International Chemical Reference Substances

The report of the WHO Collaborating Centre for Chemical Reference Substances for 2004 was presented to the Committee. The Committee noted that a number of International Chemical Reference Substances (ICRS) were distributed in 2004. The most frequently requested material was the new reference standard for artesunate (Annex 1). 

The Committee recommended that the report be adopted. It also recommended that all efforts be made to maintain this important programme and endorsed the efforts made by the Secretariat to ensure financial support for the activities of the WHO Collaborating Centre for Chemical Reference Substances. It recognized that there was a need to further promote the availability and use of ICRS. 

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The current approach of using assay methods that did not require quantitative International Chemical Reference Substances (ICRS) should be continued with respect to APIs. 

List of available International Chemical Reference Substances (ICRS) (Annex 1). 

International Chemical Reference Substances (ICRS) are established upon the advice of the WHO Expert Committee on Specifications for Pharmaceutical Preparations. They are supplied primarily for use in physical and chemical tests and assays described in the specifications for quahty control of medicines published in The International Pharmacopoeia or proposed in draft monographs. The International Chemical Reference Substances are mainly intended to be used as primary standards to calibrate secondary standards. 

International Chemical Reference Substances may also be used in tests and assays not described in The International Pharmacopoeia. However, the responsibility for assessing the suitability of the substances then rests with the user or with the pharmacopoeia commission or other authority that has prescribed this use. 

Orders for the International Chemical Reference Substances should be sent to ... 

The procedure employed for the establishment of the chemical reference substances used in these assays has been previously published (Sandrin et al. 1997). The CRSs for the microbiological assays of antibiotics are first submitted to the chemical tests of the monograph. If the results are satisfactory, a collaborative microbiological assay is carried out, using the International Standard as calibrator. Thus, these reference substances are considered to be secondary reference substances since they are calibrated against existing standards. Potency is expressed in International Units. If an International Standard does not exist, European Pharmacopoeia Units are used. 

IPCRSs International Pharmacopoeia Chemical Reference Substances... 

Authentic IR reference spectra covering the range 2000-500 cm are published in conjunction with monographs for substances of the British Pharmacopoeia (BPC, London). They are also supplied by the European Pharmacopoeia EDQM, Strasbourg) for a more limited number of official substances, where the cost, or toxicity, of a suitable chemical Reference Substance, or restrictions on its supply by post, favour identification by comparison with an official Reference Spectrum. The International Pharmacopoeia (WHO Collaborating Centre for International CRS, Stockholm) will supply on request paper or electronic copies of an authentic Reference Spectrum covering the full mid-IR range, i.e. 4000-600 cm . ... 

The WHO Collaborating Centre for Chemical Reference Substances is able to supply 69 International Infrared Reference Spectra. 

Chemical shift references for calibration of the spectrum scale may be internal or external. An internal chemical shift reference substance is dissolved... 

The external reference method is common in 31P NMR. The reference substance, 85 % H3P04 (phosphoric acid), is transferred from a cylindrical or spherical capillary tube to an NMR sample tube containing the same solvent as the test sample. Owing to its chemical reactivity, H3P04 cannot be added as an internal reference substance. Although not an exact method (21), the resonance of H3P04 is set at 0.00 ppm when the coaxial capillary tube system is used. 

If an internal chemical shift reference is to be used, a dilute solution of reference substance (e.g. TSPA-d4) is prepared in the same solvent as used for the test sample (e.g. D20). A few microliters (or a suitable amount) of this reference solution are added to the evaporated sample solution before filtration into the NMR tube. 

Two types of reference are used in NMR—Internal and external. An internal reference is a compound giving a sharp NMR line that is dissolved directly in the sample solution under study. The reference substance is then dispersed uniformly at a molecular level through the sample. The magnetic field acts equally on the sample and reference molecules, so that Eq. 4.6 and the other relations derived before are completely valid. Provided the reference compound does not react chemically with the sample, the only serious drawback of an internal reference is the possibility that intermolecular interactions might influence the resonance frequency of the reference. Usually, by careful choice of relatively inert... 

By 2006, only 72 existing substances had completed the risk assessment process under Regulation 793/93 compared with about 4,300 that have been notified with test data as new substances [47]. This does not imply that these substances are not regulated or that no data are available. Companies are required to classify all chemicals on the market based on available data [169]. This includes reviewing references available in academic articles and epidemiological studies. To assist companies in this task, an international chemical database was set up by the OECD that is frequently updated by regulators and companies across the world [166]. 

If a retrospective literature search is to be carried out back to the beginning of Chemical Abstracts, the searcher must be somewhat familiar with the nomenclature rules and substance names used at that time, as there was no Index Guide and no internal cross-references before 1946. Up to the fourth collective period (1946) the substitution positions were designated by letters ortho-, para-, meta-Y>os ons) (Fig. 60) rather than numbers. In addition, the abstract numbers were written in a different form at that time, e.g. the reference to Vol. 40 2189 in the fourth collective index. 

References D. D. Wagman, et ah, The NBS Tables of Chemical Thermodynamic Properties, in J. Phys. Chem. Ref. Data, 11 2,1982 M. W. Chase, et ah, JANAF Thermochemical Tables, 3rd ed., American Chemical Society and the American Institute of Physics, 1986 (supplements to JANAF appear in J. Phys. Chem. Ref. Data) Thermodynamic Research Center, TRC Thermodynamic Tables, Texas A M University, College Station, Texas I. Barin and O. Knacke, Thermochemical Properties of Inorganic Substances, Springer-Verlag, Berlin, 1973 J. B. Pedley, R. D. Naylor, and S. P. Kirby, Thermochemical Data of Organic Compounds, 2nd ed.. Chapman and Hall, London, 1986 V. Majer and V. Svoboda, Enthalpies of Vaporization of Organic Compounds, International Union of Pure and Applied Chemistry, Chemical Data Series No. 32, Blackwell, Oxford, 1985. 

Beilstein File. Beilstein first went on-line on STN International in December 1988 with information on 350,000 compounds, and several months later it was also on Dialog. Beilstein Online now comprises data on five million compounds. The organic substance records contain the critically reviewed and evaluated documents from the beilstein Handbook of Organic Chemist main volume and supplements 1—5, which cover the chemical Hterature from 1779 through 1979. These evaluated data are indicated as Handbook Data in the notes of Hterature references. The Beilstein Eile also contains organic substance records for unreviewed excerpts from the primary Hterature from 1980 to 1991. 

The quality of a drug substance is controlled by its specification. An internationally harmonized guideline on specifications and tests for chemical substances as active ingredients and in drug products makes reference to chiral compounds. This has recently been finalized and is discussed in Section 13.5.2. 

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