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Study the influence of formulation process parameters on solubility and dissolution enhancement of efavirenz solid solutions prepared by hot-melt extrusion: a QbD methodology

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The current study investigates the dissolution rate performance of amorphous solid solutions of a poorly water-soluble drug, efavirenz (EFV), in amorphous Soluplus® (SOL) and Kollidon® VA 64 (KVA64) polymeric systems. For the purpose of the study, various formulations with varying drug loadings of 30, 50, and 70% w/w were developed via hot-melt extrusion processing and adopting a Box–Behnken design of experiment (DoE) approach. The polymers were selected based on the Hansen solubility parameter calculation and the prediction of the possible drug-polymer miscibility. In DoE experiments, a Box–Behnken factorial design was conducted to evaluate the effect of independent variables such as Soluplus® ratio (A1), HME screw speed (A2), and processing temperature (A3), and Kollidon®VA64 ratio (B1), screw speed (B2), and processing temperature (B3) on responses such as solubility (X1 and Y1) and dissolution rate (X2 and Y2) for both ASS [EFV:SOL] and BSS [EFV:KVA64] systems. DSC and XRD data confirmed that bulk crystalline EFV transformed to amorphous form during the HME processing. Advanced chemical analyses conducted via 2D COSY NMR, FTIR chemical imaging, AFM analysis, and FTIR showed that EFV was homogenously dispersed in the respective polymer matrices. The maximum solubility and dissolution rate was observed in formulations containing 30% EFV with both SOL and KVA64 alone. This could be attributed to the maximum drug-polymer miscibility in the optimized formulations. The actual and predicted values of both responses were found precise and close to each other.

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Solid solution


Hot-melt extrusion




Kollidon® VA64


Box–Behnken design


Sodium lauryl sulfate


  1. Maurin MB, Rowe SM, Blom K, Pierce ME. Kinetics and mechanism of hydrolysis of efavirenz. Pharm Res. 2002;19(4):517–21.

    Article  CAS  PubMed  Google Scholar 

  2. Takano R, Sugano K, Higashida A, Hayashi Y, Machida M, Aso Y, et al. Oral absorption of poorly water-soluble drugs: computer simulation of fraction absorbed in humans from a miniscale dissolution test. Pharm Res. 2006;23(6):1144–56.

    Article  CAS  PubMed  Google Scholar 

  3. Sathigari SK, Radhakrishnan VK, Davis VA, Parsons DL, Babu RJ. Amorphous-state characterization of efavirenz—polymer hot-melt extrusion systems for dissolution enhancement. J Pharm Sci. 2012;101(9):3456–64.

    Article  CAS  PubMed  Google Scholar 

  4. Crowley MM, Zhang F, Repka MA, Thumma S, Upadhye SB, Battu K, et al. Pharmaceutical applications of hot-melt extrusion: part I. Drug Dev Ind Pharm. 2007;33(9):909–26.

    Article  CAS  Google Scholar 

  5. Maniruzzaman M, Nair A, Renault M, Nandi U, Scoutaris N, Farnish R, et al. Continuous twin-screw granulation for enhancing the dissolution of poorly water soluble drug. Int J Pharm. 2015;496(1):52–62.

    Article  CAS  PubMed  Google Scholar 

  6. Sun DD, Lee PI. Probing the mechanisms of drug release from amorphous solid dispersions in medium-soluble and medium-insoluble carriers. J Control Release. 2015;211:85–93.

    Article  CAS  PubMed  Google Scholar 

  7. Yu L. Amorphous pharmaceutical solids: preparation, characterization and stabilization. Adv Drug Deliv Rev. 2001;48(1):27–42.

    Article  CAS  PubMed  Google Scholar 

  8. Knopp MM, Tajber L, Tian Y, Olesen NE, Jones DS, Kozyra A, et al. Comparative study of different methods for the prediction of drug–polymer solubility. Mol Pharm. 2015;12(9):3408–19.

    Article  CAS  PubMed  Google Scholar 

  9. Tian Y, Booth J, Meehan E, Jones DS, Li S, Andrews GP. Construction of drug–polymer thermodynamic phase diagrams using Flory–Huggins interaction theory: identifying the relevance of temperature and drug weight fraction to phase separation within solid dispersions. Mol Pharm. 2012;10(1):236–48.

    Article  CAS  PubMed  Google Scholar 

  10. Shah S, Maddineni S, Lu J, Repka MA. Melt extrusion with poorly soluble drugs. Int J Pharm. 2013;453(1):233–52.

    Article  CAS  PubMed  Google Scholar 

  11. Djuris J, Ioannis N, Ibric S, Djuric Z, Kachrimanis K. Effect of composition in the development of carbamazepine hot-melt extruded solid dispersions by application of mixture experimental design. J Pharm Pharmacol. 2014;66(2):232–43.

