Sandwich Laboratories

Kings Hill, United Kingdom

Sandwich Laboratories

Kings Hill, United Kingdom

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Glossop P.A.,Sandwich Laboratories | Watson C.A.L.,Sandwich Laboratories | Price D.A.,Sandwich Laboratories | Price D.A.,Pfizer | And 26 more authors.
Journal of Medicinal Chemistry | Year: 2011

A novel tertiary amine series of potent muscarinic M 3 receptor antagonists are described that exhibit potential as inhaled long-acting bronchodilators for the treatment of chronic obstructive pulmonary disease. Geminal dimethyl functionality present in this series of compounds confers very long dissociative half-life (slow off-rate) from the M 3 receptor that mediates very long-lasting smooth muscle relaxation in guinea pig tracheal strips. Optimization of pharmacokinetic properties was achieved by combining rapid oxidative clearance with targeted introduction of a phenolic moiety to secure rapid glucuronidation. Together, these attributes minimize systemic exposure following inhalation, mitigate potential drug-drug interactions, and reduce systemically mediated adverse events. Compound 47 (PF-3635659) is identified as a Phase II clinical candidate from this series with in vivo duration of action studies confirming its potential for once-daily use in humans. © 2011 American Chemical Society.


Haynes J.J.,Sandwich Laboratories | Jones H.,Sandwich Laboratories | Gibson D.,Sandwich Laboratories | Clark G.T.,Sandwich Laboratories
Bioanalysis | Year: 2011

Background: Targeting the gonadotropin-releasing hormone pathway for the treatment of endometriosis leads to an interest in monitoring for endogenous modulators of this pathway (RFRP3 and kisspeptin) as baseline controls for treatment development. Results: Stabilization of RFRP3 was shown to be extremely difficult in a highly enzymatically active matrix, such as rat blood. Sample denaturing with solvent at collection was necessary due to enzyme inhibition being unsuccessful at stabilization leading to difficulties in sample processing. Monitoring multiple fragments formed in blood can aid in profiling these peptides once in-source conversion is controlled. Conclusion: generic high-sensitivity LC-MS/MS assay was developed for RFRP3 and the fragments formed from it in whole blood. Use of 2D chromatography circumvents concentration and retention issues related to small fragments with a normal flow setup, making a more open-access approach feasible. © 2011 Future Science Ltd.


Dunetz J.R.,Groton Laboratories | Berliner M.A.,Groton Laboratories | Xiang Y.,Groton Laboratories | Houck T.L.,Groton Laboratories | And 12 more authors.
Organic Process Research and Development | Year: 2012

This work describes the process development and manufacture of early-stage clinical supplies of a hepatoselective glucokinase activator, a potential therapy for type 2 diabetes mellitus. Critical issues centered on challenges associated with the synthesis of intermediates and API bearing a particularly racemization-prone a-aryl carboxylate functionality. In particular, a T3P-mediated amidation process was optimized for the coupling of a racemization-prone acid substrate and a relatively nonnucleophilic amine. Furthermore, an unusually hydrolytically-labile amide in the API also complicated the synthesis and isolation of drug substance. The evolution of the process over multiple campaigns is presented, resulting in the preparation of over 110 kg of glucokinase activator. © 2012 American Chemical Society.


Clegg I.M.,Pfizer | Pearce J.,Sandwich Laboratories | Content S.P.,Sandwich Laboratories
Applied Spectroscopy | Year: 2012

The application of in situ Raman spectroscopy at small scale (maximum 80 mL) during the development of a manufacturing process is disclosed. The reaction was run in aqueous solution between ambient and 100 °C. Raman spectroscopy has proven to be a viable method to track the reaction. Three distinct phases could be followed: dissolution of the starting material, production of a reactive intermediate, and then subsequent conversion of that intermediate to form product. The bjective of the work was to confirm the presence of a reactive intermediate and this could only be carried out via in situ spectroscopy as the intermediate was known to be unstable. Toward the end, the reaction passes though several neutralization points and these are consistent with changes in the pectra. Comparison of data obtained at an illumination wavelength of 998 nm with that obtained at 785 nm is also disclosed. The data obtained at shorter wavelength was contaminated by reasonably strong uorescence, whereas the data obtained at 998 nm was free of fluorescence. An unexpected observation from this work was that the reaction time was much shorter than expected and this work was key in showing that a reduction in batch cycle time was possible during commercial manufacture. © 2012 Society for Applied Spectroscopy.


PubMed | Sandwich Laboratories
Type: Journal Article | Journal: Applied spectroscopy | Year: 2012

The application of in situ Raman spectroscopy at small scale (maximum 80 mL) during the development of a manufacturing process is disclosed. The reaction was run in aqueous solution between ambient and 100 C. Raman spectroscopy has proven to be a viable method to track the reaction. Three distinct phases could be followed: dissolution of the starting material, production of a reactive intermediate, and then subsequent conversion of that intermediate to form product. The objective of the work was to confirm the presence of a reactive intermediate and this could only be carried out via in situ spectroscopy as the intermediate was known to be unstable. Toward the end, the reaction passes though several neutralization points and these are consistent with changes in the spectra. Comparison of data obtained at an illumination wavelength of 998 nm with that obtained at 785 nm is also disclosed. The data obtained at shorter wavelength was contaminated by reasonably strong fluorescence, whereas the data obtained at 998 nm was free of fluorescence. An unexpected observation from this work was that the reaction time was much shorter than expected and this work was key in showing that a reduction in batch cycle time was possible during commercial manufacture.


PubMed | Sandwich Laboratories
Type: Journal Article | Journal: Bioanalysis | Year: 2011

Targeting the gonadotropin-releasing hormone pathway for the treatment of endometriosis leads to an interest in monitoring for endogenous modulators of this pathway (RFRP3 and kisspeptin) as baseline controls for treatment development.Stabilization of RFRP3 was shown to be extremely difficult in a highly enzymatically active matrix, such as rat blood. Sample denaturing with solvent at collection was necessary due to enzyme inhibition being unsuccessful at stabilization leading to difficulties in sample processing. Monitoring multiple fragments formed in blood can aid in profiling these peptides once in-source conversion is controlled.generic high-sensitivity LC-MS/MS assay was developed for RFRP3 and the fragments formed from it in whole blood. Use of 2D chromatography circumvents concentration and retention issues related to small fragments with a normal flow setup, making a more open-access approach feasible.

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