Skip to main content
SpringerLink
Log in

Structured Development Approach for Amorphous Systems

  • Chapter
  • First Online:
Formulating Poorly Water Soluble Drugs

Part of the book series: AAPS Advances in the Pharmaceutical Sciences Series ((AAPS,volume 22))

Abstract

A structured development approach is presented to guide the development of stable and commercially viable polymer based amorphous formulations. The proposed approach should not only enable the delivery of poorly soluble drugs but also help to reduce the API needs, reduce in vivo screening, minimize risks for late-stage development, and should ensure consistent quality. During initial assessment, a guided evaluation of the physicochemical properties of the API helps to assess the degree of difficulty for the development. A range of tests including in silico evaluation, high-throughput screening assays, and miniaturized screening tools provide a road map for selecting the appropriate polymer, drug loading, and suitable manufacturing process. A dedicated section provides a review of the characterization tools to assess and quantify the crystallinity, understanding the phase behavior of amorphous solid dispersions, and designing the in vitro dissolution methods. Finally, a reference chart is provided that summarizes the key concepts proposed as part of the structured development approach that can serve as a blueprint for the development of amorphous formulations. The current authors would like to thank and acknowledge the significant contribution of the previous authors of this chapter from the first edition. This current second edition chapter is a revision and update of the original authors’ work.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 139.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 179.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Acartürk F, Kislal Ö et al (1992) The effect of some natural polymers on the solubility and dissolution characteristics of nifedipine. Int J Pharm 85(1–3):1–6

    Article  Google Scholar 

  • Adrjanowicz K, Kaminski K et al (2010) Dielectric relaxation studies and dissolution behavior of amorphous verapamil hydrochloride. J Pharm Sci 99(2):828–839

    Article  CAS  PubMed  Google Scholar 

  • Agrawal AM, Dudhedia MS et al (2016) Hot melt extrusion: development of an amorphous solid dispersion for an insoluble drug from mini-scale to clinical scale. AAPS PharmSciTech 17(1):133–147

    Article  CAS  PubMed  Google Scholar 

  • Albano AA, Phuapradit W et al (2002) Stable complexes of poorly soluble compounds in ionic polymers. US Patent Office, United States of America, F. Hoffmann-La Roche Ltd, 7

    Google Scholar 

  • Albers J (2008) Hot-melt extrusion with poorly soluble drugs. Heinrich-Heine-University, Düsseldorf

    Google Scholar 

  • Alhalaweh A, Alzghoul A et al (2015) Physical stability of drugs after storage above and below the glass transition temperature: Relationship to glass-forming ability. Int J Pharm 495(1):312–317

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Al-Obaidi H, Brocchini S et al (2009) Anomalous properties of spray dried solid dispersions. J Pharm Sci 98(12):4724–4737

    Article  CAS  PubMed  Google Scholar 

  • Aso Y, Yoshioka S (2006) Molecular mobility of nifedipine–PVP and phenobarbital–PVP solid dispersions as measured by 13 C-NMR spin-lattice relaxation time. J Pharm Sci 95(2):318–325

    Article  CAS  PubMed  Google Scholar 

  • Aso Y, Yoshioka S et al (2002) Effect of water on the molecular mobility of sucrose and poly(vinylpyrrolidone) in a colyophilized formulation as measured by 13 C-NMR relaxation time. Chem Pharm Bull 50(6):822–826

    Article  CAS  PubMed  Google Scholar 

  • Baghel S, Cathcart H et al (2016) Polymeric amorphous solid dispersions: a review of amorphization, crystallization, stabilization, solid-state characterization, and aqueous solubilization of biopharmaceutical classification system class II drugs. J Pharm Sci. doi:10.1016/j.xphs.2015.10.008

    PubMed  Google Scholar 

  • Baird JA, Van Eerdenburgh B et al (2010) A classification system to assess the crystallization tendency of organic molecules from undercooled melts. J Pharm Sci 99(9):3787–3806

    Article  CAS  PubMed  Google Scholar 

  • Barillaro V, Pescarmona PP et al (2008) High-throughput study of phenytoin solid dispersions: formulation using an automated solvent casting method, dissolution testing, and scaling-up. J Comb Chem 10(5):637–643

    Article  CAS  PubMed  Google Scholar 

  • Bates S, Zografi G et al (2006) Analysis of amorphous and nanocrystalline solids from their X-ray diffraction patterns. Pharm Res 23(10):2333–2349, Epub 2006 Sep 22

