A Validated Chiral LC Method for the Enantiomeric Separation of Repaglinide on Amylose Based Stationary Phase

A simple, isocratic, normal phase chiral HPLC method was developed and validated for the enantiomeric separation of repaglinide, (S)-(+)-2-ethoxy-4-N [1-(2-piperidinophenyl)-3-methyl-1-butyl] aminocarbonylmethyl] benzoic acid, an antidiabetic in bulk drug substance. The enantiomers of repaglinide were resolved on a ChiralPak AD-H (amylose based stationary phase) column using a mobile phase consisting of n-hexane: 2-propanol:trifluoroacetic acid (95:5:0.2 v/v/v) at a flow rate of 1.0 mL min⁻¹. The resolution between the enantiomers was found to be not >3.5 in optimized method. The presence of trifluoroacetic acid in the mobile phase played an important role, in enhancing chromatographic efficiency and resolution between the enantiomers. The developed method was extensively validated and proved to be robust. The calibration curve for (R)-enantiomer showed excellent linearity over the concentration range of 900 ng mL⁻¹ (LOQ) to 6,000 ng mL⁻¹. The limit of detection and limit of quantification for (R)-enantiomer were 300 and 900 ng mL⁻¹, respectively. The percentage recovery of the (R)-enantiomer ranged between 98.3 and 101.05% in bulk drug samples of repaglinide. Repaglinide sample solution and mobile phase were found to be stable up to 48 h. The developed method was found to be enantioselective, accurate, precise and suitable for quantitative determination of (R)-enantiomer in bulk drug substance.     

Enantiomeric Separation of Moxifloxacin and Its (R,R)-Isomer by Ligand-Exchange Chiral Chromatography

A new stereospecific LC method for the separation and quantification of moxifloxacin and its (R,R)-enantiomer in bulk drug was developed and validated by ligand-exchange liquid chromatography on a reversed phase column using aqueous mobile phase containing the chiral reagent l-isoleucine-Cu(II). The UV detector was operated at 293 nm. The flow rate of mobile phase was set at 0.9 mL min^?1. The achiral ODS column offers good separation of the two enantiomers in less than 20 min. The test concentration was 1,000 μg mL^?1 in the mobile phase. This method was capable of detecting the (R,R)-enantiomer of moxifloxacin up to 0.1 μg mL^?1 for a 20 μL injection volume. The drug was subjected to stress conditions of hydrolysis, oxidation, photolysis and thermal degradation. There was no interference of degradants with the (R,R)-enantiomer in the developed method. The developed chiral RP-LC method was validated with respect to linearity, accuracy, precision and robustness. The percentage recovery for the (R,R)-enantiomer in bulk drug samples ranged from 98.1 to 104.4%. The test solution was found to be stable in the mobile phase for 48 h after preparation.     

A Validated Chiral LC Method for the Separation and Quantification of (S,R,S)-Enantiomer and (R,R,R)-Isomer of Aprepitant

A new and accurate chiral liquid chromatographic method has been developed for the separation and quantification of (S,R,S)-enantiomer (unwanted enantiomer) and (R,R,R)-isomer (key intermediate) of aprepitant in bulk drug and formulation samples of apprepitant. The elution time was approximately 20 min using an immobilized amylose-based chiral stationary phase (Chiralpak-IA). The mobile phase was n-hexane and ethanol (90:10, v/v) and was delivered at a flow rate of 1.0 mL min^?1. Detection was carried out with a wavelength set to 220 nm. The resolution factor between enantiomers was found to be greater than five. Limit of detection for both (S,R,S) enantiomer and (R,R,R) isomer of aprepitant was 0.035 µg, and limit of quantification for both (S,R,S) enantiomer and (R,R,R) isomers of aprepitant was 0.1 µg, for a 10 µL injection. The developed method showed excellent linearity (r > 0.999) for both isomers. When the method was applied to bulk drug samples and in pharmaceutical formulations recoveries were obtained ranging from 97.2 to 103.1%. Aprepitant sample solutions were found to be stable when characterized over a period of 48 h.     

