Research on storage stability differences between ceftriaxone sodium products.

The conditions and mechanisms leading to stability differences between ceftriaxone sodium products were examined to ensure drug quality and efficacy. We used a combination of powder X-ray diffraction and thermogravimetric analysis to examine the differences between preparations for injection from different pharmaceutical processes to elucidate the changed processes by exposing samples to different humidity and high-temperature conditions. Water loss or absorption due to varying environmental humidity levels did not adversely affect the crystal structure, but could lead to the reversible redistribution of hepta-hydrate in the unit cell of generic products, causing its stability change. The irreversible distribution of hydrate may occur when generic drugs stored at 25 °C, whereas the brand-name products remained stable at 40 °C. Therefore, generic ceftriaxone sodium and its powder preparations would be acceptable by better controlled sealing and storing under cool conditions during storage period to meet the efficacy and stability.

Quality control and consistency evaluation of ceftriaxone sodium for injection.

Ceftriaxone sodium for injection is an antibiotic used clinically. Here, we developed a strategy for evaluating the consistency of ceftriaxone sodium for injection. Comparison of the quality of the generic and original raw materials, and analysis of the production process revealed that the quality of the ceftriaxone sodium raw material is the most important factor affecting the quality of preparation, while the ceftriaxone sodium crystallization process is the key factor affecting the quality of raw materials. The solution clarity of the formulation, another key aspect, was addressed by controlling the leachable components found in the rubber closures used in the packaging. The time to achieve therapeutic efficacy of the preparation could be preliminarily evaluated by evaluating the rate of salt formation and the protein binding rate. Finally, the results of the tests (including water, pH, impurity profile and solution clarity) and assay were compared with the original preparation. On this basis, the critical quality attributes (CQAs) that reflect the quality of the product could be determined and a strategy for evaluating ceftriaxone sodium for injection was developed.

Spectral Data Analysis and Identification of Vancomycin Hydrochloride.

Objective: To establish a method for the determination of the chemical structure of vancomycin hydrochloride. Methods: Nuclear magnetic resonance spectroscopy and mass spectrometry were conducted to analyze the chemical structure of vancomycin hydrochloride. Results: In this study, the target compound (1) was identified as (Sα)-(3S, 6R, 7R, 22R, 23S, 26S, 36R, 38αR)-44-[[2-O-(3-amino-2, 3, 6-trideoxy-3-C-methyl-α-L-lyso-hexopyranosyl)-ß-D-glucopyranosyl] oxy]-3-(carbamoylmethyl)-10, 19-dichloro-7, 22, 28, 30, 32-pentahydroxy-6-[[(2R)-4-methyl-2-(methylamino) pentanoyl] amino]-2, 5, 24, 38, 39-pentaoxo-2, 3, 4, 5, 6, 7, 23, 24, 25, 26, 36, 37, 38, 38α-tetradecahydro-22H-8, 11: 18, 21-dietheno-23, 36-(iminomethano)-13, 16: 31, 35-dimetheno-1H, 13H-[1, 6, 9] oxadiazacyclohexadecino [4, 5-m] [10, 2, 16]-benzoxadiazacyclotetracosine-26-carboxylic acid hydrochloride. Conclusion: The method used in this study is accurate and can be used for the production and structural elucidation of vancomycin hydrochloride.

Study on Isomeric Impurities in Cefotiam Hydrochloride.

In this study, two isomeric impurities were identified in cefotiam hydrochloride injection preparation and were characterized. Column-switching HPLC-MS and NMR techniques were used to identify the impurity 1 as the Δ3(4) isomers of cefotiam. Using software-based calculations, it was predicted that neither of the isomeric impurities was embryotoxic. This study provides a reference for the production, storage, and quality control of cefotiam and related cephalosporin antibiotics.

Research on the relationship between cephalosporin structure, solution clarity, and rubber closure compatibility using volatile components profile of butyl rubber closures.

OBJECTIVE: Establish an effective experimental strategy to determine the compatibility of rubber closures for drugs. SIGNIFICANCE: Various types of rubber closures with different compositions are available for drug packaging. Many additives of rubber closures can be released from rubber closures and may affect the quality of drugs and pose a risk to human health. In this study, we aimed to determine the relationship between cephalosporin structure, solution clarity, and rubber closure compatibility using volatile components profile of butyl rubber closures. METHODS: Two opposite polarity gas chromatography (GC) systems and GC-mass spectrometry (MS) were used to achieve rapid qualitative determination of the main volatile components in rubber closures. Simulated adsorption experiment was performed to investigate the adsorption of main volatile components in rubber closures by cephalosporins with different side chain structures, and to determine the effects of adsorption on solution clarity. RESULTS: A volatile components screening library of rubber closures was established and the structures of some volatile component were confirmed. The specific adsorption of the structure of cephalosporins on volatile components from rubber closures was studied. CONCLUSION: Based on the results of this study, rubber closures with good compatibility for cephalosporins with different side chain structures can be selected rapidly. This experimental strategy not only facilitates the screening of suitable rubber closures more effectively, but also enables the quick determination of volatile components adsorbed by drugs.

