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Release Enhancement by Plasticizer Inclusion for Amorphous Solid Dispersions Containing High Tg Drugs

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Abstract

Purpose

Plasticizers are commonly used in the preparation of amorphous solid dispersions (ASDs) with the main goal of aiding processability; however, to the best of our knowledge, the impact of plasticizers on drug release has not been explored. The goal of this study was to evaluate diverse plasticizers, including glycerol and citrate derivatives, as additives to increase the drug loading where good drug release could be achieved from copovidone (PVPVA)-based dispersions, focusing on high glass transition (Tg) drugs, atazanavir (ATZ) and ledipasvir (LED).

Methods

ASDs were prepared using the high Tg compounds, atazanavir (ATZ) and ledipasvir (LED), as model drugs. Release was evaluated using surface normalized dissolution testing. Differential scanning calorimetry was used to measure glass transition temperature and water vapor sorption was performed on select samples.

Results

The presence of a plasticizer at 5% w/w for ATZ and 10% w/w for LED ASDs, led to improved drug release. For ATZ ASDs, in the absence of plasticizer, release was very poor at drug loadings of 10% w/w and above. Good release was obtained for plasticized ASDs up to a drug loading of 25%. The corresponding improvement for LED was from 5 to 20% DL. Interestingly, for a low Tg compound, ritonavir, relatively smaller improvements in release as a function of drug loading were achieved through plasticizer incorporation.

Conclusions

The use of plasticizers represents a potential new strategy to increase drug loading in ASDs for high Tg compounds with a low tendency to crystallize and may help improve a major limitation of ASD formulations, namely the high excipient burden.

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Abbreviations

ACN:

Acetonitrile

API:

Active Pharmaceutical Ingredient

ASD:

Amorphous Solid Dispersion

ATZ:

Atazanavir

DL:

Drug Loading

DSC:

Differential Scanning Calorimetry

DVS:

Dynamic vapor sorption (DVS)

GTA:

Glycerol triacetate

GTB:

Glycerol tributyrate

LED:

Ledipasvir

LLPS:

Liquid-Liquid phase separation

LoC:

Limit of Congruency

PVPVA:

Polyvinylpyrrolidone/vinyl acetate or copovidone

PXRD:

Powder X-ray diffraction

RTV:

Ritonavir

T g :

Glass transition temperature

TBAC:

Tributyl o-acetylcitrate

TBC:

Tri-n-butyl citrate

TEAC:

Triethyl o-acetylcitrate

TEC:

Triethyl citrate

TFA:

Trifluoroacetic Acid

References

  1. Williams HD, et al. Strategies to address low drug solubility in discovery and development. Pharmacol Rev. 2013;65:315–499.

    Article  PubMed  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;535:379–92.

    Article  CAS  PubMed  Google Scholar 

  3. Van Den Mooter G. The use of amorphous solid dispersions: a formulation strategy to overcome poor solubility and dissolution rate. Drug Discov Today Technol. 2012;9:e79–85.

    Article  Google Scholar 

  4. Solanki NG, Gumaste SG, Shah AV, Serajuddin ATM. Effects of surfactants on itraconazole-hydroxypropyl methylcellulose acetate succinate solid dispersion prepared by hot melt extrusion. II: Rheological analysis and extrudability testing. J Pharm Sci. 2019;108:3063–3073.

  5. Schittny A, Philipp-Bauer S, Detampel P, Huwyler J, Puchkov M. Mechanistic insights into effect of surfactants on oral bioavailability of amorphous solid dispersions. J Control Release. 2020;320:214–25.

    Article  CAS  PubMed  Google Scholar 

  6. He Y, Ho C. Amorphous solid dispersions: utilization and challenges in drug discovery and development. J Pharm Sci. 2015;104:3237–58.

    Article  CAS  PubMed  Google Scholar 

  7. Craig DQM. The mechanisms of drug release from solid dispersions in water-soluble polymers. Int J Pharm. 2002;231:131–44.

    Article  CAS  PubMed  Google Scholar 

  8. Vasconcelos T, Sarmento B, Costa P. Solid dispersions as strategy to improve oral bioavailability of poor water soluble drugs. Drug Discov Today. 2007;12:1068–75.

    Article  CAS  PubMed  Google Scholar 

  9. Taylor LS, Zhang GGZ. Physical chemistry of supersaturated solutions and implications for oral absorption. Adv Drug Deliv Rev. 2016;101:122–42.

    Article  CAS  PubMed  Google Scholar 

  10. Corrigan OI. Mechanisms of dissolution of fast release solid dispersions. Drug Dev Ind Pharm. 1985;11:697–724.

    Article  CAS  Google Scholar 

  11. Van Duong T, Van den Mooter G. The role of the carrier in the formulation of pharmaceutical solid dispersions. Part II: amorphous carriers. Exp Opin Drug Deliv. 2016;13:1681–1694.

