Impurity profile materials

Figure 4.8. Comparison of impurity profiles for the same chemical intermediate from two different suppliers. The impurity peak-areas for each chromatogram were tallied in 0.02 area-% bins for each vendor, the data was normalized by dividing by the number of chromatograms. Vendor A s material has many more peaks in the 0.05-0.2% range, which drives the total impurity level to =5.2% (vs. 1.9 for Vendor B) for <0.2% the number of excess peaks above 0.2% does not appear as dramatic, but greatly adds to the total impurity level = 13.3 v.v. = 2.3% ...

Crystalline materials are commonly associated with purity, but recent demands lead to almost suprapure materials, and it is common to ask for an impurity profile. Crystallization epitomizes purification at the molecular level and the technology exploits the ability of a crystal surface to reject molecules that it does not recognize (Davey, 1994). This is essentially a supramolecular process. Two types of approaches are possible, viz. the use of eutectic and solid solutions. In the eutectic approach there is efficient rejection, whereas in solid solutions molecular level discrimination is difficult. 

HPLC is extremely useful in monitoring and optimizing industrial processes. Conventional process monitors measure only bulk properties, such as the temperature and pressure of a reactor, while HPLC permits continuous realtime monitoring of consumption of starting materials, product composition, and impurity profile. There are a number of new initiatives relevant to HPLC for process monitoring, including sample preparation, automation, miniaturization, and specialized detectors. 

The well documented synthetic method for 37 is chlorination of cyclopropyl-methylketone followed by base treatment [29]. However, this method did not provide a suitable impurity profile. The most convenient and suitable method we found was the one-step synthesis from 5-chloro-l-pentyne (49) by addition of 2equiv of base, as shown in Scheme 1.18 [21, 30]. Two major impurities, starting material 49 and reduced pentyne, had to be controlled below 0.2% each in the final bulk of 37, to ensure the final purity of Efavirenz . Acetylene 37 was isolated by distillation after standard work-up procedure. 

Similarly, impurity profiles may change when the formnlation is modified or a scale-up of a specific formulation is made. Pharmacentical formnlations are a complex physiochemical system that may resnlt in impnrities due to reactions between API and pharmacentical excipients and/or packaging materials. In some cases, degradants that were generated by multiple-step degradation pathways can still react with the API leading to the formation of degradants that can be difficult to identify. 

Ideally all subsequent batches will be prepared by the route and process used for tox and/or Phase 1 batches, so that on-scale impurities and impurity profiles will meet the guidelines above. Of course it is difficult to predict the final optimized process for a dmg candidate. The best approach to control impurities is to determine the optimal starting materials, reagents, process, and final form (salt, polymorph) early ( freeze the final step... 

This study evaluated the impurity profile of untreated water from a textile plant in Portugal [35]. The organic material was concentrated by extraction from 11 of water into dichloromethane and HPLC-NMR and HPLC-MS experiments were carried out using a reverse-phase separation with an acetonitrile/ D2O gradient elution with H NMR spectroscopic observation at 600 MHz. For the HPLC-NMR studies, the samples were further fractionated into two pools according to their HPLC retention times. The HPLC-NMR studies were carried out in the stop-flow mode and the combination of NMR and MS results yielded the identification or tentative identification of 14 compounds, comprising mainly surfactants, anthraquinone dyes and nonylphenol-related molecules. 

S. Gorog, B. Herenyi, and M. Renyei, Estimation of impurity profiles of drugs and related materials. Part 9 HPLC investigation of flumecinol, J. Pharm. Biomed. Anal., 70 831 (1992). 

It is clear from the conversion yield that the biological process was worthy of further development for potential use in the longer term. Work was especially needed to improve the concentration (8 g/liter at the time) and to deal with the slightly different impurity profile (total 0.3% with 0.1% identified as the R-amine VIII). Also, technologies (e.g. ultrafiltration) needed to be evaluated to ensure that proteinaceous material did not contaminate the product. 

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