Skip to main content
SpringerLink
Log in

Characterizing and Exploring the Differences in Dissolution and Stability Between Crystalline Solid Dispersion and Amorphous Solid Dispersion

  • Research Article
  • Published:
AAPS PharmSciTech Aims and scope Submit manuscript

Abstract

Solid dispersion is one of the most effective ways to improve the dissolution of insoluble drugs. When the carrier can highly disperse the drug, it will increase the wettability of the drug and reduce the surface tension, thus improving the solubility, dissolution, and bioavailability. However, amorphous solid dispersions usually have low drug loading and poor stability. Therefore, the goal of this work is to study the increased dissolution and high stability of high drug-loading crystalline solid dispersion (CSD), and the difference in dissolution and stability of high-loading and low-loading amorphous solid dispersion (ASD). A CSD of nimodipine with a drug loading of 90% was prepared by wet milling, with hydroxypropyl cellulose (model: HPC-SL) and sodium dodecyl sulfate as stabilizers and spray drying. At the same time, the gradient drug–loaded ASD was prepared by hot melt extrusion with HPC-SL as the carrier. Each preparation was characterized by DSC, PXRD, FT-IR, SEM, and in vitro dissolution testing. The results indicated that the drug in CSD existed in a crystalline state. The amorphous drug molecules in the low drug-loading ASD were uniformly dispersed in the carrier, while the drug state in the high drug-loading ASD was aggregates of the amorphous drug. At the end of the dissolution assay, the 90% drug-loading CSD increased cumulative dissolution to 60%, and the 10% drug-loading ASD achieved a cumulative dissolution rate of 90%.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10

Similar content being viewed by others

References

  1. Vasconcelos T, Marques S, das Neves J, Sarmento B. Amorphous solid dispersions: rational selection of a manufacturing process ☆. Adv Drug Deliv Rev. 2016;100(100):85–101.

    CAS  Google Scholar 

  2. Jermain SV, Brough C, Williams RO. Amorphous solid dispersions and nanocrystal technologies for poorly water-soluble drug delivery – an update. Int J Pharm. 2018;535(1):379–92.

    CAS  Google Scholar 

  3. Schammã B, et al. Investigation of drug-excipient interactions in biclotymol amorphous solid dispersions. Mol Pharm. 2018;15(3):1112–25.

    Google Scholar 

  4. Ma X, Williams RO. Characterization of amorphous solid dispersions: an update. Journal of Drug Delivery Science and Technology. 2019;50:113–24.

    CAS  Google Scholar 

  5. Dani P, Puri V, Bansal AK. Solubility advantage from amorphous etoricoxib solid dispersions. Drug Development & Industrial Pharmacy. 2014;40(1):92–101.

    CAS  Google Scholar 

  6. Truong DH, Tran TH, Ramasamy T, Choi JY, Choi HG, Yong CS, et al. Preparation and characterization of solid dispersion using a novel amphiphilic copolymer to enhance dissolution and oral bioavailability of sorafenib. Powder Technol. 2015;283:260–5.

    CAS  Google Scholar 

  7. Metre S, Mukesh S, Samal SK, Chand M, Sangamwar AT. Enhanced biopharmaceutical performance of rivaroxaban through polymeric amorphous solid dispersion. Mol Pharm. 2018;15(2):652–68.

    CAS  Google Scholar 

  8. Frizon F, Eloy JO, Donaduzzi CM, Mitsui ML, Marchetti JM. Dissolution rate enhancement of loratadine in polyvinylpyrrolidone K-30 solid dispersions by solvent methods. Powder Technol. 2013;235:532–9.

    CAS  Google Scholar 

  9. Dos Santos KM, et al. Development of solid dispersions of β-lapachone in PEG and PVP by solvent evaporation method. Drug Development & Industrial Pharmacy. 2017:1.

  10. Wlodarski K, Sawicki W, Paluch KJ, Tajber L, Grembecka M, Hawelek L, et al. The influence of amorphization methods on the apparent solubility and dissolution rate of tadalafil. Eur J Pharm Sci. 2014;62(4):132–40.

    CAS  Google Scholar 

  11. Xu W-J, Xie HJ, Cao QR, Shi LL, Cao Y, Zhu XY, et al. Enhanced dissolution and oral bioavailability of valsartan solid dispersions prepared by a freeze-drying technique using hydrophilic polymers. Drug Delivery. 2016;23(1):41–8.

    CAS  Google Scholar 

  12. Chan SY, Qi S, Craig DQM. An investigation into the influence of drug–polymer interactions on the miscibility, processability and structure of polyvinylpyrrolidone-based hot melt extrusion formulations. Int J Pharm. 2015;496(1):95–106.

