Polymorphs interconversion

Dependence of the Beta-delta-polymorph Interconversion in Octahydro-l,3,5,7-tetrani-tro-l,3,5,7-tetrazocine. 

Since polymorphs yield the same molecules upon transition to a less dense phase (liquid or vapour) and upon dissolution, the possibility of polymorph interconversion brings about the problem of structural nonrigidity in solution and in the solid state [24], Isomerization processes in the solid state are well known and there is the intriguing possibility that less stable conformations are stabilized in the solid state by the packing. 

It has been argued above that molecular crystal polymorphism can be seen as a form of crystal isomerism, and that the change in crystal structure associated with polymorph interconversion, i.e. a solid-to-solid phase transition between ordered... 

Variable-temperature SSNMR was used by Tozuka et to investigate the observed polymorphism in clarithromycin. Polymorphic interconversions were identified using both powder X-ray diffraction (PXRD) and CPMAS NMR. The authors performed quantitation of two polymorphs (forms I and II) using carbonyl resonances that exhibited 1 ppm resolution. Relaxation and CP rate constants were not taken into account instead, relative peak areas were adjusted using a term derived from the preparation and analysis of a known set of standard mixtures. The correlation coefficient of measured peak intensity and weight content was found to be >0.99. 

To gain an understanding of the solid-state chemistry of a drug within a formulation, one must fully understand the state of the matrix before and after processing, and on storage. Many solid-state reactions and changes that may have drastic effects on the stability of the API and the safety and efficacy of the formulation can occur. Accelerated stability studies are often conducted at elevated temperatures and relative humidities (RHs), both of which can induce physical changes in the API and matrix such as polymorphic interconversion, hydrate formation or dehydration, or crystallization of amorphous material. 

Another advantage of SS-NMR is that the observed chemical shift differences between polymorphs can be related to particular molecular sites based on known assignments (see Figure 6). Site-specific mobility can also be determined by probing the relaxation properties of the compound. This is an important application, since mobility is usually related to polymorphic interconversions and solid-state reactions.94 Solid-state reactions between active pharmaceutical ingredients and excipients can also be followed by SS-NMR. The study of polymorphic transitions can be performed by variable temperature experiments. 

After a temptative structure-based classification of different kinds of polymorphism, a description of possible crystallization and interconversion conditions is presented. The influence on the polymorphic behavior of comonomeric units and of a second polymeric component in miscible blends is described for some polymer systems. It is also shown that other characterization techniques, besides diffraction techniques, can be useful in the study of polymorphism in polymers. Finally, some effects of polymorphism on the properties of polymeric materials are discussed. 

The following section deals with the crystallization and interconversion of polymorphic forms of polymers, presenting some thermodynamic and kinetic considerations together with a description of some experimental conditions for the occurrence of solid-solid phase transitions. 

Crystallizations and Interconversions of Polymorphic F orms 3.1 Thermodynamic and Kinetic Considerations... 

MM deVilliers, JG Van der Watt, AP l.otter. Interconversion of the polymorphic forms of chloramphenicol palmitate (CaP) as a function of environmental temperature. Drug Dev Ind Pharm 17(10) 1295—1303, 1991. 

Crystal polymorphs will usually exhibit different melting points, with the highest melting form being regarded as the most stable. The interconversion of... 

In its heyday, DTA analysis was very useful for the study of compound polymorphism and in the characterization of solvate species of drug compounds. It was used to deduce the ability of polymorphs to undergo thermal interconversion, providing information that could be used to deduce whether the system in question was monotropic or enantiotropic in nature. For instance, the enthalpies of fusion and transition were measured for different polymorphs of sulfathiazole and methylprednisolone [24]. The DTA thermograms shown in Fig. 4.5 demonstrate that Form-I is metastable with respect to Form-II, even... 

Polymorphism is the ability of the same chemical substance to exist in different crystalline structures that have the same empirical composition [39,40]. It is now well established that DSC is one of the core technologies used to study the phenomenon. Polymorphic systems are often distinguished on the basis of the type of interconversion between the different forms, being classified as either enantiotropic or monotropic in nature. 

The principle of the method is that once a substance crystallizes, the interconversion of the various conformers stops and so the crystals correspond to one discrete conformation or another. This has established, that 1,2-dichloroethane crystallises exclusively in the anti form, while ethylene chlorohydrin crystallizes in a gauche form because of intra molecular hydrogen bonding. But when the molecule crystallizes in two or more conformations, we say that it shows polymorphism. 

The relationship between the rate of interconversion of isomers and the existence of polymorphic modifications has been discussed by Dunitz [25b], Crystals of isomers that interconvert rapidly in solution would be classed as polymorphs whereas those of slowly interconverting isomers would be classed as different... 

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