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Substitution of IR and UV absorption spectroscopy and use of the various test papers listed in the compendia provide satisfactory means of identifying drug and other substances that presently require subjective odor identification.
A simple and rapid liquid chromatographic method is described for the qualitative and quantitative determination of carbamazepine in tablet composites and individual tablets, using the internal standard technique. Analyses were performed on a C-18 reverse-phase column with tetrahydrofuran-methanol-water (8 + 37 + 55) as the mobile phase. A linear relationship was obtained between detector responses at 254 nm and amounts of carbamazepine injected ranging from 0.2 to 1.7 micrograms. The coefficient of variation for 10 consecutive injections of a standard preparation was 0.4%. Recoveries of carbamazepine from 100 and 200 mg tablets averaged 101.4 and 99.7%, respectively. Assay results for commercial tablets analyzed by the proposed method agreed favorably with those obtained by the method of USP XXI. The assay results for individual tablets indicated that deviations from the average value and the range of individual values are much wider with the compendial method than with the proposed method.
Titrimetric and spectrophotometric titration methods are described for the quantitative determination of acetylenic hypnotics ethchlorvynol, ethinamate, and meparfynol carbamate as pure substances and in dosage forms. The methods involve the use of different brominating agents. A known excess of the reagent is added and, after the specified time, the residual reagent is determined iodometrically. These procedures permit semimicro determination (1-20 mg) of the drug. Recoveries ranged from 98.48 +/- 0.76 to 102.74 +/- 2.60%. The procedures have been successfully applied to pharmaceutical dosage forms; the results agree well with those for compendial methods.
A specific liquid chromatographic method was developed for determination of clidinium bromide and clidinium bromide-chlordiazepoxide hydrochloride combinations in capsules. The procedure uses a Partisil 10 ODS-3 column and a mobile phase consisting of acetonitrile-0.3M ammonium phosphate (32 + 68) (pH = 4.3). The detection wavelength is 235 nm. Accuracy, reproducibility, and linearity were within accepted criteria. Four commercial samples of the single ingredient were tested; results compared favorably with the compendial method. Two commercial samples of the combination product were tested by the proposed method and results reported. The system was found to be free from any interferences from the 4 known related compounds of the 2 major components and is useful as a screening procedure for 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one-4-oxide, the principal degradation product of chlordiazepoxide hydrochloride.
A titrimetric method is described for the determination of three acetylenic hypnotics, namely ethchlorvynol, ethinamate, and methylpentynol carbamate, in bulk and in dosage forms. The method involves the use of either 1,3-dibromo-5,5-dimethylhydantoin (DBH), N-bromosuccinimide (NBS) or N-bromophthalimide (NBP) as titrants. A known excess volume of the reagent is added and, after the specified time, the residual reagent is determined iodometrically. This procedure permits semimicro determination (1-15 mg) of the drug. The procedure has been successfully applied to pharmaceutical dosage forms; the results agree well with those given by compendial methods. The stoichiometry of the reaction has been assessed and an explanation of the reaction pathway is presented.
A spectrophotometric method for the simultaneous determination of rifampin and isoniazid in dosage form is described. By using a mixture of methanol and water (2 + 3) as solvent, the absorbance of the mixtures of rifampin and isoniazid is measured at 264 nm and 335 nm. The concentration of each can then be calculated by solving 2 simultaneous equations. The procedure was successfully applied to a number of commercial samples; the results agreed well with those for compendial method.
A simple and rapid colorimetric method for the quantitative determination of the thioxanthene derivatives, chlorprothixene, tiotixene and metixene has been performed either in their pure form or in tablets. The procedure is based upon the formation of charge transfer complexes with the pi-acceptor tetracyanoethylene. The spectra of the complex show maxima at 415, 410 and 390 nm with a high apparent molar absorptivity which facilitates the determination of 5-100 micrograms X ml-1 of the studied compounds. The mean recoveries are 100.1 +/- 1.4%, 99.8 +/- 0.8% and 100.2 +/- 1.1% for chlorprothixene, tiotixene and metixene, respectively. This procedure is applied to determine these drugs in certain formulations and the results compare favourably to compendial methods.
