Physico-chemical determinants of dermal drug delivery: effects of the number and substitution pattern of polar groups.

The aim of this study was to investigate the effect of number and substitution pattern of -OH groups of a set of phenols on the in vitro permeation of heat-separated human epidermis. The diffusion was calculated from Log(D/x)=logk(p)-0.59logK(oct)+0.024 (D, diffusion coefficient; x, pathlength; k(p), permeability coefficient (cm/h); and K(oct), octanol-water partition coefficient). The main factors reducing D were the dipolar and hydrogen bonding capabilities of the permeants quantified as their Hansen partial solubility parameters delta(p) and delta(h). These parameters are significantly reduced by the degree of symmetry of the molecule, so that phloroglucinol (1,3,5-benzenetriol), with three -OH groups, diffuses more rapidly that phenol. When symmetry is absent, as in 1,2,4-benzenetriol, the number of -OH groups results in very slow diffusion. D/x (cm/h) was related to the combined solubility parameter delta(a) defined as radical(delta(p)(2)+delta(h)(2)) by: (D/x)=0.0024-0.000065delta(a) (n=7, R(2)=0.70, P=0.012).     

Partial-solubility Parameters of Naproxen and Sodium Diclofenac

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 lnX₂ 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 lnX₂ in association with the four-parameter model which includes the acidic and basic partial-solubility parameters δ_a and δ_b instead of the Hansen hydrogen bonding parameter δ_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 lnX₂ 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.     

Calorimetric studies of diclofenac sodium in aqueous solution of cyclodextrin and water-ethanol mixtures

The technique of solution calorimetry has been employed to study the interaction between diclofenac sodium and beta-cyclodextrin by determining the enthalpies of solution of the drug in water and in aqueous beta-cyclodextrin solution. Thermodynamic parameters characterizing the binding process such as enthalpy deltaH0, equilibrium constant K, free energy deltaG0 and entropy deltaS0 have been calculated to be 12.00 kJ mol(-1), 1670 dm3 mol(-1), -19.03kJ mol(-1) and 22.98 J K(-1) mol(-1), respectively. Enthalpies of solution of diclofenac sodium have also been determined in water-ethanol mixtures.     

The modified extended Hansen method to determine partial solubility parameters of drugs containing a single hydrogen bonding group and their sodium derivatives: benzoic acid/Na and ibuprofen/Na

Sodium salts are often used in drug formulation but their partial solubility parameters are not available. Sodium alters the physical properties of the drug and the knowledge of these parameters would help to predict adhesion properties that cannot be estimated using the solubility parameters of the parent acid. This work tests the applicability of the modified extended Hansen method to determine partial solubility parameters of sodium salts of acidic drugs containing a single hydrogen bonding group (ibuprofen, sodium ibuprofen, benzoic acid and sodium benzoate). The method uses a regression analysis of the logarithm of the experimental mole fraction solubility of the drug against the partial solubility parameters of the solvents, using models with three and four parameters. The solubility of the drugs was determined in a set of solvents representative of several chemical classes, ranging from low to high solubility parameter values. The best results were obtained with the four parameter model for the acidic drugs and with the three parameter model for the sodium derivatives. The four parameter model includes both a Lewis-acid and a Lewis-base term. Since the Lewis acid properties of the sodium derivatives are blocked by sodium, the three parameter model is recommended for these kind of compounds. Comparison of the parameters obtained shows that sodium greatly changes the polar parameters whereas the dispersion parameter is not much affected. Consequently the total solubility parameters of the salts are larger than for the parent acids in good agreement with the larger hydrophilicity expected from the introduction of sodium. The results indicate that the modified extended Hansen method can be applied to determine the partial solubility parameters of acidic drugs and their sodium salts.     

Evaluation of the surfactant properties of ascorbyl palmitate sodium salt.

