AAPS PharmSciTech

, 20:285 | Cite as

Sericin Inhibits Devitrification of Amorphous Drugs

  • Nitin Salunkhe
  • Namdeo JadhavEmail author
  • Harinath More
  • Prafulla Choudhari
Research Article


The purpose of the present investigation was to analyze devitrification of amorphous drugs such as lornoxicam, meloxicam, and felodipine in the presence of sericin. The binary solid dispersions comprising varying mass ratios of drug and sericin were subject to amorphization by spray drying, solvent evaporation, ball milling, and physical mixing. Further, obtained solid dispersions (SDs) were characterized by HPLC, ATR-FTIR, H1NMR, molecular docking, accelerated stability study at 40°C and 75 ± 2% RH (XRD and DSC), and in vitro dissolution studies. The HPLC analysis indicated no decomposition of the drugs during the spray drying process. From ATR-FTIR, NMR, and molecular docking study, it was revealed that H-bonding played a vital role in amorphous drug stabilization. An excellent devitrification inhibition was observed in case of lornoxicam (SDLS3) and meloxicam (SDMS3) SDs prepared by spray drying. On the other hand, spray-dried SD of felodipine (SDFS3) showed traces of microcrystals. The percent crystallinity of SDLS3, SDMS3, and SDFS3 was found to be 7.4%, 8.23%, and 18.31% respectively indicating adequate amorphization. The dissolution performance of SDLS, SDMS, and SDFS after 3 months showed > 85% than SDs prepared by other methods. Thus, sericin significantly inhibited crystallization and was responsible for amorphous state stabilization of pharmaceuticals.


