AI帮你理解科学

AI 生成解读视频

AI抽取解析论文重点内容自动生成视频


pub
生成解读视频

AI 溯源

AI解析本论文相关学术脉络


Master Reading Tree
生成 溯源树

AI 精读

AI抽取本论文的概要总结


微博一下
The melting point of the crystalline drug is depressed in the presence of the polymer; in contrast systems with limited miscibility showed little, if any, melting point depression

Estimation of Drug–Polymer Miscibility and Solubility in Amorphous Solid Dispersions Using Experimentally Determined Interaction Parameters

Pharmaceutical Research, no. 1 (2009): 139-151

被引用455|浏览8
WOS
下载 PDF 全文
引用
微博一下

摘要

Purpose  The amorphous form of a drug may provide enhanced solubility, dissolution rate, and bioavailability but will also potentially crystallize over time. Miscible polymeric additives provide a means to increase physical stability. Understanding the miscibility of drug–polymer systems is of interest to optimize the formulation of suc...更多

代码

数据

0
简介
  • Dispersions of organic molecules in polymeric matrices are important for a number of applications, in particular for medical devices and drug delivery systems.
  • Miscible drug–polymer blends are more resistant to drug crystallization than the amorphous drug alone [28,29], an important consideration when attempting to produce a drug delivery system that will perform consistently over time.
  • The presence of a single glass transition temperature is not an infallible indicator of miscibility and provides no information about the thermodynamics of mixing.
  • While numerous theoretical and experimental approaches have been applied to understand polymer-polymer blending [30,31,32,35,36,40,41,42,43,44], the thermodynamics of drug–polymer mixing is relatively unexplored
重点内容
  • Dispersions of organic molecules in polymeric matrices are important for a number of applications, in particular for medical devices and drug delivery systems
  • It can be seen from Eq 2 that there are two factors that would be expected to contribute to melting point depression; entropy of mixing and non-idealities of mixing as reflected by the magnitude of the interaction parameter
  • Values of the interaction parameter, as would be expected for exothermic mixing, while a lesser extent of melting point depression leads to a positive interaction parameter and is consistent with endothermic mixing
  • The melting point of the crystalline drug is depressed in the presence of the polymer; in contrast systems with limited miscibility showed little, if any, melting point depression
  • It can be concluded that the solubility of most drugs in polymeric matrices is likely to be low at room temperature unless extremely favorable cohesive interactions are formed
方法
  • Melting Point Depression

    Crystalline drug particles and non-crystalline polymer particles were sized using standard sieves.
  • The pure crystalline drug was physically mixed with either [1] pure polymer or [2] an amorphous molecular level solid dispersion of the drug in the polymer.
  • The melting temperature of each crystalline compound in the presence of [1] the pure polymer or [2] the amorphous molecular level solid dispersion was measured with a TA 2920 modulated DSC equipped with a refrigerated cooling accessory (TA instruments, New Castle, DE, USA) at a scan rate of 1°C/min.
  • The offset of melting was taken as the extrapolated offset of the bulk melting endotherm
结果
  • Systems which exhibit a sufficiently positive interaction parameter would not be expected to mix and would not be expected to show melting point depression.
  • In this case, the enthalpy of mixing cannot be measured and there is no configurational entropy introduced by the presence of the second component
结论
  • Thermodynamics of Mixing Drugs and Polymers

