Solid-state systems polymorphism

This serves as an example of the extremes one can go if one tmly wants to better understand the process and the form of the compound in the product. This approach is less important for detecting polymorphic form conversion in the solid state, since polymorphic solubility typically varies by less than a factor of two and tablets at very low strength would generally be classified as a type one by the biopharmaceutical classification system. In addition, polymorphs rarely have pronounced differences in chemical stability. On the other hand, if a compound is somewhat unstable and significant amount of amorphous material is potentially present, this approach can be used to determine if it is responsible for drug instability in the tablet formulation. In any event, this reference serves as a very good example of the strength of a powerful approach that has not been widely applied in our industry. 

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. 

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... 

In many amyloid systems, filament polymorphism has been observed by EM (e.g., Goldsbury et al., 1997, 2000). Structural variations may be expressed in terms of long-range axial repeats (Goldsbury et al, 2005 Jimenez et al., 2001), diameter (Louis et al., 2005), and/or number of protofilaments (Jimenez et al., 2002). Solid-state NMR has also been used to detect slight structural differences in Alzheimer s /1-peptide filaments... 

Metastable crystalline phases frequently crystallise to a more stable phase in accordance with Ostwald s rule of stages, and the more common types of phase transformation that occur in crystallising and precipitating systems include those between polymorphs and solvates. Transformations can occur in the solid state, particularly at temperatures near the melting point of the crystalline solid, and because of the intervention of a solvent. A stable phase has a lower solubility than a metastable phase, as indicated by the solubility curves in Figures 15.7a and 15.7/ for enantiotropic and monotropic systems respectively and,... 

W.-T. Cheng, S.-Y. Lin and M.-J. Li, Raman microspectroscopic mapping or thermal system used to investigate milling-induced solid-state conversion of famotidine polymorphs, J. Raman Spectrosc., 38, 1595-1601... 

A system that displays polymorphism is the aforementioned 2,4,6-tri-isopropylphenyl-lithium (17). It crystallized as a LiiAiSi system from DEE , but as an /j cyclic tetramer from non-coordinating solvents . Furthermore, a combined solid state Li and Ll NMR study indicates a third type of complex, notwithstanding the attempt to prepare... 

In this paper we report for the first time our studies of hydrogen bonding in the imidazole-carboxylate system, a common motif in enzyme active sites. The H solid state NMR data of polymorphic crystalline histidines were taken on a Chemagnetic... 

Similar to other binary /(-p-clcment systems, the formation of binary rare earth - antimonides with a simple stoichiometry is a characteristic feature of these systems. The largest number of structure types formed was encountered for the group of RSb2 compounds (4 members). The polymorphic modifications were observed for GdSb2 and TbSb2 as well as the RSb (R = La, Ce) and RsSb (R = Yb, Y and Sc) compounds were noted to undergo the solid state transformations. 

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