Characterization of Grades of HPMCAS Spray Dried Dispersions of Itraconazole Based on Supersaturation Kinetics and Molecular Interactions Impacting Formulation Performance

Abstract

Purpose

The objective was to characterize hydroxypropyl methylcellulose acetate succinate (HMPCAS) grades L, M, and H to enhance itraconazole (ITZ) release and permeation from spray dried dispersions (SDDs), and to investigate underpinning molecular ITZ-HPMCAS interactions that differentiated grade performance.

Methods

ITZ or its SDDs were subjected to solution stabilization assessment, one-dimensional proton nuclear magnetic resonance (NMR) spectroscopy, saturation transfer difference NMR studies, small volume dissolution, solid state transformation studies, and in vitro dissolution/permeation flux studies.

Results

HPMCAS-L was the best performing grade overall and exhibited greatest ITZ supersaturation concentration, small volume dissolution, and in vitro dissolution/permeation flux. Meanwhile, H grade retarded ITZ precipitation to the greatest extent in solution stabilization studies and exhibited greater hydrophobic interaction with ITZ in NMR studies. However, this apparent advantage of H grade through hydrophobic interactions between drug-polymer appeared to limit overall dissolution/permeation performance of SDD.

Conclusions

In vitro SDD studies and drug-polymer interaction studies provided insight into the performance of HPMCAS grades, as well as the relative contributions of various mechanisms that polymer can promote ITZ absorption from SDD.

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Abbreviations

1D - 1H NMR:

One dimensional proton nuclear magnetic resonance

API:

Active pharmaceutical ingredient

ASDs:

Amorphous solid dispersions

DCM:

Dichloromethane

DMSO:

Dimethyl sulfoxide

DSC:

Differential scanning calorimetry

HME:

Hot melt extrusion HME

HPMCAS:

Hydroxypropyl methylcellulose acetate succinate

ITZ:

Itraconazole

MeOH:

Methanol

SDDs:

Spray dried dispersions

SSNMR:

Solid state nuclear magnetic resonance

STD-NMR:

Saturation transfer difference nuclear magnetic resonance

Tg:

Glass transition temperature

References

  1. 1.

    Warren DB, Benameur H, Porter CJ, Pouton CW. Using polymeric precipitation inhibitors to improve the absorption of poorly water-soluble drugs: a mechanistic basis for utility. J Drug Target. 2010;18(10):704–31.

    CAS  Article  Google Scholar 

  2. 2.

    Butler JM, Dressman JB. The developability classification system: application of biopharmaceutics concepts to formulation development. J Pharm Sci. 2010;99(12):4940–54.

    CAS  Article  Google Scholar 

  3. 3.

    Amidon GL, Lennernas H, Shah VP, Crison JR. A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm Res. 1995;12(3):413–20.

    CAS  Article  Google Scholar 

  4. 4.

    Alonzo DE, Gao Y, Zhou D, Mo H, Zhang GGZ, Taylor LS. Dissolution and precipitation behavior of amorphous solid dispersions. J Pharm Sci. 2011;100(8):3316–31.

    CAS  Article  Google Scholar 

  5. 5.

    Brouwers J, Brewster ME, Augustijns P. Supersaturating drug delivery systems: the answer to solubility-limited oral bioavailability? J Pharm Sci. 2009;98(8):2549–72.

    CAS  Article  Google Scholar 

  6. 6.

    Deshpande TM, Shi H, Pietryka J, Hoag SW, Medek A. Investigation of polymer/surfactant interactions and their impact on Itraconazole solubility and precipitation kinetics for developing spray-dried amorphous solid dispersions. Mol Pharm. 2018;15(3):962–74.

    CAS  Article  Google Scholar 

  7. 7.

    Friesen DT, Shanker R, Crew M, Smithey DT, Curatolo WJ, Nightingale JA. Hydroxypropyl methylcellulose acetate succinate-based spray-dried dispersions: an overview. Mol Pharm. 2008;5(6):1003–19.

    CAS  Article  Google Scholar 

  8. 8.

    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.

  9. 9.

    Singh A, Van den Mooter G. Spray drying formulation of amorphous solid dispersions. Adv Drug Deliv Rev. 2016;100:27–50.

    CAS  Article  Google Scholar 

  10. 10.