  12. 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;16:1327–39.

    Article  CAS  PubMed  Google Scholar 

  13. Lang B, Liu S, McGinity JW, Williams RO. Effect of hydrophilic additives on the dissolution and pharmacokinetic properties of itraconazole-enteric polymer hot-melt extruded amorphous solid dispersions. Drug Dev Ind Pharm. 2016;42:429–45.

    Article  CAS  PubMed  Google Scholar 

  14. 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. 2019;298:68–82.

    Article  CAS  PubMed  Google Scholar 

  15. Saboo S, Moseson DE, Kestur US, Taylor LS. Patterns of drug release as a function of drug loading from amorphous solid dispersions: a comparison of five different polymers. Eur J Pharm Sci. 2020;155: 105514.

    Article  CAS  PubMed  Google Scholar 

  16. Que C, et al. Insights into the dissolution behavior of ledipasvir-copovidone amorphous solid dispersions: role of drug loading and intermolecular interactions. Mol Pharm. 2019;16:5054–67.

    Article  CAS  PubMed  Google Scholar 

  17. Saboo S, Kestur US, Flaherty DP, Taylor LS. Congruent release of drug and polymer from amorphous solid dispersions: insights into the role of drug-polymer hydrogen bonding, surface crystallization, and glass transition. Mol Pharm. 2020;17:1261–75.

    Article  CAS  PubMed  Google Scholar 

  18. Yang R, et al. Drug release and nanodroplet formation from amorphous solid dispersions: insight into the roles of drug physicochemical properties and polymer selection. Mol Pharm. 2021. https://doi.org/10.1021/acs.molpharmaceut.1c00055.

    Article  PubMed  Google Scholar 

  19. Kumar V, et al. Binary and ternary solid dispersions of an anticancer preclinical lead, IIIM-290: in vitro and in vivo studies. Int J Pharm. 2019;570: 118683.

    Article  CAS  PubMed  Google Scholar 

  20. Prasad D, Chauhan H, Atef E. Role of molecular interactions for synergistic precipitation inhibition of poorly soluble drug in supersaturated drug-polymer-polymer ternary solution. Mol Pharm. 2016;13:756–65.

    Article  CAS  PubMed  Google Scholar 

  21. Davis MT, Potter CB, Mohammadpour M, Albadarin AB, Walker GM. Design of spray dried ternary solid dispersions comprising itraconazole, soluplus and HPMCP: Effect of constituent compositions. Int J Pharm. 2017;519:365–72.

    Article  CAS  PubMed  Google Scholar 

  22. Prasad D, Chauhan H, Atef E. Amorphous stabilization and dissolution enhancement of amorphous ternary solid dispersions: Combination of polymers showing drug-polymer interaction for synergistic effects. J Pharm Sci. 2014;103:3511–23.

    Article  CAS  PubMed  Google Scholar 

  23. Song Y, et al. Acid-base interactions of polystyrene sulfonic acid in amorphous solid dispersions using a combined UV/FTIR/XPS/ssNMR study. Mol Pharm. 2016;13:483–92.

    Article  CAS  PubMed  Google Scholar 

  24. Nie H, et al. Investigating the interaction pattern and structural elements of a drug-polymer complex at the molecular level. Mol Pharm. 2015. https://doi.org/10.1021/acs.molpharmaceut.5b00162.

    Article  PubMed  Google Scholar 

  25. Song Y, et al. Investigation of drug-excipient interactions in lapatinib amorphous solid dispersions using solid-State NMR spectroscopy. Mol Pharm. 2015;12:857–66.

    Article  CAS  PubMed  Google Scholar 

  26. Singh S, et al. Supersolubilization and amorphization of a model basic drug, haloperidol, by interaction with weak acids. Pharm Res. 2013;30:1561–73.

    Article  CAS  PubMed  Google Scholar 

  27. Meng F, Ferreira R, Zhang F. Effect of surfactant level on properties of celecoxib amorphous solid dispersions. J Drug Deliv Sci Technol. 2019;49:301–7.

    Article  CAS  Google Scholar 

  28. Alhayali A, Tavellin S, Velaga S. Dissolution and precipitation behavior of ternary solid dispersions of ezetimibe in biorelevant media. Drug Dev Ind Pharm. 2017;43:79–88.

    Article  CAS  PubMed  Google Scholar 

  29. Janssens S, et al. Formulation and characterization of ternary solid dispersions made up of Itraconazole and two excipients, TPGS 1000 and PVPVA 64, that were selected based on a supersaturation screening study. Eur J Pharm Biopharm. 2008;69:158–66.

