Polymorphism Studies

The polymorphic transformations can be studied by different techniques that are illustrated below by some characteristic examples. 

---

The fluorite phase is found to be extremely high in energy (it falls outside the energy range of Figure 1). Its equilibrium volume at P=0 would be 27.648 A /mol, and calculated equation of state gives B=287 GPa and B"=4.18. These values make fluorite structure the least compressible of all titanium dioxide polymorphs studied here, but still leaves the observation of a phase with B>500 GPa unexplained. ... 

Calculated valence band (VB) densities of states (DOS) for all six polymorphs studied are presented in Figure 2. These plots correspond to zero pressure geometries. 

The reduced folate carrier is the major transporter of methotrexate into cells. The RFC gene is comprised of 40,719 base pairs, has 12 exons, and is located on 21q22.3. The primary polymorphisms studied to date is the RFCl G80A variant, which is associated with a decrease in MTX transport into cells. Rady et al. noted similar rates of variation in several ethnic groups variant homozygosity rates were 28.7% in individuals of Ashkenazi-Jewish decent, 20.8% in African-American, 29% in Caucasians, and 26% in Hispanics (23). 

Angiotensin I converting enzyme 1 (ACE1) polymorphism studies... 

Antipin, M. Y, Timofeeva, T. V., Clark, R. D., Nesterov, V. N., Dolgushin, F. M., Wu, J. and Leyderman, A. (2001). Crystal structures and molecular mechanics calculation of nonlinear optical compounds 2-cyclooctylamino-5-nitropyridine (COANP) and 2-adamantylamino-5-nitropyridine (AANP). New Polymorphic modifcation of AANP and electrooptic effects. /. Mater. Chem., 11, 351-8. [213] Apperley, D. C., Fletton, R. A., Harris, R. K., Lancaster, R. W., Tavener, S. and Threlfall, T. L. (1999). Sulfathiazole polymorphism studied by magic-angle spinning NMR. / Pharm. ScL, 88, 1275-80. [135,139f]... 

Burger, A. (1982fe). Interpretation of polymorphism studies. Acta Pharm. TechnoL, 28, 1-20. [40, 106]... 

These new emerging combined techniques enables the observation of extremely small samples with a high degree of information. They find a good place for proper screening (according to the polymorphic studies required by in order to choose the proper... 

Study (Statin) N FU (years) Polymorphism Studied Endpoint Placebo Event Rate Statin Event Rate P... 

Ghetti P, Ghedini A, Stradi R. Analytical potential of PT-IR microscopy. I. Applications to the drug polymorphism study. Boll Chin Parm 1994 133 689-697. 

The DR technique lends itself to polymorph studies since the technique is noninvasive, the polymorph character remains intact due to limited sample handling, and the technique is quantitative (4). One disadvantage to diffuse reflectance IR is that it is a particle size-dependent technique (22). Development of quantitative polymorph assays require that the particle size of each component be limited to a specific range, including both components of a mixture, and the nonabsorbing matrix if the mixture is not sampled neat. It must also be kept in mind that for a quantitative assay, all calibration, validation, and subsequent samples to be assayed must fall within the particle size range otherwise, significant prediction errors may arise. 

There are many techniques available to characterize compounds. Indeed, in polymorphism studies it is advisable to identify the modifications present by more than one technique. In 1985, the U.S. Food and Drug Administration (FDA) indicated (The Gold Sheet) that the principal physicochemical techniques (in their approximate order of usefulness) that could be used to characterize polymorphs should be (Poulson 1985)... 

The DSC analysis is amenable to a wide variety of applications. Properties of pure compounds, such as melting point, boiling point, sublimation temperature, glass-transition temperature, decomposition temperature and energetics, are readily obtainable. In situ production of polymorphs and determination of the phase transitions and their kinetics makes DSC analysis a valuable tool to investigate polymorphs. Studies of physical interactions between drug substance and excipients can be performed quickly and with a minimal amount of material. These and other applications are discussed in a series of publications by Giron [66-69]. 

Crystalline polymorphism studies (i.e., relationship of TNT crystalline form to impact stability, etc.). 

---