Journal of Pharmaceutical Investigation

, Volume 48, Issue 1, pp 19–41 | Cite as

Characterization of amorphous solid dispersions

  • Xu Liu
  • Xin Feng
  • Robert O. WilliamsIII
  • Feng ZhangEmail author


The study of amorphous solid dispersions (ASDs) is currently one of the most exciting areas in pharmaceutics. Research has shown that ASDs offer unique advantages in improving the bioavailability of poorly water-soluble drugs over conventional delivery systems. The various formulations and manufacturing processes of ASDs affect their physicochemical stability, processability, and drug release characteristics. Therefore, the characterization of ASDs is critical in all stages of product development, including preformulation screening, formulation development, process scale-up, and commercial manufacturing. Proper characterization allows for the rational selection of formulation composition and manufacturing processing methods and allows for high-quality drug products. In this review, we present the most commonly used methods for characterizing the solid-state properties of ASDs, and we discuss their mechanisms, applications, advantages, and disadvantages. We also provide a brief overview of the methods used to characterize ASDs behavior in aqueous media. These methods are divided into three different categories: microscopic and surface analysis methods, thermal analysis methods, and spectroscopic methods. In addition, this article discusses a number of emerging techniques. Last, we discuss how these methods are applied at different stages in the ASDs product development life cycle.


Amorphous solid dispersion Material characterization Physical stability Phase separation Molecular mobility Microscopic analysis Thermal analysis Spectroscopic analysis 



The authors gratefully appreciate Mr. Vincent LeCornu and Eucharist Kun for help in editing this manuscript.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Statement of human and animal right

This article does not contain any studies with human and animal subjects performed by any of the authors.


  1. Alhijjaj M, Reading M, Belton P, Qi S (2015) Thermal analysis by structural characterization as a method for assessing heterogeneity in complex solid pharmaceutical dosage forms. Anal Chem 87(21):10848–10855. doi: 10.1021/acs.analchem.5b02192 CrossRefPubMedGoogle Scholar
  2. Alhijjaj M, Yassin S, Reading M, Zeitler JA, Belton P, Qi S (2017) Characterization of heterogeneity and spatial distribution of phases in complex solid dispersions by thermal analysis by structural characterization and X-ray micro computed tomography. Pharm Res 34(5):971–989. doi: 10.1007/s11095-016-1923-3 CrossRefPubMedGoogle Scholar
  3. Almeida A, Saerens L, De Beer T, Remon JP, Vervaet C (2012) Upscaling and in-line process monitoring via spectroscopic techniques of ethylene vinyl acetate hot-melt extruded formulations. Int J Pharm 439(1):223–229CrossRefGoogle Scholar
  4. Alonzo DE, Zhang GG, Zhou D, Gao Y, Taylor LS (2010) Understanding the behavior of amorphous pharmaceutical systems during dissolution. Pharm Res 27(4):608–618. doi: 10.1007/s11095-009-0021-1 CrossRefPubMedGoogle Scholar
  5. Álvarez-Murga M, Bleuet P, Hodeau JL (2012) Diffraction/scattering computed tomography for three-dimensional characterization of multi-phase crystalline and amorphous materials. J Appl Crystallogr 45(6):1109–1124. doi: 10.1107/S0021889812041039 CrossRefGoogle Scholar
  6. Andrews GP, Zhai H, Tipping S, Jones DS (2009) Characterisation of the thermal, spectroscopic and drug dissolution properties of mefenamic acid and polyoxyethylene-polyoxypropylene solid dispersions. J Pharm Sci 98(12):4545–4556. doi: 10.1002/jps.21752 CrossRefPubMedGoogle Scholar
  7. Andrews GP, AbuDiak OA, Jones DS (2010) Physicochemical characterization of hot melt extruded bicalutamide–polyvinylpyrrolidone solid dispersions. J Pharm Sci 99(3):1322–1335. doi: 10.1002/jps.21914 CrossRefPubMedGoogle Scholar
  8. Aso Y, Yoshioka S, Kojima S (2000) Relationship between the crystallization rates of amorphous nifedipine, phenobarbital, and flopropione, and their molecular mobility as measured by their enthalpy relaxation and 1H NMR relaxation times. J Pharm Sci 89(3):408–416. doi: 10.1002/(SICI)1520-6017(200003)89:3 CrossRefPubMedGoogle Scholar
  9. Aso Y, Yoshioka S, Kojima S (2004) Molecular mobility-based estimation of the crystallization rates of amorphous nifedipine and phenobarbital in poly(vinylpyrrolidone) solid dispersions. J Pharm Sci 93(2):384–391. doi: 10.1002/jps.10526 CrossRefPubMedGoogle Scholar
  10. Aso Y, Yoshioka S, Miyazaki T, Kawanishi T (2009) Feasibility of 19F-NMR for assessing the molecular mobility of flufenamic acid in solid dispersions. Chem Pharm Bull 57(1):61–64. doi: 10.1248/cpb.57.61 CrossRefPubMedGoogle Scholar
  11. Baird JA, Taylor LS (2012) Evaluation of amorphous solid dispersion properties using thermal analysis techniques. Adv Drug Deliv Rev 64(5):396–421. doi: 10.1016/j.addr.2011.07.009 CrossRefPubMedGoogle Scholar
