Polymorphic systems

The importance of temperature-controlled scanning calorimetry for measurements of heat capacity and of scanning transitiometry for simultaneous caloric and pVT analysis has been demonstrated for polymorphic systems [9]. This approach was used to study an enantiotropic system characterized by multiphase (and hindered) transitions, the role of heat capacity as a means to understand homogeneous nucleation, and the creation of (p, T) phase diagrams. The methodology was shown to possess distinct advantages over the more commonly used combination of characterization techniques. 

In the case of DuP747 [24], XRD, DSC, and thermomicroscopic studies determined the polymorphic system to be monotropic. Distinct diffuse reflectance IR, Raman, and solid state 13C NMR spectra existed for each physical form. The complementary nature of IR and Raman gave evidence that the polymorphic pair were roughly equivalent in conformation. It was concluded that the polymorphic character of DuP 747 resulted from different modes of packing. Further crystallographic information is required in order to determine the crystal packing and molecular confirmation of this polymorphic system. 

Analogous to the DuP 747 study, complete crystallographic information was not possible on the fosinopril sodium polymorphic system [25], Two known polymorphs (A and B) were studied via a multidisciplinary approach (XRD, IR, NMR, and thermal analysis). Complementary spectral data from IR and solid state 13C NMR revealed that the environment of the acetal sidechain of fosinopril sodium differed in the two forms. In addition, possible cis-trans isomerization about the CgN peptide bond may exist. These conformational differences are postulated as the origin of the observed polymorphism in fosinopril sodium in the absence of the crystallographic data for form B (single crystals not available). 

Solid state characterization studies of the previously mentioned polymorphic systems [26-34] all utilize IR as a means to differentiate the various crystal modifications. In some cases, the observation of variations in IR absorption intensities has led to conclusions regarding intramolecular hydrogen bonding [26]. For other systems, fairly complete IR spectral band assignment has allowed for determination of structure for the polymorphic system. In one study [29], DSC-IR was used to identify the polymorphs and determine simultaneously the correlation between thermal events and structural changes. 

In addition to measuring TCH for the polymorphic system in question, the proton T value must be determined since the repetition rate of a CP experiment is dependent upon the recovery of the proton magnetization. Common convention states that a delay time between successive pulses of 1-5 X T, must be used. Figure 10B outlines the pulse sequence for measuring the proton Tx through the carbon intensity. One advantage to solids NMR work is that a common proton Tx value will be measured, since protons communicate through a spin-diffusion process. An example of spectral results obtained from this pulse sequence is displayed in Fig. 12. 

Once the proton Tx and Tcli values are determined for a polymorphic system, physical mixtures of the two polymorphs can be generated (calibration samples). Subsequent acquisition of the solid state NMR spectra under quantitative conditions yields signal intensities representative of the amount of each solid state phase... 

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... 

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. 

It is worth noting that a monotropic polymorphic system offers the potential of annealing the substance to achieve the preferred form of the thermodynamically stable phase. The use of the most stable form is ordinarily preferred to avoid the inexorable tendency of a metastable system to move toward the thermodynamic form. This is especially important especially if someone elects to use a metastable phase of an excipient as part of a tablet coating, since physical changes in the properties of the coating can take place after it has been made. Use of the most stable form avoids any solid-solid transition that could... 

The literature abounds with countless examples that illustrate how powder diffraction has been used to distinguish between the members of a polymorphic system. It is absolutely safe to state that one could not publish the results of a phase characterization study without the inclusion of XRPD data. For example, Fig. 7.11 shows the clearly distinguishable XRPD powder patterns of two anhydrous forms of a new chemical entity. These are easily distinguishable on the overall basis of their powder patterns, and one could place the identification on a more quantitative basis through the development of criteria similar to those developed for the mandelic acid system. 

Y. Hu, H. Wikstrom, S.R. Bym and L.S. Taylor, Estimation of the transition temperature for an enantiotropic polymorphic system from the transformation kinetics monitored using Raman spectroscopy, J. Pharm. Biomed. Anal, 45, 546-551 (2007). 

