Skip to main content
SpringerLink
Log in

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

  • Research Article
  • Theme: Advances in PAT, QbD, and Material Characterization
  • Published:
AAPS PharmSciTech Aims and scope Submit manuscript

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  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.

    CAS  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  4. Price CP, Grzesiak AL, Matzger AJ. Crystalline polymorph selection and discovery with polymer heteronuclei. J Amer Chem Soc. 2005;127(15):5512–7.

    CAS  Google Scholar 

  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.

  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.

    CAS  PubMed  Google Scholar 

  7. Hiestand EN. Mechanical properties of compacts and particles that control tableting success. J Pharm Sci. 1997;86(9):985–90.

    CAS  PubMed  Google Scholar 

  8. Heckel R. Density-pressure relationships in powder compaction. Trans Metall Soc AIME. 1961;221(4):671–5.

    CAS  Google Scholar 

  9. Çelik M, Marshall K. Use of a compaction simulator system in tabletting research. Drug Dev Ind Pharm. 1989;15(5):759–800.

    Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    CAS  Google Scholar 

  12. Ilic M, Galiana F, Fink L. Power systems restructuring: engineering and economics: Springer Science & Business Media, Boston, MA; 2013.

  13. Khomane KS, More PK, Bansal AK. Counterintuitive compaction behavior of clopidogrel bisulfate polymorphs. J Pharm Sci. 2012;101(7):2408–16.

    CAS  PubMed  Google Scholar 

  14. Sonnergaard JM. Quantification of the compactibility of pharmaceutical powders. Eur J Pharm Biopharm. 2006;63(3):270–7.

    CAS  PubMed  Google Scholar 

  15. Rasenack N, Müller BW. Dissolution rate enhancement by in situ micronization of poorly water-soluble drugs. Pharm Res. 2002;19(12):1894–900.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  17. Sun CC. Decoding powder tabletability: roles of particle adhesion and plasticity. J Adhes Sci Technol. 2011;25(4–5):483–99.

    CAS  Google Scholar 

  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.

    CAS  Google Scholar 

  19. Roberts RJ. Particulate analysis–mechanical properties. Solid State Characterization of Pharmaceuticals. 2011:357–386.

  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.

    PubMed  Google Scholar 

  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.

    CAS  Google Scholar 

  22. Jain S. Mechanical properties of powders for compaction and tableting: an overview. Pharm Sci Technolo Today. 1999;2(1):20–31.

    CAS  PubMed  Google Scholar 

  23. Amidon GE, Secreast PJ, Mudie D. Particle, powder, and compact characterization. In: Developing solid oral dosage forms: Elsevier; 2009. p. 163–86.

  24. Sun C, Grant DJ. Influence of crystal structure on the tableting properties of sulfamerazine polymorphs. Pharm Res. 2001;18(3):274–80.

    CAS  PubMed  Google Scholar 

  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.

    CAS  Google Scholar 

  26. Davidge R, Tappin G. The effective surface energy of brittle materials. J Mater Sci. 1968;3(2):165–73.

    CAS  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

  30. Borovik-Romanov A, Kreines NM. Brillouin-Mandelstam scattering from thermal and excited magnons. Phys Rep. 1982;81(5):351–408.

    CAS  Google Scholar 

  31. Dil J. Brillouin scattering in condensed matter. Rep Prog Phys. 1982;45(3):285–334.

    Google Scholar 

  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.

    Google Scholar 

  33. Speziale S, Marquardt H, Duffy TS. Brillouin scattering and its application in geosciences. Rev Mineral Geochem. 2014;78(1):543–603.

    CAS  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  Google Scholar 

  41. Armstrong N, Haines-Nutt R. Elastic recovery and surface area changes in compacted powder systems. J Pharm Pharmacol. 1972;24:Suppl: 135P.

  42. Kerridge J, Newton J. The determination of the compressive Young’s modulus of pharmaceutical materials. J Pharm Pharmacol. 1986;38(S12):79P.

    Google Scholar 

  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.

    Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  52. Ryshkewitch E. Compression strength of porous sintered alumina and zirconia. J Am Ceram Soc. 1953;36(2):65–8.

    Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    CAS  Google Scholar 

  56. Leuenberger H. The compressibility and compactibility of powder systems. Int J Pharm. 1982;12(1):41–55.

    CAS  Google Scholar 

  57. Pharr G. Measurement of mechanical properties by ultra-low load indentation. Mater Sci Eng A. 1998;253(1–2):151–9.

    Google Scholar 

  58. Khossravi D, Morehead WT. Consolidation mechanisms of pharmaceutical solids: a multi-compression cycle approach. Pharm Res. 1997;14(8):1039–45.

    CAS  PubMed  Google Scholar 

  59. Newnham RE. Properties of materials: anisotropy, symmetry, structure: Oxford University Press on Demand; 2005.

  60. Nye JF. Physical properties of crystals: their representation by tensors and matrices: Oxford University Press; 1985.

  61. Crosson RS, Lin JW. Voigt and Reuss prediction of anisotropic elasticity of dunite. J Geophys Res. 1971;76(2):570–8.

    Google Scholar 

  62. Ranganathan SI, Ostoja-Starzewski M. Universal elastic anisotropy index. Phys Rev Lett. 2008;101(5):055504.

    PubMed  Google Scholar 

  63. Kube CM. Elastic anisotropy of crystals. AIP Adv. 2016;6(9):095209.

    Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Pharmaceutics and Translational Therapeutics, College of Pharmacy, The University of Iowa, Iowa City, Iowa, 52242, USA

    Dherya Bahl, Aditya B. Singaraju & Lewis L. Stevens

Authors
  1. Dherya Bahl
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Aditya B. Singaraju
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lewis L. Stevens
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Lewis L. Stevens.

Additional information

Guest Editors: William C. Stagner and Rahul V. Haware

Electronic Supplementary Material

ESM 1

(DOCX 905 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bahl, D., Singaraju, A.B. & Stevens, L.L. Aggregate Elasticity and Tabletability of Molecular Solids: a Validation and Application of Powder Brillouin Light Scattering. AAPS PharmSciTech 19, 3430–3439 (2018). https://doi.org/10.1208/s12249-018-1194-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1208/s12249-018-1194-x

KEY WORDS

Search

Navigation