Molecules, polymorphic

The topic of polymorphism is of tremendous and increasing academic and industrial importance in modern crystal chemistry and crystal engineering. The industrial interest stems from the pharmaceutical industry and has stimulated wide-ranging academic study. Legally, a molecule (termed an active pharmaceutical Ingredient, API) with particular biological activity in vivo can be patented as a new invention. Moreover, particular crystal forms of that molecule (polymorphs) can be separately patented as distinct inventions. If particular polymorphs are patented after the original API patent then upon the... 

In all the polymorphs, each water molecule is hydrogen bonded to four other water molecules. Polymorphs VI has a remarkable structure which comprises two discrete interpenetrating but not interconnected frameworks of H-bonded water molecules (Kamb, 1965). Similarly ice-VII and VIII comprise two interpenetrating frameworks of water molecules (Fig. 6) each framework having the same structure as the thermodynamically unstable polymorph ice-Ic. In ice-VII the hydrogen atoms are disordered, but they are ordered in ice-VHI. 

Polymorphism can be detected by the differences in physical properties due to individual characteristics. Based on the fugacity, which relates to the thermodynamic term, entropy of the solid molecule, polymorphism may be defined as monotropic or enantiotropic. Furthermore, combination of these two systems, monotropic and enantiotropic, may yield a third system. The definition of these categories may best be illustrated by the solubility-temperature plots, based on the van t Hoff equation. In a monotropic category as shown in Figure 9, the solubility of form I (the stable form) and that of form II (the metastable form) will not intersect each other at the transition temperature calculated only from the extrapolation of the two curves. In the enantiotropic category (Fig. 10), the solubility of form I (the stable form) and that of form II (the metastable form) will intersect each other at the transition temperature. In the combined category (Fig. 11), for which there are two transition temperatures, the solubility of form III will not intersect any other curves. 

Among the long-chain molecules, polymorphism occurs quite frequently. Different crystal forms of one solid compound are usually stable in different temperature ranges, but there are also cases where two forms crystallize simultaneously from a solution. Each crystal form usually has its own spectrum, which means that a polymorphic substance can have as many spectra as it has crystal forms. When such substances are investigated it is necessary to state the crystal form of the sample, or otherwise describe thoroughly the solvent and temperature of crystallization. 

In this paper we shall discuss all four different types of crystal forms of the same molecule polymorphs of the mere molecule, solvates and hydrates, molecular salts and co-crystals (when the same molecule can be co-crystaUized with different cocrystal formers). All these crystal forms are summarized in Fig. 1. 

Many molecules are obtained and used in a crystalline form, the nature of which can have e significant impact on their properties and behaviour. Moreover, it is sometimes possible foi a given material to exist in more than one crystalline form, depending upon the conditions under which it was prepared. This is the phenomenon of polymorphism. This can be important because the various polymorphs may themselves have different properties. It is Iberefore of interest to be able to predict the three-dimensional atomic structure(s) that a gi en molecule may adopt, for those cases where it is difficult to obtain experimental data and also where one might wish to prioritise molecules not yet synthesised. 

Figure 15.18 (a) Schematic representation of the path of the polypeptide chain in the structure of the class I MHC protein HLA-A2. Disulfide bonds are indicated as two connected spheres. The molecule is shown with the membrane proximal immunoglobulin-like domains (a3 and Pzm) at the bottom and the polymorphic al and a2 domains at the top. 

The genes for MHC molecules, unlike immunoglobulin genes, do not undergo rearrangements to create structural diversity. The Pzm light chain is invariant, but the class I MHC heavy chain is the most genetically polymorphic... 

The diffusion, location and interactions of guests in zeolite frameworks has been studied by in-situ Raman spectroscopy and Raman microscopy. For example, the location and orientation of crown ethers used as templates in the synthesis of faujasite polymorphs has been studied in the framework they helped to form [4.297]. Polarized Raman spectra of p-nitroaniline molecules adsorbed in the channels of AIPO4-5 molecular sieves revealed their physical state and orientation - molecules within the channels formed either a phase of head-to-tail chains similar to that in the solid crystalline substance, with a characteristic 0J3 band at 1282 cm , or a second phase, which is characterized by a similarly strong band around 1295 cm . This second phase consisted of weakly interacting molecules in a pseudo-quinonoid state similar to that of molten p-nitroaniline [4.298]. 

Phosphorus (like C and S) exists in many allotropic modifications which reflect the variety of ways of achieving catenation. At least five crystalline polymorphs are known and there are also several amorphous or vitreous forms (see Fig. 12.3). All forms, however, melt to give the same liquid which consists of symmetrical P4 tetrahedral molecules, P-P 225 pm. The same molecular form exists in the gas phase (P-P 221pm), but at high temperatures (above 800°C) and low pressures P4 is in equilibrium with the diatomic form P=P (189.5 pm). At atmospheric pressure, dissociation of P4 into 2P2 reaches 50% at 1800°C and dissociation of P2 into 2P reaches 50% at 2800°. 

In the vapour phase As is known to exist as tetrahedral Asa molecules with (As-As 243.5 pm) and when the element is sublimed, a yellow, cubic modification is obtained which probably also contains Asa units though the structure has not yet been determined because the crystals decompose in the X-ray beam. The mineral arsenolamprite is another polymorph, e-As it is possibly isostructural with metallic orthorhombic P. 

The ring adopts the chair Ibrm and its dimensions are compared with those of other polymorphs in Table 15.5. Note that cyc/o-S has the smallest bond angle and dihedial angle of all poly-sulfur species for which data are available and this, Uigether with the small hole at the centre of the molecule and the efficient packing within the crystal, lead to the highest density of any known polymorph of sulfur (Table 15.6). 

Unsubstituted phthalocyanines and also halogenated phthalocyanines show very poor solubility in organic solvents. In the solid state, unsubstituted phthalocyanines exhibit, in most cases, inclined one-dimensional stacking of the planar molecules. Besides other polymorphous modifications PcCu shows an x- and / -arrangement.74-75... 

In about 30-40% of patients with suspected inherited thrombophilia the PC-pathway is disturbed by a mutation ofFV (FV-Leiden). TheFV-Leiden mutation affects one of the APC cleavage sites within the FV molecule. As a consequence, mutated FVa becomes resistant to rapid APC inactivation (APC resistance). About 4-7% of the middle European population cany this polymorphism of FV. Inborn deficiencies of Protein-S or Protein-C are much less frequent (< < 1% and 0.2-0.4%, respectively). 

Group of transmembrane proteins engaged in the presentation of small peptide fragments to T-cells. Two classes of Major histocompatibility complex (MHC) molecules exist both of which are encoded by a highly polymorphic gene cluster. MHC class I and class II proteins present peptide fragments to CD8+ and CD4+ T-cells, respectively. The human MHC is also known as HLA, the murine MHC as H-2 complex. 

A special case of polymorphic forms can be considered the clathrates, that is forms in which polymer molecules interact with solvents in the crystalline state and form inclusion compounds. 

Many of the investigated mesogenic compounds show solid state polymorphism. In order to obtain useful information about the arrangement of the molecules in the mesophase from the X-ray data of the single crystals, it is important to investigate the crystal structure of those solid phase which transforms into the liquid crystalline phase. For instance, only the crystal structures of the low temperature solid phases of the compounds MBBA [138, 139], MHPOBC [159], and T15 [81] could be determined, but the... 

---