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A Lower Temperature FDM 3D Printing for the Manufacture of Patient-Specific Immediate Release Tablets

Abstract

Purpose

The fabrication of ready-to-use immediate release tablets via 3D printing provides a powerful tool to on-demand individualization of dosage form. This work aims to adapt a widely used pharmaceutical grade polymer, polyvinylpyrrolidone (PVP), for instant on-demand production of immediate release tablets via FDM 3D printing.

Methods

Dipyridamole or theophylline loaded filaments were produced via processing a physical mixture of API (10%) and PVP in the presence of plasticizer through hot-melt extrusion (HME). Computer software was utilized to design a caplet-shaped tablet. The surface morphology of the printed tablet was assessed using scanning electron microscopy (SEM). The physical form of the drugs and its integrity following an FDM 3D printing were assessed using x-ray powder diffractometry (XRPD), thermal analysis and HPLC. In vitro drug release studies for all 3D printed tablets were conducted in a USP II dissolution apparatus.

Results

Bridging 3D printing process with HME in the presence of a thermostable filler, talc, enabled the fabrication of immediate release tablets at temperatures as low as 110°C. The integrity of two model drugs was maintained following HME and FDM 3D printing. XRPD indicated that a portion of the loaded theophylline remained crystalline in the tablet. The fabricated tablets demonstrated excellent mechanical properties, acceptable in-batch variability and an immediate in vitro release pattern.

Conclusions

Combining the advantages of PVP as an impeding polymer with FDM 3D printing at low temperatures, this approach holds a potential in expanding the spectrum of drugs that could be used in FDM 3D printing for on demand manufacturing of individualised dosage forms.

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Abbreviations

API:

Active pharmaceutical ingredient

CAD:

Computer aided design

DSC:

Differential scanning calorimetry

FDM:

Fused deposition modelling

HME:

Hot melt extrusion

HPLC:

High performance liquid chromatography

PLA:

Polylactic acid

PVA:

Poly(vinyl alcohol)

PVP:

Polyvinylpyrrolidone

SEM:

Scanning electron microscopy

Tg:

Glass transition temperature

TGA:

Thermal gravimetric analysis

Tm:

Melting point

XRPD:

X-ray powder diffractometry

References

  1. 1.

    Chung P, Heller JA, Etemadi M, Ottoson PE, Liu JA, Rand L, et al. Rapid and low-cost prototyping of medical devices using 3D printed molds for liquid injection molding. J Vis Exp. 2014;88:e51745.

    PubMed  Google Scholar 

  2. 2.

    Dombroski CE, Balsdon ME, Froats A. The use of a low cost 3D scanning and printing tool in the manufacture of custom-made foot orthoses: a preliminary study. BMC Res Notes. 2014;7:443.

    Article  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Aprecia. Zipdose® technology. 12/3/2015. Available from: https://aprecia.com/zipdose-platform/zipdose-technology.php.

  4. 4.

    McLean S, Sheikh A, Cresswell K, Nurmatov U, Mukherjee M, Hemmi A, Pagliari C. The impact of telehealthcare on the quality and safety of care: a systematic overview. Plos One. 2013;8(8).

  5. 5.

    Sanderson K. 3D printing: the future of manufacturing medicine? Pharm J. 2015;7865.

  6. 6.

    Goyanes A, Robles Martinez P, Buanz A, Basit AW, Gaisford S. Effect of geometry on drug release from 3D printed tablets. Int J Pharm. 2015;494(2):657–63.

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Skowyra J, Pietrzak K, Alhnan MA. Fabrication of extended-release patient-tailored prednisolone tablets via fused deposition modelling (FDM) 3D printing. Eur J Pharm Sci. 2015;68:11–7.

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Goyanes A, Buanz ABM, Basit AW, Gaisford S. Fused-filament 3D printing (3DP) for fabrication of tablets. Int J Pharm. 2014;476(1–2):88–92.

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    Goyanes A, Buanz AB, Hatton GB, Gaisford S, Basit AW. 3D printing of modified-release aminosalicylate (4-ASA and 5-ASA) tablets. Eur J Pharm Biopharm. 2015;89:157–62.

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Goyanes A, Chang H, Sedough D, Hatton GB, Wang J, Buanz A, et al. Fabrication of controlled-release budesonide tablets via desktop (FDM) 3D printing. Int J Pharm. 2015;496(2):414–20.

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Boetker J, Water JJ, Aho J, Arnfast L, Bohr A, Rantanen J. Modifying release characteristics from 3D printed drug-eluting products. Eur J Pharm Sci. 2016.

  12. 12.

