Blood levels from a sustained-release dosage form.
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A chemical method for determining the amount of niacinamide in multicomponent preparations was developed. Neither niacin resulting from the degradation of niacinamide nor vitamin A, thiamine hydrochloride, riboflavin, ascorbic acid, ergocalciferol, or calcium pantothenate interferes. The method is based on the reaction of niacinamide with 1-chloro-2,4-dinitrobenzene, followed by the spectrophotometric measurement of the colored solution obtained after treatment with sodium hydroxide. The proposed method is at least as accurate as the methods currently in use. A structure is proposed for the colored product, and its route of formation is outlined.
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A methaqualone tablet in two strengths, 150 and 300 mg, was developed. The dissolution rate of an experimental formulation in pH 7.0 phosphate buffer, measured by the resin flask method, was shown to correlate with bioavailability in humans. The dissolution rate criterion was used to develop the final tablet formulation. Bioavailability of this formulation in two strengths was compared with a commercial capsule formulation and a slowly dissolving tablet formulation. Correlation between dissolution rate and bioavailability was shown in freshly prepared methaqualone tablet formulations. Bioavailability of tablets under accelerated stability testing conditions remained unaltered, whereas the dissolution rates in pH 7 phosphate buffer decreased, using the resin flask method. A rotating-flask method was developed, and dissolution in 0.1 N HCl at 2 rpm correlated with the bioavailability of both new and aged tablet formulations.
Theophylline was determined with good precision in tablets and capsules by differential spectrophotometry. Xanthines such as caffeine and theobromine did not interfere providing the total xanthine concentration was kept below 100 mug/ml. At a higher total xanthine concentration, nonlinearity occurred, presumably due to complex formation. This interference could be minimized by proper selection of the analytical wavelength.
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Tablet formulations of spironolactone with hydrochlorothiazide were studied in vitro and in vivo to evaluate the effect of formulation parameters on the bioavailability of spironolactone. The time required for 50% tablet dissolution (T50) in simulated gastric fluid was linearly correlated with the disintegration times of four experimental formulations and one commercial tablet of spironolactone and hydrochlorothiazide. Bioavailability studies were conducted in four healthy, female beagle dogs. The mean time to peak concentration of canrenone,f cancrenone, the major metabolite of spironolactone, was proportional to the T50 dissolution parameter. A study of spironolactone administered orally with and without hydrochlorothiazide showed that the bioavailability of spironolactone is not affected by hydrochlorothiazide. No significant difference in the bioavailability of spironolactone from one 100-mg and four 25-mg tablets were observed. Estimates of some pharmacokinetic parameters for canrenone closely agreed with those previously reported.
A stability-indicating method of analysis of homatropine methylbromide in pharmaceutical formulations was developed. This method is based on the formation of a picric acid-quaternary ammonium complex, which is adsorbed on acid-washed diatomaceous earth in alkaline media followed by on-column chloroform extraction. The picrate complex is measured spectrophotometrically at 365 nm. The method was selective for homatropine methylbromide in that there was no interference from its major hydrolytic decomposition products, tropinium methylbromide and mandelic acid.
A simple, specific GLC analytical procedure for the quantitation of epinephrine, isoproterenol, and phenylephrine in commercial tablets, powders, inhalation solutions, ophthalmic and nasal drops, and injectable preparations is presented. Samples are taken to dryness where required, the dried residue is reacted with an appropriate trimethylsilylating reagent, and the derivatives are eluted from a methyl silicone column using temperature programming. Quantitation of the flame-ionization detector signal is achieved relative to the dibenzyl succinate internal standard by an electric integrator. The results obtained by applying the method to the analysis of each of the three drugs in several simulated decomposed mixtures were in good agreement with theoretical values, even at impurity levels of up to 80% by weight. When applied to commercial formulations, the procedure was feasible for tablets, powders, and solutions at drug concentrations of 0.2% or greater. The commonly incorporated buffering and antioxidant excipients did not interfere.
The plasma and urine data obtained following intravenous administration of sulfamethazine to cattle were fit to a one-compartment pharmacokinetic model with a half-life of elimination of 9 hr and a volume of distribution of 0.35 liter/kg. Sulfamethazine was eliminated by excretion of unchanged sulfamethazine (18%) into urine and by formation of three metabolites subsequently excreted into urine. Sulfamethazine also was administered as a solution, a rapid-release bolus, and a sustained-release bolus. The change in the urinary metabolic pattern with different routes of administration suggested that first-pass metabolism was occurring during the absorption process. The absorption half-life was 6 hr. The absorption process for the two solid boluses kinetically appeared to include a dissolution step.
A specific method for the direct determination of pilocarpine in aqueous pharmaceuticals in the presence of decomposition products, methylcellulose, and other ingredients usually present in pharmaceuticals is described. The method involves separation by high-speed liquid chromatography using, in series, octadecylsilane bonded to silica and cyanopropylsilane bonded to silica columns and a tetrahydrofuran-pH 9.2 borate buffer (3:7) eluant. Quantitation is achieved by monitoring the absorbance of the effluent at 254 nm and using a pyridine internal standard and a calibration curve prepared from known concentrations of pilocarpine nitrate. The reproducibility of the retention time and peak area was better than 2.0%.
A stability-indicating assay for the degradation products of procarbazine hydrochloride was developed using high-pressure liquid chromatography. The method uses a buffered methanol-water mobile phase on a reversed-phase column. Concentrations of degradation products as low as 0.04 mg/ml, 0.02% degradation, can be quantitated using an internal standard of cinnamyl alcohol. The typical range for degradation products in procarbazine capsules is 0.1-0.5% after as long as 4.5 years.
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Synthetic (--)-delta 9-trans-tetrahydrocannabinol impregnated on placebo Cannabis decomposed only 6.3% after being stored for 1 year at --18 degrees. Storage at 5 degrees and room temperature under various conditions led to severe decomposition. The amount of cannabinol observed when (--)-delta 9-trans-tetrahydrocannabinol decomposed indicates that cannabinol is not the only decomposition product.
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Phenylpropanolamine was determined by measuring its fluorescent fluorescamine derivative. The method is rapid, sensitive, and easily automated. Statistics are presented for an effervescent cold product, and recovery data are presented for other commercially available products.
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