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SR-XRPD Applications

X-Ray Powder Diffraction (XRPD) is ideal for the characterization of (bio)pharmaceuticals, supporting the Quality-by-Design (QbD) approach and the requirements of the new Food & Drugs Administration (FDA) guidance on process validation.

 

Pharmaceutical drug substances can exist in different crystalline forms (polymorphs), solvates/hydrated forms (pseudo-polymorphs) and amorphous forms, as a result of the manufacturing and storage conditions. These different forms can have a profound effect on the quality or performance (e.g. solubility, bioavailability, efficacy, safety) of the drug product [26-28]. For example, therapeutic failure has been attributed to uncontrolled hydrate formation in tablets during storage [29]. 

 

For this reason, it is now a regulatory requirement to conduct a detailed analysis of the polymorphism of the drug substance and drug product during technical development, including screening, characterization, property determination and setting of acceptance criteria for the different forms (see for instance the ICH Q6A guideline).

 

 

 

 

 

 

                                   "The Gold Standard Technique"

To meet these requirements, XRPD, and even more so SR-XRPD, stands out as the gold standard technique [3,4]. It has thus become a key tool to support research, development, manufacturing and life-cycle management activities for (bio)pharmaceuticals.

 

Typical applications include

 

  • Structural solution of the solid form of new molecular entities during screening and selection processes 
  • Development of formulation and screening of excipients, including co-crystals 
  • Quality-by-design (QbD) approach for drug development 
  • Characterization and high-accuracy quantification of all polymorphic forms in a drug substance and drug product, including in fully opaque blisters and in the presence of crystalline excipients. 
  • Detection of impurities down to a trace level (< 0.05% wt) 
  • Bi-dimensional distribution of drug substance polymorphs and excipients in a tablet 
  • Optimization of manufacturing processes, in particular crystallization, formulation, drying, lyophilization, wet granulation, tabletting and packaging operations. 
  • In situ non-ambient kinetic studies at milli-sec scale. 
  • Stability studies of polymorphic forms 
  • Continued Process Verification, in order to "maintain the process in a state of control over the life of the process" and "to continually improve [the] process", by performing "process improvement and innovation through sound science", as required by the new FDA guidance on process validation (FDA, 2011) 
  • Comparability studies following process changes or technology transfers 
  • Troubleshooting activities and investigations during commercial manufacturing 
  • Patent application for new materials and patent-life extension 
  • Detection of counterfeits even with minute differences

 

 

 

 

                                                                                                                  

                                               "Not only for pharmaceuticals"

SR-XRPD is a powerful technique in several other areas where the properties and performance of products are dependent on their crystalline structure and relative distribution of their polymorphic forms, such as:

  • Food and aroma compounds 
  • Cosmetics 
  • Pigments 
  • Catalysts 
  • Cement

Bibliography

 

