Types of Polymorphism

Conformational polymorphs conformational polymorphs are different pure crystal forms of the same snbstance that differ in one or mode bond rotations in the molecular structure. The implication is that these two or more conformers are in rapid equilibrinm under the conditions under which the crystal formed and hence usnally represent rotations about single bonds. If this were not the case the different conformers wonld be distinct isomers and would be formally different chemical substances and hence not polymorphs. Crystal packing interactions can stabilise particular conformers that are relatively unstable in solntion and hence crystals can contain sometimes surprising conformational isomers. A remarkable example is trans-l,4-diethynylcyclohexane-l,4-diol which has two forms (A and 

Concomitant polymorphs concomitant polymorphs are polymorphic forms of a substance that crystallise out at the same time from the same crystallisation mixtnre. Here at the same time does not necessarily mean that the crystals form at exactly the same instant, jnst 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 1 and 11 are concomitant. Many more interesting and beautiful examples are covered in a recent review.  

Supramolecular isomerism Supramolecular isomerism has been defined by Zaworotko as the existence of more than one type of network superstructure for the same molecular building blocks, and hence he adds that it is therefore related to structural isomerism at the molecular level. In cases where the molecular building blocks are capable of forming more than one type of supramolecular synthon then supramolecular isomerism is identical to polymorphism. Zaworotko defines another kind of supramolecular isomerism, however, in which the same building blocks exhibit different network architectures or superstructures. We will see examples of this phenomenon in chapter 9, particularly regarding interpenetrated networks. 

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Polymorphism. Many crystalline polyolefins, particularly polymers of a-olefins with linear alkyl groups, can exist in several polymorphic modifications. The type of polymorph depends on crystallisa tion conditions. Isotactic PB can exist in five crystal forms form I (twinned hexagonal), form II (tetragonal), form III (orthorhombic), form P (untwinned hexagonal), and form IP (37—39). The crystal stmctures and thermal parameters of the first three forms are given in Table 3. Form II is formed when a PB resin crystallises from the melt. Over time, it is spontaneously transformed into the thermodynamically stable form I at room temperature, the transition takes about one week to complete. Forms P, IP, and III of PB are rare they can be formed when the polymer crystallises from solution at low temperature or under pressure (38). Syndiotactic PB exists in two crystalline forms, I and II (35). Form I comes into shape during crystallisation from the melt (very slow process) and form II is produced by stretching form-1 crystalline specimens (35). 

Essential to the definition of Pharmacogenetics is the term genetic polymorphism. It is extrapolated that there are at least three million genetic polymorphisms in the human genome. Historically, a genetic polymorphism was defined as a genetic variation with a population frequency of 1% and above, but the larger inter-ethnic variation of population frequencies makes a strict definition based on such frequencies impractical. The most common molecular type of polymorphism is the... 

Knowledge of polymorphic forms is of importance in preformulation because suspension systems should never be made with a metastable form (i.e., a form other than the stable crystal form). Conversely, a metastable form is more soluble than a stable modification, and this can be of advantage in dissolution [Eq. (9)]. There are two types of polymorphism, a fact illustrated in the following discussion. 

Single-base substitutions, which affect the amino acid sequence of proteins and lead to altered protein function, are the most frequent type of polymorphisms associated with many disease phenotypes as well as with variation in drag response... 

Although the structure of CsCl is quite different from that of NaCl, even CsCl can be transformed into the sodium chloride structure when heated to temperatures above 445 °C. Some of the other alkali halides that do not have the sodium chloride structure under ambient conditions are converted to that structure when subjected to high pressure. Many solid materials exhibit this type of polymorphism, which depends on the external conditions. Conversion of a material from one structure to another is known as a phase transition. 

Infrared (IR) spectroscopy, especially when measured by means of the Fourier transform method (FTIR), is another powerful technique for the physical characterization of pharmaceutical solids [17]. In the IR method, the vibrational modes of a molecule are used to deduce structural information. When studied in the solid, these same vibrations normally are affected by the nature of the structural details of the analyte, thus yielding information useful to the formulation scientist. The FTIR spectra are often used to evaluate the type of polymorphism existing in a drug substance, and they can be very useful in studies of the water contained within a hydrate species. With modem instrumentation, it is straightforward to obtain FTIR spectra of micrometer-sized particles through the use of a microscope fitted with suitable optics. 

As mentioned, ethnic and racial differences can have a significant effect on the frequency and type of polymorphisms within a gene and could therefore affect the results for genetic association studies. A primary example of this effect occurs when considering racial or ethnic groups with broad genetic backgrounds. For... 

In geochemistry it is necessary to describe the composition of pyroxene by end-members that are compositionally simple and stoichiometrically well defined. It is also opportune to distinguish the various structural classes, because P-T stabihty and reactivity vary greatly with type of polymorph. This inevitably requires the formulation of fictitious components (i.e., components that have never been synthesized as pure phases in the structural form of interest, but that are present as members of pyroxene mixtures). For example, table 5.30 gives the list of pyroxene geochemical components proposed by Ganguly and Saxena (1987) (partly modified here). 

