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Determination of conjugated and esterified estrogens in pharmaceutical tablet dosage forms by high-pressure, normal-phase partition chromatography.

A high-pressure, normal-phase partition chromatographic method for the identification and determination of conjugated and esterified estrogens in pharmaceutical tablet dosage forms is described. The method is based on the separation of the estrogen sulfate esters on a conventional diatomaceous earth-H20 column, followed by HCI-methanol hydrolysis, and finally a chromatographic separation on a chemically bonded ether (ETH-Permaphase) column and measurement. Mobile phases found useful were combinations of 2-propanol and n-heptane. Equillin and -dehydroestrone, a structurally related isomer, not separately determined in the proposed method, are determined as a sum by performing a chromatographic study of their corresponding 2, 4-dinitrophenylhydrazine derivatives. Studies have indicated several estrogen derivatives can be rapidly formed and then separated on the same column, providing a useful qualitative analysis scheme. Commercial tablet dosage forms were analyzed for conjugated and esterified estrogens and the results are presented.

Chromatography, High Pressure Liquid

Comparison of the bioavailability of cyanocobalamin from capsule and liquid dosage forms.

Comparative in vivo absorption of cyanocobalamin from two dosage forms, gelatin capsule and liquid, was studied. Forty-two subjects received simultaneous doses of cyanocobalamin in capsule and liquid form, labeled with cobalt-57 and cobalt-60, respectively. Excretion, a measure of absorption, was between 2 percent and 66 percent greater with the liquid form. In vitro dissolution studies showed that the capsules had a tendency to collapse into a stringy mass and to dissolve slowly.

Biological Availability

Research and development of phamaceutical dosage forms.

The development of a suitable formulation and a freeze-dry cycle for a pharmaceutical dosage form requires knowledge of some basic properties such as (1) eutectic temperature, if one exists, (2) temperature effect on solubility, (3) degree of supercooling, (4) heat transfer properties of the frozen product and (5) equipment design and equipment capability. Basic work with several inorganic and organic salts shows that eutectic temperature is a function of the melting point and the differential heat of solution of a drug. From a knowledge of these parameters, a mathematical expression can be used to estimate eutectic temperature. The desired characteristics which can be achieved by proper formulation of the solution to be freeze-dried and by employing optimum freeze-drying cycles include an intact cake, sufficient strength, uniform color and rapid reconstitution. By utilizing resistivity measurements to determine eutectic temperature and supercooling properties it is possible to reformulate products, increase batch sizes and reduce overall times for freeze-drying cycles.

Bromides

Effect of food on absorption of indoprofen administered orally to man in two dosage forms.

The influence of food on the bioavailability of two oral dosage forms (100-mg capsules and 200-mg tablets) of indoprofen, a new propionic acid derivative with marked anti-inflammatory and analgesic properties, has been investigated. Plasma levels and urinary excretion of indoprofen were determined both in the fasting state and after a standard meal in healthy volunteers after administration of two 100-mg capsules (4 subjects) and of one 200-mg tablet (6 subjects). Indoprofen in biological fluids was determined by gas-liquid chromatography. The extent of absorption from tablets was not affected by food as indicated from the values of the total area under plasma level curves and urinary excretion of the drug. The rate of absorption was faster after meal than in the fasting state. The opposite was found for capsules, which showed a slightly delayed absorption after food. The results suggest that food may differently influence the absorption pattern of different pharmaceutical forms of the same drug.

Administration, Oral

Influence of food on the absorption of acetylsalicylic acid from enteric-coated dosage forms.

The absorption of acetylsalicylic acid (ASA) from two different enteric-coated dosage forms, tablets (Premaspin) and granules (Reumyl), was studied in healthy volunteers under fasting and non-fasting conditions by following the plasma concentration and urine recovery of salicylates after single doses of ASA 1 g. Conventional tablets (Aspirin) were used as the reference. Under fasting conditions the absorption of ASA from the two different enteric-coated preparations was complete. Taken with food the enteric-coated tablets gave much lower plasma concentrations than under fasting conditions, and absorption was not complete in all subjects. In contrast, absorption from the enteric-coated granules was not influenced by the intake of food. It was concluded that enteric-coated granules of ASA permit more reproducible absorption than enteric-coated tablets.

Adult

Gastric acid inactivation of erythromycin stearate in solid dosage forms.

The effect of hydrochloric acid at pH 1.2-3.2 ON ERYTHROMYCIN STEARATE AND COMMERCIAL DOSAGE FORMS OF ERYTHROMYCIN STEARATE WAS STUDIED. Under all conditions examined, erythromycin was readily dissolved from the stearate as hydrochloride, and rapidly lost its biological activity in solution. The inclusion of pepsin in the test systems did not affect the results. Although formulation differences somewhat affected the rate of destruction, acid lability was exhibited by all products examined, except enteric-coated tablets. Amounts of acid considered to be normal in the fasting stomach contents of adults during the time likely for a dose to remain in the stomach caused 70-90% destruction within 15 min after the shells started to rupture. Amounts of hydrochloric acid appreciably less than 1 mEq, representing abnormally small quantities even in the fasting state, caused destruction ranging from 30 to 70% of the doses in 15 min. These results are not reconcilable with published statements that the sensitivity of erythromycin to gastric acid is overcome by providing the antibiotic in the form of stearate salt.

Capsules

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

NMR analysis of pharmaceuticals XIV: determination of amyl nitrite in its inhalant dosage form.

