A5090646901- Crystallization and Solubility Studies
- X-ray Diffraction in Crystallography
- Crystallography and molecular interactions
- Drug Solubulity and Delivery Systems
- Computational Drug Discovery Methods
- Analytical Chemistry and Chromatography
- Advanced NMR Techniques and Applications
- Machine Learning in Materials Science
- Enzyme Structure and Function
- Molecular spectroscopy and chirality
- Chemical Synthesis and Analysis
- Material Dynamics and Properties
- Clay minerals and soil interactions
- Quinazolinone synthesis and applications
- Chemistry and Chemical Engineering
- Liquid Crystal Research Advancements
- Polymer Synthesis and Characterization
- Protein purification and stability
- Methane Hydrates and Related Phenomena
- Mesoporous Materials and Catalysis
- Spacecraft and Cryogenic Technologies
- Intellectual Property and Patents
- Advanced Drug Delivery Systems
- Layered Double Hydroxides Synthesis and Applications
- Cellular transport and secretion
Cambridge Crystallographic Data Centre
2021-2024
Eli Lilly (United States)
2013-2024
Indianapolis Zoo
2015-2021
Lilly (China)
2015-2016
Roche (Switzerland)
2015
University of Strathclyde
2013
Purdue University West Lafayette
2003
Indiana University – Purdue University Indianapolis
2003
The physicochemical properties of molecular crystals, such as solubility, stability, compactability, melting behaviour and bioavailability, depend on their crystal form1. In silico form selection has recently come much closer to realization because the development accurate affordable free-energy calculations2-4. Here we redefine state art, primarily by improving accuracy calculations, constructing a reliable experimental benchmark for solid-solid differences, quantifying statistical errors...
The solid form screening of galunisertib produced many solvates, prompting an extensive investigation into possible risks to the development favored monohydrate form. Inspired by crystal structure prediction, search for neat polymorphs was expanded unusual range experiments, including melt crystallization under pressure, work around solvate formation and thermal instability molecule. Ten were found; however, predicted be most stable has yet obtained. We present structures all ten unsolvated...
The supersaturation potential of poorly water-soluble compounds is interest in the context solubility enhancing formulations for enhanced bioavailability. In this regard, amorphous "solubility", i.e., maximum increase solution concentration that can be obtained relative to crystalline form, an important parameter, albeit a very difficult one evaluate experimentally. goal current study was develop new approaches determine "solubility" and compare experimental values theoretical predictions. A...
An extensive experimental search for solid forms of the antipsychotic compound olanzapine identified 60 distinct including three nonsolvated polymorphs, 56 crystalline solvates, and an amorphous phase. XPac analysis 35 crystal structures (30 from this work 5 CSD) containing show that they contain a specific, dispersion-bound, dimer structure which can adopt various arrangements accommodate diverse solvents to produce with similar moderate packing efficiency form I. The energy landscape...
Two effects of conformational flexibility on crystallization, namely polymorphism and reduction crystallization tendency, are discussed using examples from the literature our own studies. The preferred molecular conformations observed in several polymorphic systems correlated with nature forces present crystals. tendency for conformationally flexible molecules arises presence multiple conformers crystallizing media need certain to crystallize high-energy conformations. Despite their...
The design, synthesis, and biological characterization of an orally active prodrug (3) gemcitabine are described. Additionally, the identification a novel co-crystal solid form compound is presented. Valproate amide 3 bioavailable releases into systemic circulation after passing through intestinal mucosa. has entered clinical trials being evaluated as potential new anticancer agent.
Over the past three decades, development of methods for Crystal Structure Prediction (CSP) has primarily been curiosity-driven. Because obvious potential economic gain from CSP, commercial interests can be assumed to eventually take over as main driving force development. We argue that this transition is happening right now, not only CSP providers, but also consumers within industry. In context industry-wide efforts, we describe exploration in research and algorithm by one large...
High energy solids, such as salts, co-crystals, or amorphous solid dispersions, have been widely used to generate supersaturated aqueous solutions and improve drug bioavailability. However, most research on solubility enhancing strategies has focused the kinetics of dissolution, there is relatively little comparison different degrees supersaturation achieved by using state forms same compound. Recent studies from our group demonstrated that maximum achievable dictated form drug....
