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A specially designed tablet dosage form of the benzodiazepine clorazepate dipotassium (Tranxene) was developed for once-a-day administration. The drug was administered at a dose of 22.5 mg as (1) the tablet, (2) three 7.5 mg capsules, or (3) one 7.5-mg capsule given every 6 hours. Peak serum levels from the tablet were intermediate between those of the single- and divided-dose capsule regimens. The desired decrease in magnitude of peak levels was obtained without affecting the extent of absorption. Pharmacokinetic analysis of the data according to a two-compartment open model with first-order absorption indicated that the serum half-life (t0.5beta) of nordiazepam, the major biotransformation product present in serum, was about 48 hours and served as a basis for the design of a multiple-dose steady-state study. Multiple-dose administration of the tablet and divided-capsule regimen to two groups of subjects for ten days indicated each dosage form yielded similar minimum steady-state serum levels of about 0.6 micrograms/ml which plateaued following seven days of drug administration. The dosage forms were crossed over between the groups on day 11 and administered for an additional four days. The minimum serum levels obtained with the tablet and capsule were not statistically different. Additionally, the peak serum level and area under the curve (pi=24 hours) at steady state were equivalent between the dosage forms. Good agreement was obtained between model-predicted and observed serum levels during multiple-dose administration for both the tablet and capsule regimens. The serum half-life of nordiazepam following 14 days of clorazepate dipotassium administration was similar to that found after a single dose. These results indicate that a single daily dose of drug as the tablet produced serum levels equivalent to a divided-capsule regimen.
The stability of liquid dosage forms of ethacrynic acid (1 mg/ml), indomethacin (2 mg/ml), methyldopate hydrochloride (25 mg/ml), prednisone (0.5 mg/ml) and spironolactone (2 mg/ml), which often are compounded extemporaneously, was studied. One or two liquid dosage forms of each of the five drugs was prepared with the pure drug or the powder from a commercial dosage form using aqueous sorbitol or simple syrup alone or with a 10% (v/v) solution of alcohol in water. The dosage forms were stored at 24 C in amber-colored bottles for 21-224 days and assayed by various methods. All solutions studied were stable for at least 84 days. A solution was considered stable if it retained 90% of its drug concentration. Except for the prednisone solution, all solutions were stable for at least 164 days; however, the solution of methyldopate hydrochloride prepared from the pure drug became discolored after 98 days. The liquid dosage forms studied have limited stability but can be used by the pharmacist when extemporaneous oral solutions of these drugs are needed.
A dimensionless parameter, the dosage form index (DLtau) is proposed for evaluating the performance of drug delivery systems. The index is defined as the ratio of the maximum to minimum concentrations of the drug in plasma within each interdose interval (in hours), tau, during repetitive administration of the dosage form in the quasisteady state. Dosage form indexes can be averaged among subjects or within subjects at successive time periods to arrive at a mean value. As an example, two GI therapeutic systems--the 15- and 20-mg/hr acetazolamide systems that deliver drug at constant rates for 6 and 12 hr and contain 125 and 250 mg, respectively--were compared in normal subjects with a commercial sustained-release product containing 500 mg of acetazolamide. The dosage form index, DI24, was 4.9 for the sustained-release dosage form and 3.2 for the 20-mg/hr system; DI12 was 1.6 for the 15-mg/hr system.
Eleven lots of parenteral methotrexate (MTX) dosage forms from two manufactures have been analyzed and found to be 93.4% +/- 2.1% (SD) pure by a new procedure employing a DEAE-cellulose column adapted for high performance liquid chromatography instrumentation. In addition to 4-amino-10-methylpteroic acid and N10-methylpteroylglutamic acid, which were previously identified contaminants, and benzyl alcohol, which was added as a preservative, we have also isolated and identified 2,4-diamino-6-methylpteridine, 2,4-diamino-6-bromomethylpteridine, and p-methylaminobenzoic acid. Another impurity has tentatively been identified as 4-amino-10-methylpteroic acid amide. The individual impurities vary from 0.1% to 4.8% of the ultraviolet absorbing material which elutes from the column. Additional impurities were detected by gas chromatography-mass spectrometry. Since "high-dose" therapy may involve the administration of up to 20 g of MTX/day, the effect of the impurities present in these dosage forms on the course of the patient's therapy should be determined.
