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Purpose of the study was to enhance the solubility of chlorthalidone, poorly soluble diuretic that has been the used for lowering high blood pressure for the past half-century. Solubility is a challenge for approximately 90% of drug candidates. Chlorthalidone is BCS Class IV drug whose poor solubility needs to be improved in order to optimize its efficacy. Using a free radical polymerization technique, sodium alginate-based nanogels were formulated for enhancing solubility of chlorthalidone. The evaluation of various characteristics of nanogels was done by structural characterization, drug loading, swelling, sol-gel transition, in-vitro release, solubility, and toxicity tests. Fourier transform infrared (FT-IR) spectroscopy revealed characteristic peaks of the primary raw materials and polymeric nanogels. The FT-IR spectra of the chlorthalidone-loaded nanogels suggested discrete drug peaks confirming successful drug loading. The system's amorphous nature and thermal stability were indicated by powder x-ray diffractometry and thermal analysis. The scanning electron microscopy indicated a well-defined porous structure. The size of the nanogels was determined by zeta size analysis to be 189 ± 18.35 n·m. The solubility enhancement factor demonstrated the potential for improved solubility of the poorly soluble drug. The resulting biocompatible nanogels could be used to improve the solubility of hydrophobic drugs., (© 2024 IOP Publishing Ltd. All rights, including for text and data mining, AI training, and similar technologies, are reserved.)

The Na + -Cl - cotransporter (NCC) drives salt reabsorption in the kidney and plays a decisive role in balancing electrolytes and blood pressure. Thiazide and thiazide-like diuretics inhibit NCC-mediated renal salt retention and have been cornerstones for treating hypertension and edema since the 1950s. Here we determine NCC co-structures individually complexed with the thiazide drug hydrochlorothiazide, and two thiazide-like drugs chlorthalidone and indapamide, revealing that they fit into an orthosteric site and occlude the NCC ion translocation pathway. Aberrant NCC activation by the WNKs-SPAK kinase cascade underlies Familial Hyperkalemic Hypertension, but it remains unknown whether/how phosphorylation transforms the NCC structure to accelerate ion translocation. We show that an intracellular amino-terminal motif of NCC, once phosphorylated, associates with the carboxyl-terminal domain, and together, they interact with the transmembrane domain. These interactions suggest a phosphorylation-dependent allosteric network that directly influences NCC ion translocation., (© 2024. The Author(s).)

Central composite design based RP-HPLC method optimization for the synchronized analysis of Efonidipine Hydrochloride Ethanolate (EFE) and Chlorthalidone (CHL) in tablet. The effective separation was performed using Inertsil ODS C18 column (250 × 4.6 mm, 5 μm), PDA detector with 0.05 M KH2PO4 Buffer (pH 4.5): Acetonitrile (40:60%v/v) mobile phase. Independent variables were investigated include the concentration of KH2PO4 (X1) and flow rate of mobile phase (X2). Based on responses obtained (retention time, resolution and tailing factor), the optimum condition selected was X1 = 40% and X2 = 1 ml/min. Optimized HPLC condition was validated by assessing validation parameters and it meets the acceptance criteria set by ICH. The linear calibration curve was found to be in the quantity range 6.25-18.75 and 20-60 μg/ml Assay of drugs was 100.94 and 100.06% for CHL and EFE. The validated RP-HPLC-PDA method can be used for routine analysis of EFE and CHL in tablet., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