    Article  CAS  PubMed  Google Scholar 

  • Breitenbach J (2002) Melt extrusion: from process to drug delivery technology. Eur J Pharm Biopharm 54(2):107–117

    Article  CAS  PubMed  Google Scholar 

  • Chan KLA, Kazarian SG (2004) FTIR spectroscopic imaging of dissolution of a solid dispersion of nifedipine in poly(ethylene glycol). Mol Pharm 1(4):331–335

    Article  CAS  PubMed  Google Scholar 

  • Chiang P-C, Ran Y et al (2012) Evaluation of drug load and polymer by using a 96-well plate vacuum dry system for amorphous solid dispersion drug delivery. AAPS PharmSciTech 13(2):713–722

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chiou WL, Riegelman S (1971) Pharmaceutical applications of solid dispersion systems. J Pharm Sci 60(9):1281–1302

    Article  CAS  PubMed  Google Scholar 

  • Chiou WL, Riegelmann S (1970) Oral absorption of griseofulvin in dogs: increased absorption via solid dispersion in polyethylene glycol 6000. J Pharm Sci 59:937–942

    Article  CAS  PubMed  Google Scholar 

  • Chokshi RJ, Sandhu HK et al (2005) Characterization of physico-mechanical properties of indomethacin and polymers to assess their suitability for hot-melt extrusion processs as a means to manufacture solid dispersion/solution. J Pharm Sci 94(11):2463–2474

    Article  CAS  PubMed  Google Scholar 

  • Chokshi RJ, Shah NH et al (2008) Stabilization of low glass transition temperature indomethacin formulations: impact of polymer-type and its concentration. J Pharm Sci 97(6):2286–2298

    Article  CAS  PubMed  Google Scholar 

  • Corrigan OI, Holohan EM et al (1985) Physicochemical properties of indomethacin and related compounds co-spray dried with polyvinylpyrrolidone. Drug Dev Ind Pharm 11(2–3):677–695

    Article  CAS  Google Scholar 

  • Crowley MM, Zhang F et al (2007) Pharmaceutical applications of hot-melt extrusion: part I. Drug Dev Ind Pharm 33(9):909–926

    Article  CAS  PubMed  Google Scholar 

  • Curatolo W, Nightingale J et al (2009) Utility of hydroxypropylmethylcellulose acetate succinate (HPMC-AS) for initiation and maintenance of drug supersaturation in the GI milieu. Pharm Res 26(6):1419–1431

    Article  CAS  PubMed  Google Scholar 

  • De Maesschalk R, Stokbroekx S et al (2010) Development of a 96-well plate dissolution method for screening solid dispersions: Comparison to classical USP methods and its use in predicting oral bioavailability in animals. In: AAPS annual meeting and exposition. Ernest N. Morial Convention Center, New Orleans

    Google Scholar 

  • Deng W, Majumdar S et al (2013) Stabilization of fenofibrate in low molecular weight hydroxypropylcellulose matrices produced by hot-melt extrusion. Drug Dev Ind Pharm 39(2):290–298

    Article  CAS  PubMed  Google Scholar 

  • DiNunzio JC, Miller DA et al (2008) Amorphous compositions using concentration enhancing polymers for improved bioavailability of itraconazole. Mol Pharm 5(6):968–980

    Article  CAS  PubMed  Google Scholar 

  • Dobry DE, Settell DM et al (2009) A model-based methodology for spray-drying process development. J Pharm Innov 4(3):133–142

    Article  PubMed  PubMed Central  Google Scholar 

  • Doherty C, York P (1987) Mechanisms of dissolution of frusemide PVP solid dispersions. Int J Pharm 34(3):197–205

    Article  CAS  Google Scholar 

  • Engers D, Teng J et al (2010) A solid-state approach to enable early development compounds: selection and animal bioavailability studies of an itraconazole amorphous solid dispersion. J Pharm Sci 99(9):3901–3922

    Article  CAS  PubMed  Google Scholar 

  • Feng J, Xu L et al (2012) Evaluation of polymer carriers with regard to the bioavailability enhancement of bifendate solid dispersions prepared by hot-melt extrusion. Drug Dev Ind Pharm 38(6):735–743

    Article  CAS  PubMed  Google Scholar 

  • Forster A, Hempenstall J et al (2001a) The potential of small-scale fusion experiments and the Gordon-Taylor equation to predict the suitability of drug/polymer blends for melt extrusion. Drug Dev Ind Pharm 27(6):549–560

