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Pharmaceutical Research

, Volume 33, Issue 5, pp 1276–1288 | Cite as

Characterization of Supersaturated Danazol Solutions – Impact of Polymers on Solution Properties and Phase Transitions

  • Matthew J. Jackson
  • Umesh S. Kestur
  • Munir A. Hussain
  • Lynne S. TaylorEmail author
Research Paper

ABSTRACT

Purpose

Excipients are essential for solubility enhancing formulations. Hence it is important to understand how additives impact key solution properties, particularly when supersaturated solutions are generated by dissolution of the solubility enhancing formulation. Herein, the impact of different concentrations of dissolved polymers on the thermodynamic and kinetic properties of supersaturated solutions of danazol were investigated.

Methods

A variety of experimental techniques was used, including nanoparticle tracking analysis, fluorescence and ultraviolet spectroscopy and flux measurements to characterize the solution phase behavior.

Results

Neither the crystalline nor amorphous solubility of danazol was impacted by common amorphous solid dispersion polymers, polyvinylpyrrolidone, hydroxypropylmethyl cellulose (HPMC) or HPMC-acetate succinate. Consequently, the maximum membrane transport rate was limited only by the amorphous solubility, and not by the presence of the polymers. The polymers were able to inhibit crystallization to some extent at concentrations as low as 1 μg/mL, with the maximum effectiveness being reached at 10 μg/mL. Aqueous danazol solutions formed a drug-rich phase with a mean size of 250 nm when the concentration exceeded the amorphous solubility, and the polymers modified the surface properties of this drug-rich phase.

Conclusions

The phase behavior of supersaturated solutions is complex and the kinetics of phase transformations can be substantially modified by polymeric additives present at low concentrations. However, fortunately, these additives do not appear to impact the bulk thermodynamic properties of the solution, thus enabling supersaturated solutions, which provide enhanced membrane transport relative to saturated solutions to be generated.

KEY WORDS

crystallization liquid liquid phase separation membrane transport supersaturation 

ABBREVIATIONS

ASDs

Amorphous solid dispersions

DLS

Dynamic light scattering

DSC

Differential Scanning Calorimetry

HPMC

Hydroxypropylmethyl cellulose

HPMC-AS

Hydroxypropylmethyl cellulose acetate succinate

LLPS

Liquid-liquid phase separation

NTA

Nanoparticle tracking analysis

PVP

Polyvinylpyrrolidone

UV

Ultraviolet

Notes

ACKNOWLEDGMENTS AND DISCLOSURES

The authors would like to acknowledge the research funding from Bristol-Myers Squibb and the PhRMA Foundation for awarding a fellowship to M.J.J.

