Impact of Physicochemical Properties of Cellulosic Polymers on Supersaturation Maintenance in Aqueous Drug Solutions

Research Article
  • 51 Downloads

Abstract

The precipitation inhibitory effect of cellulosic polymers in relation to their physicochemical properties was studied. Using a poorly water-soluble model drug, griseofulvin, the precipitation inhibitory effect of a series of hydroxypropyl methylcellulose (HPMC) and methylcellulose polymers was studied using solvent–shift method. The extent of supersaturation maintenance of each polymer was then quantified by the parameter, supersaturation factor (SF). Partial least square (PLS) regression analysis was employed to understand the relative contribution from viscosity, hydroxypropyl content (HC), methoxyl content, methoxyl/hydroxypropyl ratio, and drug–polymer interaction parameter (χ) on SF. All grades of cellulosic polymers effectively prolonged supersaturation of griseofulvin. PLS regression analysis revealed that HC and χ appeared to have the strongest influence on SF response. A regression model of SF = 1.65–0.16 χ + 0.05 HC with a high correlation coefficient, r of 0.921, was obtained. Since the value of χ is inversely related to the strength of drug–polymer interaction, the result shows that SF increases with increasing drug–polymer interaction and increasing HC. As such, it can be implied that strong drug–polymer interaction and presence of hydroxypropyl groups in cellulosic polymers for hydrogen bonding are two key parameters for effective supersaturation maintenance. This knowledge on the relative contribution of polymer physicochemical properties on precipitation inhibition will allow the selection of suitable cellulosic polymers for systematic development of supersaturating drug delivery systems.

KEY WORDS

cellulosic polymers hydroxypropyl content/interaction parameter supersaturation maintenance 

Notes

Acknowledgements

Shiqi Hong acknowledges Roquette Asia Pacific Pte Ltd. for supporting the time taken for the manuscript preparation.

Compliance with Ethical Standards

Conflict of Interest

Hong Shiqi is an ex-employee of AbbVie Private Limited, Singapore and Steven A. Nowak is an employee of AbbVie, Inc. and may own AbbVie stock/options. AbbVie participated in the design, study conduct, interpretation of data, review, and approval of the publication. The authors declare no conflict of interest.