    Google Scholar 

  • Forster A, Hempenstall J et al (2001b) Selection of excipients for melt extrusion with two poorly water-soluble drugs by solubility parameter calculation and thermal analysis. Int J Pharm 226(1–2):147–161

    Article  CAS  PubMed  Google Scholar 

  • Friesen DT, Shanker R et al (2008) Hydroxypropyl methylcellulose acetate succinate-based spray-dried dispersions: an overview. Mol Pharm 5(6):1003–1019

    Article  CAS  PubMed  Google Scholar 

  • Gil M, Vicente J, Gaspar F (2010) Scale-up methodology for pharmaceutical spray drying. Chem Today 28(4):18–22

    CAS  Google Scholar 

  • Gordon M, Taylor JS (1952) Ideal copolymers and the second-order transitions of synthetic rubbers I. Noncrystalline copolymers. J Appl Chem 2:493–500

    Article  CAS  Google Scholar 

  • Greenhalgh DJ, Williams AC et al (1999) Solubility parameters as predictors of miscibility in solid dispersions. J Pharm Sci 88(11):1182–1190

    Article  CAS  PubMed  Google Scholar 

  • Gupta P, Kakumanu VK et al (2004) Stability and solubility of celecoxib-PVP amorphous dispersions: a molecular perspective. Pharm Res 21:1762–1769

    Google Scholar 

  • Gupta J, Nunes C et al (2011) Prediction of solubility parameters and miscibility of pharmaceutical compounds by molecular dynamics simulations. J Phys Chem B 115(9):2014–2023

    Article  CAS  PubMed  Google Scholar 

  • Guzmán HR, Tawa M et al (2007) Combined use of crystalline salt forms and precipitation inhibitors to improve oral absorption of celecoxib from solid oral formulations. J Pharm Sci 96(10):2686–2702

    Article  PubMed  CAS  Google Scholar 

  • Hadida S, Van Goor F et al (2014) Case history: Kalydeco® (VX-770, Ivacaftor), a CFTR potentiator for the treatment of patients with cystic fibrosis and the G551D-CFTR mutation. Annu Rep Med Chem 49:383–398

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Hancock BC, York P et al (1997) The use of solubility parameters in pharmaceutical dosage form design. Int J Pharm 148:1–21

    Article  CAS  Google Scholar 

  • He Y, Ho C (2015) Amorphous solid dispersions: utilization and challenges in drug discovery and development. J Pharm Sci 104(10):3237–3258

    Article  CAS  PubMed  Google Scholar 

  • Hu Q, Choi DS et al (2013) Highly efficient miniaturized coprecipitation screening (MiCoS) for amorphous solid dispersion formulation development. Int J Pharm 450:53–62

    Article  CAS  PubMed  Google Scholar 

  • Huang Y, Dai W-G (2014) Fundamental aspects of solid dispersion technology for poorly soluble drugs. Acta Pharm Sin B 4(1):18–25

    Article  PubMed  Google Scholar 

  • Huang J, Wigent RJ et al (2008) Drug-polymer interaction and its significance on the physical stability of nifedipine amorphous dispersion in microparticles of an ammonio methacrylate copolymer and ethylcellulose binary blend. J Pharm Sci 97(1):251–262

    Article  CAS  PubMed  Google Scholar 

  • Hugo M, Kunath K et al (2013) Selection of excipient, solvent and packaging to optimize the performance of spray-dried formulations: case example fenofibrate. Drug Dev Ind Pharm 39(2):402–412

    Article  CAS  PubMed  Google Scholar 

  • Islam M, Scoutaris N et al (2015) Implementation of transmission NIR as a PAT tool for monitoring drug transformation during HME processing. Eur J Pharm Biopharm 96:106–116

    Article  CAS  PubMed  Google Scholar 

  • Jackson MJ, Kestur US et al (2016) Dissolution of danazol amorphous solid dispersions: supersaturation and phase behavior as a function of drug loading and polymer type. Mol Pharm 13(1):223–231

    Article  CAS  PubMed  Google Scholar 

  • Janssens S, Guy VM (2010) Review: physical chemistry of solid dispersions. J Pharm Pharmacol 12:15

