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AAPS PharmSciTech

, 20:331 | Cite as

Utility of Films to Anticipate Effect of Drug Load and Polymer on Dissolution Performance from Tablets of Amorphous Itraconazole Spray-Dried Dispersions

  • Moshe Honick
  • Kanika Sarpal
  • Alaadin Alayoubi
  • Ahmed Zidan
  • Stephen W. Hoag
  • Robert G. Hollenbeck
  • Eric J. Munson
  • James E. PolliEmail author
Research Article
  • 63 Downloads

Abstract

Because spray-dried dispersion (SDD) performance depends on polymer selection and drug load, time- and resource-sparing methods to screen drug/polymer combinations before spray drying are desirable. The primary objective was to assess the utility of films to anticipate the effects of drug load and polymer grade on dissolution performance of tablets containing SDDs of itraconazole (ITZ). A secondary objective was to characterize the solid-state attributes of films and SDDs to explain drug load and polymer effects on dissolution performance. SDDs employed three different grades of hypromellose acetate succinate (i.e., either HPMCAS-L, HPMCAS-M, or HPMCAS-H). Solid-state characterization employed differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and solid-state nuclear magnetic resonance (ssNMR) spectroscopy. Results indicate that films correctly anticipated the effects of drug load and polymer on dissolution performance. The best dissolution profiles were observed under the following conditions: 20% drug loading performed better than 30% for both films and SDDs, and the polymer grade rank order was HPMCAS-L > HPMCAS-M > HPMCAS-H for both films and SDDs. No dissolution was detected from films or SDDs containing HPMCAS-H. Solid-state characterization revealed percent crystallinity and phase miscibility as contributing factors to dissolution, but were not the sole factors. Amorphous content in films varied with drug load (10% > 20% > 30%) and polymer grades (HPMCAS-L > HPMCAS-M > HPMCAS-H), in agreement with dissolution. In conclusion, films anticipated the rank-order effects of drug load and polymer grade on dissolution performance from SDDs of ITZ, in part through percent crystallinity and phase miscibility influences.

KEY WORDS

amorphous solid dispersion itraconazole spray drying dissolution hypromellose acetate succinate 

Abbreviations

ASD

Amorphous solid dispersions

CP/MAS

Cross-polarization magic angle spinning

DSC

Differential scanning calorimetry

HME

Hot melt extrusion

HPMC

Hypromellose

HPMCAS

Hypromellose acetate succinate

ITZ

Itraconazole

LOD

Loss on drying

OFAT

One factor at a time

PLM

Polarized light microscopy

PXRD

Powder X-ray diffraction

RH

Relative humidity

SDD

Spray-dried dispersion

SEM

Scanning electron microscopy

SMCC

Silicified microcrystalline cellulose

SSG

Sodium starch glycolate

ssNMR

Solid-state nuclear magnetic resonance

Tg

Glass transition temperature

TOSS

Total spinning sideband suppression

Notes

Funding Information

We are grateful to the National Institute for Pharmaceutical Technology and Education (NIPTE) and the U.S. Food and Drug Administration (FDA) for providing funds for this research. This study was funded by the FDA Grant to NIPTE titled “The Critical Path Manufacturing Sector Research Initiative (U01)”; Grant# 5U01FD004275. This scientific publication reflects the views of the authors and should not be construed to represent FDA’s views or policies.

Compliance with Ethical Standards

Conflict of Interest

The authors declare the following competing financial interest(s): E.J.M. is a partial owner of Kansas Analytical Services, a company that provides solid-state NMR services to pharmaceutical companies. The results presented here are from academic work at University of Kentucky, and no data from Kansas Analytical Services are presented.

Supplementary material

12249_2019_1541_MOESM1_ESM.docx (1.6 mb)
ESM 1 (DOCX 1669 kb)