    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. 2016;105(9):2527–44.

    CAS  Article  Google Scholar 

  11. 11.

    Riikka Laitinen PAP, Surwase S, Graeser K, Strachan CJ, Grohganz H, Rades T. Theoretical Considerations in Developing Amorphous Solid Dispersions. In: SH SN, Choi DS, Chokshi H, Malick AW, editors. Amorphous Solid Dispersions Theory and Practice. New York, NY: Advances in Delivery Science and Technology: Springer; 2014. p. 35–90.

    Google Scholar 

  12. 12.

    Tanno F, Nishiyama Y, Kokubo H, Obara S. Evaluation of hypromellose acetate succinate (HPMCAS) as a carrier in solid dispersions. Drug Dev Ind Pharm. 2004;30(1):9–17.

    CAS  Article  Google Scholar 

  13. 13.

    Alonzo DE, Zhang GG, Zhou D, Gao Y, Taylor LS. Understanding the behavior of amorphous pharmaceutical systems during dissolution. Pharm Res. 2010;27(4):608–18.

    CAS  Article  Google Scholar 

  14. 14.

    Dressman JB, Amidon GL, Reppas C, Shah VP. Dissolution testing as a prognostic tool for oral drug absorption: immediate release dosage forms. Pharm Res. 1998;15(1):11–22.

    CAS  Article  Google Scholar 

  15. 15.

    Klein S. The use of biorelevant dissolution media to forecast the in vivo performance of a drug. AAPS J. 2010;12(3):397–406.

    CAS  Article  Google Scholar 

  16. 16.

    Suarez-Sharp S, Li M, Duan J, Shah H, Seo P. Regulatory experience with in vivo in vitro correlations (IVIVC) in new drug applications. AAPS J. 2016;18(6):1379–90.

    CAS  Article  Google Scholar 

  17. 17.

    Kostewicz ES, Abrahamsson B, Brewster M, Brouwers J, Butler J, Carlert S, et al. In vitro models for the prediction of in vivo performance of oral dosage forms. European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences. 2014;57:342–66.

  18. 18.

    Ginski MJ, Taneja R, Polli JE. Prediction of dissolution-absorption relationships from a continuous dissolution/Caco-2 system. AAPS pharmSci. 1999;1(2):E3.

    CAS  Article  Google Scholar 

  19. 19.

    Hate SS, Reutzel-Edens SM, Taylor LS. Absorptive dissolution testing of supersaturating systems: impact of absorptive sink conditions on solution phase behavior and mass transport. Mol Pharm. 2017;14(11):4052–63.

    CAS  Article  Google Scholar 

  20. 20.

    Phillips DJ, Pygall SR, Cooper VB, Mann JC. Overcoming sink limitations in dissolution testing: a review of traditional methods and the potential utility of biphasic systems. J Pharm Pharmacol. 2012;64(11):1549–59.

    CAS  Article  Google Scholar 

  21. 21.

    Takeuchi S, Tsume Y, Amidon GE, Amidon GL. Evaluation of a three compartment in vitro gastrointestinal simulator dissolution apparatus to predict in vivo dissolution. J Pharm Sci. 2014;103(11):3416–22.

    CAS  Article  Google Scholar 

  22. 22.

    Bevernage J, Forier T, Brouwers J, Tack J, Annaert P, Augustijns P. Excipient-mediated supersaturation stabilization in human intestinal fluids. Mol Pharm. 2011;8(2):564–70.

    CAS  Article  Google Scholar 

  23. 23.

    Stewart AM, Grass ME, Mudie DM, Morgen MM, Friesen DT, Vodak DT. Development of a biorelevant, material-sparing membrane flux test for rapid screening of bioavailability-enhancing drug product formulations. Mol Pharm. 2017;14(6):2032–46.

    CAS  Article  Google Scholar 

  24. 24.

    Harmon P, Galipeau K, Xu W, Brown C, Wuelfing WP. Mechanism of dissolution-induced nanoparticle formation from a Copovidone-based amorphous solid dispersion. Mol Pharm. 2016;13(5):1467–81.

    CAS  Article  Google Scholar 

  25. 25.

