Purity monographs

One of the newer and more fmitful developments in this area is asymmetric hydroboration giving chiral organoboranes, which can be transformed into chiral carbon compounds of high optical purity. Other new directions focus on catalytic hydroboration, asymmetric aHylboration, cross-coupling reactions, and appHcations in biomedical research. This article gives an account of the most important aspects of the hydroboration reaction and transformations of its products. For more detail, monographs and reviews are available (1—13). 

The guideline on chiral active substances states that particular attention should be paid to identity and stereochemical purity. It states that specifications for a racemate should include a test to show that the substance is indeed a racemate and this is a position supported by the requirements of the European Pharmacopoeia for drug substance monographs [16]. 

Pharmacopoeia publications provide a final important source of information for the pharmaceutical industry, regulatory authorities, and the healthcare professions. These are concerned with establishing quality standards. These publications include monographs that define specifications for the purity and identity of established pharmaceutical ingredients, both active and non-active, together with recognised analytical methods that may be used to evaluate them. The most relevant are the United States Pharmacopoeia (USP) and the European Pharmacopoeia (Ph.Eur). 

In medicine the need for standards was just as acute. Beal (r95i) mentioned that the U.S. Pharmacopoeia VI, issued in 1880, took a big step forward by adding tests for purity and quality of the materials described in it, but the use of reference materials as an integral part of the pharmaceutical monographs for drugs did not start until the 1950 s. Another example of activities at the end of the 19th Century was associated with the introduction, by Ehrlich, of the first diphtheria antitoxin and his... 

Except in rare cases, the quality of the CRS to be established must comply with the requirements of the monograph. The purity of the candidate reference substances... 

Substances (impurities) which are not the subject of a monograph are usually synthesized or supplied by the manufacturer. In this case a purity in excess of 90.0 % is required provided that the reference substance is employed in a limit test. If the reference substance (impurity) is employed in a quantitative test then the purity requirement is normally better than 99.0 %. When it is less, then an assigned content must be established. 

For the mixtures described under (3) it is sufficient to determine the chromatographic profile of the CRS and to demonstrate that all impurities are well separated according to the monograph description. When the spiked sample is also used in the purity control, then the content of the impurity in the CRS material must be determined by appropriate chromatographic methods and a value assigned to the material. 

Purity criteria are published by JECFA as well as by national authorities. The JECFA specifications33 may be endorsed by the Codex Alimentarius as advisory specifications which means that they are equivalent to a Codex Alimentarius standard. In the EU a directive laying down special criteria of purity for sweeteners for use in foodstuffs with subsequent amendments sets the purity standards,31 while in the USA criteria may be listed in conjunction with the approval. Normally a monograph of the Food Chemicals Codex34 is considered the applicable basis for assessment of purity. 

While the above EU Directive lists the criteria only, the JECFA specifications refer to analytical methods in a Guide to Specifications35 or describe the analytical method in the specification monograph itself. Similarly, the Food Chemicals Codex lists and describes the necessary analytical methods for purity control. 

Yugoslavia. An excellent monograph by Morrison and Mosher (38) provides a comprehensive review of the pre-1969 literature on this subject. The formation of sulfoxides in the asymmetric reaction shown above typically occurred with quite low optical purities (not higher than 10%). The detailed and extensive studies of Montanari and... 

Various international pharmacopoeias help assure the quality of drugs worldwide. These pharmacopoeias constantly review and revise their monographs. A different impurity profile can be anticipated if a drug s production process is changed this results in the development of new analytical methods that need to be incorporated in the pharmacopoeias. In earlier editions, color reactions were performed for identification and purity evaluation purposes. 

At present a number of specific pharmacopoeial monographs exist in which CE is prescribed as analytical procedure for identification or (chiral) purity determination. 

In many cases, biotechnology-derived products may have many components that have biological activity. The aim should be to devise controls that monitor the various components so as to retain a consistent potency and purity. For example, the USP monograph for erythromycin [9] indicates that the principal component is erythromycin A and that the percentage of erythromycin A, erythromycin B, and erythromycin C is not less than 85.0% and not more than 100.5%. Within these parameters, the relative ratios of erythromycins A, B, and C may change. This is not always the case for biotechnology-derived products, however. For example, the USP monograph for amoxicillin [10] allows for only one active component. 

Although the majority of current pharmacopoeial methods describe the use of specific optical rotation ([a]) for the determination of stereoisomer identity and/or content, separation techniques such as HPLC and CE are now the most frequently applied technologies during drug development and for new pharmaceutical products entering the market. Indeed, Supplementary Chapter K in Volume IV of the 2004 British Pharmacopoeia (BP) deals with this specific issue [22]. It states that in future when a monograph describes an enantiomer it will include both a test for identity ([a]) and a test to control stereoisomeric purity... 

If an enantiomer is chemically pure it is possible to determine its degree of enantiomeric purity by measuring its optical rotation relative to a standard value, e.g if an enantiomeric mixture contains 1% of enantiomer A and 99% of enantiomer B [a] will be reduced by 2% compared to the value for optically pure B. Examples of the measurement of optical rotation as a quality control check are found in the BP monographs for Timolol maleate, Tobramycin and Phenylephrine Hydrochloride. 

Diethanolamine is commercially available with the following specifications purity, 99.3% min. monoethanolamine, 0.45% max. triethanolamine (see monograph in this volume), 0.25% max. and water content, 0.15% max. (Dow Chemical Company, 1998a). Diethanolamine is also available as a blend of 85% diethanolamine and 15% deionized water which is a low fieeze-grade product for use in colder temperatures (Dow Chemical Company, 1998b). 

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