  12. Baird JA, Van Eerdenbrugh B, Taylor LS (2010) A classification system to assess the crystallization tendency of organic molecules from undercooled melts. J Pharm Sci 99(9):3787–3806. doi: 10.1002/jps.22197 CrossRefPubMedGoogle Scholar
  13. Bhardwaj SP, Suryanarayanan R (2012) Molecular mobility as an effective predictor of the physical stability of amorphous trehalose. Mol Pharmaceutics 9(11):3209–3217. doi: 10.1021/mp300302g CrossRefGoogle Scholar
  14. Bohr A, Yang MS, Baldursdottir S, Kristensen J, Dyas M, Stride E, Edirisinghe M (2012) Particle formation and characteristics of Celecoxib-loaded poly(lactic-co-glycolic acid) microparticles prepared in different solvents using electrospraying. Polymer 53(15):3220–3229. doi: 10.1016/j.polymer.2012.05.002 CrossRefGoogle Scholar
  15. Bohr A, Wan F, Kristensen J, Dyas M, Stride E, Baldursdottír S, Edirisinghe M, Yang M (2015) Pharmaceutical microparticle engineering with electrospraying: the role of mixed solvent systems in particle formation and characteristics. J Mater Sci 26(2):1–13Google Scholar
  16. Brittain HG (2006) Spectroscopy of Pharmaceutical Solids. Taylor & Francis, New YorkCrossRefGoogle Scholar
  17. Bruce C, Fegely KA, Rajabi-Siahboomi AR, McGinity JW (2007) Crystal growth formation in melt extrudates. Int J Pharm 341(1–2):162–172. doi: 10.1016/j.ijpharm.2007.04.008 CrossRefPubMedGoogle Scholar
  18. Cai T, Zhu L, Yu L (2011) Crystallization of organic glasses: effects of polymer additives on bulk and surface crystal growth in amorphous nifedipine. Pharm Res 28(10):2458–2466. doi: 10.1007/s11095-011-0472-z CrossRefPubMedGoogle Scholar
  19. Chieng N, Rades T, Aaltonen J (2011) An overview of recent studies on the analysis of pharmaceutical polymorphs. J Pharm Biomed Anal 55(4):618–644. doi: 10.1016/j.jpba.2010.12.020 CrossRefPubMedGoogle Scholar
  20. Chiou WL, Riegelman S (1971) Pharmaceutical applications of solid dispersion systems. J Pharm Sci 60(9):1281–1302CrossRefGoogle Scholar
  21. Colombo S, Brisander M, Haglöf J, Sjövall P, Andersson P, Østergaard J, Malmsten M (2015) Matrix effects in nilotinib formulations with pH-responsive polymer produced by carbon dioxide-mediated precipitation. Int J Pharm 494(1):205–217. doi: 10.1016/j.ijpharm.2015.08.031 CrossRefPubMedGoogle Scholar
  22. Coombes SR, Hughes LP, Phillips AR, Wren SAC (2014) Proton NMR: a new tool for understanding dissolution. Anal Chem 86(5):2474–2480. doi: 10.1021/ac403418w CrossRefPubMedGoogle Scholar
  23. Craig DQM, Kett VL, Andrews CS, Royall PG (2002) Pharmaceutical applications of micro-thermal analysis. J Pharm Sci 91(5):1201–1213. doi: 10.1002/jps.10103 CrossRefPubMedGoogle Scholar
  24. Dahlberg C, Millqvist-Fureby A, Schuleit M (2008) Surface composition and contact angle relationships for differently prepared solid dispersions. Eur J Pharm Biopharm 70(2):478–485. doi: 10.1016/j.ejpb.2008.05.026 CrossRefPubMedGoogle Scholar
  25. Dahlberg C, Dvinskikh SV, Schuleit M, Furó I (2011) Polymer swelling, drug mobilization and drug recrystallization in hydrating solid dispersion tablets studied by multinuclear NMR microimaging and spectroscopy. Mol Pharmaceutics 8(4):1247–1256. doi: 10.1021/mp200051e CrossRefGoogle Scholar
  26. Dai X, Moffat JG, Wood J, Reading M (2012) Thermal scanning probe microscopy in the development of pharmaceuticals. Adv Drug Deliv Rev 64(5):449–460. doi: 10.1016/j.addr.2011.07.008 CrossRefPubMedGoogle Scholar
  27. Dazzi A, Prater CB, Hu Q, Chase DB, Rabolt JF, Marcott C (2012) AFM–IR: combining atomic force microscopy and infrared spectroscopy for nanoscale chemical characterization. Appl Spectrosc 66(12):1365–1384. doi: 10.1366/12-06804 CrossRefPubMedGoogle Scholar
  28. de Araujo GLB, Benmore CJ, Byrn SR (2017) Local structure of ion pair interaction in lapatinib amorphous dispersions characterized by synchrotron X-ray diffraction and pair distribution function analysis. Sci Rep 7:46367. doi: 10.1038/srep46367 CrossRefPubMedPubMedCentralGoogle Scholar
  29. Dinnebier RE (2008) Powder Diffraction: Theory and Practice. Royal Society of Chemistry, CambridgeCrossRefGoogle Scholar
  30. Dykhne T, Taylor R, Florence A, Billinge SJ (2011) Data requirements for the reliable use of atomic pair distribution functions in amorphous pharmaceutical fingerprinting. Pharm Res 28(5):1041–1048. doi: 10.1007/s11095-010-0350-0 CrossRefPubMedGoogle Scholar
  31. Egami T, Billinge SJ (2012) Underneath the Bragg Peaks: Structural Analysis of Complex Materials. Elsevier Science, BurlingtonGoogle Scholar
  32. Feng X, Ye X, Park J-B, Lu W, Morott J, Beissner B, Lian ZJ, Pinto E, Bi V, Porter S, Durig T, Majumdar S, Repka MA (2014) Evaluation of the recrystallization kinetics of hot-melt extruded polymeric solid dispersions using an improved Avrami equation. Drug Dev Ind Pharm. doi: 10.3109/03639045.2014.958755 CrossRefPubMedGoogle Scholar
  33. Feng X, Vo A, Patil H, Tiwari RV, Alshetaili AS, Pimparade MB, Repka MA (2016) 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 68(5):692–704. doi: 10.1111/jphp.12488 CrossRefPubMedGoogle Scholar
