Crystal structure concomitant polymorphs

Given the complementary nature of molecular recognition, it would appear that, when a compound crystallizes, the crystallization pathway, and hence the crystal structure obtained, should be quite specific to the molecule in question. However, the very existence of the phenomenon of polymorphism indicates that, under certain conditions, alternative crystallization pathways are feasible. In the special circumstance of concomitant polymorphism, or the simultaneous appearance of polymorphic forms in the same crystallization batch, these pathways even co-exist.1321 So, in general, the study of polymorphic systems has a bearing on a better... 

A (molecular) crystal polymorph is a solid crystalline phase of a given compound resulting from the possibility of at least two different arrangements of the molecules of that compound in the solid state Conformational polymorphs are formed by molecules that can adopt different conformations in different crystal structures formed by coordination complexes where ligands bound in delocalized bonding modes adopt different relative orientations Concomitant polymorphs are polymorphic modifications of the same substance obtained from the same crystallisation process Pseudo-polymorphs are ... 

In view of the many experiments carried out in achieving the crystallization of proteins and subsequently refining those conditions to maximize crystal size and quality for X-ray structure determination, it is not surprising that examples of concomitant crystallization are found among proteins. We cite two here. Fu et al. (1994) reported the simultaneous crystallization of three polymorphs of an m-class glutathione... 

To this point this account of instances of concomitant polymorphs has been phenomenological. We have discussed the thermodynamic and kinetic crystallization of polymorphs. There is still the question if any insight concerning controlling the polymorph obtained can be gained from the study of the crystal structure of concomitantly crystallized polymorphs. A qualitative attempt was made to see if details of the... 

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. 

Diphenyl-2,5-cyclohexadienone 3 exists as four polymorphs, labeled A-D, whose crystallographic details are summarized in Table 3-2 [14]. Polymorphs A-D are conformational polymorphs since they have different molecular conformers in their crystal structures. They are also concomitant polymorphs because they crystallized simultaneously from the same flask and under identical crystal nucleation and growth conditions. Forms B-D with multiple molecules in the asymmetric unit Z > ) may also be classified as conformational isomorphs. Such polymorph clusters with different molecular conformations, crystal packing and C—H - O... 

Figure 3-9. (a) Powder XRD of crystalline dimethyl fuschone 6 shows a mixture a (80%), /3 (18%) and y forms (2%) at 30°C. (b) Heating the concomitant mixture to 170°C shows pure /3 form in >97% polymorphic purity from PXRD match with the simulated powder profile from the X-ray crystal structure (see color plate section)... 

Two polymorphs of DL-methionine, the a- and j8-forms, have been known since 1950 as concomitant conformational polymorphs [154-157]. The crystals have almost identical shape, for which reason the second form was discovered by chance. The two forms are almost equally stable, and their crystal structures are also similar (Figure 7-6). 

L-glutamic acid provides an example of the existence of two concomitant polymorphs, of which the crystal habits differ greatly - needles and plates. Their crystal structures look very different (Figure 7-7) [158-162], but, despite the distinct... 

The phenomenon of polymorphism demonstrates that metastable erystal struetures are observed, and it is not always obvious that sueh crystal structures are metastable. The energy differences between different polymorphs crystallized out of different solvent are small, and those between concomitant polymorphs presumably are very small. Kinetics must play a major role in determining which of the approximately equi-energetic hypothetical crystal structures are actually observed. How do the kinetics of nucleation and growth, and the variations with crystallization conditions, affect which thermodynamically feasible crystal structures are actually seen How can this be incorporated in the crystal structure prediction model to produce a polymorph prediction model ... 

AA -di(m-nitrophenyl)urea or DNPU (dinitrophenyl urea) exists in three concomitant polymorphic forms (a, and S) of different colours [25], It readily forms solvates and cocrystals with compounds having strong to moderate hydrogen bond acceptors [26], The characteristic urea network is absent except in the noncentrosymmetric /3-polymorph of DNPU whereas a and y polymorphs are sustained by N-H- -Onitro H bonds. We examined hydrogen bond competition in crystal structures of N-X-phenyl-A -p-nitrophenyl urea, abbreviated as PNPU-X [27] (Figure 5.15). A variety of X groups were considered. 

The compound l,3,5-tris(4-cyanobenzoyl)benzene, 2, provides an example of an organic compound which displays both polymorphism and structural isomerism in its crystal forms. Recrystalhzation of 2 from acetone/water gave two concomitant polymorphs (forms A and B), illustrated in Figure 4. Each polymorph exists in a distinct network structure, held together by C-H- O hydrogen bonds. In form A, these generate a honeycomb network while in form B, a ladder network is produced. As both networks contain the identical molecular building blocks, they are supramolecular isomers of each other. 

The sensitivity of infrared absorption spectroscopy toward subtle changes in crystal structure has led to its widespread use in the investigations of pharmaceutical compounds that exhibit polymorphism. For example, three concomitant polymorphs of l,3-bis(w-nitro-phenyl)urea had been reported in 1899 as yellow prisms, white needles, and yellow tabular crystals, and FT IR spectroscopy was used during a more detailed investigation of the system. In this work, complete assignments for the absorption bands associated with hydroxyl, amide, nitro, and benzene-ring functional groups were developed in order to obtain a deeper... 

Cassoux et al. (1991) note that The occurrence of several phases for this compound complicates its study . While die separation of concomitantly crystallizing phases may have been an experimental compUcation in dieir particular study, we beUeve diat die existence of polymorphs greatly facilitates the study of structure-property relations, since all chemical parameters are constant among polymorphs of a particular substance and differences in properties can be related directly to differences in structure. Chapter 6 is devoted to diis subject. 

An example of a tt-bonded complex is the remarkable cyanine oxonol system, 3-XVI 3-XVII, for which at least fourteen different polymorphs or solvates have been identified (Etter et al. 1984). Two of these, a gold and a red form (each containing a molecule of CHCI3 solvent per 1 1 complex, and hence true polymorphs) crystallize concomitantly and have been structurally characterized (Etter et al. 1984). Three of these polymorphs are shown in Fig. 3.2. Despite the fact that both of these dye molecules are known to be individually self aggregating (Cash 1981) the two... 

Polymorphism may be utilized to study this phenomenon of dye aggregation, employing similar experimental spectroscopic techniques as above. As noted and discussed earlier (Sections 3.5.3 and 6.2.3) the dye molecule 6-XVn (R = Et, R = OH) with the solution spectrum shown in Fig. 6.22, has been shown to concomitantly crystallize as violet and green crystals (Tristani-Kendra et al. 1983). Of interest here are the spectral manifestations of those structural differences. 

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