References

  1. 1.
    Hancock BC, Parks M. What is the true solubility advantage for amorphous pharmaceuticals? Pharm Res. 2000;17(4):397–404.CrossRefPubMedGoogle Scholar
  2. 2.
    Qian F, Wang J, Hartley R, Tao J, Haddadin R, Mathias N, et al. Solution behavior of PVP-VA and HPMC-AS-based amorphous solid dispersions and their bioavailability implications. Pharm Res. 2012;29(10):2766–76.CrossRefGoogle Scholar
  3. 3.
    Hong S, Shen S, Tan DC, Ng WK, Liu X, Chia LS, et al. High drug load, stable, manufacturable and bioavailable fenofibrate formulations in mesoporous silica: a comparison of spray drying versus solvent impregnation methods. Drug delivery. 2016;23(1):316–27.CrossRefPubMedGoogle Scholar
  4. 4.
    Van Speybroeck M, Mellaerts R, Mols R, Thi TD, Martens JA, Van Humbeeck J, et al. Enhanced absorption of the poorly soluble drug fenofibrate by tuning its release rate from ordered mesoporous silica. Eur J Pharm Sci. 2010;41(5):623–30.CrossRefPubMedGoogle Scholar
  5. 5.
    Brouwers J, Brewster ME, Augustijns P. Supersaturating drug delivery systems: the answer to solubility-limited oral bioavailability? J Pharm Sci. 2009;98(8):2549–72.CrossRefPubMedGoogle Scholar
  6. 6.
    Serajuddin AT. Solid dispersion of poorly water-soluble drugs: early promises, subsequent problems, and recent breakthroughs. J Pharm Sci. 1999;88(10):1058–66.CrossRefPubMedGoogle Scholar
  7. 7.
    Alonzo D, Zhang GZ, Zhou D, Gao Y, Taylor L. Understanding the behavior of amorphous pharmaceutical systems during dissolution. Pharm Res. 2010;27(4):608–18.CrossRefPubMedGoogle Scholar
  8. 8.
    Alonzo DE, Gao Y, Zhou D, Mo H, Zhang GGZ, Taylor LS. Dissolution and precipitation behavior of amorphous solid dispersions. J Pharm Sci. 2011;100(8):3316–31.CrossRefPubMedGoogle Scholar
  9. 9.
    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 Target. 2010;18(10):704–31.CrossRefPubMedGoogle Scholar
  10. 10.
    Overhoff K, McConville J, Yang W, Johnston K, Peters J, Williams R III. Effect of stabilizer on the maximum degree and extent of supersaturation and oral absorption of tacrolimus made by ultra-rapid freezing. Pharm Res. 2008;25(1):167–75.CrossRefPubMedGoogle Scholar
  11. 11.
    Xu S, Dai WG. Drug precipitation inhibitors in supersaturable formulations. Int J Pharm. 2013;453(1):36–43.CrossRefPubMedGoogle Scholar
  12. 12.
    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
  13. 13.
    Chauhan H, Hui-Gu C, Atef E. Correlating the behavior of polymers in solution as precipitation inhibitor to its amorphous stabilization ability in solid dispersions. J Pharm Sci. 2013;102(6):1924–35.CrossRefPubMedGoogle Scholar
  14. 14.
    Lindfors L, Forssén S, Westergren J, Olsson U. Nucleation and crystal growth in supersaturated solutions of a model drug. J Colloid Interface Sci. 2008;325(2):404–13.CrossRefPubMedGoogle Scholar
  15. 15.
    Bevernage J, Hens B, Brouwers J, Tack J, Annaert P, Augustijns P. Supersaturation in human gastric fluids. European journal of pharmaceutics and biopharmaceutics: official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik eV. 2012;81(1):184–9.CrossRefGoogle Scholar
  16. 16.
    Miller DA, DiNunzio JC, Yang W, McGinity JW, Williams RO 3rd. Enhanced in vivo absorption of itraconazole via stabilization of supersaturation following acidic-to-neutral pH transition. Drug Dev Ind Pharm. 2008;34(8):890–902.CrossRefPubMedGoogle Scholar
  17. 17.
    Yang X, Shen B, Huang Y. Mechanistic study of HPMC-prolonged supersaturation of hydrocortisone. Cryst Growth Des. 2015;15(2):546–51.CrossRefGoogle Scholar
  18. 18.
    Curatolo W, Nightingale JA, Herbig SM. Utility of hydroxypropylmethylcellulose acetate succinate (HPMCAS) for initiation and maintenance of drug supersaturation in the GI milieu. Pharm Res. 2009;26(6):1419–31.CrossRefPubMedGoogle Scholar
  19. 19.
    Suzuki H, Sunada H. Influence of water-soluble polymers on the dissolution of nifedipine solid dispersions with combined carriers. Chemical & pharmaceutical bulletin. 1998;46(3):482–7.CrossRefGoogle Scholar
  20. 20.
    Dukeck R, Sieger P, Karmwar P. Investigation and correlation of physical stability, dissolution behaviour and interaction parameter of amorphous solid dispersions of telmisartan: a drug development perspective. Eur J Pharm Sci. 2013;49(4):723–31.CrossRefPubMedGoogle Scholar
  21. 21.
    Gao P, Guyton ME, Huang T, Bauer JM, Stefanski KJ, Lu Q. Enhanced oral bioavailability of a poorly water soluble drug PNU-91325 by supersaturatable formulations. Drug Dev Ind Pharm. 2004;30(2):221–9.CrossRefPubMedGoogle Scholar
  22. 22.
    Ilevbare GA, Liu H, Edgar KJ, Taylor LS. Maintaining supersaturation in aqueous drug solutions: impact of different polymers on induction times. Cryst Growth Des. 2012;13(2):740–51.CrossRefGoogle Scholar
  23. 23.
    Raina SA, Van Eerdenbrugh B, Alonzo DE, Mo H, Zhang GGZ, Gao Y, et al. Trends in the precipitation and crystallization behavior of supersaturated aqueous solutions of poorly water-soluble drugs assessed using synchrotron radiation. J Pharm Sci. 2015;104(6):1981–92.CrossRefPubMedGoogle Scholar
  24. 24.
    Ozaki S, Kushida I, Yamashita T, Hasebe T, Shirai O, Kano K. Inhibition of crystal nucleation and growth by water-soluble polymers and its impact on the supersaturation profiles of amorphous drugs. J Pharm Sci. 2013;102(7):2273–81.CrossRefPubMedGoogle Scholar