  34. Fotaki N, Long CM, Tang K, Chokshi H (2014) Dissolution of amorphous solid dispersions: theory and practice. In: Shah N, Sandhu H, Choi DS, Chokshi H, Malick AW (eds) Amorphous solid dispersions: theory and practice, Springer, New York, pp 487–514Google Scholar
  35. Friesen DT, Shanker R, Crew M, Smithey DT, Curatolo WJ, Nightingale JAS (2008) Hydroxypropyl methylcellulose acetate succinate-based spray-dried dispersions: an overview. Mol Pharmaceutics 5(6):1003–1019. doi: 10.1021/mp8000793 CrossRefGoogle Scholar
  36. Gamble JF, Terada M, Holzner C, Lavery L, Nicholson SJ, Timmins P, Tobyn M (2016) Application of X-ray microtomography for the characterisation of hollow polymer-stabilised spray dried amorphous dispersion particles. Int J Pharm 510(1):1–8. doi: 10.1016/j.ijpharm.2016.05.051 CrossRefPubMedGoogle Scholar
  37. Ghebremeskel AN, Vernavarapu C, Lodaya M (2007) Use of surfactants as plasticizers in preparing solid dispersions of poorly soluble API: selection of polymer-surfactant combinations using solubility parameters and testing the processability. Int J Pharm 328(2):119–129CrossRefGoogle Scholar
  38. Gilmore CJ (2011). X-ray diffraction. Solid state characterization of pharmaceuticals. Wiley, Chichester, pp 35–70CrossRefGoogle Scholar
  39. Grisedale LC, Jamieson MJ, Belton P, Barker SA, Craig DQM (2011) Characterization and quantification of amorphous material in milled and spray-dried salbutamol sulfate: a comparison of thermal, spectroscopic, and water vapor sorption approaches. J Pharm Sci 100(8):3114–3129. doi: 10.1002/jps.22484 CrossRefPubMedGoogle Scholar
  40. Grohganz H, Priemel PA, Lobmann K, Nielsen LH, Laitinen R, Mullertz A, Van den Mooter G, Rades T (2014) Refining stability and dissolution rate of amorphous drug formulations. Expert Opin Drug Delivery 11(6):977–989. doi: 10.1517/17425247.2014.911728 CrossRefGoogle Scholar
  41. Grzybowska K, Capaccioli S, Paluch M (2016) Recent developments in the experimental investigations of relaxations in pharmaceuticals by dielectric techniques at ambient and elevated pressure. Adv Drug Deliv Rev 100:158–182. doi: 10.1016/j.addr.2015.12.008 CrossRefPubMedGoogle Scholar
  42. Gupta P, Kakumanu VK, Bansal AK (2004) Stability and solubility of celecoxib-PVP amorphous dispersions: a molecular perspective. Pharm Res 21(10):1762–1769CrossRefGoogle Scholar
  43. Harding L, King WP, Dai X, Craig DQ, Reading M (2007) Nanoscale characterisation and imaging of partially amorphous materials using local thermomechanical analysis and heated tip AFM. Pharm Res 24(11):2048–2054. doi: 10.1007/s11095-007-9339-8 CrossRefPubMedGoogle Scholar
  44. Harmon P, Galipeau K, Xu W, Brown C, Wuelfing WP (2016) Mechanism of dissolution-induced nanoparticle formation from a copovidone-based amorphous solid dispersion. Mol Pharm 13(5):1467–1481. doi: 10.1021/acs.molpharmaceut.5b00863 CrossRefPubMedGoogle Scholar
  45. He Y, Ho C (2015) Amorphous solid dispersions: utilization and challenges in drug discovery and development. J Pharm Sci 104(10):3237–3258. doi: 10.1002/jps.24541 CrossRefPubMedGoogle Scholar
  46. Hedoux A (2016) Recent developments in the Raman and infrared investigations of amorphous pharmaceuticals and protein formulations: a review. Adv Drug Deliv Rev 100:133–146. doi: 10.1016/j.addr.2015.11.021 CrossRefPubMedGoogle Scholar
  47. Heinz A, Strachan CJ, Gordon KC, Rades T (2009) Analysis of solid-state transformations of pharmaceutical compounds using vibrational spectroscopy. J Pharm Pharmcol 61(8):971–988. doi: 10.1211/jpp.61.08.0001 CrossRefGoogle Scholar
  48. Höhne GWH, Hemminger W, Flammersheim H-J (1996) Theoretical fundamentals of differential scanning calorimeters. Differential scanning calorimetry Springer, New York, pp 21–40Google Scholar
  49. Huang J, Dali M (2013) Evaluation of integrated Raman-DSC technology in early pharmaceutical development: characterization of polymorphic systems. J Pharm Biomed Anal 86:92–99. doi: 10.1016/j.jpba.2013.08.004 CrossRefPubMedGoogle Scholar
  50. Ilevbare GA, Taylor LS (2013) Liquid–Liquid phase separation in highly supersaturated aqueous solutions of poorly water-soluble drugs: implications for solubility enhancing formulations. Cryst Growth Des 13(4):1497–1509. doi: 10.1021/cg301679h CrossRefGoogle Scholar
  51. Ito A, Watanabe T, Yada S, Hamaura T, Nakagami H, Higashi K, Moribe K, Yamamoto K (2010) Prediction of recrystallization behavior of troglitazone/polyvinylpyrrolidone solid dispersion by solid-state NMR. Int J Pharm 383(1–2):18–23. doi: 10.1016/j.ijpharm.2009.08.037 CrossRefPubMedGoogle Scholar
  52. Jain S, Patel N, Lin S (2015) Solubility and dissolution enhancement strategies: current understanding and recent trends. Drug Dev Ind Pharm 41(6):875–887. doi: 10.3109/03639045.2014.971027 CrossRefPubMedGoogle Scholar
  53. Janssens S, Van den Mooter G (2009) Review: physical chemistry of solid dispersions. J Pharm Pharmcol 61(12):1571–1586. doi: 10.1211/jpp.61.12.0001 CrossRefGoogle Scholar