    Google Scholar 

  • Janssens S, Nagels S et al (2008) Formulation and characterization of ternary solid dispersions made up of Itraconazole and two excipients, TPGS 1000 and PVP VA 64, that were selected based on supersaturation screening study. Eur J Pharm Biopharm 69:158–166

    Article  CAS  PubMed  Google Scholar 

  • Janssens S, De Zeure A et al (2010) Influence of preparation methods on solid state supersaturation of amorphous solid dispersions: a case study with itraconazole and eudragit E100. Pharm Res 27(5):775–785

    Article  CAS  PubMed  Google Scholar 

  • Jensen KT, Blaabjerg LI et al (2015) Preparation and characterization of spray-dried co-amorphous drug–amino acid salts. J Pharm Pharmacol. doi:10.1111/jphp.12458

    PubMed  Google Scholar 

  • Jijun F, Lili Z et al (2010) Stable nimodipine tablets with high bioavailability containing NM-SD prepared by hot-melt extrusion. Powder Technol 204:214–221

    Article  CAS  Google Scholar 

  • Just S, Sievert F et al (2013) Improved group contribution parameter set for the application of solubility parameters to melt extrusion. Eur J Pharm Biopharm 85(3):1191–1199

    Article  CAS  PubMed  Google Scholar 

  • Kalb O, Page S et al (2013) Scale-up of solid dispersions. Encyclopedia of pharmaceutical science and technology, fourth edition: doi: 10.1081/E-EPT4-120050349

  • Kaushal AM, Chakraborti AK et al (2008) FTIR studies on differential intermolecular association in crystalline and amorphous states of structurally related non-steroidal anti-inflammatory drugs. Mol Pharm 5(6):937–945

    Article  CAS  PubMed  Google Scholar 

  • Kislalioglu MS, Khan MA et al (1991) Physical characterization and dissolution properties of ibuprofen: eudragit coprecipitates. J Pharm Sci 80(8):799–804

    Article  CAS  PubMed  Google Scholar 

  • Knopp MM, Tajber L et al (2015) Comparative study of different methods for the prediction of drug–polymer solubility. Mol Pharm 12:3408–3419

    Article  CAS  PubMed  Google Scholar 

  • Knopp MM, Olesen NE et al (2016) Statistical analysis of a method to predict drug–polymer miscibility. J Pharm Sci 105:362–367

    Article  CAS  PubMed  Google Scholar 

  • Konno H, Taylor LS (2006) Influence of different polymers on the crystallization tendency of molecularly dispersed amorphous felodipine. J Pharm Sci 95(12):2692–2705

    Article  CAS  PubMed  Google Scholar 

  • Konno H, Handa T et al (2008) Effect of polymer type on the dissolution profile of amorphous solid dispersions containing felodipine. Eur J Pharm Biopharm 70(2):493–499

    Article  CAS  PubMed  Google Scholar 

  • Kwong AD, Kauffman RS et al (2011) Discovery and development of telaprevir: an NS3-4A protease inhibitor for treating genotype 1 chronic hepatitis C virus. Nat Biotechnol 29(11):993–1003

    Article  CAS  PubMed  Google Scholar 

  • Lamm MS, DiNunzio J et al (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

    Article  CAS  PubMed  Google Scholar 

  • Lauer M, Grassmann O et al (2011) Atomic force microscopy-based screening of drug-excipient miscibility and stability of solid dispersions. Pharm Res 28(3):572–584

    Article  CAS  PubMed  Google Scholar 

  • Lauer M, Siam M et al (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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Law D, Schmitt EA et al (2004) Ritonavir-PEG 8000 amorphous solid dispersions: in vitro and in vivo evaluations. J Pharm Sci 93(3):563–570

    Article  CAS  PubMed  Google Scholar 

  • Lee T, Lee J (2003) Drug-carrier screening on a chip. Pharm Technol North Am 27(1):40–48

    CAS  Google Scholar 

  • Lemmer HJR, Liebenberg W (2013) Preparation and evaluation of metastable solid-state forms of lopinavir. Pharmazie 68:327–332

    CAS  PubMed  Google Scholar 

  • Lenz E, Jensen KT et al (2015) Solid-state properties and dissolution behaviour of tablets containing co-amorphous indomethacin–arginine. Eur J Pharm Biopharm 96:44–52

    Article  CAS  PubMed  Google Scholar 

  • Leuner C, Dressman J (2000) Improving drug solubility for oral delivery using solid dispersions. Eur J Pharm Biopharm 50(1):47–60