    Article  CAS  PubMed  Google Scholar 

  30. Wan LSC, Heng PWS, Chia CGH. Plasticizers and their effects on microencapsulation process by spray-drying in an aqueous system. J Microencapsul. 1992;9:53–62.

    Article  CAS  PubMed  Google Scholar 

  31. Wan LSC, Heng PWS, Chia CGH. Citric acid as a plasticizer for spray-dried microcapsules. J Microencapsul. 1993;10:11–23.

    Article  CAS  PubMed  Google Scholar 

  32. Wan LSC, Heng PWS, Chia CGH. Preparation of coated particles using a spray drying process with an aqueous system_. Int J Pharm. 1991;77:183–91.

    Article  CAS  Google Scholar 

  33. Mendonsa N, et al. Manufacturing strategies to develop amorphous solid dispersions : an overview. J Drug Deliv Sci Technol. 2020;55: 101459.

    Article  CAS  PubMed  Google Scholar 

  34. Solanki NG, et al. Effects of surfactants on itraconazole-HPMCAS solid dispersion prepared by hot melt extrusion. I: miscibility and drug release. J Pharm Sci. 2018;1–13. https://doi.org/10.1016/j.xphs.2018.10.058.

  35. Zhu Y, Shah NH, Malick AW, Infeld MH, McGinity JW. Solid-state plasticization of an acrylic polymer with chlorpheniramine maleate and triethyl citrate. Int J Pharm. 2002;241:301–10.

    Article  CAS  PubMed  Google Scholar 

  36. Wu C, McGinity JW. Influence of ibuprofen as a solid-state plasticizer in Eudragit RS 30 D on the physicochemical properties of coated beads. AAPS PharmSciTech. 2001;2(4):24. https://doi.org/10.1208/pt020424.

  37. Correa-Soto CE, Gao Y, Indulkar AS, Zhang GGZ, Taylor LS. Role of surfactants in improving release from higher drug loading amorphous solid dispersions. Int J Pharm. 2022;625: 122120.

    Article  CAS  PubMed  Google Scholar 

  38. Miller DA, DiNunzio JC, Yang W, McGinity JW, Williams RO. Enhanced in vivo absorption of itraconazole via stabilization of supersaturation following acidic-to-neutral pH transition. Drug Dev Ind Pharm. 2008;34:890–902.

    Article  CAS  PubMed  Google Scholar 

  39. Immergut EH, Mark HF. Principles of plasticization. In: Plasticization and plasticizers processes. American Chemical Society; 1965. p. 1–26. https://doi.org/10.1021/ba-1965-0048.ch001.

  40. Labrecque LV, Kumar RA, Davé V, Gross RA, Mccarthy SP. Citrate esters as plasticizers for poly(lactic acid). J Appl Polym Sci. 1997;66:1507–13.

    Article  CAS  Google Scholar 

  41. Indulkar AS, Box KJ, Taylor R, Ruiz R, Taylor LS. pH-dependent liquid-liquid phase separation of highly supersaturated solutions of weakly basic drugs. Mol Pharm. 2015;12:2365–77.

    Article  CAS  PubMed  Google Scholar 

  42. Ilevbare GA, Taylor LS. Liquid-liquid phase separation in highly supersaturated aqueous solutions of poorly water-soluble drugs: Implications for solubility enhancing formulations. Cryst Growth Des. 2013. https://doi.org/10.1021/cg301679h.

    Article  Google Scholar 

  43. Feldman, D. Applied polymer science, 2nd ed., R. W. Tess and G. W. Poehlein Eds., ACS Symposium Series 285, Washington D.C., 1985, 1341 pp., price: $59.95 U.S. & Canada, $71.95 export price. J Polym Sci C Polym Lett. 1986;24:613–4. https://doi.org/10.1002/pol.1986.140241109.

  44. Ghebremeskel AN, Vemavarapu C, Lodaya M. Use of surfactants as plasticizers in preparing solid dispersions of poorly soluble API: Selection of polymer-surfactant combinations using solubility parameters and testing the processability. Int J Pharm. 2007;328:119–29.

    Article  CAS  PubMed  Google Scholar 

  45. Correa Soto CE, et al. Impact of surfactants on the performance of clopidogrel-copovidone amorphous solid dispersions: increased drug loading and stabilization of nanodroplets. Pharm Res. 2022;39:167–188.

  46. Mosquera-Giraldo LI, Trasi NS, Taylor LS. Impact of surfactants on the crystal growth of amorphous celecoxib. Int J Pharm. 2014;461:251–7.

