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Contents lists available at ScienceDirect
International Journal of Pharmaceutics journal homepage: www.elsevier.com/locate/ijpharm
Effect of geometry on drug release from 3D printed tablets Alvaro Goyanes a , Pamela Robles Martinez a , Asma Buanz a , Abdul W. Basit a,b , Simon Gaisford a,b, * a b
UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London, WC1N 1AX, UK FabRx Ltd., 3 Romney Road, Ashford, Kent TN24 0RW, UK
A R T I C L E I N F O
A B S T R A C T
Article history: Received 18 March 2015 Received in revised form 22 April 2015 Accepted 24 April 2015 Available online xxx
The aim of this work was to explore the feasibility of combining hot melt extrusion (HME) with 3D printing (3DP) technology, with a view to producing different shaped tablets which would be otherwise difficult to produce using traditional methods. A filament extruder was used to obtain approx. 4% paracetamol loaded filaments of polyvinyl alcohol with characteristics suitable for use in fuseddeposition modelling 3DP. Five different tablet geometries were successfully 3D-printed—cube, pyramid, cylinder, sphere and torus. The printing process did not affect the stability of the drug. Drug release from the tablets was not dependent on the surface area but instead on surface area to volume ratio, indicating the influence that geometrical shape has on drug release. An erosion-mediated process controlled drug release. This work has demonstrated the potential of 3DP to manufacture tablet shapes of different geometries, many of which would be challenging to manufacture by powder compaction. ã 2015 Elsevier B.V. All rights reserved.
Keywords: 3D printing Controlled-release Fused deposition modeling PVA paracetamol Hot melt extrusion
1. Introduction The future of medicine design and manufacture is likely to move away from mass production of tablets/capsules of limited dose range towards extemporaneous fabrication of unit dosage forms of any dose, personalised to the patient. The factors driving this change include the development of low dose drugs with narrow therapeutic indices (for instance immunosuppressants and/or blood thinners), the increasing awareness and importance of pharmacogenomics (for instance in the drug sensitivity of cancer sufferers, Kim et al., 2012) and the need to formulate drug combinations. To face this challenge, the pharmaceutical industry needs to evaluate and embrace novel manufacturing technologies. One technology with such potential is 3D printing (3DP). Of the many types of 3D printer commercially available, fuseddeposition modelling (FDM) offers perhaps the most immediate potential to unit dose fabrication. In FDM 3DP an extruded polymer filament is passed through a heated tip. The heat softens the polymer and it is then deposited on a build plate. The temperature of the build plate can be controlled and is set so that the polymer hardens. The print head deposits polymer on the build plate in the x–y dimensions, creating one layer of the object to be printed. The build plate then lowers and the next layer is deposited. In this
* Corresponding author. Tel.: +44 2077535863; fax.: +44 20 7753 5942. E-mail address: [email protected] (S. Gaisford).
fashion, an object can be fabricated in three dimensions, and in a matter of minutes. FDM technology has the significant advantages of cost (typical systems cost between £800–2000), the ability to fabricate hollow objects, and the opportunity to print a range of polymers. The printer feedstock is an extruded polymer filament, typically 1.75–3 mm in diameter and one of the prime benefits of FDM 3DP is that it is possible in principle to blend active drug and polymer into a solid dispersion prior to extrusion, so that the printed dosage form is drug loaded. This principle has been demonstrated, for example, to tablets containing fluorescein (Goyanes et al., 2014), 4-aminosalicylate and 5-aminosalicylate (Goyanes et al., 2015) and prednisolone (Skowyra et al., 2015). However, in all of these studies the percentage drug loading is low, because the drugs were loaded by passive diffusion from solution. An alternative method is to incorporate drug into polymer filaments by hot-melt extrusion (HME) processing. HME is a widely used technique in the pharmaceutical industry and is in essence a process of using a rotating screw to pump raw materials at elevated temperatures through a die to generate a product of uniform shape. Today, the interest in HME techniques for pharmaceutical applications is growing rapidly with more than 10 pharmaceutical products including oral dosage forms (e.g. Kaletra [Abbott], Rezulin [Pfizer]), implants (Ozurdex [Alergan]) and medical devices (Nuvaring [Merck]) taken to market in the last 12 years. The number of HME patents issued for pharmaceutical systems has steadily increased since the early 1980s, with ever widening international scope: to date, more than 300 such patents
http://dx.doi.org/10.1016/j.ijpharm.2015.04.069 0378-5173/ ã 2015 Elsevier B.V. All rights reserved.