According to the green chemistry approach, the usage of carcinogenic and teratogenic organic solvents should be minimized in the development of the analytical method for the safety of the environment and analysts. According to the literature review, no high-performance thin-layer chromatographic (HPTLC) method has been reported yet for concomitant analysis of azilsartan medoxomil (AZM), chlorthalidone (CTD) and cilnidipine (CDP) in human plasma. Hence, a robust and accurate HPTLC method has been developed using safe and non-toxic organic solvents for the concomitant analysis of AZM, CTD and CDP in human plasma, fixed-dose combinations (FDCs) and laboratory mixtures. The HPTLC method was developed by the implementation of the analytical quality by design approach using principles of quality risk management and design of experiments (DoE) for regulatory compliance. The principal component analysis was applied for the risk assessment and analysis of potential method variables in the method development. The principle of DoE was used for the response surface modeling to link identified critical method risk parameters with critical method performance attributes using full factorial design (FFD). The method operable design region and analytical control space were navigated for the optimization of the method as per quality target analytical profile. The developed method was also applied for concomitant analysis of AZM, CTD and CDP in their FDCs and laboratory mixture and results were found in good agreement with the labeled amount of the respective drug., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Cyclodextrin (CD) is used to solubilize poorly water-soluble drugs by inclusion complex formation. In this study, we investigated the effect of CD derivatives on stabilizing the supersaturation by inhibiting the crystallization of two poorly water-soluble drugs, carvedilol (CVD) and chlorthalidone (CLT). The phase solubility test showed that β-CD and γ-CD derivatives enhanced the solubility of CVD to a greater extent, whereas the solubility of CLT was enhanced more by β-CD derivatives. The solubilization efficacy of CD derivatives was dependent on the size fitness between the drug molecule and the CD cavity. In the drug crystallization induction time measurement, the same initial drug supersaturation ratio (S) was employed in all the CD solutions, and the methylated CD derivatives greatly outperformed unmethylated CD derivatives in stabilizing the supersaturation of both CVD and CLT. The crystallization inhibition strength of CD derivatives was strongly affected by the CD derivative substituent. Moreover, the calculated logarithm of octanol/water partition coefficients (log P) of CD derivatives showed a good correlation with drug crystallization inhibition ability. Thus, the high hydrophobicity of methylated CD plays an essential role in inhibiting crystallization. These findings can provide a valuable guide for selecting appropriate stabilizing agents for drug-supersaturation formulations., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

In this work, enantiomeric separation of a drug combination of two chiral drugs, namely, atenolol and chlorthalidone, is described. Prior investigation of the effect of different variables on the resolution of the enantiomers' peaks and the total run time represented by the retention time of the last eluted peak was conducted using face-centered composite design. Twenty-two experiments were carried out by varying the chiral stationary phase type as a categorical factor and mobile phase composition including the percentage of ethanol and percentage of diethylamine as continuous factors. According to the optimization process, a mobile phase consisting of hexane:ethanol:DEA:TFA (60:40:0.2:0.1%, v/v/v/v) pumped at flow rate 1 ml min -1 onto Lux-Cellulose 2 stationary phase was applied for the chiral separation and quantification of the drug combination at 230 nm. Application of the developed method to the pharmaceutical formulation of this combination was successfully performed, and satisfactory percentage of recoveries was obtained. The method was also fully validated following International Conference on Harmonization (ICH) guidelines. This method could be of high value and relevance for application in quality control laboratories., (© 2021 Wiley Periodicals LLC.)

Aims: Aim of the study was to enhance the solubility of Chlorthalidone by developing beta-cyclodextrin cross-linked hydrophilic nanomatrices., Main Methods: Nine different formulations were fabricated by free radical polymerization technique. All formulations were characterized through different studies. FTIR spectroscopy of unloaded and loaded nanomatrices was processed to determine compatibility of constituents and that of the drug with the system. Surface morphology of the nanomatrices was studied by SEM. The size of the optimized formulation was determined by zeta sizer. Swelling, in-vitro release and solubility studies were carried out in different media and results of in-vitro release profiles of nanomatrices and commercially available tablet of Chlorthalidone were compared. For determination of biocompatibility, toxicity studies were proclaimed in rabbits., Key Findings: Main peaks of corresponding functional groups of individual constituents and that of drug were depicted in FTIR spectra of unloaded and loaded nanomatrices. Porous and fluffy structure was visualized through SEM images. Particle size of the optimized formulation was in the range of 175 ± 5.27 nm. Percent loading of optimized formulation showed the best result. Comparing the in-vitro drug release profiles of nanomatrices and commercially available tablet, the results of the synthesized nanomatrices were quite satisfactory. Solubility profiles were also high as compared to the drug alone. Moreover, toxicity studies confirmed that nanomatrices were biocompatible and no sign of any toxic effect was found., Significance: We concluded that our developed nanomatrices had successfully enhanced the solubility of Chlorthalidone and can also be used for other poorly aqueous soluble drugs., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The main objective of this study was to establish an efficient extraction procedure for the estimation of telmisartan, amlodipine and chlorthalidone from their combination in sample matrix using an analytical quality by design approach. Initial screening studies were performed for optimization of a suitable diluent to extract active components from sample matrix. Further, the same study was extended for the identification of critical method attributes and the factors affecting the analytical target profile. This study also explains the rugged and robust quantitative determination of combinations drugs with a shorter run time. The design of experimental studies confirms that the current center point parameters are well suited to recoveries. The chromatographic separation was achieved with an X-Terra RP8, 150 × 4.6 mm, 3.5 μm column with an isocratic mobile phase (mixture of 20 mm aqueous ammonium acetate and acetonitrile). To demonstrate the stability-indicating nature of the optimized method, forced degradation studies were conducted and proved. The optimized method was validated according to International Conference on Harmonization guidelines., (© 2019 John Wiley & Sons, Ltd.)