Compilation of a Near-Infrared Library for Construction of Quantitative Models of Oral Dosage Forms for Amoxicillin and Potassium Clavulanate.

The accuracy of quantitative models for near-infrared (NIR) spectroscopy is dependent upon calibration samples with concentration variations. Conventional sample-collection methods have shortcomings (especially time-consumption), which creates a "bottleneck" in the application of NIR models for Process Analytical Technology (PAT) control. We undertook a study to solve the problem of sample collection for construction of NIR quantitative models. Amoxicillin and potassium clavulanate oral dosage forms (ODFs) were used as examples. The aim of this study was to find an approach to construct NIR quantitative models rapidly using a NIR spectral library based on the idea of a universal model. The NIR spectral library of amoxicillin and potassium clavulanate ODFs was defined and comprised the spectra of 377 batches of samples produced by 26 domestic pharmaceutical companies, including tablets, dispersible tablets, chewable tablets, oral suspensions, and granules. The correlation coefficient (rT) was used to indicate the similarities of the spectra. The calibration sets of samples were selected from a spectral library according to the median rT of the samples to be analyzed. The rT of the samples selected was close to the median rT. The difference in rT of these samples was 1.0-1.5%. We concluded that sample selection was not a problem when constructing NIR quantitative models using a spectral library compared with conventional methods of determining universal models. Sample spectra with a suitable concentration range in NIR models were collected rapidly. In addition, the models constructed through this method were targeted readily.

Rapid Analysis of the Quality of Amoxicillin and Clavulanate Potassium Tablets Using Diffuse Reflectance Near-Infrared Spectroscopy.

The cycle-closed dimer of amoxicillin influences its critical quality and is an important impurity in amoxicillin and clavulanate potassium tablets. The quality of the tablets could be rapidly evaluated using the impurity as an indicator. Here, we report a quantitative model to determine the cycle-closed dimer in samples from different manufacturers using diffuse reflectance near-infrared (NIR) spectroscopy by partial least squares regression for one y variable (PLS1) and hierarchical cluster analysis. Because the contents of the (active pharmaceutical ingredients) APIs (amoxicillin and clavulanate potassium) and water are also the important indexes of the tablet quality, three other quantitative models were used to confirm the API data and water content. All of the four models facilitate rapid and complete control of the tablet quality. In addition, quantitative models were validated in terms of specificity, linearity, accuracy, repeatability, and intermediate precision according to the International Conference on Harmonisation guidelines by evaluating the characteristics of the NIR spectra. These results confirmed that the models were satisfactory.

[The control of the critical quality attributes of amoxicillin and clavulanate potassium tablet].

The critical attribute was analyzed in clavulanate potassium tablet of amoxicillin according to the principle QbD. By investigation of the drug impurity profile, the cycle-closed dimer and penicilloic acid of amoxicillin were considered to be the critical impurities, and the sources and the degradation pathways of these two impurities were discussed. The research confirmed that crystal form was the critical attribute of drug substance. The drying process in the tablet granulation was regarded as the critical process parameter. The tablet formulation was also another factor in the impurity generation. This study provides a new idea for the evaluation of drug quality.

Influence of substituent groups at the 3-position on the mass spectral fragmentation pathways of cephalosporins.

The structural fragment ions of nine cephalosporins were studied by electrospray ionization quadrapole trap mass spectrometry (Q-Trap MS(n)) in positive mode. The influence of substituent groups in the 3-position on fragmentation pathway B, an alpha-cleavage between the C7-C8 single bond, coupled with a [2,4]-trans-Diels-Alder cleavage simultaneously within the six-membered heterocyclic ring, was also investigated. It was found that when the substituent groups were methyl, chloride, vinyl, or propenyl, fragmentations belonging to pathway B were detected; however, when the substituents were heteroatoms such as O, N, or S, pathway B fragmentation was not detected. This suggested that the [M-R(3)](+) ion, which was produced by the bond cleavage within the substituent group at the 3-position, had a key influence on fragmentation pathway B. This could be attributed to the strong electronegativity of the heteroatoms (O, N, S) that favors the production of the [M-R(3)](+) ion. Moreover, having the positive charge of the [M-R(3)](+) ion localized on the nitrogen atom in the 1-position changed the electron density distribution of the heterocyclic structure, which prohibits a [2,4]-reverse-Diels-Alder fragmentation and as a result fragmentation pathway B could not occur. The influence of the substituent group in the 3-position was determined by the intensity ratio (e/d) of ions produced by fragmentation pathway A, a [2,2]-trans-Diels-Alder cleavage within the quaternary lactam ring, including the breaking of the amide bond and the C6-C7 single bond (ion d), and fragmentation pathway B (ion e). The results indicate that the electronegativity of the substituent group was a key influencing factor of pathway B fragmentation intensity, because the intensity ratio (e/d) is higher for a chlorine atom, a vinyl, or a propenyl group than that of a methyl group. This study provided some theoretical basis for the identification of cephalosporin antibiotics and structural analysis of related substances in drugs.