    Article  CAS  PubMed  Google Scholar 

  • Liu H, Taylor LS et al (2015) The role of polymers in oral bioavailability enhancement; a review. Polymer 77:399–415

    Article  CAS  Google Scholar 

  • Löbmann K, Grohganz H et al (2013) Amino acids as co-amorphous stabilizers for poorly water soluble drugs—part 1: preparation, stability and dissolution enhancement. Eur J Pharm Biopharm 85:873–881

    Google Scholar 

  • Loftsson T, Fririksdóttir H et al (1996) The effect of water-soluble polymers on aqueous solubility of drugs. Int J Pharm 127(2):293–296

    Article  CAS  Google Scholar 

  • Ma HM, Choi DS et al (2013) Evaluation on the drug–polymer mixing status in amorphous solid dispersions at the early stage formulation and process development. J Pharm Innov 8:163–174

    Article  Google Scholar 

  • Mahlin D, Bergström CAS (2013) Early drug development predictions of glass-forming ability and physical stability of drugs. Eur J Pharm Sci 49(2):323–332

    Article  CAS  PubMed  Google Scholar 

  • Marsac PJ, Konno H et al (2006) A comparison of the physical stability of amorphous felodipine and nifedipine systems. Pharm Res 23:2306–2316

    Article  CAS  PubMed  Google Scholar 

  • Marsac PJ, Konno H et al (2008) Recrystallization of nifedipine and felodipine from amorphous molecular-level solid dispersions containing poly(vinylpyrrolidone) and sorbed water. Pharm Res 25(3):647–656

    Article  CAS  PubMed  Google Scholar 

  • Marsac PJ, Rumondor ACF et al (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

    Article  CAS  PubMed  Google Scholar 

  • Martin C (2016) Twin screw extruders as continuous mixers for thermal processing: a technical and historical perspective. AAPS PharmSciTech 17(1):3–19

    Article  PubMed  Google Scholar 

  • Masters K (1991) Spray drying handbook, Longman scientific & technical. Wiley, Burnt Mill

    Google Scholar 

  • Meng F, Dave V et al (2015) Qualitative and quantitative methods to determine miscibility in amorphous drug-polymer systems. Eur J Pharm Sci 77:106–111

    Article  CAS  PubMed  Google Scholar 

  • Miller D, DiNunzio J et al (2008) Targeted intestinal delivery of supersaturated itraconazole for improved oral absorption. Pharm Res 25(6):1450–1459

    Article  CAS  PubMed  Google Scholar 

  • Mishra DK, Dhote V et al (2015) Amorphous solid dispersion technique for improved drug delivery: basics to clinical applications. Drug Deliv Transl Res 5:552–565

    Article  CAS  PubMed  Google Scholar 

  • Mistry P, Mohapatra S et al (2015) Role of the strength of drug–polymer interactions on the molecular mobility and crystallization inhibition in ketoconazole solid dispersions. Mol Pharm 12(9):3339–3350

    Article  CAS  PubMed  Google Scholar 

  • Miyazaki T, Yoshioka S et al (2004) Ability of polyvinylpyrrolidone and polyacrylic acid to inhibit the crystallization of amorphous acetaminophen. J Pharm Sci 93:2710–2717

    Article  CAS  PubMed  Google Scholar 

  • Miyazaki T, Yoshioka S et al (2007) Crystallization rate of amorphous nifedipine analogues unrelated to the glass transition temperature. Int J Pharm 336:191–195

    Article  CAS  PubMed  Google Scholar 

  • Moes J, Koolen S et al (2011) Pharmaceutical development and preliminary clinical testing of an oral solid dispersion formulation of docetaxel (ModraDoc001). J Pharm Sci 420:244–250

    CAS  Google Scholar 

  • Moneghini M, Carcano A et al (1998) Studies in dissolution enhancement of atenolol. Int J Pharm 175:177–183

    Article  CAS  Google Scholar 

  • Oksanen CA, Zografi G (1990) The relationship between the glass transition temperature and water vapor absorption by poly(vinylpyrrolidone). Pharm Res 7(9):654–657

    Article  CAS  PubMed  Google Scholar 

  • Overhoff KA, Engstrom JD et al (2007) Novel ultra-rapid freezing particle engineering process for enhancement of dissolution rates of poorly water-soluble drugs. Eur J Pharm Biopharm 65(1):57–67

