AAPS PharmSciTech

, 20:326 | Cite as

Fabrication of Ibrutinib Nanosuspension by Quality by Design  Approach: Intended for Enhanced Oral Bioavailability and Diminished Fast Fed Variability

  • Nagarjun Rangaraj
  • Sravanthi Reddy Pailla
  • Paramesh Chowta
  • Sunitha SampathiEmail author
Research Article


Present study was aimed to increase the oral bioavailability and reduce the fast fed variability of Ibrutinib by developing nanosuspension by simple precipitation-ultrasonication method. A three factor, three level, box-behnken design was used for formulation optimization using pluronic F-127 as stabilizer. Size and polydispersity index of the developed formulations were in the range of 278.6 to 453.2 nm and 0.055 to 0.198, respectively. Field emission scanning electron microscope (FESEM) revealed discrete units of nanoparticles. Further, differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) studies confirmed the transformation of crystal drug to amorphous. The amorphous nature was retained after 6-month storage at room temperature. Size reduction to nano range and polymorphic transformation (crystalline to amorphous) increased the solubility of nanosuspension (21.44-fold higher as compared to plain drug). In vivo studies of plain drug suspension displayed a significant pharmacokinetic variation between fasting and fed conditions. The formulation had shown increased Cmax (3.21- and 3.53-fold), AUC0-t (5.21- and 5.83-fold) in fasting and fed states compared to that of values obtained for plain drug in fasting state (Cmax 48.59 ± 3.30 ng/mL and AUC0-t 137.20 ± 35.47 ng.h/mL). Significant difference was not observed in the pharmacokinetics of nanosuspension in fasting and fed states. The formulation had improved solubility in the intestinal pH, which might be the driving force behind the decreased precipitation and increased absorption at intestinal region. Optimistic results demonstrated nanosuspension as a promising approach for increasing the solubility, extent of absorption and diminishing the fast fed variability.


Box-Behnken design Damkohler number precipitation-ultrasonication method re-dispersibility index solvent anti-solvent ratio 



The authors would like to thank NIPER-HYD and Department of Pharmaceuticals (DoP) for providing the facilities and for funding the research work.

Funding Information

The NIPER-HYD and Department of Pharmaceuticals (DoP) provided funding for the research work.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material

12249_2019_1524_MOESM1_ESM.docx (21 kb)
ESM 1 (DOCX 21 kb)
12249_2019_1524_MOESM2_ESM.docx (6.9 mb)
ESM 2 (DOCX 7021 kb)


