Pharmaceutical salts of ethionamide with GRAS counter ion donors to enhance the solubility.

Pharmaceutical salts of BCS class II second line anti-tuberculosis drug ethionamide (ETH) with various counter ions namely, 2-chloro-4-nitrobenzoic acid (CNB), 2,6-dihydroxybenzoic acid (2,6HBA), 2,3-dihydroxybenzoic acid (2,3HBA) and 2,4-dinitrobenzoic acid (DNB) were synthesized by crystal engineering approach. All the synthesized salts were characterized by various spectroscopic (NMR, FT-IR,), thermal (DSC & TGA) and PXRD techniques. The crystal structure of the synthesized salts was determined by single-crystal X-ray diffraction techniques. All the reported salts, except ETH-2,3HBA exhibited charge assisted acid pyridine heterosynthon. In ETH-2,3HBA hydoxyl pyridine heterosynthon is observed. In ETH-CNB salt, both ionic and neutral acid pyridine heterosynthon were observed in the asymmetric unit. ETH-DNB salt consists of both partial and complete proton transfer from DNB to ETH in the asymmetric unit. All the synthesized salts were found to be non-hygroscopic at accelerated humid condition (~75% RH). Solubility experiment has been performed in purified water and in 0.1N HCl (pH=1) solution and found that the solubility of ETH-CNB salt was about eight-fold higher soluble than ETH in purified water. The solubility of synthesized salts follows the order of ETH

Estimation of content of anti-TB drugs supplied at centres of the Revised National TB Control Programme in Tamil Nadu, India.

OBJECTIVE: To determine the content of certain antituberculosis (TB) drugs supplied at TB treatment centres of the Revised National TB Control Programme (RNTCP) in the state of Tamil Nadu, India. METHODS: Eight districts across the state were selected, and the following drugs were collected from five settings (District TB centre, TB unit, designated microscopy centres, DOT providers) in each district: rifampicin (150 and 450 mg), isoniazid (300 mg), pyrazinamide (500 and 750 mg), ethambutol (400 and 600 mg), ethionamide (250 mg), levofloxacin (500 mg) and cycloserine (250 mg). A maximum of 10 tablets/capsules were collected from each setting. The drugs were coded prior to analysis. All drugs were assayed by validated spectrophotometric methods. The acceptable limits for drug content were taken as 90-110% of the stated content. RESULTS: More than 90% of tablets of rifampicin 450 mg, isoniazid 300 mg, pyrazinamide 500 and 750 mg, ethambutol 400 and 600 mg and ethionamide 250 mg were within acceptable limits. Eighty per cent of rifampicin 150 mg, 21% of cycloserine 250 mg and 87% of levofloxacin 500 mg were within acceptable limits. The mean cycloserine content was below the acceptable limit in all districts, the mean drug content being 200 mg (range: 108-245 mg). CONCLUSION: This systematic study showed that the stated drug content of cycloserine was not reached in all districts. Deterioration of cycloserine could be minimised by storing the drug in refrigerators. The geographical location of the districts had no influence on the drug content.

Ion-pair chromatography for simultaneous analysis of ethionamide and pyrazinamide from their porous microparticles.

Ethionamide (ETA) and pyrazinamide (PZA) are considered the drugs of choice for the treatment of multidrug-resistant tuberculosis. Current methods available in the literature for simultaneous determination of ETA and PZA have low sensitivity or involve column modifications with lipophilic cations. The aim of this study was to develop a simple and validated reversed-phase ion-pair HPLC method for simultaneous determination of ETA and PZA for the characterization of polymeric-based porous inhalable microparticles in in vitro and spiked human serum samples. Chromatographic separation was achieved on a Phenomenex C18 column (250 mm × 4.6 mm) using a Shimadzu LC 10 series HPLC. The mobile phase consisted of A: 0.01% trifluoroacetic acid in distilled water and B: ACN/MeOH at 1:1 v/v. Gradient elution was run at a flow rate of 1.5 mL/min and a fixed UV wavelength of 280 nm. The validation characteristics included accuracy, precision, linearity, analytical range, and specificity. Calibration curves at seven levels for ETA and PZA were linear in the analytical range of 0.1-3.0 µg/mL with correlation coefficient of r (2) > 0.999. Accuracy for both ETA and PZA ranged from 94 to 106% at all quality control (QC) standards. The method was precise with relative standard deviation less than 2% at all QC levels. Limits of quantitation for ETA and PZA were 50 and 70 ng/mL, respectively. There was no interference from either the polymeric matrix ions or the biological matrix in the analysis of ETA and PZA.

High-performance liquid chromatographic-tandem mass spectrometric method for the determination of ethionamide in human plasma, bronchoalveolar lavage fluid and alveolar cells.

We have developed and validated an accurate, sensitive, and rapid high-performance liquid chromatographic-tandem mass spectrometric method (HPLC-MS-MS) for the determination of ethionamide in plasma, bronchoalveolar fluid (BAL) and alveolar cells (AC). The retention times for ethionamide, clemastine fumarate (internal standard for plasma), promethazine (internal standard for plasma) and propranolol (internal standard for BAL and AC) were approximately 2.62, 1.21, 2.14, and 2.22 min, respectively, with a total run time of 3.2 min. Ethionamide detection for plasma was carried out on a PE Sciex API III (Perkin-Elmer, Foster City, CA, USA). BAL and cell pellets and some plasma specimens were analyzed on a Micromass Quattro LC (Micromass Co., Manchester, UK). The detection limits for ethionamide were 0.05 microg/ml for plasma, and 0.005 microg/ml for BAL supernatants and alveolar cell suspensions.

Therapeutic monitoring of antituberculosis drugs by direct in-line extraction on a high-performance liquid chromatography system.

A direct in-line pre-column extraction technique in which guanidinium and ammonium sulfate are used, followed by column switching, was employed to analyze serum, plasma and cerebrospinal fluid samples of patients treated for tuberculous meningitis. Resolution of a wide range of polar to non-polar xenobiotics was obtained on a C8 silica column by using a linear gradient from a binary system consisting of solvent A (0.05 M KH2PO4) and solvent B (acetonitrile-isopropanol, 4:1, v/v). Apart from the antituberculosis drugs (isoniazid, pyrazinamide, ethionamide and rifampicin) the patients received up to sixteen different medicines for prevention of complications and the treatment of symptoms. Qualitative resolution of all the drugs was obtained by the chromatographic system. Quantitation of pyrazinamide and ethionamide was achieved with high precision and low inter-sample variation.

Chromatographic analysis of antituberculosis drugs in biological samples.

Numerous chromatographic and non-chromatographic methods of analysis for anti-tuberculosis drugs and metabolites in biological tissues have been discussed in this review. Depending upon the analytical methodology selected, limits of detection range from microgram to picogram levels. A number of examples have been given of the correlation between different types of assay procedures. The metabolism and pharmacokinetics have been described along with some of the commonly associated problems of sample collection and storage.