sericin devitrification amorphous solid dispersions (ASD) solubility dissolution 



  1. 1.
    Leuner C, Dressman J. Improving drug solubility for oral delivery using solid dispersions. Eur J Pharm Biopharm. 2000;50:47–60. Scholar
  2. 2.
    Serajuddln ATM. Solid dispersion of poorly water-soluble drugs: early promises, subsequent problems, and recent breakthroughs. J Pharm Sci. 1999;88:1058–66.CrossRefGoogle Scholar
  3. 3.
    Zhou D, Zhang GGZ, Law D, Grant DJW, Schmitt EA. Physical stability of amorphous pharmaceuticals: importance of configurational thermodynamic quantities and molecular mobility. J Pharm Sci. 2002;91:1863–72.CrossRefGoogle Scholar
  4. 4.
    Graeser KA, Patterson JE, Zeitler JA, Gordon KC, Rades T. Correlating thermodynamic and kinetic parameters with amorphous stability. Eur J Pharm Sci. 2009;37:492–8.CrossRefGoogle Scholar
  5. 5.
    Ahlneck C, Zografi G. The molecular basis of moisture effects on the physical and chemical stability of drugs in the solid state. Int J Pharm. 1990;62:87–95.CrossRefGoogle Scholar
  6. 6.
    Yoshioka M, Hancock BC, Zografi G. Crystallization of lndomethacin from the amorphous state below and above its glass transition temperature. J Pharm Sci. 1994;83:1700–5.CrossRefGoogle Scholar
  7. 7.
    Trasi NS, Purohit HS, Taylor LS. Evaluation of the crystallization tendency of commercially available amorphous tacrolimus formulations exposed to different stress conditions. Pharm Res. 2017;34:2142–55.CrossRefGoogle Scholar
  8. 8.
    Baghel S, Cathcart H, O’Reilly NJ. 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 Elsevier Ltd. 2016;105:2527–44. Available from: Scholar
  9. 9.
    Hancock B, Shamblin S, Zografi G. Molecular mobility of amorphous pharmaceutical solids below their glass transition temperatures. Pharm Res. 1995;12:799–806.CrossRefGoogle Scholar
  10. 10.
    Pokharkar VB, Mandpe LP, Padamwar MN, Ambike AA, Mahadik KR, Paradkar A. Development, characterization and stabilization of amorphous form of a low Tg drug. Powder Technol. 2006;167:20–5.CrossRefGoogle Scholar
  11. 11.
    Matsumoto T, Zografi G. Physical properties of solid molecular dispersions of indomethacin with poly (vinylpyrrolidone) and poly(vinylpyrrolidone-co-vinyl-acetate) in relation to indomethacin crystallization. Pharm Res. 1999;16:1722–8.CrossRefGoogle Scholar
  12. 12.
    Pignatello R, Spadaro D, Vandelli MA, Forni F, Puglisi G. Characterization of the mechanism of interaction in ibuprofen-Eudragit RL100 coevaporates. Drug Dev Ind Pharm. 2004;30:277–88. Scholar
  13. 13.
    Shakhtshneider TP, De FDÀ, Capet F, Willart JF, Descamps M, S a M, et al. Grinding of drugs with pharmaceutical excipients at cryogenic temperatures part I. Cryogenic grinding of piroxicam – polyvinylpyrrolidone mixtures. J Therm Anal Calorim. 2007;89:699–707.CrossRefGoogle Scholar
  14. 14.
    Shakhtshneider TP, Danède F, Capet F, Willart JF, Descamps M, Paccou L, et al. Grinding of drugs with pharmaceutical excipients at cryogenic temperatures. J Therm Anal Calorim. 2007;89:709–15.CrossRefGoogle Scholar
  15. 15.
    Mulye SP, Jamadar SA, Karekar PS, Pore YV, Dhawale SC. Improvement in physicochemical properties of ezetimibe using a crystal engineering technique. Powder Technol Elsevier BV. 2012;222:131–8. Available from: Scholar
  16. 16.
    Fu Q, Fang M, Hou Y, Yang W, Shao J, Guo M, et al. A physically stabilized amorphous solid dispersion of nisoldipine obtained by hot melt extrusion. Powder Technol. 2016;301:342–8.CrossRefGoogle Scholar
  17. 17.
    Bhende S, Jadhav N. Moringa coagulant as a stabilizer for amorphous solids: part I. AAPS PharmSciTech. 2012;13:400–10. Scholar
  18. 18.
    Shilpi D, Kushwah V, Agrawal AK, Jain S. Improved stability and enhanced oral bioavailability of atorvastatin loaded stearic acid modified gelatin nanoparticles. Pharm Res. 2017;34:1505–16.CrossRefGoogle Scholar
  19. 19.
    Van den Mooter G, Wuyts M, Blaton N, Busson R, Grobet P, Augustijns P, et al. Physical stabilisation of amorphous ketoconazole in solid dispersions with polyvinylpyrrolidone K25. Eur J Pharm Sci. 2001;12:261–9.CrossRefGoogle Scholar
