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Phase Behavior of Resveratrol Solid Dispersions Upon Addition to Aqueous media

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Abstract

Purpose

To investigate the phase behavior of resveratrol amorphous solid dispersions upon addition to aqueous media.

Methods

Polymers with different crystallization inhibitor properties were used to form amorphous solid dispersions of resveratrol. Resveratrol crystallization in aqueous environments was monitored over time using Raman spectroscopy, and solution concentrations were determined by ultraviolet (UV) spectroscopy.

Results

The crystallization behavior varied depending on the type and amount of polymer present in the dispersion. Polyvinylpyrrolidone (PVP) and Eudragit E100 (E100) dispersions did not crystallize for 24 h when slurried in pH 6.8 buffer at 37°C. Even though no crystallization occurred, a supersaturated solution was not achieved, most likely because of resveratrol-polymer complexation. Dispersions formed with cellulose derivatives crystallized rapidly, and the extent of crystallization varied depending on the amount of polymer in the dispersion. The solution concentration achieved in the slurries varied considerably between the various solid dispersions and depended on several factors including the extent of resveratrol crystallization, the nature of the resveratrol-polymer interactions, and the concentration of solid dispersion added to the slurry.

Conclusions

It was found that the extent of supersaturation was limited not only by crystallization, but also by soluble and insoluble complex formation between resveratrol and the polymer.

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Abbreviations

CMCAB:

Carboxymethyl cellulose acetate butyrate

E100:

Eudragit® E100

HAS:

Hydrochloric acid solution

HPLC:

High performance liquid chromatography

HPMC:

Hydroxypropyl methyl cellulose

HPMCAS:

Hydroxypropyl methyl cellulose acetate succinate

PB:

Phosphate buffer

PVP:

Poly(vinylpyrrolidone)

RH:

Relative humidity

UV:

Ultraviolet spectroscopy

References

  1. Leuner C, Dressman J. Improving drug solubility for oral delivery using solid dispersions. Eur J Pharm Biopharm. 2000;50:47–60.

    Article  CAS  PubMed  Google Scholar 

  2. Serajuddin ATM. Solid dispersion of poorly water-soluble drugs: early promises, subsequent problems, and recent breakthroughs. J Pharm Sci. 1999;88:1058–66.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  4. Alonzo DE, Raina S, Zhou D, Gao Y, Zhang GGZ, Taylor LS. Characterizing the impact of hydroxypropylmethyl cellulose on the growth and nucleation kinetics of felodipine from supersaturated solutions. Cryst Growth Des. 2012;12:1538–47.

    Article  CAS  Google Scholar 

  5. Lechuga Ballesteros D, Rodriguez Hornedo N. Effects of molecular-structure and growth-kinetics on the morphology of L-alanine crystals. Int J Pharm. 1995;115:151–60.

    Article  CAS  Google Scholar 

  6. Vandecruys R, Peeters J, Verreck G, Brewster ME. Use of a screening method to determine excipients which optimize the extent and stability of supersaturated drug solutions and application of this system to solid formulation design. Int J Pharm. 2007;342:168–75.

    Article  CAS  PubMed  Google Scholar 

  7. Wegiel LA, Mauer LJ, Edgar KJ, Taylor LS. Crystallization of amorphous solid dispersions of resveratrol during preparation and storage—impact of different polymers. J Pharm Sci. 2013;102:171–84.

    Article  CAS  PubMed  Google Scholar 

  8. Kestura US, Taylor LS. Role of polymer chemistry in influencing crystal growth rates from amorphous felodipine. Cryst Eng Comm. 2010;12:2390–7.

    Article  Google Scholar 

  9. Kestur US, Van Eerdenbrugh B, Taylor LS. Influence of polymer chemistry on crystal growth inhibition of two chemically diverse organic molecules. Cryst Eng Comm. 2011;13:6712–8.

    Article  CAS  Google Scholar 

  10. 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 

  11. Loftsson T, Fridriksdottir H, Gudmundsdottir K. The effect of water-soluble polymers on aqueous solubility of drugs. Int J Pharm. 1996;127:293–6.

