Thermal analysis polymorphs

The Ca-Cu system has been reexamined using thermal analysis and x-ray diffraction methods an independent study of the CaCuj-Cu section has also been completed. The resultant phase diagram, although similar to that in ref. 3 at the Cu-rich end, differs markedly for Ca-rich alloys. Supporting evidence for the modifications has been obtained from the Ca-Mg-Cu ternaiy system. Three intermediate compounds are formed in the system CaCuj (950 C) melts congruently, whereas CajCu (488 C) and CaCu (567°C) are formed in peritectic reactions. Single-crystal x-ray diffraction studies verify the stoichiometry of CajCu and examine the polymorphism of CaCu. ... 

The only thermal event in the differential thermal analysis curve of (/))-penicillamine is the melting endotherm at 185 °C. Either polymorph of (z>)-penicillamine gives the same endotherm [2]. 

US patent 6,723,728, Polymorphic and other crystalline forms cis-FTC [106], The present invention relates to polymorphic and other crystalline forms of (—)-and ( )-cA-(4-amino-5-fluoro-l-(2-(hydroxymethyl)-l,3-oxathiolan-5-yl)-2(lH)-pyrimidinone, or FTC) [106]. Solid phases of (—)-cz>FTC that were designated as amorphous (—)-FTC, and Forms II and III were found to be distinguishable from Form I by X-ray powder diffraction, thermal analysis properties, and their methods of manufacture. A hydrated crystalline form of ( )-cA-FTC and a dehydrated form of the hydrate, were also disclosed, and can similarly be distinguished from other forms of FTC by X-ray powder diffraction, thermal properties, and their methods of manufacture. These FTC forms can be used in the manufacture of other forms of FTC, or as active ingredients in pharmaceutical compositions. Particularly preferred uses of these forms are in the treatment of HIV or hepatitis B. 

The sample temperature is increased in a linear fashion, while the property in question is evaluated on a continuous basis. These methods are used to characterize compound purity, polymorphism, solvation, degradation, and excipient compatibility [41], Thermal analysis methods are normally used to monitor endothermic processes (melting, boiling, sublimation, vaporization, desolvation, solid-solid phase transitions, and chemical degradation) as well as exothermic processes (crystallization and oxidative decomposition). Thermal methods can be extremely useful in preformulation studies, since the carefully planned studies can be used to indicate the existence of possible drug-excipient interactions in a prototype formulation [7]. 

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). 

The use of solid state NMR for the investigation of polymorphism is easily understood based on the following model. If a compound exists in two, true polymorphic forms, labeled as A and B, each crystalline form is conformationally different. This means for instance, that a carbon nucleus in form A may be situated in a slightly different molecular geometry compared with the same carbon nucleus in form B. Although the connectivity of the carbon nucleus is the same in each form, the local environment may be different. Since the local environment may be different, this leads to a different chemical shift interaction for each carbon, and ultimately, a different isotropic chemical shift for the same carbon atom in the two different polymorphic forms. If one is able to obtain pure material for the two forms, analysis and spectral assignment of the solid state NMR spectra of the two forms can lead to the origin of the conformational differences in the two polymorphs. Solid state NMR is thus an important tool in conjunction with thermal analysis, optical microscopy, infrared (IR) spectroscopy, and powder... 

Differential thermal analysis proved to be a powerful tool in the study of compound polymorphism, and in the characterization of solvate species of drug compounds. In addition, it can be used to deduce the ability of polymorphs to thermally interconvert, thus establishing the system to be monotropic or enantiotropic in nature. For instance, form I of chloroquine diphosphate melts at 216°C, while form II melts at 196°C [18]. The DTA thermogram of form I consists of a simple endotherm, while the thermogram of form II is complicated (see Fig. 4). The first endotherm at 196°C is associated with the melting of form II, but this is immediately followed by an exotherm corresponding to the crystallization of form I. This species is then observed to melt at 216°C, establishing it as the thermodynamically more stable form at the elevated temperature. 

Differential thermal analysis proved to be a powerful aid in a detailed study that fully explained the polymorphism and solvates associated with several sulfonamides [19]. For instance, three solvate species and four true polymorphs were identified in the specific instance of sulfabenzamide. Quantitative analysis... 

In a manner similar to that just described for differential thermal analysis, DSC can be used to obtain useful and characteristic thermal and melting point data for crystal polymorphs or solvate species. This information is of great importance to the pharmaceutical industry since many compounds can crystallize in more than one structural modification, and the FDA is vitally concerned with this possibility. Although the primary means of polymorph or solvate characterization s centered around x-ray diffraction methodology, in suitable situations thermal analysis can be used to advantage. 

