Nozzle based deposition technique involved in proper mixing of drugs with polymers to proceed on 3D printing. The challenges faced by the previously discussed technique can be overcome by this technique. The nozzle was used to extrude for producing 3D printed product by layering method. Fused Deposition Modeling (FDM) involves melting whereas Pressure-Assisted Microsyringes (PAM) doesn’t need melting of components .
Fused deposition modeling (FDM)
In FDM the hot melt extruded filament is used as primer for printing where drug loaded filament is passed through the nozzle. The melting temperature of drug-polymer mixture and extrusion temperature determines successful printing of product. The thermoplastic polymers like polyvinyl alcohol, polylactic acid and acrylonitrile butadiene styrene (ABS) are used but ABS is not sufficient for use in medical field as it is non-biodegradable polymer . The temperature used must be above the melting temperature of components. The parameters such as feed rate, nozzle diameter, pressure drop and thermal properties such as glass transition temperature (Tg), density, thermal conductivity of components determines performance of printing.
The first attempt made to print fluorescein with PVA filaments by FDM technique . It proved that infill density can be modified to obtain desired drug release pattern. In further progression 4-ASA and 5-ASA used for colon treatment. In that 4-ASA having thermolabile property it gets degraded while printing but 5-ASA thermally stable and successfully printed. It proves that FDM is suitable technique for the use of non thermolabile components .
The FDM also helps in the geometry of tablets which is impossible in other 3D printing techniques. It was successfully proved that geometrical shapes are possible such as pyramid, sphere and torus. The constant geometry with different shapes is possible by varying dimension of the filaments. Also, modification in drug loading depending upon the need of patients is possible. The drug release kinetics with certain target can be achievable with printer settings. It is one of the best techniques to prepare tailormade formulations .
Compared to powder bed technique it provides more resolution, able to prepare complex design to achieve higher drug accuracy. It also provides good mechanical strength to give different release profiles. The infill percentage can change the release pattern of the drug profile. However thermal property plays an important role to decide the extrudability of any compound therefore API’s may not be suitable for FDM printing .
The polypill is possible with various active drugs, depending upon its compatibility 2–5 drugs can be used in one matrix structure by 3D printing method. The multiple drugs can gives targeted release profiles by using different polymer and infill density. Goyanes et. al. proved that multilayer tablets are possible by 3D printing method. Paracetamol and caffeine gives drug release kinetics as per their layers and location in the multilayer region .
The impact of 3D printing by FDM is higher than any other method. Different complex geometry is possible with different suitable drug-polymers. For clinical practice in future it needs to improve its drawbacks like speed and quality for the development.
PAM technology (pressure-assisted microsyringes)
The technology depends upon the pressure applied on the piston to form desired geometry. The extruder via syringe deposits semi-liquid and viscous material. It depends upon the viscoelasticity, viscosity and elastic limit to reproduce the technique. The technology advances with use in continuous flow with room temperature which is not possible with other techniques. But solvent used might be failed at stability of certain APIs and toxic to health for human use. The technique can be used for drug delivery, tissue printing and soft tissue scaffolds [28, 35].
In the attempt to control the chitosan drug release so as to develop polylactic-coglycolic acid/nano-hydroxyapatite (PLGA/nHA) scaffolds having recombinant human bone morphogenetic protein 2 (rhBMP-2) nano-sustained release carriers with tissue engineered bone for the repairing large jaw defects . The chitosan which is a natural product obtained from crustaceans shells like crabs and shrimps. It is polysaccharide comprises of copolymers of glucosamine and N-acetylglucosamine obtained by the chitin partial deacetylation. This cationic polyamine reacts chemically with anionic systems. In case of chitosan it is considered as a nonirritant and nontoxic agent as it is biodegradable and biocompatible. It is further used in different dosage form such as films, beads, gels, microspheres, coatings for liposomes and tablets with applications in the controlled drug delivery systems like colonic drug delivery and mucoadhesive dosage forms and immediate drug release.
