Use of supercritical fluid extraction for sample preparation of sustained-release felodipine tablets.

Supercritical fluid extraction (SFE) was shown to be an accurate and precise alternative to liquid extraction for sample preparation of sustained-release felodipine tablets (5 mg potency) while realizing an 80% reduction in solvent consumption. Extractions of felodipine spiked on an inert support were used to evaluate the solubility of felodipine in CO2 as well as analyte trapping after SFE. Even though the pure drug was found to be soluble in pure CO2, extractions of felodipine from the tablet matrix required moderate modifier concentrations [8.7% (v/v) methanol in CO2] in order to overcome strong matrix-drug interactions. Sequential static/dynamic extraction steps were also required to quantitatively recover the drug from the tablet matrix, indicating that the drug extraction was diffusion-limited. Average recoveries (n = 5) for the optimized SFE method were determined to be 4.93 mg felodipine tablet (98.6% claim) with an RSD of 1.2% versus those for the liquid extraction procedure (n = 5, 4.98 mg/tablet, 99.6% claim, 2.4% RSD). Similar levels of drug degradation (0.12% expressed as felodipine) were also obtained with both the traditional liquid extraction and with the SFE method.

Determination of imipenem and cilastatin sodium in Primaxin by first order derivative ultraviolet spectrophotometry.

A UV-spectrophotometric assay to measure the concentrations of the active drug components (imipenem and cilastatin) or Primaxin for routine release testing is described. The assay is based on the use of first order derivative spectrophotometry. The trough amplitudes in the first derivative spectrophotometric spectra at 243 and 318 nm were selected to determine cilastatin and imipenem, respectively. A linear relationship (R > 0.99) between the trough amplitudes and concentrations was demonstrated over the range 14-42 micrograms ml-1 for both drug components. Commercial IV formulations and laboratory prepared mixtures containing both drugs in different proportions were assayed using the developed method with good recoveries (ave. 100.6%). The method is rapid, precise, accurate and was shown to be equivalent to the more time consuming LC method; which is currently used for routine release testing. The specificity and stability indicating properties of the method will also be addressed.

Determination of mevalonolactone in capsules by capillary gas-liquid chromatography.

A wide bore capillary gas chromatographic method was developed to determine mevalonolactone in capsule formulations. The method uses beta,beta-dimethyl-gamma-hydroxymethyl-gamma- butyrolactone as an internal standard and has been validated for its accuracy, precision and linearity. The method has been applied for stability testing of the capsule formulation. High-performance liquid chromatographic and gas chromatographic studies demonstrated cyclization of mevalonic acid (open-chain form) to mevalonolactone (cyclic form) under the described gas chromatography conditions. Mass spectrometric analysis indicated that mevalonolactone prepared in water or an organic solvent emerged from the gas chromatographic column as the intact cyclic lactone.

Determination of losartan and its degradates in COZAAR tablets by reversed-phase high-performance thin-layer chromatography.

Losartan potassium is an angiotensin II receptor blocker. It has been formulated and marketed as a tablet dosage from (COZAAR). A reversed-phase high-performance thin-layer chromatography method has been validated and shown to be sensitive, efficient, and reliable, and can be used as an excellent alternative to the HPLC stability testing of losartan potassium in COZAAR tablets.

Pharmaceutical application of LC-MS. 1--Characterization of a famotidine degradate in a package screening study by LC-APCI MS.

The application of LC-MS to characterize low-level degradates in pharmaceutical dosage formulations is a new and challenging field. In a package screening study, a low-level degradate of famotidine (1, 3-[[[2-[[aminoiminomethyl]-amino]-4-thiazolyl]methyl] thio]-N-(aminosulphonyl)-propanimid-amide, an H2-receptor antagonist, molecular weight: 337) was detected by HPLC in film-coated tablets packaged in child-resistant (CR) foil pouches which were stressed at 40 degrees C/75% relative humidities (RH) for 4 months. LC-atmospheric pressure chemical ionization (APCI) mass spectrometry using positive ion mode yielded a molecular weight of 349 for the degradate, suggesting that it was formed by the addition of one carbon to the famotidine molecule. A detailed analysis of the positive product ion mass spectrum of the protonated degradate ion in a LC-MS-MS study indicated that the carbon was added to the side of N-(aminosulphonyl)-propanimid-amide of famotidine. The structure of the degradate was determined to be 2, which was confirmed by LC-APCI MS and HPLC study of the product formed from the reaction of famotidine with formaldehyde--a one-carbon reagent.

Determination of bisphosphonate drugs in pharmaceutical dosage formulations by ion chromatography with indirect UV detection.

Application of ion chromatography (IC) to the analysis of non-chromophoric bisphosphonate drugs in pharmaceutical dosage formulations is described. The method is based on the use of single-column ion chromatography in conjunction with indirect UV detection that obviates the need for tedious chemical derivatization procedures. Diluted drug samples are chromatographed directly on a Waters IC-Pak HR anion-exchange column with dilute nitric acid (1.6-12 mM) as the mobile phase which exhibits a UV absorption maximum near 220 nm. Analyte detection is monitored by measuring the decrease in absorption of the mobile phase. The IC method has been validated and shown to be precise, accurate, specific and rugged for routine assay. Application of the method to the determination of alendronate sodium tablets, etidronate disodium injectable (which requires an eluent pH control for chromatographic resolution of active drug from chloride ions) and clodronate disodium injectable is presented. The performances of the Waters IC-Pak HR and several equivalent columns are also discussed.

Determination of alendronate in pharmaceutical dosage formulations by ion chromatography with conductivity detection.

A method was developed and validated for the direct determination in pharmaceutical dosage formulations of alendronate, a non-chromophoric compound. It is based on the use of single-column ion chromatography with conductivity detection that obviates the need for the tedious chemical derivatization procedures that are required for UV and fluorescence detection. Diluted samples of 0.05 mg/ml were chromatographed directly on a Waters IC-Pak HR anion-exchange column or a Dionex OmniPac PAX-100 column with dilute nitric acid as the mobile phase followed by conductivity detection. The method was validated and shown to be precise, accurate and specific for the assay of alendronate in intravenous (i.v.) solution and tablet formulations. The ruggedness of the assay was studied by generating data from four different instruments. Also established was the equivalence between this method and a previously reported high-performance liquid chromatographic method with 9-fluorenylmethyl chloroformate derivatization and UV detection. Application of the method to the determination of alendronate in i.v. and tablet formulations is presented and the performances of the Waters IC-Pak HR and Dionex OmniPac columns are discussed.