  54. Kanzer J, Hupfeld S, Vasskog T, Tho I, Hölig P, Mägerlein M, Fricker G, Brandl M (2010) In situ formation of nanoparticles upon dispersion of melt extrudate formulations in aqueous medium assessed by asymmetrical flow field-flow fractionation. J Pharm Biomed Anal 53(3):359–365. doi: 10.1016/j.jpba.2010.04.012 CrossRefPubMedGoogle Scholar
  55. Kaushal AM, Bansal AK (2008) Thermodynamic behavior of glassy state of structurally related compounds. Eur J Pharm Biopharm 69(3):1067–1076. doi: 10.1016/j.ejpb.2008.02.001 CrossRefPubMedGoogle Scholar
  56. Kawakami K (2016). Supersaturation and crystallization: non-equilibrium dynamics of amorphous solid dispersions for oral drug delivery. Expert Opin Drug Deliv. doi: 10.1080/17425247.2017.1230099 CrossRefPubMedGoogle Scholar
  57. Kawakami K, Usui T, Hattori M (2012) Understanding the glass-forming ability of active pharmaceutical ingredients for designing supersaturating dosage forms. J Pharm Sci 101(9):3239–3248. doi: 10.1002/jps.23166 CrossRefPubMedGoogle Scholar
  58. Kazarian SG, Ewing AV (2013) Applications of Fourier transform infrared spectroscopic imaging to tablet dissolution and drug release. Expert Opin Drug Deliv 10(9):1207–1221. doi: 10.1517/17425247.2013.801452 CrossRefPubMedGoogle Scholar
  59. Kjoller K, Rose J, Sahagian K (2010) Transition temperature microscopy: nanoscale thermal analysis for micron- and submicron-scale devices. Am Lab 913:598Google Scholar
  60. Knopp MM, Löbmann K, Elder DP, Rades T, Holm R (2016) Recent advances and potential applications of modulated differential scanning calorimetry (mDSC) in drug development. Eur J Pharm Sci 87:164–173. doi: 10.1016/j.ejps.2015.12.024 CrossRefPubMedGoogle Scholar
  61. Korhonen O, Bhura C, Pikal MJ (2008) Correlation between molecular mobility and crystal growth of amorphous phenobarbital and phenobarbital with polyvinylpyrrolidone and l-proline. J Pharm Sci 97(9):3830–3841. doi: 10.1002/jps.21273 CrossRefPubMedGoogle Scholar
  62. Kothari K, Ragoonanan V, Suryanarayanan R (2015) The role of polymer concentration on the molecular mobility and physical stability of nifedipine solid dispersions. Mol Pharm 12(5):1477–1484. doi: 10.1021/mp500800c CrossRefPubMedGoogle Scholar
  63. Lamm MS, DiNunzio J, Khawaja NN, Crocker LS, Pecora A (2016) Assessing mixing quality of a copovidone-TPGS hot melt extrusion process with atomic force microscopy and differential scanning calorimetry. AAPS PharmSciTech 17(1):89–98. doi: 10.1208/s12249-015-0387-9 CrossRefPubMedGoogle Scholar
  64. Langham ZA, Booth J, Hughes LP, Reynolds GK, Wren SAC (2012) Mechanistic insights into the dissolution of spray-dried amorphous solid dispersions. J Pharm Sci 101(8):2798–2810. doi: 10.1002/jps.23192 CrossRefPubMedGoogle Scholar
  65. Lauer ME, Grassmann O, Siam M, Tardio J, Jacob L, Page S, Kindt JH, Engel A, Alsenz J (2011) Atomic force microscopy-based screening of drug-excipient miscibility and stability of solid dispersions. Pharm Res 28(3):572–584. doi: 10.1007/s11095-010-0306-4 CrossRefPubMedGoogle Scholar
  66. Lauer M, Siam M, Tardio J, Page S, Kindt J, Grassmann O (2013) Rapid assessment of homogeneity and stability of amorphous solid dispersions by atomic force microscopy—from bench to batch. Pharm Res 30(8):2010–2022. doi: 10.1007/s11095-013-1045-0 CrossRefPubMedPubMedCentralGoogle Scholar
  67. Lee H-L, Flynn NT (2006) X-ray photoelectron. In: Vij DR (ed) Handbook of applied solid state spectroscopy, Springer, Boston, pp 485–507CrossRefGoogle Scholar
  68. Li N, Taylor LS (2016) Nanoscale infrared, thermal, and mechanical characterization of telaprevir–polymer miscibility in amorphous solid dispersions prepared by solvent evaporation. Mol Pharm 13(3):1123–1136. doi: 10.1021/acs.molpharmaceut.5b00925 CrossRefPubMedGoogle Scholar
  69. Li Y, Pang H, Guo Z, Lin L, Dong Y, Li G, Lu M, Wu C (2014) Interactions between drugs and polymers influencing hot melt extrusion. J Pharm Pharmcol 66(2):148–166CrossRefGoogle Scholar
  70. Lin S-Y, Wang S-L (2012) Advances in simultaneous DSC–FTIR microspectroscopy for rapid solid-state chemical stability studies: some dipeptide drugs as examples. Adv Drug Deliv Rev 64(5):461–478. doi: 10.1016/j.addr.2012.01.009 CrossRefPubMedGoogle Scholar
  71. Lin S-Y, Lee C-J, Lin Y-Y (1995) Drug-polymer interaction affecting the mechanical properties, adhesion strength and release kinetics of piroxicam-loaded Eudragit E films plasticized with different plasticizers. J Controlled Release 33(3):375–381. doi: 10.1016/0168-3659(94)00109-8 CrossRefGoogle Scholar
  72. Liu X, Lu M, Guo Z, Huang L, Feng X, Wu C (2012) Improving the chemical stability of amorphous solid dispersion with cocrystal technique by hot melt extrusion. Pharm Res 29(3):806–817. doi: 10.1007/s11095-011-0605-4 CrossRefPubMedGoogle Scholar
  73. Liu X, Zhou L, Zhang F (2017) Reactive melt extrusion to improve the dissolution performance and physical stability of naproxen amorphous solid dispersions. Mol Pharm. doi: 10.1021/acs.molpharmaceut.6b00960 CrossRefPubMedPubMedCentralGoogle Scholar