Solid form screening and crystal structure prediction (CSP) calculations were carried out on two related molecules, 3-(4-(benzo[d]isoxazole-3-yl)piperazin-1-yl)-2,2-dimethylpropanoic acid (B5) 3-(4-dibenzo[b,f][1,4]oxepin-11-yl-piperazin-1-yl)-2,2-dimethylpropanoic (DB7). Only one anhydrate was crystallized for B5, whereas multiple solid forms, including three neat polymorphs, found DB7. The of B5 is P21/n Z′ = 1 with intramolecular hydrogen bonding, Forms I II DB7 are conformational...
Elucidating the crystal structures, transformations, and thermodynamics of two zwitterionic hydrates (Hy2 HyA) 3-(4-dibenzo[b,f][1,4]oxepin-11-yl-piperazin-1-yl)-2,2-dimethylpropanoic acid (DB7) rationalizes complex interplay temperature, water activity, pH on solid form stability transformation pathways to three neutral anhydrate polymorphs (Forms I, II°, III). HyA contains 1.29 1.95 molecules per DB7 zwitterion (DB7z). Removal essential stabilizing causes it collapse an amorphous phase,...
Because of excessive electron delocalization, the polymorphs ROY constitute a surprisingly challenging system for crystal structure prediction.
A workflow for the digital design of crystallization processes starting from chemical structure active pharmaceutical ingredient (API) is a multistep, multidisciplinary process. simple version would be to first predict API crystal and, it, corresponding properties solubility, morphology, and growth rates, assuming that nucleation controlled by seeding, then use these parameters This usually an oversimplification as most APIs are polymorphic, stable alone may not have required development...
Olanzapine, a novel benzodiazepine agent used in the treatment of schizophrenia and related psychoses, crystallizes 25+ crystal forms, seven which are pharmaceutically relevant: three anhydrates (I−III), dihydrates (B, D, E), higher hydrate. X-ray structures thermodynamically stable anhydrous form (I), two (B D), hydrate, Rietveld-refined structure dihydrate E have permitted detailed analysis conformational, hydrogen bonding, packing preferences olanzapine. The symmetry hydrogen-bonding...
The tendency of highly supersaturated solutions poorly water-soluble drugs to undergo liquid-liquid phase separation (LLPS) into drug-rich and water-rich phases when the concentration exceeds amorphous solubility, for example, during dissolution some solid dispersions, is thought be advantageous from a bioavailability enhancement perspective. Recently, we have developed high surface area, flow-through absorptive testing apparatus that enables fast mass transfer providing more in vivo...
A new polymorph of tolfenamic acid, form IX, has been crystallised from a simple cooling crystallisation experiment raising the question as to why this had never reported before.
Investigating crystal nucleation at the nanoscale is of significant interest, in particular, as more complex, nonclassical routes have roused questions about classical view homo- and heteronucleation processes. Here, we report direct observation a two-step mechanism during transformation anhydrous olanzapine to dihydrate. Atomic force microscopy studies dominant (100)OZPNI face form I single crystals contact with water show formation growth dense nanodroplets concentrated steps. In unstirred...
The solid form landscape of 5-HT2a antagonist 3-(4-(benzo[d]isoxazole-3-yl)piperazin-1-yl)-2,2-dimethylpropanoic acid hydrochloride (B5HCl) proved difficult to establish. Many crystalline materials were produced by screening, but few forms readily grew high quality crystals afford a clear picture or understanding the landscape. Careful control crystallization conditions, range experimental methods, computational modeling solvate structures, and crystal structure prediction required see...
One of the most commonly used formulation development tools is dissolution testing. However, for solubility enhancing formulations, a simple closed compartment conventional apparatus operating under sink conditions often fails to predict oral bioavailability and differentiate between formulations. Hence, increasing attention being paid combined dissolution-absorption The currently available mass transport apparatuses, however, have certain limitations, important small membrane surface area,...