PURPOSE: Affinisol HPMC HME is a new popular form of hypromellose specifically designed for the hot melt extrusion and 3D printing of pharmaceutical products. However, reports of its thermal stability include only data obtained under inert N2 atmosphere, which is not consistent with the common pharmaceutical practice. Therefore, detailed investigation of its real-life thermal stability in air is paramount for identification of potential risks and limitations during its high-temperature processing. METHODS: In this work, the Affinisol HPMC HME 15LV powder as well as extruded filaments will be investigated by means of thermogravimetry, differential scanning calorimetry and infrared spectroscopy with respect to its thermal stability. RESULTS: The decomposition in N2 was proceeded in accordance with the literature data and manufacturer's specifications: onset at ~260°C at 0.5°C·min-1, single-step mass loss of 90-95%. However, in laboratory or industrial practice, high-temperature processing is performed in the air, where oxidation-induced degradation drastically changes. The thermogravimetric mass loss in air proceeded in three stages: ~ 5% mass loss with onset at 150°C, ~ 70% mass loss at 200°C, and ~ 15% mass loss at 380°C. Diffusion of O2 into the Affinisol material was identified as the rate-determining step. CONCLUSION: For extrusion temperatures ≥170°C, Affinisol exhibits a significant degree of degradation within the 5 min extruder retention time. Hot melt extrusion of pure Affinisol can be comfortably performed below this temperature. Utilization of plasticizers may be necessary for safe 3D printing.

Department of Physical Chemistry Faculty of Chemical Technology University of Pardubice Studentská 573 532 10 Pardubice Czech Republic

FunGlass Alexander Dubček University of Trenčín Študentská 2 SK 911 50 Trenčín Slovakia

VILA Joined Glass Centre of the IIC SAS TnUAD FChPT STU Študentská 2 SK 911 50 Trenčín Slovakia

See more in PubMed

Keseru GM, Makara GM. The influence of lead discovery strategies on the properties of drug candidates. Nat Rev Drug Discov. 2009;8(3):203–212. doi: 10.1038/nrd2796. PubMed DOI

Serajuddin ATM. Salt formation to improve drug solubility. Adv Drug Deliv Rev. 2007;59(7):603–616. doi: 10.1016/j.addr.2007.05.010. PubMed DOI

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. doi: 10.1023/A:1011984216775. PubMed DOI

Pudipeddi M, Serajuddin ATM, Mufson D. Integrated drug product development—from lead candidate selection to life-cycle management. The Process of New Drug Discovery and Development. Boca Raton: CRC Press; 2006.

Li S, He H, Parthiban LJ, Yin H, Serajuddin ATM. IV-IVC considerations in the development of immediate-release oral dosage form. J Pharm Sci. 2005;94(7):1396–1417. doi: 10.1002/jps.20378. PubMed DOI

Alonzo D, Zhang GZ, Zhou D, Gao Y, Taylor L. Understanding the behavior of amorphous pharmaceutical systems during dissolution. PharmRes. 2010;27(4):608–618. PubMed

Vasanthavada M, Tong W, Serajuddin A. Development of solid dispersion for poorly water-soluble drugs. Water-insoluble drug formulations. 2nd ed. New York: Informa Healthcare; 2008. pp. 149–184.

Surikutchi BT, Patil SP, Shete G, Patel S, Bansal AK. Drug excipient behavior in polymeric amorphous solid dispersions. J Excipients Food Chem. 2013;4(3):70–94.

Jani R, Patel D. Hot melt extrusion: an industrially feasible approach for casting orodispersible film. Asian J Pharmaceut Sci. 2015;10(4):292–305.

Patil H, Tiwari RV, Repka MA. Hot-melt extrusion: from theory to application in pharmaceutical formulation. AAPS PharmSciTech. 2016;17:20–42. doi: 10.1208/s12249-015-0360-7. PubMed DOI PMC

Breitenbach J. Melt extrusion: from process to drug delivery technology. Eur J Pharm Biopharm. 2002;54(2):107–117. doi: 10.1016/S0939-6411(02)00061-9. PubMed DOI

Forster A, Hempenstall J, Rades T. Characterization of glass solutions of poorly water-soluble drugs produced by melt extrusion with hydrophilic amorphous polymers. J Pharm Pharmacol. 2001;53(3):303–315. doi: 10.1211/0022357011775532. PubMed DOI