  1. 1.
    Burger JA, Buggy JJ. Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765). Leuk Lymphoma. 2013;54(11):2385–91.PubMedGoogle Scholar
  2. 2.
    Kokhaei P, Jadidi-Niaragh F, Sotoodeh Jahromi A, Osterborg A, Mellstedt H, Hojjat-Farsangi M. Ibrutinib-a double-edge sword in cancer and autoimmune disorders. J Drug Target. 2016;24(5):373–85.PubMedGoogle Scholar
  3. 3.
    Smith MR. Ibrutinib in B lymphoid malignancies. Expert Opin Pharmacother. 2015;16(12):1879–87.PubMedGoogle Scholar
  4. 4.
    Massó-Vallés D, Jauset T, Soucek L. Ibrutinib repurposing: from B-cell malignancies to solid tumors. Oncoscience. 2016;3(5–6):147.PubMedPubMedCentralGoogle Scholar
  5. 5.
    Haura EB, Rix U. Deploying ibrutinib to lung cancer: another step in the quest towards drug repurposing. J Natl Cancer Inst. 2014;106(9).PubMedPubMedCentralGoogle Scholar
  6. 6.
  7. 7.
    Shakeel F, Iqbal M, Ezzeldin E. Bioavailability enhancement and pharmacokinetic profile of an anticancer drug ibrutinib by self-nanoemulsifying drug delivery system. J Pharm Pharmacol. 2016;68(6):772–80.PubMedGoogle Scholar
  8. 8.
    De Jong J, Sukbuntherng J, Skee D, Murphy J, O’Brien S, Byrd JC, et al. The effect of food on the pharmacokinetics of oral ibrutinib in healthy participants and patients with chronic lymphocytic leukemia. Cancer Chemother Pharmacol. 2015;75(5):907–16.PubMedPubMedCentralGoogle Scholar
  9. 9.
    Shono Y, Jantratid E, Kesisoglou F, Reppas C, Dressman JB. Forecasting in vivo oral absorption and food effect of micronized and nanosized aprepitant formulations in humans. Eur J Pharm Biopharm. 2010;76(1):95–104.PubMedGoogle Scholar
  10. 10.
    Qiu Q, Lu M, Li C, Luo X, Liu X, Hu L, et al. Novel self-assembled Ibrutinib-phospholipid complex for potently Peroral delivery of poorly soluble drugs with pH-dependent solubility. AAPS PharmSciTech. 2018;19(8):3571–83.PubMedGoogle Scholar
  11. 11.
    Kesisoglou F, Mitra A. Crystalline nanosuspensions as potential toxicology and clinical oral formulations for BCS II/IV compounds. AAPS J. 2012;14(4):677–87.PubMedPubMedCentralGoogle Scholar
  12. 12.
    He J, Han Y, Xu G, Yin L, Neubi MN, Zhou J, et al. Preparation and evaluation of celecoxib nanosuspensions for bioavailability enhancement. RSC Adv. 2017;7(22):13053–64.Google Scholar
  13. 13.
    Müller R, Jacobs C, Kayser O. Nanosuspensions as particulate drug formulations in therapy: rationale for development and what we can expect for the future. Adv Drug Deliv Rev. 2001;47(1):3–19.PubMedGoogle Scholar
  14. 14.
    Guo L, Kang L, Liu X, Lin X, Di D, Wu Y, et al. A novel nanosuspension of andrographolide: preparation, characterization and passive liver target evaluation in rats. Eur J Pharm Sci. 2017;104:13–22.PubMedGoogle Scholar
  15. 15.
    Park J, Sun B, Yeo Y. Albumin-coated nanocrystals for carrier-free delivery of paclitaxel. J Control Release. 2017;263:90–101.PubMedGoogle Scholar
  16. 16.
    Danhier F, Ucakar B, Vanderhaegen M-L, Brewster ME, Arien T, Préat V. Nanosuspension for the delivery of a poorly soluble anti-cancer kinase inhibitor. Eur J Pharm Biopharm. 2014;88(1):252–60.PubMedGoogle Scholar
  17. 17.
    Sahu BP, Das MK. Nanosuspension for enhancement of oral bioavailability of felodipine. Appl Nanosci. 2014;4(2):189–97.Google Scholar
  18. 18.
    Reverchon E. Supercritical antisolvent precipitation of micro-and nano-particles. J Supercrit Fluids. 1999;15(1):1–21.Google Scholar
  19. 19.
    Pathak P, Meziani MJ, Desai T, Sun Y-P. Formation and stabilization of ibuprofen nanoparticles in supercritical fluid processing. J Supercrit Fluids. 2006;37(3):279–86.Google Scholar
  20. 20.
    Sarkari M, Brown J, Chen X, Swinnea S, Williams RO III, Johnston KP. Enhanced drug dissolution using evaporative precipitation into aqueous solution. Int J Pharm. 2002;243(1–2):17–31.PubMedGoogle Scholar
  21. 21.