Validated Chiral LC Method for the Enantiomeric Separation of Palonosetron Hydrochloride

A new and accurate chiral liquid chromatographic method has been developed for the separation of palonosetron hydrochloride (PALO) and its (R,R)-enantiomer in bulk drug samples with an elution time of about 20 min. The chromatographic separation was carried out by normal phase chromatography using an immobilized cellulose based chiral stationary phase (Chiralpak-IC) with a mobile phase composed of n-hexane:ethanol:1,4 dioxane:trifluoroacetic acid:diethylamine (65:30:5:0.3:0.3, v/v) pumped at a flow rate of 1.0 mL min⁻¹. The resolution (R _s ) between the enantiomers was found to be greater than 3.0 and interestingly the (R,R)-enantiomer was eluted prior to the (S,S)-enantiomer (PALO) in the developed method. Mobile phase additives, trifluoroacetic acid and diethylamine played a key role in achieving chromatographic resolution between the enantiomers and also in enhancing chromatographic efficiency. The limit of detection (LOD) and limit of quantification (LOQ) of the (R,R)-enantiomer were found to be 0.03 and 0.1 μg respectively for 10 μL injection volume. The developed method shows excellent linearity (r ² > 0.999) over a range of LOQ to 0.3% for the (R,R)-enantiomer. The percentage recovery of the (R,R)-enantiomer in bulk drug samples ranged from 97.2 to 102.3 revealing good sensitivity of the developed method. Robustness studies were also carried out on the developed method.

     

Chiral Separation of (R,R)-Tadalafil and Its Enantiomer in Bulk Drug Samples and Pharmaceutical Dosage Forms by Chiral RP-LC

A new simple isocratic chiral RP-LC method has been developed for the separation and quantification of the enantiomer of (R,R)-tadalafil in bulk drugs and dosage forms with an elution time of about 20 min. Chromatographic separation of (R,R)-tadalafil and its enantiomer was achieved on a bonded macro cyclic glycopeptide stationary phase. The method resolves the (R,R)-tadalafil and its enantiomer with a resolution (R _s) greater than 2.4 in the developed chiral RP-LC. The mobile phase used for the separation and quantification of (R,R)-tadalafil and its enantiomer involves a simple mixture of reverse phase solvents and the cost of analysis was drastically decreased. The test concentration is 0.4 mg mL⁻¹ in the mobile phase. This method is capable of detecting the enantiomer of (R,R)-tadalafil up to 0.0048 μg wrt test concentration 400 μg mL⁻¹ for a 20 μL injection volume. The drug was subjected to stress conditions of hydrolysis, oxidation, photolysis and thermal degradation. There was no interference of degradants with (R,R)-tadalafil and its enantiomer in the developed method. The developed chiral RP-LC method was validated with respect to linearity, accuracy, precision and robustness. The percentage recovery for the enantiomer of (R,R)-tadalafil in bulk drug samples and in dosage forms ranged from 97.0 to 102.5%. The test solution was found to be stable in the mobile phase for 48 h after preparation.     

LC Separation of para and meta Isomers of Zafirlukast in Bulk Drug Samples and Pharmaceutical Dosage Forms Using a Chiral Stationary Phase

A simple, rapid and sensitive high performance liquid chromatographic method was developed for the separation and quantification of positional isomers of zafirlukast in bulk drugs and dosage forms using a chiral column. Elution time was 20 min in normal phase mode and ultra violet detection was carried out at 240 nm. Efficient separation was achieved on an immobilized amylose-based Chiralpak-IA column using n-hexane/ethanol/trifluoroacetic acid/diethyl amine (65:35:0.1:0.1, v/v) as the mobile phase. Resolutions between ortho, meta and para isomers of zafirlukast were found to be >3.0. The active pharmaceutical ingredient was extracted from tablets using tetrahydrofuran. The calibration graphs for meta and para isomers of zafirlukast were linear (r ² > 0.999) when ranging from the limit of quantitation to 0.3%. The method showed excellent recoveries for both zafirlukast isomers identified in bulk and formulated products. The test solution was found to be stable in the mobile phase for 48 h after preparation. The developed LC method was validated with respect to linearity, accuracy, precision and robustness.     

