Determination of hydrazine in pharmaceuticals III: hydralazine and isoniazid using GLC.

A GLC procedure has been developed for the determination of hydrazine in hydralazine and isoniazid drug raw materials, single and multicomponent tablets, injectables, and syrups. The method is based on the derivatization of hydrazine with benzaldehyde to form benzalazine. The minimum detectable amount of hydrazine in hydralazine and isoniazid raw materials and formulations is approximately 0.0003%. No hydrazine was found in the hydralazine raw material specimens examined. Traces of hydrazine (approximately 0.0003%) were found in some tablet lots and approximately 0.02% was found in an injectable product. A trace of hydrazine was found in one lot of isoniazid raw material and low levels (0.0012 and 0.0029%) were found in isoniazid tablet products. An isoniazid syrup contained approximately 0.2% hydrazine.

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.

Determination of azobenzene and hydrazobenzene in phenylbutazone and sulfinpyrazone products by high-performance liquid chromatography.

A high-performance liquid chromatographic method has been developed for the simultaneous determination of azobenzene and hydrazobenzene in phenylbutazone and sulfinpyrazone raw materials and formulations. The drug raw material or formulation is shaken with 1N NaOH and n-hexane and centrifuged. The n-hexane layer is injected into a chromatograph equipped with a 10-micron cyano-amino bonded phase column. Azobenzene and hydrazobenzene are detected at 313 and 254 nm, respectively; the sensitivities are approximately 1 and 2 ppm, respectively, in the raw materials and formulations.

Identification of degradation products in a phenylbutazone tablet formulation.

Two previously reported but unidentified phenylburazone degradation products were isolated from a tablet that was stored at 60 degrees for 203 days. The compounds, alpha-(N-phenylcarbamoyl)-N-caproylhydrazobenzene and alpha-hydroxy-alpha-(N-phenylcarbamoyl)-N-caproylhydrazobenzene, were isolated by chromatography, identified by mass and NMR spectrometry, and synthesized by the reaction of aniline with phenylbutazone or its hydroxy analog, respectively.

Impurities in drugs I: Imipramine, desipramine, and their formulations.

Nineteen lots of imipramine tablets and four lots of desipramine tablets were examined for impurities by TLC. Iminodibenzyl, desipramine, and 10,11-dihydro-5-[3-(methylamino-3'-dimethylaminopropyl)propyl]-5H-dibenz[b,f]azepine dihydrobromide (I) were found in some imipramine tablets, and iminodibenzyl and imipramine were found in some desipramine tablets, all at levels of less than 0.3% of label claim of the drug. Except for I, the identity of the impurities was established by comparison with known standards; I was synthesized and its composition was established by elemental analysis. All impurities, including I, were characterized by TLC, GLC, and mass spectrometry.

Comparative bioavailabilities from truncated blood level curves.

The period of time after administration over which blood level measurements are required to obtain a reliable bioavailability comparison of two or more formulations of the same drug was considered by the analysis of bioavailability data taken from the literature. The drugs examined, selected to represent a range of absorption and elimination half-lives, were acetaminophen, aminosalicylic acid, chloramphenicol, chlordiazepoxide, digoxin, isoniazid, phenylbutazone, sulfamethizole, tetracycline, and warfarin. For most drugs, ratios of areas under the curve changed little between the end of the absorption period and the time when blood sampling was terminated. Reliable bioavailability comparisons among different brands of the drugs apparently could have been made by blood sampling over 24 hr or less.

High-performance liquid chromatographic determination of isoniazid and 1-isonicotinyl-2-lactosylhydrazine in isoniazid tablet formulations.

A high-performance liquid chromatographic procedure is presented for the simultaneous determination of isoniazid and 1-isonicotinyl-2-lactosylhydrazine (I) in isoniazid tablet formulations. An aliquot of a diluted aqueous tablet extract is introduced onto a microparticulate cyanopropyl bonded-phase column using a valve-loop injector and chromatographed using a mobile phase of acetonitrile--0.01 M, pH 3.5 aqueous acetate buffer (5:95). Compound I can be determined at levels as low as 0.5% of the isoniazid label claim. The relative standard deviations are 0.4 and 0.7% for the simultaneous determination of isoniazid and I, respectively. Seven commercial tablet formulations contained 93.8--97.0% of the labeled isoniazid amounts and 0.3--5.8% of I, expressed as equivalent isoniazid relative to the labeled isoniazid level.

