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Novel high-loaded, nanoparticulate and thermally stable macromolecular prodrug design of NSAIDs based on hydroxypropylcellulose

Abstract

Macromolecular prodrugs (MPDs) of aspirin and salicylic acid were synthesized by covalent attachment to hydroxypropylcellulose (HPC) using p-toluenesulfonyl chloride in N,N-dimethylacetamide. The present synthesis strategy resulted in organo-soluble MPDs with 78–86 % yield and degree of drug substitution 0.53–1.96 and 0.68–2.10 for aspirin and salicylic acid, respectively. The size exclusion chromatography showed DP 192 and 214 for HPC–aspirin and HPC–salicylic acid conjugates, respectively. HPC–aspirin and HPC–salicylic acid conjugates were found thermally more stable than native drugs. The activation energy (Ea) of thermal degradation of drugs, polymer and prodrugs was calculated with the help of Broido and Chang kinetic models. Order of reaction (n) was calculated from thermal data using Chang model. Various thermodynamic parameters, i.e., enthalpy (ΔH), Gibbs free energy (ΔG) and entropy (ΔS) were also calculated. Doyle’s method was employed on thermal data of MPDs to calculate integral procedural decomposition temperature and comprehensive index of intrinsic thermal stability. Amphiphilic HPC–aspirin conjugates showed formation of nanoparticles at water/DMSO interface with size distribution from ~500 to 750 nm by transmission electron microscopy.

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References

  • Abraham S, Furtado S, Bharath S, Basavaraj BV, Deveswaran R, Madhavan V (2009) Sustained ophthalmic delivery of ofloxacin from an ion-activated in situ gelling system. Pak J Pharm Sci 22:175–179

    CAS  Google Scholar 

  • Adel AM, El-Wahab ZHA, Ibrahim AA, Al-Shemy MT (2010) Characterization of microcrystalline cellulose prepared from lignocellulosic materials. Part I. Acid catalyzed hydrolysis. Bioresour Technol 101:4446–4455

    CAS  Article  Google Scholar 

  • Alvarez AS, Summerskill WHJ (1958) Gastrointestinal haemorrhage and salicylates. Lancet 272:920–925

    Article  Google Scholar 

  • Berger JS, Lala A, Krantz MJ, Baker GS, Hiatt WR (2011) Aspirin for the prevention of cardiovascular events in patients without clinical cardiovascular disease: a meta-analysis of randomized trials. Am Heart J 162:115–124

    CAS  Article  Google Scholar 

  • Broido A (1969) A simple, sensitive graphical method of treating thermogravimetric analysis data. J Polym Sci A-2 Pol Phys 7:1761–1773

    CAS  Article  Google Scholar 

  • Bundgaard H, Nielsen NM, Buur A (1988) Aspirin prodrugs: synthesis and hydrolysis of 2-acetoxybenzoate esters of various IV-(hydroxyalkyl) amides. Int J Pharm 44:151–158

    CAS  Article  Google Scholar 

  • Chang WL (1994) Decomposition behavior of polyurethanes via mathematical simulation. J Appl Polym Sci 53:1759–1769

    CAS  Article  Google Scholar 

  • Cides da Silva LC, Araújo AAS, Santos-Filho M, Matos JR (2006) Thermal behaviour, compatibility study and decomposition kinetics of glimepiride under isothermal and non-isothermal conditions. J Therm Anal Calorim 84:441–445

    Article  Google Scholar 

  • Doyle CD (1961) Estimating thermal stability of experimental polymers by empirical thermogravimetric analysis. Anal Chem 33:77–79

    CAS  Article  Google Scholar 

  • El Seoud OA, Heinze T (2005) Organic esters of cellulose: new perspectives of old polymer. Adv Polym Sci 186:103–149

    Article  Google Scholar 

  • Felix FS, Cides da Silva LC, Angnes L, Matos JR (2009) Thermal behavior study and decomposition kinetics of salbutamol under isothermal and non-isothermal conditions. J Therm Anal Calorim 95:877–880

    CAS  Article  Google Scholar 

  • Ghaemy M, Nasab SMA (2010) Synthesis and identification of organosoluble polyamides bearing a triaryl imidazole pendent: thermal, photophysical, chemiluminescent, and electrochemical characterization with a modified carbon nanotube electrode. React Funct Polym 70:306–313

    CAS  Article  Google Scholar 

  • Gilmer JF, Moriarty LM, Lally MN, Clancy JM (2002) Isosorbide-based aspirin prodrugs. II. Hydrolysis kinetics of isosorbide diaspirinate. Eur J Pharm Sci 16:297–304

    CAS  Article  Google Scholar 

  • Giron D (2002) Applications of thermal analysis and coupled techniques in pharmaceutical industry. J Therm Anal Calorim 68:335–357

    CAS  Article  Google Scholar 

  • Goodlett VW, Dougherty JT, Patton HW (1971) Characterization of cellulose acetates by nuclear magnetic resonance. J Polym Sci A-1 Pol Chem 9:155–161

    CAS  Article  Google Scholar 

  • Hall SL, Lorenc T (2010) Secondary prevention of coronary artery disease. Am Fam Phys 81:289–296

    Google Scholar 

  • Hussain MA (2010) Alternative routes of polysaccharide acylation: synthesis, structural analysis, properties. VDM Verlag, Saarbrücken, p 69

