Partial-solubility Parameters of Naproxen and Sodium Diclofenac

Abstract

The expanded Hansen method was tested for determination of the solubility parameters of two non-steroidal anti-inflammatory drugs, naproxen and sodium diclofenac. This work describes for the first time the application of the method to the sodium salt of a drug. The original dependent variable of the expanded Hansen method, involving the activity coefficient of the drug, was compared with the direct use of the logarithm of the mole fraction solubility 1nX2 in the solubility models. The solubility of both drugs was measured in pure solvents of several chemical classes and the activity coefficient was obtained from the molar heat and the temperature of fusion. Differential scanning calorimetry was performed on the original powder and on the solid phase after equilibration with the pure solvents, enabling detection of possible changes of the thermal properties of the solid phase that might change the value of the activity coefficient. The molar heat and temperature of fusion of sodium diclofenac could not be determined because this drug decomposed near the fusion temperature. The best results for both drugs were obtained with the dependent variable 1nX2 in association with the four-parameter model which includes the acidic and basic partial-solubility parameters delta(a) and delta(b) instead of the Hansen hydrogen bonding parameter delta(h). Because the dispersion parameter does not vary greatly from one drug to another, the variation of solubility among solvents is largely a result of the dipolar and hydrogen-bonding parameters, a fact that is being consistently found for other drugs of small molecular weight. These results support earlier findings with citric acid and paracetamol that the expanded Hansen approach is suitable for determining partial-solubility parameters. The modification introduced in the expanded Hansen method, i.e. the use of 1nX2 as the dependent variable, provides better results than the activity coefficient used in the original method. This is advantageous for drugs such as sodium diclofenac for which the ideal solubility cannot be estimated. This paper shows for the first time that the method is suitable for determination of the partial-solubility parameters of a sodium salt of a drug, sodium diclofenac.

IUPAC-NIST Solubility Data Series. 102. Solubility of Nonsteroidal Anti-inflammatory Drugs (NSAIDs) in Neat Organic Solvents and Organic Solvent Mixtures

“…Perlovich et al 163 measured naproxen solubilities in hexane, benzene, methanol, ethanol, 1-propanol, 1-butanol, 1-pentanol, 1-heptanol, and 1-octanol at 298 K based on spectroscopic methods. Bustamante et al 164 reported solubility data for naproxen at 298 K in two saturated hydrocarbons (heptane and cyclohexane), in one aromatic hydrocarbon (benzene), in one alkyl alkanoate (ethyl ethanoate), in one dialkyl ether (1,1′-oxybisethane) and one cyclic ether (1,4-dioxane), in two chloroalkanes (trichloromethane and 1,2-dichloroethane) and one chlorinated aromatic hydrocarbon (chlorobenzene), in six alcohols (methanol, ethanol, 1-pentanol, 1-octanol, 1,2-propanediol, and 1,2,3-propanetriol), in one alkanone (propanone) and one aromatic ketone (acetophenone), and four miscellaneous organic solvents (ethanoic acid, propanoic acid, formamide, and N,N-dimethylformamide). Daniels et al 165 determined the solubility of naproxen in two alkyl alkanoates (methyl ethanoate and butyl ethanoate), in three dialkyl ethers (1,1-oxybisethane, 2,2′-oxybispropane, and 1,1′-oxybisbutane), and two cyclic ethers (tetrahydrofuran and 1,4-dioxane), and in 12 alcohols (1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, 1-pentanol, 2-pentanol, 3-methyl-1-butanol, 1-hexanol, 1-heptanol, 1-octanol, and 1-decanol) at 298 K. Manrique et al, 111 Yan et al, 168 Fini et al, 60 Mora and Martínez, 167 Claramonte et al, 170 and Aragón et al 166,169 have also performed naproxen solubility measurements at 298 K. Wenkers and Lippold 64 reported solubility data for ten NSAIDs (aspirin, diclofenac, diflunisal, flufenamic acid, ibuprofen, ketoprofen, nabumetone, naproxen, piroxicam, and tenoxicam) in light mineral oil at 305 K.…”

“…Lejal et al 162 found that naproxen protected Madin-Darby canine cells against HqN1 and H3N2 viral strains, and that naproxen decreased the viral titers in mice lungs after intranasal viral infection. There have been several studies 64,65,92,111,117,[163][164][165][166][167][168][169][170] involving the solubility of naproxen in organic solvents. Perlovich et al 163 measured naproxen solubilities in hexane, benzene, methanol, ethanol, 1-propanol, 1-butanol, 1-pentanol, 1-heptanol, and 1-octanol at 298 K based on spectroscopic methods.…”

“…There have been several studies 81,100,164,[191][192][193][194][195] involving the solubility of sodium diclofenac in organic solvents. Most notably, Bustamante et al 164 measured the mole fraction solubility of sodium diclofenac in 22 different organic solvents, including two saturated hydrocarbons (heptane and cyclohexane), one aromatic hydrocarbon (benzene), one alkyl alkanoate (ethyl ethanoate), one dialkyl ether (1,1′-oxybisethane) and one cyclic ether (1,4-dioxane), two chloroalkanes (trichloromethane and 1,2-dichloroethane) and one chlorinated aromatic hydrocarbon (chlorobenzene), seven alcohols (methanol, ethanol, 1-pentanol, 1-octanol, 1,2-ethanediol, 1,2-propanediol, and 1,2,3-propanetriol), one alkanone (propanone) and one aromatic ketone (acetophenone), and four miscellaneous organic solvents (ethanoic acid, propanoic acid, formamide, and N,N-dimethylformamide) at 298 K and atmospheric pressure. The experimental results were combined with measured solubility data for diclofenac and two other carboxylic acid/sodium carboxylate pairs (e.g., 4-aminobenzoic acid/sodium 4-aminobenzoate and salicylic acid/ sodium salicylate) in developing a group-contribution method for calculating partial solubility parameters of sodium salts.…”

Thermodynamic study of the solubility of sodium naproxen in some ethanol + water mixtures

“…2 In the same way, the solution thermodynamics as non-dissociate compound in some cosolvent mixtures has also been reported. 3 Recently, Chavez studied the solubility of Na-NAP in some methanol + water and ethanol + water mixtures at several temperatures. 4 Moreover, the physicochemical aspects of transfer of this drug (as non-dissociate compound) from aqueous media up to octanol and some phospholipidic vesicles have also been reported.…”

Abraham model correlations for estimating solute transfer of neutral molecules into anhydrous acetic acid from water and from the gas phase

“…nonelectrolyte solutes, including two polycyclic aromatic hydrocarbons (naphthalene [66] and phenanthrene [73]), four nonsteroidal anti-inflammatory drugs (2-hydroxybenzoic acid [65], naproxen [72], ibuprofen [74], diclofenac [76]) and two other drug molecules (niflumic acid [77] and salicylamide [64]), nine alkanedioic acids (oxalic acid through sebacic acid) [63], and benzoic acid [70] and three substituted benzoic acid derivatives (4-hydroxybenzoic acid [69], 4-methylbenzoic acid [71], and isophthalic acid [79] The experimental log (P or (CS,organic/CS,water)) and log (K or (CS,organic/CS,gas)) values at 298.15 K for solutes dissolved in acetic acid are listed in Table 1. In total there are 68 log (P or …”