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Preformulation Studies to Guide the Production of Medicines by Fused Deposition Modeling 3D Printing

  • Research Article
  • Theme: Novel Advances in 3-D Printing Technology in Drug Delivery
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Abstract

Fused deposition modeling (FDM) 3D printing has demonstrated high potential for the production of personalized medicines. However, the heating at high temperatures inherent to this process causes unknown risks to the drug product's stability. The present study aimed to assess the use of a tailored preformulation protocol involving physicochemical assessments, including the rheological profiles of the samples, to guide the development of medicines by FDM 3D printing. For this, polymers commonly used in FDM printing, i.e., high impact polystyrene (HIPS), polylactic acid (PLA), and polyvinyl alcohol (PVA), and their common plasticizers (mineral oil, triethyl citrate, and glycerol, respectively) were evaluated using the thermolabile model drug isoniazid (INH). Samples were analyzed by chemical and physical assays. The results showed that although the drug could produce polymorphs under thermal processing, the polymeric matrix can be a protective element, and no polymorphic transformation was observed. However, incompatibilities between materials might impact their chemical, thermal, and rheological performances. In fact, ternary mixtures of INH, PLA, and TEC showed a major alteration in their viscoelastic behavior besides the chemical changes. On the other hand, the use of plasticizers for HIPS and PVA exhibited positive consequences in drug solubility and rheologic behavior, probably improving sample printability. Thus, the optimization of the FDM 3D printing based on preformulation studies can assist the choice of compatible components and seek suitable processing conditions to obtain pharmaceutical products.

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References

  1. Gaisford S. 3D printed pharmaceutical products. In: Kalaskar DM, editor. 3D Printing in Medicine. Sawston: Woodhead Publishing; 2017. p. 155–166.

  2. Araújo MRP, Sa-Barreto LL, Gratieri T, Gelfuso GM, Cunha-Filho M. The digital pharmacies era: How 3D printing technology using fused deposition modeling can become a reality. Pharmaceutics. 2019;11:128.

    Article  PubMed Central  Google Scholar 

  3. Cunha-Filho M, Araujo MR, Gelfuso GM, Gratieri T. FDM 3D printing of modified drug-delivery systems using hot melt extrusion: a new approach for individualized therapy. Ther Deliv. 2017;8:957–66.

    Article  CAS  PubMed  Google Scholar 

  4. Azad MA, Olawuni D, Kimbell G, Badruddoza AZM, Hossain MS, Sultana T. Polymers for extrusion-based 3D printing of pharmaceuticals: a holistic materials–process perspective. Pharmaceutics. 2020;12:124.

    Article  CAS  PubMed Central  Google Scholar 

  5. Viidik L, Vesala J, Laitinen R, Korhonen O, Ketolainen J, Aruväli J, et al. Preparation and characterization of hot-melt extruded polycaprolactone-based filaments intended for 3D-printing of tablets. Eur J Pharm Sci. 2021;158:105619.

    Article  CAS  PubMed  Google Scholar 

  6. Choi CH, Kim JI, Park JM. A 3D-printed patient-specific applicator guide for use in high-dose-rate interstitial brachytherapy for tongue cancer: A phantom study. Physi Med Biol. 2019;64:135002.

    Article  Google Scholar 

  7. Zema L, Melocchi A, Maroni A, Gazzaniga A. Three-Dimensional Printing of Medicinal Products and the Challenge of Personalized Therapy. J Pharm Sci. 2017;106:1697–705.

    Article  CAS  PubMed  Google Scholar 

  8. Pires FQ, Alves-Silva I, Pinho LAG, Chaker JA, Sa-Barreto LL, Gelfuso GM, et al. Predictive models of FDM 3D printing using experimental design based on pharmaceutical requirements for tablet production. Int J Pharm. 2020;588:119728.

    Article  CAS  PubMed  Google Scholar 

  9. Censi R, Di Martino P. Polymorph impact on the bioavailability and stability of poorly soluble drugs. Molecules. 2015;20:18759–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Sadia M, Sośnicka A, Arafat B, Isreb A, Ahmed W, Kelarakis A, et al. Adaptation of pharmaceutical excipients to FDM 3D printing for the fabrication of patient-tailored immediate release tablets. Int J Pharm. 2016;513:659–68.

    Article  CAS  PubMed  Google Scholar 

  11. Pereira GG, Figueiredo S, Fernandes AI, Pinto JF. Polymer selection for hot-melt extrusion coupled to fused deposition modelling in pharmaceutics. Pharmaceutics. 2020;12:795.

    Article  CAS  PubMed Central  Google Scholar 

  12. Ilyés K, Kovács NK, Balogh A, Borbás E, Farkas BB, Casian T, et al. The applicability of pharmaceutical polymeric blends for the fused deposition modelling (FDM) 3D technique: Material considerations–printability–process modulation, with consecutive effects on in vitro release, stability and degradation. Eur J Pharm Sci. 2019;129:110–23.

