Isolation of impurities

The approach taken is loosely based on the input-process-output meta-model utilized to transform a problem statement into a functional process. The section Scope definition discusses the intended purpose and potential constraints of the isolation effort, followed by an overview of the Toolbox available to the practitioner (input). The section Method development scouting and scale-up reviews platform-based, highly automated approaches to selectivity scouting, development of the isolation as well as options for scaling up the chromatographic separation depending on purpose and constraints (process). The final section. Performing the task, explores a work breakdown structure approach to the preparative isolation of impurities as a unit operation in the development process (output). 

The preparative isolation of impurities may become necessary when an unambiguous identification cannot be achieved using hyphenated chromatographic-spectroscopic techniques, as discussed in Chapter 6 and in an excellent review [1]. The purpose of the isolation is to provide material... 

This section provides a cursory overview of the equipment and systems commonly used for the isolation of impurities by chromatographic techniques (see Table 7.1). 

The approach described reflects an industrial view of the preparative isolation of impurities based on a meta-model developed with the aim of implementing a functional process while maximizing success under a given set of constraints and mitigating risk. This chapter is a snapshot of its current state of evolution. 

A second tier of tests should be designed for compounds already detected as sensitive. The goals of the second tier are the isolation of impurities and the investigation of the degradation mechanism. It is not possible to propose general protocols, as in this case the chemistry of the substance must be fully considered. In this phase we can study, by comparison with... 

A 0.1% threshold for identification and isolation of impurities from all new molecular entities is under consideration by the International Conference on Harmonization as an international regulatory standard [4,5]. However, where there is evidence to suggest the presence or formation of toxic impurities, identification should be attempted. An example of this is the 1500 reports of Eosinophilia-Mylagia Syndrome and more than 30 deaths associated with one impurity present in L-tryptophan which were present at the 0.0089% level [6]. 

The first approach attempts the isolation of impurities at a suitable step in the purification process during a manufacturing run. This isolation is followed by a further separation of the product from the impurities, which is normally achieved by immunoabsorption. 

Gravity sedimentation techniques are used commonly in effluent treatment processes for separation of activated sludge from aqueous solutions, in fuel ethanol production for recovery of yeast cells from aqueous ethanol solutions for recycle to the fermenter, and in the pharmaceutical industry for separation of solvent and aqueous phases in product recovery and isolation of impurities. 

Today, preparative HPLC has also become a powerful technology in pharmaceutical development and production either for isolation of impurities, for... 

Chapter 10 details the use of column chromatography for the isolation of impurities. It also discusses the various options that are available for stationary phases and analytical detectors, as well as the current equipment available for this work. The choice of purification techniques (prep HPLC, low-pressure silica columns, etc.) is also discussed. Finally, a procedure is described for both analytical methods development as well as scale-up to preparative columns. 

Solid-phase extraction devices and applications are evolving rapidly, and novel techniques that stretch the classical definition of SPE are becoming routine. Pawliszyn introduced solid-phase micro extraction (SPME) in 1989,5,14 and a commercial apparatus is available from Supelco (Bellefonte, PA). The SPME apparatus is merely a modified syringe that houses a fused silica optical fiber coated with an immobilized polymer film. The fiber can be exposed for extraction and then retracted for insertion or removal from the sample vial or instrument. Both manual and autosampler devices are available and each can be adjusted for proper fiber depth. Several coatings are available with varying thickness including polydimethylsiloxane, polyacrylate, polydimethylsiloxane/divinylbenzene, and carbowax/divinylben-zene. In contrast to SPE, which is an exhaustive extraction approach, SPME will extract only a fraction of an available analyte, hence it is not suitable for the isolation of impurities and degradants in most applications.15... 

Some new specialised detectors are mass spectrometry detectors (MS), evaporating light scattering detectors (ELSC) and atom specific detectors. They all have in common that the mobile phase stream has to be split to secure a safe operation of the fragile detection system. As pointed out earlier, the eluent stream can be split by active and passive principles. For certain applications, mainly in the isolation of impurities with unknown structures in the mg range, the combination of these detectors to preparative equipment is of high value. As soon as the diameter of the... 

G. Pharma D3 Degradation Database ISOLATION OF IMPURITIES/DEGRADANTS... 

SFC does have additional capital investment costs as well as chromatographic limitations. A semipreparative SFC system suitable for isolation of impurities will have a capital cost approximately twice that of a comparable semipreparative HPLC system. In addition, there are sample considerations when evaluating SFC as an isolation tool. The sample injected must be dissolved in a diluent that is miscible with CO2 and typically is the modifier. Care must also be taken when components of a sample have a reactive functionality (e.g., carboxylic acid) when alcohol modifiers are used. Ester formation of sample injected or impurity collected can complicate matters. 

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