    Amorphous molecular level solid dispersions are ideally homogeneous single phase systems.
  • Molecular Volume ΔHfus TM (K)Interaction parameters provide important information about the thermodynamics of mixing between small molecules and polymers, in other words their miscibility.
  • The experimentally derived interaction parameters were used to generate free energy of mixing profiles for the various systems and to estimate the solubility of active pharmaceutical ingredients in PVP.
  • It can be concluded that the solubility of most drugs in polymeric matrices is likely to be low at room temperature unless extremely favorable cohesive interactions are formed
表格
  • Table1: Examples of Miscible, Partially Miscible, and Immiscible Small Molecule–Polymer Systems
  • Table2: Physical Properties Used with Melting Point Depression Data to Calculate the Flory–Huggins Interaction Parameter of Each Model Compound in PVP K12, Dextran, and Eudragit E100
  • Table3: Dipole Moments as Estimated from Gaussian 03 Calculations and Carbonyl Peak Shift in an Amorphous Dispersion Containing one Hydrogen Bond Donor Group for Each Carbonyl
  • Table4: Measured Solubility in 1-Ethyl-2-Pyrrolidone Expressed as a Weight Fraction, wdrug, and as a Mole Fraction, xdrug, and the Corresponding Activity Coefficient Calculated from the Simplified Solubility Equation (Eq 1), γdrug
Download tables as Excel
基金
  • This work was supported in part by a fellowship from Merck Research Laboratories
  • AstraZeneca is acknowledged for financial support
引用论文
  • D. Gulsen, C.C. Li, and A. Chauhan. Dispersion of DMPC liposomes in contact lenses for ophthalmic drug delivery. Curr. Eye Res. 30:1071–1080 (2005). doi:10.1080/02713680500346633.
    Locate open access versionFindings
  • I.P. Kaur, and M. Kanwar. Ocular preparations: The formulation approach. Drug. Dev. Ind. Pharm. 28:473–493 (2002). doi:10.1081/DDC-120003445.
    Locate open access versionFindings
  • M. Diestelhorst, and G.K. Krieglstein. The ocular tolerability of a new ophthalmic drug-delivery system (NODS). Int. Ophthalmol. 18:1–4 (1994). doi:10.1007/BF00919405.
    Locate open access versionFindings
  • G.A. Lesher, and G.G. Gunderson. Continuous drug-delivery through the use of disposable contact-lenses. Optom. Vis. Sci. 70:1012–1018 (1993). doi:10.1097/00006324-199312000-00004.
    Locate open access versionFindings
  • M.V. Zelenskaya, E.F. Baru, G.A. Babich, A.A. Kivaev, A.A. Suprun, and A.A. Ryabtseva. Soft contact-lenses impregnated with hypotensive drugs in the treatment of glaucoma. Vestn. Oftalmol. 102(3):14–17 (1986).
    Google ScholarLocate open access versionFindings
  • V.J. Marmion, and M.R. Jain. Role of soft contact-lenses and delivery of drugs. Trans. Ophthalmol. Soc. U. K. 96:319–321 (1976).
    Google ScholarLocate open access versionFindings
  • S.R. Waltman and H.E. Kaufman. Use of hydrophilic contact lenses to increase ocular penetration of topical drugs. Invest. Ophthalmol. 9:250–255 (1970).
    Google ScholarLocate open access versionFindings
  • B. Tesfamariam. Drug release kinetics from stent device-based delivery systems. Invest. Ophthalmol. 51:118–125 (2008).
    Google ScholarLocate open access versionFindings
  • J.P. Chen. Safety and efficacy of the drug-eluting stent: A double-edged sword? South Med. J. 101:174–178 (2008).
    Google ScholarLocate open access versionFindings