    Chen X, Young TJ, Sarkari M, Williams RO III, Johnston KP. Preparation of cyclosporine a nanoparticles by evaporative precipitation into aqueous solution. Int J Pharm. 2002;242(1–2):3–14.PubMedGoogle Scholar
  22. 22.
    Peltonen L, Hirvonen J. Pharmaceutical nanocrystals by nanomilling: critical process parameters, particle fracturing and stabilization methods. J Pharm Pharmacol. 2010;62(11):1569–79.PubMedGoogle Scholar
  23. 23.
    Gera S, Talluri S, Rangaraj N, Sampathi S. Formulation and evaluation of Naringenin Nanosuspensions for bioavailability enhancement. AAPS PharmSciTech. 2017;18(8):3151–62.PubMedGoogle Scholar
  24. 24.
    Du J, Li X, Zhao H, Zhou Y, Wang L, Tian S, et al. Nanosuspensions of poorly water-soluble drugs prepared by bottom-up technologies. Int J Pharm. 2015;495(2):738–49.PubMedGoogle Scholar
  25. 25.
    Matteucci ME, Hotze MA, Johnston KP, Williams RO. Drug nanoparticles by antisolvent precipitation: mixing energy versus surfactant stabilization. Langmuir. 2006;22(21):8951–9.PubMedGoogle Scholar
  26. 26.
    Singh MK, Pooja D, Ravuri HG, Gunukula A, Kulhari H, Sistla R. Fabrication of surfactant-stabilized nanosuspension of naringenin to surpass its poor physiochemical properties and low oral bioavailability. Phytomedicine. 2018;40:48–54.PubMedGoogle Scholar
  27. 27.
    Rahim H, Sadiq A, Khan S, Khan MA, Shah SMH, Hussain Z, et al. Aceclofenac nanocrystals with enhanced in vitro, in vivo performance: formulation optimization, characterization, analgesic and acute toxicity studies. Drug Des Devel Ther. 2017;11:2443–52.PubMedPubMedCentralGoogle Scholar
  28. 28.
    Wang L, Du J, Zhou Y, Wang Y. Safety of nanosuspensions in drug delivery. Nanomedicine. 2017;13(2):455–69.PubMedGoogle Scholar
  29. 29.
    Verma S, Gokhale R, Burgess DJ. A comparative study of top-down and bottom-up approaches for the preparation of micro/nanosuspensions. Int J Pharm. 2009;380(1–2):216–22.PubMedGoogle Scholar
  30. 30.
    Kassem MA, ElMeshad AN, Fares AR. Enhanced solubility and dissolution rate of lacidipine nanosuspension: formulation via antisolvent sonoprecipitation technique and optimization using box–Behnken design. AAPS PharmSciTech. 2017;18(4):983–96.PubMedGoogle Scholar
  31. 31.
    Mishra V, Kesharwani P, Amin MC, Iyer A, editors. Nanotechnology-Based Approaches for Targeting and Delivery of Drugs and Genes. Academic Press; 2017 May 23Google Scholar
  32. 32.
    Kaithwas V, Dora CP, Kushwah V, Jain S. Nanostructured lipid carriers of olmesartan medoxomil with enhanced oral bioavailability. Colloids Surf B: Biointerfaces. 2017;154:10–20.PubMedGoogle Scholar
  33. 33.
    Shah P, Mashru R, Rane Y, Badhan A. Design and optimization of artemether microparticles for bitter taste masking. Acta Pharma. 2008;58(4):379–92.Google Scholar
  34. 34.
    Kan S, Lu J, Liu J, Wang J, Zhao Y. A quality by design (QbD) case study on enteric-coated pellets: screening of critical variables and establishment of design space at laboratory scale. AJPS. 2014;9(5):268–78.Google Scholar
  35. 35.
    Shi X, Song S, Ding Z, Fan B, Huang W, Xu T. Improving the solubility, dissolution, and bioavailability of Ibrutinib by preparing it in a Coamorphous state with saccharin. J Pharm Sci. 2019;108:3020–8.PubMedGoogle Scholar
  36. 36.
    Baumgartner R, Teubl BJ, Tetyczka C, Roblegg E. Rational design and characterization of a nanosuspension for intraoral administration considering physiological conditions. J Pharm Sci. 2016;105(1):257–67.PubMedGoogle Scholar
  37. 37.
    Shariare MH, Sharmin S, Jahan I, Reza H, Mohsin K. The impact of process parameters on carrier free paracetamol nanosuspension prepared using different stabilizers by antisolvent precipitation method. J Drug Deliv Sci Technol. 2018;43:122–8.Google Scholar
  38. 38.