    Article  PubMed  Google Scholar 

  13. Korte C, Quodbach J. Formulation development and process analysis of drug-loaded filaments manufactured via hot-melt extrusion for 3D-printing of medicines. Pharm Dev Technol. 2018;23:1117–27.

    Article  CAS  PubMed  Google Scholar 

  14. Nukala PK, Palekar S, Patki M, Patel K. Abuse deterrent immediate release egg-shaped tablet (Egglets) using 3D printing technology: quality by design to optimize drug release and extraction. AAPS PharmSciTech. 2019;20:80.

    Article  CAS  PubMed  Google Scholar 

  15. Ponsar H, Wiedey R, Quodbach J. Hot-Melt Extrusion Process Fluctuations and their Impact on Critical Quality Attributes of Filaments and 3D-printed Dosage Forms. Pharmaceutics. 2020;12:511.

    Article  CAS  PubMed Central  Google Scholar 

  16. Ghanizadeh Tabriz A, Nandi U, Hurt AP, Hui H-W, Karki S, Gong Y, et al. 3D printed bilayer tablet with dual controlled drug release for tuberculosis treatment. Int J Pharm. 2021;593:120147.

    Article  CAS  PubMed  Google Scholar 

  17. Genina N, Boetker JP, Colombo S, Harmankaya N, Rantanen J, Bohr A. Anti-tuberculosis drug combination for controlled oral delivery using 3D printed compartmental dosage forms: From drug product design to in vivo testing. J Control Release. 2017;268:40–8.

    Article  CAS  PubMed  Google Scholar 

  18. Öblom H, Zhang J, Pimparade M, Speer I, Preis M, Repka M, et al. 3D-printed isoniazid tablets for the treatment and prevention of tuberculosis—personalized dosing and drug release. AAPS PharmSciTech. 2019;20:1–13.

    Article  Google Scholar 

  19. Keating AV, Soto J, Tuleu C, Forbes C, Zhao M, Craig DQM. Solid state characterisation and taste masking efficiency evaluation of polymer based extrudates of isoniazid for paediatric administration. Int J Pharm. 2018;536:536–46.

    Article  CAS  PubMed  Google Scholar 

  20. Maiza M, Benaniba MT, Quintard G, Massardier-Nageotte V. Biobased additive plasticizing Polylactic acid (PLA). Polimeros. 2015;25:581–90.

    Article  CAS  Google Scholar 

  21. Lee M, Jung BN, Kim GH, Kang D, Park HJ, Shim JK, et al. The effect of triethyl citrate on the dispersibility and water vapor sorption behavior of polylactic acid/zeolite composites. Polym Test. 2020;89:106571.

    Article  CAS  Google Scholar 

  22. LaFountaine JS, McGinity JW, Williams RO. Challenges and strategies in thermal processing of amorphous solid dispersions: a review. AAPS PharmSciTech. 2016;17:43–55.

    Article  CAS  PubMed  Google Scholar 

  23. Nasereddin JM, Wellner N, Alhijjaj M, Belton P, Qi S. Development of a simple mechanical screening method for predicting the feedability of a pharmaceutical FDM 3D printing filament. Pharm Res. 2018;35:151.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Gao JM, Ding LX, Hu CQ. A comparative uncertainty study of the purity assessment of chemical reference substances using differential scanning calorimetry (DSC) and mass balance method. Thermochim Acta. 2011;525:1–8.

    Article  CAS  Google Scholar 

  25. Malaquias LFB, Schulte HL, Chaker JA, Karan K, Durig T, Marreto RN, et al. Hot melt extrudates formulated using design space: one simple process for both palatability and dissolution rate improvement. J Pharm Sci. 2017;107:286–96.

    Article  PubMed  Google Scholar 

  26. Daniel JSP, Cruz JC, Catelani TA, Garcia JS, Trevisan MG. Erythromycin-excipients compatibility studies using the thermal analysis and dynamic thermal infrared spectroscopy coupled with chemometrics. J Therm Anal Calorim. 2020;143:1–9.

    Google Scholar 

  27. Pires FQ, Pinho LA, Freire DO, Silva ICR, Sa-Barreto LL, Cardozo-Filho L, et al. Thermal analysis used to guide the production of thymol and Lippia origanoides essential oil inclusion complexes with cyclodextrin. J Therm Anal Calorim. 2019;137:543–53.

    Article  CAS  Google Scholar 

  28. Nishimoto Y, Hattori Y, Otsuka M. Characterization of ternary amorphous solid dispersion containing hypromellose phthalate and erythritol prepared by hot melt extrusion using melting point depression. J Drug Delivery Sci Technol. 2020;58:101797.