Laser-based writing system
The first device designed in the year 1980 by Charles Hull called as ‘Stereolithography’ (SLA). In this technique, the laser is used to photopolymerize resin for preparation. The printer consists of ultraviolet; it form laser to project on resin which is photopolymerizable in nature. The UV rays are used to interact and release free radicals from it . The first layer gets solidify and new layer is added, the process goes on until 3D printed product gets ready. The thickness can be dependent upon the UV light energy, it gets solidify eventually. The resin chosen plays a vital role into process of resin exposure with UV light. This has to be approved by regulatory agency to get approved for its safe human use [28, 33].
The laser is moved to make the layer one over the other. Tank providing resin as laser moves it solidifies the resin to form a solid base. Drug can be easily disperse or dissolve inside the resin before printing. The solid oral tablets can be made by this method. In the first attempt aspirin with polyethylene glycol diacrylate (PEGDA) resin was made . It gives complete drug release in time of 3 h. As the resin is miscible with water, hydrogels can be made easily.
In case of SLA, drug and photopolymer resin is previously mixed to make solid base. Thermal process involvement is lesser compared to the other technique like FDM. Also loading of drug is low as compared to other techniques. Recently polymers developed are diethyl fumarate (DEF), poly (propylene fumarate) (PPF), poly (2-hydroxyethyl methacrylate) (pHEMA), dimethacrylate (DMA), poly ethylene glycol and Polyethylene glycol diacrylate (PEGDA) . The SLA technique is well versed with 3D printing so as to widen the scope in bioengineering.
In selective laser sintering technique (SLS) the laser is moved on the powder bed. The heat generated in the laser melt the particles to fuse together. Similar to powder bed printing previously discussed it helps to form a solid bed over it. It doesn’t use any solvent hence widen the future scope to develop this technique used in solid dosage form .
Selecting polymer for 3D printing formulation is important factor so as to achieve different release pattern. The therapeutic need of patients depends upon different release patterns like immediate, modified or extended release. It can be achieved by using different types of polymer as per the requirement.
Selection of appropriate polymer as per the need is basic requirement for any 3D printing formulation. In case of FDM two methods used namely hot melt extrusion (HME) and impregnation . The HME technique is widely used due to its drug loading capacity is higher than any other method [40, 41]. However, currently available HME polymers sometimes not compatible to extrudable further for FDM printing . In impregnation method filament is dipped in an organic solution for certain period of time, hence it will accumulate drug loading into it, but it is less in amount. In case of immediate drug release dosage form Kollidon® VA64, is good choice. Water soluble polymer polyvinylpyrrolidone-vinyl acetate was proven to be helpful for making 3D printing formulation [30, 31, 43].
For choosing polymer of suitable kind the criteria of selection depends upon the melting point, drug-polymer compatibility and extrudability of polymer. Polymer can be helpful to achieve target release for functional activity. It gives edge over the other currently available formulation by performing more accurately by 3D printing. Selecting polymers like PVA, PCL and PLA having sufficient thermoplasticity to make 3D printing formulation. The proper grade has to be chosen for not just preparation of filament but also to make extrudable from 3D printer. For the improvement in the process of release system different plasticizers are used like Eudragit RL, RS and HPC for FDM 3D printing [43, 44].
Polyvinyl alcohol (PVA)
It is water soluble thermoplastic synthetic polymer having no odour and good mechanical properties. It is made by hydrolysis of polyvinyl acetate either full or partial way, by removing acetate group from it . This process has impact on the properties like physical, chemical and mechanical. The melting point decided by degree of hydrolysis, if it is ranging from 180 ℃ having partially hydrolyzed to 220 ℃ fully hydrolyzed. The viscosity of polymer ranging between 3.4 and 52 mPa·s is partially hydrolyzed whereas 4 to 60 mPa·s is fully hydrolyzed [28, 45]. The degree of hydrolysis and polymerization of polyvinyl alcohol is lower and higher is the solubility in water made crystallization easier . Molecular weight of any polymer is higher than its degree of hydrolization which is lower. The glass transition temperature (Tg) of PVA is 85 ℃ and temperature of degradation is about 350–450 ℃.
