Profiling impurities for the active pharmaceutical ingredients (APIs) is an indispensable step in drug development process. Nowadays, high resolution mass spectrometry is the first choice for determining the chemical formula of organic impurities. However, merely base on the accurate mass to screen the formula is obviously not a flawless method. In this paper, a reliable strategy based on Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS) was presented to profile the related impurities. Firstly, Cefteram pivoxil was subjected to forced degration under hydrolytic (acidic and basic), oxidative, photolytic and thermal conditions according to ICH guidelines. Then, a highly specific and efficient HPLC-FT-ICR MS compatible method was developed and it was used to separate and characterize the process related substances and the major degradation products in Cefteram pivoxil. Next, isotopic fine structures (IFSs) of all impurities were acquired to decisively determine their elemental composition. Finally, the possible chemical structures of impurities were predicted by combining the information of accurate mass, retention time, IFSs and characteristic fragmentation ions. As a result, a total of 20 related substances including 6 process related substances and 14 degradation products were identified and characterized. To the best of our knowledge, 13 of these related substances were not reported in the previous literature. It indicates that the developed strategy is accurate and standard independent to determine the chemical formulae of organic impurities in APIs. In conclusion, the impurity profiles obtained in this study are critical to the quality control and stability study of Cefteram pivoxil. Moreover, the developed method can be used as a versatile workflow to profile the impurities in APIs in the future, especially for the unknown impurities.
2018-01-01·Therapeutics and clinical risk management4区 · 医学
Drug-induced tubulointerstitial nephritis in a retrospective study using spontaneous reporting system database.
Tubulointerstitial nephritis (TIN) is a problem in clinical settings because drug therapy is the cause in most cases. Patients often present with nonspecific symptoms, which can lead to delays in the diagnosis and treatment of the disease. The purpose of this study was to clarify the rank-order of the association of TIN with the causative drugs using a spontaneous reporting system database.
Materials and methods:
Data were extracted from the Japanese Adverse Drug Event Report database of the Pharmaceuticals and Medical Devices Agency (Japan). Based on 5,195,890 reports of all adverse reactions, we obtained 3,088 reports of TIN caused by all drugs and calculated the reporting odds ratio (ROR) and 95% CI for TIN.
The 5 drugs with the highest RORs were gliclazide (ROR, 30.5; 95% CI, 17.4-53.2), tosufloxacin tosilate hydrate (ROR, 29.5; 95% CI, 21.3-41.0), piperacillin-tazobactam (ROR, 24.3; 95% CI, 19.4-30.5), cefteram pivoxil (ROR, 23.5; 95% CI, 12.5-44.2), and mefenamic acid (ROR, 22.5; 95% CI, 13.4-37.7). No sex-related difference was observed in drug-induced TIN. Most of the reports about TIN onset following the administration of culprit drugs were recorded within 12 weeks.
Based on the results, a comprehensive study using a pharmacovigilance database enabled us to identify the dugs that most frequently induced TIN, so these drugs should be used carefully in clinical practice to avoid TIN.
A new type of fluidized-bed granulator equipped with a particle-sizing mechanism was used for the preparation of fine particles that improved the solubility of a poorly water-soluble drug substance. Cefteram pivoxyl (CEF) was selected as a model drug substance, and its solution with a hydrophilic polymer, hydroxypropyl cellulose (HPC-L), was sprayed on granulation grade lactose monohydrate (Lac). Three types of treated particles were prepared under different conditions focused on the spraying air pressure and the amount of HPC-L. When the amount of HPC-L was changed, the size of the obtained particles was similar. However, particle size distribution was dependent on the amount of HPC-L. Its distribution became more homogenous with greater amounts of HPC-L, but the particle size distribution obtained by decreasing the spraying air pressure was not acceptable. By processing CEF with HPC-L using a complex fluidized-bed granulator equipped with a particle-sizing mechanism, the dissolution ratio was elevated by approximately 40% compared to that of unprocessed CEF. Moreover, in the dissolution profile of treated CEF, the initial burst was suppressed, and nearly zero order release was observed up to approximately 60% in the dissolution profile. This technique may represent a method with which to design fine particles of approximately 100 µm in size with a narrow distribution, which can improve the solubility of a drug substance with low solubility.