Reasons for formulation instability were investigated either encountered during production or analytical processes of azilsartan medoxomil (AZM)/chlorthalidone hydrochloride (CLT) tablets. Through the identification of the most feasible degradation pathways, several strategies were proposed to enhance the stability of AZM/CLT formulation. Furthermore, a robust HPLC-UV method was developed and validated for the determination of AZM, CLT in the presence of their possible degradation products. For chromatographic method development, typical quality by design (QbD) approach was implemented. In order to optimize fourteen chromatographic responses, we have used a central composite design with four factors (pH, temperature, flow rate, and acetonitrile %). However, the developed method provides a design space, but optimum parameters were Inertsil C8 column (150 x 4.6 mm, 5 μm), mobile phase composed of 0.025 M phosphate buffer pH 2.7 and acetonitrile (52.5: 47.5%), with flow rate of 1.5 mL.min -1 and detection wavelength 225 nm at 33 °C. The method was then validated according to ICH guidelines and applied to quantitate AZM and CLT in the pharmaceutical formulation. To the best of our knowledge, this manuscript is the first attempt to discuss such instability issues, to propose strategies that enhance the stability of AZM/CLT tablet formulation, to develop robust stability-indicating method taking into consideration the realistic degradation products in addition to minor ones., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Solid dispersions (SDs) of chlorthalidone (CTD) are promising systems to enhance drug dissolution rate, generate and maintain drug supersaturation levels in gastrointestinal fluids. In this work, SDs of CTD were prepared by spray drying using sodium alginate (SA) as carrier. Six formulations were prepared, varying the drug loading and composition, through the combination of SA with surfactants (sodium lauryl sulfate (SLS) or polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (SOL)). In all SDs, except when SA was used alone at low drug loading, CTD was in the amorphous form. At sink conditions, all SDs showed a faster dissolution rate than the crystalline drug. At non-sink conditions, the SDs prepared with SA and SLS at low drug loading exhibited the best performance to maintain supersaturating drug levels. All SDs, except those prepared with SA alone or SA-SLS at high drug loading, presented no drug recrystallization after 34 months of storage., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Azilsartan Medoxomil (AZL) angiotensin II receptor blocker and chlorthalidone (CLT) were determined by ultraperformance liquid chromatography (UPLC) method in their combined dosage form, they were both subjected to forced degradation studies under extensive stress conditions. The method is a stability indicating by resolving the investigated drugs from their degradation products. Moreover, the degradation products for both drugs obtained from forced degradation were subjected to LC-MS for structure elucidation. The UPLC technique depends on the measurement of spectra for AZL and CLT at 254 nm. Linearity, accuracy and intermediate precision were acceptable over the concentration range of 67.2-268.8 and 40-160 μg/mL for AZL and CLT, respectively. The method was applied for the determination of the studied drugs in their dosage forms. The UPLC method is inexpensive, simple and considered as green chemistry method for the routine analysis and quality control of both drugs in their combined dosage form.

A novel, precise, sensitive and accurate ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method has been developed for the simultaneous determination of a novel drug combination, candesartan (CAN) and chlorthalidone (CHL), in human plasma. Chromatographic separation was achieved on Waters Acquity UPLC BEH C 18 (50 × 2.1 mm, 1.7 μm). Mobile phase consisting of 1 mm ammonium acetate in water-acetonitrile (20:80 v/v) was used. The total chromatographic runtime was 1.9 min with retention times for CAN and CHL at 0.7 and 1.1 min respectively. Ionization and detection of analytes and internal standards was performed on a triple quadrupole mass spectrometer, operating in the multiple reaction monitoring and negative ionization mode. Quantitation was done to monitor protonated precursor → product ion transition of m/z 439.2 → 309.0 for CAN, 337.0 → 189.8 for CHL and 443.2 → 312.1 for candesartan D4 and 341.0 → 189.8 for chlorthalidone D4. The method was validated over a wide dynamic concentration range of 2.0-540.0 ng/mL for candesartan and 1.0-180.0 ng/mL for chlorthalidone. The validated method was successfully applied for the assay of CAN and CHL in healthy volunteers., (Copyright © 2017 John Wiley & Sons, Ltd.)