Please cite this article in press as: A. Goyanes, et al., Effect of geometry on drug release from 3D printed tablets, Int J Pharmaceut (2015), http:// dx.doi.org/10.1016/j.ijpharm.2015.04.069
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Fig. 1. 3D representation of the 3D geometries printed (left to right; cube, pyramid, cylinder, sphere and torus).
have been filed. Several research groups have demonstrated HME processes as a viable method to prepare a wide range of accepted pharmaceutical drug delivery systems, including granules, pellets, transdermal patches, transmucosal films systems and implants (Breitenbach, 2002; Crowley et al., 2007; Fonteyne et al., 2013). The use of HME to produce drug-loaded printable filaments has been shown to be feasible for plastics used for medical devices (Sandler et al., 2014) but has not, to our knowledge, been demonstrated for water soluble polymers suitable for fabricating oral dosage forms. A further potential benefit of FDM 3DP, also currently unexplored, is that the printer can be used to fabricate tablets of any geometry. Pretended donut-shape polymer matrices were evaluated to obtain zero-order drug release (Cheng et al., 1999; Kim, 1999), although the matrices were compacts with holes rather than real torus. The theoretical shape of tablets to obtain a uniform drug release rate from multi holed formulations was also noted but not manufactured/evaluated (Cleave, 1965). Other studies reported the use of parabolic shapes to achieve a zero-order release from a polymeric matrix (Bayomi, 1994), or differences in drug release from triangular, cylindrical and half-spherical tablets of the same formulation (Karasulu and Ertan, 2003). Siepmann et al. (2000) developed a model to predict drug release from matrix tablets of hydroxypropylmethylcellulose. They envisaged that since changing tablet shape can modify drug release rates, the optimal shape to obtain a specific release profile could be calculated. 3DP would be the only suitable method to manufacture tablets of such specific shape with precision and ease, including more elaborate shapes that would be impossible to create by powder compaction, e.g. expandable systems (Klausner et al., 2003) or platforms for improved gastrointestinal transit (Varum et al., 2013). The aims of this work, then, were to (i) produce a filament containing a model drug in a water soluble polymer (polyvinyl alcohol, PVA) suitable for printing into pharmaceutical tablets and (ii) to print tablets in a diverse range of geometries, many not attainable by powder compaction, and to correlate geometric parameters with dissolution behaviour. 2. Materials and methods Polyvinyl alcohol (molecular formula (C2H4O)n) was purchased as an extruded filament (1.75 mm diameter, print temperature 190–220 C, batch No: 2013-10-18, Makerbot Inc., USA). Paracetamol USP grade was obtained from (Sigma–Aldrich, UK). Salts for
preparing buffer dissolution media were purchased from VWR International Ltd., Poole, UK. 2.1. Preparation of PVA filament loaded with drug The commercial PVA filament (38 g) was cut into small pieces (2 mm) using a Pharma 11 Varicut Pelletizer (Thermo Fisher Scientific, UK) and mixed with paracetamol (2 g, 5% drug w/w) for 10 min in a Turbula1 T2F shaker–mixer (Glen Mills Inc., USA). The mixture was extruded using a single-screw filament extruder, FilaBot1 hot melt extruder (Filabot, USA) at 180 C through a 1.75 mm diameter nozzle (screw speed 35 rpm). The extruded filaments obtained were protected from light and kept in a vacuum desiccator until printing. The drug-loading of the filaments was determined by HPLC analysis. 