Polymorphism/polymorphs quantitative analysis

In the identification of different polymorphs in polymers the FTIR technique presents, with respect to the diffraction techniques, the advantage of easier and more rapid measurements. In particular, the high speed of the measurements allows to study the polymorphic behavior under dynamic conditions. As an example let us recall the study of the transition from the a toward the P form of PBT induced by tensile stresses, evaluated by quantitative analysis of the infrared spectra [83],... 

Applications The general applications of XRD comprise routine phase identification, quantitative analysis, compositional studies of crystalline solid compounds, texture and residual stress analysis, high-and low-temperature studies, low-angle analysis, films, etc. Single-crystal X-ray diffraction has been used for detailed structural analysis of many pure polymer additives (antioxidants, flame retardants, plasticisers, fillers, pigments and dyes, etc.) and for conformational analysis. A variety of analytical techniques are used to identify and classify different crystal polymorphs, notably XRD, microscopy, DSC, FTIR and NIRS. A comprehensive review of the analytical techniques employed for the analysis of polymorphs has been compiled [324]. The Rietveld method has been used to model a mineral-filled PPS compound [325]. 

XRD can be used for studies of polymorphic transformations in bloom formation. In combination with DTA, XRD has been used to study polymorphic transformations of Ca stearate and Ca stearate monohydrate [338]. Full pattern refinement has been used for quantitative analysis of mixtures of crystalline... 

The equations developed by Alexander and Klug [1,45] have also been used in the quantitative analysis of polymorphic mixtures. If there is a mixture of two polymorphs, one is considered the unknown component while the other is designated the matrix. The intensity of line i of component 1 (the unknown component), /il( is determined in mixtures containing different weight fractions of components 1 and 2 (the matrix). When dealing with polymorphic mixtures, however, Eq. (15) is much simplified. Since fix = /a2, Eq. (15) reduces to... 

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 PLS, the variance is generated using the quantities generated by the referee analytical method. Therefore, the factors in a PLS analysis (especially the first) resemble the spectrum of the active ingredient (assuming a quantitative analysis of a constituent). When measuring a physical attribute (hardness, polymorphic form, elasticity), the PLS factor may not resemble any of the materials present in the mixture. 

Although simple intensity correction techniques can be used to develop very adequate XRPD methods of quantitative analysis, the introduction of more sophisticated data acquisition and handling techniques can greatly improve the quality of the developed method. For instance, improvement of the powder pattern quality through the use of the Rietveld method has been used to evaluate mixtures of two anhydrous polymorphs of carbamazepine and the dihydrate solvatomorph [43]. The method of whole pattern analysis developed by Rietveld [44] has found widespread use in crystal structure refinement and in the quantitative analysis of complex mixtures. Using this approach, the detection of analyte species was possible even when their concentration was less than 1% in the sample matrix. It was reported that good quantitation of analytes could be obtained in complex mixtures even without the requirement of calibration curves. 

A.D. Patel, P.E. Luner and M.S. Kemper, Quantitative analysis of polymorphs in binary and multi-component powder mixtures by near-infrared reflectance spectroscopy, Int. J. Pharm. 206, 63-74. Erratum in Int. J. Pharm., 212, 295 (2000). 

Pacek P, Sajantila A, Syvanen AC. Determination of allele frequencies at loci with length polymorphism by quantitative analysis of DNA amplified from pooled samples. PCR Methods Appl 1993 2 313-317. 

Diffuse reflectance IR spectroscopy has become an attractive alternative to mulls with the introduction of DRIFT cell by Griffiths,29 later modified by Yang.30 Since materials are dispersed in a nonabsorbing medium and not subjected to thermal or mechanical energy during sample preparation, DRIFT spectroscopy is especially suitable for the qualitative/quantitative analysis for polymorphs, which are prone to solid-state transformations. The Kubelka-Munk (K-M) equation,31 which is analogous to Beer s law for transmission measurements, is used to quantitatively describe diffusely-reflected radiation ... 

It is important to make the distinction between the determination of polymorphic identity and polymorphic purity. The former is essentially a qualitative determination, asking the question, Ts a particular polymorph present in a given sample The latter is a question of quantitative analysis, and it is generally (though not always) assumed that the sample is chemically pure, so the analytical problem to be addressed is the determination of the relative amounts of different polymorphs in the sample. Recalling that different polymorphs are for all intents and purposes different solids, the determination of polymorphic purity is then no different in principle from quantitative determination of the composition of a mixture of solids. Such quantitative determinations comprise one of the traditional activities of analytical chemistry, especially when the materials are different chemical entities. In those cases, a variety of different analytical methods may be employed. In the case of polymorphic mixtures, or the determination of polymorphic purity, the choice of analytical method is considerably more restricted, and X-ray diffraction is one of the most definitive techniques (see e.g. Stowell 2001). 