    Article  CAS  Google Scholar 

  12. ACS. CAS Registry(r). Available from: http://www.cas.org. Accessed 8 Mar 2012.

  13. Baur JA. Resveratrol, sirtuins, and the promise of a DR mimetic. Mech Ageing Dev. 2010;131:261–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Sun X, Peng B, Yan W. Measurement and correlation of solubility of trans-resveratrol in 11 solvents at T = (278.2, 288.2, 298.2, 308.2, and 318.2) K. J Chem Thermodyn. 2008;40:735–8.

    Article  CAS  Google Scholar 

  15. Resveratrol MSDS. http://www.fishersci.com/ecomm/servlet/msdsproxy?productName=AC430075000&productDescription=RESVERATROL+99%25+500MG&catNo=AC43007-5000&vendorId=VN00032119&s. Accessed April 4 2012.

  16. Rumondor ACF, Stanford LA, Taylor LS. Effects of polymer type and storage relative humidity on the kinetics of felodipine crystallization from amorphous solid dispersions. Pharm Res. 2009;26:2599–606.

    Article  CAS  PubMed  Google Scholar 

  17. Wegiel LA, Zhao Y, Mauer LJ, Edgar KJ, Taylor LS. Curcumin amorphous solid dispersions: the role of intra and intermolecular bonding on physical stability. Pharm Dev Tech (2013).

  18. Lin-Vien D, Colthup NB, Fateley WG, Grasselli JG. The handbook of infrared and Raman characteristic frequencies of organic molecules. San Diego: Academic Press, Inc.; 1991.

    Google Scholar 

  19. Raina SA, Zhang GGZ, Alonzo DE, Wu J, Zhu D, Catron ND, et al. Enhancements and limits in drug membrane transport using supersaturated solutions of poorly water soluble drugs. J Pharm Sci. 2014;103:2736–48.

    Article  CAS  PubMed  Google Scholar 

  20. Alonzo DE, Zhang GGZ, Zhou D, Gao Y, Taylor LS. Understanding the behavior of amorphous pharmaceutical systems during dissolution. Pharm Res. 2010;27:608–18.

    Article  CAS  PubMed  Google Scholar 

  21. Mullin JW. Crystallization. Oxford: Elsiever Butterworth-Heinemann; 2001.

    Google Scholar 

  22. Miller MA, DiNunzio J, Matteucci ME, Ludher BS, Williams RO, Johnston KP. Flocculated amorphous itraconazole nanoparticles for enhanced in vitro supersaturation and in vivo bioavailability. Drug Dev Ind Pharm. 2012;38:557–70.

    Article  CAS  PubMed  Google Scholar 

  23. Dahan A, Miller JM, Hoffman A, Amidon GE, Amidon GL. The solubility–permeability interplay in using cyclodextrins as pharmaceutical solubilizers: mechanistic modeling and application to progesterone. J Pharm Sci. 2010;99:2739–49.

    CAS  PubMed  Google Scholar 

  24. Loftsson T, Frioriksdottir H, Ingvarsdottir G, Jonsdottir B, Siguroardottir A. The influence of 2-hydroxypropyl-β-cyclodextrin on diffusion rates and transdermal delivery of hydrocortisone. Drug Dev Ind Pharm. 1994;20:1699–708.

    Article  CAS  Google Scholar 

  25. Van Eerdenbrugh B, Baird JA, Taylor LS. Crystallization tendency of active pharmaceutical ingredients following rapid solvent evaporation-classification and comparison with crystallization tendency from undercooled melts. J Pharm Sci. 2010;99:3826–38.

    PubMed  Google Scholar 

  26. Kabadi BN, Hammarlu ER. Interaction of nonionic hydrophilic polymers with phenols: I. Interactions of phenol and hydroxyphenols with certain macromolecules. J Pharm Sci. 1966;55:1069–72.

    Article  CAS  Google Scholar 

  27. Molyneux P, Frank HP. Interaction of polyvinylpyrrolidone with aromatic compounds in aqueous solution: 2. Effect of interaction on molecular size of polymer. J Am Chem Soc. 1961;83:3175.