A simple, sensitive and reproducible ultra-performance liquid chromatography-tandem mass spectrometry method has been developed for the simultaneous determination of atenolol, a β-adrenergic receptor-blocker and chlorthalidone, a monosulfonamyl diuretic in human plasma, using atenolol-d7 and chlorthalidone-d4 as the internal standards (ISs). Following solid-phase extraction on Phenomenex Strata-X cartridges using 100 μL human plasma sample, the analytes and ISs were separated on an Acquity UPLC BEH C18 (50 mm × 2.1 mm, 1.7 µm) column using a mobile phase consisting of 0.1% formic acid-acetonitrile (25:75, v/v). A tandem mass spectrometer equipped with electrospray ionization was used as a detector in the positive ionization mode for both analytes. The linear concentration range was established as 0.50-500 ng/mL for atenolol and 0.25-150 ng/mL for chlorthalidone. Extraction recoveries were within 95-103% and ion suppression/enhancement, expressed as IS-normalized matrix factors, ranged from 0.95 to 1.06 for both the analytes. Intra-batch and inter-batch precision (CV) and accuracy values were 2.37-5.91 and 96.1-103.2%, respectively. Stability of analytes in plasma was evaluated under different conditions, such as bench-top, freeze-thaw, dry and wet extract and long-term. The developed method was superior to the existing methods for the simultaneous determination of atenolol and chlorthalidone in human plasma with respect to the sensitivity, chromatographic analysis time and plasma volume for processing. Further, it was successfully applied to support a bioequivalence study of 50 mg atenolol + 12.5 mg chlorthalidone in 28 healthy Indian subjects., (Copyright © 2015 John Wiley & Sons, Ltd.)

Chlortalidone (CTD) is a diuretic drug largely used as part of antihypertensive therapies. It is marketed as an equimolar mixture of its enantiomers in the racemic crystal phase named Form I, despite of the higher aqueous solubility of another crystal form. The latter, named Form II, was thought to contain both enantiomers as a racemic conglomerate, i.e., in the form of a mixture of crystals, half of which consists solely of the (R)-enantiomer, the other half the (S)-enantiomer. The occurrence of both enantiomers in individual crystals of CTD Form II was demonstrated in this study. Spontaneous resolution does really occur upon crystallization, as presumed previously even without physical evidence of the (S)-enantiomer. Both (R) and (S)-enantiomers were successfully identified as two domains of a twinned by inversion single crystal of CTD Form II. A reliable Flack parameter of 0.14(4) allowed to determine the proportion of the enantiomers in the crystal, which is formed with 86% of the (R)-enantiomer and 14% of the (S)-enantiomer., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Azilsartan medoxomil (AZM), an ester prodrug of azilsartan (AZ), and chlorthalidone (CLT) have recently been approved as a combination therapy for the management of hypertension. This is the first report which described a selective and sensitive method for the simultaneous quantification of AZ and CLT in rat and human plasma using liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). AZ and CLT were extracted from plasma by liquid-liquid extraction technique and separated on a C18 reverse phase column using ammonium acetate (10mM, pH 4)-mixture of methanol and acetonitrile (8:92, v/v) as a mobile phase at a flow rate of 0.7mL/min. Detection was performed by electrospray ionization (ESI) operated in negative multiple reaction monitoring (MRM) mode. The lower limit of quantitation (LLOQ) of this method was 1ng/mL and the calibration curves were linear (r(2)≥0.995) over the concentration range of 1-4000ng/mL for both the analytes. The intra- and inter-day precision and accuracy were well within the acceptable limits. The mean extraction recoveries were found to be about 80% and no matrix effect was observed. AZ and CLT were found to be stable under all relevant storage conditions. The method was successfully applied to the oral pharmacokinetic study of AZM and CLT in rats. Further, the sensitivity of the method enabled the determination of protein binding of AZ and CLT in human plasma., (Copyright © 2015 Elsevier B.V. All rights reserved.)