A Validated LC Method for the Determination of Chiral Purity of (1S)-6,11-Dioxo-1,2,3,4,6,11-Hexahydropyridazino[1,2-b]Phthalazine-1-Carboxylic Acid: A Key Intermediate of Cilazapril

A simple and accurate normal phase liquid chromatographic method was developed for the determination of chiral purity of (1S)-6,11-dioxo-1,2,3,4,6,11-hexahydropyridazino[1,2-b]phthalazine-1-carboxylic acid, S-enantiomer used as key intermediate in the manufacturing of cilazapril bulk drug. Chromatographic separation between (1S)-6,11-dioxo-1,2,3,4,6,11-hexahydropyridazino[1,2-b]phthalazine-1-carboxylic acid, and its opposite enantiomer (1R)-6,11-dioxo-1,2,3,4,6,11-hexahydropyridazino[1,2-b]phthalazine-1-carboxylic acid, R-enantiomer was achieved using a Chiralpak AD-H column using a mobile phase containing hexane, isopropyl alcohol and tri-fluoro acetic acid (80:20:0.1 v/v/v). The resolution between the two enantiomers was found to be more than 3.2. The limit of detection (LOD) and limit of quantitation (LOQ) of the R-enantiomer was 0.15 and 0.5 μg mL^?1, respectively, for 10 μL injection volume. The percentage recoveries of the R-enantiomer ranged from 96.5 to 105.3 in the bulk samples of (1S)-6,11-dioxo-1,2,3,4,6,11-hexahydropyridazino[1,2-b]phthalazine-1-carboxylic acid. The test solution and mobile phase was observed to be stable up to 24 h after the preparation. The developed method was validated as per International Conference on Harmonization guidelines in terms of LOD, LOQ, precision, linearity, accuracy, robustness and ruggedness.     

A Validated Chiral LC Method for the Enantiomeric Separation of Cinacalcet Hydrochloride

A rapid isocratic chiral LC method has been developed for the separation of (S)-cinacalcet from (R)-cinacalcet. Good resolution with R _S  > 3 was obtained using a Chiralpak-IA column (250 × 4.6 mm, particle size 5 μm) and n-hexane, ethanol and trifluoroacetic acid as the mobile phase (95:5:0.1, v/v) at ambient temperature. Flow rate was kept at 1.0 mL min^–1 and elution was monitored by UV detection at 223 nm. This method was further used to determine the presence of (S)-cinacalcet in enantiopure pharmaceutical formulations containing (R)-cinacalcet. This method allowed for the detection and quantitation of (S)-cinacalcet of levels at 0.04 and 0.16 μg mL^–1, respectively. The method was validated following ICH guidelines.     

A Validated Chiral LC Method for the Determination of Enantiomeric Purity of Pemetrexed Disodium on an Amylose-Based Chiral Stationary Phase

A simple and new isocratic normal phase chiral HPLC method has been developed for the determination of enantiomeric purity of pemetrexed disodium (l-enantiomer) in bulk drugs with a short run time of about 20 min. Chromatographic separation of l and d-enantiomers of pemetrexed disodium was achieved on an amylose based chiral stationary phase using a mobile phase consists of hexane, ethanol and trifluoro acetic acid. The resolution between the enantiomers was found to be more than 2.0. The system precision and method precision were found to be within 5% RSD for the distomer (d-enantiomer) at its specification level (i.e. not more than 1.0% w/w). The limit of detection and limit of quantification of distomer were 1.6 and 5 μg mL⁻¹, respectively for 10 μL injection volume. The percentage recovery of distomer was ranged from 90.6 to 105.7 in bulk drug samples. The test solution was found to be stable in the diluent for 48 h. The method was found to be specific for the enantiomers of pemetrexed disodium and can be conveniently used for the quantification of undesired d-enantiomer present in the bulk drug samples of pemetrexed disodium.     

A Validated LC Method for Determination of the Enantiomeric Purity of Montelukast Sodium in Bulk Drug Samples and Pharmaceutical Dosage Forms

A new and accurate chiral liquid chromatographic method has been developed for determination of the enantiomeric purity of montelukast sodium (R enantiomer) in bulk drugs and dosage forms. Normal phase chromatographic separation was performed on an immobilized amylose-based chiral stationary phase with n-hexane–ethanol–1,4-dioxane–trifluoroacetic acid–diethylamine 65:25:10:0.3:0.05 (v/v) as mobile phase at a flow rate of 1.0 mL min^?1. The elution time was approximately 15 min. The resolution (R _S) between the enantiomers was >3. The mobile phase additives trifluoroacetic acid and diethylamine played a key role in achieving chromatographic resolution between the enantiomers and also in enhancing chromatographic efficiency. Limits of detection and quantification for the S enantiomer were 0.07 and 0.2 μg, respectively, for a test concentration of montelukast sodium of 1,000 μg mL^?1 and 10 μL injection volume. The linearity of the method for the S enantiomer was excellent (R ² > 0.999) over the range from the LOQ to 0.3%. Recovery of the S enantiomer from bulk drug samples and dosage forms ranged from 97.0 to 103.0%, indicative of the high accuracy of the method. Robustness studies were also conducted. The sample solution stability of montelukast sodium was determined and the compound was found to be stable for a study period of 48 h.     

