Fundamental Research And Application Of The Knowledge Base For Residual Solvents Determination In Pharmaceuticals

Residual solvents in pharmaceuticals are defined as organic volatile chemicals thatare used or produced in the manufacture of drug substances or excipients, or in thepreparation of drug products. The solvents are not completely removed by practicalmanufacturing techniques. Residual solvents that are often used in the manufacturingof pharmaceuticals are divided into four classes in terms of their level of hazard tohumans and the environment and regulated the level of each solvent by theInternational Conference on Harmonization of Technical Requirements forRegistration of Pharmaceuticals for Human Use (ICH). A knowledge base for residualsolvents determination in pharmaceuticals has been established aim directly at theindeterminateness in the determination of residual solvents, from prescreening toaccurate qualitation, which can solve the difficult problem of residual solventdetermination.In this paper, sixty nine solvents were studied according to the guideline by ICH.The knowledge base for prescreening was improved, and a knowledge base foridentification and also a knowledge base for selection of the column were established,respectively.The knowledge for prescreening contained two parts. One was established usingdual columns. The adjusted relative retention time (RRT) was selected as the basis ofidentification in this knowledge base. Two columns with opposite polarities, SPB-1and HP-INNOWAX, were used to study fifty-two solvents using static headspace gaschromatography. The elution order and RRT of the fifty-two solvents under isothermalconditions and programmed temperature conditions were obtained. The other wasestablished using dual pathways with parallel columns system. Non-polar column andpolar column were connected by a 'Y' splitter, and the preliminary qualitative andquantitative results can be obtained only through a single experiment.The knowledge base for identification was established using gaschromatograph-mass spectrometry and gas chromatograph-Fourier transform infraredspectrometry. The standard mass spectra library, the limit of detection mass spectra library, the standard vapor-phase infrared spectra library, and the limit of detectionvapor-phase infrared spectra library of sixty solvents were established and constitutedthe identification knowledge base. The knowledge base can be used to identify theresidual solvents without using reference organic solvents.The retention characteristics of organic solvents on six different stationary phaseswere studied under 40℃, 60℃, 80℃and 100℃, respectively. The solvation parametermodel of the six columns were also established. These constituted the knowledge basefor selection of columns, and it can provide the reference for selecting the columnsand optimizing the methods.The utilization method of the knowledge base was studied. By carrying out a largenumber of sample determinations, it proved that the knowledge base had significantcontribution in the residual solvent determination, such as rapid identification theunknown peak and elimination the interference of co-ehtion. In addition, Cefetametpivoxil hydrochloride was chosen as samples, and the general process of establishinga uniform method for determination of residual solvents in the pharmaceuticals forquality control purpose was approached using the knowledge base.The knowledge base can prescreen and identify the residual solvents in thepharmaceuticals comprehensively and rapidly, and it is a powerful tool for thedetermination of residual solvents:...