Polymers for Extrusion-Based 3D Printing of Pharmaceuticals: A Holistic Materials–Process Perspective
Three dimensional (3D) printing as an advanced manufacturing technology is progressing to be established in the pharmaceutical industry to overcome the traditional manufacturing regime of ‘one size fits for all’. Using 3D printing, it is possible to design and develop complex dosage forms that can be suitable for tuning drug release. Polymers are the key materials that are necessary for 3D printing. Among all 3D printing processes, extrusion-based (both fused deposition modeling (FDM) and pressure-assisted microsyringe (PAM)) 3D printing is well researched for pharmaceutical manufacturing.
It is important to understand which polymers are suitable for extrusion-based 3D printing of pharmaceuticals and how their properties, as well as the behavior of polymer–active pharmaceutical ingredient (API) combinations, impact the printing process. Especially, understanding the rheology of the polymer and API–polymer mixtures is necessary for successful 3D printing of dosage forms or printed structures. This review has summarized a holistic materials–process perspective for polymers on extrusion-based 3D printing.
The main focus herein will be both FDM and PAM 3D printing processes. It elaborates the discussion on the comparison of 3D printing with the traditional direct compression process, the necessity of rheology, and the characterization techniques required for the printed structure, drug, and excipients. The current technological challenges, regulatory aspects, and the direction toward which the technology is moving, especially for personalized pharmaceuticals and multi-drug printing, are also briefly discussed.
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3.1. Materials Perspective
3.1.1. Carbopol®
Carbopol® homopolymers are high molecular weight, crosslinked polyacrylic acid polymers [78]. Crosslinking is done with allyl sucrose or allyl pentaerythritol. Polymers are synthesized in either ethyl acetate or cosolvent ethyl acetate/cyclohexane mixture. Carbopol® 971P and 974P are suitable for PAM 3D printing. Carbopol® 971P is a lightly crosslinked polymer having a viscosity of 4000–11,000 cP (0.5 wt% suspension), which will result in flow like honey in a semisolid formulation [78,79]. It is suitable for extended/controlled-release tablets, oral liquids and suspension [79]. Carbopol® 974P is a highly crosslinked polymer and produces highly viscous gels [80]. The viscosity of 0.5 wt% suspension of Carbopol® 974P is 29,400–39,400 cP [78]. It is suitable for extended-release tablet formulation.
3.1.2. Ethylcellulose (EC)
Ethylcellulose (EC) is often used as a polymer in pharmaceuticals and has recently found use in 3D printed pharmaceuticals. It is a water-insoluble thermoplastic polymer. These properties associated with EC are taken advantage of its usage in FDM 3D printing in the pharmaceutical industry. As a polymer in drug formulations, it is often used for its sustained release capabilities [81]. EC must undergo some form of sample preparation, such as dissolution in acetone or the addition of a plasticizer before it can be used in FDM printing [82].
3.1.3. Eudragit®
Eudragit® polymers are a set of synthetic polymethacrylate used in pharmaceutical drug formulations. They are non-biodegradable, non-absorbable, nontoxic and amorphous polymer [83]. According to Evonik, all Eudragit polymers have thermoplastic properties, low glass transition temperatures (between 9 °C and > 150 °C), high thermostability, and high miscibility with APIs and other excipients [83,84]. Hence, they are suitable for hot-melt extrusion. Varying the functional group on the polymer dictates the type of drug release it is best suited for. For example, the Eudragit E series is for immediate release drugs. Eudragit® E series is suitable for gastric fluid as it is soluble at lower pH up to pH-5. Eudragit® L and S series show delayed release in drug formulations. The L and S series vary in pH. Eudragit® RL and Eudragit® RS are used for time-controlled release purposes. These series are insoluble with pH-independent swelling [84]. Eudragit® RL has high permeability while Eudragit® RS has low permeability. Combining the series together enables pharmaceuticals with customized time-controlled release profiles. While it has been used successfully with FDM methods to create immediate-release tablets when used with a plasticizer, the 3D printing process was unreliable and the nozzle was frequently clogged [85].
3.1.4. Hydroxypropyl Cellulose (HPC)
Hydroxypropyl cellulose (HPC) is a flexible, water-soluble polymer. HPC is made up of a monomer that is comprised of a glucose molecule with multiple hydroxypropyl substituents. HPC is available in different viscosity grades, making it suitable for formulating drugs with different release profiles. Overheating and rapid changes in temperature drastically affect the stability of HPC and its viscosity. HPC has a low glass transition temperature in the range of −25 °C to 0 °C as moisture varies from ~10% to 1%approximately [86]. It has high thermostability, making it suitable for processes that require melting and extrusion. The viscosity of HPC decreases as temperature increases, which in turn increases the release rate of the selected API. High molecular weight HPC, compared to its low molecular weight counterparts, exhibits high swellability that is suitable for controlled-release matrices [87].