  25. 25.
    Tian F, Saville DJ, Gordon KC, Strachan CJ, Zeitler JA, Sandler N, et al. The influence of various excipients on the conversion kinetics of carbamazepine polymorphs in aqueous suspension. J Pharm Pharmacol. 2007;59(2):193–201.CrossRefPubMedGoogle Scholar
  26. 26.
    Zimmermann A, Millqvist-Fureby A, Elema MR, Hansen T, Mullertz A, Hovgaard L. Adsorption of pharmaceutical excipients onto microcrystals of siramesine hydrochloride: effects on physicochemical properties. European journal of pharmaceutics and biopharmaceutics: official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik eV. 2009;71(1):109–16.CrossRefGoogle Scholar
  27. 27.
    DiNunzio JC, Miller DA, Yang W, McGinity JW, Williams RO 3rd. Amorphous compositions using concentration enhancing polymers for improved bioavailability of itraconazole. Mol Pharm. 2008;5(6):968–80.CrossRefPubMedGoogle Scholar
  28. 28.
    Raghavan SL, Trividic A, Davis AF, Hadgraft J. Crystallization of hydrocortisone acetate: influence of polymers. Int J Pharm. 2001;212(2):213–21.CrossRefPubMedGoogle Scholar
  29. 29.
    Chavan RB, Thipparaboina R, Kumar D, Shastri NR. Evaluation of the inhibitory potential of HPMC, PVP and HPC polymers on nucleation and crystal growth. RSC Adv. 2016;6(81):77569–76.CrossRefGoogle Scholar
  30. 30.
    Douroumis D, Fahr A. Stable carbamazepine colloidal systems using the cosolvent technique. Eur J Pharm Sci. 2007;30(5):367–74.CrossRefPubMedGoogle Scholar
  31. 31.
    Gao P, Akrami A, Alvarez F, Hu J, Li L, Ma C, et al. Characterization and optimization of AMG 517 supersaturatable self-emulsifying drug delivery system (S-SEDDS) for improved oral absorption. J Pharm Sci. 2009;98(2):516–28.CrossRefPubMedGoogle Scholar
  32. 32.
    Bi M, Kyad A, Alvarez-Nunez F, Alvarez F. Enhancing and sustaining AMG 009 dissolution from a bilayer oral solid dosage form via microenvironmental pH modulation and supersaturation. AAPS PharmSciTech. 2011;12(4):1401–6.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Ilevbare GA, Liu H, Edgar KJ, Taylor LS. Understanding polymer properties important for crystal growth inhibition—impact of chemically diverse polymers on solution crystal growth of ritonavir. Cryst Growth Des. 2012;12(6):3133–43.CrossRefGoogle Scholar
  34. 34.
    Huggins ML. Thermodynamic properties of solutions of long-chain compounds. Ann N Y Acad Sci. 1942;43(1):1–32.CrossRefGoogle Scholar
  35. 35.
    Baghel S, Cathcart H, O’Reilly NJ. Theoretical and experimental investigation of drug-polymer interaction and miscibility and its impact on drug supersaturation in aqueous medium. Eur J Pharm Biopharm. 2016;107(Supplement C):16–31.CrossRefPubMedGoogle Scholar
  36. 36.
    Marsac P, Shamblin S, Taylor L. Theoretical and practical approaches for prediction of drug–polymer miscibility and solubility. Pharm Res. 2006;23(10):2417–26.CrossRefPubMedGoogle Scholar
  37. 37.
    Bansal K, Baghel US, Thakral S. Construction and validation of binary phase diagram for amorphous solid dispersion using Flory–Huggins theory. AAPS PharmSciTech. 2016;17(2):318–27.CrossRefPubMedGoogle Scholar
  38. 38.
    Archer WL. Hansen solubility parameters for selected cellulose ether derivatives and their use in the pharmaceutical industry. Drug Dev Ind Pharm. 1992;18(5):599–616.CrossRefGoogle Scholar
  39. 39.
    Methocel cellulose ethers: technical handbook. The Dow Chemical Company; 2013.Google Scholar
  40. 40.
    Dahlberg C, Millqvist-Fureby A, Schuleit M, Furó I. Polymer–drug interactions and wetting of solid dispersions. Eur J Pharm Sci. 2010;39(1):125–33.CrossRefPubMedGoogle Scholar
  41. 41.
    Abu-Diak OA, Jones DS, Andrews GP. An investigation into the dissolution properties of celecoxib melt Extrudates: understanding the role of polymer type and concentration in stabilizing supersaturated drug concentrations. Mol Pharm. 2011;8(4):1362–71.CrossRefPubMedGoogle Scholar
  42. 42.
    Trasi NS, Abbou Oucherif K, Litster JD, Taylor LS. Evaluating the influence of polymers on nucleation and growth in supersaturated solutions of acetaminophen. CrystEngComm. 2015;17(6):1242–8.CrossRefGoogle Scholar
  43. 43.
    Abbou Oucherif K, Raina S, Taylor LS, Litster JD. Quantitative analysis of the inhibitory effect of HPMC on felodipine crystallization kinetics using population balance modeling. CrystEngComm. 2013;15(12):2197–205.CrossRefGoogle Scholar
  44. 44.
    Bevernage J, Forier T, Brouwers J, Tack J, Annaert P, Augustijns P. Excipient-mediated supersaturation stabilization in human intestinal fluids. Mol Pharm. 2011;8(2):564–70.CrossRefPubMedGoogle Scholar
  45. 45.
    Dai WG, Dong LC, Li S, Deng Z. Combination of pluronic/vitamin E TPGS as a potential inhibitor of drug precipitation. Int J Pharm. 2008;355(1–2):31–7.CrossRefPubMedGoogle Scholar
  46. 46.
    Usui F, Maeda K, Kusai A, Nishimura K, Keiji Y. Inhibitory effects of water-soluble polymers on precipitation of RS-8359. Int J Pharm. 1997;154(1):59–66.CrossRefGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2018

Authors and Affiliations

  1. 1.GEA-NUS Pharmaceutical Processing Research Laboratory, Department of PharmacyNational University of SingaporeSingaporeSingapore
  2. 2.Research and DevelopmentRoquette Asia Pacific Pte. Ltd.SingaporeSingapore
  3. 3.Drug Product DevelopmentResearch and Development, Abbvie Inc.North ChicagoUSA

Personalised recommendations