The particulate levels found on supplier microcleaned rubber closures were compared to those of stoppers processed by a pharmaceutical manufacturer. The particle monitoring was performed using two official compendial methods: light blockage using a HIAC/ROYCO counter, and optical microscopy using a polarizing research microscope. The supplier-microcleaned stoppers were found to contain relatively few particles per stopper by both instrumental and microscopic counting. The cleaning process used by the pharmaceutical manufacturer was effective in reducing the particle load on their stoppers by factors of 2 to 20 fold as compared to the unwashed stoppers for the different size ranges measured. However, the supplier-microcleaned stoppers were found to be cleaner than those processed by the pharmaceutical manufacturer by a factor of 10 to 20 times for particle sizes greater than 10 microns using the instrumental method. Differences in the counts by microscopic and light blockage methods were attributed to the sampling and agitation procedures. Both the supplier-microcleaned and manufacturer's processed closures were found to meet the USP XXI limits for allowable particulate contamination in small volume parenterals.
The determination of Edrophonium Chloride Injection involves a modification of a procedure for phenylephrine and offers an alternative to the compendial assay. Edrophonium chloride forms an ion-pair with di-(2-ethylhexyl) phosphoric acid which can be extracted with an immiscible solvent such as ether. When this procedure is coupled with partition chromatography, the drug can be isolated from preservatives and quantitatively determined by its ultraviolet absorbance. Recovery data on synthetic mixtures ranged from 99.8 to 101.9% and were in good agreement with the compendial method.
BACKGROUND: Hazardous solvents, such as dichloromethane (DCM), n-hexane, and acetonitrile (ACN), are widely used in HPLC methods, posing significant health and environmental risks. OBJECTIVE: To evaluate the feasibility and impact of substituting hazardous solvents with greener alternatives in USP monograph methods. METHODS: Six high-impact solvents were identified from USP-NF monographs. Two representative monographs per solvent were selected. Substitution strategies were assessed, and performance was compared using system suitability and sample acceptance criteria. Greenness improvement was evaluated using the Analytical GREEnness (AGREE) metric. RESULTS: Performance remained equivalent across all twelve substitution cases. In almost every instance, only the mobile phase required modification, either by direct substitution or by adjusting the solvent-to-buffer ratio, except for one case that required a minor adjustment in column temperature. The AGREE Greenness metric increased by 18-65% in ten out of twelve cases; for n-hexane, improvements were modest at just 6% when replaced with n-heptane but exceeded 40% when substituted with supercritical CO₂. CONCLUSIONS: Greener solvents are highly likely to replace hazardous solvents used in compendial chromatography methods without loss of performance. HIGHLIGHTS: Demonstrated performance equivalency for greener solvent substitutions; Quantified greenness improvements using AGREE; Discussed strategies to implement greener solvents in USP monograph methods.
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.
The suitability of NIR spectroscopy as an alternative to several compendial test methods is discussed. Using ampicillin trihydrate as an example it is demonstrated that eight quality criteria are controlled by recording the NIR spectrum of a batch sample and calculating its Conformity Index.
The United States Pharmacopoeia (USP) uses acidified potassium permanganate to test for dissolved organics in pharmaceutical-grade water. In the test, a standard permanganate concentration is added to a boiling, acidified water sample. Visually inspecting the sample for residual permanganate determines whether the sample passes (pink color remains) or fails (pink color disappears) the test. The permanganate redox chemistry is complex, however, and test samples are prone to developing suspended particulate and colors other than pink. Forming hazy or off-colored solutions interferes with the subjective end point determination according to the USP test. We report two alternative end point determinations that essentially eliminate interferences from the compendial test method. The first alternative involves recording a uv-visible spectrum of the reduced permanganate test solution. Residual permanganate shows three distinct absorbance maxima at 510, 526, and 545 nm. It is straightforward to differentiate the characteristic permanganate fingerprint from the broad, lower-wavelength extinction that results from interfering substances. The second alternative involves filtering the reduced permanganate test solution through sintered glass. This filtration step removes manganese oxides and other colloidal particles that contribute to haze and off color formation in test samples. Visually inspecting the filtrate for residual pink color remains the end point determination for the test method. A third alternative method, namely spectrophotometric determination of permanganate loss rate constants is not a suitable alternative owing to a strong dependence of permanganate reduction rate on organic substrate structure.
