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PubMed1989

Determination of thymol in halothane anaesthetic preparations by high-performance liquid chromatography.

A high-performance liquid chromatographic (HPLC) procedure has been developed for the isolation and quantification of thymol, a stabilizing agent present in halothane anaesthetic preparations. The method offers improvements in specificity and simplicity with respect to a current official procedure for thymol in halothane. Results for commercial preparations obtained by the proposed procedure demonstrate excellent precision and accuracy with RSD values for replicate analysis ranging from 0.11 to 0.74% and recoveries via fortification from 99.6 to 100.1%. The HPLC method was compared to compendial procedures for thymol bulk substance and halothane products. Chromatographic separation of other related phenolic preservatives used in pharmaceuticals suggests a more extensive application of the proposed procedure.

Chromatography, High Pressure Liquid↗
PubMed2002

[Investigation of the sorption properties and pharmaceutical application of alpha1-acid glycoprotein by liquid chromatography].

The separation and quantitation of the enantiomers and also the determination of the enantiomeric purity are all current and indispensable tasks for the pharmaceutical analysis. The aim of this work was to study the sorption properties of the alpha 1-acid glycoprotein (AGP) based stationary phase, which may have crucial importance for the enantioselectivity. New binding data are presented for the mechanism of the chromatographic separation, which has not clarified in the literature yet. On the basis of these new findings the composition of the mobile phase for a given analytical separation can be designed, including the preparative separation, as well. Binding data for dioxane, known as a solvent with low dielectric constant, are determined at first time. It was found that the sorption of both acetonitrile and dioxane is pH-dependent: as at pH 7.2 the binding can be characterized by a saturation curve, while at pH 4.0 by a twostep, monotone curve. The pH-dependence of the adsorption has been explained by conformational changes of the selector, which were confirmed by CD-spectroscopic and fluorescence quenching study of the native AGP. In accordance with the binding study by increasing the acetonitrile percentage at pH 4.0 a tipical alpha-helical peak was observed in the CD-spectrum. Opposite that at pH 7.2 the increase in the acetonitrile content does not result in any changes in the spectra. Effective dynamic quenching constants of AGP have been determined at given acetonitrile concentrations using 2,2,2-trichloroethanol as fluorescence quencher. In agreement with the results of the CD measurements at pH 4.0 it was found that the degree of quenching enhanced by increasing the amount of the acetonitrile, that can be explained by enhanced exposure of the buried tryptophan residues. Taking these results into account, new optimized and validated HPLC methods have been developed for compendial control in testing the enantiomeric purity of an acidic (ibuprophen), a basic (propranolol) and a neutral (norgestrel) drug molecule.

Adsorption↗
PubMedDate not supplied

Evaluation of current compendial physiochemical test procedures for pharmaceutical elastomeric closures and development of an improved HPLC procedure.

The interaction between elastomeric container closures and the solutions they confine presents a potential hazard to the consumer due to extraction of closure ingredients into the dosage form. Each of the major Pharmacopeias, the United States, the European, and the Japanese, prescribe testing procedures for elastomeric closures. These consist of a series of non-specific wet chemical analyses performed on samples extracted into water or, in some cases, isopropanol (IPA) or the drug product vehicle. No consideration is given to the extracting potential of the drug product. Results from our testing on ten randomly selected closure samples indicated that these tests are not sensitive or specific enough to accurately measure the levels of extractables. Therefore, an HPLC gradient method was developed which had the required sensitivity and specificity. The prescribed compendial extractions, when performed on the various stopper types, proved inefficient and experiments were conducted in an attempt to improve them. These included increasing the time of the extractions, increasing the closure surface area, and increasing the strength of the extracting solvent (methylene chloride). The HPLC gradient method and the compendial wet chemical tests were then used to evaluate the stopper extractables. Results of the compendial analyses on the prescribed aqueous extractions were inconclusive as the number and relative amount of extractables in the closure could not be measured. The results of the compendial testing were only marginally improved using the stronger extraction conditions. Testing was dramatically improved, however, using the HPLC gradient method. As many as twenty extractables were detected in some of the samples and, unlike the compendial analysis, low level extractables were detected in the water samples. Identification of some of the extractables was accomplished via GC/MS.

Chemical Phenomena↗
PubMed1990

Rational limits for drug impurities.