Chiral Separation of Tenatoprazole and Several Related Benzimidazoles by Normal Phase LC Using Amylose-Based Stationary Phase

Simple and efficient analytical LC methods using amylose-based stationary phase Chiralpak AS-H were developed for direct enantioseparation of tenatoprazole and several related benzimidazoles. The chromatographic experiments were performed in the normal phase mode with n-hexane–ethanol–triethylamine (TEA) as mobile phase. The effects of the mobile phase additive, concentration of organic modifiers and column temperature were studied for the enantioseparation. The thermodynamic parameters were also calculated from the van’t Hoff plots. It was found that the enantioseparations were all enthalpy driven. The enantiomers of all compounds were resolved (R _s  > 3.3) within 14 min using n-hexane–ethanol–TEA (20:80:0.1%, v/v/v) as mobile phase with a flow rate of 0.4 mL min^?1 at 40 °C. The optimized method was validated for determination of the enantiomers of tenatoprazole in terms of linearity, precision and accuracy according to ICH guidelines and applied to the assay of tenantoprazole bulk drugs. The proposed method was shown to be accurate and suitable for the quantitative determination of tenatoprazole enantiomers.     

A Validated LC Method for Determination of the Enantiomeric Purity of Darifenacin in Bulk Drug and Extended Release Tablets

A new and accurate chiral liquid chromatographic method has been developed for the determination of enantiomeric purity of darifenacin [(S)-enantiomer] in bulk drugs and extended release tablets. Normal phase chromatographic separation was performed on an immobilized cellulose based chiral stationary phase (Chiralpak-IC) with n-hexane:ethanol:diethylamine (50:50:0.3, v/v/v) as mobile phase at a flow rate of 1.0 mL min^?1. The elution time was ~15 min. The resolution (R _s ) between the enantiomers was greater than four and interestingly the (R)-enantiomer was eluted prior to darifenacin in the developed method. The limit of detection (LOD) and limit of quantification (LOQ) for the (R)-enantiomer were 0.02 μg and 0.07 μg, respectively, for a 10 μL injection volume. The method was extensively validated in terms of linearity, precision and accuracy and satisfactory results were obtained. Robustness studies were also conducted. The sample solution stability of darifenacin was determined and the compound was found to be stable for a study period of 48 h.     

Enantiomeric LC Separation of Epinephrine on Amylose based sorbent

A simple, rapid, and robust chiral HPLC method has been developed and validated for separation of the enantiomers of epinephrine, l-1-(3,4-dihydroxyphenyl)-2-(methylamino)ethanol, an antihypertensive drug, in the bulk drug. The enantiomers were resolved on an amylose-based stationary phase with n-hexane–2-propanol–methanol–trifluoroacetic acid–diethylamine 90:05:05:0.2:0.2 (v/v) as mobile phase at a flow rate of 1.0 mL min^?1. In the optimized method resolution between the enantiomers was not less than 3.0. The trifluoroacetic acid and diethylamine in the mobile phase were important for enhancing chromatographic efficiency and hence the resolution of the enantiomers. The method was extensively validated and proved to be robust. The calibration plot for the d enantiomer was highly linear over the concentration range 100–2,000 μg mL^?1. The limits of detection and quantification for the d enantiomer were 0.15 and 0.45 μg mL^?1, respectively. Recovery of the d enantiomer from bulk drug samples of epinephrine ranged between 99.5 and 101.5%. Epinephrine sample solution was stable for up to 48 h. The method was suitable for accurate quantitative determination of the d enantiomer in the bulk drug substance     

Quantitative Analysis and Separation of Chiral (S)-Ethyl 3-Hydroxyglutarate in Bioconversion Mixtures by LC and TLC