  1. Bish, DL and Post, JE, editors. 1989. Modern Powder Diffraction. Reviews in Mineralogy, Vol. 20. Mineralogical Society of America
  2. Cullity, B. D. 1978. Elements of X-ray diffraction. 2nd ed. Addison-Wesley, Reading, Mass
  3. I. Ivanisevic, R. B. McClurg and P. J. Schields: Uses of X-Ray Powder Diffraction in the Pharmaceutical Industry, Pharmaceutical Sciences Encyclopedia: Drug Discovery, Development and Manufacturing, Ed. by Shayne C. Gad., p. 1-42 (2010).
  4. S. R. Byrn, S. Bates and I. Ivanisevic: Regulatory Aspects of X-ray Powder Diffraction, Part 1, American Pharmaceutical Review, p.55-59 (2005).
  5. D. Beckers: The power of X-ray analysis, Pharmaceutical Technology Europe (2010), p.29,30.
  6. M. Sakata, S. Aoyagi, T. Ogura & E. Nishibori (2007): Advanced Structural Analyses by Third Generation Synchrotron Radiation Powder Diffraction, AIP Conference Proceedings, Vol. 879, pp. 1829-1832 (2007).
  7. Bergamaschi, A.; Cervellino, A.; Dinapoli, R.; Gozzo, F.; Henrich, B.; Johnson, I.; Kraft, P.; Mozzanica, A.; Schmitt, B.; Shi, X.: The MYTHEN detector for X-ray powder diffraction experiments at the Swiss Light Source. J. Synchrotron Rad. 17 (2010) 653–668.
  8. R.B. Von Dreele, P.W. Stephens, G.D. Smith, and R.H. Blessing: The First Protein Crystal Structure Determined from X-ray Powder Diffraction Data: a Variant of T3R3 Human Insulin Zinc Complex Produced by Grinding,Acta Cryst. D 56, 1549-53 (2000).
  9. Margiolaki, I., Wright, J. P., Fitch, A. N., Fox, G. C. & Von Dreele, R. B.: Synchrotron X-ray powder diffraction study of hexagonal turkey egg-white lysozyme, Acta Cryst. D61, 423–432 (2005). See also: Margiolaki, I. & Wright, J. P.: Powder crystallography on macromolecules, Acta Cryst. A64, 169–180 (2008).
  10. Fundamentals of Crystallography,C. Giacovazzo Ed., International Union of Crystallography, Oxford Science Publications, Third Edition (2011).
  11. The basics of Crystallography and Diffraction (Third edition, 2010), Christopher Hammond, IUCr, Oxford Science Publications; ISBN 978-0-19-954645-9. See also: X-Ray Structure Determination, A practical Guide, George H. Stout and Lyle H. Jensen, Wiley Interscience.
  12. Bruni G, Gozzo F, Capsoni D, Bini M, Macchi P, Simoncic P, Berbenni V., Milanese C., Girella A., Ferrari S. and Marini A., Thermal, Spectroscopic, and Ab Initio Structural Characterization of Carprofen Polymorphs, J. Pharm. Sciences 100(6), 2321 (2011).
  13. Brunelli, M., Wright, J. P., Vaughan, G. B. M., Mora, A. J. & Fitch, A. N.: Solving Larger Molecular Crystal Structures from Powder Diffraction Data by Exploiting Anisotropic Thermal Expansion. Angew. Chem. (2003) 115, 2075–2078.
  14. T. Wessels, Ch. Baerlocher and L.B. McCusker: Single-crystal-like diffraction data from polycrystalline materials, Science (1999), 284, 477-479.
  15. Shankland, K., David, W. I. F., Csoka, T. & McBride, L.: Structure solution of Ibuprofen from powder diffraction data by the application of a genetic algorithm combined with prior conformational analysis,  Intl. J. Pharmaceut. (1998) 165, 117–126.
  16. A. Altomare, C. Cuocci, C. Giacovazzo, A. Moliterni and R. Rizzi: The dual-space resolution bias correction algorithm: applications to powder data, J. Appl. Cryst. (2010). 43, 798-804.
  17. G.Oszlanyi and A. Suto: The charge flipping algorithm, Acta Cryst. (2008). A64, 123–134 and references herein.
  18. Boccaleri, E., Carniato, F., Croce, G., Viterbo, D., van Beek, W., Emerich H. and Milanesio, M., In-situ simultaneous Raman/high-resolution X-ray powder diffraction study of transformations occurring in materials at non-ambient conditions, J. Appl. Cryst., 2007, 40, 684-693.
