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Your search keyword '"Bhardwaj, Rajni M."' showing total 102 results
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102 results on '"Bhardwaj, Rajni M."'

1. An integrated approach combining experimental, informatics and energetic methods for solid form derisking of PF-06282999

Author

Sadiq, Ghazala, Sharma, Shubham, Stevens, Joanna S., Martinez-Bulit, Pablo, Hunnisett, Lily M., Cameron, Christopher, Samas, Brian, Hawking, Emma, Francia, Nicholas, Lengyel, Jeff, Pidcock, Elna, Rahman, Sadia, Nisbet, Matthew, Back, Kevin, Doherty, Cheryl, Basford, Patricia, Cooper, Timothy G., O'Connor, Garry, and Bhardwaj, Rajni M.

Published
2024
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20. Synthesis and Pharmacological Characterization of 2-(2,6-Dichlorophenyl)-1-((1S,3R)-5-(3-hydroxy-3-methylbutyl)-3-(hydroxymethyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one (LY3154207), a Potent, Subtype Selective, and Orally Available Positive Allosteric Modulator of the Human Dopamine D1 Receptor

Author

Hao, Junliang, primary, Beck, James P., additional, Schaus, John M., additional, Krushinski, Joseph H., additional, Chen, Qi, additional, Beadle, Christopher D., additional, Vidal, Paloma, additional, Reinhard, Matthew R., additional, Dressman, Bruce A., additional, Massey, Steven M., additional, Boulet, Serge L., additional, Cohen, Michael P., additional, Watson, Brian M., additional, Tupper, David, additional, Gardinier, Kevin M., additional, Myers, Jason, additional, Johansson, Anette M., additional, Richardson, Jeffery, additional, Richards, Daniel S., additional, Hembre, Erik J., additional, Remick, David M., additional, Coates, David A., additional, Bhardwaj, Rajni M., additional, Diseroad, Benjamin A., additional, Bender, David, additional, Stephenson, Greg, additional, Wolfangel, Craig D., additional, Diaz, Nuria, additional, Getman, Brian G., additional, Wang, Xu-shan, additional, Heinz, Beverly A., additional, Cramer, Jeff W., additional, Zhou, Xin, additional, Maren, Deanna L., additional, Falcone, Julie F., additional, Wright, Rebecca A., additional, Mitchell, Stephen N., additional, Carter, Guy, additional, Yang, Charles R., additional, Bruns, Robert F., additional, and Svensson, Kjell A., additional

Published
2019
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25. Spray drying as a reliable route to produce metastable carbamazepine form IV

Author

Halliwell, Rebecca A., Bhardwaj, Rajni M., Brown, Cameron, Briggs, Naomi E. B., Dunn, Jaclyn, Robertson, John, Nordon, Alison, and Florence, Alastair J.

Subjects
RS
Abstract

Carbamazepine is an active pharmaceutical ingredient used in the treatment of epilepsy that can form at least five polymorphic forms. Metastable form IV was originally discovered from crystallisation with polymer additives however has not been observed from subsequent solvent only crystallisation efforts. This work reports the reproducible formation of phase pure crystalline form IV by spray drying of methanolic carbamazepine solution. Characterisation of the material was carried out using diffraction, SEM and DSC. In situ Raman spectroscopy was used to monitor the spray dried product during the spray drying process. This work demonstrates spray drying provides a robust method for the production of form IV carbamazepine and the combination of high supersaturation and rapid solid isolation from solution overcomes the apparent limitation of more traditional solution crystallisation approaches to produce metastable crystalline forms.

Published
2017

28. Synthesis and Pharmacological Characterization of C4β-Amide-Substituted 2-Aminobicyclo[3.1.0]hexane-2,6-dicarboxylates. Identification of (1S,2S,4S,5R,6S)-2-Amino-4-[(3-methoxybenzoyl)amino]bicyclo[3.1.0]hexane-2,6-dicarboxylic Acid (LY2794193), a Highly Potent and Selective mGlu3 Receptor Agonist

Author

Monn, James A., primary, Henry, Steven S., additional, Massey, Steven M., additional, Clawson, David K., additional, Chen, Qi, additional, Diseroad, Benjamin A., additional, Bhardwaj, Rajni M., additional, Atwell, Shane, additional, Lu, Frances, additional, Wang, Jing, additional, Russell, Marijane, additional, Heinz, Beverly A., additional, Wang, Xu-shan, additional, Carter, Joan H., additional, Getman, Brian G., additional, Adragni, Kofi, additional, Broad, Lisa M., additional, Sanger, Helene E., additional, Ursu, Daniel, additional, Catlow, John T., additional, Swanson, Steven, additional, Johnson, Bryan G., additional, Shaw, David B., additional, McKinzie, David L., additional, and Hao, Junliang, additional

Published
2018
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30. Complex Polymorphic System of Gallic Acid—Five Monohydrates, Three Anhydrates, and over 20 Solvates

Author

Braun, Doris E., Bhardwaj, Rajni M., Florence, Alastair J., Tocher, Derek A., and Price, Sarah L.