  20. 20.
    Knopp MM, Olesen NE, Holm P, Langguth P, Holm R, Rades T. Influence of polymer molecular weight on drug-polymer solubility: a comparison between experimentally determined solubility in PVP and prediction derived from solubility in monomer. J Pharm Sci. 2015;104:2905–12.CrossRefGoogle Scholar
  21. 21.
    Zhang P, Forsgren J, Strømme M. Stabilisation of amorphous ibuprofen in Upsalite, a mesoporous magnesium carbonate, as an approach to increasing the aqueous solubility of poorly soluble drugs. Int J Pharm Elsevier BV. 2014;472:185–91. Available from: Scholar
  22. 22.
    Lin S, Cheng C. Solid state interaction studies of drug-polymers (II): warfarin-Eudragit E, RL or S resins Shan-Yang. Eur J Pharm Sci. 1994;1:313–22.CrossRefGoogle Scholar
  23. 23.
    Bley H, Fussnegger B, Bodmeier R. Characterization and stability of solid dispersions based on PEG/polymer blends. Int J Pharm Elsevier BV. 2010;390:165–73. Available from: Scholar
  24. 24.
    Vasa DM, Dalal N, Katz JM, Roopwani R, Nevrekar A, Patel H, et al. Physical characterization of drug: polymer dispersion behavior in polyethylene glycol 4000 solid dispersions using a suite of complementary analytical techniques. J Pharm Sci. 2014;103:2911–23.CrossRefGoogle Scholar
  25. 25.
    Ueda H, Aikawa S, Kashima Y, Kikuchi J, Ida Y, Tanino T, et al. Anti-plasticizing effect of amorphous indomethacin induced by specific intermolecular interactions with PVA copolymer. J Pharm Sci Elsevier Masson SAS. 2014;103:2829–38. Available from: Scholar
  26. 26.
    Shimpi SL, Chauhan B, Mahadik KR, Paradkar A. Stabilization and improved in vivo performance of amorphous etoricoxib using Gelucire 50/13. Pharm Res. 2005;22:1727–34.CrossRefGoogle Scholar
  27. 27.
    Sarode AL, Malekar SA, Cote C, Worthen DR. Hydroxypropyl cellulose stabilizes amorphous solid dispersions of the poorly water soluble drug felodipine. Carbohydr Polym Elsevier Ltd. 2014;112:512–9. Available from: Scholar
  28. 28.
    Konno H, Taylor LS. Influence of different polymers on the crystallization tendency of molecularly dispersed amorphous felodipine. J Pharm Sci. 2006;95:2692–705.CrossRefGoogle Scholar
  29. 29.
    Liu J, Cao F, Zhang C, Ping Q. Use of polymer combinations in the preparation of solid dispersions of a thermally unstable drug by hot-melt extrusion. Acta Pharm Sin B. 2013;3:263–72. Scholar
  30. 30.
    Aramwit P. Effectiveness of inflammatory cytokines induced by sericin compared to sericin in combination with silver sulfadiazine cream on wound healing. Wounds. 2009;21:198–206.PubMedGoogle Scholar
  31. 31.
    Aramwit P, Keongamaroon O, Siritientong T, Bang N, Supasyndh O. Sericin cream reduces pruritus in hemodialysis patients: a randomized, double-blind, placebo-controlled experimental study. BMC Nephrol. 2012;13:119. Scholar
  32. 32.
    Kitisin T, Maneekan P, Luplertlop N. In-vitro characterization of silk sericin as an anti-aging agent. J Agric Sci. 2013;5:54–63.Google Scholar
  33. 33.
    Zhaorigetu S, Yanaka N, Sasaki M, Watanabe H, Kato N. Inhibitory effects of silk protein, sericin on UVB-induced acute damage and tumor promotion by reducing oxidative stress in the skin of hairless mouse. J Photochem Photobiol B Biol. 2003;71:11–7.CrossRefGoogle Scholar
  34. 34.
    Takasu Y, Yamada H, Tsubouchi K. Isolation of three main sericin components from the cocoon of the silkworm, Bombyx mori. Biosci Biotechnol Biochem. 2002;66:2715–8.CrossRefGoogle Scholar
  35. 35.
    Tao W, Li M, Xie R. Preparation and structure of porous silk sericin materials. Macromol Mater Eng. 2005;290:188–94.CrossRefGoogle Scholar
  36. 36.
    Aramwit P, Siritientong T, Srichana T. Potential applications of silk sericin, a natural protein from textile industry by-products. Waste Manag Res. 2012;30:217–24. Scholar
  37. 37.
    Morikawa M, Kimura T, Murakami M, Katayama K, Terada S, Yamaguchi A. Rat islet culture in serum-free medium containing silk protein sericin. J Hepato-Biliary-Pancreat Surg. 2009;16:223–8.CrossRefGoogle Scholar
  38. 38.