2.2. Printing of paracetamol dosage forms Tablets were fabricated with the drug-loaded filament using a standard fused-deposition modelling 3D printer, MakerBot Replicator 2X Desktop 3D printer (MakerBot Inc., USA). The templates used to print the tablets were designed with AutoCAD 20141 (Autodesk Inc., USA) and exported as a stereolithography (.stl) file into MakerWare v. 2.4.1 (MakerBot Inc., USA). The .stl format encodes only the surface data of the object to be printed and requires the thickness of the surface to be defined in order to print the desired object. The printer settings were as follows: standard resolution with the raft option deactivated and an extrusion temperature of 180 C, speed while extruding (90 mm/s), speed while travelling (150 mm/s), number of shells (2) and layer height (0.20 mm). The infill percentage was 100% in order to produce tablets of high density. The selected 3D geometries were cube, pyramid, cylinder, sphere and torus (Fig. 1). The sizes of the shapes were varied using the scale function of the software to fabricate tablets of constant surface area (275 mm2), surface area/volume ratio (1:1) or weight (500 mg), Tables 1–3. In all cases, however, the ratio of the length, width and height of each shape was kept constant. 2.3. Scanning electron microscopy (SEM) Surface and cross-section images of the filaments were taken with an SEM (JSM-840A Scanning Microscope, JEOL GmbH, Eching,
Table 1 Physical parameters for tablets with similar surface areas. Shape
Surface area (mm2)
Volume (mm3)
SA/V ratio
Weight (mg)
Density (mg/mm3)
Cube Pyramid Cylinder Sphere Torus
287.9 2.1 270.4 0.4 268.5 3.9 280.8 1.4 266.8 1.0
332.3 3.6 231.3 0.5 314.4 6.5 442.3 3.2 266.4 1.9
0.866 0.003 1.169 0.001 0.854 0.005 0.634 0.002 1.002 0.004
268.2 15.7 187.5 3.9 355.3 23.7 505.3 36.0 276.0 19.6
0.81 0.05 0.81 0.02 1.13 0.05 1.14 0.08 1.04 0.08
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Table 2 Physical parameters for tablets with similar surface/volume ratios. Shape
Surface area (mm2)
Volume (mm3)
SA/V ratio
Weight (mg)
Density (mg/mm3)
Cube Pyramid Cylinder Sphere Torus
212.1 2.2 356.1 2.7 200.8 3.2 111.5 1.2 266.8 1.0
210.1 3.3 353.7 5.2 202.3 4.0 110.7 1.9 266.4 1.9
1.009 0.005 1.007 0.008 0.992 0.004 1.007 0.006 1.002 0.004
186.9 19.3 451.2 12.0 197.6 4.0 98.5 0.9 276.0 19.6
0.89 0.11 1.28 0.05 0.97 0.18 0.89 0.05 1.04 0.08
Germany). All samples for SEM testing were coated with carbon (30–40 nm).
the eluent was screened at a wavelength of 247 nm. All measurements were made in duplicate.
2.4. Thermal analysis
2.7. Dissolution testing
Filaments were characterised with differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). DSC measurements were performed with a Q2000 DSC (TA instruments, Waters, LLC, USA) at a heating rate of 10 C/min. Calibration for cell constant and enthalpy was performed with indium (Tm = 156.6 C, DHf = 28.71 J/g) according to the manufacturer instructions. Nitrogen was used as a purge gas with a flow rate of 50 mL/min for all the experiments. Data were collected with TA Advantage software for Q series (version 2.8.394), and analysed using TA Instruments Universal analysis 2000. All melting temperatures are reported as extrapolated onset unless otherwise stated. TA aluminium pans and lids (TZero) were used with an average sample mass of 8–10 mg. For TGA analysis, samples were heated at 10 C/min in open aluminium pans with a Discovery TGA (TA instruments, Waters, LLC, USA). Nitrogen was used as a purge gas with a flow rate of 25 mL/min. Data collection and analysis were performed using TA Instruments Trios software and % mass loss and/or onset temperature were calculated.
Dissolution profiles were obtained using a USP-II apparatus (Model PTWS, Pharmatest, Germany). In each assay, the tablets were placed at the bottom of the vessel in phosphate buffer pH 6.8 (0.05 M, 900 mL) under constant paddle stirring (50 rpm) at 37 C. During the dissolution test, samples of paracetamol were automatically removed and filtered through 10 mm filters and drug concentration was determined using an in-line UV spectrophotometer (Cecil 2020, Cecil Instruments Ltd., Cambridge, UK) operated at the wavelength of maximum absorbance of the drug in phosphate buffer (243 nm). Data were processed using Icalis software (Icalis Data Systems Ltd., Berkshire, UK). Tests were conducted in triplicate under sink conditions. Data are reported throughout as mean standard deviation.