A convenient ion-pair LC procedure was firstly established for rapid analysis of ethyl 3-hydroxyglutarate (3-EHG) in an enzymatic-hydrolysis mixture, and the detection limit was as low as 0.45 μmol L^?1; high repeatability was achieved with intra-day (n = 5) and inter-day (n = 5) relative standard deviation (RSD) values of 1.56 and 2.38%, respectively. The good linearity was established for 3-EHG concentration in the broad range from 0.005 to 0.30 mol L^?1, with a coefficient (r) of 0.9992. (S)- and (R)-3-EHG were separated by normal-phase LC after simple derivatization with (R)-(+)-phenylethanamine, ee value (≥95%) of 3-EHG prepared by Lipase B catalyzed hydrolysis of diethyl 3-hydroxyglutatate (3-DHG) was determined after optimization of the mobile phase, and the RSD was 0.75% (n = 9) for repeatability. The results showed that the above methods were highly reproducible and reliable for analysis and separation of (S)-3-EHG from bioconversion mixture.     

Chiral Separation of Nateglinide and its L Enantiomer on a Molecularly Imprinted Polymer-Based Stationary Phase

A new chiral stationary phase for nateglinide (N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine) based on a molecularly imprinted polymer has been prepared by non-covalent imprinting. For chromatographic analysis the effects on the separation of mobile phase composition, flow rate, and temperature were investigated, and the optimum conditions for HPLC were shown to be: mobile phase, acetonitrile; flow rate, 0.5 mL min^?1; temperature, 25 °C. It was shown that the nateglinide-imprinted polymer was capable of recognizing the enantiomeric difference between nateglinide and its L enantiomer, whereas the non-imprinted polymer had no such ability. Scatchard analysis was used to investigate the binding characteristics of the nateglinide-imprinted stationary phase; this indicated that two classes of binding site were present in the imprinted polymer. The equilibrium dissociation constant (K _D) and the apparent maximum number (Q _max) of high- and low-affinity binding sites were 3.7 × 10^?4 mol L^?1 and 11.38 μmol g^?1, and 1.81 × 10^?3 mol L^?1 and 27.73 μmol g^?1, respectively.     

A Validated Stability Indicating LC Method for Mitotane in Bulk Drugs and Pharmaceutical Dosage Forms

A novel, sensitive, stability indicating RP-LC method has been developed for the quantitative determination of mitotane, its impurity in both bulk drugs and pharmaceutical dosage forms. Efficient chromatographic separation was achieved using a C18 stationary phase with simple mobile phase combination delivered in an isocratic mode and quantitation was by ultraviolet detection at a wavelength of 230 nm. The mobile phase consisted of buffer and acetonitrile (25:75, v/v) delivered at a flow rate of 1.0 mL min^?1. Buffer consisted of 10 mM potassium dihydrogen orthophosphate monohydrate, pH adjusted to 2.5 by orthophosphoric acid. In the developed LC method the resolution (R _s ) between mitotane and its impurity namely Imp-1 was found to be greater than 2.5. Regression analysis shows an r value (correlation coefficient) greater than 0.999 for mitotane and its impurity. This method was capable to detect the impurity of mitotane at a level of 0.003% with respect to test a concentration of 0.2 mg mL^?1 for a 10 μL injection volume. The inter- and intra-day precision values for mitotane and its impurity was found to be within 2.0% RSD. The method has shown good and consistent recoveries for mitotane in bulk drugs (99.2–101.5%), pharmaceutical dosage forms (98.2–103.1%) and for its impurity (99.7–102.1%). The test solution was found to be stable in diluent for 48 h. The drug was subjected to stress conditions of hydrolysis, oxidation, photolysis and thermal degradation. Considerable degradation was found to occur in basic stress hydrolysis. The stress samples were assayed against a qualified reference standard and the mass balance was found close to 99.97%. The developed RP-LC method was validated with respect to linearity, accuracy, precision and robustness.     