Drug permeation through membranes V: interaction of diazepam with common excipients.

The effects of common tablet excipients on the permeation of diazepam through polydimethylsiloxane membranes and on the turnover time of goldfish were studied. The permeability coefficient decreased and the turnover time increased in the presence of talc, polysorbate 80, and, possibly, fumed silicon dioxide, but these parameters were unaffected by lactose, microcrystalline cellulose, and starch.

Simple GLC analysis of anticonvulsant drugs in commercial dosage forms.

A simple, specific GLC procedure is described for the analysis of one sedative and six anticonvulsant drugs in pharmaceutical dosage forms. Sample aliquots of ethotoin, glutethimide, mephenytoin, methsuximide, and phensuximide were shaken with or extracted into ethyl acetate, diluted with the internal standard (diphenyl phthalate) solution, injected into a gas chromatograph, and eluted from a methylsilicon column. Primidone and phenytoin samples (extracted as the free acid) required derivatization with N,O-bis(trimethylsilyl)acetamide prior to chromatography. The same temperature programming conditions and flow rate settings were used for all seven drugs. The GLC results agreed well with those obtained using the pharmacopeial methods.

Simultaneous determination of reserpine and hydrochlorothiazide in two-component tablet formulations by high-performance liquid chromatography.

A high-performance liquid chromatographic procedure is presented for the simultaneous determination of reserpine and hydrochlorothiazide in two-component tablet formulations. An aliquot of a tetrahydrofuran extract of the tablet, containing polylythiazide as an internal standard, is chromatographed on a microparticulate silica gel column using a mobile phase of 0.01% (v/v) diethylamine, 5% (v/v) chloroform, and 18% (v/v) 2-propanol in n-hexane. The relative standard deviations are 1.2 and 0.6% for the simultaneous determination of reserpine and hydrochlorothiazide, respectively. Seven commericial tablet formulations were found to contain 92.7--101.0% and 98.3--101.4% of the labeled amounts of reserpine and hydrochlorothiazide, respectively.

Impurities in drugs II: meperidine and its formulations.

Three lots of meperidine hydrochloride, seven lots of meperidine tablets, and 41 lots of meperidine injectables were examined for impurities by TLC. Impurities found were ethyl 1-benzyl-4-phenyl-4-piperidinecarboxylate, methyl-4-piperidinecarboxylate, ethyl-4-phenyl-4-piperidinecarboxylate, and three unidentified compounds. Not all impurities were found in every lot of drug investigated, and none of the impurities exceeded a concentration of 1% of the meperidine present.

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.

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.

Hydrazine levels in formulations of hydralazine, isoniazid, and phenelzine over a 2-year period.

Hydrazine levels in formulations of hydralazine, isoniazid, and phenelzine have been measured over a 2-year period under ambient conditions and under temperature and humidity stress. Hydralazine tablets are stable under ambient conditions, but the hydrazine level in an injectable formulation increased from 4.5 to 10 micrograms/ml over a 23-month period. Isoniazid tablets are also stable, but hydrazine levels in an elixir and a pyridoxine combination product doubled to 44 micrograms/ml and 19 micrograms/tablet, respectively. Levels in phenelzine tablets appeared to remain constant at approximately 60 micrograms/tablet, with considerable tablet-to-tablet variation.

Routine quality evaluation of benzodiazepine drugs to USP-NF specifications.