    Article  CAS  Google Scholar 

  29. Kennedy SR, Jones CD, Yufit DS, Nicholson CE, Cooper SJ, Steed JW. Tailored supramolecular gel and microemulsion crystallization strategies-is isoniazid really monomorphic? CrystEngComm. 2018;20:1390–8.

    Article  CAS  Google Scholar 

  30. Zhang K, Fellah N, Shtukenberg AG, Fu X, Hu C, Ward MD. Discovery of new polymorphs of the tuberculosis drug isoniazid. CrystEngComm Royal Society of Chemistry. 2020;22:2705–8.

    CAS  Google Scholar 

  31. Bhutani H, Singh S, Vir S, Bhutani KK, Kumar R, Chakraborti AK, et al. LC and LC-MS study of stress decomposition behaviour of isoniazid and establishment of validated stability-indicating assay method. J Pharm Biomed Anal. 2007;43:1213–20.

    Article  CAS  PubMed  Google Scholar 

  32. Pessoa AS, Aguiar GPS, Vladimir Oliveira J, Bortoluzzi AJ, Paulino A, Lanza M. Precipitation of resveratrol-isoniazid and resveratrol-nicotinamide cocrystals by gas antisolvent. J Supercrit Fluids. 2019;145:93–102.

    Article  CAS  Google Scholar 

  33. Afinjuomo F, Barclay TG, Parikh A, Chung R, Song Y, Nagalingam G, et al. Synthesis and characterization of pH-sensitive inulin conjugate of isoniazid for monocyte-targeted delivery. Pharmaceutics. 2019;11:555.

    Article  CAS  PubMed Central  Google Scholar 

  34. Carazo E, Cerezo P, Aguzzi C, Viseras C. Applied clay science adsorption and characterization of palygorskite-isoniazid nanohybrids. Appl Clay Sci. 2018;160:180–5.

    Article  CAS  Google Scholar 

  35. Cunha-Filho MSS, Martínez-Pacheco R, Landín M, Cunha-filho SS, Landı M. Dissolution rate enhancement of the novel antitumoral β-lapachone by solvent change precipitation of microparticles. Eur J Pharm Biopharm. 2008;69:871–7.

    Article  CAS  PubMed  Google Scholar 

  36. Bochmann ES, Üstüner EE, Gryczke A, Wagner KG. Predicting melt rheology for hot-melt extrusion by means of a simple Tg-measurement. Eur J Pharm Biopharm. 2017;119:47–55.

    Article  CAS  PubMed  Google Scholar 

  37. Mashhadi SMA, Yufit D, Liu H, Hodgkinson P, Yunus U. Synthesis and structural characterization of cocrystals of isoniazid and cinnamic acid derivatives. J Mol Struct. 2020;1219:128621.

    Article  CAS  Google Scholar 

  38. Farah S, Anderson DG, Langer R. Physical and mechanical properties of PLA, and their functions in widespread applications — A comprehensive review. Adv Drug Deliv Rev. 2016;107:367–92.

    Article  CAS  PubMed  Google Scholar 

  39. Wang L, Gramlich WM, Gardner DJ. Improving the impact strength of Poly(lactic acid) (PLA) in fused layer modeling (FLM). Polymer. 2017;114:242–8.

    Article  CAS  Google Scholar 

  40. Ferreira-Nunes R, Gratieri T, Gelfuso GM, Cunha-Filho M. Mixture design applied in compatibility studies of catechin and lipid compounds. J Pharm Biomed Anal. 2018;149:612–7.

    Article  CAS  PubMed  Google Scholar 

  41. Stipa P, Marano S, Galeazzi R, Minnelli C, Mobbili G, Laudadio E. Prediction of drug-carrier interactions of PLA and PLGA drug-loaded nanoparticles by molecular dynamics simulations. Eur Polym J. 2021;147:110292.

    Article  CAS  Google Scholar 

  42. Pires FQ, Angelo T, Silva JKR, Sá-Barreto LCL, Lima EM, Gelfuso GM, et al. Use of mixture design in drug-excipient compatibility determinations: Thymol nanoparticles case study. J Pharm Biomed Anal. 2017;137:196–203.

    Article  CAS  PubMed  Google Scholar 

  43. Bagchi S, Sharma K, Chakrabortty A, Lahiri SC. Spectrophotometric, FTIR and theoretical studies of the charge-transfer complexes between isoniazid (pyridine-4-carboxylic acid hydrazide) and the acceptors (p-chloranil, chloranilic acid and tetracyanoethylene) in acetonitrile, their association constant. Spectrochimica Acta - Part A: Molecular and Biomolecular Spectroscopy. 2012;95:637–47.

    Article  CAS  Google Scholar 

  44. Pandey G, Yadav SK, Mishra B. Preparation and characterization of isoniazid and lamivudine co-loaded polymeric microspheres. Artificial Cells, Nanomedicine and Biotechnology. 2016;44:1867–77.

