Mixtures of polymorphs

Absorption of x-rays by a powdered sample of soHd fat has been a useful method for determination of polymorphic character as discussed eadier. The a, and P forms may be distinguished however, interpretation is made more difficult because subsets of the P and P forms have often been encountered. Also, a fat may contain mixtures of polymorphic forms and properties may therefore be difficult to relate to the spectra. 

Fig. 13 Determination of 31P Tx values for fosinopril sodium using the inversion-recovery method. The spectra represent approximately a 50/50% w/w mixture of polymorphic forms A (8 = 52 ppm) and B (8 = 55 ppm). Spinning sidebands are represented by asterisks. 

This chapter has been concerned mainly with the chemistry of making pigments but has also stressed the importance of preparing them in the correct physical form. In the case of those pigments which can be made in more than one crystal form, such as the anatase and rutile forms of titanium dioxide, this may mean that all the pigment should be in one form only. In others, a mixture of polymorphic forms may be required, and it is then necessary to ensure that the desired ratio of these forms is present. 

This method of analysis is particularly valuable when chemical methods are inadequate or inapplicable. For instance, for complex mixtures where the different elements or ions may be associated in many different ways, all compatible with the analytical figures or for mixtures of polymorphous forms of the same substance, such as the three crystalline forms of CaC03 (calcite, aragonite, and vaterite) or the three crystalline forms of FeO(OH) (goethite, lepidocrocite, and P FeO(OH)—see Bunn, 1941)—mixtures for which chemical analytical methods are irrelevant. 

In the pharmaceutical industry, typically one will examine the previously defined API either as mixture of polymorphic forms or as a mixture of crystalline and amorphous phases (both having a simple linear intensity proportionality to concentration). Alternatively one may encounter a mixture of hydration or solvation states, in which cases the intensity would not necessarily be directly proportional to concentration. Figure 12.4 demonstrates the deviation from linearity resulting from differences in... 

As we document further in a number of chapters towards the end of the book, polymorphism can and does play an important role in a number of industrial and commercial applications. Again, the overriding reason for this is the variation in properties that often accompany differences in structure. Obviously, if two polymorphs exhibited the same properties required for a certain product specification, there would be no concern about which polymorph (or what mixture of polymorphs) was actually present. A number of examples will serve to demonstrate the scope of this role. 

The molecule under study was Pd[(dmpz)2(Hdmpz)2]2, where Hdmpz = 3,5-dimethylpyrazole, 3-XXIII. The material is trimorphic. The reaction mixture yields mostly (90 per cent) the monoclinic (C2/c, racemic) a phase, the remainder being the triclinic (PI, racemic) y phase. The latter can be removed by recrystallization from 1,2-dichloroethane, which suggests that it is the more soluble and hence, the less stable polymorph in that solvent. Masciocchi et al. (1997) found that mixtures of various amounts of a and y polymorphs could be obtained by varying the solvent and precipitation temperature (-70 °C to -1-50 °C), with a preferred at higher temperatures, consistent with the earlier observation of relative stability. Pure polymorph y may be obtained by a different synthetic route which, when employing an excess of 3,5-dimethylpyrazole, leads to an approximately 50 50 mixture of polymorphs a and y. This system thus also represents a case in which the polymorph obtained, or the polymorphic mixture obtained, depends on the synthetic route to the desired material. It is probably more correct to state that as usual, the polymorph or polymorphic mixture depends on the crystallization conditions, and these will clearly differ in the solvent/reagent/product compositions resulting from different synthetic conditions and routes. 

Fig. 4.26 Calibration curve for mixtures of polymorphs A and B using laboratory X-ray data and Rietveld analysis. The value for the 50 per cent mixture was obtained from synchrotron data. (From Newman et al. 1999, with permission.)...

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). 

Fig. 4.35 CPMAS NMR spectra of sulphathiazole. Top Spectra for a genuine sample of each of the five polymorphs. (From Apperley et al. 1999, with permission.) Bottom effect of a mixture of polymorphs. The lower two spectra are of pure polymorphic forms, while the upper one is a mixture of the two lower ones. (From ThrelfaU 1999, with permission.)...

