Automation screening procedures

An automated screening procedure for barbiturates, benzodiazepines, antidepressants, morphine, and cocaine in blood after SPE and trimethylsilylation was developed [7,14], The sample preparation consists of SPE and TMS derivatization, both automated using an HP PrepStation. 

Finally, libraries aimed to chiral resolution of racemates will be covered here in particular, the use of chiral stationary phases (CSPs) has recently been reported for the identification of materials to be used for chiral separation of racemates by HPLC. The group of Frechet reported the selection of two macroporous poly methacrylate-supported 4-aryl-1,4-dihydropyrimidines (DHPs) as CSPs for the separation of amino acid, anti-inflammatory drugs, and DHP racemates from an 140-member discrete DHP library (214,215) as well as a deconvolutive approach for the identification of the best selector phase from a 36-member pool library of macroporous polymethacrylate-grafted amino acid anilides (216,217). Welch and co-workers (218,219) reported the selection of the best CSP for the separation of a racemic amino acid amide from a 50-member discrete dipeptide iV-3,5-dinitrobenzoyl amide hbrary and the follow-up, focused 71-member library (220). Wang and Li (221) reported the synthesis and the Circular Dichroism- (CD) based screening of a 16-member library of CSPs for the HPLC resolution of a leucine ester. Welch et al. recentiy reviewed the field of combinatorial libraries for the discovery of novel CSPs (222). Dyer et al. (223) reported an automated synthetic and screening procedure based on Differential Scanning Calorimetry (DSC) for the selection of chiral diastereomeric salts to resolve racemic mixtures by crystallization. Clark Still rejxrrted another example which is discussed in detail in Section 9.5.4. 

The fully automated computational procedure is a valuable ne v tool in virtual screening and in early ADME-Tox, vhere drug safety and metabolic profile patterns must be evaluated in order to enhance and streamline the process of developing neiv drug candidates. 

If no rational starting point for the separation of a racemate can be found, a random screening procedure has to be applied. In most cases 250 X 4 or 4.6 mm columns are used for this purpose. Modern HPLC systems often include a column switching device with up to 12 columns. Most systems have programmable software options for the set of different mobile phase compositions. Combination of UV and polarimetric detection allows even very small selectivities to be found and used as a starting point for further optimization. Commercial systems with deconvolution and optimization options are available, together with a given set of 12 different chiral stationary phases (www.pdr-chiral.com). After an initial detection of selectivity on a CSP, the mobile phase composition and additives as well as temperature have to be varied either manually or by means of an automated system. 

---