C. Starbuck, A. Spartalis, L. Wai, et al., Process optimization of a complex pharmaceutical polymorphic system via in situ Raman spectroscopy, Cryst. Growth Des., 2(6), 515-522 (2002). 

Starbuck, C. Spartalis, A. Wai, L. etal Process Optimization of a Complex Pharmaceutical Polymorphic System Via In Situ Raman Spectroscopy Cryst. Growth Des. 2002, 2, 515-522. 

A total of 163 clusters were obtained, where a cluster is a group of polymorphic crystal structures of the same compound. Of the 163 clusters, 147 contained two structures, 13 had three, and three had four structures. The authors note that these numbers are first evidence of the high frequency of polymorphism in organic crystals , although the number of clusters is a relatively small percentage of the entries in the database. The number of these clusters is probably more a measure of certain authors interest in the particular polymorphic system in question. A more realistic measure (although certainly not precise because of the caveats mentioned above) of the frequency of polymorphism in these compounds wouid be the fraction of compounds in the database known to be polymorphic, whether multiple structures have been done or not. 

Fig. U Example of the bibliographic entries in the PDF for substances listed by compound name. Each name is followed by the formula and the d-spacings of the three strongest diffraction hnes, with the relative intensity as a subscript. The last column on the right is the card number in the PDF. Multiple entries with different principle lines are indications of polymorphic systems, for instance the three entries for sulphapyridine and sulphathiazole, the four entries for sulphanilamide and the two entries for sulphathiazole sodium hydrate, but additional bibliographic and crystallographic information should be obtained from the entries themselves.

For polymorphic systems of a particular material we are interested in the relationship between polymorphs of one component. A maximum of three polymorphs can coexist in equilibrium in an invariant system, since the system cannot have a negative number of degrees of freedom. This will also correspond to a triple point. For the more usual case of interest of two polymorphs the system is monovariant, which means that the two can coexist in equilibrium with either the vapour or the liquid phases, but not both. In either of these instances there will be another invariant triple point for the two solid phases and the vapour on the one hand, or for the two solid phases and the liquid on the other hand. These are best understood in terms of phase diagrams, which are discussed below, following a review of some fundamental thermodynamic relationships that are important in the treatment of polymorphic systems. 

In terms of thermodynamics, one of the key questions regarding polymorphic systems is the relative stability of the various crystal modifications and the changes in thermodynamic relationships accompanying phase changes and different domains of temperature, pressure, and other conditions. Buerger s (1951) treatment of these questions provides the fundamentals upon which to base further discussion. 

None of these rules is foolproof. However, they are useful guidelines, and the combination of relatively simple techniques can often be used to get a good estimate of the relative stability of polymorphs under a variety of conditions, information which is useful in understanding polymorphic systems, the properties of different polymorphs and the methods to be used to selectively obtain any particular polymorph (see Section 3.2). As noted above, much of that information can be included in the energy/temperature diagram, and the actual preparation of that diagram from experimentally determined quantities is described in Sections 4.2 and 4.3 following the description of the techniques used to obtain those physical data. 

In dealing with a polymorphic system perhaps the fundamental question is how similar or how different are the various crystal structures. Although Gavezzotti and Fillippini (1995) have attempted to provide a quantitative measure to this comparison, we believe that investigation of this question should include a close visual examination of the crystal structures as outlined in the next section. 

Structure, or in the case of polymorphs, with a limited number of well-defined structures. Those structures are invariant across a wide variety of conditions, in some cases almost under any conditions for which crystals form. Two of the principal questions to be asked for such a process is how it begins and how it proceeds, especially in the context of polymorphic systems. A great deal of work has been devoted to attempts to answer these questions, and in spite of considerable progress especially on experimental and empirical fronts, there is still much to be learnt in developing current models. Historical treatments of the classic notions of crystallization and recrystallization, including many important references, have been given by Tipson (1956) and van Hook (1961). A more recent thorough account may be found in Mullin s book (1993). 

From a practical point of view, control over nucleation, and in cases of polymorphic systems, control over the polymorph obtained as a result of nucleation, has been... 

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