The United States Pharmacopeia (USP) has developed policies on drug substance purity and organic volatile impurities. This paper will include the historical background and the scientific basis of these policies and will give several examples of how they are reflected in the tests that are included in USP monographs. Data on the types of analytical methods used in assessing the purity of compendial articles will also be presented.

Chemical Phenomena↗
PubMed2002

Screening extemporaneously compounded intraspinal injections with the bacterial endotoxins test.

Development of a validated bacterial endotoxins test (BET) method for screening extemporaneously compounded intraspinal injections was studied. In accordance with compendial requirements, interference studies were conducted in injectable-grade intraspinal medications using reagents licensed by the Food and Drug Administration. Positive controls were inoculated into a series of decreasing concentrations of each drug (range, 0.05-4 mg/mL) and tested by gel-clot and kinetic-turbidimetric BET methods to determine valid non-interfering concentrations. A simplified BET procedure was used for preparing drug samples, inoculating positive controls, conducting the test, and interpreting the results. The most robust test concentrations were < or = 0.5 mg/mL for baclofen, bupivacaine, clonidine, and morphine and < or = 0.1 mg/mL for hydromorphone. BET interference studies were also done for mixtures of morphine and baclofen, bupivacaine or clonidine. The mixtures were compatible when morphine was diluted to a concentration of < or = 0.25 mg/mL. The substantial dilution required to overcome test inhibition did not compromise the tests sensitivity when compared to the endotoxin limit for intraspinal infusions. Validated BET procedures for intraspinal drugs were sufficiently sensitive to assure the absence of endotoxin contamination.

Bacteriological Techniques↗
PubMed1984

Determination of the chemical constituents and spectral properties of commercial and NF reference standard potassium guaiacolsulfonate: implications of the findings on compendial analytical methodology.

HPLC analysis confirmed a difference in the chemical composition of commercial versus NF reference standard potassium guaiacolsulfonate. After separation by fractional crystallization, the two constituents comprising the former sample were identified by 1H-NMR as potassium guaiacol-4- and -5-sulfonate, respectively. The former isomer predominated. The reference standard material was identified as the 4-sulfonate salt by HPLC, NMR, IR, and UV. This difference raises questions concerning the validity of the compendial identification tests and assay procedure for the drug, which are based on methods requiring direct comparison between it and the reference standard. In fact, the IR test has now been shown to be unreliable as a rigorous criterion for identification, in light of significant differences found in the fingerprint regions of the spectra of the two isomers. However, because the two isomers exhibit identical UV absorption characteristics in solutions of pH less than or equal to 7 (but not in alkaline solution), the compendial UV identification test and assay procedure appear to be valid under the conditions specified. The pKa values of the isolated isomers were estimated by a spectrophotometric method to be 8.74 and 9.16 for the phenolic group of potassium guaiacol-4- and -5-sulfonate, respectively.

Acetylation↗
PubMed1998

Evaluation of various dissolution media for predicting in vivo performance of class I and II drugs.

PURPOSE: In this paper we seek to verify the differences in dissolution behavior between class I and class II drugs and to evaluate the suitability of two new physiologically based media, of Simulated Gastric Fluid (SGF) and of milk for their ability to forecast trends in the in vivo performance of class II compounds and their formulations. METHODS: Dissolution behavior of two class I drugs, i.e. acetaminophen and metoprolol, and of three class II drugs, i.e. danazol, mefenamic acid and ketoconazole, was studied with USP Apparatus 2 in water, SGF, milk, Simulated Intestinal Fluid without pancreatin (SIFsp) and in two media simulating the small intestinal contents in the fed (FeSSIF) and fasted (FaSSIF) states, respectively. RESULTS: Class I powders dissolved rapidly in all media tested. Acetaminophen dissolution in milk was slow from one tablet formulation, in all other cases dissolution was more than 85% complete in 15 minutes. The dissolution rate of metoprolol was shown to be dependent on formulation and manufacturing method, and one of the three tablet formulations did not meet compendial specifications (80%/30 minutes). Dissolution behavior of class II drugs was greatly affected by choice of medium. Dissolution from a capsule formulation of danazol proved to be dependent on the concentration of solubilizing agents, with a the 30-fold increase in percentage dissolved within 90 minutes upon changing from aqueous media without surfactants to FaSSIF. Use of FeSSIF or milk as the dissolution medium resulted in an even greater increase in percentage dissolved, 100 and 180-fold respectively. Dissolution of the weak acid mefenamic acid from a capsule formulation is dependent on both pH and bile salt concentration, which leads to an offset between increased bile salt concentration and lower pH in the fed state compared to the fasted state medium. The weak base ketoconazole showed complete dissolution from a tablet formulation in Simulated Gastric Fluid without pepsin (SGFsp) within 30 minutes, 70% dissolution in 2 hours under fed state simulated upper jejunal conditions but only 6% dissolution in 2 hours under fasted state conditions. CONCLUSIONS: As predicted, dissolution of class II drugs proved to be in general much more dependent on the medium than class I drugs. With the array of compendial and physiological media available, it should be possible to design a suitable set of tests to predict the in vivo dissolution of both class I and II drugs from immediate release formulations.