The maintenance mechanism of the supersaturated state of poorly water-soluble drugs, glibenclamide (GLB) and chlorthalidone (CLT), in hydroxypropyl methylcellulose acetate succinate (HPMC-AS) solution was investigated at a molecular level. HPMC-AS suppressed drug crystallization from supersaturated drug solution and maintained high supersaturated level of drugs with small amount of HPMC-AS for 24 h. However, the dissolution of crystalline GLB into HPMC-AS solution failed to produce supersaturated concentrations, although supersaturated concentrations were achieved by adding amorphous GLB to HPMC-AS solution. HPMC-AS did not improve drug dissolution and/or solubility but efficiently inhibited drug crystallization from supersaturated drug solutions. Such an inhibiting effect led to the long-term maintenance of the amorphous state of GLB in HPMC-AS solution. NMR measurements showed that HPMC-AS suppressed the molecular mobility of CLT depending on their supersaturation level. Highly supersaturated CLT in HPMC-AS solution formed a gel-like structure with HPMC-AS in which the molecular mobility of the CLT was strongly suppressed. The gel-like structure of HPMC-AS could inhibit the reorganization from drug prenuclear aggregates to the crystal nuclei and delay the formation of drug crystals. The prolongation subsequently led to the redissolution of the aggregated drugs in aqueous solution and formed the equilibrium state at the supersaturated drug concentration in HPMC-AS solution. The equilibrium state formation of supersaturated drugs by HPMC-AS should be an essential mechanism underlying the marked drug concentration improvement.

Chlorthalidone (CTD) is an antihypertensive drug and exhibits four crystalline forms: I, II, III and IV. In this paper, the incidence of CTD polymorphs in raw materials and in tablets as well as the solubility and dissolution properties of forms I and II have been studied. Raw materials were named as A, B, C, D, and E and tablets as Reference, G1, G2 and S. Using powder X-ray diffraction and infrared spectroscopy analyses we found that A, B, E, Reference and G1 contain CTD form I; C, D and S contain predominantly form II; and G2 contain a mixture of both forms. Solubility experiments showed that form II is up to 49% more soluble than form I and dissolution studies showed a significantly effect of the polymorphism on the dissolution of CTD from tablets. Based on these results, it was concluded that only the CTD form I is acceptable for preparation of tablet form. Moreover, we proposed the polymorphic quality control of CTD raw materials and tablets., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Two stability-indicating chromatographic methods are described for simultaneous determination of amiloride hydrochloride (AMI), atenolol (ATE), and chlorthalidone (CHL) in combined dosage forms. The first method was based on HPTLC separation of the three drugs followed by densitometric measurements of their bands at 274 nm. The separation was carried out on Merck HPTLC silica gel 60F254 aluminum sheets using chloroform-methanol-ammonia 27%, w/w (9 + 2 + 0.3, v/v/v) mobile phase. Analysis data was used for the linear regression graph in the range of 0.1-0.5, 0.8-5.0, and 0.3-1.5 microg/band for AMI, ATE, and CHL, respectively. The second method was based on an RP-HPLC separation of the cited drugs performed on an RP stainless steel C18 analytical column (250 x 4.6 mm id) with a gradient elution system of methanol and 0.05 M aqueous phosphate buffer adjusted to pH 4 as the mobile phase, at the flow rate of 1.0 mL/min. Quantitation was achieved with photodiode array detection at 275 nm for AMI and 225 nm for ATE and CHL. The calibration graphs for each drug were rectilinear in the range of 2-50, 25-150, and 2-100 microg/mL for AMI, ATE, and CHL, respectively. The proposed chromatographic methods were successfully applied for determination of the investigated drugs in pharmaceutical preparations. Both methods were validated in compliance with International Conference on Harmonization guidelines in terms of linearity, accuracy, precision, robustness, LOD, and LOQ.

Thiazide and high ceiling diuretics were recently shown to inhibit all mammalian isoforms of carbonic anhydrase (CA, EC 4.2.1.1) with a very different profile as compared to classical inhibitors, such as acetazolamide, methazolamide, and ethoxzolamide. Some of these structurally related compounds have a very different behavior against the widespread isozyme CA II, with chlorthalidone, trichloromethiazide, and furosemide being efficient inhibitors against CA II (K(I)s of 65-138 nM), whereas indapamide is a much weaker one (K(I) of 2520 nM). Furthermore, some of these diuretics are quite efficient (low nanomolar) inhibitors of other isoforms, for example, chlorthalidone against hCA VB, VII, IX, and XIII; indapamide against CA VII, IX, XII, and XIII, trichloromethiazide against CA VII and IX, and furosemide against CA I and XIV. Examining the four X-ray crystal structures of their CA II adducts, we observed several (2-3) active site water molecules interacting with the chlorthalidone, trichloromethiazide, and furosemide scaffolds which may be responsible for this important difference of activity. Indeed, indapamide bound to CA II has no interactions with active site water molecules. Chlorthalidone bound within the CA II active site is in an enolic (lactimic) tautomeric form, with the enolic OH also participating in two strong hydrogen bonds with Asn67 and a water molecule. The newly evidenced binding modes of these diuretics may be exploited for designing better CA II inhibitors as well as compounds with selectivity/affinity for various isoforms with medicinal chemistry applications.