    Terada S, Nishimura T, Sasaki M, Yamada H, Miki M. Sericin, a protein derived from silkworms, accelerates the proliferation of several mammalian cell lines including a hybridoma. Cytotechnology. 2003;40:3–12.CrossRefGoogle Scholar
  39. 39.
    Tsujimoto K, Takagi H, Takahashi M, Yamada H, Nakamori S, Tagaki H, et al. Cryoprotective effect of the serine-rich repetitive sequence in silk protein sericin. J Biochem. 2001;986:979–86.CrossRefGoogle Scholar
  40. 40.
    Salunkhe NH, Jadhav NR, More HN, Jadhav AD. Screening of drug-sericin solid dispersions for improved solubility and dissolution. Int J Biol Macromol Elsevier BV. 2018;107:1683–91. Available from. Scholar
  41. 41.
    Zhang YQ. Applications of natural silk protein sericin in biomaterials. Biotechnol Adv. 2002;20:91–100.CrossRefGoogle Scholar
  42. 42.
    Rawlinson CF, Williams AC, Timmins P, Grimsey I. Polymer-mediated disruption of drug crystallinity. Int J Pharm. 2007;336:42–8.CrossRefGoogle Scholar
  43. 43.
    Deodware SA, Sathe DJ, Choudhari PB, Lokhande TN, Gaikwad SH. Development and molecular modeling of Co(II), Ni(II) and Cu(II) complexes as high acting anti breast cancer agents. Arab J Chem The Authors. 2017;10:262–72. Available from: Scholar
  44. 44.
    Abhale YK, Shinde AD, Deshmukh KK, Nawale L, Sarkar D, Choudhari PB, et al. Synthesis, antimycobacterial screening and molecular docking studies of 4-aryl-4′-methyl-2′-aryl-2,5′-bisthiazole derivatives. Med Chem Res Springer US. 2017;26:1–11. Available from: Scholar
  45. 45.
    Patravale AA, Gore AH, Kolekar GB, Deshmukh MB, Choudhari PB, Bhatia MS, et al. Synthesis, biological evaluation and molecular docking studies of some novel indenospiro derivatives as anticancer agents. J Taiwan Inst Chem Eng Elsevier BV. 2016;68:105–18. Available from: Scholar
  46. 46.
    Shibata YFM, Kokudai M, Noda S, Okada H, Kondoh M, Watanabe Y. Effect of characteristics of compounds on maintenance of an amorphous state in solid dispersion with crospovidone. J Pharm Sci. 2007;96:1537–47.CrossRefGoogle Scholar
  47. 47.
    Savolainen M, Kogermann K, Heinz A, Aaltonen J, Peltonen L, Strachan C, et al. Better understanding of dissolution behaviour of amorphous drugs by in situ solid-state analysis using Raman spectroscopy. Eur J Pharm Biopharm Elsevier BV. 2009;71:71–9. Available from: Scholar
  48. 48.
    Ahmed MO, Al-Badr AA. Lornoxicam. 1st ed. profiles drug Subst. Excipients Relat. Methodol. Elsevier Inc.; 2011. Available from: Scholar
  49. 49.
    Ozaki S, Minamisono T, Yamashita T, Kato T, Kushida I. Supersaturation–nucleation behavior of poorly soluble drugs and its impact on the oral absorption of drugs in thermodynamically high-energy forms. J Pharm Sci. 2012;101:214–22.CrossRefGoogle Scholar
  50. 50.
    Ozaki S, Kushida I, Yamashita T, Hasebe T, Shirai O, Kano K. Evaluation of drug supersaturation by thermodynamic and kinetic approaches for the prediction of oral absorbability in amorphous pharmaceuticals. J Pharm Sci. 2012;101:4220–30.CrossRefGoogle Scholar
  51. 51.
    Ozaki S, Kushida I, Yamashita T, Hasebe T, Shirai O, Kano K. Inhibition of crystal nucleation and growth by water-soluble polymers and its impact on the supersaturation profiles of amorphous drugs. J Pharm Sci. 2013;102:2273–81.CrossRefGoogle Scholar
  52. 52.
    Saboo S, Mugheirbi NA, Zemlyanov DY, Kestur US, Taylor LS. Congruent release of drug and polymer: a “sweet spot” in the dissolution of amorphous solid dispersions. J Control Release Elsevier BV. 2019;298:68–82. Available from. Scholar
  53. 53.
    Sethia S, Squillante E. Solid dispersion of carbamazepine in PVP K30 by conventional solvent evaporation and supercritical methods. Int J Pharm. 2004;272:1–10.CrossRefGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2019

Authors and Affiliations

  • Nitin Salunkhe
    • 1
  • Namdeo Jadhav
    • 2
    Email author
  • Harinath More
    • 2
  • Prafulla Choudhari
    • 2
  1. 1.Department of PharmaceuticsAdarsh College of PharmacyVitaIndia
  2. 2.Department of PharmaceuticsBharati Vidyapeeth College of PharmacyKolhapurIndia

Personalised recommendations