The good biodegradability and its less adverse effects make it suitable for biomedical pharmaceutical applications . It is one of the applications in 3D printing is to produce multiple layers by inkjet printing method. The printable ink with glycerin is used to avoid blocking in nozzle allowing for easy printing of product. Molecular weight decides the inkjet printing capacity depending upon viscosity of ink. Higher molecular weight didn’t accumulate any color and stable enough for six months period. But the lower molecular weight forms milky appearance resulting into unsuitable for inkjet printing .
Apart from application in inkjet printing, PVA is also successfully applied in FDM technique. Depending upon the factors like infill density ranging from 0 to 100% it defines the structure. The extruder speed, layer height and temperature nozzle are different parameters taken in the consideration while using FDM technique. In case of filament impregnation first it is dried and later printed as per the need . The previous attempt proved that drug can be successfully loaded up to 10%. In one of the attempt by Goyanes et. al. paracetamol and caffeine successfully loaded drug by hot melt extrusion with PVA filaments. The drug loading within range 4–10%, as loading is lower drug release is also becomes decrease. In setting parameters for FDM is 100% infill, 200 ℃ temperature of extrusion and extruding speed of 90 mm/s .
Polylactic acid (PLA)
The biodegradable polymer is suitable for applications in medical fields such as drug delivery, regenerative medicines, stent applications and tissue engineering. It is accepted by the United States Food and Drug Administration (FDA) and considered as safe for use . The different properties depend upon the process temperature, molecular weight and isomers ratio. The PLA having melting point 150–175 ℃; Tg = 55 ℃ [29, 48] and it is soluble in dioxane, methylene chloride, acetonitrile, 1, 1, 2-trichloroethane, dichloroacetic acid and chloroform. The solubility is poor in water, propylene glycol, alcohols like methanol, ethanol and unsubstituted hydrocarbons like hexane and heptanes. But when solvents heated to boiling temperature solubility increased rapidly .
The PLA has one effective application that it doesn’t cause any toxic or carcinogenic effect. Administration into human body it gets hydrolyzes into alpha hydroxylic acid. Later, it gets into tricarboxylic acid cycle and excreted out from the body. Also, rate of degradation is depending upon factors like molecular weight, stereochemistry and crystallinity. The PLA has slower rate of degradation making it sustain for longer time in vivo type .
Thermal degradation can possibly cause due to lactide formation, hydrolysis and oxidative scission of chains. The degradation process lose 5% polymer at 325 ℃ and at 500 ℃ doesn’t have any residue. Because of low cell affinity causes inflammatory response when it has comes in direct contact with biological fluids. It is brittle polymer as compared to other polymers . Considering all the factors PLA becomes the good choice for 3D printing technique .
It is the hydrophobic semi-crystalline polymer with melting point 59–64 ℃ with Tg-60 ℃. It has good solubility in benzene, toluene, cyclohexane, carbon tetrachloride, chloroform, dichloromethane and 2-nitropropane at room temperature. Also, low solubility observed in acetonitrile, acetone, ethyl acetate, 2-butanone, dimethylformamide and insoluble in diethyl ether, alcohol and petroleum ether . It gets degraded in environment by bacteria and fungi not by human body because it doesn’t contain necessary enzymes for its biodegradation. The PCL is bioresorbable later on start the hydrolytic degradation.
The molecular weight, degradation conditions and degree of crystallinity are the deciding factors for homopolymer polycaprolactone . As crystallinity increases molecular weight decreases. As compared to PLA, PGA the time of degradation becomes longer in case of PCL. It helps to deliver drug for longer period of time by extending degradation period by at least a year. The various factors like low melting point, solubility and blend compatibility make PCL applied in the biomedical applications like wound dressings , tissue engineering  and drug delivery systems .