Acetaminophen↗
PubMed1999

Simultaneous high-performance liquid chromatographic analysis for famotidine, ranitidine HCl, cimetidine, and nizatidine in commercial products.

A high-performance liquid chromatographic (HPLC) procedure for the simultaneous determination of famotidine (FMT), ranitidine HCl (RNT), cimetidine (CMT), and nizatidine (NZT) was developed using a two-level, full-factorial design with three variables (volume of methanol, percentage of triethylamine, and concentration of phosphate buffer) to select an acceptable mobile phase. A column (15 cm x 4.6 mm ID) of Inertsil ODS-2 (5 microns) was used, and 0.04 M aqueous sodium dihydrogen phosphate/acetonitrile/methanol/TEA at a proportion of 345/20/35/0.7 (v/v/v/v) was the selected mobile phase (1 ml/min). The detection wavelength was set at 230 nm, and procaine HCl was used as the internal standard. Precision and linearity of the method were assessed. None of the commercial samples was found to be outside the compendial limits of 90.0% to 110.0% of the claim amount.

Algorithms↗
PubMed1979

GLC determination of trihexyphenidyl hydrochloride dosage forms.

A rapid, sensitive, and specific GLC method for the quantitation of trihexyphenidyl hydrochloride in various pharmaceutical dosage forms is described. The procedure involves chloroform extraction of the active ingredient from a weakly acidic solution, followed by GLC determination using a 3% methyl silicone column. The specificity of the system in relation to several compendial drug analogs also is reported.

Capsules↗
PubMed1975

Determination of mercury-containing pharmaceuticals by vapor phase atomic absorption spectroscopy.

A procedure was developed for the determination of mercurials of pharmaceutical interest. Protic acid cleavage of the compound was followed by reduction of the resulting mercuric ion and vapor phase atomic absorption spectroscopy. This procedure was applied to 11 different mercurial compounds in various pharmaceutical preparations and offers excellent sensitivity with respect to presently used compendial assays. Comparative analytical data between this procedure and compendial methodology are presented.

Chemistry, Pharmaceutical↗
PubMed1975

Determination of estrogens in dosage forms by fluorescence using dansyl chloride.

A sensitive, reproducible, fluorometric procedure for the determination of estrogens in pharmaceutical preparations is presented. The estrogens are determined fluorometrically following their reaction with dansyl chloride. The optimum conditions for the reaction such as pH, reaction solvent composition variations, and speed of reaction are discussed. In addition, a linearity study of the relationship between concentration and fluorescence intensity for estrone, estradiol, and ethinyl estradiol is reported. Solvent extraction procedures based on acid-base behavior or column chromatography are used when necessary to isolate the estrogen prior to reaction with dansyl chloride and fluorometric measurement. The recovery of estrogens from spiked samples indicated that the proposed method is efficient and reproducible. Comparison of the dansyl procedure with the official NF method in the analysis of estrone aqueous suspension showed the proposed method to be accurate and more precise than the NF assay. Estrone aqueous suspension, estradiol in sesame oil, estradiol valerate in castor oil and in sesame oil (in the latter case, in the presence of testosterone), estradiol benzoate in sesame oil, and ethinyl estradiol tablets (0.5 mg/tablet) from commercial sources were satisfactorily analyzed, with average results within compendial limits and no coefficient of variation greater than 2%.

Castor Oil↗
PubMed1988

Application of difference spectroscopy to the determination of some pharmaceutically important nitro compounds.

A simple and selective spectrophotometric method for the determination of some pharmaceutically important nitro compounds has been developed. The suggested method depends upon the spectral changes induced by reduction using either Zn/HCl or Zn/NH4Cl. The different experimental parameters were studied and incorporated into the procedure. The mean percentage recovery ranged from 99 to 101. The proposed method was applied to the determination of the studied compounds in dosage forms, and the results obtained were compared favourably with those given with the compendial ones.

