Polymorphism minimization

Two new polymorphs of (2E)-2-cyano-3-[4-(diethylamino)phenyl]-prop-2-enethioamide and an acetone solvate were crystallized, and the structures compared to the known nonsolvated form [11]. One of the new forms was found to be considerably more stable than the others, and subsequently the other two new forms became vanishing polymorphs that could only be produced under strictly controlled conditions. The structures of all three polymorphs could be found using polymorph predictor, if the initial molecular structure was obtained from the X-ray data, the molecule held to be rigid during the energy minimization, and both VDW and Coulomb interactions taken into account. 

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. 

The most thermodynamically stable polymorph is usually desired for the API product to maximize its formulated stability. Selecting the thermodynamically stable form does however, have the disadvantage of minimizing the solubility and bioavailability. Although less desirable and common it is feasible to use an amorphous solid form of the API if it can be demonstrated that it is stable in the formulation. 

Whenever the solubility curve is crossed for the less stable Form II there is a risk that it will nucleate and contaminate the product. This situation is very probable when the solubility curves of the two polymorphs lie close together, as shown in Figure 21 of the Cimetidine case study. The addition of seed crystals of Form I, close to its solubility curve, and minimization of the supersaturation during the growth process is a good method of control in this instance. Solvent selection to extend the width of the Form II metastable zone would also be desired, as discussed in section 2.4.4. 

Experimental tilt angles have usually an accuracy of at best 3°, leading to an error of about 0.1 A in cell axes. The calculated third cell axis will show a higher deviation. If possible an internal standard should be used for calibration purposes but a higher accuracy will be obtained with a Pawley fit (e.g. fit forP CuPc in Fig. 6) from x-ray powder diffraction data [11]. Especially for packing energy minimization used for simulation methods it is essential to determine the cell parameters as precise as possible. In the case of polymorphism, it is essential to use x-ray powder diffraction to ensure that bulk and investigated nano crystals represent the same modifications. 

A NIR identification library shonld encompass all the raw materials used by the manufacturer in order to be able to identify all possible snbstances and avoid or minimize errors. The method to be nsed should allow the unequivocal identification of each componnd present in the library and the exclnsion of those not present. It should also be able to distinguish between very similar compounds nsed in different applications (e.g. products with different particle sizes, polymorphs, products in different grades or from different suppliers). 

Effective chemical process R D speeds a drug to market. In the discovery laboratory, paying attention to the practices of process research is likely to improve yields of laboratory reactions, reproduce small-scale runs more easily, and scale up to 100 -I- g runs more efficiently. Observations may lead to better processes in later development, for example, by minimizing byproducts, easing work-ups and purification, and by detecting polymorphs. 

In general, a low-temperature polymorph has lower symmetry than a high-temperature polymorph. So, in the phase transformation from high- to low-temperature polymorph, the low-temperature polymorph can have two orientations, which leads to twin formation. This is called the transformation twin. To minimize the interface energy between twinned individuals through transfer-... 

These studies suggest that the variability between tumor and germline genotype at the SNP level is minimal and the germline genome can be used as a surrogate to assess polymorphism status in the tumor. However, these studies were all performed on small sample numbers and do not represent all tumor types. 

Alemtuzumab has shown impressive results in refractory or relapsed CLL as well as up-front therapy for untreated CLL (35). The use of alemtuzumab to eradicate minimal residual disease of CLL is also reasonable (36). The role of Fey receptor polymorphisms on the clinical activity of alemtuzumab for CLL has not been extensively studies and will be discussed later. 

Both low-power and high-power microscope observations are useful in markedly minimizing interobserver variation. The characteristics observed at low magnification include atypia, location of immature cells, and stratification/polarization. At high magnification, detailed morphological characteristics, such as location of immature cells and stratification/ polarization (differentiation), nucleus/cytoplasm ratio, hyperchromasia, polymorphous nuclei (cell characteristics), and the location and appearance of mitotic activity, are scored (Vetetal., 1995). 

L2. Lee, D. Y., Kim, W., and Kang, S. K., Angiotensin-converting enzyme gene polymorphism in patients with minimal-change nephrotic syndrome and focal segmental glomerulosclerosis. Nephron 77,471-473 (1997). 

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