  74. Lust A, Strachan CJ, Veski P, Aaltonen J, Heinämäki J, Yliruusi J, Kogermann K (2015) Amorphous solid dispersions of piroxicam and Soluplus®: qualitative and quantitative analysis of piroxicam recrystallization during storage. Int J Pharm 486(1–2):306–314. doi: 10.1016/j.ijpharm.2015.03.079 CrossRefPubMedGoogle Scholar
  75. Ma H, Choi DS, Zhang Y-E, Tian H, Shah N, Chokshi HP (2013) Evaluation on the drug–polymer mixing status in amorphous solid dispersions at the early stage formulation and process development. J Pharm Innov 8(3):163–174. doi: 10.1007/s12247-013-9156-z CrossRefGoogle Scholar
  76. Maniruzzaman M, Snowden MJ, Bradely MS, Douroumis D (2015) Studies of intermolecular interactions in solid dispersions using advanced surface chemical analysis. RSC Adv 5(91):74212–74219. doi: 10.1039/C5RA13176F CrossRefGoogle Scholar
  77. Marsac PJ, Li T, Taylor LS (2009) Estimation of drug-polymer miscibility and solubility in amorphous solid dispersions using experimentally determined interaction parameters. Pharm Res 26(1):139–151. doi: 10.1007/s11095-008-9721-1 CrossRefPubMedGoogle Scholar
  78. Marsac PJ, Rumondor AC, Nivens DE, Kestur US, Stanciu L, Taylor LS (2010) Effect of temperature and moisture on the miscibility of amorphous dispersions of felodipine and poly(vinyl pyrrolidone). J Pharm Sci 99(1):169–185. doi: 10.1002/jps.21809 CrossRefPubMedGoogle Scholar
  79. Meeus J, Scurr DJ, Chen X, Amssoms K, Davies MC, Roberts CJ, Van den Mooter G (2014). Combination of (M) DSC and surface analysis to study the phase behaviour and drug distribution of ternary solid dispersions. Pharm Res 32(4):1407–1416CrossRefGoogle Scholar
  80. Mistry P, Mohapatra S, Gopinath T, Vogt FG, Suryanarayanan R (2015) Role of the strength of drug–polymer interactions on the molecular mobility and crystallization inhibition in ketoconazole solid dispersions. Mol Pharm. doi: 10.1021/acs.molpharmaceut.5b00333 CrossRefPubMedGoogle Scholar
  81. Moffat J, Qi S, Craig DM (2014) Spatial characterization of hot melt extruded dispersion systems using thermal atomic force microscopy methods: the effects of processing parameters on phase separation. Pharm Res 31(7):1744–1752. doi: 10.1007/s11095-013-1279-x CrossRefPubMedPubMedCentralGoogle Scholar
  82. Newman A, Engers D, Bates S, Ivanisevic I, Kelly RC, Zografi G (2008) Characterization of amorphous API: polymer mixtures using X-ray powder diffraction. J Pharm Sci 97(11):4840–4856. doi: 10.1002/jps.21352 CrossRefPubMedGoogle Scholar
  83. Newman JA, Schmitt PD, Toth SJ, Deng F, Zhang S, Simpson GJ (2015) Parts per million powder X-ray diffraction. Anal Chem 87(21):10950–10955. doi: 10.1021/acs.analchem.5b02758 CrossRefPubMedPubMedCentralGoogle Scholar
  84. Nichols G (2006) Light microscopy. In: Hilfiker R (ed) Polymorphism, Wiley, Weinheim, pp 167–209CrossRefGoogle Scholar
  85. Nollenberger K, Gryczke A, Meier C, Dressman J, Schmidt MU, Brühne S (2008) Pair distribution function X-ray analysis explains dissolution characteristics of felodipine melt extrusion products. J Pharm Sci 98(4):1476–1486. doi: 10.1002/jps.21534 CrossRefGoogle Scholar
  86. Nunes C, Mahendrasingam A, Suryanarayanan R (2005) Quantification of crystallinity in substantially amorphous materials by synchrotron X-ray powder diffractometry. Pharm Res 22(11):1942–1953. doi: 10.1007/s11095-005-7626-9 CrossRefPubMedGoogle Scholar
  87. Østergaard J, Lenke J, Jensen SS, Sun Y, Ye F (2014) UV imaging for in vitro dissolution and release studies: initial experiences. Dissolut Technol 21(4):27–38CrossRefGoogle Scholar
  88. Paudel A, Geppi M, Van den Mooter G (2014a) Structural and dynamic properties of amorphous solid dispersions: the role of solid-state nuclear magnetic resonance spectroscopy and relaxometry. J Pharm Sci 103(9):2635–2662. doi: 10.1002/jps.23966 CrossRefPubMedGoogle Scholar
  89. Paudel A, Meeus J, Mooter GVD (2014b) Structural characterization of amorphous solid dispersions. In: Shah N, Sandhu H, Choi DS, Chokshi H, Malick AW (eds) Amorphous solid dispersions: theory and practice, Springer, New York, pp 421–485Google Scholar
  90. Paudel A, Raijada D, Rantanen J (2015) Raman spectroscopy in pharmaceutical product design. Adv Drug Deliv Rev 89:3–20. doi: 10.1016/j.addr.2015.04.003 CrossRefPubMedGoogle Scholar
  91. Pham TN, Watson SA, Edwards AJ, Chavda M, Clawson JS, Strohmeier M, Vogt FG (2010) Analysis of amorphous solid dispersions using 2D solid-state NMR and 1H T1 relaxation measurements. Mol Pharm 7(5):1667–1691. doi: 10.1021/mp100205g CrossRefPubMedGoogle Scholar
  92. Pili B, Bourgaux C, Amenitsch H, Keller G, Lepêtre-Mouelhi S, Desmaële D, Couvreur P, Ollivon M (2010) Interaction of a new anticancer prodrug, gemcitabine–squalene, with a model membrane: coupled DSC and XRD study. Biochim Biophys Acta 1798(8):1522–1532. doi: 10.1016/j.bbamem.2010.04.011 CrossRefPubMedGoogle Scholar
  93. Priemel PA, Laitinen R, Grohganz H, Rades T, Strachan CJ (2013) In situ amorphisation of indomethacin with Eudragit (R) E during dissolution. Eur J Pharm Biopharm 85(3):1259–1265. doi: 10.1016/j.ejpb.2013.09.010 CrossRefPubMedGoogle Scholar