2.5. Characterisation of tablet morphology The physical dimensions of the tablets were measured using a digital calliper. Pictures of the tablets were taken with a Nikon CoolpixS6150 with the macro option of the menu. The surface areas and volumes of the tablets were calculated based on these dimensions. The surface area to volume ratio was obtained by dividing these values. 2.6. Determination of drug loading A tablet or a section of drug-loaded strand (approx. 0.3 g) was placed in a volumetric flask with deionized water (1 L) with magnetic stirring until complete dissolution (3 h). Samples of solution were then filtered through 0.45 mm filters (Millipore Ltd., Ireland) and the concentration of drug determined with HPLC (Hewlett Packard 1050 Series HPLC system, Agilent Technologies, UK). The validated high performance liquid chromatographic assay entailed injecting 20 mL samples for analysis using a mobile phase, consisting of methanol (15%) and water (85%), through a Luna 5 mm C8 column, 25 4.6 cm (Phenomenex, UK) maintained at 40 C. The mobile phase was pumped at a flow rate of 1 mL/min and
3. Results and discussion Firstly, it was possible to prepare drug-loaded filaments by HME that were suitable for 3D printing. The drug loading percentage was 3.95% w/w 0.01 and the mechanical behaviour of the extruded filament did not appear to be significantly different from the commercial product, indicating paracetamol did not plasticise the polymer. Higher drug-loading percentages may require the addition of plasticizing agents to give a filament with suitable flexibility and softening temperature for printing. The single screw extruder used in this study was designed to produce filaments from pelletized feedstock, and so blending PVA pellets with powdered drug led to a lower drug encapsulation percentage than expected (5% w/w), probably because the fine powder adhered to the container during the mixing process and to the walls of the barrel of the HME. It would be possible to obtain higher drug loading by obtaining mixtures of drug and polymer of similar particle size. Nevertheless, filament extruder appears to be a cheap alternative to the twin-screw HME apparatus typically used to manufacture pharmaceutical products. Secondly, it was possible to fabricate all of the shapes by 3DP with the paracetamol loaded filament, Fig. 2. Five shapes were printed; four compact geometries with different edges and surfaces (cube, pyramid, cylinder and sphere) and one with a hole in the middle (torus). Manufacture of such complex and intricate shapes by powder compaction would be extremely challenging and so the study immediately suggests that 3DP offers a route of manufacture of dosage forms of novel geometries not
Table 3 Physical parameters for tablets with similar weights. Shape
Surface area (mm2)
Volume (mm3)
SA/V ratio
Weight (mg)
Density (mg/mm3)
Cube Pyramid Cylinder Sphere Torus
341.4 0.5 393.0 15.2 335.0 15.7 280.8 1.4 387.0 3.0
429.2 1.0 406.2 23.4 438.3 29.3 442.3 3.2 479.5 4.3
0.795 0.001 0.968 0.019 0.765 0.016 0.634 0.002 0.807 0.001
477.9 11.9 494.8 16.6 480.0 11.0 505.3 36.0 509.9 29.0
1.11 0.03 1.22 0.03 1.10 0.06 1.14 0.08 1.06 0.05
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previously possible. FDM appears as versatile approach suitable for manufacturing multiple drugs e.g. fluorescein (Goyanes et al., 2014), aminosalicylates (Goyanes et al., 2015) and herein paracetamol. As found in previous studies, 3D printed PVA tablets were not friable and so easy to handle (Goyanes et al., 2014, 2015). DSC and TGA analyses of the pure substances and extruded filament were performed in order to understand how the drug was incorporated in the polymer (Figs. 3–5). It is apparent that paracetamol raw material melts around 168 C (Fig. 3), indicative of form I while PVA shows a glass transition around 135 C and melting between 175 and 200 C (Fig. 4). Significant degradation of PVA is seen above 260 C, but the printhead temperature used during tablet fabrication is 180 C. The DSC data of the paracetamol-loaded PVA filament shows no evidence of melting around 168 C, indicating that the drug is molecularly dispersed within the polymer matrix as a solid solution. A glass transition is seen in both samples containing PVA, but the transition temperature remains the same whether the drug is present or not, suggesting paracetamol does not exert a plasticising effect. TGA data suggests
Power / arbitrary units
Fig. 2. Images of the 3DP fabricated tablets at constant (A) surface area, (B) surface area/volume ratio and (C) mass (scale bar in cm).
PVA-paracetamol filament
PVA filament
50
100
150
200
250
Temperature / oC Fig. 4. DSC thermal traces for PVA and PVA-paracetamol filaments. The PVA melts between 175 and 200 C.
100
Power / arbitrary units
PVA
Mass loss / %
80 PVA-paracetamol
60 40 20 Paracetamol
0
80
100
120
140
160
180
200
220
240
o
Temperature / C Fig. 3. DSC thermal trace for paracetamol raw material, showing melt of the stable form I at 168 C.