In case of 3D printing it was studied for tablets loaded with polymeric nanocapsules made up of Eudragit RL100 and PCL produced by FDM printer. The temperature of extrusion used was at 110 ℃ for Eudragit and at 65 ℃ for PCL. The printing temperature of Eudragit filaments was at 170 ℃ and at 95 ℃ for PCL. The settings for the FDM printer were 90 mm/s extruding speed and 100% infill percentage along with Eudragit filaments with 50% infill percentage so as to prepare tablets. Polymer decides the drug loading and drug content available in the 3D printed tablet. The Eudragit tablets have a higher drug content as compared to polycaprolactone due to its swelling indices is high. The release profile is high in case of Eudragit compared to PCL tablets .
Polyphenylene sulfide (PPS)
It is asymmetrical rigid backbone chain consists of Para substituted phenylene rings and sulfur atoms. It is semi-crystalline material with thermoplastic property; it has high temperature stability, good dimensional stability, flame retardance and chemical resistance for easy processability. It also has the capacity for radiation resistance, aging resistance and nontoxicity [53, 54].
In other sectors like aerospace, electronics and automotive it also has wider applications. In 3D printing thermal process involved affecting mechanical properties depending upon the temperature and cross-linking of polymers . In analysis by the Park et. al.  it was observed that in the range of 200–250 ℃; higher oxygen concentration and rise in temperature effectively increases cross linking of polymers.
In case of PPS the studies carried out towards the parameters of printing, composites and effect on warpage. The semi-crystalline thermoplastic PPS and polyether ketone analyzed the material properties like rheology and thermal properties. From this, printing parameters are selected for printing. In another study, elemental analysis is done for residual stresses observed during the process of cooling PPS and PP for variation in printing speed .
Drug development in 3D printing formulation
The various formulations are made by the different strategies for the formulation. Mostly FDM (Fused deposition modeling) is widely used in 3D printing pharmaceutical formulations. The percentage drug loading depends upon the physiochemical properties of drug, polymer used and printing setup. The FDM is mainly well explored with different model drugs to well-established prototype for 3D printing solid dosage form like tablet.
Amongst all one of the first attempt for modified release formulation by using FDM method was made with the model drug fluorescein. PVA filament was used with fluorescein with the swelling of PVA in ethanolic drug solution. The drug loading achieved was 0.29% w/w by this method. Appearance of tablet was strong enough and no drug degradation was observed. The tablets of 10 mm diameter were printed by using 3D printer. By change in the infill percentage it shows modified release profiles .
Immediate release is giving quick onset of action within shorter time period. The making physical modifications with low dose model drug Pramipexole by using Eudragit® EPO and polyethylene oxide. The drug achieves complete release within 5 min by change in physical modification along with Hot melt Extrusion and FDM 3D printing. So, synergistic approaches of techniques avoid the use of other disintegrating or filling agents. Different infill percentages like 10%, 25%, 50% and 75% extruded effectively with the use Eudragit® EPO-POLYOX. After POLYOX concentration decrease it helps to deform matrix structure and makes tablet release rapidly. The thickness of tablets can be decreased and creating space in between them to increase drug release. It is able to increase the drug release rate and possibly up to 5 min .
In another attempt Theophylline or dipyridamole loaded with PVP filament. For PVP filament ideal temperature for extrusion is ranging between 200 and 220 ℃ but in this case it extrudes easily at 110 ℃. In spite of hydrophilic polymer (PVP) it is able to achieve faster drug release. It is one of the first attempts to reduce temperature and preparing immediate release tablet with talc as thermostable filler and matrix former .
Similar work also done by lower dose of Pantoprazole sodium (20 mg) processed below 100 ℃. Different polymer concentration tried but PEG 6000 and PVP K 12 found suitable for faster drug release. The porosity of tablet plays a vital role in it; infill percentage % can be lower down to 50% helps to reduce drug release up to 3 min. It is one of the futuristic approaches for thermo-sensitive drugs via this technique .
The drug paracetamol which is higher drug content requires different strategies to formulate tablet. It mainly needs excipients which equally contribute in formulation leads to increase the tablet weight. High drug loading paracetamol (80%) prepared using grind with PVP K-25 and CCS for the certain period of time. The cartridge was used to load it into the printer. The oval-shaped tablet is prepared so as to achieve drug release more than 90% within first 10 min. This effort can be utilized further in case of high dose formulation. This technique can fulfill all the needs of immediate release dosage form .
