Concomitant polymorphism crystallization

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. 

Concomitant polymorphs crystallize simultaneously from the same solvent or melt and in the same crystallizing flask under identical crystal growth conditions. However, the possibility that concomitant polymorphs grow in stages by means of a solvent-mediated phase transformation cannot easily be ruled out." ... 

The isolation of crystalline products having mixed polymorphic compositions (often referred to as concomitant polymorphism) remains a topic of interest, even though the phase rule predicts that a system at equilibrium consisting two components (solvent + solute) and three phases (solution + Form I + Form II) is uni variant. Hence, for crystallizations performed at a fixed pressure (typically atmospheric) the system becomes nonvariant and genuine equilibrium can exist at only one temperature. Therefore, concomitant products must be obtained under nonequilibrium conditions. Flexibility in molecular conformation was attributed to the concomitant polymorphs of a spirobicyclic dione [34] and of 3-acetylcoumarin [35],... 

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... 

Concomitant polymorphs concomitant polymorphs are polymorphic forms of a substance that crystallise out at the same time from the same crystallisation mixture. Here at the same time does not necessarily mean that the crystals form at exactly the same instant, just that they can be observed co-existing at some point during the crystallisation process. We have already come across concomitant polymorphs in the early example of benzamide where forms I and II are concomitant. Many more interesting and beautiful examples are covered in a recent review.62... 

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 ... 

Two-component (i.e. two molecules) systems also exhibit concomitant polymorphism, implying a balance for the equilibrium situations governing the formation of the isomeric complexes as well as the kinetic and thermodynamic factors associated with the crystallization processes. The often serendipitous nature of the discovery of concomitant polymorphs is also illustrated by an example of a hydrogen-bonded two-component system, pyromellitic acid 3-XIV and 2,4,6-trimethylpyridine 3-XV (Biradha and Zaworotko 1998). The first polymorph (A) was obtained by reacting 3-XIV with four equivalents of 3-XV in a methanolic solution. Using 3-XV as the solvent yielded a second polymorph (B) in 15 min. Modification A was found to have crystallized as well in the same reaction vessel after about 24 h. These two polymorphs are not readily distinguishable by their morphology. However, the authors point out that the experimental evidence indicates that Form B is the kinefically controlled one, while Form A is the thermodynamically preferred one. 

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... 

Fig. 3.2 (See also plate section.) Three of the concomitant polymorphs of the cyanine oxonol dyes 3-XVI and 3-XVII. Gold (by reflection otherwise red by transmission) and red forms mentioned in the text are easily distinguishable. The third form is a purple one, normally diamond shaped as on the middle right, but many of these crystals are undergoing conversion, as indicated by varying degrees of mottled surfaces. (From Bernstein et al. 1999, with permission.)...

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... 

The induction times of carbamazepine polymorphs [monoclinic, CBZ(M) and trigonal, CBZ(Trg)] were evaluated by optical microscopy. The polymorphs were identified by their crystal morphology where CBZ(M) crystallizes as prismatic crystals and CBZ(Trg) crystallizes as needles, which were confirmed by X-ray powder diffraction. It was determined that under constant supersaturation concomitant crystallization is favored in solvents that accept and donate hydrogen bonds (ethanol, methanol, isopropanol, etc.). However, the metastable CBZ(Trg) polymorph preferentially crystallized in solvents that primarily accept hydrogen bonds (ethyl acetate, methyl acetate, 2-butanone, etc.) with the stable CBZ(M) polymorph crystallizing at least an hour later. The induction times of CBZ polymorphs did not decrease with increases in solubility, suggesting that nucleation is not controlled by solubility differences. It was determined that CBZ polymorph nucleation was governed by the specific solute-solvent interactions that occurred in solution to... 

When the concentration and temperature of crystallization falls outside of the shaded regimes, the polymorphic outcome will be under kinetic control and therefore may depend on the solvent. For instance, a solution of concentration C cooled to a crystallization point Cl will be outside the metastable zones of both polymorphs I and II, such that the either or both may crystallize. The polymorphic outcome will be governed by the relative nucleation rates of the polymorphs, which depend directly on the solvent. Solution D cooled to point D1 will be outside the metastable zone of polymorph I yet still within the metastable zone of polymorph II. The expected outcome would be polymorph I in this case although the solvent may be important. Cooling a solution of concentration E to points El or E2 will result in solutions that are within the metastable zones of both polymorphs I and II. Here the polymorphic outcome will also depend directly on solvent and will be particularly sensitive to accidental seeding. Both polymorphs are likely to crystallize in this regime leading to so-called concomitant polymorphs. ... 

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... 

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 crystal growth of amino acids is puzzling. As already mentioned, they commonly grow as concomitant polymorphs. An altered rate of crystallization resuits readily in the formation of a hydrate instead of an anhydrous form. For example, attempts to grow L-serine by slow evaporation of its aqueous solutions yield a monohydrate, unstable in air [81, 169]. If a powder sample of L-serine is added to the solution (ethanol and H2O, 1 1), large single crystals of the stable anhydrous L-serine precipitate immediately [81]. The latter process is not observed when D-serine is taken instead of L-serine, likely because of the presence of other impurities in the o-serine powder [170]. The dissolution of OL-serine powder produces... 

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. 

OLS is generally valid for all polymorphic systems. However, if the nucleation rates and growth rates of stable and metastable polymorphs are eqnal, then they tend to crystallize together (a case of concomitant polymorphism)." In such a scenario, OLS cannot be applied but the metastable polymorphs that appear concomitantly with other polymorphs can convert to the stable polymorph under different experimental conditions. 

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