    Rosenzweig DH, Carelli E, Steffen T, Jarzem P, Haglund L. 3D-printed ABS and PLA scaffolds for cartilage and nucleus pulposus tissue regeneration. Int J Mol Sci. 2015;16(7):15118–35.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Senatov FS, Niaza KV, Zadorozhnyy MY, Maksimkin AV, Kaloshkin SD, Estrin YZ. Mechanical properties and shape memory effect of 3D-printed PLA-based porous scaffolds. J Mech Behav Biomed Mater. 2016;57:139–48.

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Sandler N, Salmela I, Fallarero A, Rosling A, Khajeheian M, Kolakovic R, et al. Towards fabrication of 3D printed medical devices to prevent biofilm formation. Int J Pharm. 2014;459(1–2):62–4.

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Marketsandmarkets. Drug delivery technology market. 15/10/2015. Available from: http://www.marketsandmarkets.com/Market-Reports/drug-delivery-technologies-market-1085.html?gclid=CIXRuMT5osQCFe6WtAodmiUAZg.

  16. 16.

    GBIResearch. Oral drug delivery market report. 16/11/2015. Available from: http://www.contractpharma.com/issues/2012-06/view_features/oral-drug-delivery-market-report/.

  17. 17.

    Pietrzak K, Isreb A, Alhnan MA. A flexible-dose dispenser for immediate and extended release 3D printed tablets. Eur J Pharm Biopharm. 2015;96:380–7.

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    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(9):2905–12.

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Shah J, Vasanti S, Anroop B, Vyas H. Enhancement of dissolution rate of valdecoxib by solid dispersions technique with PVP K 30 & PEG 4000: preparation and in vitro evaluation. J Incl Phenom Macrocycl Chem. 2008;63(1):69–75.

    Google Scholar 

  20. 20.

    Sharma A, Jain CP. Preparation and characterization of solid dispersions of carvedilol with PVP K30. Res Pharm Sci. 2010;5(1):49–56.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    SIGMA-ALDRICH. Theophylline melting point standard. 2016 16/06. Available from: http://www.sigmaaldrich.com/catalog/product/sial/phr1151?lang=en&region=GB.

  22. 22.

    SIGMA-ALDRICH. Dipyridamole. 2016 16/06. Available from: http://www.sigmaaldrich.com/catalog/product/sigma/d9766?lang=en&region=GB.

  23. 23.

    Agrawal AM, Dudhedia MS, Patel AD, Raikes MS. Characterization and performance assessment of solid dispersions prepared by hot melt extrusion and spray drying process. Int J Pharm. 2013;457(1):71–81.

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Alsulays BB, Park JB, Alshehri SM, Morott JT, Alshahrani SM, Tiwari RV, et al. Influence of molecular weight of carriers and processing parameters on the extrudability, drug release, and stability of fenofibrate formulations processed by hot-melt extrusion. J Drug Delivery Sci Technol. 2015;29:189–98.

    CAS  Article  Google Scholar 

  25. 25.

    Agrawal A, Dudhedia M, Deng W, Shepard K, Zhong L, Povilaitis E, et al. Development of tablet formulation of amorphous solid dispersions prepared by hot melt extrusion using quality by design approach. AAPS PharmSciTech. 2016;17(1):214–32.

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    LaFountaine JS, Prasad LK, Brough C, Miller DA, McGinity JW, Williams 3rd RO. Thermal processing of PVP- and HPMC-based amorphous solid dispersions. AAPS PharmSciTech. 2016;17(1):120–32.

    CAS  Article  PubMed  Google Scholar 

  27. 27.

    Martinez-Marcos L, Lamprou DA, McBurney RT, Halbert GW. A novel hot-melt extrusion formulation of albendazole for increasing dissolution properties. Int J Pharm. 2016;499(1–2):175–85.

    CAS  Article  PubMed  Google Scholar 

  28. 28.

    Alexander V, Gerasimov MAZ, Gorbatchuk VV, Usmanova LS. Increasing the solubility of dipyridamole using polyethylene glycols. Int J Pharm Pharm Sci. 2014;6(9):244–7.

    Google Scholar 

  29. 29.

    Silva Oliveira M, Miguel Agustinho SC, Guzzi Plepis AMD, Tabak M. On the thermal decomposition of dipyridamole: thermogravimetric, differential scanning calorimetric and spectroscopic studies. Spectrosc Lett. 2006;39(2):145–61.

    Article  Google Scholar 

  30. 30.

    Enderle JD, Bronzino JD, Blanchard SM. Introduction to biomedical engineering. Elsevier Academic Press; 2005.

  31. 31.

    Yang Z, Yu J, Yang T, Xing H, Zhang J, Xian L, Ding P, Wang D. A method for the preparation of sustained release-coated Metoprolol Succinate pellet-containing tablets. Pharm Dev Technol. 2015:1–8.

  32. 32.

    Ammar HO, Ghorab MM, Felton LA, Gad S, Fouly AA. Effect of antiadherents on the physical and drug release properties of acrylic polymeric films. AAPS PharmSciTech. 2016;17(3):682–92.

