent iron(II) precipitation.

Effect of the temperature on a hydrate diclofenac salt

The salt Diclofenac/N-(2-hydroxyethyl) pyrrolidine when crystallizes from water forms a di-hydrate, which looses the crystallization water molecules on heating or in the presence of silica gel, undergoing a phase transition. The two processes were followed at room temperature, at 40 and 50 degrees C by thermal analysis and analyzing the dimensional parameters obtained by scanning electron microscopy as a function of the changes occurring in the solid state. The fractal dimension of the particle surface (DS) was determined for the di-hydrate, the anhydrate and the anhydrous forms: DS values are close together suggesting that the processes modify only slightly the external morphology of the particles. The reactive dimension (DR) to dissolution suggests that the salt after the thermal treatment has a dissolution behaviour identical to that observed for the salt obtained from organic solvents. The two processes de-hydration and phase transition can be carried out at relatively low temperature, suggesting an important pathway to obtain the anhydrous form starting from the di-hydrate one.

Fractal and reactive dimensions of some ursodeoxycholic acid salts

Abstract Six salts of ursodeoxycholic acid, a bile acid largely administered for the dissolution of cholesterol gallstones, were obtained as powders by lyophilization of their aqueous solutions. The salts were prepared using lithium, sodium and potassium hydroxide; and using arginine, pyrrolidine ethanol and Tris as organic bases. Thermal, microscopy and EDAX analysis were carried out to identify the nature of the salts. Using the parameters of fractal geometry, fractal surface dimension (DS) and reactive dimension (DR) to dissolution were also obtained. The very low values (2.02–2.15) for the fractal dimension (DS) of the particle surface suggest that, except in the case of the lithium (2.29) and pyrrolidine ethanol (2.43) salts, the particles thus obtained are characterized by smooth and regular surfaces. The DR for most salts were found to be higher than the corresponding DS and in a very narrow range of values (2.79–2.84). This fact was briefly discussed and compared with previous results obtained with other surfactants. The behaviour of the salt with the Tris base was considered separately.

Dehydration and rehydration of a hydrate diclofenac salt at room temperature.

The salt diclofenac/N-(2-hydroxyethyl) pyrrolidine crystallizes from water as a dihydrate, while it precipitates from organic solvents anhydrously: the two salts have different crystal structures. Dehydration of the dihydrate salt was carried out in a desiccator over silica gel at room temperature: the process occurs with the retention of the crystal structure. Slight changes observed in the diffractograms suggest, that soon after dehydration, a phase transition starts, slowly due to the low temperature of the process. The reaction was followed determining the loss of weight as a function of time and by thermal analysis, since the dihydrate and the dehydrate forms have different thermograms, but similar diffractograms. The reaction was complete after 24 h. The analysis of the experimental data suggests a kinetic process related to a one-dimensional diffusion of the crystallization water molecules outwards the solid particles. At room temperature, the dehydrate material rapidly back-absorbs the two molecules of crystallization water from the atmosphere moisture. The interaction with water of the different forms of the salt was discussed as a function of their solid structures as well as of the complex equilibria present in aqueous solution: these can explain previous apparently anomalous results.

Fractal and reactive dimension of a diclofenac salt: effect of the experimental conditions

The characterization of five samples from different batches of the same salt, Diclofenac/N-(2-hydroxyethyl)pyrrolidine, was realized by means of fractal analysis. When the samples were subjected to weak heating, the fractal dimension of the surface obtained, before and after thermal treatment, suggest that no great modifications occurred on the particles surface. On the contrary, the analysis of reactive dimension toward dissolution, DR, showed that much more reactive points appear on the particles surface after the heating process. Different values of DR were obtained as result of changes in the composition of the dissolution medium.