Polymorphic purity

M. Blanco, J. Coello, H. Iturriaga, S. Maspoch and C. Perez-Maseda, Determination of polymorphic purity by near infrared spectrometry. Anal. Chim. Acta, 407, 247-254 (2000). 

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). 

Qualitative and quantitative analytical applications of X-ray diffraction both require reference diffraction patterns to identify and quantify the different polymorphic modifications. Experimental powder patterns may be suspect for their use as standards as a result of experimentally induced errors or aberrations or the lack of polymorphic purity in the sample itself (which may even result from the sample preparation). The availability of full crystal structure determinations for any or all of the polymorphic modifications can considerably facilitate generation of standard powder patterns. A variety of public domain software is now available for calculating powder diffraction patterns from single crystal data (ICDD 2001, lUCr 2001)." ... 

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). 

Polymorphism purity. Pressure and temperature influence this property. For instance, salmeterol xinofoate, an antiasthmatic drug, was processed to obtain the right polymorph with a particle size of 5 pm, which is suitable for respiratory delivery (133). More generally, the SEDS process can accurately control these two parameters. 

The enhanced physical properties for supercritically produced salme-terol (e.g., high crystallinity, polymorphic purity, powder uniformity) correlate well with the enhanced dispersion and flow behavior of this powder. However, as shown in some other investigations (12,28), particle size and shape, surface energy, and crystallinity may have to be optimized separately, using all process parameters available, perhaps including a coformulation step. For some compounds with low solubility in water, a compromise must be found between improved bioavailability and physicochemical stability. 

Polymorphic purity of solid drug substances is an important parameter for consideration in pharmaceutical formulation. Since different polymorphs or crystalline forms of the same drug exhibit different physical properties, chemical stability, solubility, dissolution rate, and possibly bioavailability, the presence of the alternative (metastable) crystal form(s) may have an adverse impact on the manufacturing and in vivo performance of the drug product. 

The foregoing approach serves well for assessing the polymorphic purity of SX materials and can potentially be applied to other enantiotropic pairs showing similar thermal behavior. 

Figure 3-9. (a) Powder XRD of crystalline dimethyl fuschone 6 shows a mixture a (80%), /3 (18%) and y forms (2%) at 30°C. (b) Heating the concomitant mixture to 170°C shows pure /3 form in >97% polymorphic purity from PXRD match with the simulated powder profile from the X-ray crystal structure (see color plate section)... 

Application of powder X-ray diffraction for the analysis of polymorphic purity of A/-(4-nitrophenyl)-A/-morpholinothiourea (37) samples prepared by conventional solution synthesis in dichloromethane and mechanochemical liquid-assisted grinding approach. At low concentration, polycrystalline powder of form I precipitates out, while of form II precipitates from more concentrated soiution and mechanochemical synthesis. 

Each initial salt needs to be studied for polymorphic purity, and the presence of solvates. Ideally, only one polymorphic form will be present. This polymorphic purity will be measured by one of the solid-state technique s) listed in Section II.D. Initial screening will typically be conducted with less labor intensive and less expensive methods such as differential scanning calorimetry (DSC) and TGA. 

Gabbott P. Confirming polymorphic purity with HyperDSC . PerkinElmer Application Note... 

Confirming polymorphic purity using fast scan rates... 

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