Bennett R, Keen J, Bi Y, Porter S, Dürig T, Mcginity J. Investigation of the interactions of enteric and hydrophilic polymers to enhance dissolution of griseofulvin following hot melt extrusion processing. J Pharma Pharma. 2015;67(7):918–938. doi: 10.1111/jphp.12388. PubMed DOI

O’Donnell KP, Woodward WHH. Dielectric spectroscopy for the determination of the glass transition temperature of pharmaceutical solid dispersions. Drug Dev Industr Pharma. 2015;41:959–68. PubMed

Siew A. New excipient options for oral solid dosage drugs. PharmTech (online edition). January 30, 2015 (http://www.pharmtech.com/new-excipient-options-oral-solid-dosage-drugs). Accessed 16 June 2023.

Huang S, O’Donnell KP, Keen JM, et al. A new Extrudable form of Hypromellose: AFFINISOL™ HPMC HME. AAPS PharmSciTech. 2016;17:106–119. doi: 10.1208/s12249-015-0395-9. PubMed DOI PMC

Gupta SS, Solanki N, Serajuddin ATM. Investigation of thermal and viscoelastic properties of polymers relevant to hot melt extrusion, IV: Affinisol™ HPMC HME polymers. AAPS PharmSciTech. 2016;17:148–157. doi: 10.1208/s12249-015-0426-6. PubMed DOI PMC

Khatri P, Katikaneni P, Desai D, Minko T. Evaluation of Affinisol® HPMC polymers for direct compression process applications. J Drug Deliv Sci Technol. 2018;47:461–467. doi: 10.1016/j.jddst.2018.08.018. DOI

Prasad E, Islam MT, Goodwin DJ, Megarry AJ, Halbert GW, Florence AJ, Robertson J. Development of a hot-melt extrusion (HME) process to produce drug loaded Affinisol™ 15LV filaments for fused filament fabrication (FFF) 3D printing. Addit Manuf. 2019;29:100776.

Mora-Castaño G, Millán-Jiménez M, Linares V, Caraballo I. Assessment of the extrusion process and printability of suspension-type drug-loaded Affinisol™ filaments for 3D printing. Pharmaceutics. 2022;14:871. doi: 10.3390/pharmaceutics14040871. PubMed DOI PMC

Tahir F, Islam MT, Mack J, Robertson J, Lovett D. Process monitoring and fault detection on a hot-melt extrusion process using in-line Raman spectroscopy and a hybrid soft sensor. Comput Chem Eng. 2019;125:400–414. doi: 10.1016/j.compchemeng.2019.03.019. DOI

Devi D, Ghosh A, Mandal UK. Sustained release matrix tablet of 100 mg losartan potassium: formulation development and in vitro characterization. Braz J Pharm Sci. 2022;58:1–16. doi: 10.1590/s2175-97902022e20079. DOI

Skalická B, Matzick K, Komersová A, Svoboda R, Bartoš M, Hromádko L. 3D-printed coating of extended-release matrix tablets: effective tool for prevention of alcohol-induced dose dumping effect. Pharmaceutics. 2021;13:2123. doi: 10.3390/pharmaceutics13122123. PubMed DOI PMC

Huang S, O'Donnell KP, Delpon de Vaux SM, O'Brien J, Stutzman J, Williams RO. Processing thermally labile drugs by hot-melt extrusion: the lesson with gliclazide. Eur J Pharm Biopharm. 2017;119:56–67. doi: 10.1016/j.ejpb.2017.05.014. PubMed DOI

Bordos E, Islam MT, Florence AJ, Halbert GW, Robertson J. Use of terahertz-Raman spectroscopy to determine solubility of the crystalline active pharmaceutical ingredient in polymeric matrices during hot melt extrusion. Mol Pharm. 2019;16(10):4361–4371. doi: 10.1021/acs.molpharmaceut.9b00703. PubMed DOI PMC

Solanki NG, et al. Formulation of 3D printed tablet for rapid drug release by fused deposition modeling: screening polymers for drug release, drug-polymer miscibility and printability. J Pharm Sci. 2018;107:390–401. doi: 10.1016/j.xphs.2017.10.021. PubMed DOI

Liu Y, Thompson MR, O’Donnell KP. Impact of non-binder ingredients and molecular weight of polymer binders on heat assisted twin screw dry granulation. Int J Pharm. 2018;536:336–344. doi: 10.1016/j.ijpharm.2017.11.061. PubMed DOI