    CAS  Article  PubMed  Google Scholar 

  33. 33.

    Kuno Y, Kojima M, Nakagami H, Yonemochi E, Terada K. Effect of the type of lubricant on the characteristics of orally disintegrating tablets manufactured using the phase transition of sugar alcohol. Eur J Pharm Biopharm. 2008;69(3):986–92.

    CAS  Article  PubMed  Google Scholar 

  34. 34.

    American Pharmacists Association, Quinn ME, Rowe RC, Sheskey PJ. Handbook of pharmaceutical excipients. London: Pharmaceutical Press; 2009.

    Google Scholar 

  35. 35.

    Verdonck E, Schaap K, Thomas LC. A discussion of the principles and applications of Modulated Temperature DSC (MTDSC). Int J Pharm. 1999;192(1):3–20.

    CAS  Article  PubMed  Google Scholar 

  36. 36.

    Szakonyi G, Zelkó R. The effect of water on the solid state characteristics of pharmaceutical excipients: Molecular mechanisms, measurement techniques, and quality aspects of final dosage form. Int J Pharm Investig. 2012;2(1):18–25.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Lai MC, Hageman MJ, Schowen RL, Borchardt RT, Laird BB, Topp EM. Chemical stability of peptides in polymers. 2. Discriminating between solvent and plasticizing effects of water on peptide deamidation in poly(vinylpyrrolidone). J Pharm Sci. 1999;88(10):1081–9.

    CAS  Article  PubMed  Google Scholar 

  38. 38.

    Nair R, Nyamweya N, Gönen S, Martı́nez-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.

    CAS  Article  PubMed  Google Scholar 

  39. 39.

    Vepuri SB. Studies based on supramolecular chemistry in drug design and improvement of pharmaceutical solids. In. Department of Pharmacy: Acharya Nagarjuna University; 2014. p. 212.

  40. 40.

    Rasanen E, Rantanen J, Jorgensen A, Karjalainen M, Paakkari T, Yliruusi J. Novel identification of pseudopolymorphic changes of theophylline during wet granulation using near infrared spectroscopy. J Pharm Sci. 2001;90(3):389–96.

    CAS  Article  PubMed  Google Scholar 

  41. 41.

    Makerbot. Replicator 2X Experimental 3D Printer User Manual., http://downloads.makerbot.com/replicator2x/MakerBot_Replicator2X_UserManual_Eng.pdf In. 2013.

  42. 42.

    Khaled SA, Burley JC, Alexander MR, Roberts CJ. Desktop 3D printing of controlled release pharmaceutical bilayer tablets. Int J Pharm. 2014;461(1–2):105–11.

    CAS  Article  PubMed  Google Scholar 

  43. 43.

    Yu D-G, Branford-White C, Yang Y-C, Zhu L-M, Welbeck EW, Yang X-L. A novel fast disintegrating tablet fabricated by three-dimensional printing. Drug Dev Ind Pharm. 2009;35(12):1530–6.

    CAS  Article  PubMed  Google Scholar 

  44. 44.

    Katstra WE, Palazzolo RD, Rowe CW, Giritlioglu B, Teung P, Cima MJ. Oral dosage forms fabricated by three dimensional printing™. J Control Release. 2000;66(1):1–9.

    CAS  Article  PubMed  Google Scholar 

  45. 45.

    Liu X, Lu M, Guo Z, Huang L, Feng X, Wu C. Improving the chemical stability of amorphous solid dispersion with cocrystal technique by hot melt extrusion. Pharm Res. 2012;29(3):806–17.

    CAS  Article  PubMed  Google Scholar 

  46. 46.

    Yu DG, Li XY, Wang X, Yang JH, Bligh SW, Williams GR. Nanofibers fabricated using triaxial electrospinning as zero order drug delivery systems. ACS Appl Mater Interfaces. 2015;7(33):18891–7.

    CAS  Article  PubMed  Google Scholar 

  47. 47.

    Yang C, Yu DG, Pan D, Liu XK, Wang X, Bligh SWA, et al. Electrospun pH-sensitive core shell polymer nanocomposites fabricated using a tri-axial process. Acta Biomater. 2016;35:77–86.

    Article  PubMed  Google Scholar 

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ACKNOWLEDGMENTS AND DISCLOSURES

The authors would like to thank UCLAN Innovation Team for their support and Mrs Rim Arafat for her help with graphics design.

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Correspondence to Mohamed A. Alhnan.

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Okwuosa, T.C., Stefaniak, D., Arafat, B. et al. A Lower Temperature FDM 3D Printing for the Manufacture of Patient-Specific Immediate Release Tablets. Pharm Res 33, 2704–2712 (2016). https://doi.org/10.1007/s11095-016-1995-0

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KEY WORDS

  • fused filament fabrication
  • HME
  • immediate release
  • patient-specific