    Article  CAS  PubMed  Google Scholar 

  • Pajula K, Taskinen M et al (2010) Predicting the formation and stability of amorphous small molecule binary mixtures from computationally determined Flory–Huggins interaction parameter and phase diagram. Mol Pharm 7(3):795–804

    Article  CAS  PubMed  Google Scholar 

  • Palermo RN, Anderson CA et al (2012) Review: use of thermal, diffraction, and vibrational analytical methods to determine mechanism of solid dispersion stability. J Pharm Innov 7:2–12

    Article  Google Scholar 

  • Park K (2015) Drug release mechanism from amorphous solid dispersions. J Control Release 211:171

    Article  CAS  PubMed  Google Scholar 

  • Patel KP, Pathak CJ et al (2015) Nanostructured lipid carrier—a novel dosage form to improve the oral bioavailability of lopinavir. Eur J Biomed Pharm Sci 2(2):295–311

    CAS  Google Scholar 

  • Patil H, Tiwari R et al (2016) Hot-melt extrusion: from theory to application in pharmaceutical formulation. AAPS PharmSciTech 17(1):20–42

    Article  CAS  PubMed  Google Scholar 

  • Patterson JE, James MB et al (2007) Preparation of glass solutions of three poorly water soluble drugs by spray drying, melt extrusion and ball milling. Int J Pharm 336(1):22–34

    Article  CAS  PubMed  Google Scholar 

  • Patterson JE, James MB et al (2008) Melt extrusion and spray drying of carbamazepine and dipyridamole with polyvinylpyrrolidone/vinyl acetate copolymers. Drug Dev Ind Pharm 34:95–106

    Article  CAS  PubMed  Google Scholar 

  • Paudel A, Van den Mooter G (2012) Influence of solvent composition on the miscibility and physical stability of naproxen/PVP K 25 solid dispersions prepared by cosolvent spray-drying. Pharm Res 29:251–270

    Article  CAS  PubMed  Google Scholar 

  • Paudel A, Van Humbeeck J et al (2010) Theoretical and experimental investigation on the solid solubility and miscibility of naproxen in poly(vinylpyrrolidone). Mol Pharm 7(4):1133–1148

    Article  CAS  PubMed  Google Scholar 

  • Paudel A, Nies E et al (2012) Relating hydrogen-bonding interactions with the phase behavior of naproxen/PVP K 25 solid dispersions: evaluation of solution-cast and quench-cooled films. Mol Pharm 9(11):3301–3317

    Article  CAS  PubMed  Google Scholar 

  • Paus R, Ji Y et al (2015) Predicting the solubility advantage of amorphous pharmaceuticals: a novel thermodynamic approach. Mol Pharm 12(8):2823–2833

    Article  CAS  PubMed  Google Scholar 

  • Purohit HS, Taylor LS (2015) Miscibility of itraconazole-hydroxypropyl methylcellulose blends: insights with high resolution analytical methodologies. Mol Pharm 12(12):4542–4553

    Article  CAS  PubMed  Google Scholar 

  • Qi S, Belton P et al (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 localized thermal analysis approach. Pharm Res 28(9):2311–2326

    Article  CAS  PubMed  Google Scholar 

  • Qian F, Tao J et al (2007) Mechanistic investigation of pluronic® based nano-crystalline drug-polymer solid dispersions. Pharm Res 24(8):1551–1560

    Article  CAS  PubMed  Google Scholar 

  • Read MD, Coppens KA et al (2010) Hot melt extrusion technology for the manufacture of poorly soluble drugs with controlled release dissolution profiles. ANTEC:1203–1206

    Google Scholar 

  • Repka M, Langley N et al (2013) Melt extrusion; materials, technology and drug product design. Springer, New York

    Google Scholar 

  • Rowe R, Shesky P et al (2010) Handbook of pharmaceutical excipients, 4th edn. APhA, Washington

    Google Scholar 

  • Rumondor A, Stanford L et al (2009a) Effects of polymer type and storage relative humidity on the kinetics of felodipine crystallization from amorphous solid dispersions. Pharm Res 26(12):2599–2606

    Article  CAS  PubMed  Google Scholar 

  • Rumondor ACF, Marsac PJ et al (2009b) Phase behavior of poly(vinylpyrrolidone) containing amorphous solid dispersions in the presence of moisture. Mol Pharm 6(5):1492–1505