Differential scanning calorimetry (DSC) and x-ray diffraction (XRD) are the techniques most widely used for the characterization of crystallinity and polymorphism of solid lipid particles. Although DSC is usually more sensitive in detecting crystalline material, XRD is much more reliable in determining the type of polymorph present in the dispersions because it provides structural data. In contrast, DSC can detect the type of polymorph only indirectly via the transition temperatures and enthalpies. Because these parameters may be different from those observed in the bulk material, particularly for small colloidal particles [1,62], assigmnent of polymorphic forms in DSC curves should be supported by x-ray data. 

Figure 8.41 Schematic illustrating the relationship between various types of polymorph.

Preferential Enrichment is a secondary phenomenon caused by a polymorphic transition occurring during crystallization from a highly supersaturated solution. This unique dynamic enantiomeric resolution phenomenon has proved to be observable for a fairly ordered racemic mixed crystal showing a polymorphism a solvent-assisted solid-to-sohd type of polymorphic transition from the kinetically-formed metastable crystalline phase comprising homochiral R and S chains into the thermodynamically stable crystalline phase consisting of a heterochiral 2D sheet structure during crystallization is responsible for this phenomenon. That is, it is essential that homochiral R and S ID chain structures are stable in solution while a heterochiral 2D sheet structure is stable in the crystal. 

Apart from the significance as a novel enantiomeric resolution phenomenon, the investigation on the mechanism of Preferential Enrichment has also shed light on the hitherto unknown mechanism of a polymorphic transition occurring during crystallization from a supersaturated solution. A combination of several techniques employed here would also be useful to elucidate the unknown mechanism of another type of polymorphic transition... 

The 4-(3 -butenyl)-2,5-cyclohexadien-l-one derivative 8 functionalized with a chiral substituent group produced two types of polymorphic crystals, the a- and p-forms. Solid-state irradiation of the a-crystal caused [2 + 2] photocyclization to give 10 in 80% diastereomeric excess at 60% conversion (Scheme 1) [38]. In contrast, photolysis of the (3-crystals afforded almost complete reversal of the sense of diastereoselection resulting in the formation of 9 in 90% de at very low conversion. Photolysis of 8 in benzene solution resulted in low diastereodifferentiation. 

Amphiphilic lipopeptides with a hydrophobic paraffinic chain containing from 12 to 18 carbon atoms and a hydrophilic peptidic chain exhibit lyotropic meso-phases and good emulsifying properties. The X-ray diffraction study of the mesophases and of dry lipopeptides showed the existence of three types of mesomorphic structures lamellar, cylindrical hexagonal and body-centred cubic. Two types of polymorphism were also identified one as a function of the length of the peptidic chain and the other as a function of the water content of the mesophases. The emulsifying properties of the lipopeptides in numerous pairs of immiscible liquids such as water/ hydrocarbons and water/base products of the cosmetic industry showed that small amounts of lipopeptides easily give three types of emulsions simple emulsions, miniemulsions and microemulsions. 

It would be of interest to n fibers from solutions of cellulose or cellulose-PET at concentrations in the 6-10% (w/w) range to further study the type of polymorph produced and to examine die posability of obtaining high strength and modulus cellulose fibers and characteristics of intimate blends of cellulose and PET. Ternary Systems - Block CoDolvmers. As (tiscussed above, mixtures of cellulose or CTA with PET and CTA with PMMA obey Florys prediction and separate into isotropic and anisotropic phases. 

By now, we have discussed the polymorphism of mono-acid and mixed-acid TAGs. To summarize. Table 6 shows the number and types of polymorphic forms of principal TAGs. 

While all three types of polymorphisms have been identified in human genes responsible for drug response, SNPs are the most numerous and have become the target of intense study. 

When polymers crystallize from the melt or solution, the crystalline regions may exhibit various types of polymorphic modification, depending on the cooling rate, evaporation rate of solvent, temperature and other conditions. These crystal modifications differ in their molecular and crystal structures as well as in their physical properties. Many types of crystalline modifications have been reported (Tashiro Tadokoro, 1987). (See also Chapter 4.)... 

The greatest concern with this approach is lack of nucleation of the most stable form. If the starting API does not contain seeds of the stable form, a successful screen will produce nucleation of the stable form within the duration of the slurry experiments in at least one of the solvents. Lack of adequate solubility, or inhibition of nucleation due to solvent-solute interactions, may preclude transformation to the stable polymorph (Gu et al., 2001). Moreover, impurities or additives, even in trace amounts, can dramatically affect the rate of solvent-mediated polymorphic transformation (Gu et al., 2002 Okamata et al., 2004 Mukuta et ah, 2005). Thus, it is important to have starting API with the highest possible purity. Recrystallization prior to starting this or any type of polymorph screen can be used in an attempt to purify the API. While this could reduce an impurity that might stifle solvent-mediated transformation to the most stable polymorph, it should be noted that recrystallization from solution does not... 

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