Polymorphism flexible molecules

Conformational polymorphism refers to the occurrence of different molecular conformations in different polymorphs. Flexible molecules with several degrees of freedom and low-energy conformers are likely to adopt different conformations leading to conformational polymorphs. Many APIs are conformationally flexible and possess rotatable C-C, C-N, and C-0 bonds, and conformational polymorphism in these compounds can be observed (Figure 3). 5-Methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile, which is commonly known as ROY for its red, orange, and yellow crystals, holds the current record for the highest number of polymorphs (i.e., seven)... 

Examination of the sources of error in the equations suggests the contribution of a number of factors. The purity of dyes, differences in solubilities of polymorphic forms of dyes, tau-tomerization, hydrogen bonding, and polarization all can contribute to the difficulty in accurately measuring the S and Kow. The use of an "average" value of ASf in the presence of variability of a factor of two in the values for rigid structures (e.g., anthraquinone dyes) versus more flexible molecules (e.g., azo dyes) may lead to significant errors in estimation. 

At first glance this definition seems straightforward. What are some of the complications For flexible molecules McCrone would include conformational polymorphs, wherein the molecule can adopt different conformations in the different crystal structures (Corradini 1973 Panagiotopoulis et al. 1974 Bernstein and Hagler 1978 Bernstein 1987). But this is a matter of degree dynamic isomerism or tautomerism... 

The term Conformational Polymorphism has been used to describe flexible molecules which are dimorphic and adopt different conformations in the two crystal forms (see J. Bernstein and A. T. Hagler, /. Am, Chem. Soc., 1978,100, 673, and references therein). 

Polymorphs are classified according to the following terminologies. Concomitant polymorphs crystallize simultaneously from the same solvent and crystallization flask under identical crystal growth conditions. They may be viewed as supramolec-ular isomers in a chemical reaction. Conformational polymorphs occur for flexible molecules, i.e. these molecules can adopt more than one conformation under ambient conditions. When different conformers of the same molecule are present in the same crystal structure the situation represents conformational isomorphs. Conformational isomorphism, the existence of multiple conformations in the same crystal structure, is closely related to the presence of more than one molecule in the asymmetric unit, i.e. Z >1. The exact reasons why some crystals have Z > 1 are still not properly understood even as several research groups are working to seek answers to this enigma [9]. Pseudopolymorphism, [10] the occurrence of the same molecule with different solvent molecules in the crystal lattice or the same solvent in a different stoichiometry, is closely related to polymorphism. 

The existence of more than one type of network super-stracture for the same molecular building block represents supramolecular isomerism. Therefore, it is related to stractural isomerism at the molecular level. Supramolecular isomerism is the existence of different architectures (i.e., architectural isomerism) or superstructures. Polymorphism is a type of supramolecular isomerism but not vice versa. Supramolecular isomerism can be classified as structural (the same components result in different network superstructures), conformational (different conformations of a flexible molecule generate different, but often related, network architectures), catenane (the different maimer and degrees in which networks interpenetrate or interweave), and optical (chirai networks that... 

Thus, solid 1 exists as at least four forms differing in both crystalline and molecular structure two yellow crystalline 1 1 solvates with toluene and THF (lb and Ic), and two solvent-free forms orange crystals (la) and a yellow powder (Id). Bernstein [10] uses a term conformational polymorphism for this phenomenon, that is, existence of several forms of a conformationally flexible molecule (with energy difference between the conformers less then 2 kcal/mol) depending on crystallization conditions. Our experience with a step-by-step serendipitous finding of new conformational polymorphs of 1 ([1, 4-6] and this paper) closely resembles the classical story about analogous forms of dimethylbenzylideneaniline, described vividly in [10]. 

Computational methods could, therefore, potentially impact on polymorph screening, salt or co-crystal selection, as well as the avoidance of solvates. The outline of such a possibility should not be viewed as an over-optimistic assessment of current capabilities, but rather a goal towards which developments should aim. Given that progress is being made on flexible molecules and multi-component crystal structures, the methods that are necessary for such in silico screens are attainable, although it is difficult to predict the rate of progress and, therefore, when such calculations will be practical for the typical pharmaceutical molecule. Moreover, results will always need to be interpreted with care and a realistic view of the approximations and limitations of the methods. This is where continued assessment of methods on well-characterized systems is needed, to inform our level of confidence in the calculations. 

Computational assessment of the likelihoods of occurrence and the relative stabilities of polymorphs is not necessarily more effective than the experimental approach. Whilst great advances have been made in the field of ab initio crystal structure prediction (CSP), as documented in five international blind tests spanning the years 1999-2010 [5], it is still not routinely possible to predict whether a molecule is likely to be polymorphic or to confirm whether the most thermodynamically stable structure has been found experimentally, especially for molecules of the complexity of a typical drug. It is possible to compute the polymorph landscape for a specific flexible molecule, but the calculations require considerable expertise, and the timescales and computing resources can render CSP impractical for application to even a limited portfolio of candidate APIs. 

A molecnle whose polymorphism emphasizes the challenge in nnderstanding such conformationally flexible molecules is ortho-acetamidobenzamide, which has two known polymorphs. In the low-temperature a polymorph (Figure 4a,b), each molecule donates and accepts two inter-molecular hydrogen bonds and the conformation is stabilized by an intramolecular hydrogen bond between the... 

When flexible molecules (or flexible ligands in coordination networks) are employed, different network architectures may be generated from the same building blocks. An analogy can be drawn to conformational polymorphism such as that seen in acetone tosylhydrazone, 4. A monoclinic and a triclinic form are obtained from anhydrous ethanol, sometimes together. The conformations differ by about 15° about the S-C exocyclic bond. 

Conformational Conformational changes in flexible molecules can generate different, but often related, nets. This is related to conformational polymorphism. 

Polymorphs are common in organic chemistiy and are prevalent when hydrogen bonding is involved in the crystal lattice. 2,6 di-hydroxybenzoic acid [13] is a well documented example. Polymorphism is more probable when molecules are large and possess conformational flexibility, which increases the number of feasible molecular arrangements that can produce a stable ciystal... 

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