Mora-Castaño G, Millán-Jiménez M, Caraballo I. Hydrophilic high drug-loaded 3D printed Gastroretentive system with robust release kinetics. Pharmaceutics. 2023;15:842. doi: 10.3390/pharmaceutics15030842. PubMed DOI PMC

Rahimi SK, et al. Supercritical-CO2 foam extrusion of Hydroxypropyl methyl cellulose acetate succinate/Itraconazole amorphous solid dispersions: processing-structure-property relations. J Pharm Sci. 2021;110. PubMed

Parulski C, Gresse E, Jennotte O, Felten A, Ziemons E, Lechanteur A, Evrard B. Fused deposition modeling 3D printing of solid oral dosage forms containing amorphous solid dispersions: how to elucidate drug dissolution mechanisms through surface spectral analysis techniques? Int J Pharm. 2022;626:122157. doi: 10.1016/j.ijpharm.2022.122157. PubMed DOI

Pistone M, Racaniello GF, Arduino I, et al. Direct cyclodextrin-based powder extrusion 3D printing for one-step production of the BCS class II model drug niclosamide. Drug Deliv and Transl Res. 2022;12:1895–1910. doi: 10.1007/s13346-022-01124-7. PubMed DOI PMC

Adye DR, Jorvekar SB, Murty US, Banerjee S, Borkar RM. Analysis of NSAIDs in rat plasma using 3D-printed sorbents by LC-MS/MS: an approach to pre-clinical pharmacokinetic studies. Pharmaceutics. 2023;15:978. doi: 10.3390/pharmaceutics15030978. PubMed DOI PMC

Đuranović M, Madžarević M, Ivković B, Ibrić S, Cvijić S. The evaluation of the effect of different superdisintegrants on the drug release from FDM 3D printed tablets through different applied strategies: in vitro-in silico assessment. Int J Pharm. 2021;610:121194. doi: 10.1016/j.ijpharm.2021.121194. PubMed DOI

Patel NG, Serajuddin ATM. Development of FDM 3D-printed tablets with rapid drug release, high drug-polymer miscibility and reduced printing temperature by applying the acid-base supersolubilization (ABS) principle. Int J Pharm. 2021;600:120524. doi: 10.1016/j.ijpharm.2021.120524. PubMed DOI

Zhao X, et al. 3D printed Intragastric floating and sustained-release tablets with air chambers. J Pharm Sci. 2022;111:116–123. doi: 10.1016/j.xphs.2021.07.010. PubMed DOI

A.M. Stewart, M.E. Grass, TJ. Brodeur, A.K. Goodwin, M.M. Morgen, D.T. Friesen, D.T. Vodak. Impact of drug-rich colloids of Itraconazole and HPMCAS on membrane flux in vitro and Oral bioavailability in rats. Mol Pharm. 2017, 14, 7, 2437–2449. PubMed

Thiry J, Lebrun P, Vinassa C, Adam M, Netchacovitch L, Ziemons E, Hubert P, Krier F, Evrard B. Continuous production of itraconazole-based solid dispersions by hot melt extrusion: Preformulation, optimization and design space determination. Int J Pharm. 2016;515:114–124. doi: 10.1016/j.ijpharm.2016.10.003. PubMed DOI

Oladeji S, Mohylyuk V, Jones DS, Andrews GP. 3D printing of pharmaceutical oral solid dosage forms by fused deposition: the enhancement of printability using plasticised HPMCAS. Int J Pharm. 2022;616:121553. doi: 10.1016/j.ijpharm.2022.121553. PubMed DOI

Hanada M, Jermain SV, Thompson SA, Furuta H, Fukuda M, Williams RO. Ternary amorphous solid dispersions containing a high-viscosity polymer and mesoporous silica enhance dissolution performance. Mol Pharm. 2021;18(1):198–213. doi: 10.1021/acs.molpharmaceut.0c00811. PubMed DOI

Chatterjee T, O’Donnell KP, Rickard MA, Nickless B, Li Y, Ginzburg VV, Sammler RL. Rheology of cellulose ether excipients designed for hot melt extrusion. Biomacromolecules. 2018;19(11):4430–4441. doi: 10.1021/acs.biomac.8b01306. PubMed DOI

Musarrat WH, Mohammad Y, Majed AR, Maria K, Abdul M, Saba K. 3D printing methods for pharmaceutical manufacturing: opportunity and challenges. Curr Pharm Des. 2018;24(42). PubMed