An NMR procedure is described for the analysis of amyl nitrite as a drug entity and in inhalant dosage forms. The choices of solvent (carbon tetrachloride) and internal standards (biphenyl or benzyl benzoate) were made with respect to stability problems and the presence of stabilizers in the formulation. The method is precise, with a standard deviation of +/-0.5. The NMR results of synthetic solutions and commercial preparations were compared with those obtained by a published relative NMR procedure and a compendial titrimetric method. The results were generally satisfactory.

Amyl Nitrite

Simultaneous determination of pseudoephedrine and chlorpheniramine in pharmaceutical dosage forms.

A simple and sensitive high-pressure liquid chromatographic (HPLC) determination of pseudoephedrine and chlorpheniramine in a pharmaceutical dosage form is described. Quantities of 1.5 microgram of pseudoephedrine and 0.1 microgram of chlorpheniramine are sufficient to determine concentrations in an aqueous solution. Small volume samples, without any extraction procedures, can be treated for direct drug concentration measurement with a high-pressure liquid chromatograph. The stability-indicating property and the accuracy of this method are comparable to those of an established GLC method. The HPLC method can be applied directly and successfully for dissolution studies. The latter application eliminates the need for volume replacement or subsequent mathematical corrections.

Capsules

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.

Anticonvulsants

High-performance liquid chromatographic assay of cyclophosphamide in raw material and parenteral dosage forms.

A simple, specific, high-performance liquid chromatographic method is described for the assay of cyclophosphamide as the raw material and in parenteral dosage forms. The assay involves dilution, addition of an internal standard (methyl 4-aminobenzoate), injection onto a reversed-phase C18 column, and quantitation with a UV detector at 200 nm. Sensitivity is approximately 40 micrograms/ml. Decomposition products elute at the void volume and do not interfere.

Chromatography, High Pressure Liquid

High-performance liquid chromatography of two peripheral vasodilators, nylidrin hydrochloride and isoxsuprine hydrochloride, in pharmaceutical dosage forms.

A reliable and selective high-pressure liquid chromatographic (HPLC) procedure for the quantitative determination of nylidrin hydrochloride or isoxsuprine hydrochloride in pharmaceutical dosage forms is described. The specificity of the stability-indicating HPLC procedure is presented for nylidrin hydrochloride.

Chromatography, High Pressure Liquid

Quantitative dexamethasone and dexamethasone sodium phosphate determinations in pharmaceutical dosage forms by high-pressure liquid chromatography.

A high-pressure liquid chromatographic procedure for quantitative dexamethasone and dexamethasone sodium phosphate determinations in all types of commercially available pharmaceutical dosage forms was developed. The method also separates dexamethasone from its phosphate salt and separates dexamethasone or its salt from a number of inactive ingredients such as benzoic acid, benzyl alcohol, some colors, creatinine, and parabens. Inactive ingredient concentrations may be estimated without additional cost. Part of the parabens present in the commercial injections may be adsorbed by the rubber closures.

Chromatography, High Pressure Liquid

Computerized automated system for determining dissolution rate profiles for solid dosage forms.

A unique automated system was developed for the measurement of dissolution rates of tablets and capsules. This system, which adheres to principles set forth in the compendia, can test six dosage forms simultaneously. It is modular in form and capable of maintaining sink conditions, and it can handle any type of chemistry amenable to an automatic analyzer. In addition to the usual dissolution apparatus, the system includes a 12-channel combination sampling and solvent addition pump, a sequence control module, pertinent automated analyzer components, a spectrophotometer or fluorometer, an optional recorder, a specially designed digitizing system, and a teletype equipped with a paper tape punch reader and acoustic coupler. Each dissolution flask is automatically sampled every 6 min. Standards may be run either before or after the samples. Since dissolution, sampling, chemistry, and readout are all accomplished simultaneously, the complete test time is essentially reduced to the dissolution time itself. At the completion of sample dissolution, raw dissolution profile data are on the punched paper tape ready for computer processing via a time-sharing system. Developed software provides for the printout of a complete test report in less than 15 min.

Capsules

Liquid chromatography in pharmaceutical analysis VI: determination of dantrolene sodium in a dosage form.

Operating conditions are described for the qualitative and quantitative determination of dantrolene sodium by high-pressure liquid chromatography. A 10-mum porous silica column was employed, using carbon tetrachloride-dimethylformamide (90:10) as the mobile phase. The flow rate was 2.0 ml/min (1800 psig), and the peaks were detected at 375 nm. The analysis of a dosage form can be carried out within 30 min with an accuracy of 3.1%. The results agree favorably with those obtained with a modified spectrophotofluorometric method.

Capsules

Comparative bioavailability of oral dosage forms of oxazepam--correlation with in vitro dissolution rate.

Four oxazepam tablet preparations and a suspension of micronized oxazepam in water were given to healthy, fasting volunteers in a comparative bioavailability study using a partial cross-over design. Urinary recovery (0-72 hours) was used as a measure of extent of absorption. Peak serum concentration was used as a measure of rate of absorption. The three dosage forms having the highest dissolution rate in vitro were absorbed to the same extent, while slower dissolving tablets were not as fully absorbed. Peak serum concentration correlated linearly with in vitro dissolution rate. Single oral doses of oxazepam tablets containing 10, 15 and 25 mg showed equal rates and extents of absorption and produced serum concentrations linearly correlated with dose.

Administration, Oral