    Google Scholar 

  • Hussain MA, Badshah M, Iqbal MS, Tahir MN, Tremel W, Bhosale SV, Sher M, Haseeb MT (2009) HPMC-salicylate conjugates as macromolecular prodrugs: design, characterization and nano-rods formation. J Polym Sci A Polym Chem 47:4202–4208

    CAS  Article  Google Scholar 

  • Hussain MA, Abbas K, Sher M, Tahir MN, Tremel W, Iqbal MS, Amin M, Badshah M (2011) Macromolecular prodrugs of aspirin with HPMC: a nano particulate drug design, characterization, pharmacokinetic studies. Macromol Res 19:1296–1302

    CAS  Article  Google Scholar 

  • Hussain MA, Abbas K, Lodhi BA, Sher M, Ali M, Tahir MN, Tremel W, Iqbal S (2013a) Fabrication, characterization, thermal stability and nanoassemblies of novel pullulan-aspirin conjugates. Arab J Chem. doi:10.1016/j.arabjc.2013.06.001

    Google Scholar 

  • Hussain MA, Zarish A, Abbas K, Sher M, Tahir MN, Tremel W, Amin M, Ghafoor A, Lodhi BA (2013b) Hydroxypropylcellulose-aceclofenac conjugates: high covalent loading design, structure characterization, nano-assemblies and thermal kinetics. Cellulose 20:717–725

    CAS  Article  Google Scholar 

  • Iqbal MS, Akbar J, Saghir S, Karim A, Koschella A, Heinze T, Sher M (2011) Thermal studies of plant carbohydrate polymer hydrogel. Carbohydr Polym 86:1775–1783

    CAS  Article  Google Scholar 

  • Jones G (1985) Decreased toxicity and adverse reaction via prodrugs. In: Bundgaard H (ed) Design of prodrugs. Elsevier, Amsterdam, pp 199–241

    Google Scholar 

  • Karewicz A, Zasada K, Szczubiatka K, Zapotoczny S, Lach R, Nowakowska M (2010) “Smart” alginate-hydroxypropylcellulose microbeads for controlled release of heparin. Int J Pharm 385:163–169

    CAS  Article  Google Scholar 

  • Loftsson T, Bodor N (1981) Improved delivery through biological membranes IX: kinetics and mechanism of hydrolysis of methylsulfinylmethyl 2-acetoxybenzoate and related aspirin prodrugs. J Pharm Sci 70:750–755

    CAS  Article  Google Scholar 

  • Moriarty LM, Lally MN, Carolan CG, Jones M, Clancy JM, Gilmer JF (2008) Discovery of a true aspirin prodrug. J Med Chem 51:7991–7999

    CAS  Article  Google Scholar 

  • Muhi-Eldeen Z, Kawahara M, Dakkuri A, Hussain A (1985) Kinetics and mechanism of the enzymatic hydrolysis of aspirin phenylalanine ethyl ester. Int J Pharm 261:15–23

    Article  Google Scholar 

  • Neto HS, Barros FAP, de Sousa Carvalho FM, Matos JR (2010) Thermal analysis of prednicarbate and characterization of thermal decomposition product. J Therm Anal Calorim 102:277–283

    Article  Google Scholar 

  • Picker-Freyer KM, Durig T (2007) Physical mechanical and tablet formation properties of hydroxypropylcellulose: in pure form and in mixtures. AAPS PharmSciTech 8:82–90

    Article  Google Scholar 

  • Rainsford KD, Whitehouse MW (1980) Anti-inflammatory/anti-pyretic salicylic acid esters with low gastric ulcerogenic activity. Agents Act 10:451–456

    CAS  Article  Google Scholar 

  • Rezende RLO, Santoro MIRM, Matos JR (2008) Stability and compatibility study on enalapril maleate using thermoanalytical techniques. J Therm Anal Calorim 93:881–886

    CAS  Article  Google Scholar 

  • Roderick PJ, Wilkes HC, Meade TW (1993) The gastrointestinal toxicity of aspirin: an overview of randomized controlled trials. Br J Clin Pharmacol 35:219–226

    CAS  Article  Google Scholar 

  • Sharma R, Sharma CL (2008) Macromolecular drugs: novel strategy in target specific drug delivery. J Clin Diagn Res 2:1020–1023

    CAS  Google Scholar 

  • Sovizi MR (2010) Thermal behavior of drugs: investigation on decomposition kinetic of naproxen and celecoxib. J Therm Anal Calorim 102:285–289

    CAS  Article  Google Scholar 

  • Stulzer HK, Rodrugues PO, Cardoso TM, Matos JR, Silva MAS (2008) Compatibility studies between captopril and pharmaceutical excipients used in tablets formulations. J Therm Anal Calorim 91:323–328

    CAS  Article  Google Scholar 

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Acknowledgments

K. Abbas acknowledges the funding provided by Higher Education Commission (HEC), Pakistan under “HEC Indigenous 5000 Fellowships Scheme”.

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Correspondence to Muhammad Ajaz Hussain.

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Hussain, M.A., Abbas, K., Amin, M. et al. Novel high-loaded, nanoparticulate and thermally stable macromolecular prodrug design of NSAIDs based on hydroxypropylcellulose. Cellulose 22, 461–471 (2015). https://doi.org/10.1007/s10570-014-0464-3

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  • DOI: https://doi.org/10.1007/s10570-014-0464-3

Keywords

  • Hydroxypropylcellulose
  • Prodrugs
  • Aspirin
  • Salicylic acid
  • Nanoparticles
  • Thermal analysis
  • Decomposition kinetics