Skip to main content
SpringerLink
Log in

Preparation, Characterization, and Evaluation of Dipfluzine–Benzoic Acid Co-crystals with Improved Physicochemical Properties

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

ABSTRACT

Purpose

To prepare and characterize the co-crystal of dipfluzine and benzoic acid. To investigate the feasibility of the co-crystal for improving solubility and a faster dissolution rate in vitro and evaluate the bioavailability and tissue distribution of co-crystal in vivo.

Methods

A novel dipfluzine–benzoic acid co-crystal prepared using the solvent-assisted co-grinding and the solvent ultrasonic methods were identified and characterized by powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA), as well as Raman, solid-state nuclear magnetic resonance (ssNMR), and terahertz (THz) spectroscopy. Pharmacokinetics and tissue distribution were tested in vivo using murine models. Statistics analysis for dissolution data of co-crystal in vitro and animal experiment data in vivo were evaluated using t-test.

Results

Results of PXRD and DSC identified the dipfluzine–benzoic acid co-crystals were formed with a molar ratio of 1:2. The IR, Raman, and ssNMR spectra verified the formation of O-H · · · O and O-H · · · F hydrogen bonds. The complex constant, K, was evaluated to be 109 orders of magnitude with Δ r G < 0. The co-crystal solubility, the rate of drug dissolution and the relative bioavailability were approximately 500 times, five times and double that of dipfluzine, respectively. Increased solubility of co-crystal did not reduce distribution in the brain; the mean concentrations in the brain increased, but the differences had no statistic significance (p > 0.05).

Conclusions

The co-crystal of dipfluzine–benzoic acid improved the physicochemical properties of dipfluzine, such as solubility and dissolution rate. Furthermore, the increased relative bioavailability of co-crystal indicated the potential use in further clinical study

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
Fig. 10
Fig. 11
Fig. 12
Fig. 13

Similar content being viewed by others

Abbreviations

APIs:

Active pharmaceutical ingredients

BA:

Benzoic acid

CP:

Cross-polarization

Dif:

Dipfluzine

DSC:

Differential scanning calorimetry

FT-IR:

Fourier-transform infrared

MAS:

Magic-angle spinning

PXRD:

Powder X-ray diffraction

SD:

Spraque–Dawley

ssNMR:

Solid-state nuclear magnetic resonance

TGA:

Thermogravimetric analysis

THz:

Terahertz

TPPM:

Two pulse phase modulation

REFERENCES

  1. Hauss DJ. Oral lipid-based formulations. Adv Drug Deliv Rev. 2007;59(7):667–76.

    Article  CAS  PubMed  Google Scholar 

  2. Connors RD, Elder EJ. Using a portfolio of particle growth technologies to enable delivery of drugs with poor water solubility. Drug Deliv Technol. 2004;4(8):78–83.

    CAS  Google Scholar 

  3. Limwikrant W, Higashi K, Yamamoto K, Moribe K. Characterization of ofloxacin-oxalic acid complex by PXRD, NMR, and THz spectroscopy. Int J Pharm. 2009;382(1–2):50–5.

    Article  CAS  PubMed  Google Scholar 

  4. Fand L, Numajiri S, Kobayashi D, Ueda H, Nakayama K, Miyamae H, et al. Physicochemical and crystallographic characterization of mefenamic acid complexes with alkanolamines. J Pharm Sci. 2004;93(1):144–54.

    Article  Google Scholar 

  5. Blagden N, de Matas M, Gavan PT, York P. Crystal engineering of active pharmaceutical ingredients to improve solubility and dissolution rates. Adv Drug Deliv Rev. 2007;59(7):617–30.

    Article  CAS  PubMed  Google Scholar 

  6. Stanton MK, Bak A. Physicochemical properties of pharmaceutical co-crystals: a case study of ten AMG 517 co-crystals. Cryst Growth Des. 2008;8(10):3856–62. doi:10.1021/cg800173d.

    Article  CAS  Google Scholar 

  7. Schultheiss N, Newman A. Pharmaceutical cocrystals and their physicochemical properties. Cryst Growth Des. 2009;9(6):2950–67.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Aaltonen J, Alles M, Mirza S, Koradia V, Gordon KC, Rantanen J. Solid form screening–a review. Eur J Pharm Biopharm. 2009;71(1):23–37.

    Article  CAS  PubMed  Google Scholar 

  9. Aaltonen J, Gordon KC, Strachan CJ, Rades T. Perspectives in the use of spectroscopy to characterise pharmaceutical solids. Int J Pharm. 2008;364(2):159–69.

    Article  CAS  PubMed  Google Scholar 

  10. Ueno Y, Ajito K. Analytical terahertz spectroscopy. Anal Sci. 2008;24(2):185–92.

    Article  CAS  PubMed  Google Scholar 

  11. Taday PF, Bradley IV, Arnone DD, Pepper M. Using terahertz pulse spectroscopy to study the crystalline structure of a drug: a case study of the polymorphs of ranitidine hydrochloride. J Pharm Sci. 2003;92(4):831–8.