Thiazide diuretics inhibit all mammalian isoforms of carbonic anhydrase (CA, EC 4.2.1.1) with a different profile as compared to classical inhibitors. Acting as moderate-weak inhibitors of CA II and CA I, chlorthalidone and indapamide considerably inhibit other isozymes among the 16 CAs present in vertebrates. These compounds show a different behavior against CAs I and II, with chlorthalidone being 18.3 times more potent against CA II and 150 times more potent against CA I, as compared to indapamide. In the X-ray crystal structures of the CA II-chlorthalidone adduct three active site water molecules interacting with the inhibitor scaffold were observed that lack in the corresponding indapamide adduct. Chlorthalidone bound within the active site is in an enolic tautomeric form, with the OH moiety participating in two strong hydrogen bonds with Asn67 and a water molecule. This binding mode may be exploited for designing better CA II inhibitors.

A high-performance liquid chromatographic method was optimized and validated for the determination of atenolol and chlorthalidone (CT) in human breast milk. The milk samples were extracted and purified using ACN and phosphoric acid for precipitation of proteins followed by removal of ACN and milk fats by extraction with methylene chloride. The samples were applied, after an extraction procedure, to a cyanide column using a mobile phase consisting of ACN/water (35:65 v/v) and buffered at pH 4.0 with flow rate of 1.0 mL/min. Quantitation was achieved with UV detection at 225 nm using guaifenesin as the internal standard. The effectiveness of protein precipitation and clean up procedure were investigated. The method was validated over the range of 0.3-20 microg/mL for atenolol and 0.25-5 microg/mL for CT.

A reversed-phased liquid chromatographic method for the control of impurities of nine impurities in Chlortalidone drug substance is presented. The method is sufficiently sensitive to quantify down to the level of 0.0015 per cent equivalent to a concentration of 15 microg/ml.

The aim of this study was to compare the miniaturised techniques, capillary electrochromatography (CEC) and capillary liquid chromatography (CLC), for the chiral separation of chlorthalidone. In both cases, hydroxypropyl-beta-cyclodextrin was used as a chiral selector in the mobile phase, while an achiral stationary phase was used. Earlier, this separation was already optimised in CEC. Now, the separation was optimised in CLC. The influence of the organic modifier content and the cyclodextrin concentration on the separation was studied by means of a central composite design. Optimal separation conditions were determined, after response modelling, from the response surface contour plots. When these conditions were compared with those of the CEC optimisation, we can see the potential of using CLC as a chiral separation technique since less chiral selector was used, faster separations were obtained and better repeatability was observed in comparison with its electrical-driven counterpart., (Copyright 2004 Elsevier B.V.)

Resolution of binary mixtures of atenolol (ATE) and chlorthalidone (CTD) with minimum sample pre-treatment and without analyte separation has been successfully achieved, using a new and rapid method based on partial least squares (PLS1) analysis of UV spectral data. The simultaneous determination of both analytes was possible by PLS1 processing of sample absorbances between 255 and 300 nm for ATE and evaluation of absorbances in the 253-268 nm region for CTD. The mean recoveries for synthetic samples were 100.3 +/- 1.0% and 100.7 +/- 0.7% for ATE and CTD, respectively. Application of the proposed method to two commercial tablet preparations in the content uniformity test showed them to contain 103.5 +/- 0.8% and 104.9 +/- 1.8% ATE respectively, as well as 103.4 +/- 1.2% and 104.5 +/- 2.2% CTD. Use of this method also allowed the elaboration of dissolution profiles of the drugs in two commercial combined formulation products, through the simultaneous determination of both drugs during the dissolution test. At the dissolution time of 45 min specified by USP XXIV, both pharmaceutical formulations complied with the test.