It is important to ascertain whether the solid phase of the solute changes during equilibration to produce a different polymorph or solvate, by analyzing the solid phase (using either chemical or thermal analysis, or x-ray diffraction). If a solid-solid phase transition occurs during equilibration, the measured equilibrium solubility will be that of the new solid phase of the solute. Methods of circumventing this problem have been proposed and evaluated [26]. 

Differential Thermal Analysis (DTA) and Thermal Gravimetric Analysis (TGA). CTC-HC1 is stable until it begins to decompose exothermically at approximately 230°C (Figures 2 and 3) (15). The compound does not lose any mass until the final decomposition takes place. No polymorphs have been seen in the samples examined. 

There is no evidence for polymorphism from infrared spectroscopy and differential thermal analysis, and only inconclusive data from x-ray diffraction and microscopy studies. 

Considerable attention has been directed toward development of IR spectral analytical techniques for HMX and related compds. Ref 56 discusses the analysis of alpha, gamma and delta HMX in beta HMX, and presents a detailed literature survey of the properties of HMX polymorphs, and hazard.aspects connected with the transitions between the stable beta form and its polymorphs, Spectrophotometric analysis of HMX in PBX 9404 (a plastic bonded expl) is documented in Ref 53. IR techniques have also been useful in. the determination of the effects of Idw level gamma radiation on the thermal sensitivity of HMX, RDX and HMX—RDX mixts (Ref 61)... 

Giron, D. (1995). Thermal analysis and calorimetric methods in the characterization of polymorphs and solvates, Thermochim. Acta, 248 1-59. 

Physical characteristics of active API (aspect, thermal analysis, particle size distribution, optical activity, polymorphic forms, moisture content, loss on drying, microbial content, etc.)... 

In many cases, high-temperature modifications of sulfidic compounds cannot be quenched for room temperature examination. Inversion twinnings, crystal morphology, or other crystallographic features may indicate the appearance of polymorphism. Under these circumstances differential thermal analysis (DTA) can be suitable for the determination of the exact phase transition temperatures. DTA determinations are practically valuable if used in conjunction with high-temperature X-ray diffraction methods. DTA apparatus can operate up to 1100 °C and can be specially designed for sulfides2-4) individual experimental techniques are included in these references. 

Fessas, D., Signorelli, M. and Schiraldi, A. (2005). Polymorphous transitions in cocoa butter -a quantitative dsc siuAy.Joumal Of Thermal Analysis And Calorimetry, 82(3) 691-702. 

Whereas hot stage microscopy can be used to obtain qualitative information on polymorphic behaviour, thermal analysis provides quantitative information about the relative stability of polymorphic modifications, the energies involved in phase changes between them and the monotropic or enantiotropic nature of those transitions. The two techniques are best used in conjunction. 

Much of the literature on the thermal analysis of polymorphic systems up to 1995 has been cited by Giron (1995), along with many illustrative examples. Perrenot and Widmann (1994), Threlfall (1995), Kuhnert-Brandstatter (1996) and Vippagunta etal. (2001) have also provided excellent discussions of many of the practical aspects of the application of thermal analysis to polymorphic systems. The following discussion draws much from these contributions. 

Giron, D., Piechon, R, Goldbronn, S. and Pfeffer, S. (1999). Thermal analysis, microcalorimetry and combined techniques techniques for the study of the polymorphic behaviour of a purine derivative. J. Therm. Anal Calorim., 57, 61-73. [250]... 

Ed. Engl, 31,1-26. This reference contains a historical account of the phenomenon of optical anomalies, a field which went dormant for nearly half a century for reasons similar to those involving activity in the field of polymorphism. [10, 214] Kalinkova, G. N. and Hristov, S. (1996). Infrared spectroscopic and thermal-analysis of different modifications of calcium valproate. Vib. Spectrosc., 11, 1443-9. [5] Kalinkova, G. N. and Stoeva, S. (1996). Polymorphism of azlocillin sodium. Int. J. Pharmacol, 135, 111. [245]... 

The thermal analysis methods reported for the characterization of ezeti-mibe were conducted using thermogravimetric analysis (TGA), differential thermal analysis (DTA), and differential scanning calorimetry (DSC). As detailed in Table 3.2, the TGA and DSC characterization of polymorphs of ezefimibe was reported in a patent publication. 

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