Skip to main content
SpringerLink
Log in

Characterization of Medicinal Compounds Confined in Porous Media by Neutron Vibrational Spectroscopy and First-Principles Calculations: A Case Study with Ibuprofen

  • Research Paper
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Purpose

Amorphous formulations of ibuprofen were prepared by confining the drug molecules into the porous scaffolds. The molecular interactions between ibuprofen and porous media were investigated using neutron vibrational spectroscopy.

Methods

Ibuprofen was introduced into the pores using sublimation and adsorption method. Neutron vibrational spectra of both neat and confined ibuprofen were measured, and compared to the simulated ibuprofen spectra using first-principles phonon calculations.

Results

The neutron vibrational spectra showed marked difference between the neat crystalline and the confined ibuprofen in low-frequency region, indicating a loss of the overall structural order once the ibuprofen molecules were in the pores. Furthermore, the formation of ibuprofen dimers, which is found in the crystal structure, was greatly inhibited, possibly due to the preferential interactions between the carboxylic acid group of ibuprofen (−COOH) and the surface hydroxyl groups of porous scaffolds (Si–OH).

Conclusions

The experimental evidence suggests that, at the current drug loading, most, if not all, of the confined ibuprofen molecules were bound to the pore surfaces via hydrogen bonding. The structural arrangement of ibuprofen in the pores appears to be monolayer coverage. In addition, neutron vibrational spectroscopy is proven an exceedingly useful technique to study adsorbent-adsorbate interactions.

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
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

References

  1. Hancock BC, Zografi G. Characteristics and significance of the amorphous state in pharmaceutical systems. J Pharm Sci. 1997;86:1–12.

    Article  PubMed  CAS  Google Scholar 

  2. Yu L. Amorphous pharmaceutical solids: preparation, characterization and stabilization. Adv Drug Deliv Rev. 2001;48:27–42.

    Article  PubMed  CAS  Google Scholar 

  3. Sing KSW, Everett DH, Haul RAW, Moscou L, Pierotti RA, Rouquerol J, et al. Reporting physisorption data for gas/solid systems with special reference to the determination of surface area and porosity. Pure Appl Chem. 1985;57:603–19.

    Article  CAS  Google Scholar 

  4. Mellaerts R, Aerts CA, Humbeeck JV, Augustijns P, Van den Mooter G, Martens JA. Enhanced release of itraconazole from ordered mesoporous SBA-15 silica materials. Chem Commun. 2007;1375–77.

  5. Qian KK, Bogner RH. Application of mesoporous silicon dioxide and silicate in oral amorphous drug delivery systems. J Pharm Sci. 2012;101:444–63.

    Article  PubMed  CAS  Google Scholar 

  6. Qian KK, Bogner RH. Spontaneous crystalline-to-amorphous phase transformation of organic or medicinal compounds in the presence of porous media. Part 1: thermodynamics of spontaneous amorphization. J Pharm Sci. 2011;100:2801–15.

    Article  PubMed  CAS  Google Scholar 

  7. Qian KK, Suib SL, Bogner RH. Spontaneous crystalline-to-amorphous phase transformation of organic or medicinal compounds in the presence of porous media. Part 2: amorphization capacity and mechanisms of interaction. J Pharm Sci. 2011;100:4674–86.

    Article  PubMed  CAS  Google Scholar 

  8. Qian KK, Wurster DE, Bogner RH. Spontaneous crystalline-to-amorphous phase transformation of organic or medicinal compounds in the presence of porous media. Part 3: effect of moisture. Pharmaceutical Research (In press, doi:10.1007/s11095-012-0734-4).

  9. Klafter J, Drake JM. Molecular dynamics in restricted geometries. New York: Wiley; 1989.

    Google Scholar 

  10. Mellaerts R, Jammaer JAG, Van Speybroeck M, Chen H, Humbeeck JV, Augustijns P, et al. Physical state of poorly water soluble therapeutic molecules loaded into SBA-15 ordered mesoporous silica carriers: a case study with itraconazole and ibuprofen. Langmuir. 2008;24:8651–9.

    Article  PubMed  CAS  Google Scholar 

  11. Bras AR, Merino EG, Neves PD, Fonseca IM, Dionisio M, Schonhals A, et al. Amorphous ibuprofen confined in nanostructured silica materials: A dynamical approach. J Phys Chem C. 2011;115:4616–23.

    Article  CAS  Google Scholar 

  12. Iler RK. The chemistry of silica. New York: Wiley; 1979.

    Google Scholar 

  13. Vansant EF, Van der Voort P, Vrancken KC. Characterization and chemical modification of the silica surface. Amsterdam: Elsevier; 1995.

    Google Scholar 

  14. Zhuravlev LT. The surface chemistry of amorphous silica. Zhuravlev model. Colloids Surf A Physicochem Eng Aspects. 2000;173:1–38.

    Article  CAS  Google Scholar 

  15. Colthup NB, Daly LH, Wiberley SE. Introduction to infrared and Raman spectroscopy. Boston: Academic; 1990.

    Google Scholar 

  16. Mitchell PCH. Vibrational spectroscopy with neutrons with applications in chemistry, biology, material science and catalysis. New Jersey: World Scientific; 2005.

    Book  Google Scholar 

  17. Willis BTM, Carlile CJ. Experimental neutron scattering. Oxford: Oxford University Press; 2009.

    Google Scholar 

  18. Certain trade names and company products are identified in this paper in order to specify adequately the experimental procedure Such identification does not imply recommendation or endorsement by the National Institute of Standards and Technology, nor does it imply that the instruments, materials or suppliers identified are necessarily the best available for the purpose.

