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ABSTRACT: Excipients often used in pharmaceutical formulations have been reported to have inhibitory effects on P-glycoprotein, an important membrane-associated transport protein. Because inhibition of efflux transporters can have an effect on drug bioavailability, identification of these excipients and their extent of inhibition are therefore important for pharmaceutical development. We have developed an automated and integrated high-throughput process for identifying these excipients and their combinations. Common excipients containing polyethylene glycol (PEG) in the chemical structure were screened using a cytotoxic cell growth assay, and excipients giving inhibition were further combined to identify synergistic effects. Our screens identified excipients previously reported to inhibit P-glycoprotein, such as PEG stearates, PEG fatty acid esters, polysorbates, and poloxamers. We also found new excipients, such as those in the PEG glyceryl fatty acid family, which were among the best inhibitors identified. Dose-response studies of these compounds and of cyclosporin A indicated that the extent of inhibition depended logarithmically on the concentration. This suggests a similar mechanism by which inhibition is obtained, despite widely varying chemical structures. In the particular set of combinatorial studies performed, which involved >20,000 samples, we found that inhibitory effects in binary combinations followed the single-excipient logarithmic trend, rather than being synergistic. These experiments showcased the potential for integrated high-throughput processes that enable combinatorial screens which would otherwise be difficult to perform manually.
Journal of Pharmaceutical Sciences 11/2004; 93(11):2755-67. · 3.06 Impact Factor
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Matthew L Peterson,
Sherry L Morissette,
Chris McNulty,
Andrew Goldsweig,
Paul Shaw,
Martin LeQuesne, Julie Monagle,
Nicolas Encina,
Joseph Marchionna,
Alasdair Johnson,
Javier Gonzalez-Zugasti,
Anthony V Lemmo,
Stephen J Ellis,
Michael J Cima,
Orn Almarsson
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ABSTRACT: Three crystal forms of acetaminophen were prepared and characterized using a newly developed high-throughput crystallization platform, CrystalMax. The platform consists of design software, robotic sample dispensing and handling, and high-throughput microanalytics and is capable of running thousands of crystallizations in parallel using several different methods to drive supersaturation and subsequent crystallization. Additionally, structural models of the elusive third form of acetaminophen will be discussed on the basis of powder X-ray diffraction data. One structure suggested has a bilayer motif, held together by O-H...O(H) hydrogen bonds, and helps explain the difficulty associated with preparing this form from solution.
Journal of the American Chemical Society 10/2002; 124(37):10958-9. · 9.91 Impact Factor
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Colin R Gardner,
Orn Almarsson,
Hongming Chen,
Sherry Morissette,
Matt Peterson,
Zhong Zhang,
Szu Wang,
Anthony Lemmo,
Javier Gonzalez-Zugasti, Julie Monagle,
Joseph Marchionna,
Steve Ellis,
Chris McNulty,
Alasdair Johnson,
Doug Levinson,
Michael Cima
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ABSTRACT: This presentation describes the application of novel high throughput physical–chemical technologies to the pharmaceutical discovery and development process. The rationale for such platforms is described in light of the changes that have occurred in the biological and chemical processes leading to drug target evaluation and lead identification. Several high throughput platforms are described for identification and evaluation of solid forms and formulations of drug candidates including salt, hydrate and solvate selection and polymorph discovery and evaluation. The application to the development of oral and intravenous formulations for animal model and human clinical evaluation is also discussed. The importance of informatics to design experiments and capture and analyze data is highlighted. Examples are described showing the power of high throughput systems to discover knowledge that enables pharmaceutical scientists to make more informed and better decisions about product development choices.
Computers & Chemical Engineering.
