Primary reference substance

The infrared spectrum of phenoxymethyl penicillin (free acid) is number 88 in Hayden s compilation of spectra measured on a Perkin-Elmer Model 21 sodium chloride prism spectrophotometer. Infrared spectra of fourteen penicillins in the 1580 to 1880 cm-1 region are discussed by Ovechkin4. Figure 1 is the spectrum of the Squibb Primary Reference Substance of potassium phenoxymethyl penicillin recorded as a potassium bromide... 

Figure 1. Infrared Spectrum. Potassium Phenoxymethyl Penicillin Squibb Primary Reference Substance 1.5 mg/300 mg KBr...

Structural assignments have been made for each peak in the proton magnetic resonance spectrum of sodium phenoxymethyl penicillin (fourth line of Table 5 in reference 5) by Green and co-workers. Proton resonance lines were measured in D2O solution at 38°,with either t-butyl alcohol or sodium 3-(trimethylsilyl) propane-l-sulfonate (assumed to be 2 cycles per second below Me Si) as the internal standard, with the results referred to tetramethylsilane (Me4Si=10.Ot). Cohen and Puar made structural assignments for the peaks of potassium phenoxymethyl penicillin measured in D2O solution at 33° with the results referred to tetramethylsilane as the external standard (Me Si O. Ot). Figure 2 is the spectrum of the Squibb Primary Reference Substance from which proton assignments were made . Spectra in both laboratories were measured on Varian A-60 spectrophotometers. 

The infrared spectra of penicillin analogues have been discussed. The infrared spectrum of ampicillin trihydrate was measured on a Perkin-Elmer Model 21 double-beam spectro-photometer S. Ttie infrared absorption of penicillin derivatives has been recorded and discussed. Figure 1 and Figure 2 are the spectra of the Squibb Primary Reference Substances of ampicillin trihydrate and anhydrous ampicillin recorded as mineral oil mull and potassium bromide pellets with a Perkin-Elmer Model 21 spectrophotometer. Interpretation of the spectrum of ampicillin trihydrate has been re-ported °and is given in Table 1. 

The NMR spectra of the Squibb Primary Reference Substance are given in Fig. 3 and Fig. 4. The assignments are reported in Table II. 

Ultraviolet spectra of ampicillin trihydrate, Squibb Primary Reference Substance were recorded on a Cary Model 15 spectrophotometer and values calculated. The results... 

A DuPont Thermogravimetric Analyzer, Model 950, indicated total volatile material to be 13.8% in ampicillin trihydrate Squibb Primary Reference Substance. The theory is 13.39%. 

In 1975 the World Health Organization produced a guideline for the establishment, maintenance and distribution of chemical reference substances (WHO 1975). This document was intended to foster collaboration and harmonization of approval for the provision of reference substances by national authorities and organizations responsible for reference substances collections. This guideline was revised in 1982 (WHO 1982) and a further revision was completed more recently (WHO 1999) to take into account progress in pharmaceutical analysis. The latest guidehne defines both primary chemical reference substance and secondary chemical reference substance as follows ... 

A designated primary chemical reference substance is widely acknowledged as having appropriate qualities within a specified context, and whose value is accepted without reliance on comparison to another chemical substance. 

A secondary chemical reference substance is a substance whose characteristics are assigned and/or calibrated by comparison with a primary chemical reference substance. The extent of characterization and testing of a secondary chemical reference substance may be less extensive than for a primary chemical reference substance. This definition may apply to some substances termed Working Standards . 

A pharmacopoeial reference substance is intended for the determination of the main component of a substance or for the active ingredient of a pharmaceutical formulation which is usually present at a high proportion of the total. The reference substance is to be used as a primary standard in a specific method validated as prescribed in the ICH Guideline Validation of Analytical Procedure Methodology" (Technical Guide for the Elaboration of Monographs 1996 ICH Guideline 1997). the reproducibility of which is known. This is taken into account when the limits of acceptance (tolerance) for the substance or product are fixed (Daas and Miller 1997,1998). 

Figure 2.8, is generated, presenting peaks correspondent to functional groups, such as epoxide, primary and secondary amines, and hydroxyl. The values of the absorption bands for these groups can be found in the papers referenced earlier. The basic principle of all these methods is the comparison between the spectrum of reference substances and spectra of the reactants and products of a curing reaction subjected to radiation. A qualitative and quantitative identification of the components is then possible. 

When a calibration hierarchy starts with the definition of an SI unit followed by a primary reference measurement procedure and descends through commutable calibrators and specific and selective measurement procedures full calibration hierarchy above the traceability to an SI unit is automatically ensured. The other four types of hierarchy do not preclude the use of a bona fide SI unit in the expression of a measurement result for a differential or rational quantity, but it is mandatory to specify the top measurement procedure and/or calibrator in the designation for the measurand. For example, amount-of-substance concentration of nitrogen(N) in human plasma by Kjeldahl procedure no. 3 (referring to the laboratory s list of procedures). The result in millimole per litre, however, is not unequivocally comparable with that of another Kjeldahl procedure, because the kinds-of-quanti-ty are differently specified, but the unit is unchanged. 