    Article  CAS  Google Scholar 

  45. Oliveira PM, Matos BN, Pereira PAT, Gratieri T, Faccioli LH, Cunha-Filho MSS, et al. Microparticles prepared with 50–190 kDa chitosan as promising non-toxic carriers for pulmonary delivery of isoniazid. Carbohyd Polym. 2017;174:421–31.

    Article  CAS  Google Scholar 

  46. Worzakowska M. Thermal and mechanical properties of polystyrene modified with esters derivatives of 3-phenylprop-2-en-1-ol. J Therm Anal Calorim. 2015;121:235–43.

    Article  CAS  Google Scholar 

  47. Jang J, Lee DK. Plasticizer effect on the melting and crystallization behavior of polyvinyl alcohol. Polymer. 2003;44:8139–46.

    Article  CAS  Google Scholar 

  48. Aho J, Genina N, Edinger M, Bøtker J, Baldursdóttir S, Rantanen J. Drug-loaded poly (-caprolactone) for 3D printing of personalized medicine : A rheological study. Proceedings of the 25th Nordic Rheology Conference. Helsinki, Finland; 2016. p. 97–100.

  49. Gorain B, Choudhury H, Pandey M, Madheswaran T, Kesharwani P, Tekade RK. Drug-excipient interaction and incompatibilities. In: Tekade RK editor. Dosage form design parameters. Cambridge: Academic Press; 2018. p. 363–402.

  50. Santos F, Branco LC, Duarte ARC. Organic salts based on isoniazid drug: Synthesis, bioavailability and cytotoxicity studies. Pharmaceutics. 2020;12:952.

  51. Yang F, Su Y, Zhu L, Brown CD, Rosen LA, Rosenberg KJ. Rheological and solid-state NMR assessments of copovidone/clotrimazole model solid dispersions. Int J Pharm. 2016;500:20–31.

    Article  CAS  PubMed  Google Scholar 

  52. Isreb A, Baj K, Wojsz M, Isreb M, Peak M, Alhnan MA. 3D printed oral theophylline doses with innovative “radiator-like” design: Impact of polyethylene oxide (PEO) molecular weight. Int J Pharm. 2019;564:98–105.

    Article  CAS  PubMed  Google Scholar 

  53. Sadia M, Isreb A, Abbadi I, Isreb M, Aziz D, Selo A, et al. From “fixed dose combinations” to “a dynamic dose combiner”: 3D printed bi-layer antihypertensive tablets. Eur J Pharm Sci. 2018;123:484–94.

    Article  CAS  PubMed  Google Scholar 

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ACKNOWLEDGEMENTS

This research was supported by the Brazilian agencies FAP-DF (193.001.741/2017) and National Council for Scientific and Technological Development–CNPq (408291/2018-4).

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Authors and Affiliations

  1. Laboratory of Food, Drug, and Cosmetics (LTMAC), School of Health Sciences, University of Brasilia, Brasília, DF, 70910-900, Brazil

    Ludmila A. G. Pinho, Ana Luiza Lima, Tais Gratieri, Guilherme M. Gelfuso & Marcilio Cunha-Filho

  2. Faculty of Ceilândia, University of Brasília, Brasília, DF, 72220-900, Brazil

    Livia L. Sa-Barreto

  3. Laboratory of Nanosystems and Drug Delivery Devices (NanoSYS), School of Pharmacy, Federal University of Goiás, Goiânia, GO, 74605-170, Brazil

    Ricardo Neves Marreto

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  1. Ludmila A. G. Pinho
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  2. Ana Luiza Lima
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  4. Tais Gratieri
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  7. Marcilio Cunha-Filho
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Contributions

Ludmila A. G. Pinho: conceptualization, investigation, methodology, formal analysis, writing—original draft. Ana Luiza Lima: investigation, methodology, formal analysis, writing—original draft. Livia L. Sa-Barreto: conceptualization, resources, writing—review and editing. Tais Gratieri: conceptualization, resources, writing—review and editing. Guilherme M. Gelfuso: conceptualization, resources, writing—review and editing. Ricardo Neves Marreto: conceptualization, investigation, formal analysis, writing—review and editing. Marcilio Cunha-Filho: conceptualization, resources, supervision, project administration, investigation, formal analysis, resources, writing—review and editing. All authors read and approved the final manuscript.

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Correspondence to Marcilio Cunha-Filho.

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Theme: Novel Advances in 3-D Printing Technology in Drug Delivery

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Pinho, L.A.G., Lima, A.L., Sa-Barreto, L.L. et al. Preformulation Studies to Guide the Production of Medicines by Fused Deposition Modeling 3D Printing. AAPS PharmSciTech 22, 263 (2021). https://doi.org/10.1208/s12249-021-02114-7

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