  • N. Kukreja, Y. Onuma, J. Daemen, and P.W. Serruys. The future of drug-eluting stents. Pharmacol. Res. 57:171–180 (2008). doi:10.1016/j.phrs.2008.01.012.
    Locate open access versionFindings
  • J.L. Ifkovits, and J.A. Burdick. Review: Photopolymerizable and degradable biomaterials for tissue engineering applications. Tissue Eng. 13:2369–2385 (2007). doi:10.1089/ten.2007.0093.
    Locate open access versionFindings
  • W.K. Wan, L. Yang, and D.T. Padavan. Use of degradable and nondegradable nanomaterials for controlled release. Nanomedicine. 2:483–509 (2007). doi:10.2217/17435889.2.4.483.
    Locate open access versionFindings
  • T. Sharkawi, F. Cornhill, A. Lafont, P. Sabaria, and M. Vert. Intravascular bioresorbable polymeric stents: A potential alternative to current drug eluting metal stents. J. Pharm. Sci. 96:2829–2837 (2007). doi:10.1002/jps.20957.
    Locate open access versionFindings
  • C.B. Packhaeuser, J. Schnieders, C.G. Oster, and T. Kissel. In situ forming parenteral drug delivery systems: An overview. Eur. J. Pharm. Biopharm. 58:445–455 (2004). doi:10.1016/j. ejpb.2004.03.003.
    Locate open access versionFindings
  • C. Vauthier, C. Dubernet, E. Fattal, H. Pinto-Alphandary, and P. Couvreur. Poly(alkylcyanoacrylates) as biodegradable materials for biomedical applications. Adv. Drug Deliv. Rev. 55:519–548 (2003). doi:10.1016/S0169-409X(03)00041-3.
    Locate open access versionFindings
  • H. Kimura, and Y. Ogura. Biodegradable polymers for ocular drug delivery. Ophthalmologica. 215:143–155 (2001). doi:10.1159/ 000050849.
    Locate open access versionFindings
  • J. Heller. Biodegradable polymers in controlled drug delivery. Crit. Rev. Ther. Drug Carrier Syst. 1:39–90 (1984).
    Google ScholarLocate open access versionFindings
  • R.G. Buckles. Biomaterials for drug delivery systems. J. Biomed. Materi. Res. 17:109–128 (1983). doi:10.1002/jbm.820170110.
    Locate open access versionFindings
  • W. Schneider, W.D. Bussmann, A. Hartmann, and M. Kaltenbach. Nitrate therapy in heart-failure. Cardiology. 79:5–13 (1991).
    Google ScholarLocate open access versionFindings
  • P.A. Todd, K.L. Goa, and H.D. Langtry. Transdermal nitroglycerin (glyceryl trinitrate)—A review of its pharmacology and therapeutic use. Drugs. 40:880–902 (1990). doi:10.2165/00003495199040060-00009.
    Locate open access versionFindings
  • J.L. Ford. The current status of solid dispersions. Pharm. Acta Helv. 61:69–88 (1986).
    Google ScholarLocate open access versionFindings
  • A.T.M. Serajuddin. Solid dispersion of poorly water-soluble drugs: Early promises, subsequent problems, and recent breakthroughs. J. Pharm. Sci. 88:1058–1066 (1999). doi:10.1021/ js980403l.
    Locate open access versionFindings
  • S. Sethia, and E. Squillante. Solid dispersions: Revival with greater possibilities and applications in oral drug delivery. Crit. Rev. Ther. Drug Carr. Syst. 20:215–247 (2003). doi:10.1615/ CritRevTherDrugCarrierSyst.v20.i23.40.
    Google ScholarLocate open access versionFindings
  • V. Mummaneni, and R.C. Vasavada. Solubilization and dissolution of famotidine from solid glass dispersions of xylitol. Int. J. Pharm. 66:71–77 (1990). doi:10.1016/0378-5173(90)90386-I.
    Locate open access versionFindings
  • D.Q.M. Craig. The mechanisms of drug release from solid dispersions in water-soluble polymers. Int. J. Pharm. 231:131– 144 (2002). doi:10.1016/S0378-5173(01)00891-2.
    Locate open access versionFindings