REFERENCES

  1. 1.
    Dahan A, Hoffman A. Rationalizing the selection of oral lipid based drug delivery systems by an in vitro dynamic lipolysis model for improved oral bioavailability of poorly water soluble drugs. J Control Rel. 2008;129(1):1–10.CrossRefGoogle Scholar
  2. 2.
    Di L, Kerns E, Carter G. Drug-like property concepts in pharmaceutical design. Curr Pharm Design. 2009;15(19):2184–94.CrossRefGoogle Scholar
  3. 3.
    Hancock BC, Parks M. What is the true solubility advantage for amorphous pharmaceuticals? Pharm Res. 2000;17(4):397–404.CrossRefPubMedGoogle Scholar
  4. 4.
    Leuner C, Dressman J. Improving drug solubility for oral delivery using solid dispersions. Eur J Pharm Sci. 2000;50:47–60.Google Scholar
  5. 5.
    Konno H, Handa T, Alonzo DE, Taylor LS. Effect of polymer type on the dissolution profile of amorphous solid dispersions containing felodipine. Eur J Pharm Biopharm. 2008;70(2):493–9.CrossRefPubMedGoogle Scholar
  6. 6.
    Murdande SB, Pikal MJ, Shanker RM, Bogner RH. Solubility advantage of amorphous pharmaceuticals: I. A thermodynamic analysis. J Pharm Sci. 2010;99(3):1254–64.CrossRefPubMedGoogle Scholar
  7. 7.
    Law D, Schmitt EA, Marsh KC, Everitt EA, Wang W, Fort JJ, et al. Ritonavir-PEG 8000 amorphous solid dispersions: in vitro and in vivo evaluations. J Pharm Sci. 2003;93(3):563–70.CrossRefGoogle Scholar
  8. 8.
    Vaughn JM, McConville JT, Crisp MT, Johnston KP, Williams 3rd RO. Supersaturation produces high bioavailability of amorphous danazol particles formed by evaporative precipitation into aqueous solution and spray freezing into liquid technologies. Drug Dev Ind Pharm. 2006;32(5):559–67.CrossRefPubMedGoogle Scholar
  9. 9.
    Frank KJ, Westedt U, Rosenblatt KM, Holig P, Rosenberg J, Magerlein M, et al. The amorphous solid dispersion of the poorly soluble ABT-102 forms nano/microparticulate structures in aqueous medium: impact on solubility. Int J Nanomedicine. 2012;7:5757–68.PubMedPubMedCentralGoogle Scholar
  10. 10.
    Aisha AF, Ismail Z, Abu-Salah KM, Majid AM. Solid dispersions of alpha-mangostin improve its aqueous solubility through self-assembly of nanomicelles. J Pharm Sci. 2012;101(2):815–25.CrossRefPubMedGoogle Scholar
  11. 11.
    Ilevbare GA, Liu H, Pereira J, Edgar KJ, Taylor LS. Influence of additives on the properties of nanodroplets formed in highly supersaturated aqueous solutions of ritonavir. Mol Pharmaceutics. 2013;10(9):3392–403.CrossRefGoogle Scholar
  12. 12.
    Ilevbare GA, Taylor LS. Liquid–liquid phase separation in highly supersaturated aqueous solutions of poorly water-soluble drugs: implications for solubility enhancing formulations. Cryst Growth Des. 2013;13(4):1497–509.CrossRefGoogle Scholar
  13. 13.
    Frenkel YV, Clark JAD, Das K, Wang Y-H, Lewi PJ, Janssen PAJ, et al. Concentration and pH dependent aggregation of hydrophobic drug molecules and relevance to oral bioavailability. J Med Chem. 2005;48:1974–83.CrossRefPubMedGoogle Scholar
  14. 14.
    Hsieh YL, Ilevbare GA, Van Eerdenbrugh B, Box KJ, Sanchez-Felix MV, Taylor LS. pH-Induced precipitation behavior of weakly basic compounds: determination of extent and duration of supersaturation using potentiometric titration and correlation to solid state properties. Pharm Res. 2012;29(10):2738–53.CrossRefPubMedGoogle Scholar
  15. 15.
    Derdour L. A method to crystallize substances that oil out. Chem Eng Res Des. 2010;88(9):1174–81.CrossRefGoogle Scholar
  16. 16.