In this paper we report on the physicochemical surface properties of ascorbyl palmitate (Asc16) and of its sodium salt (Asc16Na) with a view to their use as surfactants. Asc16Na was synthesized from ascorbyl palmitate by neutralizing the -OH groups in position 3 of the ascorbyl ring. The acid-base properties, thermal analysis and stability of Asc16Na monomers were determined. Self-assembling parameters of micellar aggregates in aqueous dispersions through critical micellar concentration (CMC) and critical micellar temperature (CMT) were measured. Asc16Na micellar dispersions efficiently solubilize poorly soluble drugs such as phenacetin and griseofulvin, and enhance their apparent solubility in aqueous environments. Stability tests showed that Asc16Na is more unstable than ascorbyl palmitate. Ascorbyl palmitate and its sodium salt are insoluble at room temperature in water, but their solubilities strongly depend on temperature, and largely increase above the CMT. Although Asc16Na is insoluble at room temperature, it is more soluble than Asc16, and its CMT significantly lowers in the undissociated acidic form. The apparent solubilities of phenacetin and griseofulvin are increased in Asc16Na aqueous solutions. The Asc16Na potential use as surfactant is restricted by its low stability in water, therefore the addition of some antioxidant species is necessary.     

The effect of terpene concentrations on the skin penetration of diclofenac sodium

Terpenes and sesquiterpenes have been suggested as promising non-toxic, non-irritating transdermal penetration enhancers. This investigation aimed to study the effect of terpene concentration on the transdermal absorption of diclofenac sodium from ethanol:glycerin:phosphate buffer solution (60:10:30). Therefore, enhancing effects of various terpenes (menthone, limonenoxide, carvone, nerolidol and farnsol) with different concentrations (0.25, 0.5, 1, 1.5 and 2.5%, v/v) on the permeation of diclofenac sodium were evaluated using Franz diffusion cells fitted with rat skin. Furthermore, solubility of diclofenac sodium in the vehicle in presence of different concentrations of terpenes was determined. The results showed that despite the negligible effect of terpenes on the drug solubility, there was a profound skin penetration enhancement effect, although the terpene enhancers varied in their ability to enhance the flux of diclofenac sodium. The results showed that at the highest concentration of terpene (2.5%, v/v) the rank order of enhancement effect for diclofenac sodium was nerolidol>farnesol>carvone>methone>limonenoxide, whereas at the low concentration of 0.25% the rank order was farnesol>carvone>nerolidol>menthone>limonenoxide. No direct relationship existed between terpene concentration and the permeation rate. The most outstanding penetration enhancer was nerolidol, providing an almost 198-fold increase in permeability coefficient of diclofenac sodium, followed by farnesol with a 78-fold increase.     

Energetic aspects of diclofenac acid in crystal modifications and in solutions--mechanism of solvation, partitioning and distribution

Temperature dependency of saturated vapor pressure and heat capacity for the diclofenac acid (Form II) were measured and thermodynamic functions of sublimation calculated (DeltaG(sub)(298) = 49.3 kJ x mol(-1); DeltaH(sub)(298) = 115.6 +/- 1.3 kJ x mol(-1); DeltaS(sub)(298) = 222 +/- 4 J x mol(-1) x K(-1)). Crystal polymorphic Forms I (P2(1)/c) and II (C2/c) of diclofenac acid have been prepared and characterized by X-ray diffraction experiments. The difference between crystal lattice energies of the two forms were obtained by solution calorimetry: DeltaDeltaH(sol)(I --> II) = 1.6 +/- 0.4 kJ x mol(-1). Temperature dependencies of the solubility in buffers with pH 2.0 and 7.4, n-octanol and n-hexane were measured. The thermodynamic functions of solubility, solvation, and transfer processes were deduced. Specific and non-specific solvation terms were distinguished using the transfer from the "inert" n-hexane to the other solvents. The transfer of diclofenac acid molecules from the buffers to n-octanol (partitioning and distribution) is an entropy driven process.     