Subjects
Communication
Abstract

We report the structure of the fifth monohydrate of gallic acid and two additional anhydrate polymorphs and evidence of at least 22 other solvates formed, many containing water and another solvent. This unprecedented number of monohydrate polymorphs and diversity of solid forms is consistent with the anhydrate and monohydrate crystal energy landscapes, showing both a wide range of packing motifs and also some structures differing only in proton positions. By aiding the solution of structures from powder X-ray diffraction data and guiding the screening, the computational studies help explain the complex polymorphism of gallic acid. This is industrially relevant, as the three anhydrates are stable at ambient conditions but hydration/dehydration behavior is very dependent on relative humidity and phase purity., An extensive experimental screen for solid forms, driven by computationally generated anhydrate and monohydrate crystal energy landscapes, revealed the fifth (!) monohydrate structure of gallic acid, structures of two additional anhydrate polymorphs, and evidence of at least 22 solvates. The application of computational studies in combination with other analytical techniques helps unravel the complex polymorphic system of gallic acid.

Published
2012

31. Atomic force microscopy studies on two-step nucleation and epitaxial growth

Author

Monika Warzecha, Bhardwaj, Rajni M., Susan Reutzel-Edens, Lamprou, Dimitrios A., and Alastair Florence

Subjects
RS
Abstract

Continues advancement and rapid development of techniques operating at the nanoscale open new opportunities to revise and question commonly accepted nucleation and crystal growth theories. Atomic Force Microscopy (AFM) has been successfully involved in various aspects of active pharmaceutical ingredient (API) characterisation including crystal growth, stability of solid dispersions, surface morphology, phase changes and dissolution [1]. Recent studies conducted on proteins crystallisation at nanoscale show new evidence disproving generally accepted Classical Nuclea/on Theory (CNT)[2]. Currently, ‘dense liquid droplets’ seen in protein crystallisation and ‘pre-nucleation clusters’ [3] seen mostly in inorganic salt crystallisation, are two main concepts of non-classical nucleation theory, although no significant progress has been made towards better understanding of mechanisms controlling heterogeneous nucleation in small organic molecules systems, what is in particular interest, as an epitaxial ordering phenomenon is frequently used to enhance nucleation rates and control properties of materials. Our studies present a new light on heteronucleation and the epitaxial growth mechanisms based epitaxial growth of olanzapine dihydrate D on the surface of olanzapine form I (OZPN I) both in high humidity conditions and water solu*on. Results obtained from Peak Force Quan/ta/ve Nanomechanical Mapping Atomic Force Microscopy (PF- QNM-AFM) [4] indicate the presence of intermediate dense liquid-like phase in process of dihydrate D nucleation.

Published
2015

32. A Prolific Solvate Former, Galunisertib, under the Pressure of Crystal Structure Prediction, Produces Ten Diverse Polymorphs

Author

Bhardwaj, Rajni M., McMahon, Jennifer A., Nyman, Jonas, Price, Louise S., Konar, Sumit, Oswald, Iain D. H., Pulham, Colin R., Price, Sarah L., and Reutzel-Edens, Susan M.

Abstract

The solid form screening of galunisertib produced many solvates, prompting an extensive investigation into possible risks to the development of the favored monohydrate form. Inspired by crystal structure prediction, the search for neat polymorphs was expanded to an unusual range of experiments, including melt crystallization under pressure, to work around solvate formation and the thermal instability of the molecule. Ten polymorphs of galunisertib were found; however, the structure predicted to be the most stable has yet to be obtained. We present the crystal structures of all ten unsolvated polymorphs of galunisertib, showing how state-of-the-art characterization methods can be combined with emerging computational modeling techniques to produce a complete structure landscape and assess the risk of late-appearing, more stable polymorphs. The exceptional conformational polymorphism of this prolific solvate former invites further development of methods, computational and experimental, that are applicable to larger, flexible molecules with complex solid form landscapes.

Published
2024
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37. BackMatter.

Author

Bhardwaj, Rajni M.

Published
2016

47. A random forest model for predicting the crystallisability of organic molecules.

Author

Bhardwaj, Rajni M., Johnston, Andrea, Johnston, Blair F., and Florence, Alastair J.

Subjects
*ORGANIC compounds, *RANDOM forest algorithms, *CRYSTALLIZATION, *MOLECULAR crystals, *SUBSTITUENTS (Chemistry), *PREDICTION models
Abstract

A random forest model has for the first time enabled the prediction of the crystallisability (crystals vs. no crystals) of organic molecules with ~70% accuracy. The predictive model is based on calculated molecular descriptors and published experimental crystallisation propensities of a library of substituted acylanilides. [ABSTRACT FROM AUTHOR]

Published
2015
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48. From discovery to scale-up: α-lipoic acid : nicotinamide co-crystals in a continuous oscillatory baffled crystalliser.