References

  1. 1.
    Williams III RO, Watts AB, Miller DA, editors. Formulating poorly water soluble drugs. Cham: Springer International Publishing; 2016. (AAPS Advances in the Pharmaceutical Sciences Series; vol. 22).Google Scholar
  2. 2.
    Friesen DT, Shanker R, Crew M, Smithey DT, Curatolo WJ, Nightingale JAS. Hydroxypropyl methylcellulose acetate succinate-based spray-dried dispersions: an overview. Mol Pharm. 2008;5(6):1003–19.CrossRefGoogle Scholar
  3. 3.
    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. 2016;105(9):2527–44.CrossRefGoogle 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.CrossRefGoogle Scholar
  5. 5.
    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. American Chemical Society. 2018;15(3):962–74.CrossRefGoogle Scholar
  6. 6.
    Liu C, Chen Z, Chen Y, Lu J, Li Y, Wang S, et al. Improving oral bioavailability of Sorafenib by optimizing the “spring” and “parachute” based on molecular interaction mechanisms. Mol Pharm. American Chemical Society. 2016;13(2):599–608.CrossRefGoogle Scholar
  7. 7.
    Purohit HS, Taylor LS. Phase behavior of ritonavir amorphous solid dispersions during hydration and dissolution. Pharm Res. 2017;34(12):2842–61.CrossRefGoogle Scholar
  8. 8.
    Xie T, Taylor LS. Effect of temperature and moisture on the physical stability of binary and ternary amorphous solid dispersions of celecoxib. J Pharm Sci. 2017;106(1):100–10.CrossRefGoogle Scholar
  9. 9.
    Mistry P, Suryanarayanan R. Strength of drug–polymer interactions: implications for crystallization in dispersions. Cryst Growth Des American Chemical Society. 2016;16(9):5141–9.CrossRefGoogle Scholar
  10. 10.
    Nair R, Nyamweya N, Gönen S, Martínez-Miranda LJ, Hoag SW. Influence of various drugs on the glass transition temperature of poly(vinylpyrrolidone): a thermodynamic and spectroscopic investigation. Int J Pharm. 2001;225(1–2):83–96.CrossRefGoogle Scholar
  11. 11.
    Weuts I, Van Dycke F, Voorspoels J, De Cort S, Stokbroekx S, Leemans R, et al. Physicochemical properties of the amorphous drug, cast films, and spray dried powders to predict formulation probability of success for solid dispersions: etravirine. J Pharm Sci. 2011;100(1):260–74.CrossRefGoogle Scholar
  12. 12.
    Parikh T, Gupta SS, Meena AK, Vitez I, Mahajan N, Serajuddin ATM. Application of film-casting technique to investigate drug–polymer miscibility in solid dispersion and hot-melt extrudate. J Pharm Sci. 2015;104(7):2142–52.CrossRefGoogle Scholar
  13. 13.
    Shanbhag A, Rabel S, Nauka E, Casadevall G, Shivanand P, Eichenbaum G, et al. Method for screening of solid dispersion formulations of low-solubility compounds—miniaturization and automation of solvent casting and dissolution testing. Int J Pharm. 2008;351(1–2):209–18.CrossRefGoogle Scholar
  14. 14.
    Duarte Í, Santos JL, Pinto JF, Temtem M. Screening methodologies for the development of spray-dried amorphous solid dispersions. Pharm Res Springer US. 2015;32(1):222–37.CrossRefGoogle Scholar
  15. 15.
    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.CrossRefGoogle Scholar
  16. 16.
    Zhang S, Lee TWY, Chow AHL. Crystallization of Itraconazole polymorphs from melt. Cryst Growth Des American Chemical Society. 2016;16(7):3791–801.CrossRefGoogle Scholar
  17. 17.
    Zhang S, Lee TWY. Chow AHL. Crystallization of itraconazole polymorphs from melt. Cryst Growth Des. 2016;16(7)3791–3801CrossRefGoogle Scholar
  18. 18.
    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.CrossRefGoogle Scholar
  19. 19.
    Purohit HS, Ormes JD, Saboo S, Su Y, Lamm MS, Mann AKP, et al. Insights into nano- and micron-scale phase separation in amorphous solid dispersions using fluorescence-based techniques in combination with solid state nuclear magnetic resonance spectroscopy. Pharm Res. Springer US. 2017;34(7):1364–77.CrossRefGoogle Scholar
  20. 20.
    Woertz C, Kleinebudde P. Development of orodispersible polymer films containing poorly water soluble active pharmaceutical ingredients with focus on different drug loadings and storage stability. Int J Pharm. 2015;493(1–2):134–45.CrossRefGoogle Scholar
  21. 21.
    Woertz C, Kleinebudde P. Development of orodispersible polymer films with focus on the solid state characterization of crystalline loperamide. Eur J Pharm Biopharm. 2015;94:52–63.CrossRefGoogle Scholar
  22. 22.
