Commercial Dosage Forms Research Articles

Determination of Ephedrine, Pseudoephedrine, and Norephedrine in Mixtures (Bulk and Dosage Forms) by Proton Nuclear Magnetic Resonance Spectroscopy

A simple, specific, and accurate 1H nuclear magnetic resonance (NMR) spectroscopic method has been developed for quantitative determination of the Ephedra alkaloids (-)-ephedrine, (+)-pseudoephedrine, and (+/-)-norephedrine, either singly or in mixtures with each other. Determination of individual alkaloids was carried out in D2O solution, with acetamide as internal standard. Although calculations were based on integrals for the C-CH3 protons, those for the N-CH3 and -CH-O- protons may also be useful, depending on the compound. Determination of diastereomeric cross-contamination of ephedrine and pseudoephedrine--or of the concentrations of these alkaloids in the presence or absence of (+/-)-norephedrine--was feasible by using the integrals for the -CH-O- protons after addition of a trace of DCl. Mean recoveries for ephedrine and pseudoephedrine from their respective synthetic mixtures with the internal standard (acet- amide) were > or = 99.9 +/- 0.6% (n = 10) and 99.6 +/- 0.8% (n = 10) of the amount added. Recovery for pseudoephedrine from diastereomeric mixtures with ephedrine was > 99.4 +/- 0.7% (n = 10) of the amount added, with as little as 1.92% still being measurable. Mean recovery of (+/-)-norephedrine from mixtures with ephedrine and pseudoephedrine was > 99.7 +/- 2.5% (n = 4) of the amount added, with about 1% still being measurable. Application of the proposed NMR spectroscopic method to commercial dosage forms, including ephedrine sulfate injections and pseudoephedrine hydrochloride tablets, yielded assay results ranging from 97.8 to 100.2% (mean, 99.2%) and from 98.7 to 100.5% (mean, 99.7%) of declared, respectively.

Characterization of theIn VitroDissolution of Some Commercial Sustained Release Theophylline Dosage Forms

AbstractA dissolution study of five commercial sustained release theophylline dosage forms, concerning their pH dependency, is described. The experiment was carried out in a flow through dissolution apparatus, at constant pH and at pH gradient, being the pH values of 1, 2, 6, 5 and 7, 5. In both cases, they were treated in terms of the dissolution profile and the dissolution rate, complemented with the dissolution efficiency at pH gradient in order to make a correlation with the in vivo experiments that will be done in the future. The absorbance was measured at a wavelength of 264 nm. According to the results obtained, was selected the best pharmaceutical form, concerning the pH dependency and taking as a basis, just, the in vitro experiments.

Ion-Pair Reversed-Phase Liquid Chromatographic identification and Quantitation of Papaverine Congeners

A reversed-phase ion-pair high-performance liquid chromatographic separation was developed for identification and quantitation of papaverine drug congeners, namely papaverine (1), moxaverine (2), drotaverine (3), and ethaverine (4) hydrochlorides. A synthetic reference mixture of the four congeners in the range 1–4 μg showed good separation. With a reference standard (codeine phosphate), the relative retention times to codeine were 1.356, 1.984, 2.46, and 2.91 (mean of six) for 1,2,3, and 4, respectively. Good linearity was obtained in the quantitation of 1 and 2 in the range 1–2 μg [correlation coefficient (r), 0.9978 and 0.9997, respectively] and 3 and 4 in the range 2–4 μg, (r, 0.9998 and 0.9991, respectively). Analysis of some commercial dosage forms containing one Pf these congeners showed good recovery with sufficient accuracy and precision. The method was sensitive and permitted the use of small sample sizes or unit doses.

HPLC analysis of imidazole antimycotic drugs in pharmaceutical formulations

Reversed-phase HPLC on different column packing materials (Hypersil C-18, Spherisorb-CN, Chromspher-B) is used to obtain selective separations of imidazole antimycotic drugs, such as ketoconazole, clotrimazole, tioconazole, bifonazole, isoconazole, econazole, miconazole and fenticonazole. The use of a post-column on-line photochemical reactor is shown to be useful for the enhancement of the sensitivity of the HPLC analysis with UV detection. The proposed HPLC methods are applied to the analysis of commercial dosage forms (creams) with solid-phase extraction (SPE) procedure, using a diol sorbent, being found to be a convenient technique for the sample preparation giving quantitative drug recovery.

