Grinding effects polymorphism

Preferred orientation of the particles must be minimized. One of the most effective ways to achieve this is to reduce the particle size by grinding the sample [1], As already discussed in Section III.A, however, grinding can disorder the crystal lattice. Grinding can also induce other undesirable transitions, such as polymorphic transformations [59]. In order to obtain reproducible intensities, there is an optimum crystallite size. The crystallites have to be sufficiently small so that the diffracted intensities are reproducible. Careful studies have been carried out to determine the desired crystallite size of quartz, but no such studies have been reported for pharmaceutical solids [60]. Care should be taken to ensure that the crystallites are not very small, since decreased particle size can cause a broadening of x-ray lines. This effect, discussed earlier (Eq. 9), usually becomes apparent when the particle size is below 0.1 jum. 

Kaneniwa, N. and Otsuka, M. (1985). Effect of grinding on the transformations of polymorphs of chloramphenicol palmitat hem. Pharm. Bull., 33 1660-1668. 

Otsuka, M. Matsumoto, T. Kaneniwa, N. Effect of environmental temperature on polymorphic solid-state transformation of indomethacin during grinding. Chem. Pharm. Bull. 1986, 54, 1784-1793. 

Otsuka, M. Ofusa, T. Matsuda, Y. Effect of environmental humidity on the transformation pathway of carbamaze-pine polymorphic modifications during grinding. Colloids Surf B Biointerfaces 1999, 15, 263-273. 

FIGURE 3.8 Interconversion of polymorphic forms of chloramphenicol palmitate induced by grinding (a) effect of grinding on forms A and B (XRD data) (o Form A, Form B), (b) effect of grinding on Form C (XRD data) (O content of Form B, content of Form A), and (c) change in melting point of forms A (o), B ( ) and C ( ) on grinding. (Reproduced from Kaneniwa, N. and Otsuka, M., Chem. Pharm. Bull., 33, 1660, 1985.)... 

In a later study, Otsuka et al. (32) examined the effects of grinding on the polymorphic forms of cephalexin, chloramphenicol palmitate, and indomethacin. Cephalexin was converted into an amorphous form whereas chloramphenicol palmitate tranformed from the metastable B and C forms to the stable A form. Indomethacin was found to transform to an amorphous form on grinding at 4°C but formed a metastable polymorph on grinding at 30°C. 

Solvent-drop grinding is a novel, efiScient and green procedure for polymorphic control [15,16]. It involves grinding a known polymorph of a compound with a very small amount of solvent added in order to effect a polymorphic transformation. Variation of the solvent may lead to different polymorphic outcomes. For example, polymorphic Form I of anthranilic acid (Figure 1, 2), ground in the presence of heptane, transforms to Form II, which in turn converts to Form III whai ground in tiie presence of chloroform [15]. 

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