    Article  CAS  PubMed  Google Scholar 

  • Saerens L, Dierickx L et al (2011) Raman spectroscopy for the in-line polymer-drug quantification and solid state characterization during pharmaceutical hot-melt extrusion process. Eur J Pharm Biopharm 77:158–163

    Google Scholar 

  • Sanghvi T, Katstra J et al (2015) Pharmaceutical amorphous solid dispersions. In: Formulation development of amorphous dispersions, 1st edn. Wiley, Hoboken

    Google Scholar 

  • Sarode AL, Sandhu H et al (2013) Hot melt extrusion (HME) for amorphous solid dispersions: Predictive tools for processing and impact of drug–polymer interactions on supersaturation. Eur J Pharm Sci 48:371–384

    Article  CAS  PubMed  Google Scholar 

  • Serajuddin ATM (1999) Solid dispersion of poorly water-soluble drugs: early promises, subsequent problems, and recent breakthroughs. J Pharm Sci 88:1058–1066

    Article  CAS  PubMed  Google Scholar 

  • Shah N, Sandhu H et al (2008) Solid complexes with ionic polymers: pharmaceutical technology is pleased to recognize the winners of its innovations in pharma science awards. Pharm Technol 32(12):2

    Google Scholar 

  • Shah N, Iyer RM et al (2013) Improved human bioavailability of vemurafenib, a practically insoluble drug, using an amorphous polymer-stabilized solid dispersion prepared by a solvent-controlled coprecipitation process. J Pharm Sci 102(3):967–981

    Article  CAS  PubMed  Google Scholar 

  • Shanbhag A, Rabel S et al (2008) Method for screening of solid dispersion formulations of low-solubility compounds-miniaturization and automation of solvent casting and dissolution testing. Int J Pharm 351(1–2):209–218

    Article  CAS  PubMed  Google Scholar 

  • Siew A (2014) Solving poor solubility with amorphous solid dispersions: weighing the pros and cons of hot-melt extrusion and spray drying. Pharm Technol 38(1):30–35

    Google Scholar 

  • Simonelli AP, Mehta SC et al (1969) Dissolution rates of high energy polyvinylpyrrolidone (PVP)-sulfathiazole coprecipitates. J Pharm Sci 58(5):538–549

    Article  CAS  PubMed  Google Scholar 

  • Singh H, Atef E et al (2007) High throughput screening of solid dispersion using solvent evaporation technique aaps annual meeting and exposition. San Diego Convention Center, San Diego

    Google Scholar 

  • Six K, Verreck G et al (2004) Increased physical stability and improved dissolution properties of itraconazole, a class II drug, by solid dispersions that combine fast- and slow-dissolving polymers. J Pharm Sci 93(1):124–131

    Article  CAS  PubMed  Google Scholar 

  • Song Y, Zemlyanov D et al (2016) 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

    Article  CAS  PubMed  Google Scholar 

  • Sun DD, Lee PI (2013) Evolution of supersaturation of amorphous pharmaceuticals: the effect of rate of supersaturation generation. Mol Pharm 10(11):4330–4346

    Article  CAS  PubMed  Google Scholar 

  • Swinney K, Herman J et al (2009) Configuration of an automated screening tool to facilitate solid dispersion development AAPS annual meeting and exposition. Los Angeles Convention Center, Los Angeles

    Google Scholar 

  • Tanno F, Nishiyama Y et al (2004) Evaluation of hypromellose acetate succinate (HPMC-AS) as a carrier in solid dispersions. Drug Dev Ind Pharm 30(1):9–17

    Article  CAS  PubMed  Google Scholar 

  • Taylor LS, Zografi G (1997) Spectroscopic characterization of interactions between PVP and indomethacin in amorphous molecular dispersions. Pharm Res 14:1691–1698

    Article  CAS  PubMed  Google Scholar 

  • Thybo P, Hovgaard L et al (2008) Scaling up the spray drying process from pilot to production scale using an atomized droplet size criterion. Pharm Res 25(7):1610–1620

    Article  CAS  PubMed  Google Scholar 

  • Tian B, Wang X et al (2015) Theoretical prediction of a phase diagram for solid dispersions. Pharm Res 32:840–851

    Article  CAS  PubMed  Google Scholar 

  • Usui F, Maeda K et al (1997) Inhibitory effects of water-soluble polymers on precipitation of RS-8359. Int J Pharm 154(1):59–66