    Liu D, Pan H, He F, Wang X, Li J, Yang X, et al. Effect of particle size on oral absorption of carvedilol nanosuspensions: in vitro and in vivo evaluation. Int J Nanomedicine. 2015;10:6425.PubMedPubMedCentralGoogle Scholar
  39. 39.
    Colombo M, Staufenbiel S, Rühl E, Bodmeier R. In situ determination of the saturation solubility of nanocrystals of poorly soluble drugs for dermal application. Int J Pharm. 2017;521(1–2):156–66.PubMedGoogle Scholar
  40. 40.
    Zhang X, Guan J, Ni R, Li LC, Mao S. Preparation and solidification of redispersible nanosuspensions. J Pharm Sci. 2014;103(7):2166–76.PubMedGoogle Scholar
  41. 41.
    Kho K, Cheow WS, Lie RH, Hadinoto K. Aqueous re-dispersibility of spray-dried antibiotic-loaded polycaprolactone nanoparticle aggregates for inhaled anti-biofilm therapy. Powder Technol. 2010;203(3):432–9.Google Scholar
  42. 42.
    Afifi SA, Hassan MA, Abdelhameed AS, Elkhodairy KA. Nanosuspension: an emerging trend for bioavailability enhancement of etodolac. Int J Polym Sci. 2015;2015:1–16.Google Scholar
  43. 43.
    Karakucuk A, Celebi N, Teksin ZS. Preparation of ritonavir nanosuspensions by microfluidization using polymeric stabilizers: I. a Design of Experiment approach. Eur J Pharm Sci. 2016;95:111–21.PubMedGoogle Scholar
  44. 44.
    Doktorovová S, Araújo J, Garcia ML, Rakovský E, Souto EB. Formulating fluticasone propionate in novel PEG-containing nanostructured lipid carriers (PEG-NLC). Colloids Surf B: Biointerfaces. 2010;75(2):538–42.PubMedGoogle Scholar
  45. 45.
    Gadadare R, Mandpe L, Pokharkar V. Ultra rapidly dissolving repaglinide nanosized crystals prepared via bottom-up and top-down approach: influence of food on pharmacokinetics behavior. AAPS PharmSciTech. 2015;16(4):787–99.PubMedGoogle Scholar
  46. 46.
    Talekar M, Ganta S, Amiji M, Jamieson S, Kendall J, Denny WA, et al. Development of PIK-75 nanosuspension formulation with enhanced delivery efficiency and cytotoxicity for targeted anti-cancer therapy. Int J Pharm. 2013;450(1–2):278–89.PubMedGoogle Scholar
  47. 47.
    Singh A, Neupane YR, Panda BP, Kohli K. Lipid based nanoformulation of lycopene improves oral delivery: formulation optimization, ex vivo assessment and its efficacy against breast cancer. J Microencapsul. 2017;34(4):416–29.PubMedGoogle Scholar
  48. 48.
    Berben P, Ashworth L, Beato S, Bevernage J, Bruel J-L, Butler J, et al. Biorelevant dissolution testing of a weak base: Interlaboratory reproducibility and investigation of parameters controlling in vitro precipitation. Eur J Pharm Biopharm. 2019;140:141–8.PubMedGoogle Scholar
  49. 49.
    Dai W-G, 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.PubMedGoogle Scholar
  50. 50.
    Dalvi SV, Dave RN. Controlling particle size of a poorly water-soluble drug using ultrasound and stabilizers in antisolvent precipitation. Ind Eng Chem Res. 2009;48(16):7581–93.Google Scholar
  51. 51.
    Kakran M, Sahoo NG, Tan I-L, Li L. Preparation of nanoparticles of poorly water-soluble antioxidant curcumin by antisolvent precipitation methods. J Nanopart Res. 2012;14(3):757.Google Scholar
  52. 52.
    Wang Y, Zheng Y, Zhang L, Wang Q, Zhang D. Stability of nanosuspensions in drug delivery. J Control Release. 2013;172(3):1126–41.PubMedGoogle Scholar
  53. 53.
    Tuomela A, Hirvonen J, Peltonen L. Stabilizing agents for drug nanocrystals: effect on bioavailability. Pharmaceutics. 2016;8(2):16.PubMedCentralGoogle Scholar
  54. 54.
    Lee J, Lee S-J, Choi J-Y, Yoo JY, Ahn C-H. Amphiphilic amino acid copolymers as stabilizers for the preparation of nanocrystal dispersion. Eur J Pharm Sci. 2005;24(5):441–9.PubMedGoogle Scholar
  55. 55.
    Pitto-Barry A, Barry NP. Pluronic® block-copolymers in medicine: from chemical and biological versatility to rationalisation and clinical advances. Polym Chem. 2014;5(10):3291–7.Google Scholar
  56. 56.