50
100
150
200
250
300
o
Temperature / C Fig. 5. TGA thermal traces for paracetamol raw material and PVA and PVAparacetamol filaments.
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Fig. 6. SEM images of the surface and cross-section of; (Top) PVA filament, (middle) PVA-paracetamol filament and (bottom) a section of a printed geometry (in this case from the torus).
that PVA is stable until 260 C, consistent with the DSC data, while paracetamol degrades significantly above 200 C (Fig. 5). When paracetamol is incorporated into the PVA, no appreciable mass loss is seen, suggesting the polymer is stabilising the drug. The drug loading of the printed tablets was 3.78% 0.01, similar to that of the filament, which indicates little degradation of the drug occurred during printing, consistent with the thermal stability of paracetamol above its melting point seen by DSC. Electron micrographs show little evidence of paracetamol crystallites within the polymer filaments (Fig. 6), also consistent with the DSC data. Images of the cross-section of a printed torus clearly show the individual strands deposited by the printer (Fig. 6). The 3D printed strands are ca. 100 mm in diameter, consistent with the
nozzle diameter of the printhead, and there is some evidence of fusion of strands, leading to the strength of the tablet noted earlier. This observation also suggests that the surface areas calculated in Tables 1–3 may in reality be slightly larger than expected. Dissolution tests confirm that geometry plays an important role in defining drug release profiles, Fig. 7. When the surface area of the tablets was kept constant, drug release rates were in the following order (fastest first); pyramid > torus > cube > sphere and cylinder. The time to 90% release (t90) varied from just under 2 h (pyramid) to nearly 12 h (sphere and cylinder). This order matches the surface area/volume ratio order of the tablets, with the pyramid having the highest value (1.169) and the sphere the lowest (0.634). Reynolds et al. (2002) noted the same trend, tablets with
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Constant Surface Area 100
Drug Released (%)
80
60
40
Pyramid Torus Cube Sphere Cylinder
20
0 0
60
120
180
240
300
360
420
480
540
600
Time (Min) Constant Surface Area/Volume ratio 100
Drug Released (%)
80
60
40
Cube Sphere Torus Cylinder Pyramid
20
0 0
60
120
180
240
300
360
420
480
540
600
Time (Min)
Constant Weight 100
Drug Released (%)
80
60
area to volume ratio) and noted that (i) tablets with a high aspect ratio had fastest dissolution and (ii) for tablets of different volume, smaller tablets had faster dissolution rates, because their surface area to volume ratio is highest. They suggest that either aspect ratio or surface area to volume ratio would be suitable parameters with which to predict and achieve defined release kinetics. Studies performed with discrete element method (DEM) modelling have similarly suggested that drug release profiles from swelling tablets is independent of tablet shape and directly related to the surface area/volume ratio (SA/V) (Kimber et al., 2013). When tablets were prepared with a constant surface area/ volume ratio, the order of drug release rates was (fastest first); sphere and cube > torus > cylinder > pyramid. In line with the observations above, less differentiation was seen in the t90 values, with most shapes having a value between 2 and 3 h. Notably, only the pyramid gave noticeably slower release (9 h). The fact that dissolution profiles were not identical, however, suggests that in the case of the PVA matrix used here erosion plays a role in defining release kinetics. Drug release rate from water soluble and swellable polymers is governed by the relative contribution of two mechanisms, drug diffusion and polymer dissolution (surface erosion) (Reynolds et al., 2002). The predominance of one or other mechanism depends on different factors such drug solubility and nature of the excipients. Some previous work on the influence of tablet shape used HPMC (to minimise erosion of the tablet) and several models accounting for geometry were developed, but generally these are applicable only to specific formulations (Siepmann et al., 2000, 1999). Drug release profiles from tablets of constant weight were very similar (Fig. 7). Previous studies with 3D printed PVA tablets noted that the drug release was through an erosion-mediated process (Goyanes et al., 2014, 2015), and the erosion may explain why tablets of similar mass show little difference in dissolution profiles. A magnetic resonance imaging based method, used recently to compare the behaviour of different geometries during dissolution studies (Dorozynski et al., 2014), could help to understand the dissolution process involved for these 3D printed formulations. The data do show, however, that it is possible to design a tablet with a controlled-drug release profile (varying over 10 h) by careful selection of shape and/or size. It also worthy to mention that the geometry not only affects the drug dissolution release in vitro but also the transit time in vivo. In expandable oral drug delivery systems (easily swallowed systems that reach a significantly larger size in the stomach due to swelling or unfolding processes), tetrahedron shaped devices remained in the stomach for longer periods of time than other shapes of similar size (Klausner et al., 2003).
