A molecular picture of the problems in ensuring structural purity of tazofelone

Price, Louise S.; McMahon, Jennifer A.; Lingireddy, Sreenivas R.; Lau, Suk-Fai; Diseroad, Benjamin A.; Price, Sarah L.; Reutzel‐Edens, Susan M.

doi:10.1016/j.molstruc.2014.01.014

Cited by 37 publications

(49 citation statements)

References 70 publications

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“…A complementary approach to analyse structures and rationalize the stability of polymorphs has been introduced in Mercury through visualization of knowledge-based interaction maps around molecules in a crystal structure (Wood et al, 2013). The 'Full Interaction Maps' component within CSD-Materials can be used to evaluate the preferred interactions of a molecule (Honorato et al, 2019;Price et al, 2014).…”

Section: Structure Analysismentioning

confidence: 99%

Mercury 4.0: from visualization to analysis, design and prediction

et al. 2020

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The program Mercury, developed at the Cambridge Crystallographic Data Centre, was originally designed primarily as a crystal structure visualization tool. Over the years the fields and scientific communities of chemical crystallography and crystal engineering have developed to require more advanced structural analysis software. Mercury has evolved alongside these scientific communities and is now a powerful analysis, design and prediction platform which goes a lot further than simple structure visualization.

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Section: Structure Analysismentioning

confidence: 99%

Mercury 4.0: from visualization to analysis, design and prediction

et al. 2020

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“…8,11 For example, molecules that can pack in hydrogen-bonded layers that can stack in different ways with similar energies could form polytypic packings or have stacking faults. 20 Closely related structures can manifest as static or dynamic disorder depending on the energy barriers. 17 Hence, decisions about the extent of the search and the clustering criteria can have a major effect on the number of structures that need to be considered and their interpretation.…”

Section: Discussionmentioning

confidence: 99%

“…8 For pharmaceuticals with few intramolecular degrees of freedom, several successful CSP studies have been conducted. [17][18][19][20][21][22][23][24] However, the CSP search space grows exponentially with conformational exibility and hence more efficient methods are needed for application to modern pharmaceuticals. The challenge of dealing with molecular exibility is compounded by small changes in some bond or torsion angles having a signicantly greater effect on the overall molecule shape in large pharmaceuticals than in smaller molecules.…”

Section: Introductionmentioning

confidence: 99%

“…A possible solution is the use of an intermediate optimisation method, which can bridge the gap between the simple models used to generate the crystal structures and the more accurate ones used to generate an accurate nal energy ranking. For exible molecules, several intermediate methods are used in different CSP workows, such as optimising some torsion angles with a transferable force-eld to improve the molecular conformation geometries, 43,44 single-point energy calculations with a more accurate description of the intra-and intermolecular interactions 18,20 or partial lattice energy optimisations. 1,22 Recently, semi-empirical QM methods have been applied to large chemical and biochemical systems; 45,46 these methods do not have the transferability problems of standard force elds but are signicantly less demanding than other QM methods.…”

Section: Introductionmentioning

confidence: 99%

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Crystal structure prediction of flexible pharmaceutical-like molecules: density functional tight-binding as an intermediate optimisation method and for free energy estimation

et al. 2018

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Successful methodologies for theoretical crystal structure prediction (CSP) on flexible pharmaceutical-like organic molecules explore the lattice energy surface to find a set of plausible crystal structures. The initial search stages of CSP studies use relatively simple lattice energy approximations as hundreds of thousands of minima have to be considered. These generated crystal structures often have poor molecular geometries, as well as inaccurate lattice energy rankings, and performing reasonably accurate but computationally affordable optimisations of the crystal structures generated in a search would be highly desirable. Here, we seek to explore whether semi-empirical quantum-mechanical methods can perform this task. We employed the dispersion-corrected tight-binding Hamiltonian (DFTB3-D3) to relax all the inter- and intra-molecular degrees of freedom of several thousands of generated crystal structures of five pharmaceutical-like molecules, saving a large amount of computational effort compared to earlier studies. The computational cost scales better with molecular size and flexibility than other CSP methods, suggesting that it could be extended to even larger and more flexible molecules. On average, this optimisation improved the average reproduction of the eight experimental crystal structures (RMSD15) and experimental conformers (RMSD1) by 4% and 23%, respectively. The intermolecular interactions were then further optimised using distributed multipoles, derived from the molecular wave-functions, to accurately describe the electrostatic components of the intermolecular energies. In all cases, the experimental crystal structures are close to the top of the lattice energy ranking. Phonon calculations on some of the lowest energy structures were also performed with DFTB3-D3 methods to calculate the vibrational component of the Helmholtz free energy, providing further insights into the solid-state behaviour of the target molecules. We conclude that DFTB3-D3 is a cost-effective method for optimising flexible molecules, bridging the gap between the approximate methods used in CSP searches for generating crystal structures and more accurate methods required in the final energy ranking.

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“…Moreover, it does not depend upon the kinetics of crystallization which can further vary on a wide range of controllable and less easily controlled crystallization conditions. CSP is already beginning to play an important role in understanding the organic solid-form landscape, as seen in some recent industrial examples from glaxo smithkline [10], eli lilly [11], pfizer [12] and others [13][14][15]. Pharmaceutical crystals can exist as single molecular entities or as molecular adducts [16].…”

Section: Introductionmentioning

confidence: 99%

Crystal Structure Prediction in the Context of Pharmaceutical Polymorph Screening and Putative Polymorphs of Ciprofloxacin

Singh

Chadha

2017

Int J Pharm Pharm Sci

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Molecular simulation is increasingly used by medicinal chemists in the process and product development. Reliable computational predictions are of great value not only for the design of an active pharmaceutical ingredient with novel properties but also for the avoidance of an undesirable change of form in the late stages of development of an industrially important molecule. In the pharmaceutical industry, drug polymorphism can be a critical problem and is the subject of various regulatory considerations. This contribution tried to review the fuzzy frontiers between the chemical structure of the molecule and its crystal energy landscape with a particular focus on the crystal structure prediction (CSP) methodology to complement polymorph screening. A detailed application of CSP in the pharmaceutical industry is illustrated on ciprofloxacin; describing its putative polymorphs. This approach successfully identifies the known crystal form within this class, as well as a large number of other low-energy structures. The performance of the approach is discussed in terms of both the quality of the results and computational aspects. CSP methods are now being used as part of the interdisciplinary range of studies to establish the range of solid forms of a molecule. Moreover, further methodological improvements aimed at increasing the accuracy of the predictions and at broadening the range of molecules i.e. co-crystals, salts and solvates.

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A molecular picture of the problems in ensuring structural purity of tazofelone

Cited by 37 publications

References 70 publications

Mercury 4.0: from visualization to analysis, design and prediction

Mercury 4.0: from visualization to analysis, design and prediction

Crystal structure prediction of flexible pharmaceutical-like molecules: density functional tight-binding as an intermediate optimisation method and for free energy estimation

Crystal Structure Prediction in the Context of Pharmaceutical Polymorph Screening and Putative Polymorphs of Ciprofloxacin

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