Separation of non-steroidal anti-inflammatory agents using supercritical fluid chromatography

Supercritical fluid chromatography (SFC) was investigated for the separation of non-steroidal anti-inflammatory agents (NSAIs). Three different stationary phases (SB-methyl-100, SB-biphenyl-30, and SB-cyanopropyl-50) were compared for the separation of the compounds. Baseline separation of a flufenamic acid, mefenamic acid, fenbufen and indomethacin mixture was achieved on the SB-biphenyl-30 column using a pressure gradient. A mixture containing flufenamic acid, mefenamic acid, acetylsalicylic acid, ketoprofen and fenbufen and another mixture containing ibuoprofen, fenoprofen, naproxen, ketoprofen and tolmetin were well separated on the SB-cyanopropyl-50 column using pressure gradients. Typical analysis time for a mixture of NSAIs on the biphenyl or cyanopropyl column was approximately 20–25 min. Application of the method using the biphenyl column to the determination of NSAIs present in selected commercial dosage forms was demonstrated.

The preparation and evaluation of a tablet dosage form of cyclosporine in dogs.

Cyclosporine (CsA) is commercially available for oral administration as a solution in olive oil with alcohol and an emulsifier. To improve its variable absorption and low patient acceptability, several oral formulations were prepared and tested in vitro and in vivo in dogs. A tablet formulation prepared by direct compression was then selected for comparison with the commercial oil solution placed into soft gelatin capsules. The study involved a randomized crossover design in six dogs. In order to determine absolute bioavailability and to compensate for any time-dependent changes in clearance, an intravenous tracer dose of 3H-CsA was administered along with each oral test product on each of two occasions. Absolute bioavailability (mean +/- SD) was 46.0 +/- 11.1 and 45.4 +/- 9.9% for the capsules and tablets, respectively. Cmax, tmax, and mean absorption time were not significantly different between the two products. No differences were observed in the pharmacokinetics of the intravenously administered CsA in the two experiments, which were separated by 8-13 days. We conclude that the proposed tablet formulation for CsA is equivalent in dogs to the commercial dosage form placed into soft gelatin capsules.

Analysis of flucytosine dosage forms by derivative UV spectroscopy and liquid chromatography

A simple second-order derivative spectrophotometric method was developed for the selective determination of flucytosine (an antimycotic drug) in the presence of 5-fluorouracil (a cytotoxic agent), its synthetic precursor and degradation product. Traces of 5-fluorouracil in flucytosine were also determined by derivative UV spectroscopy; flucytosine was removed by a selective solid-phase extraction (SPE) procedure using a strong cation-exchange sorbent. The spectrophotometric methods were applied successfully to the quality control of commercial dosage forms of flucytosine and the results were compared with those obtained by a HPLC procedure (cyano column) developed as a reference method.

Quantitation of insulin injection by high-performance liquid chromatography and high-performance capillary electrophoresis

High-performance capillary electrophoresis (HPCE) was evaluated as a potential technique for the regulatory analysis of commercial dosage forms of insulin. A comparison was made to a liquid chromatographic analysis presently being proposed as an official monograph in the United States Pharmacopeia. The salient points of this comparison were accuracy, precision and ease of use. Both authentic ( i.e. single blind, spiked) samples and commercial pharmaceutical formulations (injections) were examined. Chromatographic analyses of both commercial formulations and authentic samples were characterized by good precision, with accuracy being supported by results from authentic (spiked) samples. Conventional HPCE (by which is meant a non-micellar electrolyte used with an uncoated, unmodified fused-silica capillary) achieved reasonable accuracy, but less than impressive precision, when applied to authentic samples. When used for commercial formulations, this type of HPCE did not produce a level of accuracy suitable for regulatory purposes, even with the use of an internal standard.