The study performed for identification of acceptable polymers suitable for 3D printed tablets with the help of FDM. The filament of drug-polymer was prepared by HME, Haloperidol was chosen as a basic drug with pH-dependent solubility in aqueous media. The crushed filament gives rapid drug release when it is compared with various set of polymers. For infill density it was observed that 60% infill was faster than 100% infill to achieve the drug release in case of immediate release dosage forms .
For inflammatory bowel disease treatment, the model drug chosen was 4-aminosalicylic acid and 5-aminosalicylic acid (aminosalicylate isomers). The available PVA filaments which incorporates the drug with the filaments were prepared by loading APIs onto PVA filaments. The drug loading was found to be 0.06% w/w and 0.25% w/w for 4-ASA and 5-ASA, respectively. The tablet prepared with 10.5 mm diameters for both the drugs. The infill percentage was in the 10%, 50% and 90% to check with release pattern. The infill percentage can correlate to the release profile, lower infill percentage can gives faster drug release pattern. Release profile mainly dependent on printing parameters that can easily modified as per the need. The higher temperature for extrusion is 2100C for PVA to print the filament. It is drawback of filament, whereas other polymeric filaments can easily print at the temperature below the decomposition temperature so that it will not degrade. In this case, 5-ASA was found to be the ideal drug for FDM process which melts at 2780 C but 4-ASA was found to be thermally degraded at 130 ℃, that was the major problem occurred in the process .
Geometry of tablets
The effect of geometry is one of the pioneer works which explored the possibilities with different shape of tablets and its effect on release pattern. The 3D printing is only possible methods which effectively formulate the shapes like cylinder, cube, torus, pyramid and sphere. It overcomes the boundaries of traditional methods and easily forms the design of required size and shape by using the software. Otherwise by the use of powder compaction method it is impossible to create different geometries. About 4% Paracetamol is loaded successfully with PVA filaments, from the release data it confirms that geometry plays a vital role. By keeping surface area constant the observed release pattern was (fastest first) pyramid > torus > cube > sphere > cylinder. Sometimes amount of drug loading percentage is higher needing some plasticizing agent for the proper flexibility and temperature while printing .
One of the novel concepts of channeled tablets is introduced in the tablet design. It helps to increase the surface area of the tablet with media perforation through its structure. The shorter channels give more efficient drug release than the longer channels. The size of ≥ 0.6 mm is essential to accelerate the drug release and meet pharmacopeial criterion for immediate release products. It is anticipated that a new generation of dosage form of complex geometry will emerge to tailormade drug release via controlling the media flow through these built-in channels .
In extended release, ellipse-shaped solid tablets were prepared by using prednisolone. Model drug used in the study because of its (melting point: 235 ℃) high thermal stability and neutral nature. It helps to test the filament ability of API content in the dose and its release before going in the nozzle of printer. Saturated methanolic solution of drug was used for loading due its drug solubilising ability and swelling of PVA without hampering the filament structure. The maximum drug loading is about 1.9% w/w; thermal analysis and PXRD study confirms the amorphous form within the PVA matrix. The FDM 3D printers can be exploited as a platform to construct flexible dose tablets from purpose built drug containing filaments for drug release over the 24 h .
Abuse deterrent formulations
Drug abuse is the biggest concern in the recent past. The opioid drugs are misused via oral way, nasal pathway or by making fine particles with directly or dissolved in solvents to intake. The metformin is used as model drug because of its aqueous and alcohol solubility similar to abuse drug oxycodone. The egg-shaped tablet is made in such a way that it will remain intact after mechanical force applied externally. Shape will not be easy to break as that of normal tablet. The various household and laboratory tools used to confirm the resistance of formulation but it found to be negative. Particles obtained are higher in particle size that it will not easily useful for snorting. PVA and sorbitol extrudes at 170 ℃. For immediate drug release ideal formulation was found to be 45% infill density and 15% w/w drug load. It is one of the essential needs to made abuse deterrent formulation for avoid its unethical use .