As can be seen from the tables, the terminal half-life of clobazam is about 50 hours, and from a solid dosage form the peak plasma level occurs approximately 1.5 hours after ingestion. Thus, there is a significant, yet relatively short, dosage form delay effect when the solid dosage forms are compared to the rapidly available solution of the drug. However, based on the areas under the curve, comparison of the solid dosage forms with the solution indicates that the fraction of clobazam absorbed is 1. Pupil diameter measurement at 2, 4, and 6 hours after ingestion of clobazam correlated well with the plasma levels at these times. Pupils were constricted to the highest degree at 2 hours and approached the initial pupillary diameter at the 6-hour measurement.
The bioavailability of sustained-release papaverine HCl dosage forms were compared to equivalent doses of the drug administered as an elixir and conventional compressed tablets to 12 healthy human subjects. Papaverine plasma levels were determined using a gas-chromatographic procedure. The drug was absorbed more rapidly and completely from the two nonsustained-release formulations. There was a large intersubject variability, and the plasma half-life of the drug was esstimated to be 1 hour. The area under the plasma level-time curve for the nine sustained-release products ranged from 18 to 64% relative to the area achieved by the papaverine elixir. It was concluded that the sustained-release dosage forms of papaverine included in each study group could be considered bioequivalent, but they exhibited inadequate bioavailability relative to either the elixir or the compressed tablet dosage form.
A high-performance liquid chromatographic analysis is described for isoniazid as a drug entity and in its tablet and injectable dosage forms. After incorporation of the drug or dosage form in a solvent mixture and addition of an internal standard, tribenzylamine, an aliquot is chromatographed using a pellicular silica gel medium followed by UV spectrophotometric detection at 254 nm. The response of the chromatographic system was linear over a concentration range corresponding to 20-200% of the labelled amount of isoniazid. Comparison of the results with those obtained by the official USP XIX method indicates similar accuracy and precision. The advantages of the proposed method are its simplicity and rapidity, its potential for automation, and its specificity. The specificity was demonstrated in the presence of potential degradation products of isoniazid, other drugs used with isoniazid in combination dosage forms, and an adduct formed by the reaction of isoniazid with lactose in the tablet.
A crossover, randomized, eight-week trial using eight adult volunteers was undertaken to (1) determine the efficacy of aluminum hydroxide in decreasing gastrointestinal phosphate absorption, (2) compare the effectiveness of "with meal" and "between meal" dosing schedules, and (3) compare the effectiveness of the capsule and liquid dosage forms. Four treatments, each with a daily dose of approximately 6 g, were taken on a three-times-a-day regimen. The effectiveness of the treatment regimens was measured by using two variables: the decrease in total urinary phosphorus excretion, and the increase in the percent tubular reabsorption of phosphorus (TRP). Aluminum hydroxide treatment produced a significant change in urinary phosphorus excretion (p less than 0.0005) and in percent TRP (p less than 0.0005). For the study population, total urinary phosphorus excretion was the determining factor in changing the percent TRP. The increase in TRP and the decrease in total urinary phosphorus excretion was of the same degree regardless of dosage form or dosage schedule. Aluminum hydroxide was effective in decreasing phosphorus absorption as measured in this study. It appears that aluminum hydroxide capsules could be used with equal efficacy as the liquid dosage form in controlling hyperphosphatemia in patients with chronic renal failure who will not comply with a treatment program using the liquid.