    CAS  Google Scholar 

  13. Li Y, Pang H, Guo Z, Lin L, Dong Y, Li G, et al. Interactions between drugs and polymers influencing hot melt extrusion. J Pharm Pharmacol. 2014;66(2):148–66.

    CAS  Google Scholar 

  14. Agrawal AM, Dudhedia MS, Zimny E. Hot melt extrusion: development of an amorphous solid dispersion for an insoluble drug from mini-scale to clinical scale. AAPS PharmSciTech. 2016;17(1):1–15.

    Google Scholar 

  15. Nakach M, Authelin JR, Perrin MA, Lakkireddy HR. Comparison of high pressure homogenization and stirred bead milling for the production of nano-crystalline suspensions. Int J Pharm. 2018;547(1–2):61–71.

    CAS  Google Scholar 

  16. Raida A-K, Mahima B, John S. Nanosizing techniques for improving bioavailability of drugs. Journal of controlled release : official journal of the Controlled Release Society. 2017;260:202–12.

    Google Scholar 

  17. Srivalli KMR, Mishra B. Drug nanocrystals: a way toward scale-up. Saudi Pharmaceutical Journal. 2016;24(4):386–404.

    Google Scholar 

  18. Ahmed B, Brown CJ, McGlone T, Bowering DL, Sefcik J, Florence AJ. Engineering of acetaminophen particle attributes using a wet milling crystallisation platform. Int J Pharm. 2019;554:201–11.

    CAS  Google Scholar 

  19. Kumar D, Worku ZA, Gao Y, Kamaraju VK, Glennon B, Babu RP, et al. Comparison of wet milling and dry milling routes for ibuprofen pharmaceutical crystals and their impact on pharmaceutical and biopharmaceutical properties. Powder Technol. 2018;330:228–38.

    CAS  Google Scholar 

  20. Philip Chi Lip K, et al. Nanotechnology versus other techniques in improving drug dissolution. Curr Pharm Des. 2014;3(20):474–82.

    Google Scholar 

  21. Shah SR, Parikh RH, Chavda JR, Sheth NR. Glibenclamide nanocrystals for bioavailability enhancement: formulation design, process optimization, and pharmacodynamic evaluation. J Pharm Innov. 2014;9(3):227–37.

    Google Scholar 

  22. Chengyu, et al. Oral bioavailability enhancement of β-lapachone, a poorly soluble fast crystallizer, by cocrystal, amorphous solid dispersion, and crystalline solid dispersion. European Journal of Pharmaceutics & Biopharmaceutics. 2018;124:73–81.

    Google Scholar 

  23. Chen J, Chen Y, Huang W, Wang H, du Y, Xiong S. Bottom-up and top-down approaches to explore sodium dodecyl sulfate and soluplus on the crystallization inhibition and dissolution of felodipine extrudates. J Pharm Sci. 2018;107:2366–76.

    CAS  Google Scholar 

  24. Reema N, et al. A top-down technique to improve the solubility and bioavailability of aceclofenac: in vitro and in vivo studies. Int J Nanomedicine. 2017;12:4921–35.

    Google Scholar 

  25. Hasegawa Y, Higashi K, Yamamoto K, Moribe K. Direct evaluation of molecular states of piroxicam/poloxamer nanosuspension by suspended-state NMR and Raman spectroscopies. Mol Pharm. 2015;12(5):1564–72.

    CAS  Google Scholar 

  26. Kojima T, Karashima M, Yamamoto K, Ikeda Y. A combination of NMR methods to reveal the interfacial structure of a pharmaceutical nanocrystal and nanococrystal in the suspended state. Mol Pharm. 2018;15(9):3901–8.

    CAS  Google Scholar 

  27. Thombre AG, Caldwell WB, Friesen DT, McCray SB, Sutton SC. Solid nanocrystalline dispersions of ziprasidone with enhanced bioavailability in the fasted state. Mol Pharm. 2012;9(12):3526–34.

    CAS  Google Scholar 

  28. Qian F, Tao J, Desikan S, Hussain M, Smith RL. Mechanistic investigation of Pluronic based nano-crystalline drug-polymer solid dispersions. Pharm Res. 2007;24(8):1551–60.

    CAS  Google Scholar 

  29. Shah N, Iyer RM, Mair HJ, Choi D, Tian H, Diodone R, et al. 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. 2013;102(3):967–81.