Indicators and Reagents↗
PubMed2003

Development of a high-performance-liquid-chromatographic method for the determination of biapigenin in biorelevant media.

A new precise, rapid and selective high-performance-liquid-chromatographic (HPLC) method has been developed to quantify biapigenin in St. John's Wort (SJW) preparations and to investigate its release characteristics in the dissolution test using both compendial and biorelevant media. Experiments were carried out on a LiChroCart 125-4, RP-18 (5 microm) column, using gradient elution at a flow rate of 1 ml/min. The binary mobile phase consisted of solvent A (acetic acid, 5:100, w:w) and B (a mixture of acetonitrile and methanol (3:1, v:v)). Detection was performed at a wavelength of 270 nm using a photodiodearray detector. The limit of detection was 0.05 microg/ml, the injection volume 20 microl. Five SJW preparations were chosen to determine the amount of biapigenin in the dosage form and to investigate their release characteristics. Best results in terms of release as well as discriminating the tested products were obtained, using fed state simulated intestinal fluid (FeSSIF), where over 80% of biapigenin was dissolved after 20 min comparing to 70% using simulated gastric fluid sine pepsin (SGF(sp)) as compendial medium. Experiments in fasted state simulated intestinal fluid (FaSSIF) show 80% release of biapigenin within 80 min.

Apigenin↗
PubMed2001

Biorelevant dissolution testing to predict the plasma profile of lipophilic drugs after oral administration.

PURPOSE: To quantitatively compare in vitro dissolution data in biorelevant and compendial media, to investigate whether in vitro differences are reflected in the simulated plasma profile and to specify under which circumstances prediction of the plasma profile of orally administered lipophilic drugs can be achieved. METHODS: Previously published dissolution data from seven products of four lipophilic drugs were compared using the first order model, the RRSBW distribution, and a model based on the Noyes-Whitney theory. Simulated plasma profiles were then obtained using a model-dependent approach. Simulated and observed plasma profiles were compared with the difference factor, f1. RESULTS: No model consistently provided the best fit to the in vitro data, which varied significantly with medium composition. Prediction of the plasma profile was possible (9.6 < or = f1 < or = 34.2) in seven out of eleven cases. CONCLUSIONS: Although prediction of the plasma profile of lipophilic drugs solely on the basis of in vitro data remains an ambitious target, this study shows that the plasma profile of a lipophilic drug can be predicted with appropriate in vitro dissolution data, provided that the absolute bioavailability of the drug is known and the drug has dissolution limited absorption.

Adamantane↗
PubMed1994

Evaluation of tetracycline raw materials and finished products found on the Kenyan market.

Contents of tetracycline, its degradation products (epitetracycline, epianhydrotetracycline, anhydrotetracycline) and a fermentation impurity (2-acetyl-2-decarboxamidotetracycline) were determined in four raw materials, 12 batches of six ointment products, four eye ointment products and nine batches of five capsule products, all sampled from the Kenyan market. The analytical method was liquid chromatography on a column packed with a poly(styrenedivinyl-benzene) material (8-microns PLRP-S 100 A). All raw materials and finished products had tetracycline contents and impurity levels within the prescribed compendial limits.

Capsules↗
PubMed1996

Quantitation of 5-hydroxymethylfurfural (5-HMF) and related substances in dextrose injections containing drugs and bisulfite.

The spectrophotometric test for 5-hydroxymethylfurfural and related substances, which is included in multiple compendial monographs for dextrose-containing injections, was modified to eliminate interference of bisulfite anion. Experimental formulations containing heparin or dopamine hydrochloride were used in this study. The modified assay was shown to be accurate, precise and rugged. With an appropriate standard, the method can be used to measure 5-HMF in solutions with an approximate quantitation limit of 0.06 ppm.

Dopamine↗
PubMed1982

NMR determination of isosorbide dinitrate and beta-adrenergic blocking agents in tablets.

An NMR spectroscopic method for the determination of isosorbide dinitrate, alone or together with alprenolol or propranolol, is described. Spectra are determined in dimethyl sulfoxide-d6 containing maleic acid or 1,4-dinitrobenzene as internal standards. Both synthetic mixtures and commercial formulations were assayed, and the results were compared using compendial procedures.

Adrenergic beta-Antagonists↗