40
Torus Pyramid Cube Sphere Cylinder
20
0 0
60
120
180
240
300
360
420
480
540
600
Time (Min) Fig. 7. Paracetamol dissolution profiles from 3DP solid dosage with (top) surface area 275 mm2, (middle) surface area/volume ratio 1 and (bottom) 500 mg mass all in phosphate buffer (pH 6.8).
larger surface area/volume values had faster drug release, in a study of HPMC tablets in a diffusion-controlled release process. Siepmann et al. (1999) studied dissolution rates from tablets of different aspect ratio (height to radius ratio) and volume (surface
4. Conclusions A filament extruder was successfully used to obtain paracetamol-loaded filaments of PVA with appropriate characteristics for use in FDM 3DP. The printer software enabled easy fabrication of tablets with different geometries (cube, pyramid, cylinder, sphere and torus), many of which would be challenging to manufacture by powder compaction, demonstrating the potential of 3DP as a novel manufacturing technology in pharmaceutics. Drug release kinetics from tablets showed no dependence on the surface area but rather on surface are to volume ratio, indicating the influence that geometrical shape has on drug release profile. Tablets of similar mass showed little difference in dissolution profiles that could be explained by the erosion-mediated process that drives the drug dissolution. Fabrication of different shaped objects with 3D printing may modulate drug dissolution profiles and can aid in
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the rational design of new dosage forms with specific pharmacokinetics characteristic or targeted to different sites of the gut. Acknowledgements The authors would like to acknowledge the assistance provided by John Frost to operate the hot melt extruder. Alvaro Goyanes would like to thank Fundación Alfonso Martín Escudero for the post-doctoral fellowship. References Bayomi, M.A., 1994. Geometric approach for zero-order release of drugs dispersed in an inert matrix. Pharm. Res. 11, 914–916. Breitenbach, J., 2002. Melt extrusion: from process to drug delivery technology. Eur. J. Pharm. Biopharm. 54, 107–117. Cheng, K., Zhu, J., Song, X., Sun, L., Zhang, J., 1999. Studies of hydroxypropyl methylcellulose donut-shaped tablets. Drug Dev. Ind. Pharm. 25, 1067–1071. Cleave, J.P., 1965. Some geometrical considerations concerning the design of tablets. J. Pharm. Pharmacol. 17, 698–702. Crowley, M.M., Zhang, F., Repka, M.A., Thumma, S., Upadhye, S.B., Battu, S.K., McGinity, J.W., Martin, C., 2007. Pharmaceutical applications of hot-melt extrusion: part I. Drug Dev. Ind. Pharm. 33, 909–926. Dorozynski, P., Kulinowski, P., Jamroz, W., Juszczyk, E., 2014. Geometry of modified release formulations during dissolution—influence on performance of dosage forms with diclofenac sodium. Int. J. Pharm. 477, 57–63. Fonteyne, M., Vercruysse, J., Diaz, D.C., Gildemyn, D., Vervaet, C., Remon, J.P., De Beer, T., 2013. Real-time assessment of critical quality attributes of a continuous granulation process. Pharm. Dev. Technol. 18, 85–97.