In such conditions what is needed are RMs containing an accurately known concentration of the analytes as they appear in a well-characterised solid material in its natural status (thus not as a doped substance). At present it is an open question as to what methods are applicable to round robins and certification exercises and what methods ultimately could serve as the primary reference to the SI. None of the so-called primary methods of analysis is appropriate for the purpose. 

In the field of chemical measurements, the question as to which are the national measurement standards is far from being completely answered. There is no doubt, however, that primary reference materials, e.g. high-purity substances which are ultimately necessary as reference points, will play a role as national (or even better international) measurement standards. But these alone will not be sufficient. As the task of chemical analysis is usually the determination of chemical composition, national reference points closer to this task, namely standard reference mixtures, are also required, and if the preparation of these is not feasible, e.g. due to instability problems, devices and procedures furnishing well-known compositions with small uncertainties must also be included as national measurement standards. All these kinds of national references or standards are currently in use or under development. 

The Slovak Institute of Metrology (SMU) has recently rebuilt its high-precision coulometric equipment to be used as a national standard for amount of substance measurements. Its main purpose is certification of primary reference materials of composition with directly determined main component. These primary reference materials can be subsequently used for disseminating traceability into different chemical measurements. 

Keywords Amount of substance standards Chemical composition standards Traceability Third party assessment Primary reference materials... 

In this scheme, the primary reference material is defined as a chemical substance of the highest (and known) purity, or a well-characterized substance in a matrix, This classification of materials is, however, fairly arbitrary. It is ideal when used in connection with standards characterized in terms of biological activity. Primary standards are thus the International Reference Preparations (IRP) produced by the World Health Organization (WHO). In this case the primary standard for a particular antibiotic is the WHO reference preparation which constitutes the unit of that antibiotic. When people wish to use it they have to prepare a large batch of samples calibrated to the primary. This is then called a secondary standard. However, for well-defined chemical parameters, the term certified reference material is preferred. 

Primary Reference method (confirmatory test 648/2000/EC) EN ISO 11733 Indicator or specific instrumental analysis of surfactant active substances 80% or greater... 

Reference Standard. Characterization and structure elucidation data are typically derived from tests conducted on the primary reference standard. Its suitability must be documented by information much more extensive than prescribed in the specifications. In addition to the prescribed analyses—especially levels of impurities—other tests normally conducted include elemental analysis and ultraviolet, infrared, nuclear magnetic resonance, and mass spectrometry, along with reviews of each providing assignments of the important features supporting the structure(s) of the drug substance. Other tests such as... 

The primary reference material for Hg NMR spectroscopy is dimethylmercury(II). However, a lethal accident caused by the cutaneous absorption of a few drops of this substance in 1996 cautions against its routine experimental... 

Table 1.3. Standard reference substances for the quadrupolar and integer-spin nuclei, with compounds commonly used as secondary references and their shift relative to the primary reference.

Nucleus Reference substance Secondary reference compound Shift from the primary compound (ppm)... 

It is important that pharmacists are aware of the contents of the relevant part of the Drug Tariffs. Each Drug Tariff is updated on a monthly basis and so is the primary reference source for information on borderline substances. However, the British National Formulary does also indicate whether an item would need to be endorsed ACBS before being supplied by listing the various product in Appendix 7. 

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. 

Reference standard, primary A substance that has been shown by an extensive set of analytical tests to be authentic material that should be of high purity. This standard can be (1) obtained from an officially recognized source, (2) prepared by independent synthesis, (3) obtained from existing production material of high purity, or (4) prepared by further purification of existing production material. 

Reference standard, secondary A substance of established quality and purity, as shown by comparison with a primary reference standard, used as a reference standard for routine laboratory analysis. 

Primary Reference Material PRM a reference material certified with (a) primary method(s). In practice such materials are mainly pure substances, manufactured materials, rarely matrix materials as already explained above. PRMs of matrix materials are very limited in number. NIST has available some CRMs certified with thermal ionisation-isotope dilution mass spectrometry (TMDMS) which has been classified by the Comite Consultatif sur la Quantite de Matiere (CCQM) of BIPM as primary method. PRMs also exist for gas analysis. The Netherlands Meet Instituut (NMI) in Delft, The Netherlands has available several primary gas RMs prepared by gravimetry... 

All common gases exist in very pure forms and can serve as calibration substances in routine measurement. It is, together with metal analysis, the best provided field in terms of primary reference materials. One important producer is NMI, who has developed several procedures to produce gases traceable to the mole of substance. NIST has also a large offer in pure gases. All commercially important industrial gases are nowadays available. Toxic gaseous substances are not yet all available. 

Moreover, it should be emphasized that the classic solvosystem concept considers the auto-ionization process to be primary, whereas substances dissolved are referred to as acids and bases by the formation of their adducts with cations and anions of the solvent. 

Authors) Year No of patients Inclusion diagnoses [Classification] Test preparation/daily dose Reference substance/daiiy dose Duration of treatment Analysis/ Results (bold print primary outcome variable if specified)... 

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