Fig. 4.38 Qualitative recognition of mixtures of polymorphs by CP/MAS NMR spectra of D-mannitol obtained under different crystallization conditions (a) absence of Keggin anions, P form (b) presence of [PWi204o] , a mixture of k and a forms (the latter indicated by arrows) (c) presence of [SiWi204o] , a form. (From Trovao et al. 1998, with permission.)...

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]... 

When attempting quantitation of a mixture of polymorphs, the first step is to identify which peaks are due to each polymorph, and to select two well-resolved peaks corresponding to the same carbon in each polymorph. A multiple-contact time experiment is then acquired to determine the rates of magnetization transfer (7ch) and decay (Tip) for each form. If these rates are identical in each form, direct integration of the peaks will provide quantitative data, with the relative areas representing the amount of each form present in the mixture. An example of the results of a multiple-contact time experiment is shown in Fig. 2—a plot of the natural logarithm of relative peak area as a function of contact time for neotame forms A and It is clear from this plot that spectra acquired at any contact time will not give equal peak area for both forms. 

Padden, B.E. Zell, M.T. Dong, Z. Schroeder, S.A. Grant, D.J.W. Munson, E.J. Comparison of sohd-state NMR spectroscopy and powder X-ray diffraction for analyzing mixtures of polymorphs of neotame. Anal. Chem. 1999, 71 (16), 3325-3331. 

A particular form or a mixture of polymorphs is identified based on comparison of the sample NMR spectrum with standard spectra of... 

Due to efficient spin diffusion, homogeneous crystalline solids present a unique relaxation time, regardless of chemical differences. Then different polymorphs can be differentiated by using pulse sequences able to discriminate substances on the basis of their different relaxation properties. In particular cases it has been possible to extract the individual subspectra from a mixture of polymorphs, by modifying the inversion recovery pulse sequence to decompose the spectra [43]. 

Whilst examples of disappearing polymorphs exist, perhaps more common is the crystallization of mixtures of polymorphs. Many analytical techniques have been used to quantitate mixtures of polymorphs, e.g., XRPD has been used to quantitate the amount of cefepime 2HC1 dihydrate in cefepime 2HC1 monohydrate (Bugay et al. 1996). As noted by these workers, a crucial factor in developing an assay based on a solid-state technique is the production of pure calibration and validation samples. Moreover, whilst the production... 

By some investigators the transition temperature has been found to vary somewhat according to the previous history of the substance, a behaviour interpreted by Smits as confirming his view (p. 28) that polymorphic forms are equilibrium mixtures of different molecular species. The necessity of making sure that one is dealing with a pure homogeneous solid and not with a mixture of polymorphous forms must also be emphasised (p. 46). 

Today, the manufacturers of chemical compounds provide Ga203 at different levels of purity, produced by a variety of (usually unspecified) methods. Such commercially available samples often contain mixtures of polymorphs, especially of the P-Ga203 and a-Ga203 phases, although pure samples of P-Ga203 can be obtained by heating the mixture, for example, at a temperature of 800 °C for 10-12 h [163]. Yet, the different materials obtained from the same supplier can correspond to different polymorphs. For example, the Aldrich 99.99 + % sample studied by Machon et al. corresponded to a 70 30 mixture of the P- and a-phases, whereas a sample purchased from the same supplier with 99.999 + % purity consisted mainly of the 8-Ga203 polymorph (D. Machon et al., unpublised work). 

Electron diffraction has been used to investigate bulk structures of pigments as well as thin layers. A strength of this method is the spatial resolution which allows the structural characterization of single microcrystals even in mixtures of polymorphs . Even more striking, the occurrence of two polymorphs in the same submicron crystal may be analyzed, as in the case of a/p copper phthalocyanine . ... 

Three different crystal forms are present in raw TATP needles, prisms, and plates. X-ray crystallography revealed that these three forms represent three different polymorphs needles form monoclinic, prisms form orthorhombic, and plates form triclinic crystal systems. Strong acids (sulfuric, nitric, and hydrochloric) produce a mixture of polymorphs where the major one is needle crystals while weak acids (acetic, citric) produce a mixture of needles and plates. Another three polymorphs (aU are monoclinic) form by crystallization from various organic solvents [30]. 

---