A GLC procedure was developed for the evaluation of diazepam, chlordiazepoxide, and flurazepam formulations to USP-NF specifications for drug content, content uniformity, impurities, and identity by retention times and peak areas. The polyimide column, instrument zone temperatures, gas flows, internal standard solution, extraction solvent, and auxiliary equipment were the same for each drug. No derivatization of the samples was required. The GLC assay values (mean of 10 individual dosage units) for diazepam and flurazepam products were in good agreement with the results obtained by the pharmacopeial composite assays. With chlordiazepoxide capsules, when the levels of the two pharmacopeial impurities determined by GLC were added to the GLC assay results (mean of 10), athe aggregate values were consistent wit the drug content results found by the nonspecific USP method. The procedure can be made sensitive to impurity levels of approximately 0.01% for 2-amino-5-chlorobenzophenone and to approximately 0.2% for 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one 4-oxide. With the equipment used, the estimated potential outputs in lots per working day for a complete quality profile (drug content, content uniformity, purity, and identity) were seven for chlordiazepoxide if no impurity test was required, five if such a test was required, eight for diazepam, and seven for flurazepam.

Impurities in drugs III: Trihexyphenidyl.

Two lots of trihexyphenidyl hydrochloride raw material, one lot of elixir, and 10 lots of tablets were examined for impurities by TLC. Impurities found were 1-phenyl-2-propenone, 3-piperidinopropiophenone, and 3-aminopropiophenone. Not all impurities were present in all lots, and none exceeded 1.9% of the label drug claim. Impurities were identified by mass spectrometry and by comparison of TLC Rf values and GLC retention times to those of synthesized specimens of the impurities.

Stability-indicating high-performance liquid chromatographic determination of chlorpropamide, tolbutamide, and their respective sulfonamide degradates.

A quantitative high-performance liquid chromatographic method for the determination of chlorpropamide, tolbutamide, and their respective hydrolysis products, p-chlorobenzenesulfonamide and p-toluenesulfonamide, in solid dosage forms was developed. The method is stability indicating and can be used to determine the sulfonamide hydrolysis product and the intact drug in the presence of minor degradates. Method reproducibility, demonstrated by repeated injections of a calibration standard, was 1.21%. The lower limit of quantitation of the hydrolysis products, p-chlorobenzenesulfonamide and p-toluenesulfonamide, was 0.2 microgram/5-microliter injection. The accuracy of the method for intact drugs was determined by comparison of the HPLC results to those obtained by the appropriate USP or BP assays. The mean of the results obtained by the two methods differed by 0.7% for chlorpropamide and 0.3% for tolbutamide. Pure drug samples were spiked with amounts of the hydrolysis products ranging from 20 to 120% of the intact content. The mean percent recovery for p-chlorobenzenesulfonamide was 98.6%; for p-toluenesulfonamide, it was 100.6%. A qualitative TLC procedure for the detection of chlorpropamide, p-chlorobenzenesulfonamide, dipropylurea, propylurea, n-propylamine, tolbutamide, p-toluenesulfonamide, dibutylurea, butylurea, and n-butylamine is also described.

Impurities in drugs IV: Indomethacin.

One lot of indomethacin raw material, five lots of capsule preparations, and three lots of supporitory formulations were screened for impurities by TLC. Only the suppository products exhibited impurities above trace levels. The two main impurities were present at levels estimated at approximately 0.5 and 2%. After isolation from preparative TLC plates, they were identified by NMR, IR, and mass spectroscopy as the alpha-substituted monoglyceryl esters of 4-chlorobenzoic acid and indomethacin, respectively.

Impurities in drugs V: Meprobamate.

One lot of meprobamate raw material and 28 lots of tablets were examined for impurities by TLC. All lots contained di-(2-methyl-2-propyl-3-carbamoyloxypropyl) carbonate (V) at levels that ranged between 0.1 and 1.0% of the total drug content. Nine lots also contained low levels of a second impurity (approximately 0.1%), and one of these lots contained a third impurity (approximately 0.1%), neither of which was identified. Estimates of the unidentified impurities were based on the assumption of a TLC response with furfural-hydrochloric acid spray equivalent to that of meprobamate. Compound V was identified by mass spectrometry and PMR and IR spectroscopy and by comparison of the TLC Rf value to that of a synthesized sample of V.

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.