    Shaarani S, Hamid SS, Kaus NHM. The influence of Pluronic F68 and F127 nanocarrier on physicochemical properties, in vitro release, and antiproliferative activity of Thymoquinone drug. Pharm Res. 2017;9(1):12.Google Scholar
  57. 57.
    Chouhan P, Saini T. D-optimal design and development of microemulsion based transungual drug delivery formulation of ciclopirox olamine for treatment of onychomycosis. Indian J Pharm Sci. 2016;78(4):498–511.Google Scholar
  58. 58.
    Lin Y, Alexandridis P. Temperature-dependent adsorption of Pluronic F127 block copolymers onto carbon black particles dispersed in aqueous media. J Phys Chem B. 2002;106(42):10834–44.Google Scholar
  59. 59.
    Instruments M. Zetasizer nano series user manual. MAN0317. 2004;1:2004.Google Scholar
  60. 60.
    Hassani S, Laouini A, Fessi H, Charcosset C. Preparation of chitosan–TPP nanoparticles using microengineered membranes–effect of parameters and encapsulation of tacrine. Colloids Surf A Physicochem Eng Asp. 2015;482:34–43.Google Scholar
  61. 61.
    Shah B, Khunt D, Bhatt H, Misra M, Padh H. Application of quality by design approach for intranasal delivery of rivastigmine loaded solid lipid nanoparticles: effect on formulation and characterization parameters. Eur J Pharm Sci. 2015;78:54–66.PubMedGoogle Scholar
  62. 62.
    Junghanns J-UA, Müller RH. Nanocrystal technology, drug delivery and clinical applications. Int J Nanomedicine. 2008;3(3):295.PubMedPubMedCentralGoogle Scholar
  63. 63.
    Chen Z, Zhai J, Liu X, Mao S, Zhang L, Rohani S, et al. Solubility measurement and correlation of the form a of ibrutinib in organic solvents from 278.15 to 323.15 K. J Chem Thermodyn. 2016;103:342–8.Google Scholar
  64. 64.
    Eloy JO, Marchetti JM. Solid dispersions containing ursolic acid in Poloxamer 407 and PEG 6000: a comparative study of fusion and solvent methods. Powder Technol. 2014;253:98–106.Google Scholar
  65. 65.
    Hao J, Gao Y, Zhao J, Zhang J, Li Q, Zhao Z, et al. Preparation and optimization of resveratrol nanosuspensions by antisolvent precipitation using box-Behnken design. AAPS PharmSciTech. 2015;16(1):118–28.PubMedGoogle Scholar
  66. 66.
    Karolewicz B, Gajda M, Górniak A, Owczarek A, Mucha I. Pluronic F127 as a suitable carrier for preparing the imatinib base solid dispersions and its potential in development of a modified release dosage forms. J Therm Anal Calorim. 2017;130(1):383–90.Google Scholar
  67. 67.
    Müller RH, Peters K. Nanosuspensions for the formulation of poorly soluble drugs: I. preparation by a size-reduction technique. Int J Pharm. 1998;160(2):229–37.Google Scholar
  68. 68.
    Liu D, Xu H, Tian B, Yuan K, Pan H, Ma S, et al. Fabrication of carvedilol nanosuspensions through the anti-solvent precipitation–ultrasonication method for the improvement of dissolution rate and oral bioavailability. AAPS PharmSciTech. 2012;13(1):295–304.PubMedPubMedCentralGoogle Scholar
  69. 69.
    Nagaraj K, Narendar D, Kishan V. Development of olmesartan medoxomil optimized nanosuspension using the box–Behnken design to improve oral bioavailability. Drug Dev Ind Pharm. 2017;43(7):1186–96.PubMedGoogle Scholar
  70. 70.
    Beg S, Chaudhary V, Sharma G, Garg B, Panda SS, Singh B. QbD-oriented development and validation of a bioanalytical method for nevirapine with enhanced liquid–liquid extraction and chromatographic separation. Biomed Chromatogr. 2016;30(6):818–28.PubMedGoogle Scholar
  71. 71.
    Gao L, Liu G, Ma J, Wang X, Zhou L, Li X, et al. Application of drug nanocrystal technologies on oral drug delivery of poorly soluble drugs. Pharm Res. 2013;30(2):307–24.PubMedGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2019

Authors and Affiliations

  • Nagarjun Rangaraj
    • 1
  • Sravanthi Reddy Pailla
    • 1
  • Paramesh Chowta
    • 1
  • Sunitha Sampathi
    • 1
    Email author
  1. 1.Department of PharmaceuticsNational Institute of Pharmaceutical Education and ResearchHyderabadIndia

Personalised recommendations