  • L.H. Emara, R.M. Badr, and A. Abd Elbary. Improving the dissolution and bioavailability of nifedipine using solid dispersions and solubilizers. Drug Dev. Ind. Pharm. 28:795–807 (2002). doi:10.1081/DDC-120005625.
    Locate open access versionFindings
  • A. Fahr, and X. Liu. Drug delivery strategies for poorly watersoluble drugs. Expert Opinion on Drug Delivery. 4:403–416 (2007). doi:10.1517/17425247.4.4.403.
    Locate open access versionFindings
  • V. Andronis, and G. Zografi. Crystal nucleation and growth of indomethacin polymorphs from the amorphous state. J. Non-Cryst. Solids. 271:236–248 (2000). doi:10.1016/S0022-3093(00)00107-1.
    Locate open access versionFindings
  • K.J. Crowley, and G. Zografi. The effect of low concentrations of molecularly dispersed poly(vinylpyrrolidone) on indomethacin crystallization from the amorphous state. Pharm Res. 20:1417– 1422 (2003). doi:10.1023/A:1025706110520.
    Locate open access versionFindings
  • S. Vanhee, R. Koningsveld, H. Berghmans, K. Solc, and W.H. Stockmayer. Thermodynamic stability of immiscible polymer blends. Macromolecules. 33:3924–3931 (2000). doi:10.1021/ma9918102.
    Locate open access versionFindings
  • J.W. Barlow, and D.R. Paul. Polymer alloys. Annu. Rev. Mater. Sci. 11:299–319 (1981). doi:10.1146/annurev.ms.11.080181.001503.
    Locate open access versionFindings
  • M.M. Coleman, J.F. Graf, and P.C. Painter. Specific Interactions and the Miscibility of Polymer Blends. Technomic Publishing AG, Lancaster, Pennsylvania, 1991.
    Google ScholarFindings
  • K.K. Chee. Thermodynamic study of glass transitions in miscible polymer blends. Polymer. 36:809–813 (1995). doi:10.1016/00323861(95)93112-Y.
    Locate open access versionFindings
  • E. Meaurio, E. Zuza, and J.R. Sarasua. Miscibility and specific interactions in blends of poly(L-lactide) with poly(vinylphenol). Macromolecules. 38:1207–1215 (2005). doi:10.1021/ma047818f.
    Findings
  • P. Perrin, and R.E. Prudhomme. Miscibility behavior of PVC polymethacrylate blends—Temperature and composition analysis. Polymer. 32:1468–1473 (1991). doi:10.1016/0032-3861(91)90428-L.
    Locate open access versionFindings
  • Y. Park, B. Veytsman, M. Coleman, and P. Painter. The miscibility of hydrogen-bonded polymer blends: Two self-associating polymers. Macromolecules. 38:3703–3707 (2005). doi:10.1021/ ma0473115.
    Locate open access versionFindings
  • S.B. Ahn, and H.M. Jeong. Phase behavior and hydrogen bonding in poly(ethylene-co-vinyl alcohol) poly(N-vinyl-2-pyrrolidone) blends. Korea Polym. J. 6:389–395 (1998).
    Google ScholarLocate open access versionFindings
  • S.L. Shamblin, E.Y. Huang, and G. Zografi. The effects of colyophilized polymeric additives on the glass transition temperature and crystallization of amorphous sucrose. J. Therm. Anal. 47:1567–1579 (1996). doi:10.1007/BF01992846.
    Locate open access versionFindings
  • P.J. Marsac, S.L. Shamblin, and L.S. Taylor. Theoretical and practical approaches for prediction of drug–polymer miscibility and solubility. Pharm. Res. 23:2417–2426 (2006). doi:10.1007/ s11095-006-9063-9.
    Locate open access versionFindings
  • E.J. Moskala, D.F. Varnell, and M.M. Coleman. Concerning the miscibility of poly(vinyl phenol) blends—FTi.r. study. Polymer. 26:228–234 (1985). doi:10.1016/0032-3861(85)90034-5.
    Locate open access versionFindings
  • M.M. Coleman, and P.C. Painter. Hydrogen-bonded polymer blends. Prog. Polym. Sci. 20:1–59 (1995). doi:10.1016/0079-6700 (94)00038-4.