毛细管区带电泳电化学检测人体尿样中的双氯灭痛、氯丙嗪

目的建立毛细管区带电泳法测定人体尿样中双氯灭痛、氯丙嗪含量的方法。方法采用弹性石英毛细管（31.5cm,25μmi.d.,360μmo.d.）,以4.90×10-3mol/LNa2HPO4-7.80×10-3mol/LNaH2PO4（pH=7）为缓冲液,10kV分离电压,5kV电渗进样10s,碳纤维电极工作电极（长200μm,直径8μm）,检测电势0.72V。结果双氯灭痛、氯丙嗪两种药物分别在9.90×10-6～5.00×10-4mol/L（r=0.9982）、5.0×10-7～1.0×10-4mol/L（r=0.9998）范围内表现出良好的线性,其回收率分别为104%,96.0%。结论该方法简便、快速、准确,可作为人体尿样中双氯灭痛、氯丙嗪的分离检测方法。     

Microcalorimetric studies to determine the enthalpy of solution of diclofenac sodium,paracetamol and their binary mixtures at 310.15 K

A sensitive and selective microcalorimetric technique has been used to determine the enthalpy of solution of diclofenac sodium (DS), paracetamol (PC) and their binary mixtures over a wide range of composition in the pH range 4-12. The systems showed endothermic behavior. The molar enthalpies of solutions of DS vary between 42.26+/-0.16 and 50.48+/-0.03 kJ mol(-1) at pH 4-9 and for PC from 24.28+/-0.05 to 36.03+/-0.01 kJ mol(-1) at pH 5-12. The excess molar enthalpy of their mixtures has also been determined. The values of excess molar enthalpy of solutions are negative and very low in magnitude indicating no specific interaction between DS and PC in solution.     

维生素C和焦亚硫酸钠与溶解氧反应机理的探讨

目的:确定维生素C溶液中维生素C和抗氧剂焦亚硫酸钠与溶解氧的反应机理。方法:将维生素C和焦亚硫酸钠分别于敞开容器中进行试验,分别测定其降解动力学参数,求得其降解速率常数。再将维生素C和焦亚硫酸钠混合,在敞开容器中试验,分别测定其降解动力学参数,求得其降解速率常数。结果:维生素C和焦亚硫酸钠在敞开容器中都为表观零级降解,其降解速率常数分别为:kA,ap=2.2×10-3(mol·L-1·h-1)和kB,ap=1.12×10-4(mol·L-1·h-1)。维生素C和焦亚硫酸钠混合时,其降解速率常数分别为:kA,ap=2.0×10-3(mol·L-1·h-1)和kB,ap=1.13×10-4(mol·L-1·h-1)。当在维生素C溶液中加入焦亚硫酸钠时,两者的降解速率常数几乎不变,表明维生素C和焦亚硫酸钠同时与氧气进行反应。结论:维生素C溶液中,维生素C和焦亚硫酸钠与氧气的反应同时进行,为平行反应。     

Kinetics of degradation of diclofenac sodium in aqueous solution determined by a calorimetric method

An isothermal heat conduction microcalorimeter has been used to study the stability of diclofenac sodium both alone and its inclusion complex with beta-cyclodextrin in aqueous solution. The rates of heat evolved during degradation of diclofenac sodium have been measured by a highly sensitive microcalorimetric technique as function of concentration, pH and temperature. The calorimetric accessible data have been incorporated in the equations for determination of rate constants, change in enthalpy and order of reaction. The decomposition of diclofenac sodium both alone and its inclusion complex with beta-cyclodextrin in solution corresponds to a pseudo-first order reaction. The values of rate constants, k's at 338.15 K, (calculated from the variation of heat evolution with the time) for the degradation of diclofenac sodium at pH 5, 6, 7, 8 and its inclusion complex with beta-cyclodextrin at pH 7 are found to be 4.71 x 10(-4), 5.69 x 10(-4), 6.12 x 10(-)4, 6.57 x 10(-4) and 4.26 x 10(-4) h(-1) respectively. There is good agreement between calorimetric determined t(0.5) and literature values. It has been found that beta-cyclodextrin retards the degradation of diclofenac sodium. The kinetic parameters have been calculated for the reaction. The negative entropy of activation suggests the formation of an ordered transition state.     

