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An automated, stability-indicating, UV spectrophotometric assay for cefazolin is presented. The method employs a reaction with hydroxylamine and derives its stability-indicating power through comparison of reacted and unreacted aliquots of the sample. A double-probe sampling procedure is used. Good agreement with microbiological assays is obtained, and the coefficient of variation is about 1%.
A rapid, automated method for the determination of phenylbutazone in plasma and urine was developed. The method offers distinct advantages over earlier procedures and is particularly suitable for large-scale bioavailability studies.
Isosorbide dinitrate and two isomeric isosorbide mononitrates are shown to be polarographically reducible in aqueous sodium perchlorate or potassium chloride solution. The current, measured at -1.6 v, versus the saturated calomel electrode is proportional to the concentration of organic nitrate in the 10-100-mug/ml range. Inorganic nitrate produces no interference. However, the mononitrate isomers produce an additive response to isosorbide dinitrate and cannot be determined individually. The polarographic method is applicable to single-tablet assay for content uniformity determination, with precision and accuracy comparable to automated colorimetric analysis. Comparison is made between replicate analyses obtained polarographically and by IR and automated colorimetric analysis for six different commercially available formulations. The polarographic determination is sensitive, specific for nitrate esters, precise, requires little sample preparation, and utilizes relatively inexpensive apparatus.
A natural membrane was employed in an automated diffusion system. A mature male Mongolian gerbil sebaceous gland pad was excised and mounted into a suitable retainer so that the external surface was oriented toward the concentrated aqueous drug solution. Aqueous solutions of benzoic acid and the three commonly used parabens were studied. The gerbil sebaceous pad effectively prevented any diffusion of these drug solutions within 15 hr. Water by itself, however, was transported through the skin even against a pressure gradient. Although no apparent diffusion of these compounds occurred, a significant amount of drug was retained by the sebaceous pad. An expression for membrane-water partition coefficients could be calculated. Based upon thicknesses of natural and synthetic membranes, theoretical approximations of diffusion rates were found using lag time calculations.
A rapid automated method for determining epinephrine in lidocaine hydrochloride injection is presented. The method is an adaptation of the official USP XIX fluorometric procedure and yields equivalent results. The linearity, accuracy, precision, excipient/background effect, and carryover characteristics of the automated system are described. A recovery study indicated that intact epinephrine is measured accurately in the presence of its degradation products. Analysis of several commercial preparations is reported.
An automated procedure was developed for the determination of warfarin sodium by following the steps of the manual USP procedure. The automated procedure is applicable to single tablets and composites of 20 tablets at different tablet concentrations. Sensitivity, precision, accuracy, and reproducibility are equivalent to the manual USP procedure. Sensitivity was approximately 15 mug/ml, with a coefficient of variation of 0.711%.
Antihistamine preparations containing methapyrilene hydrochloride, pyrrobutamine phosphate, and cyclopentamine hydrochloride were assayed by introducing an aqueous sample solution into the appropriate automated system. Methapyrilene hydrochloride was determined by UV spectrophotometry. Pyrrobutamine phosphate was extracted as an ion-pair and quantitated colorimetrically by forming the bromcresol purple acid-dye complex. Cyclopentamine hydrochloride was determined colorimetrically by using the copper dithiocarbamate reaction for secondary amines.
A simple and specific method for the quantitative determination of cephapirin, a cephalosporin antibacterial, in finished bulk and dosage forms is reported. The method is based on reproducible degradation under controlled conditions to an unidentified species, which is measured spectrophotometrically at 375 nm. The procedure can be performed manually on a short series of samples in about 15 min or can be automated for large runs. Precursors and related substances show minimal interference. The coefficient of variation of the automated system is about 1% within days and 1.3% among days.
An automated two-phase method for the simultaneous fluorometric determination of the spironolactone metabolites canrenone (II) and canrenoic acid (III) in serum is described. The determination is performed by two dichloroethane extractions of the same serum sample at different pH values. The fluorescence developed in 65% (v/v) sulfuric acid is measured in two separate fluorometers (one each for canrenone and canrenoic acid). Comparable specificity and sensitivity to the manual procedure are obtained, with sensitivity limits of 20 ng of II/ml and of 30 ng of III/ml in serum. This method is applicable to the automated determination of drugs and metabolites in biological material when several extraction steps are involved.
Methods for the determination of diphenoxylate hydrochloride and atropine sulfate combinations in solutions and powdered tablet composites are presented. A semiautomated assay for diphenoxylate hydrochloride in individual tablets (content uniformity) also is presented. The USP XIX assays for these products are cumbersome and, in the case of solutions, inaccurate due to spectral interferences; the proposed methods offer substantial improvements in sensitivity, specificity, and speed. Results obtained by the USP and proposed methods are compared for several lots of commercial products. The accuracy and precision of the proposed methods are shown by standard recovery studies.