    Article  CAS  PubMed  Google Scholar 

  12. Li D, Wang M, Yang CQ, Wang J, Ren GD. Solid state characterizations and analysis of stability in azelnidipine polymorphs. Chem Pharm Bull. 2012;60(8):995–1002.

    Article  CAS  PubMed  Google Scholar 

  13. Yang CQ, Zhang ZW, Zeng YL, Wang J, Wang YL, Ma BQ. Structures and characterizations of m-nisoldipine polymorphs. CrystEngComm. 2012;14(7):2589–94.

    Article  CAS  Google Scholar 

  14. Lian WG, Lin YL, Wang M, Yang CQ, Wang J. Crystal engineering approach to produce complex of azelnidipine with maleic acid. CrystEngComm. 2013;15(19):3885–91.

    Article  CAS  Google Scholar 

  15. Miao QF, Su SW, Zhang W, Guo MF, Li LF, Meng J, et al. Effects of dipfluzine on experimental arrhythmias and cytosolic calcium concentration. Chin J Pharmacol Toxicol. 2006;20(6):448–54.

    CAS  Google Scholar 

  16. Wang C, Zhang YJ, Wang YL. Effects of dipfluzine on delayed afterdepolarizations and triggered activity induced by ouabain in guinea pig papillary muscles. Acta Pharmacol Sin. 2002;23(10):905–9.

    CAS  PubMed  Google Scholar 

  17. Zhang YJ, Wang YL, He RR. Effect of dipfluzine on isop renaline induced early afterdepolarizations and triggered activity. Chin J Pharmacol Toxicol. 2000;14(4):318–20.

    CAS  Google Scholar 

  18. Du YM, Wang YL, Zhang K, Gu JM. The synthesis methods of dipfluzine complex salts, Chinses patent CN101381349A; Mar 11, 2009.

  19. Yang CQ, Wang J, Zhang ZW. Synthesis and spectra chatacteristic of pharmaceutical dipfluzine hydrochloride-benzoic acid co-crystal. Spectrosc Spectr Anal. 2011;31(9):2476–9.

    CAS  Google Scholar 

  20. 20 Wang YL, Chen ZM, Bao CH, Zhang YJ. The synthesis methods of dipfluzine, Chinses patent CN 1326845C; July 18, 2007

  21. Jin YH, Preparation and study of dipfluzine intragastric floating and residence sustained-release tablet. Master dissertation, Hebei Medical University. 2004

  22. Schultheiss N, Newman A. Pharmaceutical cocrystals and their physicochemical properties. Cryst Growth Des. 2009;9(6):2950–67.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Aakeröy CB, Desper J, Scott BMT. Balancing supramolecular reagents for reliable formation of co-crystals. Chem Comm. 2006;13:1445–7.

    Article  PubMed  Google Scholar 

  24. Aakeröy CB, Desper J, Leonard B, Urbina JF. Toward high-yielding supramolecular synthesis: directed assembly of ditopic imidazoles/benzimidazoles and dicarboxylic acids into cocrystals via selective O-H · · · N hydrogen bonds. Cryst Growth Des. 2005;5(3):865–73.

    Article  Google Scholar 

  25. Aakeröy CB, Fasulo ME, Desper J. Cocrystal or salt: does it really matter? Mol Pharm. 2007;4(3):317–22.

    Article  PubMed  Google Scholar 

  26. Wang J, Wang YL, Yang CQ. 1-Diphenylmethyl-4-[3-(4-fluorobenzoyl)propyl]piperazine-1,4-diium dichloride monohydrate. Acta Cryst. 2011;E67(10):o2719.

    Google Scholar 

Download references

ACKNOWLEDGMENTS AND DISCLOSURES

This work was supported by the Fund of research and development in Science and Technology of Hebei Province of China (12276402D), the National Natural Science Funds of China (NSFC 81202504 and 11204191). The authors would like to express their sincere gratitude to Department of Physics, Capital Normal University, Beijing, China, for the terahertz spectroscopy equipment and School of Chemistry and Material Science, Hebei Normal University, Shijiazhuang, China, for DFT modeling simulation.

Author information

Authors and Affiliations

  1. School of Pharmaceutical Sciences, Hebei Medical University, Shijiazhuang, 050017, China

    Yulong Lin, Huan Yang, Caiqin Yang & Jing Wang

Authors
  1. Yulong Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Huan Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Caiqin Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jing Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jing Wang.

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

(DOC 520 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lin, Y., Yang, H., Yang, C. et al. Preparation, Characterization, and Evaluation of Dipfluzine–Benzoic Acid Co-crystals with Improved Physicochemical Properties. Pharm Res 31, 566–578 (2014). https://doi.org/10.1007/s11095-013-1181-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-013-1181-6

KEY WORDS

Search

Navigation