Effect of sodium ozagrel on the activity of rat CYP2D6

The aim of the study was to investigate the influence of sodium ozagrel on CYP2D6 (cytochromeP450 2D6) activity. The studies were performed with rat urine and liver microsomes and chemical inhibitors. The metabolism of dextromethorphan (dextrophan/dextromethorphan, dextrophan is a metabolite of dextromethorphan) and phenacetin (paracetamol/phenacetin, paracetamol is a metabolites of phenacetin) was used as probe to measure CYP2D6 and CYP1A2 (cytochromeP450 1A2) activity, respectively, determined by high-performance liquid chromatography (HPLC). The results showed that the metabolism of dextrophan/dextromethorphan in the sodium ozagrel-treated group (37 mg/kg) was higher than that of the control (P<0.05/6) in both in vivo and in vitro studies (r=0.9811). The rate of dextromethorphan metabolism was inhibited by sodium ozagrel and cimetidine in rat liver microsomes prepared from sodium ozagrel-treated rats and control rats group (sodium ozagrel IC(50)=26.5 microM, cimetidine IC(50)=86.3 microM in sodium ozagrel-treated group; sodium ozagrel IC(50)=13.9 microM, cimetidine IC(50)=24.8 microM in control group). The inhibitory effect of sodium ozagrel on CYP2D6 activity was noncompetitive with dextromethorphan with a K(i) of 324.94 microM. Kinetic parameters of the reactions were established by using Lineweaver-Burk with K(m)=0.67 mM and V(max)=2.13 pm/min/mg protein for the sodium ozagrel-treated group and K(m)=0.29 mM, and V(max)=0.91 pm/min/mg protein for the control group, respectively. The expression of CYP2D6 protein in the treated group was higher than that of the control group, as determined by Western blotting. The activity and expression of CYP1A2 did not show obvious differences in the control group and sodium ozagrel treated group. In conclusion, sodium ozagrel metabolism in rats is mediated primarily through CYP2D6, and sodium ozagrel can induce CYP2D6 activity.     

Effects of diclofenac sodium and disodium ethylenediaminetetraacetate on electrical parameters of the mucosal membrane and their relation to the permeability enhancing effects in the rat jejunum

The effects of diclofenac sodium and disodium ethylenediaminetetraacetate (EDTA) on electrical parameters of rat jejunal membrane were investigated, together with measurement of the mucosal-to-serosal flux of sulphanilic acid or L-phenylalanine. Both adjuvants increased the flux rate of sulphanilic acid to a similar extent when added to the mucosal solution at 10 mM, but there were apparent differences in their effects on the electrical parameters. The addition of EDTA induced the gradual reduction in the membrane resistance (Rm) by 6-8 ohm cm-2, while the effect of diclofenac on Rm was complicated and concentration-dependent. The short circuit current (Isc) was reduced rapidly to the level of 30-40 microA cm-2 by the addition of diclofenac, but was less affected by EDTA. The flux rate of L-phenylalanine was decreased extensively by diclofenac or the 10 mM concentration of EDTA, suggesting an inhibition of carrier-mediated transport systems in the membrane. Together with our preceding communication (Yamashita et al 1985, J. Pharm. Pharmacol. 37: 512-513), it became obvious that the sites of action of diclofenac and EDTA were different, the former directly interacting with the epithelial cell to alter the permeability and functions of the cell membrane, while the primary effect of EDTA could be at the intercellular junctions.     

Kinetics of talampicillin decomposition in solutions

Talampicillin stability in aqueous solutions was studied in a broad range of pH values using as medium solutions of hydrochloric acid (pH 0.4-1.8), phosphate buffers (pH 2.05-3.13 and 6.03-8.04), acetate buffer (pH 3.87-5.28) and borate buffer (pH 8.90-9.10) as well as sodium hydroxide solution (pH 11.48). For the determination of talampicillin concentration changes in kinetic studies, two methods were used: iodometric and spectrophotometric in UV (lambda(max) = 254.5 nm). The catalytic velocity constants (k(H+), k(x), k(o)) were established, the log k-pH profile (35 degrees C) was found, thermodynamic parameters were calculated of the hydrolysis reaction of the beta-lactam bond (k(H+): E(A)= 67.9 kJ mol(-1), delta S = -92.4 J K(-1) mol(-1), delta G = 92.6 kJ mol(-1); k(x): E(A) = 31.8 kJ mol(-1), delta S = -347.1 J K(-1) mol(-1), delta G = 131.1 kJ mol(-1); k(o), pH = 5.28: E(A) = 98.0 kJ mol(-1), delta S = -50.3 J K(-1) mol(-1), delta G = 110.3 kJ mol(-1) at 20 degrees C), and the stability of the lactone bond was studied in the medium with the highest stability of beta-lactam bond of talampicillin (pH 5.28: k(o): E(A)= 32.5 kJ mol(-1), delta S = -220.5 J K(-1) mol(-1), delta G = 94.7 kJ mol(-1) in 20 degrees C), at controlled ionic strength (mu = 0.5 mol l(-1)).     