Author

Lihua Zhao, Raval, Vishal, Briggs, Naomi E. B., Bhardwaj, Rajni M., McGlone, Thomas, Oswald, Iain D. H., and Florence, Alastair J.

Subjects
LIPOIC acid, CRYSTAL structure research, NICOTINAMIDE, CRYSTALLIZATION, THERMAL stability
Abstract

The crystalline nutritional supplement α-lipoic acid degrades rapidly on exposure to temperatures above its melting point 65 °C and to light. A small-scale experimental co-crystal screen has produced three novel co-crystals of α-lipoic acid that each display enhanced thermal stability and differences in aqueous solubilities compared to α-lipoic acid. In each case, the initial screening procedure produced tens of milligrams of material enabling initial identification, characterisation and crystal structure determination. The structure of the α-lipoic acid: nicotinamide co-crystal was determined by single crystal X-ray diffraction and used for subsequent phase identification. Scale-up of the co-crystallisation process of α-lipoic acid with nicotinamide was then investigated in a continuous oscillatory baffled crystalliser. Over 1 kg of solid co-crystals was produced using a continuous crystallisation process in a continuous oscillatory baffled crystalliser at a throughput of 350 g h-1 yielding a purity of 99% demonstrating this as an effective route to rapid scale-up of a novel co-crystal system. [ABSTRACT FROM AUTHOR]

Published
2014
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49. Exploring the Experimental and Computed Crystal EnergyLandscape of Olanzapine.

Author

Bhardwaj, Rajni M., Price, Louise S., Price, Sarah L., Reutzel-Edens, Susan M., Miller, Gary J., Oswald, Iain D. H., Johnston, Blair F., and Florence, Alastair J.

Subjects
*CRYSTAL structure, *OLANZAPINE, *SOLVATION, *THERMODYNAMICS, *KINETIC energy, *DISPERSION (Chemistry)
Abstract

An extensive experimental searchfor solid forms of the antipsychoticcompound olanzapine identified 60 distinct solid forms including threenonsolvated polymorphs, 56 crystalline solvates, and an amorphousphase. XPac analysis of the 35 experimental crystal structures (30from this work and 5 from the CSD) containing olanzapine show thatthey contain a specific, dispersion-bound, dimer structure which canadopt various arrangements and accommodate diverse solvents to producestructures with a similar moderate packing efficiency to form I. Thecrystal energy landscape confirms the inability of olanzapine to packwith an efficiency of more than 70%, explains the role of solventin stabilizing the solvate structures, and identifies a hypotheticalstructural type that offers an explanation for the inability to obtainthe metastable forms II and III separately. The calculations findthat structures that do not contain the observed dimer are thermodynamicallyfeasible, suggesting that kinetic effects are responsible for allthe observed structures being based on the dimer. Thus, this extensivescreen probably has not found all possible physical forms of olanzapine,and further form diversity could be targeted with a better understandingof the role of kinetics in its crystallization. [ABSTRACT FROM AUTHOR]

Published
2013
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50. The seventh blind test of crystal structure prediction: structure generation methods.

Author

Hunnisett, Lily M., Nyman, Jonas, Francia, Nicholas, Abraham, Nathan S., Adjiman, Claire S., Aitipamula, Srinivasulu, Alkhidir, Tamador, Almehairbi, Mubarak, Anelli, Andrea, Anstine, Dylan M., Anthony, John E., Arnold, Joseph E., Bahrami, Faezeh, Bellucci, Michael A., Bhardwaj, Rajni M., Bier, Imanuel, Bis, Joanna A., Boese, A. Daniel, Bowskill, David H., and Bramley, James

Subjects
*CRYSTAL structure, *COPPER compounds, *MORPHOLINE, *SERVER farms (Computer network management), *STOICHIOMETRY
Abstract

A seventh blind test of crystal structure prediction was organized by the Cambridge Crystallographic Data Centre featuring seven target systems of varying complexity: a silicon and iodine‐containing molecule, a copper coordination complex, a near‐rigid molecule, a cocrystal, a polymorphic small agrochemical, a highly flexible polymorphic drug candidate, and a polymorphic morpholine salt. In this first of two parts focusing on structure generation methods, many crystal structure prediction (CSP) methods performed well for the small but flexible agrochemical compound, successfully reproducing the experimentally observed crystal structures, while few groups were successful for the systems of higher complexity. A powder X‐ray diffraction (PXRD) assisted exercise demonstrated the use of CSP in successfully determining a crystal structure from a low‐quality PXRD pattern. The use of CSP in the prediction of likely cocrystal stoichiometry was also explored, demonstrating multiple possible approaches. Crystallographic disorder emerged as an important theme throughout the test as both a challenge for analysis and a major achievement where two groups blindly predicted the existence of disorder for the first time. Additionally, large‐scale comparisons of the sets of predicted crystal structures also showed that some methods yield sets that largely contain the same crystal structures. [ABSTRACT FROM AUTHOR]

Published
2024
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