    Locate open access versionFindings
  • R.S. Stein. Crystallization from polymer blends. Mater. Res. Soc. Symp. Proc. 321:531–542 (1994).
    Google ScholarLocate open access versionFindings
  • A.R. Kamdar, Y.S. Hu, P. Ansems, S.P. Chum, A. Hiltner, and E. Baer. Miscibility of propylene-ethylene copolymer blends. Macromolecules. 39:1496–1506 (2006). doi:10.1021/ma052214c.
    Locate open access versionFindings
  • D. Frezzotti, and G.P. Ravanetti. Evaluation of the Flory– Huggins interaction parameter for poly(styrene-co-acrylo-nitrile) and poly(methylmethacrylate) blend from enthalpy of mixing measurements. J. Therm. Anal. 41:1237–1243 (1994). doi:10.1007/ BF02549918.
    Google ScholarLocate open access versionFindings
  • P.C. Painter, J.F. Graf, and M.M. Coleman. Effect of hydrogenbonding on the enthalpy of mixing and the composition dependence of the glass-transition temperature in polymer blends. Macromolecules. 24:5630–5638 (1991). doi:10.1021/ma00020a023.
    Locate open access versionFindings
  • K. Khougaz, and S.D. Clas. Crystallization inhibition in solid dispersions of MK-0591 and poly(vinylpyrrolidone) polymers. J. Pharm. Sci. 89:1325–1334 (2000). doi:10.1002/1520-6017(200010) 89:10<1325::AID-JPS10>3.0.CO;2-5.
    Locate open access versionFindings
  • H. Konno, and L.S. Taylor. Influence of different polymers on the crystallization tendency of molecularly dispersed amorphous felodipine. J. Pharm. Sci. 95:2692–2705 (2006). doi:10.1002/ jps.20697.
    Locate open access versionFindings
  • L.S. Taylor, and G. Zografi. Spectroscopic characterization of interactions between PVP and indomethacin in amorphous molecular dispersions. Pharm. Res. 14:1691–1698 (1997). doi:10.1023/ A:1012167410376.
    Google ScholarLocate open access versionFindings
  • L.S. Taylor, and G. Zografi. Sugar-polymer hydrogen bond interactions in lyophilized amorphous mixtures. J. Pharm. Sci. 87:1615–1621 (1998). doi:10.1021/js9800174.
    Locate open access versionFindings
  • P. Di Martino, E. Joiris, R. Gobetto, A. Masic, G.F. Palmieri, and S. Martelli. Ketoprofen-poly(vinylpyrrolidone) physical interaction. J. Cryst. Growth. 265:302–308 (2004). doi:10.1016/j.jcrysgro. 2004.02.023.
    Locate open access versionFindings
  • P.J. Marsac, H. Konno, and L.S. Taylor. A comparison of the physical stability of amorphous felodipine and nifedipine systems. Pharm. Res. 23:2306–2316 (2006). doi:10.1007/s11095-0069047-9.
    Locate open access versionFindings
  • S.I. Sandler. Chemical & Engineering Thermodynamics. Wiley, New York, 1999.
    Google ScholarFindings
  • S.H. Yalkowsky. Solubility and Solubilization in Aqueous Media. Oxford University Press, New York, 1999.
    Google ScholarFindings
  • P.J. Flory. Principles of Polymer Chemistry. Cornell University Press, Ithaca, 1953.
    Google ScholarFindings
  • L. Mandelkern. Crystallization of polymers. McGraw-Hill, New York, 1964.
    Google ScholarFindings
  • T. Nishi, and T.T. Wang. Melting-point depression and kinetic effects of cooling on crystallization in poly(vinylidene fluoride) poly(methyl methacrylate) mixtures. Macromolecules. 8:909–915 (1975). doi:10.1021/ma60048a040.
    Locate open access versionFindings
  • M. Rubinstein, and R.H. Colby. Polymer Physics. Oxford University Press, New York, 2003.
    Google ScholarFindings
  • R.J. Young, and P.A. Lovell. Introduction to Polymers. Nelson Thornes, Cheltenham, UK, 1991.