    Article  CAS  Google Scholar 

  28. Bandyopa P, Rodrigue F. Interaction of polyvinyl pyrrolidone with phenolic cosolutes. Polymer. 1972;13:119–23.

    Article  Google Scholar 

  29. Ueda K, Higashi K, Limwikrant W, Sekine S, Horie T, Yamamoto K, et al. Mechanistic differences in permeation behavior of supersaturated and solubilized solutions of carbamazepine revealed by nuclear magnetic resonance measurements. Mol Pharmaceut. 2012;9:3023–33.

    Article  CAS  Google Scholar 

  30. Ueda K, Higashi K, Yamamoto K, Moribe K. Inhibitory effect of hydroxypropyl methylcellulose acetate succinate on drug recrystallization from a supersaturated solution assessed using nuclear magnetic resonance measurements. Mol Pharmaceut. 2013;10:3801–11.

    Article  CAS  Google Scholar 

  31. Alonzo DE, Gao Y, Zhou D, Mo H, Zhang GG, Taylor LS. Dissolution and precipitation behavior of amorphous solid dispersions. J Pharm Sci. 2011;100:3316–31.

    Article  CAS  PubMed  Google Scholar 

  32. Li B, Harich K, Wegiel L, Taylor LS, Edgar KJ. Stability and solubility enhancement of ellagic acid in cellulose ester solid dispersions. Carbohydr Polym. 2013;92:1443–50.

    Article  CAS  PubMed  Google Scholar 

  33. Li B, Konecke S, Harich K, Wegiel L, Taylor LS, Edgar KJ. Solid dispersion of quercetin in cellulose derivative matrices influences both solubility and stability. Carbohydr Polym. 2013;92:2033–40.

    Article  CAS  PubMed  Google Scholar 

  34. Li B, Konecke S, Wegiel LA, Taylor LS, Edgar KJ. Both solubility and chemical stability of curcumin are enhanced by solid dispersion in cellulose derivative matrices. Carbohydr Polym. 2013;98:1108–16.

    Article  CAS  PubMed  Google Scholar 

  35. Li B, Liu H, Amin M, Wegiel LA, Taylor LS, Edgar KJ. Enhancement of naringenin solution concentration by solid dispersion in cellulose derivative matrices. Cellulose. 2013;20:2137–49.

    Article  CAS  Google Scholar 

  36. Li B, Wegiel LA, Taylor LS, Edgar KJ. Stability and solution concentration enhancement of resveratrol by solid dispersion in cellulose derivative matrices. Cellulose. 2013;20:1249–60.

    Article  CAS  Google Scholar 

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ACKNOWLEDGMENTS AND DISCLOSURES

We thank the USDA (Grant number 09-35603-05068) and Purdue Research Foundation for financial support. Eastman Chemical Company and Shin-Etsu Ltd. are acknowledged for their gracious donations of CMCAB and HPMCAS, respectively.

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Authors and Affiliations

  1. Department of Industrial and Physical Pharmacy, College of Pharmacy, Purdue University, West Lafayette, Indiana, 47907, USA

    Lindsay A. Wegiel, Laura I. Mosquera-Giraldo & Lynne S. Taylor

  2. Department of Food Sciences, Purdue University, West Lafayette, Indiana, 47907, USA

    Lisa J. Mauer

  3. Department of Sustainable Biomaterials, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, 24061, USA

    Kevin J. Edgar

Authors
  1. Lindsay A. Wegiel
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  2. Laura I. Mosquera-Giraldo
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  3. Lisa J. Mauer
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  4. Kevin J. Edgar
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  5. Lynne S. Taylor
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Correspondence to Lynne S. Taylor.

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Wegiel, L.A., Mosquera-Giraldo, L.I., Mauer, L.J. et al. Phase Behavior of Resveratrol Solid Dispersions Upon Addition to Aqueous media. Pharm Res 32, 3324–3337 (2015). https://doi.org/10.1007/s11095-015-1709-z

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  • DOI: https://doi.org/10.1007/s11095-015-1709-z

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