    Article  CAS  Google Scholar 

  • Van den Mooter G, Wuyts M et al (2001) Physical stabilisation of amorphous ketoconazole in solid dispersions with polyvinylpyrrolidone K25. Eur J Pharm Sci 12(3):261–269

    Article  PubMed  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Van Eerdenburgh B, Baird JA et al (2010) Crystallization tendency of active pharmaceutical ingredients following rapid solvent evaporation—classification and comparison with crystallization tendency from undercooled melts. J Pharm Sci 99(9):3826–3838

    Article  CAS  Google Scholar 

  • Vandecruys R, Peeters J et al (2007) Use of screening method to determine excipients which optimize the extend and stability of supersaturated drug solutions and application of this system to solid formulation design. Int J Pharm 342:168–175

    Article  CAS  PubMed  Google Scholar 

  • Warren DB, Benameur H et al (2010) Using polymeric precipitation inhibitors to improve the absorption of poorly water-soluble drugs: a mechanistic basis for utility. J Drug Target 18:704–731

    Article  CAS  PubMed  Google Scholar 

  • Weuts I, Van Dycke F et al (2011) Physicochemical properties of the amorphous drug, cast films, and spray dried powders to predict formulation probability of success for solid dispersions: etravirine. J Pharm Sci 100(1):260–274

    Article  CAS  PubMed  Google Scholar 

  • Wyttenbach N, Janas C et al (2013) Miniaturized screening of polymers for amorphous drug stabilization (SPADS): rapid assessment of solid dispersion systems. Eur J Pharm Biopharm 84:583–598

    Article  CAS  PubMed  Google Scholar 

  • Wyttenbach N, Kirchmeyer W et al (2016) Theoretical considerations of the Prigogine–Defay ratio with regard to the glass-forming ability of drugs from undercooled melts. Mol Pharm 13:241–250

    Article  CAS  PubMed  Google Scholar 

  • Xie T, Taylor LS (2016) Improved release of celecoxib from high drug loading amorphous solid dispersions formulated with polyacrylic acid and cellulose derivatives. Mol Pharm 13(3):873–884

    Article  CAS  PubMed  Google Scholar 

  • Yamashita T, Kokubo T et al (2010) Antiprecipitant screening system for basic model compounds using bio-relevant media. J Assoc Lab Automat 15(4):306–312

    Article  CAS  Google Scholar 

  • Yang Z, Han CD (2008) Rheology of miscible polymer blends with hydrogen bonding. Macromolecules 41(6):2104–2118

    Article  CAS  Google Scholar 

  • Yoo S-u, Krill SL et al (2009) Miscibility/stability considerations in binary solid dispersion systems composed of functional excipients towards the design of multi-component amorphous systems. J Pharm Sci 98(12):4711–4723

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Zhao Y, Inbar P et al (2011) Prediction of the thermal phase diagram of amorphous solid dispersions by flory-huggins theory. J Pharm Sci 100(8):3196–3207

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors of the second edition of the book chapter would like to thank their former co-workers Navnit Shah, Harpreet Sandhu, Duk Soon Choi and Oskar Kalb for the great work done together for the first edition.

Author information

Authors and Affiliations

  1. F. Hoffmann-La Roche AG, Grenzacherstrasse 124, 4070, Basel, Switzerland

    Susanne Page, Reto Maurer & Nicole Wyttenbach

Authors
  1. Susanne Page
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Reto Maurer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nicole Wyttenbach
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Susanne Page .

Editor information

Editors and Affiliations

  1. Division of Pharmaceutics, College of Pharmacy, The University of Texas at Austin, Austin, Texas, USA

    Robert O. Williams III

  2. Division of Pharmaceutics, College of Pharmacy, The University of Texas at Austin, Austin, Texas, USA

    Alan B. Watts

  3. DisperSol Technologies, LLC, Georgetown, Texas, USA

    Dave A. Miller

Rights and permissions

Reprints and permissions

Copyright information

© 2016 American Association of Pharmaceutical Scientists

About this chapter

Cite this chapter

Page, S., Maurer, R., Wyttenbach, N. (2016). Structured Development Approach for Amorphous Systems. In: Williams III, R., Watts, A., Miller, D. (eds) Formulating Poorly Water Soluble Drugs. AAPS Advances in the Pharmaceutical Sciences Series, vol 22. Springer, Cham. https://doi.org/10.1007/978-3-319-42609-9_8

Download citation

Publish with us

Policies and ethics

Search

Navigation