    Article  CAS  PubMed  Google Scholar 

  47. Chen J, Ormes JD, Higgins JD, Taylor LS. Impact of surfactants on the crystallization of aqueous suspensions of celecoxib amorphous solid dispersion spray dried particles. Mol Pharm. 2015;12:533–41.

    Article  CAS  PubMed  Google Scholar 

  48. Indulkar AS, Gao Y, Raina SA, Zhang GGZ, Taylor LS. Impact of monomeric versus micellar surfactant and surfactant-polymer interactions on nucleation-induction times of atazanavir from supersaturated solutions. Cryst Growth Des. 2020;20:62–72.

    Article  CAS  Google Scholar 

  49. Yu J, et al. Surface enrichment of surfactants in amorphous drugs: an x-ray photoelectron spectroscopy study. Mol Pharm. 2022;19:654–60.

    Article  CAS  PubMed  Google Scholar 

  50. Saboo S, Bapat P, Moseson DE, Kestur US, Taylor LS. Exploring the role of surfactants in enhancing drug release from amorphous solid dispersions at higher drug loadings. Pharmaceutics. 2021;13:1–22.

    Article  Google Scholar 

  51. Devotta I, Badiger MV, Rajamohanan PR, Ganapathy S. Unusual retardation and enhancement in the polymer dissolution: role of disengagement dynamics. Chem Eng Sci. 1995;50:2557–2569.

  52. Zi P, et al. Solubility and bioavailability enhancement study of lopinavir solid dispersion matrixed with a polymeric surfactant - Soluplus. Eur J Pharm Sci. 2019;134:233–45.

    Article  CAS  PubMed  Google Scholar 

  53. Marcilla A, Beltrán M. Mechanisms of plasticizers action. Handb Plast Third Ed. 2017;119–134. https://doi.org/10.1016/B978-1-895198-97-3.50007-X.

  54. Williams ML, Landel RF, Ferry JD. The temperature dependence of relaxation mechanisms in amorphous polymers and other glass-forming liquids. J Am Chem Soc. 1955;77:3701–7.

    Article  CAS  Google Scholar 

  55. Cooper WJ, Krasicky PD, Rodriguez F. Dissolution rates of poly(methyl methacrylate) films in mixed solvents. J Appl Polym Sci. 1986;31:65–73.

    Article  CAS  Google Scholar 

  56. Cooper WJ, Krasicky PD, Rodriguez F. Effects of molecular weight and plasticization on dissolution rates of thin polymer films. Polymer (Guildf). 1985;26:1069–72.

    Article  CAS  Google Scholar 

  57. Devotta I, Mashelkar RA. Role of thermodynamic and kinetic factors in polymer dissolution in mixed solvents. Chem Eng Commun. 1996;156:31–43.

    Article  Google Scholar 

  58. Devotta I, Ambeskar VD, Mandhare AB, Mashelkar RA. The life time of a dissolving polymeric particle. Chem Eng Sci. 1994;49:645–54.

    Article  CAS  Google Scholar 

  59. Ouano AC, Carothers JA. Dissolution dynamics of some polymers: solvent-polymer boundaries. Polym Eng Sci. 1980;20:160–6.

    Article  Google Scholar 

  60. Ouano AC. Dissolution Kinetics of Polymers: Effect of Residual Solvent Content. Organic Coatings and Plastics Chemistry: Preprints of Papers presented at the Meeting of the Ameri vol. 45. Pergamon Press Inc.;1981.

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Acknowledgements

The authors would like to thank AbbVie Inc., for the financial support.

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Author notes

  1. Clara E. Correa-Soto

    Present address: Pivotal Drug Product, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA, USA

Authors and Affiliations

  1. Department of Industrial and Physical Pharmacy, College of Pharmacy, Purdue University, West Lafayette, IN, 47907, USA

    Clara E. Correa-Soto & Lynne S. Taylor

  2. Development Sciences, Research and Development, AbbVie Inc., North Chicago, IL, 60064, USA

    Yi Gao, Anura S. Indulkar & Geoff G. Z. Zhang

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Correspondence to Geoff G. Z. Zhang or Lynne S. Taylor.

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AbbVie and Purdue University jointly participated in study design, research, data collection, analysis and interpretation of data, writing, reviewing, and approving the publication. C.E.C.S. and L.S.T. have no additional conflicts of interest to report. A.S.I., Y.G., and G.G.Z.Z. are employees of AbbVie and may own AbbVie stock.

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Correa-Soto, C.E., Gao, Y., Indulkar, A.S. et al. Release Enhancement by Plasticizer Inclusion for Amorphous Solid Dispersions Containing High Tg Drugs. Pharm Res 40, 777–790 (2023). https://doi.org/10.1007/s11095-023-03483-3

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