Nadolol: high-pressure liquid chromatographic methods for assay, racemate composition and related compounds.

High-pressure liquid chromatographic (HPLC) methods have been developed for the determination of drug content, racemate A and related compounds in nadolol raw materials. The method for drug content and related substances resolved seven related compounds and several unknown impurities from the drug. The minimum quantifiable levels were 0.05% or less for four of the seven related compounds and 0.3% or less for the remainder. Total impurities in eight raw material samples ranged from 0.06 to 0.96% and assay levels ranged from 98.7 to 101.0%. The method was adapted for the determination of nadolol racemate A by a change in mobile phase composition. One raw material sample contained less than 40% of racemate A. Two samples which had a granular appearance were variable in racemate A content. The methods were adapted for the determination of drug and racemate A in nadolol tablets. Drug content in three tablet samples was between 96.2 and 98.4% and racemate A content was about 52%.

High-performance liquid chromatographic method for the assay of verapamil hydrochloride and related compounds in raw material.

A modification of the USP HPLC method [ United States Pharmacopeia XXII, pp. 1444-1446] for the assay of the purity of verapamil hydrochloride has been evaluated for the determination of the drug content and related compounds in drug raw material. The method enables the resolution of 16 related compounds from the parent drug and, in most cases, from each other. The minimum quantifiable amount for most related compounds is less than 0.05%. Six drug raw material samples are analysed and the total impurities found to be 0.3% or less. All drug assay values were within the USP recommended limits of 99.0-100.5%.

Determination of diclofenac sodium and related compounds in raw materials and formulations.

A liquid chromatographic method has been developed for determination of drug and related compounds in diclofenac sodium raw material, slow-release, and enteric coated tablets. The method specifies a 5 microns octadecylsilane bonded phase column, a mobile phase of tetrahydrofuran-acetonitrile-buffer, pH 5 (1 + 4 + 8.3), and detection at 229 nm. The method resolves 10 known related compounds with limits of quantitation of 0.2% or less. Seventeen drug raw material samples were evaluated. Total impurity levels ranged from 0.1 to 0.9%. The method has also been used for determination of drug content in raw materials and formulations. Mean assay levels in drug raw materials ranged between 98.3% and 101.8%.

Liquid chromatographic determination of pindolol and related compounds in raw materials.

A liquid chromatographic method for the assay of pindolol and related compounds in the bulk drug has been developed. The method resolves 6 known and several unknown impurities from the drug and each other by using a nitrile column, an acetonitrile-sodium acetate buffer (35 + 65), and a UV detector set at 219 nm. Minimum quantifiable amounts of impurities are 0.02% or less relative to the drug. Ten lots of pindolol raw material were evaluated for purity and drug content. Total levels of impurities in these samples, quantitated against pindolol, ranged from about 0.03 to 0.24%. Assay results were within the range of 98.5 to 101.5%.

Liquid chromatographic methods for the determination of albuterol (salbutamol), albuterol sulphate and related compounds in drug raw materials, tablets and inhalers.

Liquid chromatographic methods for the determination of albuterol (salbutamol), albuterol sulphate and related compounds in drug raw materials, tablets and inhalers are described. The methods resolve five known related compounds from the drug and, in the case of inhalers, several compounds not related to the drug. Two of these were identified as 2,6-di-t-butyl-4-methylphenol, a common antioxidant, and 2,2'-methylene bis(6-t-butyl-4-methylphenol). Related compounds are detectable at levels of about 0.03%. Eleven albuterol and 12 albuterol sulphate raw materials and eight tablet formulations were found to contain related compounds ranging from 0.03 to 0.54%, 0.09 to 0.50% and 0.32 to 0.95%, respectively. Non-drug compounds in three inhaler samples ranged from 4.6 to 12% of the drug delivered through the valve. Some of the non-drug compounds may be excipients.

Determination of size distribution of fat globules in intravenous fat emulsions by photon correlation spectroscopy.

A photon correlation spectroscopy method has been developed to characterize the size distribution of fat globules in intravenous fat emulsions (IFE) in terms of mean diameter, standard deviation of the distribution, and percentage of large particles outside the distribution. Mean fat globule diameters of samples of all IFE products available in Canada were about 0.3 microns, similar to values reported in the literature. The methodology is sufficiently sensitive to detect the presence of 5% by weight of 2 microns polystyrene microspheres in an intravenous fat emulsion. The effect of changes in instrument settings and variables on the results has been evaluated.

Liquid chromatographic methods for vitamins A and D in multivitamin-mineral formulations.

Liquid chromatographic screening procedures have been developed for the estimation of vitamins A and D in multivitamin-mineral tablet, capsule, gelatin capsule, and syrup formulations. The procedure can be used for measuring vitamin A present as either retinyl acetate or retinyl palmitate, and also for measuring the contribution to total vitamin A activity from 13-cis retinyl esters. The retinyl esters and their isomers are resolved from each other and their oxidation products. Ergocalciferol and cholecalciferol are not resolved from each other but they are resolved from other vitamin D isomers and from vitamins A, E, and K and their degradation products. Both assays use a 3 microns amino column, with a mobile phase of hexane for vitamin A and 1% isopropanol in hexane for vitamin D. The precision of replicate injections for vitamins A and D is better than 1% and the recovery from spiked syrups is better than 98%. The coefficient of variation for both assay methods is about 5%. Twenty formulations were analyzed for vitamin A and 24 were analyzed for vitamin D.

High-performance liquid chromatography method for assay of diltiazem hydrochloride and its related compounds in bulk drug and finished tablets.