A method is described for the determination of (-)-adrenaline in certain formulations containing adrenaline hydrogen tartrate at concentrations down to 0.18 mg ml-1 (1:10 000 adrenaline). The assay is based upon a spectropolarimetric measurement at 249 nm of sample solutions, suitably treated to remove interfering substances. The rotation of the sample solutions is corrected for the rotation of the tartaric acid species which is determined by a difference rotation measurement on equimolar sample solutions at pH 1.1 and pH 5.6. The concentration of (-)-adrenaline in the sample is calculated from the net rotation at 249 nm due to the (-)-adrenaline and the total concentration of adrenaline (+)-and (-)-isomers) determined by a published spectrofluorimetric method. The assay is specific for (-)-adrenaline in the presence of (+)-adrenaline, (+)-tartaric acid, adrenaline sulphonic acid and low levels of adrenochrome.
Accurate enumeration and sizing of contaminant particles in parenteral solutions are critical to the assessment of product quality and suitability for patient use. Current manual microscopic and instrumental (light obscuration) methodologies specified by the USP both result in data of high variability. The microscopic assay for large volume parenterals is time consuming and incorporates an undesirable level of subjectivity; light obscuration counters tend to undersize larger particles and fibers and have low detection efficiency for some particle types commonly present in small volume injections. Light microscopic image analysis is proposed as a method which combines the best features of the two present methods and allows an accurate, precise, and cost effective analysis of parenteral contaminant particles. This paper briefly summarizes the principles of microscopic image analysis and discusses its application in concert with optimized sampling and counting techniques as an improved compendial methodology. Instrument performance requirements are discussed with reference to a number of currently available image analysis systems.
A reverse-phase liquid chromatographic method is described for the assay of medroxyprogesterone acetate in tablets. An octadecylsilane (C18) column with a mobile phase of methanol-0.01M dibasic ammonium phosphate (80 + 20 v/v, pH 7.2 +/- 0.1) and photometric detection at 254 nm separates medroxyprogesterone acetate from excipients. Detector responses were linear to concentrations of medroxyprogesterone acetate over the range 50-150 micrograms/mL (r = 0.999). Mean recovery of medroxyprogesterone acetate added to tablet excipients was 100.8%. Mean assay results were 101.3% (n = 3). The assay results are comparable to those obtained by the compendial liquid chromatographic method.
Pharmacopoeias have been established by governmental authorities to serve three primary purposes: 1) to compile a select list of currently utilized drugs, including the most efficient forms for their application; 2) to distinguish these articles by convenient and definite names; and 3) to publish objective standards and analytical methods suitable for testing the integrity of commercially available preparations. In addition, some pharmacopoeias also offer informational text intended to instruct pharmacists on the compounding, use, storage and labeling of drugs; to advise physicians about dosage regimens and preferred modes of administration; to counsel producers about good manufacturing practices, and to edify drug analysts by explaining the theories underlying methods employed in compendial tests and assays. Examples of informational chapters in USP XIX are those on Pharmaceutical Dosage Forms, Stability Considerations in Dispensing Practice, and Sterilization. Because of the official status of national pharmacopoeias and their use as regulatory instruments in drug control, pharmacopoeial text intended merely for the information of the reader should be identified as such, and should be separated and distinguished from the mandatory, legally enforceable requirements.
A high-performance liquid chromatographic (HPLC) procedure has been developed for the isolation and quantification of thymol, a stabilizing agent present in halothane anaesthetic preparations. The method offers improvements in specificity and simplicity with respect to a current official procedure for thymol in halothane. Results for commercial preparations obtained by the proposed procedure demonstrate excellent precision and accuracy with RSD values for replicate analysis ranging from 0.11 to 0.74% and recoveries via fortification from 99.6 to 100.1%. The HPLC method was compared to compendial procedures for thymol bulk substance and halothane products. Chromatographic separation of other related phenolic preservatives used in pharmaceuticals suggests a more extensive application of the proposed procedure.