  19. Perlovich GL, Kurkov SV, Hansen LK, Bauer-Brandl A. Thermodynamics of sublimation, crystal lattice energies, and crystal structures of racemates and enantiomers: Ibuprofen. J Pharm Sci. 2004;93:654–66.

    Article  PubMed  CAS  Google Scholar 

  20. Azais T, Tourne-Peteilh C, Aussenac F, Baccile N, Coelho C, Devoisselle J-M, et al. Solid-state NMR study of ibuprofen confined in MCM-41 material. Chem Mater. 2006;18:6382–90.

    Article  Google Scholar 

  21. Barrett EP, Joyner LG, Halenda PP. The determination of pore volume and area distributions in porous substances. I. Computations from nitrogen isotherms. J Am Chem Soc. 1951;73:373–80.

    Article  CAS  Google Scholar 

  22. Udovic TJ, Brown CM, Leao JB, Brand PC, Jiggetts RD, Zeitoun R, et al. The design of a bismuth-based auxiliary filter for the removal of spurious background scattering associated with filter-analyzer neutron spectrometers. Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment. 2008;588:406–13.

    Article  CAS  Google Scholar 

  23. Yildirim T. Structure and dynamics from combined neutron scattering and first-principles studies. Chem Phys. 2000;261:205–16.

    Article  CAS  Google Scholar 

  24. Barone V, Casarin M, Forrer D, Pavone M, Sambi M, Vittadini A. Role and effective treatment of dispersive forces in materials: polyethylene and graphite crystals as test cases. J Comput Chem. 2009;30:934–9.

    Article  PubMed  CAS  Google Scholar 

  25. Shankland N, Wilson CC, Florence AJ, Cox PJ. Refinement of ibuprofen at 100K by single-crystal pulsed neutron diffraction. Acta Crystallogr Sect C Cryst Struct Commun. 1997;C53:951–4.

    Article  CAS  Google Scholar 

  26. Gregg SJ, Sing KSW. Adsorption, surface area, and porosity. London: Academic; 1967.

    Google Scholar 

  27. Glatter O, Kratky O. Small angle X-ray scattering. London: Academic; 1982.

    Google Scholar 

  28. Hailu SA, Bogner RH. Effect of the pH grade of silicates on chemical stability of coground amorphous quinapril hydrochloride and its stabilization using pH-modifiers. J Pharm Sci. 2009;98:3358–72.

    Article  PubMed  CAS  Google Scholar 

  29. Hailu SA, Bogner RH. Solid-state surface acidity and pH-stability profiles of amorphous quinapril hydrochloride and silicate formulations. J Pharm Sci. 2010;99:2786–99.

    PubMed  CAS  Google Scholar 

  30. Hailu SA, Bogner RH. Complex effects of drug/silicate ratio, solid-state equivalent pH, and moisture on chemical stability of amorphous quinapril hydrochloride coground with silicates. J Pharm Sci. 2011;100:1503–15.

    Article  CAS  Google Scholar 

  31. Yoshioka S, Aso Y. Correlations between molecular mobility and chemical stability during storage of amorphous pharmaceuticals. J Pharm Sci. 2007;96:960–81.

    Article  PubMed  CAS  Google Scholar 

Download references

AcknowledgmentS AND DISCLOSURES

The authors acknowledge the helpful discussions with Dr. John J. Rush at NIST. This work utilized facilities supported in part by the National Science Foundation (NSF) under Agreement No. DMR-0944772. The National Research Council (NRC) Research Associateship Programs (RAP) is acknowledged for a postdoctoral fellowship to KKQ.

Author information

Authors and Affiliations

  1. National Institute of Standards and Technology (NIST), NIST Center for Neutron Research (NCNR), 100 Bureau Drive, Gaithersburg, Maryland, 20899, USA

    Ken K. Qian, Wei Zhou & Terrence J. Udovic

  2. Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, 69 North Eagleville Road, Unit 3092, Storrs, Connecticut, 06269, USA

    Xiaoming Xu

Authors
  1. Ken K. Qian
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Wei Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xiaoming Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Terrence J. Udovic
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ken K. Qian.

Appendix

Appendix

The volume occupied by the amorphized ibuprofen in the system:

$$ \frac{{0.33\,g\,Ibuprofen}}{{g\,Porous\,material}} \times \frac{{mol}}{{206.29\,g}} \times \frac{{6.022 \times {{10}^{{23}}}}}{{1\,mol}} \times \left( {5 \times 7.6 \times 11.5} \right) \times {10^{{ - 24}}}c{m^3} = 0.42\;\frac{{c{m^3}}}{{g\,Porous\,material}} $$
(1)

Total area covered by the carboxylic acid group (−COOH) of an ibuprofen molecule:

$$ 0.33\,g\,Ibuprofen \times \frac{{mol}}{{206.29\,g}} \times \frac{{6.022 \times {{10}^{{23}}}}}{{1\,mol}} \times \left( {5 \times 7.6} \right) \times {10^{{ - 20}}}\,{m^2} = 366.1\,{m^2} $$
(2)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Qian, K.K., Zhou, W., Xu, X. et al. Characterization of Medicinal Compounds Confined in Porous Media by Neutron Vibrational Spectroscopy and First-Principles Calculations: A Case Study with Ibuprofen. Pharm Res 29, 2432–2444 (2012). https://doi.org/10.1007/s11095-012-0771-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-012-0771-z

Key Words

Search

Navigation