The method provides for the resolution of trans-diltiazem and seven known and several unknown related compounds from diltiazem HCl. Minimum detectable amounts were less than 0.1%, except for an intermediate which originates early in the synthetic process, for which the sensitivity is approximately 2%. The relative standard deviation of the assay procedure is 0.15%. Total related compounds in four bulk drug and four tablet samples were less than 0.25%. The specific rotation of four samples of diltiazem HCl analyzed in duplicate was between +112 and +114 degrees. The UV absorption spectra of all compounds exhibited two maxima, one between 203 and 213 nm and the other between 230 and 244 nm.

Validation of a method for the assay of related compounds in famotidine raw materials and formulations.

A high-performance liquid chromatographic (HPLC) method has been developed for the determination of famotidine and related compounds in drug raw materials and formulations. The minimum detectable amount of the available related compounds is less than 0.02% and the minimum quantifiable amount is less than 0.1%. Famotidine impurity levels were between 0.5 and 2.5% in raw materials. 0.44% in one tablet sample and about 3% in an IV solution, allowing for stabilizers.

High-performance liquid chromatographic methods for the determination of ranitidine and related substances in raw materials and tablets.

High-performance liquid chromatographic methods have been developed for the determination of ranitidine and related compounds in drug raw material and tablets. The method has been shown to resolve at least nine related compounds from the drug. The sensitivity of the method to related compounds is better than 0.01%. Eight raw material samples and 11 tablet samples were examined for related compounds. Total impurities found ranged from 0.31 to 0.79% in raw materials and from 0.40 to 1.75% in tablets. Drug raw materials and tablets were assayed by HPLC; results for raw materials were between 98.2 and 101.1%, and those for tablets were between 96.1 and 102.2%, with a relative standard deviation for the assay of less than 1%. Raw material assay results were confirmed by nonaqueous titration.

Titrimetric determination of nonesterified fatty acids in intravenous fat emulsions.

A titrimetric method, suitable for use at a limit of 5 mEq/L, has been developed for the determination of total nonesterified fatty acids in intravenous fat emulsion preparations. The method differentiates titrant consumed by the nonesterified fatty acids from that consumed by egg yolk phospholipids, usually present as an emulsifying agent. The total nonesterified fatty acids in 8 products from 4 manufacturers were in the range from 0.4 to 3.8 mEq/L. The mean standard deviation of the method is 0.09 mEq/L.

Liquid chromatographic methods for assay of carbamazepine, 10,11-dihydrocarbamazepine, and related compounds in carbamazepine drug substance and tablets.

Liquid chromatographic (LC) methods have been developed for the determination of carbamazepine, the impurity 10,11-dihydrocarbamazepine, and related compounds in carbamazepine drug substance and tablets. The LC methods specify a 5 micron diol column and a mobile phase of acetonitrile-methanol-0.05% aqueous acetic acid (5 + 5 + 90). Iminodibenzyl and iminostilbene, starting materials for some routes of synthesis, elute late in the LC system; therefore, a thin-layer chromatographic method for their detection at the 0.05% level has been developed. Eight tablet and 13 raw material samples from several sources were examined. The impurities most frequently found were 10, 11-dihydrocarbamazepine and a compound identified as 10-bromocarbamazepine at levels up to 1.3 and 0.5%, respectively; minimum detectable amounts were about 0.01 and 0.03%, respectively.

Liquid chromatographic method for perphenazine and its sulfoxide in pharmaceutical dosage forms for determination of stability.

A liquid chromatographic method is described for determination of perphenazine and perphenazine sulfoxide in representative dosage forms. Sulfoxide levels were nondetectable or less than 1% in tablets and in an injectable product. Sulfoxide levels increase with time in some syrup formulations and may be as high as 11% in syrup formulations before their expiration date.

Liquid chromatographic determination of identity, content, and content uniformity of desipramine, fluphenazine, and promazine.

A liquid chromatographic procedure has been developed for the assay, content uniformity, and identification of single active ingredient formulations of desipramine, fluphenazine, and promazine. The drugs are extracted from formulations with methanol or dilute hydrochloric acid and quantitated against an internal standard (norephedrine). The drugs are identified by comparison of retention times with those of the reference standards.

Liquid chromatographic method for identity, assay, and content uniformity of five tricyclic drugs.

A liquid chromatographic (LC) procedure has been developed for the assay, content uniformity, and identification of single active ingredient solid and liquid formulations of amitriptyline, chlorpromazine, imipramine, thioridazine, and trifluoperazine. The drugs are extracted from their formulations with methanol or dilute hydrochloric acid, and identified by comparison of retention times with those of known standards; drugs are quantitated against these standards with dl-norephedrine hydrochloride as the internal standard. The precision of replicate injections is better than 2.5% for peak area and better than 1% for peak height. The precision of triplicate determinations of tablet composites is better than 2.2%.

Determination of hydrazine in pharmaceuticals IV: Hydrazine and benzylhydrazine in isocarboxazid.

A GC procedure for the simultaneous determination of hydrazine and benzylhydrazine in isocarboxazid raw material and tablet formulations has been developed. The method is based on the reaction of benzoyltrifluoroacetone with hydrazine and benzylhydrazine to form the corresponding pyrazole derivatives. The minimum detectable amounts of hydrazine and benzylhydrazine in isocarboxazid are 0.002 and 0.02%, respectively.

Gas chromatographic method for solvent residues in drug raw materials.

A gas chromatographic (GC) method for screening drug raw materials, soluble in aqueous media, for volatile solvent residues has been developed. After dissolution, separate portions of the drug are each separately extracted with n-octane, toluene, and ether and injected into a chromatograph equipped with a porous polymer column and a flame ionization detector. The range of extractant polarities provides chromatograms which, taken together, are free of interfering peaks from 0 to approximately 20 min. Peaks due to solvent residues in the drug are identified by retention time with confirmation of identity by GC-MS.