  94. Pudlas M, Kyeremateng SO, Williams LAM, Kimber JA, van Lishaut H, Kazarian SG, Woehrle GH (2015) Analyzing the impact of different excipients on drug release behavior in hot-melt extrusion formulations using FTIR spectroscopic imaging. Eur J Pharm Sci 67:21–31. doi: 10.1016/j.ejps.2014.10.012 CrossRefPubMedGoogle Scholar
  95. Punčochová K, Ewing AV, Gajdošová M, Pekárek T, Beránek J, Kazarian SG, Štěpánek F (2016) The combined use of imaging approaches to assess drug release from multicomponent solid dispersions. Pharm Res 34(5):990–1001CrossRefGoogle Scholar
  96. Qi S, Belton P, Nollenberger K, Gryczke A, Craig DQM (2011) Compositional analysis of low quantities of phase separation in hot-melt-extruded solid dispersions: a combined atomic force microscopy, photothermal fourier-transform infrared microspectroscopy, and localised thermal analysis approach. Pharm Res 28(9):2311–2326. doi: 10.1007/s11095-011-0461-2 CrossRefPubMedGoogle Scholar
  97. Qi S, Moffat JG, Yang Z (2013) Early stage phase separation in pharmaceutical solid dispersion thin films under high humidity: improved spatial understanding using probe-based thermal and spectroscopic nanocharacterization methods. Mol Pharm 10(3):918–930. doi: 10.1021/mp300557q CrossRefPubMedGoogle Scholar
  98. Qian F, Huang J, Zhu Q, Haddadin R, Gawel J, Garmise R, Hussain M (2010) Is a distinctive single Tg a reliable indicator for the homogeneity of amorphous solid dispersion? Int J Pharm 395(1–2):232–235CrossRefGoogle Scholar
  99. Raina SA, Alonzo DE, Zhang GG, Gao Y, Taylor LS (2014) Impact of polymers on the crystallization and phase transition kinetics of amorphous nifedipine during dissolution in aqueous media. Mol Pharm 11(10):3565–3576. doi: 10.1021/mp500333v CrossRefPubMedGoogle Scholar
  100. Raina S, Alonzo D, Zhang GZ, Gao Y, Taylor L (2015). Using environment-sensitive fluorescent probes to characterize liquid–liquid phase separation in supersaturated solutions of poorly water soluble compounds. Pharm Res. doi: 10.1007/s11095-015-1725-z CrossRefPubMedGoogle Scholar
  101. Ricarte RG, Lodge TP, Hillmyer MA (2015) Detection of pharmaceutical drug crystallites in solid dispersions by transmission electron microscopy. Mol Pharm 12(3):983–990. doi: 10.1021/mp500682x CrossRefPubMedGoogle Scholar
  102. Righetti MC, Cardelli C, Scalari M, Tombari E, Conti G (2002) Thermodynamics of mixing of poly(vinyl chloride) and poly(ethylene-co-vinyl acetate). Polymer 43(18):5035–5042. doi: 10.1016/S0032-3861(02)00323-3 CrossRefGoogle Scholar
  103. Rodrigues AC, Viciosa MT, Danède F, Affouard F, Correia NT (2014) Molecular mobility of amorphous S-flurbiprofen: a dielectric relaxation spectroscopy approach. Mol Pharm 11(1):112–130. doi: 10.1021/mp4002188 CrossRefPubMedGoogle Scholar
  104. Rumondor AC, Taylor LS (2010) Effect of polymer hygroscopicity on the phase behavior of amorphous solid dispersions in the presence of moisture. Mol Pharm 7(2):477–490. doi: 10.1021/mp9002283 CrossRefPubMedGoogle Scholar
  105. Rumondor AC, Marsac PJ, Stanford LA, Taylor LS (2009a) Phase behavior of poly(vinylpyrrolidone) containing amorphous solid dispersions in the presence of moisture. Mol Pharm 6(5):1492–1505. doi: 10.1021/mp900050c CrossRefPubMedGoogle Scholar
  106. Rumondor AC, Stanford LA, Taylor LS (2009b) Effects of polymer type and storage relative humidity on the kinetics of felodipine crystallization from amorphous solid dispersions. Pharm Res 26(12):2599–2606. doi: 10.1007/s11095-009-9974-3 CrossRefPubMedGoogle Scholar
  107. Rumondor ACF, Ivanisevic I, Bates S, Alonzo DE, Taylor LS (2009c) Evaluation of drug-polymer miscibility in amorphous solid dispersion systems. Pharm Res 26(11):2523–2534. doi: 10.1007/s11095-009-9970-7 CrossRefPubMedGoogle Scholar
  108. Rumondor ACF, Marsac PJ, Stanford LA, Taylor LS (2009d) Phase behavior of poly(vinylpyrrolidone) containing amorphous solid dispersions in the presence of moisture. Mol Pharm 6(5):1492–1505. doi: 10.1021/mp900050c CrossRefPubMedGoogle Scholar
  109. Saerens L, Vervaet C, Remon JP, De Beer T (2014) Process monitoring and visualization solutions for hot-melt extrusion: a review. J Pharm Pharmcol 66(2):180–203. doi: 10.1111/jphp.12123 CrossRefGoogle Scholar
  110. Shah B, Kakumanu VK, Bansal AK (2006) Analytical techniques for quantification of amorphous/crystalline phases in pharmaceutical solids. J Pharm Sci 95(8):1641–1665. doi: 10.1002/jps.20644 CrossRefPubMedGoogle Scholar
  111. Shen Y-C (2011) Terahertz pulsed spectroscopy and imaging for pharmaceutical applications: a review. Int J Pharm 417(1–2):48–60. doi: 10.1016/j.ijpharm.2011.01.012 CrossRefPubMedGoogle Scholar
  112. Sibik J, Zeitler JA (2016) Direct measurement of molecular mobility and crystallisation of amorphous pharmaceuticals using terahertz spectroscopy. Adv Drug Deliv Rev 100:147–157. doi: 10.1016/j.addr.2015.12.021 CrossRefPubMedGoogle Scholar
  113. Sibik J, Löbmann K, Rades T, Zeitler JA (2015) Predicting crystallization of amorphous drugs with terahertz spectroscopy. Mol Pharm 12(8):3062–3068. doi: 10.1021/acs.molpharmaceut.5b00330 CrossRefPubMedGoogle Scholar