In vitro diffusion cell design and validation. I. A stability-indicating high-performance liquid chromatographic assay for betamethasone 17-valerate in purified isopropyl myristate receptor phase.

The development of a reliable in vitro permeation system necessitates the use of a precise and accurate method of quantifying tb~ amount of permeant partitioning from the membrane into the cell receptor phase. Aqueous donor and receptor chamber fluids have ~en used in the majority of reported investigations, which makes quantitative permeant analysis relatively facile. Alternatively, radiolabelled diffusants have been used and flux rates monitored by scintillation counting, obviating the need for chromatographic separation of the receptor-phase components. However, this technique is not applicable when nonlabelled compounds or commercial dosage forms are to be evaluated by a cell system. Furthermore, several studies indicate that aqueous receptor phases may not present an optimal partitioning environment for certain lipophilic permeants (1~), thereby impairing accurate flux monitoring due to limited diffusant solubility. Several attempts have thetefore been made to improve the partitioning environment within these systems, by the addition of surfactants for example (4). A lipophilic receptor environment appears beneficial for corticosteroid partitioning, and thus, the use of isopropyl myristate has been investigated because of its bipolar properties that tend to mimic the biochemical composition of the skin (5,6). Betamethasone 17-valerate and its 21-valerate degradation product are highly soluble in isopropyl myristate and this nonaqueous solvent willnot augmentC-17-to-C-21ester degradation reactions. The UV absorbance of the receptor-phase solutions has been measured directly by spectrophotometry without prior chromat9graphic'separation (7-10). However, compounds other than the diffusant of interest may permeate from the donor compartment, or may leach fromthe membrane, and may contribute to this measured absorbance. Therefore,

Reverse-Phase Liquid Chromatographic Analysis of Cephalosporins

A simple and rapid reverse-phase liquid chromatographic method was developed for the qualitative and quantitative analysis of 13 cephalosporin compounds. A mixture of cefaclor, cefadroxil, cefamandole nafate, cefamandole sodium, cefazolin, cefoperazone, cefotaxime, cefoxitin, ceftizoxime, cephalothin, cephalexin, cephapirin, and cephradine was resolved into its components in raw material and dosage form samples by using a C18 column, a methanol-water-acetic acid (30 + 70 + 0.1) mobile phase, and a UV detector set at 254 nm. The proposed method is suited both for the determination of cephalosporins in a wide variety of commercial dosage forms and for the investigation of related compounds and other impurities in samples of 7 of the cephalosporins.

HPLC determination of thiol drugs in pharmaceutical formulations using ethacrynic acid as a precolumn ultraviolet derivatization reagent

A high performance liquid chromatographic method has been developed for the determination of aliphatic thiol drugs, such as N-acetyl-L-cysteine, captopril and mercaptopropionylglycine in pharmaceutical formulations. The procedure involves a precolumn derivatization of the thiol drug with ethacrynic acid followed by reversedphase HPLC separation and UV detection. The conditions for a rapid and selective reaction of the thiols with ethacrynic acid have been investigated. The method proved to be suitable for a reliable and selective quality control of commercial dosage forms of the examined thiol drugs.

Quantitation of Sulfacetamide, Sulfadiazine, Sulfamerazine and Sulfame Thazine in Various Cominations Dsing High-Performance Liquid Chromatography

AbstractA reverse phase high-performance liquid chromatography method for the quantitation of sulfacetamide, sulfadiazine, sulfamerazine, and sulfamethazine in various combinations has been developed. The method is simple, accurate, precise and reproducible. The percent relative standard deviations based on 6 injections were 2.1, 0.6, 1.9, and 1.6 for sulfacetamide, sulfadiazine, sulfamerazine, and sulfamethazine, respectively. The ratio of peak heights (drug/internal standard) wer closely related (r value 0.99 or better) to concentrations (± 20% of the standard solution concentrations). The results of synthetic mixtures showed quantitative recovery and method was successfully applied to commercial dosage forms (tablets and suspension). Extraction of sulfa drugs from the dosage forms required a very simple procedure.

