Articles The Development of a Semiautomated Procedure for the Synthesis and Screening of a Large Group of Molecularly Imprinted Polymers Myra T. Koesdjojo, † Henrik T. Rasmussen, ‡ Adam M. Fermier, ‡ Payal Patel, § and Vincent T. Remcho* ,† Department of Chemistry, Oregon State UniVersity, CorVallis, Oregon, Johnson and Johnson Pharmaceutical Research and DeVelopment, LLC, P.O. Box 300, Route 202, Raritan, New Jersey, and Department of Biomedical Engineering, Rutgers UniVersity, New Brunswick, New Jersey ReceiVed February 13, 2007 A method for synthesis and evaluation of molecularly imprinted polymers (MIPs) on a semiautomated miniature scale is reported. This technique combines molecular imprinting with the combinatorial chemistry approach, allowing rapid screening and optimizations of libraries of MIPs. The polymers were prepared and evaluated in situ by rebinding utilizing powder dispensing and liquid handling systems. MIPs were prepared by a combinatorial approach using methacrylic acid (MAA), 4-vinylpyridine (4-VP), acrylamide, and styrene as functional monomers, and acetonitrile and toluene as porogenic solvents. A drug substance having aromatic, hydroxyl, –O–CONH 2 functional groups was selected as the template molecule for this study. The MIP library results demonstrated that the polymer prepared with MAA as functional monomer shows the strongest binding affinity, and therefore, is preferred for the preparation of this particular template molecule. Due to the low consumption of reagents, and more importantly, the demonstrated ability of this method to effectively identify optimal imprinting conditions, this small-scale combinatorial protocol is well suited for fast and efficient screening and optimizations of MIPs. 1. Introduction Molecularly imprinted polymers (MIPs) have been shown to possess unique and predetermined selectivity for target analytes. MIPs can selectively recognize a template molecule used in the imprinting process even in the presence of compounds having similar structure and functionality to the template. 1–10 The pharmaceutical industries have continuously invested heavily in research and development for the production of novel drug substances. The demand for rapid and effective analytical strategies of this industry that drive improvements in the quality of their products results in a constant search for new analytical methods. The advantages of MIPs, e.g. physical robustness, resistance to high pressure and temper- ature, and tolerance of different solvents and media, have led to modest increases in their use in the pharmaceuticals sector. MIPs have been implemented in various applications, including sample preparation, as stationary phases for analytical separations, and as analyte recognition materials in affinity assays. 11–16 Solid phase extraction (SPE) based on molecularly im- printed polymers (MIPs) is a novel approach for sample preparation and preconcentration. The implementation of MIPs in SPE devices for the separation and detection of drugs and drug metabolites has great potential in the pharmaceutical industry. The control of pharmaceutical impurities is a critical issue. HPLC methods applicable to the analysis of drug substances/drug products should be able to separate the active pharmaceutical ingredients (API) from the impurities and degradation products. Analysis of these trace amounts of impurities in the presence of a large quantity of API is problematic, in particular because the impurities are usually structurally related to the API. The use of imprinted polymers as separation media for drug substance and drug product analyses is particularly important for the isolation of degradation products and impurities from the API. In this work, MIPs that exhibit a high binding specificity for a drug substance were synthesized as sorbents in small scale. These sorbents, when produced in bulk, could be used as solid phase extraction devices for the isolation of impurities and degradation products in drug substances and drug products. This isolation allows for impurity profiling in the absence of the API. 17 As coelution between impurities, degradation products, and the API are frequently a significant concern, this approach is likely to be a useful addition to * Corresponding author phone: 541 737 2081; fax: 541 737 2062; e-mail: Vincent.Remcho@oregonstate.edu. † Oregon State University. ‡ Johnson and Johnson Pharmaceutical Research and Development, LLC. § Rutgers University. J. Comb. Chem. 2007, 9, 929–934 929 10.1021/cc0700243 CCC: $37.00  2007 American Chemical Society Published on Web 10/26/2007