    Honick M, Sarpal K, Alayoubi A, Zidan A, Hoag SW, Hollenbeck RG, et al. Utility of films to anticipate effect of drug load and polymer on dissolution performance from tablets of amorphous Itraconazole spray-dried dispersions. AAPS PharmSciTech. 2019;20(8):331.

  26. 26.

    Claridge TDW. Protein - ligand screening by NMR. High-Resolution NMR Techniques in Organic Chemistry. 3 ed. ProQuest Ebook Central: Elsevier Science & Technology; 2016. p. 421–56.

  27. 27.

    Angulo J, Enriquez-Navas PM, Nieto PM. Ligand-receptor binding affinities from saturation transfer difference (STD) NMR spectroscopy: the binding isotherm of STD initial growth rates. Chemistry (Weinheim an der Bergstrasse, Germany). 2010;16(26):7803–12.

    CAS  Google Scholar 

  28. 28.

    Viegas A, Manso J, Nobrega FL, Cabrita EJ. Saturation-transfer difference (STD) NMR: a simple and fast method for ligand screening and characterization of protein binding. J Chem Educ. 2011;88(7):990–4.

    CAS  Article  Google Scholar 

  29. 29.

    Ueda K, Higashi K, Yamamoto K, Moribe K. Inhibitory effect of Hydroxypropyl methylcellulose acetate succinate on drug recrystallization from a supersaturated solution assessed using nuclear magnetic resonance measurements. Mol Pharm. 2013;10(10):3801–11.

    CAS  Article  Google Scholar 

  30. 30.

    DiNunzio JC, Hughey JR, Brough C, Miller DA, Williams RO 3rd, McGinity JW. Production of advanced solid dispersions for enhanced bioavailability of itraconazole using KinetiSol dispersing. Drug Dev Ind Pharm. 2010;36(9):1064–78.

    CAS  Article  Google Scholar 

  31. 31.

    Sarabu S, Kallakunta VR, Bandari S, Batra A, Bi V, Durig T, et al. Hypromellose acetate succinate based amorphous solid dispersions via hot melt extrusion: effect of drug physicochemical properties. Carbohydr Polym. 2020;233:115828.

  32. 32.

    Handbook AHPCP. In: Ashland, editor. https://www.ashland.com/file_source/Ashland/Industries/Pharmaceutical/Links/PC-126246_AquaSolve_HPMCAS_Physical_Chemical_Propertiespdf.

  33. 33.

    Inactive Ingredient Search for Approved Drug Products, (2020).

  34. 34.

    Gray V. Dissolution testing using Fiber optics— a regulatory perspective. Dissolution Technologies. 2003;10:33–6.

    Article  Google Scholar 

  35. 35.

    Tsinman K, Tsinman O, Lingamaneni R, Zhu S, Riebesehl B, Grandeury A, et al. Ranking Itraconazole formulations based on the flux through artificial lipophilic membrane. Pharm Res. 2018;35(8):161.

  36. 36.

    Stewart AM, Grass ME, Brodeur TJ, Goodwin AK, Morgen MM, Friesen DT, et al. Impact of drug-rich colloids of Itraconazole and HPMCAS on membrane flux in vitro and Oral bioavailability in rats. Mol Pharm. 2017;14(7):2437–49.

  37. 37.

    Guidance for Industry, dissolution testing of immediate release solid dosage forms, (1997).

  38. 38.

    Ueda K, Higashi K, Yamamoto K, Moribe K. The effect of HPMCAS functional groups on drug crystallization from the supersaturated state and dissolution improvement. Int J Pharm. 2014;464(1):205–13.

    CAS  Article  Google Scholar 

  39. 39.

    Van Eerdenbrugh B, Baird JA, Taylor LS. Crystallization tendency of active pharmaceutical ingredients following rapid solvent evaporation—classification and comparison with crystallization tendency from undercooled melts. J Pharm Sci. 2010;99(9):3826–38.

    Article  Google Scholar 

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Adhikari, A., Polli, J.E. Characterization of Grades of HPMCAS Spray Dried Dispersions of Itraconazole Based on Supersaturation Kinetics and Molecular Interactions Impacting Formulation Performance. Pharm Res 37, 192 (2020). https://doi.org/10.1007/s11095-020-02909-6

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KEY WORDS

  • hydroxypropyl methylcellulose acetate succinate
  • interactions
  • itraconazole
  • spray dried dispersions
  • supersaturation