    CAS  Google Scholar 

  30. Williams HD, Trevaskis NL, Charman SA, Shanker RM, Charman WN, Pouton CW, et al. Strategies to address low drug solubility in discovery and development. Pharmacol Rev. 2013;65(1):315–499.

    Google Scholar 

  31. Choi J-S, Park J-S. Design of PVP/VA S-630 based tadalafil solid dispersion to enhance the dissolution rate. Eur J Pharm Sci. 2017;97:269–76.

    CAS  Google Scholar 

  32. Andres L, et al. Amorphous solid dispersions of piroxicam and Soluplus(®): qualitative and quantitative analysis of piroxicam recrystallization during storage. Int J Pharm. 2015;486(1–2):306–14.

    Google Scholar 

  33. Chen H, Pui Y, Liu C, Chen Z, Su CC, Hageman M, et al. Moisture-induced amorphous phase separation of amorphous solid dispersions: molecular mechanism, microstructure, and its impact on dissolution performance. J Pharm Sci. 2018;107(1):317–26.

    CAS  Google Scholar 

  34. S FD, J MA. Effect of polymer hydrophobicity on the stability of amorphous solid dispersions and supersaturated solutions of a hydrophobic pharmaceutical. Mol Pharm. 2019;16(2):682–8.

    Google Scholar 

  35. Lin SY, Lin HL, Chi YT, Huang YT, Kao CY, Hsieh WH. Thermoanalytical and Fourier transform infrared spectral curve-fitting techniques used to investigate the amorphous indomethacin formation and its physical stability in indomethacin-Soluplus® solid dispersions. Int J Pharm. 2015;496(2):457–65.

    CAS  Google Scholar 

  36. Wlodarski K, Sawicki W, Kozyra A, Tajber L. Physical stability of solid dispersions with respect to thermodynamic solubility of tadalafil in PVP-VA. European Journal of Pharmaceutics & Biopharmaceutics. 2015;96:237–46.

    CAS  Google Scholar 

  37. Onoue S, Aoki Y, Kawabata Y, Matsui T, Yamamoto K, Sato H, et al. Development of inhalable nanocrystalline solid dispersion of tranilast for airway inflammatory diseases. J Pharm Sci. 2011;100(2):622–33.

    CAS  Google Scholar 

  38. Bilgili E, Li M, Afolabi A. Is the combination of cellulosic polymers and anionic surfactants a good strategy for ensuring physical stability of BCS class II drug nanosuspensions? Pharmaceutical Development & Technology. 2015;21(4):499–510.

    Google Scholar 

  39. Karmwar P, Graeser K, Gordon KC, Strachan CJ, Rades T. Investigation of properties and recrystallisation behaviour of amorphous indomethacin samples prepared by different methods. Int J Pharm. 2011;417(1–2):94–100.

    CAS  Google Scholar 

  40. Tian B, Zhang L, Pan Z, Gou J, Zhang Y, Tang X. A comparison of the effect of temperature and moisture on the solid dispersions: aging and crystallization. Int J Pharm. 2014;475(1–2):385–92.

    CAS  Google Scholar 

  41. REVESZ A. Melting behavior and origin of strain in ball-milled nanocrystalline Al powders. J Mater Sci. 2005;40(7):1643–6.

    CAS  Google Scholar 

  42. Ng WK, Kwek JW, Yuen A, Tan CL, Tan R. Effect of milling on DSC thermogram of excipient adipic acid. AAPS PharmSciTech. 2010;11(1):159–67.

    CAS  Google Scholar 

  43. Analía S, et al. Development and in vitro evaluation of solid dispersions as strategy to improve albendazole biopharmaceutical behavior. Ther Deliv. 2018;9(9):623–38.

    Google Scholar 

  44. Paredes AJ, Bruni SS, Allemandi D, Lanusse C, Palma SD. Albendazole nanocrystals with improved pharmacokinetic performance in mice. Ther Deliv. 2018;9(2):89–97.

    CAS  Google Scholar 

  45. Paredes AJ, Llabot JM, Sánchez Bruni S, Allemandi D, Palma SD. Self-dispersible nanocrystals of albendazole produced by high pressure homogenization and spray-drying. Drug Dev Ind Pharm. 2016;42(10):1564–70.

    Google Scholar 

  46. Turpin ER, Taresco V, al-Hachami WA, Booth J, Treacher K, Tomasi S, et al. In Silico screening for solid dispersions the trouble with solubility parameters and χFH. Mol Pharm. 2018;15(10):4654–67.