3.1.5. Hydroxypropyl Methylcellulose (HPMC)
Hydroxypropyl methylcellulose (HPMC) is a swellable, water-soluble polymer that enhances the sustained release capabilities of active ingredients in pharmaceuticals [88]. The high swellability of HPMC has significant effects on the release kinetics of pharmaceuticals [89]. HPMC E5 is used for immediate-release tablets and suitable for the PAM printing method [11]. Under high UV-light exposure, HPMC remains stable [90]. The glass transition temperature (Tg) of HPMC is 170–198 °C [91]. When heated above certain temperatures, an aqueous solution composed of HPMC will gel out of the solution. The thermal gelation may impact drug stability in regards to 3D printing.
3.1.6. Polycaprolactone (PCL)
Polycaprolactone (PCL) is a semi-crystalline, biocompatible polyester with a melting point of 55–60 °C and Tg of −54°C [92,93]. It has a great organic solvent solubility. It is used for long-term implant delivery devices due to its very low in vivo degradation [92,94]. PCL is often blended or co-polymerized with PLLA (poly(l-lactic acid)), PDLLA (a racemic mixture of PLLA and PDLA (poly(d-lactic acid)), PLGA poly(lactic-co-glycolic acid), etc. to improve polymer erosion [94]. PCL is considered a good elastic biomaterial due to its low tensile strength (~0.023 GPa) and high elongation at breakage (4700%) [95].
3.1.7. Polylactic Acid (PLA)
Polylactic acid (PLA) is an insoluble, synthetic biodegradable polymer [96,97]. It is the most extensively researched and utilized biodegradable aliphatic polyester. PLA is a thermoplastic, high-strength, and high modulus polymer [93,98]. It is non-toxic because its monomers can be made from the fermentation of sugar. The drug release of PLA encapsulated medicines can be influenced by the manipulation of PLA crystallinity degree and mechanical stability [98]. PLA is a very brittle material with less than 10% elongation at break, which limits its use in the application where plastic deformation is required at higher stress levels [98]. PLA has four forms as it possesses chiral molecules. Among them PLLA and PDLLA are promising for pharmaceutical applications. PLLA has a melting temperature of around 175 °C, a Tg of 60–65 °C, and a mechanical strength of 4.8 GPa; whereas, PDLLA has a slightly lower Tg of 55–60 °C and a mechanical strength of 1.9 GPa [94]. PLA can last up to three hours in acid, which is more suited to drugs that require a delayed release [99].
3.1.8. Polyvinyl Alcohol (PVA)
Polyvinyl alcohol (PVA) is a biocompatible, swellable water-soluble synthetic polymer [100,101]. It is also a thermoplastic polymer [62], exhibiting a Tg of 85 °C, melting point range of 180 (partially hydrolyzed) to 228 °C (fully hydrolyzed), and a partially hydrolyzed viscosity ranging from 3.4 mPa·s to 52 mPa·s [11,52]. It is widely used in FDM [102]. PVA is suitable for immediate release tablets as it dissolves more readily in hydrochloric acid [99]. However, controlled release can be achieved using PVA if the capsule is designed as a series of concentric circles to delay release [103].
3.1.9. Polyvinylpyrrolidone (PVP)
Polyvinylpyrrolidone (PVP) is a water-soluble polymer [53]. It is also capable of solubilizing in other organic solvents. PVP’s solubility properties are attributed to its chemical structure, where it displays hydrophilic and hydrophobic components [104]. The chemical structure also yields hydrogen bonding of PVP. The hydrogen bonding causes interactions and the formation of complexes with low molecular weight compounds. The Tg of PVP has a direct relationship with its molecular weight and it reaches a plateau at about 175 °C which corresponds to a molecular weight of 100,000 [104].
3.1.10. Poly(Ethylene Glycol) (PEG)
PEG is a water-soluble, biocompatible, and amphiphilic polymer whose derivatives are used for a variety of applications. PEG is also known as polyethylene oxide (PEO) or polyoxyethylene (POE), depending on its molecular weight [105]. Polymers with Mw <100,000 are usually called PEGs, while higher molecular weight polymers are classified as PEOs [105]. PEGDA (PEG diacrylate) is a polymer that is a derivative of polyethylene glycol (PEG). To create PEGDA, an acrylic group is added to the terminal hydroxyl end group in PEG. The acrylic groups aid in its polymerization process where photopolymerization and other techniques are used [106]. PEGDA has better mechanical strength than PEG due to the formation of cross-link [94].
3.1.11. Soluplus®
Soluplus® is a polymeric solubilizer with an amphiphilic chemical structure. It is a graft copolymer composed of polyethylene glycol, polyvinyl acetate, and polyvinyl caprolactam. BASF designed this copolymer to solubilize APIs that are typically poorly soluble. It is also very suitable for HME because of its Tg of about 70 °C and low hygroscopicity [107].
In summary, all the polymers available are classified based on water solubility and the types of drug release which have been summarized in Figure 5a. Figure 5b shows their suitability to use for either FDM or PAM 3D printing process.
Article information: Azad, M.A.; Olawuni, D.; Kimbell, G.; Badruddoza, A.Z.M.; Hossain, M.S.; Sultana, T. Polymers for Extrusion-Based 3D Printing of Pharmaceuticals: A Holistic Materials–Process Perspective. Pharmaceutics 2020, 12, 124. https://doi.org/10.3390/pharmaceutics12020124
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