    Google ScholarFindings
  • S.L. Shamblin, X.L. Tang, L.Q. Chang, B.C. Hancock, and M.J. Pikal. Characterization of the time scales of molecular motion in pharmaceutically important glasses. J. Phys. Chem. B. 103:4113– 4121 (1999). doi:10.1021/jp983964+.
    Locate open access versionFindings
  • B.C. Hancock, and M. Parks. What is the true solubility advantage for amorphous pharmaceuticals? Pharm. Res. 17:397–404 (2000). doi:10.1023/A:1007516718048.
    Locate open access versionFindings
  • X.L.C. Tang, M.J. Pikal, and L.S. Taylor. A spectroscopic investigation of hydrogen bond patterns in crystalline and amorphous phases in dihydropyridine calcium channel blockers. Pharm. Res. 19:477–483 (2002). doi:10.1023/A:1015147729564.
    Locate open access versionFindings
  • G.A. Jeffrey. An Introduction to Hydrogen Bonding. Oxford University Press, New York, 1997.
    Google ScholarFindings
  • G. Van den Mooter, M. Wuyts, N. Blaton, R. Busson, P. Grobet, P. Augustijns, and R. Kinget. Physical stabilisation of amorphous ketoconazole in solid dispersions with polyvinylpyrrolidone K25. Eur. J. Pharm. Sci. 12:261–269 (2001). doi:10.1016/S0928-0987 (00)00173-1.
    Locate open access versionFindings
  • D.J. Greenhalgh, A.C. Williams, P. Timmins, and P. York. Solubility parameters as predictors of miscibility in solid dispersions. J. Pharm. Sci. 88:1182–1190 (1999). doi:10.1021/js9900856.
    Locate open access versionFindings
  • K. Six, C. Leuner, J. Dressman, G. Verreck, J. Peeters, N. Blaton, P. Augustijns, R. Kinget, and G. Van den Mooter. Thermal properties of hot-stage extrudates of itraconazole and eudragit E100—Phase separation and polymorphism. J. Therm. Anal. Calorim. 68:591–601 (2002). doi:10.1023/A:1016056222881.
    Locate open access versionFindings
  • S.L. Shamblin, L.S. Taylor, and G. Zografi. Mixing behavior of colyophilized binary systems. J. Pharm. Sci. 87:694–701 (1998). doi:10.1021/JS9704801.
    Locate open access versionFindings
  • M. Yoshioka, B.C. Hancock, and G. Zografi. Inhibition of indomethacin crystallization in poly(vinylpyrrolidone) coprecipitates. J. Pharm. Sci. 84:983–986 (1995). doi:10.1002/jps. 2600840814.
    Locate open access versionFindings
  • A. Saleki-Gerhardt, and G. Zografi. Nonisothermal and isothermal crystallization of sucrose from the amorphous state. Pharm. Res. 11:1166–1173 (1994). doi:10.1023/A:1018945117471.
    Locate open access versionFindings
  • P. Tong, and G. Zografi. A study of amorphous molecular dispersions of indomethacin and its sodium salt. J. Pharm. Sci. 90:1991–2004 (2001). doi:10.1002/jps.1150.
    Locate open access versionFindings
  • C.Q. Sun. A novel method for deriving true density of pharmaceutical solids including hydrates and water-containing powders. J. Pharm. Sci. 93:646–653 (2004). doi:10.1002/jps.10595.
    Locate open access versionFindings
  • K. Six, H. Berghmans, C. Leuner, J. Dressman, K. Van Werde, J. Mullens, L. Benoist, M. Thimon, L. Meublat, G. Verreck, J. Peeters, M. Brewster, and G. Van den Mooter. Characterization of solid dispersions of itraconazole and hydroxypropylmethylcellulose prepared by melt extrusion, part II. Pharm. Res. 20:1047– 1054 (2003). doi:10.1023/A:1024414423779.
    Locate open access versionFindings
您的评分 :
0

 

标签
评论
数据免责声明
页面数据均来自互联网公开来源、合作出版商和通过AI技术自动分析结果,我们不对页面数据的有效性、准确性、正确性、可靠性、完整性和及时性做出任何承诺和保证。若有疑问,可以通过电子邮件方式联系我们:report@aminer.cn
小科