双氯芬酸钠在不同凝胶基质中透皮扩散特征的研究

目的：研究双氯芬酸钠在凝胶贮库中的扩散特征及其对双氯芬酸钠透皮扩散速率的影响。方法：以改良的 Ｆｒａｎｚ 扩散池为实验装置,回归分析双氯芬酸钠在二种凝胶基质、共十二种条件下经微孔滤膜或透过离体小鼠皮的累积透过量。结果：在亲水的高分子凝胶基质中,离子形式的双氯芬酸钠扩散速率大于分子形成的扩散速率。经皮扩散时,分子形式的双氯芬酸钠在海藻酸凝胶中的扩散速率大于离子形式的扩散速率;在卡波普凝胶中结果则相反。双氯芬酸钠从含有月桂氮苷卓酮的凝胶中透皮扩散的速率比从相应没有月桂氮苷卓酮的凝胶中透皮扩散的速率有所增加,但增加的程度不明显。特别是当卡波凝胶中是离子形式的双氯芬酸钠时,其有无促透剂的２４ ｈ 累积透过量之比值只为１ ．１７ 。     

Controlled-release of diclofenac sodium from wax matrix granule

A twin-screw compounding extruder was used to prepare wax matrix granules (WMG) consisting of carnauba wax, diclofenac sodium (DS) as a model drug, and rate-controlling agents such as hydroxypropylcellulose (HPC-SL), methacylic acid copolymer L (Eudragit L-100), and sodium chloride (NaCl). In this preparation, a wax matrix with high mechanical strength was obtained even at temperatures lower than the wax melting point. Dissolution behaviors of DS from WMG were strongly influenced by granule formulation, in which an increase in the content of HPC-SL or Eudragit L-100 brought a significant increase in the dissolution rate. The extent of this enhancing effect in HPC-SL was identical in two different dissolution mediums (pH 6.8 buffer solution and water), but in Eudragit L-100 was more significant in pH 6.8 buffer solution than in water. Only a small increase in the dissolution rate was observed in NaCl-containing WMG. These different behaviors were attributed to the physicochemical properties (i.e. swelling and solubility) of the rate-controlling agent in the dissolution medium. Further, mechanical strengths of the wetted WMG after dissolution studies were > 70 g/mm² suggesting that burst release of DS in the gastrointestinal tract would be avoided.     

A multi-centre comparative study of diclofenac sodium and a dipyrone/spasmolytic combination, and a single-centre comparative study of diclofenac sodium and pethidine in renal colic patients in India

A single-blind, randomized clinical trial was carried out to compare the analgesic effectiveness in patients with renal colic of single intramuscular doses of diclofenac sodium (75 mg) versus a dipyrone (1 g)/spasmolytics combination, and diclofenac sodium (75 mg) versus pethidine (75 mg). The first study involved three centres, the second study one centre. In total, 107 patients were treated with diclofenac sodium, 85 with dipyrone/spasmolytics, and 25 with pethidine. Assessments were made during the first hour after drug administration of the degree of pain relief, the severity of pain using a visual analogue scale, and the duration of analgesia. A global assessment of treatment efficacy was made by the participating physicians at the end of the study period. Patients treated with diclofenac sodium showed an earlier onset of analgesia and a higher incidence of total pain relief compared to those treated with dipyrone/spasmolytics or pethidine. Although the mean duration of analgesia was only slightly greater in the diclofenac sodium group than in the dipyrone/spasmolytics group, a significantly longer effect was seen when diclofenac sodium was compared with pethidine (p less than 0.01). Pain severity assessments revealed that diclofenac sodium caused a significantly greater improvement in pain after 60 minutes compared to dipyrone/spasmolytics (p less than 0.05) and after 30 minutes compared to pethidine (p less than 0.05). Global efficacy assessments by the physician rated diclofenac sodium as significantly superior to dipyrone/spasmolytics (p less than 0.01) and pethidine (p less than 0.001). Moreover, diclofenac sodium was better tolerated than either of the comparative treatments. The results indicate that intramuscular diclofenac sodium is a useful alternative to the drugs commonly used in India in the treatment of renal colic.     

