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and XRPD can be used to evaluate crystallinity. DSC can be used to evaluate miscibility on a small scale.35


7. Solid-state nuclear magnetic


resonance has recently been shown to be able to predict miscibility on the nanometer scale.36


The amorphous sample must be stressed under


temperature and humidity and then reexamined to determine if the dispersion is physically and chemically stable. Material with a glass transition of less than 50 to 75°C should not be developed.32


Impurities


Process impurities can have a profound effect on the forms found during the screening activities. There are literature reports and many anecdotal reports that impurities can change the form isolated and result in the discovery of a more stable, and less soluble, form.36 Typically one lot of purified API is used for form screening. It is highly recommended that different lots of API are used for the different screens, that polymorph screens should be repeated after changes in the API manufacturing process and that crude API be used for screening.


Comprehensive Screens


Comprehensive polymorph screens, salt selections, and cocrystal screens should be conducted after completion of the preliminary screens.1


These screens may include specialized screening and are beyond the scope of this article. Conclusion


This article described a rational process, although imperfect, for form screening suitable for early development. It is viewed as an iterative process with screening activities becoming more comprehensive as more material and resources become available. Polymorph screening of the free form was recommended first provided it had the solubility and dissolution rate acceptable for early studies. Salt selection can be done either after the polymorph screen or concurrently if material is available. Cocrystal and amorphous screening are recommended if the salt and polymorph screens fail to find a suitable form. These screens can be conducted earlier if the API is incapable of forming a salt.


References


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Collman B, Miller, JM, Seadeek C, Stambek JA, Blackburn AC. Drug Development and Industrial Pharmacy. 2013;39:29–38.


11. Bastin RJ, Bowker MJ, Slater BJ. Org Proc Res Dev. 200;4:427-435. 12.


Stahl PH, Wermuth CG, eds. Handbook of Pharmaceutical Salts Properties, Selection, and Use. NY: Wiley; 2008.


13. Thackaberry EA. Expert Opin Drug Metab Toxicol. 2012;8:419-1433. 14. Paulekuhn GS, Dressman JB, Saal C. J Med Chem. 2007;50:6665-6672. 15. Alleso M, Tian F, Cornett C, Rantanen J. J Pharm Sci. 2010;99:3711. 16.


Reutzel-Edens SR, Stephenson GA. Solid-state pharmaceutical development: Ensuring stability through salt and polymorph screening. Baertschi SW, Alsante KM, Reed RA, eds. Pharmaceutical Stress Testing, Predicting Drug Degradation. 2nd 2011: 254-285.


ed. NY: Infoma Healthcare;


17. Govindarajam R, Zinchuk A, Hancock B, Shalaev E, Suryanarayanan R. Pharm. Res. 2006;23:2454-2468.


18. Sheikh AY, Rahim SA, Hammond RB, Roberts KJ. Cryst Eng Comm. 2009;11:501. 19. Trask AV, Jones W. Topics Curr Chem. 2005;254:41-70. 20.


Friščić T, Jones W. Cryst Growth Des. 2009;9:1621-1637.


21. Friščić T, Childs SL, Rizvi SAA, Jones W. Cryst Eng Comm. 2009:11:418. 22. Zhang GGZ, Henry RF, Borchardt TB, Lou X. J Pharm Sci. 2007;96:990-995. 23. Weyna DR, Shattock T, Vishweshwar P, Zaworotko MJ. Cryst Growth Des. 2009;9:1106-1123. 24. McNamara DP, Childs SL, Giordano J, et al. Pharm Res. 2006;23:1888. 25. Lu E, Rodriguez-Hornedo N, Suryanarayanan R. Cryst Eng Comm. 2008;8:665 26. ter Horst JH, Deij MA, Cains PW. Cryst Growth Des. 2009;9:1531-1537. 27. Nehm S, Rodríguez-Spong B, Rodríguez-Hornedo N. Cryst. Growth & Des., 2006;6:592-600. 28. Good D, Rodríguez-Hornedo N. Cryst Growth Des. 2010;10:1028-1032. 29. 30.


Reddy LS, Bethune SJ, Kampf JW, Rodriguez-Hornedo N. Cryst Growth Des. 2009;9:378-385.


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31. Mukuta T, Lee AY, Kawakami T, Myerson AS. Cryst Growth Des. 2005;5:1429. 32. Yu L. Advanced Drug Delivery Reviews. 2001;48:27–42. 33. Chiou WL, Riegelman S. J Pharm Sci. 1971;60:1281-1302. 34.


Huang Y, Dai W. Acta Pharma Sinica B. 2014;4:18-25.


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Author Biography


Jeff Stults received his PhD in Organic Chemistry from the University of Wisconsin-Madison. He has worked in the chemical and pharmaceutical industries for almost 3 decades. His career in pharmaceutical solid state chemistry began about 12 years ago at SSCI, Inc., a contract research organization specializing in solid state chemistry. He is currently employed in the Small Molecule Pharmaceutics Group at Genentech, a Roche company, as a Senior Scientist specializing in solid state chemistry. His principal duties include polymorph screening, salt and cocrystal selection, crystallization, and preparation of amorphous materials including dispersions with an aim to deliver the appropriate developable form.


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