As noted above, the traditional methods of quantitative analysis make use of one or a small number of non-overlapping peaks from the diffraction patterns of the different component (e.g. polymorphic) phases. With the advent of more powerful laboratory X-ray sources and synchrotron radiation, faster and more sensitive detectors, computer controlled diffractometers and the almost universal use of digitized data there is increasing use of the full diffraction pattern for quantitative X-ray diffraction analysis (Zevin and Kimmel 1995). 

Because of the general similarities in the diffraction patterns, and the lack of clearly resolvable distinguishing peaks, they employed the Rietveld method (Young 1993). In the Rietveld method, the entire experimental diffraction pattern for each solid phase is used as a basis for comparison. For structure determination using powder diffraction, this comparison is made with a structural model used to generate a calculated pattern. In quantitative analysis of polymorphic phases, the known crystal stmctures are used to generate the standard diffraction patterns and these are then refined against the experimental powder pattern of the mixture to obtain the relative amounts of the polymorphs. 

As with other analytical techniques previously widely used for polymorph characterization (i.e. polymorph identity), IR spectroscopy is being increasingly employed as a technique for quantitative analysis (e.g. polymorphic purity) (Aldridge et al. 1996 Blanco et al. 2000 Bugay 2001 Stephenson et al. 2001 Patel et al. 2001). 

Some of the previous references contain descriptions of the use of Raman spectroscopy for quantitative analysis of mixtures of polymorphs. Additional examples may be found in Deeley et al. (1991), Petty et al. (1996), Langkilde et al. (1997), Findlay and Bugay (1998) and Bugay (2001). 

The theoretical basis and practical considerations for the application of SSNMR to the smdy of polymorphism may be found in a number of references, which themselves contain additional primary sources (for instance Yannoni 1982 Fyfe 1983 Komorski 1986 Bugay 1993 Harris 1993 Brittain 1997 Byrn etal. 1999). As with many of the analytical techniques described in this chapter, SSNMR is a rapidly developing field with great potential in the investigation of polymorphic systems. It is not limited to a single nucleus (although most studies to date have concentrated on the nucleus) and it is being adapted for quantitative analysis of polymorphic mixtures and other multicomponent systems. 

The IR spectra of all four crystal modifications were reported by Cady and Smith (1962) and by Holston (1962). The latter did point out some distinguishing features among the polymorphs, but Cady and Smith noted that problems with sample preparation and conversions among forms indicated that the optical properties described by McCrone (1950a) were the basis for the best rapid qualitative and even rough quantitative analysis. Raman spectroscopy, which requires less potentially destructive sample preparation, has been used to distinguish the polymorphs (Goetz and Brill 1979). The low resolution NMR spectra of the four crystal modifications were reported by Landers et al. (1985). The nuclear quadrupole resonance spectrum... 

Hartauer, K. J., Miller, E. and Guillory, J. K. (1992). Diffuse reflectance infrared Eourier transform spectroscopy for the quantitative analysis of mixtures of polymorphs. Int. J. Pharmacol, 85, 163-74. [129, 130]... 

Tudor, A. M., Church, S. J., Hendra, P. J., Davies, M. C. and Melia, C. D. (1993). The qualitative and quantitative analysis of chlorpropanide polymorphic mixtures by near-infrared Fourier transform Raman spectroscopy. Pharm. Res., 10, 1772-6. [130, 132]... 

A quantitative analysis of the heat of adsorption data enables the separation of hydration enthalpies and surface enthalpies for the two alumina polymorphs (McHale et al. 1997b). The resulting variation of enthalpy of the anhydrous material with surface area is shown in Figure 3. The enthalpy (and free energy) crossover postulated above is clearly demonstrated. 

There is no doubt that single crystal X-ray diffraction is a powerful technique for the study of polymorphs and solvatomorphs, but it is equally apparent that this methodology is not well suited for the routine evaluation of the crystalline state of powdered solids. It is definitely not a technique that one would want to use in the determination of polymorphic phase impurities in a sample, since by definition only a single crystal is studied at one time. That crystal would certainly be phase-pure, and its quantitative analysis not... 

The feasibility of using FTIR-ATR spectroscopy for qualitative and quantitative analysis was investigated using the three known polymorphs of ganciclovir as a model system.65 Definitive identification of each polymorph was obtained from materials that did not need to be subjected to any sample handling or preparation. Quantitation of mixtures was carried out using a partial least-squares procedure, with mean absolute errors of less than 3% being reported for Form-I and Form-II, and about 6% for Form-Ill. 

Culler, S. R., Diffuse Reflectance Infrared Spectroscopy Sampling Techniques for Qualita-tive/Quantitative Analysis of Solids. In Polymorphism in Pharmaceutical Solids Brittain, H. G., Ed. Marcel Dekker New York 1999, pp. 93. 

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