AAPS PharmSciTech

, Volume 19, Issue 8, pp 3430–3439 | Cite as

Aggregate Elasticity and Tabletability of Molecular Solids: a Validation and Application of Powder Brillouin Light Scattering

  • Dherya Bahl
  • Aditya B. Singaraju
  • Lewis L. StevensEmail author
Research Article Theme: Advances in PAT, QbD, and Material Characterization
Part of the following topical collections:
  1. Theme: Advances in PAT, QbD, and Material Characterization


Describing the elastic deformation of single-crystal molecular solids under stress requires a comprehensive determination of the fourth-rank stiffness tensor (Cijkl). Single crystals are, however, rarely utilized in industrial applications, and thus averaging techniques (e.g., the Voigt or Reuss approach) are employed to reduce the Cijkl (or its inverse Sijkl) to polycrystalline aggregate mechanical moduli. With increasing elastic anisotropy, the Voigt and Reuss-averaged aggregate moduli can diverge dramatically and, provided that drug molecules almost exclusively crystallize into low-symmetry space groups, warrants a significant need for accurate aggregate mechanical moduli. This elasticity data, which currently is largely absent for pharmaceutical materials, is expected to aid understanding how materials respond to direct compression and tablet formation. Powder Brillouin light scattering (p-BLS) has recently demonstrated facile access to porosity-independent, aggregate mechanical moduli. In this study, we extend our previous p-BLS model for obtaining mechanical properties and validate our approach against a broad library of molecular solids with diverse intermolecular interaction topologies and with previously determined Cijkl which permits benchmarking our results. Our Young’s and shear moduli determined with p-BLS strongly correlate, with limited bias (i.e., a near 1:1 relation), with the Voigt-averaged Young’s and shear moduli determined using the Cijkl. Through follow-on tabletability studies, we introduce initial classifications of tabletability behavior based on the results of our p-BLS studies and the apparent elastic anisotropy. With further development, this approach represents a robust and novel method to potentially identify materials for optimum tabletability at early developmental stages.


mechanical properties spectroscopy tabletability compression anisotropy 

Supplementary material

12249_2018_1194_MOESM1_ESM.docx (905 kb)
ESM 1 (DOCX 905 kb)