  19. Scarlett N.V.Y. and Madsen I. C., Quantification of phases with partial or no known crystal structures, Powder Diffraction (2006) 21, 278-284
  20. Giannini C., Guagliardi A. and Millini R., Quantitative phase analysis by combining the Rietveld and the whole-pattern decomposition methods, J. Appl. Cryst., 2002, 35, 481-490.
  21. Scardi, P.; Leoni, M.: Line profile analysis: pattern modeling versus profile fitting, J. Appl. Cryst. 39 (2006) 24–31. Scardi, P.; Leoni, M.: Whole Powder Pattern Modelling, Acta Crystall. A58 (2002) 190–200
  22. Local structure from total scattering and atomic pair distribution function (PDF) analysis, In Powder diffraction: theory and practice, (Royal Society of Chemistry, London England, 2008), Robert E. Dinnebier and Simon J. L. Billinge, Eds., pp. 464 – 493.
  23. Neder R. B. And Korsunskiy V. I., Structure of nanoparticles from powder diffraction data using the pair distribution function, 2005 J. Phys.: Condens. Matter 17 S125
  24. A. Cervellino, C. Giannini, A. Guagliardi, Determination of nanoparticle, size distribution and lattice parameter from x-ray data for monoatomic materials with f.c.c. cubic unit cell, J. Appl. Cryst. 36, 1148-1158 (2003).
  25. P.W. Stephens, D.E. Cox, and A.N. Fitch, Synchrotron Radiation Powder Diffraction in Structure Determination by Powder Diffraction, pp. 49-87, edited by W.I.F. David, K.
    Shankland, L.B. McCusker, and C. Baerlocher, (Oxford University Press, 2002)
  26. Joel Bernstein: Polymorphism in Molecular Crystals, IUCr Monographs on Crystallography (2002), Oxford Science Publications.
  27. Polymorphism in Pharmaceutical Solids, Ed. By Harry G. Brittain, Drugs and The Pharmaceutical Sciences, Vol. 192
  28. Tremayne, M.: The impact of powder diffraction on the structural study of organic materials., Philosophical Transactions of the Royal Society of London Series A: Chemistry and Life Sciences Triennial Issue, 362: 2691 (2004).
  29. Law D, Schmitt EA, Marsh KC, Everitt EA,Wang W, Fort JJ, Krill SL, Qiu Y. Ritonavir-PEG 8000 amorphous solid dispersions: in vitro and in vivo evaluations. J. Pharm. Sci. 2004; 93 (3): 563–567.
  30. Bruni G., Berbenni V., Milanese C., Girella A., Cardini A., Lanfranconi S. and Marini A., Determination of the nateglinide polymorphic purity through DSC, J. Pharm. and Biomed. Anal. 54 (2011) 1196-1199.
  31. Aaltonen J., Alleso M., Mirza S., Koradia V., Gordon K.C and Rantanen J., Solid form screening – A review. European Journal of Pharmaceutics and Biopharmaceutics 71 (2009), 23-37.
  32. Srivastava D., The Food and Drug Administration and Patent Law at a Crossroads: The Listing of Polymorph Patents as a Barrier to Generic Drug Entry. Food and Drug Law Journal, Vol. 59, No.2 (2004), 339-354.
  33. Grabowski H. G., Kyle M., Mortimer R., Long G. & Kirson N., Evolving Brand-name And Generic Drug Competition May Warrant A Revision Of The Hatch-Waxman Act. Health Affairs, 30, no.11 (2011):2157-2166.
  34. Rakowski W. A and Mazzochi D. M., The case of disappearing polymorph: 'Inherent anticipation' and the impact of Smithkline Beecham Corp. v Apotex Corp. (Paxil®) on patent validity and infringement by inevitable conversion'. Journal of Generic Medicine, Vol.1, No.2 (2006):131-139.
  35. Cabri W., Ghetti P., Pozzi G. and Alpegiani M., Polymorphisms and Patent, Market, and Legal Battles: Cefdinir Case Study. Organic Process Research & Development 2007, 11, 64-72.
  36. Bauer J, Spanton S, Henry R, Quick J, Dziki W, Porter W, Morris J., Ritonavir: an extraordinary example of conformational polymorphism, Pharm Res. 2001 Jun;18(6):859-66.

 

 
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