An automated system for the simultaneous dissolution testing of six samples was developed consisting of four basic units: dissolution vessels and stirring unit, a peristaltic pump, a rotary stream multiport switching valve and programmer, and a UV spectrophotometer with recorder. Among the major advantages of such a system are: (a) paddle or basket stirring with variable speed is used, (b) the tablet or capsule (wire coil required) locates reproducibly at the bottom of a round-bottom reaction flask when utilizing paddle-type stirring, (c) a USP basket for tablet or capsule dissolution testing can be used, (d) continuous or intermittent sampling is possible, (e) the flow system readily adapts to UV-visible detector or fluorescence spectroscopy, (f) the system readily adapts to automated determination of the intrinsic dissolution of a material, and (g) the cost is low because of the multiport switching valve and inexpensive UV monitor required. Studies were performed using this apparatus to demonstrate the response characteristics of the system, its reproducibility, potential problems, and precautions required. This dissolution system was used to determine the dissolution characteristics of a new steroid tablet formulation, including a formulation and lot demonstrated to be bioavailable.
Chlorthalidone was analyzed in the concentration range of 0.1-3.0 microgram/ml with a precision of +/- 0.05 microgram/ml. Chlorthalidone inhibition of the enzymatic hydrolysis rate of p-nitrophenyl acetate by bovine erythrocyte carbonic anhydrase was used as a basis for the determination. The amount of p-nitrophenol formed was measured by monitoring the absorbance at 400 nm, and its formation rate was proportional to the chlorthalidone concentration. The mixing of the enzyme, substrate, and sample, the incubation of the reaction mixture, and the recording of the absorbance were automated. A survey of urine samples from 26 normal human subjects did not reveal any endogenous substances that interfered with the assay. Analyses of urine samples from six subjects after oral administration of 100 mg of chlorthalidone indicated rapid absorption and a biphasic elimination. The alpha-phase half-life was 1.5 hr, and the beta-phase half-life was 35 hr.
The precision of and correlation between the USP membrane filtration-microscopic method and the instrumental method for sizing and quantifying particulate matter in small-volume parenteral products were determined using simulated products. The total variance for the instrumental counts was lower than the USP method for all products in the 10--25-mum particle range and for most products in the greater than or equal to 25--50-mum range. A linear relationship between the instrumental counts and the USP counts was demonstrated for the 10--25-mum particle range. However, the instrumental reading was higher than the USP method for counts of 10 or more particles/ml. The instrumental and the USP methods failed to correlate on particulate sizes greater than 25 mum. The content of particulate matter in over 100 small-volume parenteral products was sized and quantified by the USP and the instrumental methods. From the instrumental data, a statistical treatment for the analysis of particulate data is presented as an objective method of evaluating acceptance criteria on particulate matter in small-volume parenteral products.
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An automated potentiometric procedure was used for studying in vitro dissolution kinetics of acidic drugs. Theoretical considerations indicated that the pH-stat method could be used to establish approximate sink conditions or, possibly, a perfect sink. Data obtained from dissolution studies using the pH-stat method were compared with data obtained from known sink and nonsink conditions. These comparisons indicated that the pH-stat method can be used to establish a sink condition for dissolution studies. The effective diffusion layer thicknesses for benzoic and salicylic acids dissolving in water were determined, and a theoretical dissolution rate was calculated utilizing these values. The close agreement between the experimental dissolution rates obtained under pH-stat conditions and theoretical dissolution rates indicated that perfect sink conditions were established under the experimental conditions used.
A new semiautomated high-pressure liquid chromatographic (HPLC) system is described to determine the dissolution rate of fludrocortisone acetate tablets. The system uses a miniaturized dissolution basket and shaft assembly having the same geometry as that given in USP XIX. This reduced size permits use of smaller volumes of dissolution medium, allowing most very low dose oral solid dosage forms to be handled. The USP dissolution kettle was also replaced with a new miniaturized vessel that continuously filters the sample solution before it enters the flow system. Volumes of dissolution medium as small as 15 ml can be accommodated, depending on the sensitivity of the assay employed and the solubility of the drug substance under study. The concentration of fludrocortisone acetate in solution was monitored by a new HPLC system employing a reversed-phase column compatible with the aqueous dissolution medium used. A comparative dissolution study of different lots was made using different basket rotation speeds.
Chlorthalidone inhibition of the enzymatic hydrolysis rate of p-nitrophenyl acetate by bovine erythrocyte carbonic anhydrase was used as a basis for chlorthalidone determination in plasma and urine. For urinary samples, a completely automated, continuous flow system was developed to extract the samples and perform the enzymatic reaction. Over 100 samples per day could be assayed by one person. The assay had a sensitivity of 0.5 micrograms/ml and thus could determine urinary concentrations after a therapeutic chlorthalidone dose. To determine plasma concentrations after a therapeutic dose, a manual extraction procedure was used in combination with a second continuous flow system for the enzymatic reaction. This system was optimized to detect the lowest chlorthalidone concentration allowed by the enzymatic inhibition constant and could detect 25 ng/ml.
A fully automated method for the determination of sulfisoxazole, N4-acetylsulfisoxazole, sulfamethoxazole, and N4-acetylsulfamethoxazole in human plasma and urine was developed. Untreated plasma is analyzed by automation of dialysis, hydrolysis, color development, and quantitation. The method has a sensitivyt limit of 2 microgram/ml of plasma and has been used successfully to determine sulfonamide levels following administration of sulfoxazole and a combination drug product containing sulfamethoxazole and trimethoprim in humans. Samples are processed at the rate of 40 per hour, with a minimum of sample handling, data reduction, and materials.