  1. 1.
    Duncan-Hewitt WC, Weatherly GC. Evaluating the hardness, Young’s modulus and fracture toughness of some pharmaceutical crystals using microindentation techniques. J Mater Sci Lett. 1989;8(11):1350–2.CrossRefGoogle Scholar
  2. 2.
    Katz JM, Buckner IS. Characterization of strain rate sensitivity in pharmaceutical materials using indentation creep analysis. Int J Pharm. 2013;442(1–2):13–9.CrossRefGoogle Scholar
  3. 3.
    Egart M, Ilić I, Janković B, Lah N, Srčič S. Compaction properties of crystalline pharmaceutical ingredients according to the Walker model and nanomechanical attributes. Int J Pharm. 2014;472(1–2):347–55.CrossRefGoogle Scholar
  4. 4.
    Price CP, Grzesiak AL, Matzger AJ. Crystalline polymorph selection and discovery with polymer heteronuclei. J Amer Chem Soc. 2005;127(15):5512–7.CrossRefGoogle Scholar
  5. 5.
    Reddy CM, Basavoju S, Desiraju GR. Sorting of polymorphs based on mechanical properties. Trimorphs of 6-chloro-2, 4-dinitroaniline. Chem Commun. 2005;(19):2439–41.Google Scholar
  6. 6.
    Khomane KS, More PK, Raghavendra G, Bansal AK. Molecular understanding of the compaction behavior of indomethacin polymorphs. Mol Pharm. 2013;10(2):631–9.CrossRefGoogle Scholar
  7. 7.
    Hiestand EN. Mechanical properties of compacts and particles that control tableting success. J Pharm Sci. 1997;86(9):985–90.CrossRefGoogle Scholar
  8. 8.
    Heckel R. Density-pressure relationships in powder compaction. Trans Metall Soc AIME. 1961;221(4):671–5.Google Scholar
  9. 9.
    Çelik M, Marshall K. Use of a compaction simulator system in tabletting research. Drug Dev Ind Pharm. 1989;15(5):759–800.CrossRefGoogle Scholar
  10. 10.
    Duberg M, Nyström C. Studies on direct compression of tablets XVII. Porosity—pressure curves for the characterization of volume reduction mechanisms in powder compression. Powder Technol. 1986;46(1):67–75.CrossRefGoogle Scholar
  11. 11.
    Ilkka J, Paronen P. Prediction of the compression behaviour of powder mixtures by the Heckel equation. Int J Pharm. 1993;94(1–3):181–7.CrossRefGoogle Scholar
  12. 12.
    Ilic M, Galiana F, Fink L. Power systems restructuring: engineering and economics: Springer Science & Business Media, Boston, MA; 2013.Google Scholar
  13. 13.
    Khomane KS, More PK, Bansal AK. Counterintuitive compaction behavior of clopidogrel bisulfate polymorphs. J Pharm Sci. 2012;101(7):2408–16.CrossRefGoogle Scholar
  14. 14.
    Sonnergaard JM. Quantification of the compactibility of pharmaceutical powders. Eur J Pharm Biopharm. 2006;63(3):270–7.CrossRefGoogle Scholar
  15. 15.
    Rasenack N, Müller BW. Dissolution rate enhancement by in situ micronization of poorly water-soluble drugs. Pharm Res. 2002;19(12):1894–900.CrossRefGoogle Scholar
  16. 16.
    Shariare MH, Leusen FJ, de Matas M, York P, Anwar J. Prediction of the mechanical behaviour of crystalline solids. Pharm Res. 2012;29(1):319–31.CrossRefGoogle Scholar
  17. 17.
    Sun CC. Decoding powder tabletability: roles of particle adhesion and plasticity. J Adhes Sci Technol. 2011;25(4–5):483–99.CrossRefGoogle Scholar
  18. 18.
    Egart M, Janković B, Srčič S. Application of instrumented nanoindentation in preformulation studies of pharmaceutical active ingredients and excipients. Acta Pharma. 2016;66(3):303–30.CrossRefGoogle Scholar
  19. 19.
    Roberts RJ. Particulate analysis–mechanical properties. Solid State Characterization of Pharmaceuticals. 2011:357–386.Google Scholar
  20. 20.
    Nordström J, Klevan I, Alderborn G. A protocol for the classification of powder compression characteristics. Eur J Pharm Biopharm. 2012;80(1):209–16.CrossRefGoogle Scholar
  21. 21.
    Roberts R, Rowe R, York P. The relationship between the fracture properties, tensile strength and critical stress intensity factor of organic solids and their molecular structure. Int J Pharm. 1995;125(1):157–62.CrossRefGoogle Scholar
  22. 22.
    Jain S. Mechanical properties of powders for compaction and tableting: an overview. Pharm Sci Technolo Today. 1999;2(1):20–31.CrossRefGoogle Scholar
  23. 23.
    Amidon GE, Secreast PJ, Mudie D. Particle, powder, and compact characterization. In: Developing solid oral dosage forms: Elsevier; 2009. p. 163–86.Google Scholar
  24. 24.