A colorimetric procedure for benzocaine and a number of its dosage forms was developed; it offers improvement in ease, speed, and sensitivity over the official method. The method is based on the formation of a red Schiff base between benzocaine and p-dimethylaminocinnamaldehyde in a nonaqueous acidic medium. At the maximum absorption of 544 nm, the Beer-Lambert law was adhered to over the 0.025--2.5-microgram/ml range. Best accuracy can be obtained for solutions containing 0.25--1.25 microgram/ml. The color was stable for at least 2 hr. Analysis of benzocaine in the dosage forms studied can be directly performed without prior drug extraction.
A specific assay for nitroglycerin dosage forms using high-performance liquid chromatography was developed. Sublingual nitroglycerin tablets are dissolved in 25 ml of water and injected directly into the chromatograph. Chromatographic conditions are: mobile phase, 60% methanol in water; flow rate, 2 ml/min; column, microparticulate reversed phase; and detection, 200 nm. The glyceryl mononitrate and dinitrate degradation products of nitroglycerin are separated from nitroglycerin and can be identified by altering the mobile phase composition of methanol.
A high-performance liquid chromatographic (HPLC) method is described for determining oxytocin, lypressin and other nonapeptides and their by-products in liquid and solid pharmaceutical dosage forms. The use of injection volumes up to 750 microliter permits accurate determination of, e.g., oxytocin in injection solutions containing only 1 I.U. (international unit) per ml. Reproducibilities between 1.0 and 1.5% (relative S.D) have been obtained for liquid dosage forms and up to 3% (relative S.D.) for tablets. The correlation between results obtained by bioassay and by the proposed method is highly significant and suggests the use of HPLC as an alternative technique for stability and content-uniformity tests on dosage forms and concentrates.
The purposes of this investigation were to determine and to compare the oral absorption characteristics of micronized griseofulvin (500 mg) after its administration to humans in the form of a corn oil-in-water emulsion containing dispersed drug, an aqueous suspension, and two different commercial tablets (A and B). The four dosage forms were administered in a random crossover fashion to five fasting subjects, and drug absorption was assessed from urinary excretion data for the major metabolite of the antibiotic (6-desmethylgriseofulvin). The drug was most rapidly, uniformly, and completely absorbed from the corn oil-in-water emulsion. As compared to either the aqueous suspension, Tablet A, or Tablet B, three- to fourfold increases in the maximum body levels and a twofold enhancement in the bioavailability of the antibiotic were observed after administration of the emulsion dosage form. A mechanism based on the ability of the linoleic and oleic acids liberated during the digestion of corn oil to inhibit GI motility and stimulate gallbladder evacuation may explain the marked enhancing effect of emulsified corn oil on griseofulvin absorption in humans. This new lipid-in-water emulsion dosage form of micronized griseofulvin appears to offer several clinical advantages in the treatment of fungal infections.
The development of a new type of parenteral dosage form is described. A system of microencapsulation was formulated which produced microcapsules containing a water-soluble core material. The basic microencapsulation system could be altered to produce microcapsules with varied timed-release characteristics. Tracer methodology was employed as a sensitive and versatile analytical tool for the development and evaluation of the microencapsulation system. The core material was labeled by neutron activation after microcapsule formulation, which eliminated the radiation hazard and contamination problems that could occur during formulation with a labeled core material. Both in vitro and in vivo testing showed that the release patterns of labeled core material could be altered and detected. The microcapsules developed have potential as a timed-release parenteral dosage form and as an organ-imaging radiopharmaceutical.
A high-performance liquid chromatographic (HPLC) analysis is described for dienestrol as a drug substance and in cream, foam, and tablet dosage forms. After incorporation of the drug or dosage form into a solvent mixture containing an internal standard, biphenyl, an aliquot was chromatographed using a reversed-phase medium, followed by UV spectrophotometric detection at 254 nm. The response of the chromatographic system was linear over a concentration range corresponding to 50-200% of the labeled amount of dienestrol. Satisfactory accuracy and precision were confirmed by analyzing cream by the standard addition method. The advantages of the HPLC method are its simplicity, speed, and sensitivity, which permit direct analysis of single-dose quantities of dienestrol.
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.
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.