  114. Sitterberg J, Özcetin A, Ehrhardt C, Bakowsky U (2010) Utilising atomic force microscopy for the characterisation of nanoscale drug delivery systems. Eur J Pharm Biopharm 74(1):2–13. doi: 10.1016/j.ejpb.2009.09.005 CrossRefPubMedGoogle Scholar
  115. Six K, Murphy J, Weuts I, Craig DM, Verreck G, Peeters J, Brewster M, Van den Mooter G (2003) Identification of phase separation in solid dispersions of itraconazole and Eudragit® E100 using microthermal analysis. Pharm Res 20(1):135–138. doi: 10.1023/A:1022219429708 CrossRefPubMedGoogle Scholar
  116. Song Y, Yang X, Chen X, Nie H, Byrn S, Lubach JW (2015) Investigation of drug–excipient interactions in lapatinib amorphous solid dispersions using solid-state NMR spectroscopy. Mol Pharm 12(3):857–866. doi: 10.1021/mp500692a CrossRefPubMedGoogle Scholar
  117. Song Y, Zemlyanov D, Chen X, Nie H, Su Z, Fang K, Yang X, Smith D, Byrn S, Lubach JW (2016a) Acid-base interactions of polystyrene sulfonic acid in amorphous solid dispersions using a combined UV/FTIR/XPS/ssNMR study. Mol Pharm 13(2):483–492. doi: 10.1021/acs.molpharmaceut.5b00708 CrossRefPubMedGoogle Scholar
  118. Song Y, Zemlyanov D, Chen X, Su ZY, Nie HC, Lubach JW, Smith D, Byrn S, Pinal R (2016b) Acid-base interactions in amorphous solid dispersions of lumefantrine prepared by spray-drying and hot-melt extrusion using X-ray photoelectron spectroscopy. Int J Pharm 514(2):456–464. doi: 10.1016/j.ijpharm.2016.06.126 CrossRefPubMedGoogle Scholar
  119. Stevens JS, Byard SJ, Seaton CC, Sadiq G, Davey RJ, Schroeder SLM (2014) Proton transfer and hydrogen bonding in the organic solid state: a combined XRD/XPS/ssNMR study of 17 organic acid-base complexes. Phys Chem Chem Phys 16(3):1150–1160. doi: 10.1039/C3CP53907E CrossRefPubMedGoogle Scholar
  120. Sun Y, Østergaard J (2016). Application of UV imaging in formulation development. Pharm Res. doi: 10.1007/s11095-016-2047-5 CrossRefPubMedPubMedCentralGoogle Scholar
  121. Takeuchi I, Shimakura K, Kuroda H, Nakajima T, Goto S, Makino K (2015) Estimation of crystallinity of nifedipine–polyvinylpyrrolidone solid dispersion by usage of terahertz time-domain spectroscopy and of X-ray powder diffractometer. J Pharm Sci 104(12):4307–4313. doi: 10.1002/jps.24671 CrossRefPubMedGoogle Scholar
  122. Tao J, Sun Y, Zhang GGZ, Yu L (2009) Solubility of small-molecule crystals in polymers: d-mannitol in PVP, indomethacin in PVP/VA, and nifedipine in PVP/VA. Pharm Res 26(4):855–864. doi: 10.1007/s11095-008-9784-z CrossRefPubMedGoogle Scholar
  123. Taylor LS, Zhang GGZ (2016) Physical chemistry of supersaturated solutions and implications for oral absorption. Adv Drug Deliv Rev. doi: 10.1016/j.addr.2016.03.006 CrossRefPubMedGoogle Scholar
  124. Telang C, Mujumdar S, Mathew M (2009) Improved physical stability of amorphous state through acid base interactions. J Pharm Sci 98(6):2149–2159. doi: 10.1002/jps.21584 CrossRefPubMedGoogle Scholar
  125. Thakral S, Terban MW, Thakral NK, Suryanarayanan R (2016) Recent advances in the characterization of amorphous pharmaceuticals by X-ray diffractometry. Adv Drug Deliv Rev 100:183–193. doi: 10.1016/j.addr.2015.12.013 CrossRefPubMedGoogle Scholar
  126. Tian B, Tang X, Taylor LS (2016) Investigating the correlation between miscibility and physical stability of amorphous solid dispersions using fluorescence-based techniques. Mol Pharm 13(11):3988–4000. doi: 10.1021/acs.molpharmaceut.6b00803 CrossRefPubMedGoogle Scholar
  127. Tobyn M, Brown J, Dennis AB, Fakes M, Gao Q, Gamble J, Khimyak YZ, McGeorge G, Patel C, Sinclair W, Timmins P, Yin S (2009) Amorphous drug–PVP dispersions: application of theoretical, thermal and spectroscopic analytical techniques to the study of a molecule with intermolecular bonds in both the crystalline and pure amorphous state. J Pharm Sci 98(9):3456–3468. doi: 10.1002/jps.21738 CrossRefPubMedGoogle Scholar
  128. Tong P, Taylor LS, Zografi G (2002) Influence of alkali metal counterions on the glass transition temperature of amorphous indomethacin salts. Pharm Res 19(5):649–654. doi: 10.1023/a:1015310213887 CrossRefPubMedGoogle Scholar
  129. Tres F, Treacher K, Booth J, Hughes LP, Wren SAC, Aylott JW, Burley JC (2014) Real time Raman imaging to understand dissolution performance of amorphous solid dispersions. J Controlled Release 188:53–60. doi: 10.1016/j.jconrel.2014.05.061 CrossRefGoogle Scholar
  130. Tres F, Coombes SR, Phillips AR, Hughes LP, Wren SA, Aylott JW, Burley JC (2015) Investigating the dissolution performance of amorphous solid dispersions using magnetic resonance imaging and proton NMR. Molecules 20(9):16404–16418. doi: 10.3390/molecules200916404 CrossRefPubMedGoogle Scholar
  131. Turner YTA, Roberts CJ, Davies MC (2007) Scanning probe microscopy in the field of drug delivery. Adv Drug Deliv Rev 59(14):1453–1473. doi: 10.1016/j.addr.2007.08.020 CrossRefPubMedGoogle Scholar