    Sun C, Grant DJ. Influence of crystal structure on the tableting properties of sulfamerazine polymorphs. Pharm Res. 2001;18(3):274–80.CrossRefGoogle Scholar
  25. 25.
    Taylor L, Papadopoulos D, Dunn P, Bentham A, Mitchell J, Snowden M. Mechanical characterisation of powders using nanoindentation. Powder Technol. 2004;143:179–85.CrossRefGoogle Scholar
  26. 26.
    Davidge R, Tappin G. The effective surface energy of brittle materials. J Mater Sci. 1968;3(2):165–73.CrossRefGoogle Scholar
  27. 27.
    Meier M, John E, Wieckhusen D, Wirth W, Peukert W. Influence of mechanical properties on impact fracture: prediction of the milling behaviour of pharmaceutical powders by nanoindentation. Powder Technol. 2009;188(3):301–13.CrossRefGoogle Scholar
  28. 28.
    Govedarica B, Ilić I, Srčič S. The use of single particle mechanical properties for predicting the compressibility of pharmaceutical materials. Powder Technol. 2012;225:43–51.CrossRefGoogle Scholar
  29. 29.
    Brillouin L, editor Diffusion de la lumière et des rayons X par un corps transparent homogène-Influence de l’agitation thermique. Ann Phy; 1922: EDP Sciences.Google Scholar
  30. 30.
    Borovik-Romanov A, Kreines NM. Brillouin-Mandelstam scattering from thermal and excited magnons. Phys Rep. 1982;81(5):351–408.CrossRefGoogle Scholar
  31. 31.
    Dil J. Brillouin scattering in condensed matter. Rep Prog Phys. 1982;45(3):285–334.CrossRefGoogle Scholar
  32. 32.
    Krüger J, Marx A, Peetz L, Roberts R, Unruh H-G. Simultaneous determination of elastic and optical properties of polymers by high performance Brillouin spectroscopy using different scattering geometries. Colloid Polym Sci. 1986;264(5):403–14.CrossRefGoogle Scholar
  33. 33.
    Speziale S, Marquardt H, Duffy TS. Brillouin scattering and its application in geosciences. Rev Mineral Geochem. 2014;78(1):543–603.CrossRefGoogle Scholar
  34. 34.
    Singaraju AB, Nguyen K, Jain A, Haware RV, Stevens LL. Aggregate elasticity, crystal structure, and tableting performance for p-aminobenzoic acid and a series of its benzoate esters. Mol Pharm. 2016;13(11):3794–806.CrossRefGoogle Scholar
  35. 35.
    Hernandez J, Li G, Cummins HZ, Callender RH, Pick RM. Low-frequency light-scattering spectroscopy of powders. JOSA B. 1996;13(6):1130–4.CrossRefGoogle Scholar
  36. 36.
    Newton J, Rowley G, Fell J, Peacock D, Ridgway K. Computer analysis of the relation between tablet strength and compaction pressure. J Pharm Pharmacol. 1971;23(S1):195S–201S.CrossRefGoogle Scholar
  37. 37.
    Haussühl S. Elastic and thermoelastic properties of selected organic crystals: acenaphthene, trans-azobenzene, benzophenone, tolane, trans-stilbene, dibenzyl, diphenyl sulfone, 2, 2′-biphenol, urea, melamine, hexogen, succinimide, pentaerythritol, urotropine, malonic acid, dimethyl malonic acid, maleic acid, hippuric acid, aluminium acetylacetonate, iron acetylacetonate, and tetraphenyl silicon. Z Kristallogr Cryst Mater. 2001;216(6):339–53.CrossRefGoogle Scholar
  38. 38.
    Dye R, Eckhardt CJ. A complete set of elastic constants of crystalline anthracene by Brillouin scattering. J Chem Phys. 1989;90(4):2090–6.CrossRefGoogle Scholar
  39. 39.
    Mohapatra H, Eckhardt CJ. Elastic constants and related mechanical properties of the monoclinic polymorph of the carbamazepine molecular crystal. J Phys Chem B. 2008;112(8):2293–8.CrossRefGoogle Scholar
  40. 40.
    Bauer JD, Haussühl E, Br W, Arbeck D, Milman V, Robertson S. Elastic properties, thermal expansion, and polymorphism of acetylsalicylic acid. Cryst Growth Des. 2010;10(7):3132–40.CrossRefGoogle Scholar
  41. 41.
    Armstrong N, Haines-Nutt R. Elastic recovery and surface area changes in compacted powder systems. J Pharm Pharmacol. 1972;24:Suppl: 135P.Google Scholar
  42. 42.
    Kerridge J, Newton J. The determination of the compressive Young’s modulus of pharmaceutical materials. J Pharm Pharmacol. 1986;38(S12):79P.CrossRefGoogle Scholar
  43. 43.
    Church M, Kennerley J. A comparison of the mechanical properties of pharmaceutical materials obtained by the flexure testing of compacted rectangular beams. J Pharm Pharmacol. 1983;35:43P.CrossRefGoogle Scholar
  44. 44.