Chiral selectors for enantioresolution and quantitation of the antidepressant drug fluoxetine in pharmaceutical formulations by (19)F NMR spectroscopic method

¹⁹F NMR spectroscopy was applied to the quantitative determination of fluoxetine enantiomers using different chiral recognition agents in pharmaceutical formulations. Several parameters affecting the enantioresolution including the type and concentration of chiral selector, concentration of fluoxetine and temperature were studied. The chiral selectors investigated are the cyclic oligosaccharides α-, β- and γ-cyclodextrin and a diamino derivative of methylated α-cyclodextrin (DAM-α-CD), linear polysaccharides (maltodextrin with dextrose equivalents of 4.0-7.0, 13.0-17.0 and 16.5-19.5) and the macrocyclic antibiotic vancomycin. Among the chiral selectors used, DAM-α-CD turned out to give the best resolution of the ¹⁹F NMR signals of (R)- and (S)-fluoxetine. The calibration curve was linear for (R)- and (S)-fluoxetine over the range 0.10-1.35 mg mL⁻¹, the detection limits (S/N = 3) being 5.9 and 7.5 μg mL⁻¹ for the pure solutions of (R)- and (S)-fluoxetine, respectively. The recovery studies performed on pharmaceutical samples ranged from about 90 to 110% with relative standard deviations of <8%. The results showed that the proposed method is rapid, precise and accurate. Applying statistical Student's t-test revealed insignificant difference between the real and measured contents at the 95% confidence level.     

Development and Validation of a Stability Indicating LC Method for the Determination of Faropenem in Pharmaceutical Formulations

A simple, selective and sensitive stability indicating LC method has been developed and validated for the determination of faropenem in bulk drug and pharmaceutical formulations in the presence of degradation products. The separation was achieved by using an isocratic mobile phase mixture of acetate buffer of pH 3.5 and methanol (65:35, v/v) and 250 mm × 4.6 mm I.D., 5 μm particle size SGE make Wakosil C-18 AR column at flow rate of 1.0 mL min^?1 with detection at 305 nm. The retention time of faropenem is 6.63 min and was linear in the range of 5–75 μg mL^?1 (r = 0.9999). The drug was subjected to stress conditions of hydrolysis, oxidation, photolysis and thermal degradation and was found to be unstable in all the stress conditions. The proposed method was successfully employed for quantification of faropenem in bulk drug and its pharmaceutical formulations.     

Enantiomeric separation of a melatonin agonist Ramelteon using amylose-based chiral stationary phase

A new simple isocratic chiral liquid chromatographic method was developed for the enantiomeric purity of Ramelteon[(S)-N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl) ethyl]-propionamide], a melatonin agonist in bulk drugs. The chromatographic separation was achieved on Chiralpak AD-H, 250 mm × 4.6 mm, 5 μm column using a mobile phase system consisting of n-hexane, ethanol and methanesulfonic acid in the ratio of 900:100:0.1 (v/v/v). The mobile phase was pumped on the column at the flow rate of 1 mL min^?1. Addition of methane sulfonic acid in the mobile phase enhanced chromatographic efficiency and resolution between the enantiomers. The resolution between the enantiomers was found to be more than four. The developed method was subsequently validated and proved to be accurate and precise. The experimentally established limit of detection and quantification of (R)-enantiomer were found to be 25.5 and 77.2 ng ml^?1, respectively, for 20 μl injection volumes. The percentage recovery of (R)-enantiomer was ranged from 98.5 to 101.9 in bulk drug samples of Ramelteon. The stability of Ramelteon sample in analytical solution was checked for about 48 h at room temperature and was found to be stable for about 48 h. The proposed method was found to be suitable and accurate for the quantitative determination of (R)-enantiomer in drug substance.     

Investigation of Micellar and Phase Separation Phenomenon of the Amphiphilic Drug Amitriptyline Hydrochloride with Cationic Hydrotropes

Micellization and phase separation of the amphiphilic drug amitriptyline hydrochloride (AMT) in the absence and presence of cationic hydrotropes (aniline hydrochloride, para-toluidine hydrochloride, and ortho-toluidine hydrochloride) have been investigated in the present study. The experimental critical micelle concentration (cmc) values are lower than cmc ^id values (cmc ^id is the cmc value at ideal mixing state), indicating attractive interactions between the two components (drug and hydrotrope) in mixed micelles. The bulk behaviors were investigated using the different theoretical models of Clint, Rubingh, Motomura, and Rodenas for comparison of the results of different binary combinations of the drug and hydrotropes. Synergistic interactions were confirmed in all binary combinations at all temperatures, which increase with increasing concentration of hydrotropes. Activity coefficients (f ₁ and f ₂) were found to be consistently less than unity indicating nonideality in the systems. At a fixed drug concentration (50 mmol·dm^?3) and pH (6.7), the hydrotropes showed a continuous increase in the cloud point. Thermodynamic parameters were also evaluated and discussed in detail.