    Article  CAS  PubMed  Google Scholar 

  12. Li M, Gogos CG, Ioannidis N. Improving the API dissolution rate during pharmaceutical hot-melt extrusion I: effect of the API particle size, and the co-rotating, twin-screw extruder screw configuration on the API dissolution rate. Int J Pharm. 2015;478(1):103–12.

    Article  CAS  PubMed  Google Scholar 

  13. Fule R, Paithankar V, Amin P. Hot melt extrusion based solid solution approach: exploring polymer comparison, physicochemical characterization and in-vivo evaluation. Int J Pharm. 2016;499(1):280–94.

    Article  CAS  PubMed  Google Scholar 

  14. Marasini N, Yan YD, Poudel BK, Choi HG, Yong CS, Kim JO. Development and optimization of self-nanoemulsifying drug delivery system with enhanced bioavailability by Box–Behnken design and desirability function. J Pharm Sci. 2012;101(12):4584–96.

    Article  CAS  PubMed  Google Scholar 

  15. Abdelbary AA, AbouGhaly MH. Design and optimization of topical methotrexate loaded niosomes for enhanced management of psoriasis: application of Box–Behnken design, in-vitro evaluation and in-vivo skin deposition study. Int J Pharm. 2015;485(1):235–43.

    Article  CAS  PubMed  Google Scholar 

  16. Maniruzzaman M, Morgan DJ, Mendham AP, Pang J, Snowden MJ, Douroumis D. Drug–polymer intermolecular interactions in hot-melt extruded solid dispersions. Int J Pharm. 2013;443(1):199–208.

    Article  CAS  PubMed  Google Scholar 

  17. Van Krevelen DW, Te Nijenhuis K. Properties of polymers: their correlation with chemical structure; their numerical estimation and prediction from additive group contributions: Elsevier; 2009.

  18. Greenhalgh DJ, Williams AC, Timmins P, York P. Solubility parameters as predictors of miscibility in solid dispersions. J Pharm Sci. 1999;88(11):1182–90.

    Article  CAS  PubMed  Google Scholar 

  19. Maddineni S, Battu SK, Morott J, Soumyajit M, Repka MA. Formulation optimization of hot-melt extruded abuse deterrent pellet dosage form utilizing design of experiments. J Pharm Pharmacol. 2014;66(2):309–22.

    Article  CAS  PubMed  Google Scholar 

  20. Lauer ME, Siam M, Tardio J, Page S, Kindt JH, Grassmann O. Rapid assessment of homogeneity and stability of amorphous solid dispersions by atomic force microscopy—from bench to batch. Pharm Res. 2013;30(8):2010–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Tho I, Liepold B, Rosenberg J, Maegerlein M, Brandl M, Fricker G. Formation of nano/micro-dispersions with improved dissolution properties upon dispersion of ritonavir melt extrudate in aqueous media. Eur J Pharm Sci. 2010;40(1):25–32.

    Article  CAS  PubMed  Google Scholar 

  22. Lauer ME, Grassmann O, Siam M, Tardio J, Jacob L, Page S, et al. Atomic force microscopy-based screening of drug-excipient miscibility and stability of solid dispersions. Pharm Res. 2011;28(3):572–84.

    Article  CAS  PubMed  Google Scholar 

  23. Fule R, Dhamecha D, Maniruzzaman M, Khale A, Amin P. Development of hot melt co-formulated antimalarial solid dispersion system in fixed dose form (ARLUMELT): evaluating amorphous state and in vivo performance. Int J Pharm. 2015;496(1):137–56.

    Article  CAS  PubMed  Google Scholar 

  24. Zhou P, Xie X, Knight DP, Zong XH, Deng F, Yao WH. Effects of pH and calcium ions on the conformational transitions in silk fibroin using 2D Raman correlation spectroscopy and 13C solid-state NMR. Biochemist. 2004;43(35):11302–11.

    Article  CAS  Google Scholar 

  25. Mahesh KV, Singh SK, Gulati M. A comparative study of top-down and bottom-up approaches for the preparation of nanosuspensions of glipizide. Powd Technol. 2014;256:436–49.

    Article  CAS  Google Scholar 

  26. Kaur P, Singh SK, Garg V, Gulati M, Vaidya Y. Optimization of spray drying process for formulation of solid dispersion containing polypeptide-k powder through quality by design approach. Powd Technol. 2015;284:1–11.

    Article  CAS  Google Scholar 

  27. Pawar JN, Shete RT, Gangurde AB, Moravkar KK, Javeer SD, et al. Development of amorphous dispersions of artemether with hydrophilic polymers via spray drying: physicochemical and in silico studies. Asi J Pharm Sci. 2016;11(3):385–95.

    Google Scholar 

  28. Hancock BC, Parks M. What is the true solubility advantage for amorphous pharmaceuticals? Pharm Res. 2000;17(4):397–404.