    Mashadi AB, Newton J. The characterization of the mechanical properties of microcrystalline cellulose: a fracture mechanics approach. J Pharm Pharmacol. 1987;39(12):961–5.CrossRefGoogle Scholar
  45. 45.
    Bassam F, York P, Rowe R, Roberts R. Young’s modulus of powders used as pharmaceutical excipients. Int J Pharm. 1990;64(1):55–60.CrossRefGoogle Scholar
  46. 46.
    Akseli I, Becker DC, Cetinkaya C. Ultrasonic determination of Young’s moduli of the coat and core materials of a drug tablet. Int J Pharm. 2009;370(1–2):17–25.CrossRefGoogle Scholar
  47. 47.
    Lee J-U, Yoon D, Cheong H. Estimation of Young’s modulus of graphene by Raman spectroscopy. Nano Lett. 2012;12(9):4444–8.CrossRefGoogle Scholar
  48. 48.
    Peiponen K-E, Bawuah P, Chakraborty M, Juuti M, Zeitler JA, Ketolainen J. Estimation of Young’s modulus of pharmaceutical tablet obtained by terahertz time-delay measurement. Int J Pharm. 2015;489(1–2):100–5.CrossRefGoogle Scholar
  49. 49.
    Ketolainen J, Oksanen M, Rantala J, Stor-Pellinen J, Luukkala M, Paronen P. Photoacoustic evaluation of elasticity and integrity of pharmaceutical tablets. Int J Pharm. 1995;125(1):45–53.CrossRefGoogle Scholar
  50. 50.
    Gupta A, Peck GE, Miller RW, Morris KR. Real-time near-infrared monitoring of content uniformity, moisture content, compact density, tensile strength, and Young’s modulus of roller compacted powder blends. J Pharm Sci. 2005;94(7):1589–97.CrossRefGoogle Scholar
  51. 51.
    Busignies V, Tchoreloff P, Leclerc B, Hersen C, Keller G, Couarraze G. Compaction of crystallographic forms of pharmaceutical granular lactoses. II. Compacts mechanical properties. Eur J Pharm Biopharm. 2004;58(3):577–86.CrossRefGoogle Scholar
  52. 52.
    Ryshkewitch E. Compression strength of porous sintered alumina and zirconia. J Am Ceram Soc. 1953;36(2):65–8.CrossRefGoogle Scholar
  53. 53.
    Newton J, Mashadi A, Podczeck F. The mechanical-properties of an homologous series of benzoic-acid esters. Eur J Pharm Biopharm. 1993;39(4):153–7.Google Scholar
  54. 54.
    Krycer I, Pope DG, Hersey JA. An evaluation of the techniques employed to investigate powder compaction behaviour. Int J Pharm. 1982;12(2–3):113–34.CrossRefGoogle Scholar
  55. 55.
    Spriggs R. Expression for effect of porosity on elastic modulus of polycrystalline refractory materials, particularly aluminum oxide. J Am Ceram Soc. 1961;44(12):628–9.CrossRefGoogle Scholar
  56. 56.
    Leuenberger H. The compressibility and compactibility of powder systems. Int J Pharm. 1982;12(1):41–55.CrossRefGoogle Scholar
  57. 57.
    Pharr G. Measurement of mechanical properties by ultra-low load indentation. Mater Sci Eng A. 1998;253(1–2):151–9.CrossRefGoogle Scholar
  58. 58.
    Khossravi D, Morehead WT. Consolidation mechanisms of pharmaceutical solids: a multi-compression cycle approach. Pharm Res. 1997;14(8):1039–45.CrossRefGoogle Scholar
  59. 59.
    Newnham RE. Properties of materials: anisotropy, symmetry, structure: Oxford University Press on Demand; 2005.Google Scholar
  60. 60.
    Nye JF. Physical properties of crystals: their representation by tensors and matrices: Oxford University Press; 1985.Google Scholar
  61. 61.
    Crosson RS, Lin JW. Voigt and Reuss prediction of anisotropic elasticity of dunite. J Geophys Res. 1971;76(2):570–8.CrossRefGoogle Scholar
  62. 62.
    Ranganathan SI, Ostoja-Starzewski M. Universal elastic anisotropy index. Phys Rev Lett. 2008;101(5):055504.CrossRefGoogle Scholar
  63. 63.
    Kube CM. Elastic anisotropy of crystals. AIP Adv. 2016;6(9):095209.CrossRefGoogle Scholar
  64. 64.
    Singaraju AB, Iyer M, Haware RV, Stevens LL. Caffeine co-crystal mechanics evaluated with a combined structural and spectroscopic approach. Cryst Growth Des. 2016;16(8):4383–91.CrossRefGoogle Scholar
  65. 65.
    Singaraju AB, Nguyen K, Gawedzki P, Herald F, Meyer G, Wentworth D, et al. Combining crystal structure and interaction topology for interpreting functional molecular solids: a study of theophylline cocrystals. Cryst Growth Des. 2017;17(12):6741–51.CrossRefGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2018

Authors and Affiliations

  1. 1.Division of Pharmaceutics and Translational Therapeutics, College of PharmacyThe University of IowaIowa CityUSA

Personalised recommendations