双氯芬酸钠自乳化给药系统的研制

目的研制双氯芬酸钠自乳化给药系统。方法通过测定双氯芬酸钠在各种溶剂中的平衡溶解度,选择适宜油相、乳化剂、助乳化剂,并在此基础上绘制伪三元相图。通过对各处方比例的筛选,结合各处方载药量以及所形成微乳的稳定性,确定最佳处方。结果以油相为三辛酸/癸酸甘油酯,乳化剂为Cremophor EL,助乳化剂为丙二醇,Km1为4∶1,Km2为1∶9,双氯芬酸钠在微乳中的质量浓度为25g.L-1,该处方为最佳处方。结论所研制的自乳化给药系统具有粒径小、载药量高、性质稳定的优势,可作为进一步研究的基础。     

HPTLC determination of diclofenac sodium from serum

Diclofenac sodium is one of the potent Non Steroidal Anti-Inflammatory Drugs (NSAID) used in the treatment of inflammatory conditions. The present work deals with the estimation of diclofenac sodium from serum by a novel High Performance Thin Layer Chromatographic (HPTLC) method developed in our laboratory. Standard diclofenac sodium was spotted on Silica Gel 60 F(254) precoated plates, which were developed using the mobile phase toluene:acetone:glacial acetic acid (80:30:1,v/v/v). Densitometric analysis of diclofenac sodium was carried out at 280 nm with diclofenac being detected at an R(f) of 0.58. The method was subsequently developed to estimate diclofenac sodium from serum. Diclofenac sodium was extracted with ethyl acetate from serum samples, spotted on Silica Gel 60 F(254) plates and the plates were developed using the above mentioned mobile phase. The method was validated for selectivity, extraction efficiency, sensitivity, accuracy, and intra and inter-day reproducibility studies. The extraction efficiency was found to range from 76 to 80%. The Limit of Detection (LOD) and Limit of Quantification (LOQ) of diclofenac sodium in serum were found to be 90 and 120 ng, respectively. The calibration curve of diclofenac sodium in serum was found to be linear in the range of 200-800 ng. The mean values (+/-S.D.) of correlation coefficient, slope and intercept were found to be 0.9876 (+/-0.0105), 0.0228 (+/-0.0036) and 6.15 (+/-1.4), respectively. The mean percentage coefficient of variation for accuracy, intra-day and inter-day analysis at 200-800 ng of diclofenac sodium were found to be 3.2, 6.35 and 8.025, respectively. The proposed method is a simple and sensitive method with good precision and reproducibility for the estimation of diclofenac sodium form serum samples.     

Diclofenac solubility: independent determination of the intrinsic solubility of three crystal forms

The solubility in water of diclofenac ({2-[(2,6-dichlorophenyl)amino]phenyl}acetic acid), a potent nonsteroidal anti-inflammatory drug, has been investigated. The various solid forms have been characterized by thermogravimetric analysis, differential scanning calorimetry, and X-ray diffraction. The commercially available form of diclofenac is the anhydrous sodium salt. This was recrystallized from ethanol and precipitated as a hydrate containing four diclofenac anions, four sodium cations, and nineteen water molecules per unit cell. This crystal structure is similar to but different from an earlier report of the structure. Crystals of the acid form of diclofenac were anhydrous and corresponded to an earlier crystal structure. Separate solubility measurements on all three of these solid forms of diclofenac gave consistent results for the intrinsic solubility. The aqueous solubility values reported in the literature for diclofenac are spread over a large range, with a factor of 100 separating the largest and the smallest. Our value is at the smaller end of this range. It is the only one supported by three independent procedures and rigorous characterization of the solid forms. The experimental conditions were precisely controlled.