Polymorphs control

In electrolytic systems the crystallization solvent type will affect the degree of solute ionization. This is an important factor in the rate of nucleation and can be successfully utilized for polymorphic control [11]. 

Field, L. L., Bonnevie-Nielsen, V., Pociot, F., Lu, S., Nielsen, T. B., and Beck-Nielsen, H. (2005) OAS1 splice site polymorphism controlling antiviral enzyme activity influences susceptibility to type 1 diabetes. Diabetes. 54, 1588-1591. 

Polymorph selectivity can be achieved through two-dimensional epitaxy which allows efficient screening of substrates for polymorph control through geometric lattice modeling prior to performing experiments with actual libraries. (Adapted from Mitchell et ah, 2001)... 

Ganin AY, Takabayashi Y, Jeglic P, Arcon D, Potocnik A, Baker PJ, Ohishi Y, McDonald MT, Tzirakis MD, McLennan A, Darling GR, Takata M, Rosseinsky MJ, Prassides K (2010) Polymorphism control of superconductivity and magnetism in CssCgo close to the Mott transition. Nature 466 221-225... 

A.V. Trask, W.D.S. Motherwell, W. Jones, Solvent-drop grinding green polymorph control of cocrystallization, Chem. Commun. (2004) 890-891. 

Agilent Technologies 2003. Palo Alto, California, Agilent Technologies Impedance Measurement Handbook (December) www.optics.arizona.edu/Palmer/OPTI380B/PDFdocs/5950-3000.pdf. Allais, C., Keller, G., Lesieur, P., Ollivon, M., Artzner, F. 2003. X-ray diffraction/calorimetry coupling. A new tool for polymorphism control. J. Thermal Anal. Cal. 74, 723-728. Barnes, H.A., Hutton, J.F., Walters, K. 1989. An Introduction to Rheology. Elsevier, Amsterdam. 

The second, (b), shows clear liquid overflow, as in a well-behaved fluidized bed crystallizer or in the semicontinuous stirred tank (SCST) operation illustrated in Example 7-5. The SCST has proven to be a versatile and practical method of maintaining control in critical separation and polymorph control, and can be operated in small and large conflgurations. 

Saranteas, K., R. Bakale, Y. Hong, H. Luong, R. Foroughi, and S. Wald (2005). Process design and scale-up elements for solvent mediated polymorphic controlled tecastemizole crystallization. Organic Process R <11 D 9, 911 -922. 

The genetic polymorphism controlling N-acetylation may be demonstrated readily in human populations, where the distribution of the phenotypes shows marked ethnic variability (22) ... 

SEDS Organic solvent Antisolvent effect + solvent evaporation 10-30 308-363 0.05-10 Polar molecules, small particles, polymorphism control Organic solvent use (small quantities) separation of solvent and fluid semicontinuous process Acetominophen, insulin, salmeterol-xinofoate... 

Kordikowski A, Shekunov T, York P. Polymorph control of sulfathiazole in supercritical CO2. Pharm Res 2001 18 685-688. 

Green KM, Browning SR, Seward TS et al (2008) The elk PRNP codon 132 polymorphism controls cervid and scrapie prion propagation. J Gen Virol 89 598-608... 

Many individuals have genetic susceptibility to certain chemicals (Calabrese 1978). The influence of these genetic differences likely produces sub- and supersensitivity to OP insecticides and warfare agents (Russell and Overstreet 1987). Several enzymes with variations or polymorphisms control sensitivity to OPs red blood cell acetylcholinesterase, serum cholinesterase or pseudocholinesterase, lymphocyte neuropathy target esterase or platelet neuropathy target esterase (NTE), serum paroxonase, butyrylcholinesterase, and serum arylesterase (Costa et al. 1999 LaDu 1988 Li et al. 1993 Mutch et al. 1992). Inhibition of red blood cell acetylcholinesterase, in both the central and the peripheral nervous systems, produces acute symptoms (Mutch et al. 1992). Paroxonase and arylesterase further modify the response (LaDu 1988 Li et al. 1993). Variant, inactive butyrylcho-linesterases increase sensitivity to OPs (Lockridge and Masson 2000 Schwarz et al. 1995). OP-induced delayed polyneuropathy results... 

Zhang, N.L., Molenda, J.A., Mancoci, S., Zhou, X.F., Murphy, W.L., and Sahai, N. (2013) Crystal structures of CaSi03 polymorphs control growth and osteogenic differentiation of human mesenchymal stem cells on bioceramic surfaces. Biomater. Sci., 1 (10), 1101-1110. 

Sun, X., Garetz, B.A., Myerson, A.Y Supersaturation and polarization dependence of polymorph control in the nontopochemical laser-induced nucleation (NPLIN) of aqueous glycine solutions, Crystal Growth and Design. 1 (2001) 5-8. 

The API, as an outcome of the designed processes, needs to be fit for use in the formulating of the drug product where the requirements need to be well defined and understood. Increased API complexity, lower solubility and bioavailability, less stable APIs, and more complicated intelligent formulations as a result impose specific form requirements (salts, particles, etc.) calling for the process chemist s creativity and expertise to find adequate solutions. Polymorphism continues to be an important aspect to be managed, and there is an excellent chapter on crystallization and polymorph controls in this book. 

The general considerations above highlight the importance of nucleation and the role of environmental conditions (e.g. solvent, temperature) in the crystallization of polymorphs as well as their interconversions. These areas continue to be the subject of intense interest especially in the context of polymorphic control in crystallization. 

Desolvation of pseudopolymorphs may be considered as a means of polymorphic control. This was discussed earlier in this report in the context of... 

Recent application of these principles to polymorphic control is shown schematically in Fig. 15 for a hypothetical dimorphic system in which one polymorph is centrosymmetric and the other crystallizes in a polar space group [36]. In the former crystal, the molecules are arranged in antiparallel orientation whereas in the latter they are aligned along a common direction. A tailor-made auxiliary which binds to both crystals would do so at the two (indistinguishable) ends of the centrosymmetric crystal but only at one end of the polar crystal. The latter would therefore grow at the expense of the former and polymorphic control will have been achieved. 

---