Discovery of three polymorphs of 7-fluoroisatin reveals challenges in using computational crystal structure prediction as a complement to experimental screening

Mohamed, Sharmarke; Barnett, Sarah A.; Tocher, Derek A.; Price, Sarah L.; Shankland, Kenneth; Leech, Charlotte K.

doi:10.1039/b714566g

Cited by 17 publications

(21 citation statements)

References 26 publications

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“…54 However, predicting whether the solvate or cocrystal will be formed in preference to the pure compounds can be very demanding of the relative accuracy of the three crystal energies, even assuming that it is thermodynamically determined. 55 Thus, computing the crystal energy landscape and contrasting the packing motifs can provide valuable insight into the possible solid-state forms for a given molecule.…”

Section: Discussionmentioning

confidence: 99%

Computed Crystal Energy Landscapes for Understanding and Predicting Organic Crystal Structures and Polymorphism

2008

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The phenomenon of polymorphism, the ability of a molecule to adopt more than one crystal structure, is a well-established property of crystalline solids. The possible variations in physical properties between polymorphs make the reliable reproduction of a crystalline form essential for all research using organic materials, as well as quality control in manufacture. Thus, the last two decades have seen both an increase in interest in polymorphism and the availability of the computer power needed to make the computational prediction of organic crystal structures a practical possibility. In the past decade, researchers have made considerable improvements in the theoretical basis for calculating the sets of structures that are within the energy range of possible polymorphism, called crystal energy landscapes. It is common to find that a molecule has a wide variety of ways of packing with lattice energy within a few kilojoules per mole of the most stable structure. However, as we develop methods to search for and characterize "all" solid forms, it is also now usual for polymorphs and solvates to be found. Thus, the computed crystal energy landscape reflects and to an increasing extent "predicts" the emerging complexity of the solid state observed for many organic molecules. This Account will discuss the ways in which the calculation of the crystal energy landscape of a molecule can be used as a complementary technique to solid form screening for polymorphs. Current methods can predict the known crystal structure, even under "blind test" conditions, but such successes are generally restricted to those structures that are the most stable over a wide range of thermodynamic conditions. The other low-energy structures can be alternative polymorphs, which have sometimes been found in later experimental studies. Examining the computed structures reveals the various compromises between close packing, hydrogen bonding, and pi-pi stacking that can result in energetically feasible structures. Indeed, we have observed that systems with many almost equi-energetic structures that contain a common interchangeable motif correlate with a tendency to disorder and problems with control of the crystallization product. Thus, contrasting the computed crystal energy landscape with the known crystal structures of a given molecule provides a valuable complement to solid form screening, and the examination of the low-energy structures often leads to a rationalization of the forms found.

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Section: Discussionmentioning

confidence: 99%

Computed Crystal Energy Landscapes for Understanding and Predicting Organic Crystal Structures and Polymorphism

2008

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“…However, the restriction to Z 0 = 1 would miss many polymorphs, with the importance of Z 0 > 1 structures becoming more appreciated as crystallographers solve more such structures. 25 Whilst some Z 0 > 1 polymorphs are closely related to simpler Z 0 = 1 structures and can be viewed as trapped ''crystals on the way'' or incomplete crystallisations, or may be lower temperature polymorphs, there are structures that are intrinsically Z 0 > 1, for example the most stable polymorph of 7-fluoroisatin 26 (Fig. 5).…”

Section: Extent Of Searchmentioning

confidence: 99%

Predicting crystal structures of organic compounds

Price¹

2014

Chem. Soc. Rev.

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462

456

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Currently, organic crystal structure prediction (CSP) methods are based on searching for the most thermodynamically stable crystal structure, making various approximations in evaluating the crystal energy. The most stable (global minimum) structure provides a prediction of an experimental crystal structure. However, depending on the specific molecule, there may be other structures which are very close in energy. In this case, the other structures on the crystal energy landscape may be polymorphs, components of static or dynamic disorder in observed structures, or there may be no route to nucleating and growing these structures. A major reason for performing CSP studies is as a complement to solid form screening to see which alternative packings to the known polymorphs are thermodynamically feasible.

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“…No crystal structures have been reported for 7‐fluoroisatin, so a combined computational and experimental search for polymorphs was undertaken to establish the crystal forms and to evaluate the value of crystal structure prediction studies as an aid to solid form discovery 27. The experimental work yielded three polymorphs and two solvates, but the computed relative energies of the three polymorphic forms were not in accord with the experimental results.…”

Section: Computational and Theoretical Studiesmentioning

confidence: 99%

Polymorphism Solvatomorphism 2008

Brittain¹

2010

Journal of Pharmaceutical Sciences

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Discovery of three polymorphs of 7-fluoroisatin reveals challenges in using computational crystal structure prediction as a complement to experimental screening

Cited by 17 publications

References 26 publications

Computed Crystal Energy Landscapes for Understanding and Predicting Organic Crystal Structures and Polymorphism

Computed Crystal Energy Landscapes for Understanding and Predicting Organic Crystal Structures and Polymorphism

Predicting crystal structures of organic compounds

Polymorphism Solvatomorphism 2008

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