  132. Van Eerdenbrugh B, Taylor LS (2010) Small scale screening to determine the ability of different polymers to inhibit drug crystallization upon rapid solvent evaporation. Mol Pharm 7(4):1328–1337. doi: 10.1021/mp1001153 CrossRefPubMedGoogle Scholar
  133. Van Eerdenbrugh B, Lo M, Kjoller K, Marcott C, Taylor LS (2012) Nanoscale mid-infrared imaging of phase separation in a drug-polymer blend. J Pharm Sci 101(6):2066–2073. doi: 10.1002/jps.23099 CrossRefPubMedGoogle Scholar
  134. Vasanthavada M, Tong WQ, Joshi Y, Kislalioglu MS (2004) Phase behavior of amorphous molecular dispersions I: determination of the degree and mechanism of solid solubility. Pharm Res 21(9):1598–1606CrossRefGoogle Scholar
  135. Vasanthavada M, Tong WQ, Joshi Y, Kislalioglu MS (2005) Phase behavior of amorphous molecular dispersions - II: role of hydrogen bonding in solid solubility and phase separation kinetics. Pharm Res 22(3):440–448. doi: 10.1007/s11095-004-1882-y CrossRefPubMedGoogle Scholar
  136. Vasconcelos T, Marques S, Das Neves J, Sarmento B (2016) Amorphous solid dispersions: rational selection of a manufacturing process. Adv Drug Deliv Rev 100:85–101CrossRefGoogle Scholar
  137. Vogt FG (2015) Solid state characterization of amorphous solid dispersions. Pharm Amorph Solid Dispers. doi: 10.1002/9780470571224.pse525 CrossRefGoogle Scholar
  138. Wan F, Bohr A, Maltesen M, Bjerregaard S, Foged C, Rantanen J, Yang M (2013) Critical solvent properties affecting the particle formation process and characteristics of celecoxib-loaded PLGA microparticles via spray-drying. Pharm Res 30(4):1065–1076. doi: 10.1007/s11095-012-0943-x CrossRefPubMedGoogle Scholar
  139. Wartewig S, Neubert RHH (2005) Pharmaceutical applications of Mid-IR and Raman spectroscopy. Adv Drug Deliv Rev 57(8):1144–1170. doi: 10.1016/j.addr.2005.01.022 CrossRefPubMedGoogle Scholar
  140. Weuts I, Kempen D, Decorte A, Verreck G, Peeters J, Brewster M, Van den Mooter G (2004) Phase behaviour analysis of solid dispersions of loperamide and two structurally related compounds with the polymers PVP-K30 and PVP-VA64. Eur J Pharm Sci 22(5):375–385. doi: 10.1016/j.ejps.2004.04.002 CrossRefPubMedGoogle Scholar
  141. Weuts I, Kempen D, Verreck G, Peeters J, Brewster M, Blaton N, Van den Mooter G (2005) Salt formation in solid dispersions consisting of polyacrylic acid as a carrier and three basic model compounds resulting in very high glass transition temperatures and constant dissolution properties upon storage. Eur J Pharm Sci 25(4–5):387–393. doi: 10.1016/j.ejps.2005.04.011 CrossRefPubMedGoogle Scholar
  142. Williams RO III, Watts AB, Miller DA (2011) Formulating poorly water soluble drugs. Springer Science & Business Media, New YorkGoogle Scholar
  143. Wong J, D’Sa D, Foley M, Chan JG, Chan H-K (2014) NanoXCT: a novel technique to probe the internal architecture of pharmaceutical particles. Pharm Res 31(11):3085–3094. doi: 10.1007/s11095-014-1401-8 CrossRefPubMedGoogle Scholar
  144. Wu T, Lin SY, Lin HL, Huang YT (2011) Simultaneous DSC-FTIR microspectroscopy used to screen and detect the co-crystal formation in real time. Bioorg Med Chem Lett 10(21):3148–3151CrossRefGoogle Scholar
  145. Ye X, Patil H, Feng X, Tiwari RV, Lu J, Gryczke A, Kolter K, Langley N, Majumdar S, Neupane D, Mishra SR, Repka MA (2016) Conjugation of hot-melt extrusion with high-pressure homogenization: a novel method of continuously preparing nanocrystal solid dispersions. AAPS PharmSciTech 17(1):78–88. doi: 10.1208/s12249-015-0389-7 CrossRefPubMedGoogle Scholar
  146. Young CA, Goodwin AL (2011) Applications of pair distribution function methods to contemporary problems in materials chemistry. J Mater Chem 21(18):6464–6476. doi: 10.1039/C0JM04415F CrossRefGoogle Scholar
  147. Yu L (2001) Amorphous pharmaceutical solids: preparation, characterization and stabilization. Adv Drug Deliv Rev 48(1):27–42CrossRefGoogle Scholar
  148. Yu L (2016) Surface mobility of molecular glasses and its importance in physical stability. Adv Drug Deliv Rev 100:3–9. doi: 10.1016/j.addr.2016.01.005 CrossRefPubMedGoogle Scholar
  149. Zeitler JA, Taday PF, Pepper M, Rades T (2007) Relaxation and crystallization of amorphous carbamazepine studied by terahertz pulsed spectroscopy. J Pharm Sci 96(10):2703–2709. doi: 10.1002/jps.20908 CrossRefPubMedGoogle Scholar
  150. Zhang J, Bunker M, Chen X, Parker AP, Patel N, Roberts CJ (2009) Nanoscale thermal analysis of pharmaceutical solid dispersions. Int J Pharm 380(1–2):170–173. doi: 10.1016/j.ijpharm.2009.07.003 CrossRefPubMedGoogle Scholar
  151. Zhu Q, Toth SJ, Simpson GJ, Hsu HY, Taylor LS, Harris MT (2013) Crystallization and dissolution behavior of naproxen/polyethylene glycol solid dispersions. J Phys Chem B 117(5):1494–1500. doi: 10.1021/jp3106716 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© The Korean Society of Pharmaceutical Sciences and Technology 2017

Authors and Affiliations

  1. 1.College of PharmacyUniversity of Texas at AustinAustinUSA
  2. 2.Department of Pharmaceutics and Drug DeliveryThe University of MississippiUniversityUSA

Personalised recommendations