Skip to main content
Log in

Exploring Molecular Speciation and Crystallization Mechanism of Amorphous 2-Phenylamino Nicotinic Acid

  • Research Paper
  • Theme: Formulation and Manufacturing of Solid Dosage Forms
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Purpose

Molecular understanding of phase stability and transition of the amorphous state helps in formulation and manufacturing of poorly-soluble drugs. Crystallization of a model compound, 2-phenylamino nicotinic acid (2PNA), from the amorphous state was studied using solid-state analytical methods. Our previous report suggests that 2PNA molecules mainly develop intermolecular –COOH∙∙∙pyridine N (acid-pyridine) interactions in the amorphous state. In the current study, the molecular speciation is explored with regard to the phase transition from the amorphous to the crystalline state.

Methods

Using spectroscopic techniques, the molecular interactions and structural evolvement during the recrystallization from the glassy state were investigated.

Results

The results unveiled that the structurally heterogeneous amorphous state contains acid-pyridine aggregates – either as hydrogen-bonded neutral molecules or as zwitterions – as well as a population of carboxylic acid dimers. Phase transition from the amorphous state results in crystal structures composed of carboxylic acid dimer (acid-acid) synthon or acid-pyridine chains depending on the crystallization conditions employed.

Conclusions

The study underlines the structural evolvement, as well as its impact on the metastability, of amorphous samples from local, supramolecular assemblies to long-range intermolecular ordering through crystallization.

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

Access this article

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

Instant access to the full article PDF.

Institutional subscriptions

Scheme 1
Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11

Similar content being viewed by others

References

  1. Janssens S, Van den Mooter G. Review: physical chemistry of solid dispersions. J Pharm Pharmacol. 2009;61:1571–86.

    Article  CAS  PubMed  Google Scholar 

  2. Konno H, Taylor LS. Influence of different polymers on the crystallization tendency of molecularly dispersed amorphous felodipine. J Pharm Sci. 2006;95:2692–705.

    Article  CAS  PubMed  Google Scholar 

  3. Chen J, Sarma B, Evans JM, Myerson AS. Pharmaceutical crystallization. Cryst Growth Des. 2011;11:887–95.

    Article  CAS  Google Scholar 

  4. Davey RJ, Schroeder SL, ter Horst JH. Nucleation of organic crystals--a molecular perspective. Angew Chem Int Ed Engl. 2013;52:2166–79.

    Article  CAS  PubMed  Google Scholar 

  5. Davey RJ, Blagden N, Righini S, Alison H, Quayle MJ, Fuller S. Crystal polymorphism as a probe for molecular self-assembly during nucleation from solutions 2,6-dihydroxybenzoic acid. Cryst Growth Des. 2001;1:59–65.

    Article  CAS  Google Scholar 

  6. Davey RJ, Dent G, Mughal RK, Parveen S. Concerning the relationship between structural and growth synthons in crystal nucleation- solution and crystal chemistry of carboxylic acids as revealed through ir spectroscopy. Cryst Growth Des. 2006;6:1788–96.

    Article  CAS  Google Scholar 

  7. Apperley DC, Forster AH, Fournier R, Harris RK, Hodgkinson P, Lancaster RW, et al. Characterisation of indomethacin and nifedipine using variable-temperature solid-state nmr. Magn Reson Chem. 2005;43:881–92.

    Article  CAS  PubMed  Google Scholar 

  8. Taylor LS, Zografi G. Spectroscopic characterization of interactions between pvp and indomethacin in amorphous molecular dispersions. Pharm Res. 1997;14:1691–8.

    Article  CAS  PubMed  Google Scholar 

  9. Yaun X, Xiang T-X, Anderso BD, Munson EJ. Hydrogen bonding interactions in amorphous indomethacin and its amorphous solid dispersions with poly(vinylpyrrolidone) and poly(vinylpyrrolidone-co-vinyl acetate) studied using 13c solid-state nmr. Mol Pharm. 2015;12:4518–28.

    Article  Google Scholar 

  10. Andronis V, Zografi G. Crystal nucleation and growth of indomethacin polymorphs from the amorphous state. J Non-Cryst Solids. 2000;271:236–48.

    Article  CAS  Google Scholar 

  11. Yoshioka M, Hancock BC, Zografi G. Crystallization of indomethacin from the amorphous state below and above its glass transition temperature. J Pharm Sci. 1994;83:1700–5.

    Article  CAS  PubMed  Google Scholar 

  12. Kalra A, Luner P, Taylor LS, Byrn SR, Li T. Gaining thermodynamic insight from distinct glass formation kinetics of structurally similar organic compounds. J Pharm Sci 2017.

  13. Kalra A, Tishmack P, Lubach JW, Munson EJ, Taylor LS, Byrn SR, et al. Impact of supramolecular aggregation on the crystallization kinetics of organic compounds from the supercooled liquid state. Mol Pharm. 2017;14:2126–37.

    Article  CAS  PubMed  Google Scholar 

  14. Long SH, Parkin S, Siegler MA, Cammers A, Li TL. Polymorphism and phase behaviors of 2-(phenylamino)nicotinic acid. Cryst Growth Des. 2008;8:4006–13.

