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For all applications of organic analysis, which includes areas of critical economic and social importance such as environmental, clinical, pharmaceutical, food safety, primary produce and forensic testing, among many others, pure compounds are ultimately used as the primary calibrators and source of higher-order metrological traceability. Access to organic compounds with correctly assigned purity is an essential element in the delivery of reliable, comparable measurements while the standard uncertainty associated with purity measurements establishes the baseline level of uncertainty achievable for any organic measurement procedure.
In the area of organic analysis, purity is generally described in terms of mass fraction of the main component in the material. This can be determined either by approaches that directly measure the mass fraction or mole fraction of the main component, or by so-called "mass balance" approaches that estimate the mass fraction of all significant individual impurities and, by subtraction, provides a measure for the content of main component. This latter approach is the most robust and widely applicable method for organic purity assignment.
The BIPM is coordinating an ongoing series of comparisons in this area and has established unique laboratory facilities to support these activities, which are essential for realizing traceability and high accuracy chemical measurements. The comparisons run by the BIPM are part of the CCQM's Organic Analysis Working Group (CCQM-OAWG) strategy to enable National Measurement Institutes (NMIs) to demonstrate their measurement capabilities in the area of organic analysis, and their basis for metrological traceability. In recent years the BIPM has piloted:
- CCQM-P20.e - Theophylline purity (a monitored therapeutic drug, low molecular weight, medium polarity)
- CCQM-P20.f - Digoxin purity (a monitored cardiac drug, high molecular weight, high polarity)
- CCQM-K55.a - Estradiol purity (a steroid hormone, high molecular weight, medium polarity)
- CCQM-K55.b - Aldrin (a pesticide, high molecular weight, low polarity)
- CCQM-K55.c - L-Valine (an amino acid, low molecular weight, high polarity, planned for 2012)
- CCQM-K55.d - Chloramphenicol (an antibiotic, high molecular weight, high polarity, planned for 2013)
The compounds selected for analysis in purity comparisons coordinated by the BIPM are shown for the CCQM-P20 pilot studies in Figure 1 and for current and future CCQM-K55 key comparisons in Figure 2. These were chosen to reflect current priorities within NMIs and to be representative of the variety of structural types, physical properties and measurement challenges provided by organic compounds, so that a small number of on-going comparisons can underpin NMI measurement capabilities for a wide range of organic compounds of differing relative molecular weight and polarity.
CCQM-P20.e : Theophylline
CCQM-P20.f : Digoxin
Figure 1: Analytes for CCQM-P20 pilot studies coordinated by the BIPM
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CCQM-K55.a : Estradiol
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CCQM-K55.b : Aldrin
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CCQM-K55.c : L-(+)-Valine
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CCQM-K55.d : Chloramphenicol
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Figure 2: Analytes for CCQM-K55 key comparisons completed (CCQM-K55.a),
in progress (CCQM-K55.b and CCQM-K55.c) or planned (CCQM-K55.d) by the BIPM
Reference values for the main classes of potential impurities (structurally related substances, water, volatile organic compounds or VOCs) are assigned from participants' results. These values are then combined to assign the reference value for the mass fraction of the main component.
For each participant and each class of impurity in each study, plots are prepared to show the extent of agreement, within their stated uncertainties, of a participant's reported result with the reference values. This provides a mechanism for the ongoing demonstration of the robustness of individual NMIs capabilities for purity assignment by the mass balance approach.
As an example, the agreement of BIPM results with the derived reference values by impurity class are shown in Figure 3 for all the comparisons coordinated to date by the BIPM. The results demonstrate excellent overall agreement of our data with the reference values for all classes of organic impurity present in the range of analytes encountered in the course of these comparisons.
Figure 3
The current series of CCQM purity comparisons coordinated by the BIPM extends to purity capabilities for compounds that have a relative molecular mass generally smaller than 500. Extension of the series of comparisons to purity of higher molecular weight compounds is required to underpin NMI capabilities for large molecules. The NIST and BIPM are currently collaborating on a project on Angiotensin I purity, a large molecule peptide involved in blood pressure regulation, in order to develop methods for future large molecule purity comparisons.
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Summary
