A5011956431- X-ray Diffraction in Crystallography
- Crystallization and Solubility Studies
- Crystallography and molecular interactions
- Computational Drug Discovery Methods
- Enzyme Structure and Function
- Chemical Thermodynamics and Molecular Structure
- Machine Learning in Materials Science
- Biochemical and Molecular Research
- HIV/AIDS drug development and treatment
- Drug Solubulity and Delivery Systems
- Mathematical and Theoretical Epidemiology and Ecology Models
- DNA and Nucleic Acid Chemistry
- Protein purification and stability
- Porphyrin Metabolism and Disorders
- Molecular spectroscopy and chirality
- Carbohydrate Chemistry and Synthesis
- Analytical Methods in Pharmaceuticals
- thermodynamics and calorimetric analyses
- Synthesis and biological activity
- Tuberculosis Research and Epidemiology
- Plant biochemistry and biosynthesis
- Metal-Organic Frameworks: Synthesis and Applications
- Chemical Synthesis and Analysis
Merck & Co., Inc., Rahway, NJ, USA (United States)
2021-2025
University College London
2016-2018
The sixth blind test of organic crystal structure prediction (CSP) methods has been held, with five target systems: a small nearly rigid molecule, polymorphic former drug candidate, chloride salt hydrate, co-crystal and bulky flexible molecule. This seen substantial growth in the number participants, broad range giving unique insight into state art field. Significant progress treating molecules, usage hierarchical approaches to ranking structures, application density-functional...
A combined experimental NMR and DFT computational analysis of molnupiravir, an orally dosed antiviral effective for treatment patients with COVID-19, determined that the molecule primarily exists as oxime tautomer both in solution solid state. Both Z E stereoisomers were observed various solvents, being major form, consistent calculations. An amine form was not detected directly, but results strongly suggest it transient intermediate responsible interconversion isomers solution. The...
Periodic DFTB3-D3 calculations allow the refinement of molecular conformations within crystal structures and estimates phonons for flexible pharmaceutical molecules.
Crystal structure prediction (CSP) is an invaluable tool in the pharmaceutical industry because it allows to predict all possible crystalline solid forms of small-molecule active ingredients. We have used a CSP-based cocrystal method rank ten potential coformers by energy cocrystallization reaction with antiviral drug candidate, MK-8876, and triol process intermediate, 2-ethynylglyclerol. For was performed retrospectively successfully predicted maleic acid as most likely be observed. The...
Crystalline suspensions of monoclonal antibodies (mAbs) have great potential to improve drug substance isolation and purification on a large scale be used for delivery via high-concentration formulations. mAb are expected enhanced chemical physical properties relative solutions delivered intravenously, making them attractive candidates subcutaneous delivery. In contrast small molecules, the development protein crystalline is not widely approach in pharmaceutical industry. This mainly due...
A new polymorph of succinic acid is an unusually challenging test for metastable prediction.
We report the process development for active pharmaceutical ingredient (API) step of commercial manufacturing route to nemtabrutinib (MK-1026), a reversible Bruton’s Tyrosine Kinase (BTK) inhibitor currently under investigation treatment several hematological malignancies. Significant improvements on efficiency were achieved by direct isolation leveraging optimal reaction conditions and synergistic API solubility in an ethanol/water system. In combination with additional robustness impurity...
Although the crystal structures of small-molecule compounds are often determined from single-crystal X-ray diffraction (scXRD), recent advances in three-dimensional electron (3DED) and structure prediction (CSP) methods promise to expand elucidation toolbox available crystallographer. Herein, a comparative assessment scXRD, 3DED, CSP combination with powder is carried out on two former drug candidate multicomponent key building block synthesis gefapixant citrate.
Determining the range of conformations that a flexible pharmaceutical-like molecule could plausibly adopt in crystal structure is key to successful prediction (CSP) studies. We aim use conformational information from structures Cambridge Structural Database (CSD) facilitate this task. The produced by CSD Conformer Generator are reduced number considering underlying rotamer distributions, an analysis changes molecular shape, and minimal ab initio calculations. This method tested for five...
Amorphous solid dispersions (ASDs) are a well-documented formulation approach to improve the rate and extent of dissolution for hydrophobic pharmaceuticals. However, weakly basic compounds can complicate standard approaches ASDs due pH-dependent solubility, resulting in uncontrolled drug release gastric conditions unstabilized supersaturated solutions prone precipitation at neutral pH. This work examines mechanisms amorphous containing model pharmaceuticals posaconazole lumefantrine from...
Crystal polymorphism, characterized by different packing arrangements of the same compound, strongly ties to physical properties a molecule. Determining polymorphic landscape is complex and time-consuming, with number experimentally observed polymorphs varying widely from molecule Furthermore, disappearing polymorphs, phenomenon whereby forms cannot be reproduced, pose significant challenge for pharmaceutical industry. Herein, we focused on oxindole (OX), small rigid four known including...
Marcus Neumann opened discussion of the paper by Andrew I. Cooper: In Fig. 3 your you compare lattice energies structures different chemical compositions. Each filled circle corresponds to a solvate and various solvents all have their own, temperature dependent,
Solid form screens of active pharmaceutical ingredients are a key component drug development. Beyond forming multiple neat crystal structures, also known as polymorphs, drugs can crystallize with variety solvent molecules to solvates. They display physiochemical properties different from the solid selected for Hence, using computational structure prediction (CSP) methods predict formation solvates would be valuable industry. However, CSP solvate faces range obstacles. This work addresses two...
J. Christian Schön opened the discussion of paper by Gregory O. Beran: Concerning multi-tier approach to improving quality computations, where you did a careful analysis different types approximations, it is still very disconcerting that there appears be no inhere
Abstract Crystal polymorphism, characterized by different packing arrangements of the same compound, strongly ties to physical properties a molecule. Determining polymorphic landscape is complex and time‐consuming, with number experimentally observed polymorphs varying widely from molecule Furthermore, disappearing polymorphs, phenomenon whereby forms cannot be reproduced, pose significant challenge for pharmaceutical industry. Herein, we focused on oxindole (OX), small rigid four known...
This article reports a rare example of the crystallization cocrystal an organic molecule with its epimer. In this case, belzutifan, novel treatment for von Hippel–Lindau (VHL) disease-associated renal cell carcinoma (RCC), crystallizes as 1:1 one epimers (inversion stereochemistry at hydroxyl position). observation is particular importance to controlling purity API in commercial manufacturing process. After discovery cocrystal, crystalline structure was determined through combination crystal...
During large-scale crystallization of the ethyl ester (EE) starting material Doravirine (MK-1439) (Huang et al. ACS Infectious Dis. 2020, 6, 64–73) four out nine batches exhibited unique infrared spectra upon release testing and atypical powder X-ray diffraction (PXRD) patterns not conforming to target crystalline phase, Form 1. This work presents investigations triggered within MSD's laboratories on polymorphism EE strategy employed for identifying nature form impurity understanding its...