    Kothari BH, Fahmy R, Claycamp HG, Moore CMV, Chatterjee S, Hoag SW. A systematic approach of employing quality by design principles: risk assessment and design of experiments to demonstrate process understanding and identify the critical process parameters for coating of the ethylcellulose pseudolatex dispersion using non-conventional fluid bed process. AAPS PharmSciTech Springer US. 2017;18(4):1135–57.CrossRefGoogle Scholar
  23. 23.
    Kozyra A, Mugheirbi NA, Paluch KJ, Garbacz G, Tajber L. Phase diagrams of polymer-dispersed liquid crystal systems of itraconazole/component immiscibility induced by molecular anisotropy. Mol Pharm. 2018;15(11):5192–206.CrossRefGoogle Scholar
  24. 24.
    Brostow W, Chiu R, Kalogeras IM, Vassilikou-Dova A. Prediction of glass transition temperatures: binary blends and copolymers. Mater Lett North-Holland. 2008;62(17–18):3152–5.Google Scholar
  25. 25.
    Dixon W, Schaefer J, Sefcik M, Stejskal E, McKay R. Total suppression of sidebands in CPMAS C-13 NMR. J Magn Reson. Academic Press. 1982;49(2):341–5.Google Scholar
  26. 26.
    Fung BM, Khitrin AK, Ermolaev K. An improved broadband decoupling sequence for liquid crystals and solids. J Magn Reson Academic Press. 2000;142(1):97–101.CrossRefGoogle Scholar
  27. 27.
    Barich DH, Gorman EM, Zell MT, Munson EJ. 3-Methylglutaric acid as a 13C solid-state NMR standard. Solid State Nucl Magn Reson. 2006;30(3–4):125–9.CrossRefGoogle Scholar
  28. 28.
    Yu T, Guo M. Recent developments in 13C solid state high-resolution NMR of polymers. Prog Polym Sci Pergamon. 1990;15(6):825–908.CrossRefGoogle Scholar
  29. 29.
    Shah B, Kakumanu VK, Bansal AK. Analytical techniques for quantification of amorphous/crystalline phases in pharmaceutical solids. J Pharm Sci. 2006;95(8):1641–65.CrossRefGoogle Scholar
  30. 30.
    Kennedy JF, Knill CJ. NMR of polymers, F.A. Bovey, P.A. Mirau, Academic, San Diego, 1996, pp. x + 459, Price $85-00, ISBN 0-12-119765-4. Carbohydr Polym. Elsevier; 1999;39(3):291.Google Scholar
  31. 31.
    Aso Y, Yoshioka S, Miyazaki T, Kawanishi T, Tanaka K, Kitamura S, et al. Miscibility of nifedipine and hydrophilic polymers as measured by (1)H-NMR spin-lattice relaxation. Chem Pharm Bull (Tokyo). 2007;55(8):1227–31.CrossRefGoogle Scholar
  32. 32.
    Alhalaweh A, Alzghoul A, Mahlin D, Bergström CAS. Physical stability of drugs after storage above and below the glass transition temperature: relationship to glass-forming ability. Int J Pharm Elsevier. 2015;495(1):312–7.CrossRefGoogle Scholar
  33. 33.
    Chakravarty P, Lubach JW, Hau J, Nagapudi K. A rational approach towards development of amorphous solid dispersions: experimental and computational techniques. Int J Pharm. 2017;519(1–2):44–57.CrossRefGoogle Scholar
  34. 34.
    Seo PR, Shah VP, Polli JE. Novel metrics to compare dissolution profiles. Pharm Dev Technol. 2002;7(2):257–65.CrossRefGoogle Scholar
  35. 35.
    Chen H, Pui Y, Liu C, Chen Z, Su C-C, 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.CrossRefGoogle Scholar
  36. 36.
    Mugheirbi NA, Marsac PJ, Taylor LS. Insights into water-induced phase separation in itraconazole–hydroxypropylmethyl cellulose spin coated and spray dried dispersions. Mol Pharm. American Chemical Society. 2017;14(12):4387–402.CrossRefGoogle Scholar
  37. 37.
    Mistry P, Amponsah-Efah KK, Suryanarayanan R. Rapid assessment of the physical stability of amorphous solid dispersions. Cryst Growth Des American Chemical Society. 2017;17(5):2478–85.CrossRefGoogle Scholar
  38. 38.
    Vodak DT, Morgen M. Design and development of HPMCAS-based spray-dried dispersions. New York: Springer; 2014. p. 303–22.Google Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2019

Authors and Affiliations

  • Moshe Honick
    • 1
  • Kanika Sarpal
    • 2
  • Alaadin Alayoubi
    • 3
  • Ahmed Zidan
    • 3
  • Stephen W. Hoag
    • 1
  • Robert G. Hollenbeck
    • 1
  • Eric J. Munson
    • 2
    • 4
  • James E. Polli
    • 1
    Email author
  1. 1.Department of Pharmaceutical SciencesUniversity of Maryland School of PharmacyBaltimoreUSA
  2. 2.Department of Pharmaceutical SciencesUniversity of Kentucky College of PharmacyLexingtonUSA
  3. 3.Food and Drug AdministrationSilver SpringUSA
  4. 4.Department of Industrial and Physical PharmacyPurdue University College of PharmacyWest LafayetteUSA

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