Comparison of inter- and intra-subject variation in oral absorption of theophylline from sustained-release products

A comparative study of inter- and intra-subject variation in the bioavailability of theophylline from two commercial sustained-release dosage forms (a beaded capsule and a tablet formulation) was performed in 12 healthy adult volunteers. The disposition kinetics of theophylline was characterized in each subject following a single 250 mg oral dose of a fully bioavailable liquid formulation. Duplicate single dose studies of each of the two sustained-release products were then performed on 4 separate occasions in a randomized crossover fashion. On the average, the extent of theophylline bioavailability from the two sustained-release dosage forms was equivalent and essentially complete as compared to that from the liquid formulation. Both sustained-release formulations exhibited reasonable consistency in the extent of bioavailability when tested on two different trial days in a given subject (the mean percentage difference in extent of absorption was 11.5 ± 8.3% for the beaded capsule and 11.8 ± 12.3% for the tablet). The rate of theophylline absorption from the beaded capsule formulation was more rapid than from the tablet formulation as indicated by an earlier time to reach peak serum concentration (6.0 ± 1.9 vs 8.9 ± 2.5 h). Individual time course of cumulative absorption from the sustained-release formulations was determined using the Wagner-Nelson procedure. The overall variability in the cumulative absorption profile was greater for the tablet as compared to the capsule formulation. More significant was the fact that within each subject the absorption profiles were less reproducible between trials with the tablet as compared to the capsule. Dose-to-dose variation in the release/absorption kinetics of theophylline from these sustained-release products may lead to unpredictable fluctuations in steady-state serum theophylline concentration-time profiles during chronic drug administration.

Separation and Identification of Nine Penicillins by Reverse Phase Liquid Chromatography

A simple and rapid high performance liquid chromatographic method was developed for the separation and identification of amoxicillin, ampicillin, cloxacillin, dicloxacillin, methicillin, oxacillin, nafcillin, penicillin G potassium, and penicillin V potassium. The antibiotics were separated at ambient temperature on a Chromegabond 10 microns C18 column with acetonitrile-methanol-0. 01M potassium dihydrogen phosphate buffer, pH 4.7 (19 + 11 + 70), at 1 mL/min. A variable wavelength detector set at 225 nm, 0.16 AUFS , and a recorder set at 0.25 cm/min were used for the detection. Individual antibiotics and their mixtures were dissolved in the mobile phase and injected into the chromatograph through a 20 microL injection loop. Baseline separation was observed for virtually all 9 antibiotics. The entire mixture was resolved in less than 30 min. The method was sensitive, reproducible, and applicable to the qualitative analysis of commercial dosage forms.

Assay of Chlordiazepoxide and Demoxepam in Chlordiazepoxide Formulations by Difference Spectrophotometry

□ Rapid difference spectrophotometric methods for chlordiazepoxide and demoxepam in chlordiazepoxide formulations are described which overcome the nonspecificity of the official spectrophotometric assays. The procedures are based on the measurement of the difference absorbance at 269 nm of equimolar solutions of chlordiazepoxide at pH 8 and pH 3 and the difference absorbance at 263 nm of equimolar solutions of demoxepam at pH 13 and pH 8. The methods are specific for chlordiazepoxide and demoxepam in the presence of both compounds, 2-amino-5-chlorobenzophenone, certain coformulated drugs, and formulation excipients. Analyses of commercial dosage forms of chlordiazepoxide have shown the presence of demoxepam at concentrations in excess of the pharmacopoeial specifications in some aged samples.

Urinary excretion kinetics of intact quinidine and 3-OH-quinidine after oral administration of a single oral dose of quinidine gluconate in the fasting and non-fasting state.