The photodegradation process of the phototoxic diuretic drug chlorthalidone was studied. The products of its photolysis under UV-B were isolated and identified. Chlorthalidone was found to be active when examined by photohemolysis on human erythrocytes, but not in the presence of the isolated photoproducts. Inhibition of the photohemolysis process induced by chlorthalidone on addition of reduced glutathione (GSH) or ascorbic acid suggests the involvement of radicals species. The inhibition with 1,4-diazabycyclo [2.2.2] octane (DABCO), sodium azide (NaN3) sowie 2,5-dimethylfuran proof the participation of singlet oxygen (1O2) in this process.

In pharmaceutical technological research, optimization studies generally deal with the search for the formulation that is as effective and as functional as possible. The effect of a formulation parameter (the amount of lactose in the composition of the tablets) and of a technological parameter (compression pressure) on four physical characteristics (tablet thickness, friability, hardness, and drug dissolution rate) of tablets containing the antihypertensive drug chlorthalidone were studied. The results obtained indicate that, in the development of a tablet formulation, it is possible to identify the most suitable formulation by applying a simple optimization method. The effect of the microclimatic stress (temperature and humidity) was also evaluated, and it was found that the optimized tablets were no longer within limits that had been established for them. This may indicate that it is opportune to keep the storage conditions of the excipients under control before their use.

Dynamic electrokinetic chromatography (DEKC) and computer simulation have been used to determine the enantiomerization barrier of the drug chlorthalidone, which is commonly employed as a diuretic. The separation of enantiomers was performed in an aqueous 100 mM citric acid/phosphate buffer system at pH 5 containing 12.5 mg/mL carboxymethyl-beta-cyclodextrin and dimethyl-beta-cyclodextrin each as a dual chiral recognition system. The enantiomerization that occurred during separation resulted in a peak distortion, i.e., plateau formation and peak broadening. The interconversion profiles were simulated with ChromWin software, which is based on the theoretical plate as well as on the stochastic model using the experimental data plateau height, hplateau; peak width at half height, Wh, and total retention time, tR. Peak form analysis yielded the rate constants, k1 and k(-1) as well as the kinetic activation parameters, deltaG++, deltaH++, and deltaS++ of the enantiomerization reaction of chlorthalidone 1. At 37.5 degrees C, the enantiomerization barrier, deltaG++, was determined to be 100.6 +/- 0.4 kJ/mol(-1); the activation parameters by temperature-dependent measurement, deltaH++ = 69.2 +/- 0.2 kJ/mol , deltaS++ = -101 +/- 6 J K(-1) mol(-1) and the half-life, tau, was found to be approximately 2.5 hr.

The solubility of chlorthalidone in 16 solvent systems was determined in the absence and presence of different amounts of beta-cyclodextrin (beta-CD). Chlorthalidone (CT) was shown to be more soluble in hydrophilic organic solvents, with the highest solubility in ethylacetate (EtOAc) saturated with water. The solubility of CT in water, butanol, octanol, and dichloromethane (DCM) was enhanced by the addition of beta-cyclodextrin. The enantioselective partitioning of CT between water and EtOAc, DCM, butan-1-ol, butan-2-ol, and octan-1-ol was determined in the presence of beta-CD at pH 5, 7, and 9. According to the results, both the solubility and partitioning properties of CT are affected by beta-CD in aqueous solution. It was also shown that the solubility of the individual enantiomers differs in the presence of beta-CD.

beta-Cyclodextrin, 1, can act as a chiral buffer additive in capillary zone electrophoresis (CZE) owing to its ability to form diastereomeric complexes with the enantiomers of ionic compounds. Reaction of 1 with 2,3-epoxy-propyltrimethylammonium chloride gave preponderantly 6-O-(2-hydroxy-3-trimethylammoniopropyl) derivatives (2) of varying degrees of substitution (d.s.). Analogous reaction of 1 with 1,3-propanesultone yielded 6-O-(sulfo-n-propyl) derivatives (SPE-beta-CD, 3) of varying d.s. The purity and the d.s. of 2 and 3 were determined by 1H NMR and electrospray ionization mass spectrometry (ESI-MS). These charged beta-cyclodextrin derivatives were used for the chromatographic enantiomer separation of a series of neutral barbiturates, of chlorthalidone, terbutaline, warfarin, salbutamol and brompheniramine by cyclodextrin electrokinetic chromatography (CD-EKC). During the separation of chlorthalidone with 3 as chiral additive, a reversible interconversion of the enantiomers (enantiomerization) was observed at temperatures below 20 degrees C.