Chemistry Reference
In-Depth Information
Instruments are first calibrated using standard metal solutions and need
regular cleaning, delaying the analysis for hours. Upon completion of these
preparatory steps, samples are injected one at a time, with extensive washing
with acids between samples to minimize memory effects. Although ICP-MS,
ICP-OES and AAS are well established, it should be noted that the accuracy
continues to be improved.
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With these analytical techniques, the whole operation at a pharmaceutical
company may be as follows: a synthetic chemist carries out a palladium-
catalyzed reaction, adds an aqueous solution containing metal scavengers,
extracts the product by adding an organic solvent and removes the aqueous
layer, evaporates the organic solvent, purifies the resulting crude material by
recrystallization or column chromatography, isolates the product and veri-
fies the chemical structure. After isolation or during the extraction step, the
synthetic chemist employs as many methods as are available to remove
palladium. This synthetic chemist fills many vials with these samples and
submits them to an analytical laboratory. Some companies have the facility
for trace metal analysis on-site, whereas other, less well equipped companies
may ship the samples to an external analytical laboratory. In both cases, the
synthetic process is on hold until the data for metal analysis become
available. If the analysis shows sucient sample purity, the drug production
will resume. If the analysis reveals the palladium content to be too high, a
second round of metal scavenging and analysis must be carried out, further
delaying the synthetic process. In order to supply APIs in a timely manner to
clinics, the metal removal and analytical processes must be expedited.
16.2 Expediting Palladium Analysis by New Detection
Methods
One approach for expediting the purification process during drug pro-
duction is to change the paradigm of metal analysis. If a synthetic chemist
can quantify trace metals without extensive training, delays in pharma-
ceutical production will be minimal. This should sound familiar to synthetic
organic chemists, as we all appreciate the accessibility of NMR, IR and LC-
MS instruments to gain insights quickly into the reaction events without any
direct help from others (of course, instruments must be maintained by ex-
perts). HPLC techniques allow synthetic organic chemists to measure purity
and enantiomeric excess values routinely within the same facility.
Colorimetric methods have had an impact on the practice of synthetic
organic chemistry. For example, the presence of primary and secondary
amines and formyl groups can readily be confirmed by a ninhydrin test and
Fehling's test, respectively. Likewise, it will be beneficial if synthetic chem-
ists can measure trace palladium in their laboratories so that the pharma-
ceutical production can proceed without cumbersome analytical techniques.
Many groups have developed fluorimetric and colorimetric methods to try to
accomplish such a change.
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