    Warren DB, Benameur H, Porter CJ, Pouton CW. Using polymeric precipitation inhibitors to improve the absorption of poorly water-soluble drugs: a mechanistic basis for utility. J Drug Targeting. 2010;18(10):704–31.CrossRefGoogle Scholar
  17. 17.
    Feng BY, Shelat A, Doman TN, Guy RK, Shoichet BK. High-throughput assays for promiscuous inhibitors. Nature Chemical Biology. 2005;1(3):146–8.CrossRefPubMedGoogle Scholar
  18. 18.
    McGovern SL, Caselli E, Grigorieff N, Shoichet BK. A common mechanism underlying promiscuous inhibitors from virtual and high-throughput screening. J Med Chem. 2002;45:1712–22.CrossRefPubMedGoogle Scholar
  19. 19.
    McGovern SL, Helfand BT, Feng B, Shoichet BK. A specific mechanism of nonspecific inhibition. J Med Chem. 2003;46:4265–72.CrossRefPubMedGoogle Scholar
  20. 20.
    Jackson MJ, Toth SJ, Kestur US, Huang J, Qian F, Hussain MA, et al. Impact of polymers on the precipitation behavior of highly supersaturated aqueous danazol solutions. Mol Pharmaceutics. 2014;11(9):3027–38.CrossRefGoogle Scholar
  21. 21.
    Chen J, Ormes JD, Higgins JD, Taylor LS. Impact of surfactants on the crystallization of aqueous suspensions of celecoxib amorphous solid dispersion spray dried particles. Mol Pharmaceutics. 2015;12(2):533–41.CrossRefGoogle Scholar
  22. 22.
    Raina SA. Phase Behavior of Supersaturated Solutions of Poorly Soluble Small Molecules: Purdue University; 2014Google Scholar
  23. 23.
    Gad Keriem EA, Abounassif MA, Hagga ME, Al-Khamees HA. Photodegredation kinetic study and stability-indicating assay of danazol using high-performace liquid chromatography. J Pharm Biomed Analy. 2000;23:413–20.CrossRefGoogle Scholar
  24. 24.
    Almeida e Sousa L, Reutzel-Edens SM, Stephenson GA, Taylor LS. Assessment of the amorphous “solubility” of a group of diverse drugs using new experimental and theoretical approaches. Mol Pharmaceutics. 2015;12(2):484–95.CrossRefGoogle Scholar
  25. 25.
    Baird JA, Van Eerdenbrugh B, Taylor LS. A classification system to assess the crystallization tendency of organic molecules from undercooled melts. J Pharm Sci. 2010;99(9):3787–806.CrossRefPubMedGoogle Scholar
  26. 26.
    Raina SA, Zhang GG, 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(9):2736–48.CrossRefPubMedGoogle Scholar
  27. 27.
    Ilevbare GA, Liu H, Edgar KJ, Taylor LS. Maintaining supersaturation in aqueous drug solutions: impact of different polymers on induction times. Cryst Growth Des. 2013;13(2):740–51.CrossRefGoogle Scholar
  28. 28.
    Mosquera-Giraldo LI, Taylor LS. Glass-liquid phase separation in highly supersaturated aqueous solutions of telaprevir. Mol Pharmaceutics. 2015;12(2):496–503.CrossRefGoogle Scholar
  29. 29.
    Kirby B. Micro- and nanosclae fluid mechanics : transport in microfluidic devices. New York: Cambridge University Press; 2010. p. 512.Google Scholar
  30. 30.
    Filipe V, Hawe A, Jiskoot W. Critical evaluation of nanoparticle tracking analysis (NTA) by NanoSight for the measurement of nanoparticles and protein aggregates. Pharm Res. 2010;27(5):796–810.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Higuchi T. Physical chemical analysis of percutaneous absorption process from creams and ointments. Journal of the Society of Cosmetic Chemists. 1959;11:85–97.Google Scholar
  32. 32.
    Davis AF, Hadgraft J. Effect of supersaturation on membrane transport: 1 hydrocortisone acetate. Int J Pharm. 1991;76:1–8.CrossRefGoogle Scholar
  33. 33.
    Pellett MA, Davis AF, Hadgraft J. Effect of supersaturation on membrane transport: 2. Piroxicam. Int J Pharm. 1994;111:1–6.CrossRefGoogle Scholar