    Article  CAS  Google Scholar 

  15. Dixon WT. Spinning-sideband-free and spinning-sideband-only nmr spectra in spinning samples. J Chem Phys. 1982;77:1800.

    Article  CAS  Google Scholar 

  16. Fung BM, Khitrin AK, Ermolaev K. An improved broadband decoupling sequence for liquid crystals and solids. J Magn Reson. 2000;142:97–101.

    Article  CAS  PubMed  Google Scholar 

  17. Metz G, Wu X, Smith SO. Ramped-amplitude cross polarization in magic-angle-spinning nmr. J Magn Res. 1994;110:219–27.

    Article  CAS  Google Scholar 

  18. Song Z, Antzutkin ON, Feng X, Levitt MH. Sideband suppression in magic-angle-spinning nmr by a sequence of 5 pi pulses. Solid State Nucl Magn Reson. 1993;2:143–6.

    Article  CAS  PubMed  Google Scholar 

  19. Simon S, Duran M, Dannenberg JJ. How does basis set superposition error change the potential surfaces for hydrogen bonded dimers? J Chem Phys. 1996;105:11024–31.

    Article  CAS  Google Scholar 

  20. Ditchfie R. Self-consistent perturbation-theory of diamagnetism .1. Gauge-invariant lcao method for nmr chemical-shifts. Mol Phys. 1974;27:789–807.

    Article  Google Scholar 

  21. Wolinski K, Hinton JF, Pulay P. Efficient implementation of the gauge-independent atomic orbital method for nmr chemical-shift calculations. J Am Chem Soc. 1990;112:8251–60.

    Article  CAS  Google Scholar 

  22. Cheeseman JR, Trucks GW, Keith TA, Frisch MJ. A comparison of models for calculating nuclear magnetic resonance shielding tensors. J Chem Phys. 1996;104:5497–509.

    Article  CAS  Google Scholar 

  23. Casabianca LB, De Dios AC. Ab initio calculations of nmr chemical shifts. J Chem Phys. 2008;128:10.

    Article  Google Scholar 

  24. Bernstein J. Polymorphism in molecular crystals. New York: Oxford University Press. 2002;

  25. Sundaraganesan N, Ilakiamani S, Saleem H, Wojciechowski PM, Michalska D. Ft-raman and ft-ir spectra, vibrational assignments and density functional studies of 5-bromo-2-nitropyridine. Spectrochim Acta A Mol Biomol Spectrosc. 2005;61:2995–3001.

    Article  CAS  PubMed  Google Scholar 

  26. Li ZJ, Abramov Y, Bordner J, Leonard J, Medek A, Trask AV. Solid-state acid-base interactions in complexes of heterocyclic bases with dicarboxylic acids: crystallography, hydrogen bond analysis, and 15n nmr spectroscopy. J Am Chem Soc. 2006;128:8199–210.

    Article  CAS  PubMed  Google Scholar 

  27. Song Y, Yang X, Chen X, Nie H, Byrn SR, Lubach JW. Investigation of drug–excipient interactions in lapatinib amorphous solid dispersions using solid-state nmr spectroscopy. Mol Pharm. 2015;12:857–66.

    Article  CAS  PubMed  Google Scholar 

  28. Babu NJ, Nangia A. Solubility advantage of amorphous drugs and pharmaceutical cocrystals. Cryst Growth Des. 2011;11:2662–79.

    Article  CAS  Google Scholar 

  29. Milletti F, Storchi L, Sforna G, Cruciani G. New and original pka prediction method using grid molecular interaction fields. J Chem Inf Model. 2007;47:2172–81.

    Article  CAS  PubMed  Google Scholar 

  30. Kilburn D, Townrow S, Meunier V, Richardson R, Alam A, Ubbink J. Organization and mobility of water in amorphous and crystalline trehalose. Nat Mater. 2006;5:632–5.

    Article  CAS  PubMed  Google Scholar 

  31. Bates S, Zografi G, Engers D, Morris K, Crowley K, Newman A. Analysis of amorphous and nanocrystalline solids from their x-ray diffraction patterns. Pharm Res. 2006;23:2333–49.

    Article  CAS  PubMed  Google Scholar 

  32. Li T, Zhou P, Mattei A. Electronic origin of pyridinyl n as a better hydrogen-bonding acceptor than carbonyl o. CrystEngComm. 2011;13:6356–60.

    Article  CAS  Google Scholar 

Download references

ACKNOWLEDGMENTS AND DISCLOSURES

We thank CPD (Center for Pharmaceutical Development) and CPPR (Center for Pharmaceutical Processing Research) for providing partial financial support for this study. The authors declare the following competing financial interest(s): E.J.M. is a partial owner of Kansas Analytical Services, a company that provides solid-state NMR services to the pharmaceutical industry. The results presented here are from academic work at the University of Kentucky, and no data from Kansas Analytical Services are presented.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Tonglei Li.

Additional information

Guest Editors: Tony Zhou and Tonglei Li

Electronic supplementary material

ESM 1

(DOCX 198 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kalra, A., Lubach, J.W., Munson, E.J. et al. Exploring Molecular Speciation and Crystallization Mechanism of Amorphous 2-Phenylamino Nicotinic Acid. Pharm Res 35, 51 (2018). https://doi.org/10.1007/s11095-018-2346-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s11095-018-2346-0

Key words

Navigation