Rahman Z, Barakh Ali SF, Ozkan T, et al. Additive manufacturing with 3D printing: Progress from bench to bedside. AAPS J. 2018;20:101. doi: 10.1208/s12248-018-0225-6. PubMed DOI

Pavan Kalyan B, Kumar L. 3D printing: applications in tissue engineering, medical devices, and drug delivery. AAPS PharmSciTech. 2022;23:92. doi: 10.1208/s12249-022-02242-8. PubMed DOI PMC

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. doi: 10.3390/pharmaceutics12060511. PubMed DOI PMC

Windolf H, Chamberlain R, Delmotte A, Quodbach J. Blind-watermarking—proof-of-concept of a novel approach to ensure batch traceability for 3D printed tablets. Pharmaceutics. 2022;14:432. doi: 10.3390/pharmaceutics14020432. PubMed DOI PMC

Sahoo S, Chaktaborti CK, Behera PK. Characterization of controlled release Ofloxacin suspensions by Fourier transform infrared spectroscopy. Res J Pharm Bio Chem Sci. 2011;2:926–939.

Wang Q, Song H, Pan S, et al. Initial pyrolysis mechanism and product formation of cellulose: An Experimental and Density functional theory(DFT) study. Sci Rep. 10:3626. PubMed PMC

D’Acierno F, Hamad WY, Michal CA, MacLachlan MJ. Thermal degradation of cellulose filaments and nanocrystals. Biomacromolecules. 2020;21:3374–3386. doi: 10.1021/acs.biomac.0c00805. PubMed DOI

Shen DK, Gu S. The mechanism for thermal decomposition of cellulose and its main products. Bioresour Technol. 2009;100:6496–6504. doi: 10.1016/j.biortech.2009.06.095. PubMed DOI

Lim W-S, Choi J-W, Iwata Y, Koseki H. Thermal characteristics of Hydroxypropyl methyl cellulose. J Loss Prev Process Ind. 2009;22:182–186. doi: 10.1016/j.jlp.2008.11.003. DOI

Viswanathan V, Rao TKG, Iyer PB. Raman spectrum of cellulose from cotton. Ind J Fibre Text Res. 1999;24:78–80.

Šesták J. Thermophysical properties of solids, Their Measurements and Theoretical Analysis. Amsterdam: Elsevier; 1984.

Vyazovkin S, Burnham AK, Criado JM, Pérez-Maqueda LA, Popescu C, Sbirrazzuoli N. ICATC kinetics committee recommendations for performing kinetic computations on thermal analysis data. Thermochim Acta. 2011;520:1–19. doi: 10.1016/j.tca.2011.03.034. DOI

Šesták J. Science of heat and Thermophysical studies: a generalized approach to thermal analysis. Amsterdam: Elsevier; 2005.

Kissinger HE. Reaction kinetics in differential thermal analysis. Anal Chem. 1957;29:1702–1706. doi: 10.1021/ac60131a045. DOI

Svoboda R, Chovanec J, Slang S, Beneš L, Konrád P. Single-curve multivariate kinetic analysis: application to the crystallization of commercial Fe-Si-Cr-B amorphous alloys. J Alloys Compd. 2022;889:161672. doi: 10.1016/j.jallcom.2021.161672. DOI

Svoboda R, Málek J. Applicability of Fraser-Suzuki function in kinetic analysis of complex processes. J Therm Anal Cal. 2013;111:1045–1056. doi: 10.1007/s10973-012-2445-9. DOI

Svoboda R, Košťálová D, Krbal M, Komersová A. Indomethacin: the interplay between structural relaxation, Viscous Flow and Crystal Growth. Molecules. 2022;27:5668. doi: 10.3390/molecules27175668. PubMed DOI PMC

Romanová J, Svoboda R, Obadalová I, Beneš L, Pekárek T, Krejčík L, Komersová A. Amorphous enzalutamide – non-isothermal recrystallization kinetics and thermal stability. Thermochim Acta. 2018;655:134–141. doi: 10.1016/j.tca.2018.05.020. DOI

Svoboda R, Romanová J, Šlang S, Obadalová I, Komersová A. Influence of particle size and manufacturing conditions on the recrystallization of amorphous enzalutamide. Eur J Pharm Sci. 2020;153:105468. doi: 10.1016/j.ejps.2020.105468. PubMed DOI