Polymorphism recrystallisation

Supercritical C02 extraction coupled with a fractional separation technique is used by producers of flavours and fragrances to separate and purify volatile flavour and fragrance concentrates. Like any solvent, supercritical C02, it allows processing chemicals by predpita-tion or recrystallisation, obtaining partides of controlled size and shape, without excessive fines without thermal stresses and controlling the shape of a polymorphic substance. 

Crystal solvates exhibit a wide range of behaviour depending on the interaction between the solvent and the crystal stmcture. With some solvates the solvent plays a key role in holding the crystal together for example, it may he part of a hydrogen-honded network within the crystal stmcture. These solvates are very stable and are difficult to desolvate. When these crystals lose their solvent they collapse and recrystallise in a new crystal form. We can think of these as polymorphic solvates. In other solvates, the solvent is not part of the crystal bonding and merely occupies... 

When some dmgs crystallise they may entrap solvent in their crystals and so form different crystal solvates. In some solvates the solvent plays an important role in holding the crystal together. These solvates, called polymorphic solvates, are very stable, and when they lose their solvent they recrystallise in a different crystal form. In other solvates, referred to as pseudopoly-morphic solvates, the solvent is not part of the crystal bonding and merely occupies voids in the crystal. These solvates can lose their solvent more readily and desolvation does not alter the crystal lattice. Solvated and anhydrous forms of a drug differ in... 

In the vast majority of chemical destabilisation/bioinactivation processes, water acts either as a catalyst or it participates as a reactant and/or product. It therefore seems logical to conclude that the removal of water should eliminate many causes of chemical instability. The situation is not quite so clear however in the case of physical instability. Processes of concern that can take place in the solid state include polymorphic solid/ solid transitions and the compaction of powders. Even low levels of water vapour sorption may lead to other undesirable changes, e.g. solid/ liquid phase separations, recrystallisation in the solid state or polymorphic transitions. Since all these processes occur only in the solid state, it follows that they cannot necessarily be eliminated by drying. The important factors in physical and mechanical stabilisation are the actual state of the solid produced by drying, the level of residual water and the temperature and pressure employed during processing and storage. 

It is not easy to predict which frameworks will remain intact upon template removal, and which will collapse, but it should be borne in mind that all open frameworks are less stable (when empty) than dense crystalline forms, and barriers to recrystallisation are kinetic rather than thermodynamic. High-temperature treatment of microporous solids eventually results in recrystallisation to dense ceramics rather than other microporous solids. For example, the magnesium form of zeolite P transforms to magnesian cordierite, and aluminophosphates transform to dense AIPO4 polymorphs. 

Organic compounds are considered to be colourless unless otherwise stated. Where the compound contains a chromophore which would be expected to lead to visible colour, but no colour is mentioned in the literature, the Carbohydrates entry will mention this fact if it has been noticed by the contributor. An indication of crystal form and of recrystallisation solvent is often given but these are imprecise items of data most compounds can be crystallised from several solvent systems and the crystal form often varies. In the case of the small number of compounds where crystal behaviour has been intensively studied (e.g. pharmaceuticals), it is found that polymorphism is a very common phenomenon and there is no reason to believe that it is not widespread among organic compounds generally. 

Certain thermoplastics, e.g., PET, can be frozen in the amorphous state below the Tg by quench-cooling of the melt. The occurrence of different crystal forms (polymorphism of polyamides (PA), as an example) and melting gaps caused by tempering can be read from the DSC curve. If recrystallisation is studied, crystal growth rate and supercooling can be measured. 

Polymorphism Differences are usually observed in the (infrared or Raman) spectra of different crystalline forms of the same substance. Therefore, it should be borne in mind that a different crystalline phase may he obtained after recrystallisation from a solvent. Also, in the preparation of a mull or disc, a change in the crystalline phase may occur. 

Many pharmaceuticals and foods are prone to polymorphism, where exist a number of distinct crystal structures, and recrystallisation between polymorphs can occur. These are usually fairly rapid events compared to the cure reaction, particularly if resulting from desolvation or dehydration where a solvent or water molecule has been ejected from a crystal leaving it unstable. A typical example is shown in Figure 1.21. 

Figure 2.29 Chlorpropamide heated at 5°C/min showing melting, recrystallisation and then further melting. This is a classic example of polymorphism in a pharmaceutical material as observed by DSC.

When the melting profile of a polymorphic material is obtained from a DSC, it is often found to contain a number of endothermic peaks corresponding to the melting of different crystal forms, possibly separated by an exothermic peak as molten material recrystallises... 

Figure 8.5 Typical polymorphic behaviour as seen with DSC. The initial crystal form melts upon heating (at about 175°C), giving the initial endotherm, and recrystallises into a second form which shows as an exotherm. This then melts at a higher temperature. It is probable that melting of the initial form and...

A melt to recrystallisation to melt phenomenon on a DSC curve may represent either monotropic or enantiotropic conversion. Small amounts of decomposition may favour transitions or the apparent production of a polymorph. Frequently thermogravimetry will detect this decomposition. An example of monotropic polymorphism is displayed by temazepam [11]. 

Matsuda et al [146] provided evidence, via DTA, of the polymorphic transformation in spray dried phenylbutazone encouraged by varying the inlet temperature from 30° to 120°C. Importantly and indicative of its use, TGA was utilised to confirm that there was no residual solvent in the sample, in the form of a solvate. Two or three crystal forms were present. At 120°C the 5-form was produced, at 80° and 100°C, a mixture of two forms was formed and a third form was apparent at 70°C [146]. Mixtures containing two forms contained the P- and 8-form, and when three forms were present, they corresponded to the P-, 5- and s-forms. A single DTA endotherm was found in samples prepared at 100° and 120°C with an endothermic peak at 103°C, equivalent to the 5-form. Melting endotherms at 91-92°C were found for samples obtained at 70°C and 80°C. In these samples a recrystallisation exotherm at 93°C, corresponding to the 5-form was found again the 5-form subsequently melted as an endotherm at 103°C [146]. 

---