Journal of Laboratory Automation

Aqueous solubility is one of the most critical physicochemical properties to be determined in the process of drug lead optimization. Particularly, an equilibrium solubility method is highly valuable to the study of structure property relationship (SPR), while meeting the needs of analytical sensitivity, reproducibility, and throughput. In this report, an automated solubility assay in a 96-well library format was designed and developed by means of robotic liquid handling, centrifugal separation, and HPLC-UV quantification. Requiring 1 mg of solid compound, this assay was used to determine the equilibrium solubility in three user-selected media, that is, 0.01 N HCl, phosphate buffer saline (PBS), and fasted state simulated intestinal fluid (SIF), with a throughput of up to 192 compounds a week. The assay parameters, including the equilibration time and the separation technique, were optimized to ensure that the thermodynamic solubility was measured at the presence of excess solid compound. A fast gradient HPLC method was developed with single-point on-plate calibration for each compound, followed by a customized 96-well chromatographic data analysis. The reporting solubility range was 1–200 μg/mL, appropriate for oral drug candidate selection at the stage of discovery lead optimization. Based on the test results obtained on the commercially available drugs and Amgen research compounds, this assay was considered to be equivalent to the conventional shake-flask methods. Examples were given to demonstrate that the thermodynamic solubility determined by this assay enabled the SPR study to support drug lead optimization.

An integrated high-throughput tool for forced degradation studies during pharmaceutical development is described. A series of experiments are conducted with the Symyx Technologies (Santa Clara, CA) Automated Forced Degradation System. The hardware and software of the workflow are described. Degradation libraries of stressed samples of liquid formulations of drug A were created, analyzed for room temperature solubility, and then replicates of each library were heated and sampled over time at 55, 70, and 85 °C to monitor for parent product degradation. Library arrays of first-order kinetic plots were generated, and predictions of room temperature stability were made. Several viable solution formulations were identified. (JALA 2005;10:374–80)

A unique high-performance liquid chromatographic (HPLC) workflow specifically designed for the rigors of process development has been developed. A key feature of the workflow is the creation of an HPLC software–hardware platform designed to automatically and systematically screen samples using a matrix of columns and eluents to aggressively search for impurities. The workflow platform was assembled from commercial hardware components and both custom and commercial HPLC software. The platform can be used to challenge existing HPLC methods or to develop new methods. The screening conditions are complementary to each other, and are useful to assess the complexity of a sample and to chromatographically resolve impurities that may coelute using any single method. The workflow has been designed to support several different modes of HPLC, and can be used with absorption detection, photodiode array spectrometers, evaporative light scattering (ELS) devices, and mass spectrometric (MS) detection. The custom software interface contains a data-viewing feature to simplify analysis of results. The platform is designed to be used by process scientists, and the same simple user-interface is used to control analytical HPLC, LC–MS, and preparative HPLC. Three real world examples are provided to illustrate the utility of the platform to rigorously assess the complexity of samples and to develop new and improved HPLC methods. (JALA 2005;10:381–93)

The application of automation in conjunction with DoE designs towards the rapid discovery and optimization of metal-catalyzed reactions used in the synthetic preparation of clinical drug candidates at Merck Process Research is demonstrated with three examples. A description of the software and hardware is provided, followed by three examples highlighting these applications. The first example highlights a DoE optimization of a platinum-catalyzed chemoselective hydrogenation of a nitroaromatic nitrile. In the second example, automated screening is employed to discover a highly efficient palladium catalyst that affects nitrostyrene cyclization under a carbon monoxide reducing atmosphere. In the last example, a rapid discovery and DoE optimization of a rhodium-catalyzed diastereoselective hydrogenation of an unsaturated ester is detailed.

In chemical development, broad knowledge of solubilities of all reactants, reagents, and products is important because these data are needed for cleaning operations of multipurpose equipment in pilot and production plants. A fully automated workflow on a high-throughput robotic system for determination of solid material solubility in different aqueous and organic solvents is described. Automated solid dispensing, weighing, and solvent addition are performed followed by direct measurement of turbidity with an integrated three-wavelength turbidity probe. Finally, a report is generated containing all solubility information of the solid in a clearly arranged manner. (JALA 2005;10:408–11)

Microwave-assisted organic chemistry has received considerable attention during the last decade and nowadays, more and more research chemists are applying microwave technology to organic reactions on a small scale successfully. However, efficient application of this technology to cover the specific needs of larger-scale preparations, e.g., in a kilolab, remains to be shown. Therefore, the current study was initiated to investigate the scalability of the microwave technology. Two different microwave systems designed for large-scale operation (Multiwave 3000 and CEM Voyager SF) were evaluated to characterize strengths and weaknesses of each instrument for special use in a kilolab with focus on temperature/pressure limits, handling of suspensions, ability for rapid heating and cooling, robustness, and overall processing time. (JALA 2005;10:412–7)

As parallel experimentation workflows become more complex, additional functionality and capability is required from laboratory robotics. These robotic platforms are no longer being used exclusively for liquid handling or for dedicated workflows but are being tasked to support a variety of analytical probes, heated tips, vial grippers, and a variety of other functions. To respond to this need, Symyx Technologies (Santa Clara, CA) has introduced the Extended Core Module (XCM) robotic system. The XCM features a robust robotic platform designed with a unique architecture that enables the straightforward addition of functionality through self-contained elements. These elements only require power, pneumatic connections (if required) and communication connections, which are provided by standard interfaces within the XCM deck. The XCM operates using Symyx Technologies, Inc. Renaissance® Software. Several workflows have been built using the Symyx XCM configurable architecture, encompassing both chemical and pharmaceutical workflows, and are described herein.