    Article  CAS  PubMed  Google Scholar 

  29. Alshahrani SM, Lu W, Park JB, Morott JT, Alsulays BB, Majumdar, et al. Stability-enhanced hot-melt extruded amorphous solid dispersions via combinations of Soluplus® and HPMCAS-HF. AAPS PharmSciTech. 2015;16(4):824–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Pawar J, Tayade A, Gangurde A, Moravkar K, Amin P. Solubility and dissolution enhancement of efavirenz hot melt extruded amorphous solid dispersions using combination of polymeric blends: a QbD approach. Eur J Pharm Sci. 2016;88:37–49.

    Article  CAS  PubMed  Google Scholar 

  31. Sarode AL, Sandhu H, Shah N, Malick W, Zia H. Hot melt extrusion (HME) for amorphous solid dispersions: predictive tools for processing and impact of drug–polymer interactions on supersaturation. Eur J Pharm Sci. 2013;48(3):371–84.

    Article  CAS  Google Scholar 

  32. Alves LDS, Soares MFDLR, de Albuquerque CT, da Silva, et al. Solid dispersion of efavirenz in PVP K-30 by conventional solvent and kneading methods. Carbohyd Polym. 2014;104:166–74.

    Article  CAS  Google Scholar 

  33. Meer T, Fule R, Khanna D, Amin P. Solubility modulation of bicalutamide using porous silica. J Pharm Inv. 2013;43(4):279–85.

    Article  CAS  Google Scholar 

  34. Sinclair W, Leane M, Clarke G, Dennis A, Tobyn M, Timmins P. Physical stability and recrystallization kinetics of amorphous ibipinabant drug product by Fourier transform Raman spectroscopy. J Pharm Sci. 2011;100(11):4687–99.

    Article  CAS  PubMed  Google Scholar 

  35. Ueda H, Muranushi N, Sakuma S, Ida Y, Endoh T, Kadota K, et al. A strategy for co-former selection to design stable co-amorphous formations based on physicochemical properties of non-steroidal inflammatory drugs. Pharm Res. 2016;33(4):1018–29.

    Article  CAS  PubMed  Google Scholar 

  36. Gaur PK, Mishra S, Bajpai M, Mishra A. Enhanced oral bioavailability of efavirenz by solid lipid nanoparticles: in vitro drug release and pharmacokinetics studies. BioMed Res Int. 2014;2014:363404.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Rumondor AC, 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(12):2599–606.

    Article  CAS  PubMed  Google Scholar 

  38. 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 Pharm. 2013;10(10):3801–11.

    Article  CAS  PubMed  Google Scholar 

  39. Ambrogi V, Perioli L, Pagano C, Marmottini F, Ricci M, Sagnella A, et al. Use of SBA-15 for furosemide oral delivery enhancement. Eur J Pharm Sci. 2012;46(1):43–8.

    Article  CAS  PubMed  Google Scholar 

  40. Feng X, Vo A, Patil H, Tiwari RV, Alshetaili AS, Pimparade MB, Repka MA. The effects of polymer carrier, hot melt extrusion process and downstream processing parameters on the moisture sorption properties of amorphous solid dispersions. J Pharm Pharmacol. 2016;68(5):692–704.

    Article  CAS  Google Scholar 

  41. Alhijjaj M, Bouman J, Wellner N, Belton P, Qi S. Creating drug solubilization compartments via phase separation in multicomponent buccal patches prepared by direct hot melt extrusion–injection molding. Mol Pharm. 2015;12(12):4349–62.

    Article  CAS  PubMed  Google Scholar 

  42. Kyeremateng SO, Pudlas M, Woehrle GH. A fast and reliable empirical approach for estimating solubility of crystalline drugs in polymers for hot melt extrusion formulations. J Pharm Sci. 2014;103(9):2847–58.

    Article  CAS  PubMed  Google Scholar 

  43. Pham TN, Watson SA, Edwards AJ, Chavda M, Clawson JS, Strohmeier M, et al. Analysis of amorphous solid dispersions using 2D solid-state NMR and 1H T 1 relaxation measurements. Mol Pharm. 2010;7(5):1667–91.

    Article  CAS  PubMed  Google Scholar 

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The authors would like to acknowledge Laurus Labs, Hyderabad, India, for the genuine gift sample of efavirenz. The author is thankful to Dr. Rahul Aware and Vasant Shetty from ACG Machines Pvt., Ltd., for allowing their twin-screw HME facility at Pune, India. The authors are thankful to University Grants Commission India for providing the research fellowship. The authors are thankful to S.A.I.F., Department at Indian Institute of Technology, Mumbai, for FTIR imaging analysis and 2D COSY analysis of the samples.

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Correspondence to Jaywant Pawar.

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Pawar, J., Suryawanshi, D., Moravkar, K. et al. Study the influence of formulation process parameters on solubility and dissolution enhancement of efavirenz solid solutions prepared by hot-melt extrusion: a QbD methodology. Drug Deliv. and Transl. Res. 8, 1644–1657 (2018).

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