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Importance: Health care practitioners and patients must have information to support their confidence in the quality of prescription pharmaceuticals., Objective: To determine whether there were clear and substantive differences in major quality attributes between difficult-to-make solid oral dosage form pharmaceutical products marketed in the US., Design, Setting, and Participants: This quality improvement study analyzed US Food and Drug Administration-collected samples of 252 drug products marketed in the US and manufactured in the US, Canada, Europe, India, and the rest of Asia. These drug products were immediate-release solid oral dosage forms considered difficult to make on the basis of product quality history. This sampling included 35 innovator and 217 generic drug samples manufactured by 46 different firms containing 17 different active ingredients. Statistical analysis was performed from February to November 2019., Main Outcomes and Measures: All products were tested within their shelf life on the basis of the legally recognized tests of the US Pharmacopeia for the major quality attributes of dosage unit uniformity and dissolution. These tests measure dosage consistency and drug release, respectively. The consistency of either attribute was used to calculate a process performance index to describe the variability in manufacturing., Results: All 252 drug product samples met the US market standards for dosage unit uniformity and dissolution, although the process performance index (Ppk) for dissolution fell below the level of 4-sigma capability (ie, <1 error per 1600) for 11 different manufacturers and for generics in 4 of 5 regions, including the US. As part of a retrospective analysis, manufacturers performing above the median Ppk for either dissolution or dosage unit uniformity submitted fewer product quality defect reports (mean field alert reports of 0.22 and 0.63, respectively) than those falling at or below the median Ppk for these attributes (mean field alert reports of 2.1 and 1.7, respectively)., Conclusions and Relevance: All samples met the US market standards for dosage unit uniformity and dissolution, indicating acceptability for use by patients regardless of manufacturer or region. To our knowledge, this is the largest sampling study of pharmaceutical manufacturers for the US market and these data provide objective insight into the quality of prescription drugs with high manufacturing risks.

This work proposed a procedure for microwave-assisted sample preparation of medicines using diluted nitric acid followed by determination of elemental impurities using inductively coupled plasma optical emission spectrometry (ICP OES) and inductively coupled plasma mass spectrometry (ICP-MS) according to the United States Pharmacopeia Chapters 232 and 233. Three solutions, i.e. inverse aqua regia, 7.0 and 2.0 mol L -1 HNO 3 , were evaluated for microwave-assisted digestion of nine drugs samples. The applicability of each digestion procedure was assessed by comparison of analyte concentrations determined using total (reference procedure) and partial digestions (proposed procedure) as well as by determining dissolved carbon content and evaluating matrix effects. There were none significant differences at a 95% confidence level among the concentrations determined applying reference and proposed procedures. Internal standardization (ICP OES) and aerosol dilution (ICP-MS) were applied for minimization and correction of matrix effects. Addition and recovery experiments were performed according to oral permissible daily exposures values specific for each element and each sample was spiked with element concentrations of 0.5J and 1.5J in order to check accuracies for 24 analytes. Recoveries ranged from 70 to 138% for ICP OES and from 72 to 128% for ICP-MS, for all elements but Os. All analytes were below the respective limits of quantification when applying all sample preparation procedures, except As, Ba, Co, Cu, Cr, Mo, Ni, Pb, Sb, Sn, Tl and V, however the determined concentrations for these elements were lower than the limits proposed by Chapter 232., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Ibuprofen tablets on the market in Japan and the USA were compared by manual- and automatic-dissolution tests according to USP24 criteria. Dissolution test were performed in 900 ml of phosphate buffer of pH 7.2 at 37.0+/-0.5 degrees C at 50 rpm for 60 min, and the time required for 70% dissolution (T70%) and 5% dissolution after 60 min (A60) were evaluated. The dissolution profiles of both Japanese and American tablets by the automatic-method showed almost the same profiles as those of the manual method. T70% of the American and Japanese tablets by the manual method were not significantly different (p>0.05) from the automatic-method at various sampling positions. The A60 of the American and Japanese tablets by the manual-method was not significantly different (p>0.05) except at one position. The results indicate that the automatic-method was more reproducible than the manual-method, and also that systematic error was negligible. The T70% and A60 of the American tablets were significantly different (p<0.05) from the Japanese tablets. The American tablets were a film-coated over-the-counter drug and the Japanese tablets were a sugar-coated prescription drug. There was a difference in dissolution behavior between the dosage forms of the two countries.

An investigation of the USP assay of chlorthalidone tablets showed that variable degradation of chlorthalidone occurred during assay preparation. The degradation products were isolated and identified. A stability-indicating high-performance liquid chromatographic (HPLC) assay which separates the degradation products from chlorthalidone was developed and used to examine the present USP preparation. The HPLC assay is suggested as an alternate.

Modified USP procedures are described for the simultaneous determination of nonaspirin salicylates and aspirin in aspirin and buffered aspirin tablets. The existing USP procedures are not stability indicating for intact aspirin when significant levels of nonaspirin salicylates are present, as is often the case in short-term, high temperature stability programs. The modified procedures yeld considerably shorter analysis times and stability-indicating assays for intact aspirin without the need for sophisticated equipment other than that presently required by USP XIX.

Five lots of prednisone tablets that disintegrate within 5 min were collaboratively studied by 11 laboratories using USP Apparatus 2 under carefully controlled conditions. One lot gave complete dissolution. The reproducibility and repeatability of Apparatus 2 for the four lots still dissolving at the end of the test were 2.6 and 1.6% of label claim, respectively, for the 11 laboratories.

A new method for the determination of inorganic salts of chloride and bromide is described. The method is based on the facts that iodine forms complexes with the anions and that these complexes absorb strongly in the UV region. The molar absorptivities of I2Br- at 265 nm and I2Cl- at 245 nm were calculated to be 3.27 X 10(4) and 2.3 X 10(4) M-1 cm-1, respectively.

Ion exchange chromatography is used to separate mephentermine sulfate from drug formulations. The drug is subsequently measured by ultraviolet spectrophotometry. Assays on 4 commercial samples of tablets and injectables gave recoveries from 97.6 to 104% of declared. A collaborative study involving 2 tablet and 2 liquid formulations gave mean recoveries ranging from 94.7 to 99.3% and coefficients of variation from 1.39 to 2.00%.