  34. 34.
    Bonnett PE, Carpenter KJ, Dawson S, Davey RJ. Solution crystallisation via a submerged liquid–liquid phase boundary: oiling out. Chem Comm. 2003;6:698–9.CrossRefPubMedGoogle Scholar
  35. 35.
    Codan L, Bäbler MU, Mazzotti M. Phase diagram of a chiral substance exhibiting oiling out in cyclohexane. Cryst Growth Des. 2010;10(9):4005–13.CrossRefGoogle Scholar
  36. 36.
    Lafferrère L, Hoff C, Veesler S. Study of liquid–liquid demixing from drug solution. J Crys Growth. 2004;269(2–4):550–7.CrossRefGoogle Scholar
  37. 37.
    Lafferrère L, Hoff C, Veesler S. In situ monitoring of the impact of liquid-liquid phase separation on drug crystallization by seeding. Cryst Growth Des. 2004;4(6):1175–80.CrossRefGoogle Scholar
  38. 38.
    Veesler S, Lafferrère L, Garcia E, Hoff C. Phase transitions in supersaturated drug solution. Org Process Res Dev. 2003;7:983–9.CrossRefGoogle Scholar
  39. 39.
    Veesler S, Revalor E, Bottini O, Hoff C. Crystallization in the presence of a liquid-liquid phase separation. Org Process Res Dev. 2006;10:841–5.CrossRefGoogle Scholar
  40. 40.
    Steele G, Deneau E. An in-line study of oiling out and crystallization. Org Process Res Dev. 2006;9:943–50.Google Scholar
  41. 41.
    Maeda K, Aoyama Y, Fukui K, Hirota S. Novel phenomena of crystallization and emulsification of hydrophobic solute in aqueous solution. J Colloid Interf Sci. 2001;234(1):217–22.CrossRefGoogle Scholar
  42. 42.
    Erlich L, Yu D, Pallister DA, Levinson RS, Gole DG, Wilkinson PA, et al. Relative bioavailability of danazol in dogs from liquid-filled hard gelatin capsules. Inter J Pharm. 1999;179:49–53.CrossRefGoogle Scholar
  43. 43.
    Hu J, Johnston KP, Williams III RO. Rapid dissolving high potency danazol powders produced by spray freezing into liquid process. Inter J Pharm. 2004;271:145–54.CrossRefGoogle Scholar
  44. 44.
    Mithani SD, Bakateslou V, TenHoor CN, Dressman JB. Estimation of the increase in solubility of drugs as a function of bile salt concentration. Pharm Res. 1996;13(1):163–7.CrossRefPubMedGoogle Scholar
  45. 45.
    Wegiel LA, Mosquera-Giraldo LI, Mauer LJ, Edgar KJ, Taylor LS. Phase Behavior of Resveratrol Solid Dispersions in Slurries. Pharm Res. 2015.Google Scholar
  46. 46.
    Song R-Q, Cölfen H. Additive controlled crystallization. CrystEngComm. 2011;13(5):1249.CrossRefGoogle Scholar
  47. 47.
    Lindfors L, Forssen S, Westergren J, Olsson U. Nucleation and crystal growth in supersaturated solutions of a model drug. J Colloid Interf Sci. 2008;325(2):404–13.CrossRefGoogle Scholar
  48. 48.
    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(1–2):168–75.CrossRefPubMedGoogle Scholar
  49. 49.
    Alonzo DE, Zhang GG, Zhou D, Gao Y, Taylor LS. Understanding the behavior of amorphous pharmaceutical systems during dissolution. Pharm Res. 2010;27(4):608–18.CrossRefPubMedGoogle Scholar
  50. 50.
    Raghavan SL, Trividic A, Davis AD, Hadgraft J. Crystallization of hydrocortisone acetate: influence of polymers. Inter J Pharm. 2001;212:213–21.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Matthew J. Jackson
    • 1
  • Umesh S. Kestur
    • 2
  • Munir A. Hussain
    • 2
  • Lynne S. Taylor
    • 1
    Email author
  1. 1.Department of Industrial and Physical PharmacyCollege of Pharmacy, Purdue UniversityWest LafayetteUSA
  2. 2.Bristol-Myers Squibb CompanyNew BrunswickUSA

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