Preparative 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 

Time Solubility Stability y-Selectivity Productivity Direction 

Availability of stationary phases Removal of trace metals 

Flash chromatography Continuous chromatography Solubility determination  

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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. 

Terfloth, G. Preparative isolation of impurities. Analysis of Drug Impurities 215-234, 2007. 

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. 

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... 

Aranyi, A. Isolation of impurities by (semi)preparative HPLC. Progress in Pharmaceutical and Biomedical Analysis 240-251, 2000. 

Direct preparation of the gas is potentially hazardous, and explosive decomposition of the impure gas in the condensed state (below -20°C) has occurred. A safe procedure involving isolation of the 1 1 adduct with 9,10-dimethylanthracene is preferred. The impure gas contains nitrogen oxide and it is known that nitrosyl cyanide will react with the latter to form an explosive compound [1], The need to handle this compound of high explosion risk in small quantities, avoiding condensed states, is stressed [2],... 

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