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Chromtech application bulletin no.5-2004ChromTech Application Bulletin No.5 (2004)
Chiral separation of multifunctional complex drug compounds
New drug compounds often contain several functional Benazepril
groups. This means that they are not easily classified, (J.Chrom. A, 818 (1998) 53-60, R.Cirilli et al) ie. if they are acidic, basic or ampholytic. In addition
they may also contain several stereogenic centers. When
developing a method on CHIRAL-AGP, the Method
Development Schemes are very useful, even for multi-
functional compounds. Below are two examples of
compounds with many functionalities as well as withtwo stereogenic centers.
Benazepril contains different nonprotolytic functionalities, aswell as an acidic group. This protolytic function is the most Roxifiban
important group in order to determine the method development (J.Chrom. A, 844 (1999) 171-179, R.C. Williams et al) strategy. Benazepril is a strong acid. In the Method Develop-ment Scheme the starting mobile phase for strong acids is 10mM sodium phosphate buffer pH 7.0. Depending on the resultobtained with this mobile phase, optimization is carried out us-ing variables as pH, organic modifier and buffer. Benazeprilcontains two stereogenic centers. A further complication in thisanalysis is that benazepril is administered as the (S,S)-configu- Roxifiban contains many different nonprotolytic functionalities ration and hydrolyzed in vivo to its active dicarboxylic acid me- together with a basic benzamidine group with a pKa of 11. This tabolite, benazeprilat. Benazeprils enantiomer and the diastere- protolytic group is the most important to consider when develop- oisomeric pair of enantiomers are potential impurities, as well ing a method. When analyzing the structure, it can be described as the dicarboxylic acid. In the article an extensive investiga- as a hydrophilic amine. In the Method Development Scheme the tion of mobile phase parameters was carried out. An optimized starting mobile phase for hydrophilic amines is 5% 2-propanol mobile phase was found (see figure below). By characterizing in 10 mM sodium phosphate buffer pH 7.0.The compound has benazepril as a strong acid and following the Method Develop- two stereogenic centers and is developed as a single stereoisomer ment Scheme for strong acids, it would also have been possible in the RS configuration, which means that the RR and SS diaste- to develop a similar optimal mobile phase.
reoisomers and the SR enantiomer are possible impurities. In the Benazeprilat
article an experimental design study was used in order to opti-mize the different variables for the separation of the four iso-mers. However, the optimized mobile phase was found to be the SS RR diastereoisomers
starting mobile phase for hydrophilic amines in the Method De-velopment Scheme, see figure below.
CHIRAL-AGP 100x4.0 mm
SR RR SS Roxifiban
7.5% 2-propanol in 60 mM potassiumphosphate buffer pH 4.0 When developing a method for a multifunctional complex com- CHIRAL-AGP 100x4.0 mm
pound on the CHIRAL-AGP column, look for protolytic func-
5% 2-propanol in 10 mM sodium phosphate tions. Decide which protolytic group might decide the character of the compound. Then test the corresponding starting mobilephase from the Method Development Scheme. If the compoundcontains protolytic groups of different character, in addition you The New Chiral Application handbook is now
may have to test another starting mobile phase corresponding to available. Please order your copies from
the other protolytic function. Another possibility is to test the [email protected]
three starting mobile phases in the Method Development Schemein an unprejudiced way, in order to find the best route for method www.chromtech.co.uk
ChromTech Ltd., Congleton, U.K. Tel: +44 1260 270153 Fax: +44 1260 274394 E-mail: [email protected]
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