    CAS  Google Scholar 

  47. Ye S, et al. Solubilities of crystalline drugs in polymers: an improved analytical method and comparison of solubilities of indomethacin and nifedipine in PVP, PVP/VA, and PVAc. J Pharm Sci. 2010;99(9):4023–31.

    Google Scholar 

  48. Gramaglia D, Conway BR, Kett VL, Malcolm RK, Batchelor HK. High speed DSC (hyper-DSC) as a tool to measure the solubility of a drug within a solid or semi-solid matrix. Int J Pharm. 2005;301(1):1–5.

    CAS  Google Scholar 

  49. Rumondor ACF, Wikström H, van Eerdenbrugh B, Taylor LS. Understanding the tendency of amorphous solid dispersions to undergo amorphous–amorphous phase separation in the presence of absorbed moisture. AAPS PharmSciTech. 2011;12(4):1209–19.

    CAS  Google Scholar 

  50. Tong P, Zografi G. Effects of water vapor absorption on the physical and chemical stability of amorphous sodium indomethacin. AAPS PharmSciTech. 2004;5(2):9–16.

    Google Scholar 

  51. Lin X, et al. Physical stability of amorphous solid dispersions: a physicochemical perspective with thermodynamic. Kinetic and Environmental Aspects Pharmaceutical Research. 2018;35(6):125.

  52. Frank DS, Matzger AJ. Effect of polymer hydrophobicity on the stability of amorphous solid dispersions and supersaturated solutions of a hydrophobic pharmaceutical. Mol Pharm. 2019;16(2):682–8.

    CAS  Google Scholar 

  53. Indulkar AS, Lou X, Zhang GGZ, Taylor LS. Insights into the dissolution mechanism of ritonavir–copovidone amorphous solid dispersions: importance of congruent release for enhanced performance. Mol Pharm. 2019;16(3):1327–39.

    CAS  Google Scholar 

  54. Purohit HS, Taylor LS. Phase behavior of ritonavir amorphous solid dispersions during hydration and dissolution. Pharm Res. 2017;34(12):2842–61.

    CAS  Google Scholar 

  55. Calahan JL, Zanon RL, Alvarez-Nunez F, Munson EJ. Isothermal Microcalorimetry to investigate the phase separation for amorphous solid dispersions of AMG 517 with HPMC-AS. Mol Pharm. 2013;10(5):1949–57.

    CAS  Google Scholar 

  56. Dalsania S, et al. Impact of drug-polymer miscibility on enthalpy relaxation of Irbesartan amorphous solid dispersions. Pharm Res. 2018;35(2):1–11.

    CAS  Google Scholar 

  57. Marsac PJ, Li T, Taylor LS. Estimation of drug–polymer miscibility and solubility in amorphous solid dispersions using experimentally determined interaction parameters. Pharm Res. 2008;26(1):139–51.

    Google Scholar 

  58. Zhang J, Bunker M, Parker A, Madden-Smith CE, Patel N, Roberts CJ. The stability of solid dispersions of felodipine in polyvinylpyrrolidone characterized by nanothermal analysis. Int J Pharm. 2011;414(1–2):210–7.

    CAS  Google Scholar 

  59. Lin D, Huang Y. A thermal analysis method to predict the complete phase diagram of drug–polymer solid dispersions. Int J Pharm. 2010;399(1):109–15.

    CAS  Google Scholar 

Download references

Acknowledgments

We are thankful for Amanda Pearce’s correction for the manuscript.

Funding

The authors received financial support from the National Natural Science Foundation of China (No. 81673378) and Program for Liaoning Innovative Talents in University (2012520007).

Author information

Author notes

  1. Xiaolin Wang and Lu Zhang contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmaceutics Science, Shenyang Pharmaceutical University, Shenyang, 110016, China

    Xiaolin Wang, Lu Zhang, Danyang Ma, Xing Tang, Yu Zhang, Jingxin Gou, Yanjiao Wang & Haibing He

  2. School of Functional Food and Wine, Shenyang Pharmaceutical University, Shenyang, 110016, China

    Tian Yin

Authors
  1. Xiaolin Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lu Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Danyang Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xing Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yu Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Tian Yin
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jingxin Gou
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yanjiao Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Haibing He
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Haibing He.

Ethics declarations

Conflict of Interest

The authors declare have no conflicts of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, X., Zhang, L., Ma, D. et al. Characterizing and Exploring the Differences in Dissolution and Stability Between Crystalline Solid Dispersion and Amorphous Solid Dispersion. AAPS PharmSciTech 21, 262 (2020). https://doi.org/10.1208/s12249-020-01802-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1208/s12249-020-01802-0

KEY WORDS

Search

Navigation