To obtain more precise urinary excretion data of intact quinidine (D) and its main metabolite, 3-OH-quinidine (DM), the specific HPLC method of Bonora et al has been used to follow its urinary excretion kinetics. In a cross-over study, 2 commercial dosage forms of quinidine gluconate, fast- and slow-release, were administered to 18 healthy subjects who had fasted for 10 hours in 3 treatments which were administered during the fasting period (T1), and before (T2) of after (T3) a standard breakfast. The urine was collected at fixed time intervals for 72 hours after the administration of a single dose (405 mg of quinidine base). The difference between the drug release characteristics of the two products was studied by analysing the cumulative amount of D and DM excreted as a function of time, and the time required to reach the maximum value for the urinary excretion rate of intact quinidine. A food effect could be noticed among treatments with the conventional fast-release dosage form when comparing the maximum values of the urinary excretion rate of D (T2 greater than T1). There was no significant difference in the percentage of drug absorbed from the 2 products, according to the data on the cumulative amount of D and DM. The parameters estimated for quinidine and the metabolite were: the apparent half-life of elimination, the urinary excretion rates and the time to reach a maximum value in the urinary excretion rate. The urinary excretion rate constant and the renal clearance were also quantified for quinidine by combining urinary parameters with the corresponding serum data previously reported.

Simultaneous Stability-Indicating Determination of Phenylephrine Hydrochloride, Phenylpropanolamine Hydrochloride, and Guaifenesin in Dosage Forms by Reversed-Phase Paired-Ion High-Performance Liquid Chromatography

AbstractA method for the quantitative determination of phenylephrine hydrochloride, phenylpropanolamine hydrochloride, and guaifenesin in commercial formulations was developed. A reversed-phase paired-ion high-performance liquid chromatographic technique resolves the active from degradation products, colorings, and flavor and was found applicable to seven commercial dosage forms.

Stability of haloperidol in 5% dextrose injection

The stability of haloperidol in 5% dextrose injection using a high-pressure liquid chromatographic (HPLC) method is reported. A solution of haloperidol 10 mg/dl in 5% dextrose injection was prepared using commercially available haloperidol injection. The solution was stored at 24 degrees C, half in an amber glass bottle and half in a plastic bag. These were assayed on days 0, 1, 7, 14, and 38. Solutions prepared from commercial dosage forms of haloperidol (injection, oral liquid concentrate, and tablets) were assayed to verify the accuracy of the HPLC assay to quantify haloperidol. There was no loss of haloperidol potency in 38 days when stored 24 degrees C in either the amber glass bottle or plastic bag. There was a substantial loss of methylparaben and propylparaben (present in commercial haloperidol injection) in the solution stored in the plastic bag. Oxidation products of haloperidol did not interfere with the assay, and the HPLC assay accurately measured haloperidol in solutions prepared from commercial dosage forms. The results show that haloperidol 10 mg/dl in 5% dextrose injection was stable for at least 38 days. While the loss of parabens is not of practical importance, the HPLC method developed provided this information while the previously used USP-NF procedure did not. The assay can be used to quantify haloperidol in commercial dosage forms.

High-pressure liquid chromatographic (HPLC) analysis of imidazole antifungals in commercial dosage forms

A high-pressure liquid cliromatographic (HPLC) method is presented for determining clotrimazole, miconazole nitrate and econazole nitrate in various commercial formulations. The analysis was performed on a reversed-phase column (RP 18) under isocratic conditions using a UV detector (230 nm). The described procedure proved to be more specific and versatile than the pharmacopoeia methods.

Applications of Paired Ion High-Pressure Liquid Chromatography: Quantitative Determination of Potassium Guaiacolsulfonate and Other Ingredients in Cough Syrups

A method for the quantitative determination of potassium guaiacolsulfonate and phenylephrine hydrochloride in commercial dosage forms was developed. The method is based on paired ion high-pressure liquid chromatography with tetrabutylammonium as the counterion. The method not only separates potassium guaiacolsulfonate from phenylephrine hydrochloride but also from some other ingredients: chlorpheniramine maleate, sodium benzoate, colors, and flavors. Furthermore, two isomers of potassium guaiacolsulfonate, potassium salts of 4- and 5-guaiacolsulfonic acid, also separate from each other. The method was tried on five different commercial dosage forms (all with different colors) with excellent results on three. In the other two samples, which also contained codeine, there may have been a stability problem.