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Goyanes, A., Buanz, A.B., Basit, A.W., Gaisford, S., 2014. Fused-filament 3D printing (3DP) for fabrication of tablets. Int. J. Pharm. 476, 88–92. Goyanes, A., Buanz, A.B., Hatton, G.B., Gaisford, S., Basit, A.W., 2015. 3D printing of modified-release aminosalicylate (4-ASA and 5-ASA) tablets. Eur. J. Pharm. Biopharm. 89, 157–162. Karasulu, H.Y., Ertan, G., 2003. Different geometric shaped hydrogel theophylline tablets: statistical approach for estimating drug release. II Farmaco 57, 939–945. Kim, C.J., 1999. Release kinetics of coated: donut-shaped tablets for water soluble drugs. Eur. J. Pharm. Sci. 7, 237–242. Kim, N., He, N., Kim, C., Zhang, F., Lu, Y., Yu, Q., Stemke-Hale, K., Greshock, J., Wooster, R., Yoon, S., Mills, G.B., 2012. Systematic analysis of genotype-specific drug responses in cancer. Int. J. Cancer 131, 2456–2464. pánek, F., 2013. DEM simulation of drug release from Kimber, J.A., Kazarian, S.G., Šte structurally heterogeneous swelling tablets. Powder Technol. 248, 68–76. Klausner, E.A., Lavy, E., Friedman, M., Hoffman, A., 2003. Expandable gastroretentive dosage forms. J. Control. Release 90, 143–162. Reynolds, T.D., Mitchell, S.A., Balwinski, K.M., 2002. Investigation of the effect of tablet surface area/volume on drug release from hydroxypropylmethylcellulose controlled-release matrix tablets. Drug Dev. Ind. Pharm. 28, 457–466. Sandler, N., Salmela, I., Fallarero, A., Rosling, A., Khajeheian, M., Kolakovic, R., Genina, N., Nyman, J., Vuorela, P., 2014. Towards fabrication of 3D printed medical devices to prevent biofilm formation. Int. J. Pharm. 459, 62–64. Siepmann, J., Podual, K., Sriwongjanya, M., Peppas, N.A., Bodmeier, R., 1999. A new model describing the swelling and drug release kinetics from hydroxypropyl methylcellulose tablets. J. Pharm. Sci. 88, 65–72. Siepmann, J., Kranz, H., Peppas, N.A., Bodmeier, R., 2000. Calculation of the required size and shape of hydroxypropyl methylcellulose matrices to achieve desired drug release profiles. Int. J. Pharm. 201, 151–164. Skowyra, J., Pietrzak, K., Alhnan, M.A., 2015. Fabrication of extended-release patient-tailored prednisolone tablets via fused deposition modelling (FDM) 3D printing. Eur. J. Pharm. Sci. 68, 11–17. Varum, F.J., Hatton, G.B., Basit, A.W., 2013. Food, physiology and drug delivery. Int. J. Pharm. 457, 446–460.
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International Journal of Pharmaceutics xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
International Journal of Pharmaceutics journal homepage: www.elsevier.com/locate/ijpharm
Effect of geometry on drug release from 3D printed tablets Alvaro Goyanes a , Pamela Robles Martinez a , Asma Buanz a , Abdul W. Basit a,b , Simon Gaisford a,b, * a b
UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London, WC1N 1AX, UK FabRx Ltd., 3 Romney Road, Ashford, Kent TN24 0RW, UK
A R T I C L E I N F O
A B S T R A C T
Article history: Received 18 March 2015 Received in revised form 22 April 2015 Accepted 24 April 2015 Available online xxx
The aim of this work was to explore the feasibility of combining hot melt extrusion (HME) with 3D printing (3DP) technology, with a view to producing different shaped tablets which would be otherwise difficult to produce using traditional methods. A filament extruder was used to obtain approx. 4% paracetamol loaded filaments of polyvinyl alcohol with characteristics suitable for use in fuseddeposition modelling 3DP. Five different tablet geometries were successfully 3D-printed—cube, pyramid, cylinder, sphere and torus. The printing process did not affect the stability of the drug. Drug release from the tablets was not dependent on the surface area but instead on surface area to volume ratio, indicating the influence that geometrical shape has on drug release. An erosion-mediated process controlled drug release. This work has demonstrated the potential of 3DP to manufacture tablet shapes of different geometries, many of which would be challenging to manufacture by powder compaction. ã 2015 Elsevier B.V. All rights reserved.
Keywords: 3D printing Controlled-release Fused deposition modeling PVA paracetamol Hot melt extrusion
1. Introduction The future of medicine design and manufacture is likely to move away from mass production of tablets/capsules of limited dose range towards extemporaneous fabrication of unit dosage forms of any dose, personalised to the patient. The factors driving this change include the development of low dose drugs with narrow therapeutic indices (for instance immunosuppressants and/or blood thinners), the increasing awareness and importance of pharmacogenomics (for instance in the drug sensitivity of cancer sufferers, Kim et al., 2012) and the need to formulate drug combinations. To face this challenge, the pharmaceutical industry needs to evaluate and embrace novel manufacturing technologies. One technology with such potential is 3D printing (3DP). Of the many types of 3D printer commercially available, fuseddeposition modelling (FDM) offers perhaps the most immediate potential to unit dose fabrication. In FDM 3DP an extruded polymer filament is passed through a heated tip. The heat softens the polymer and it is then deposited on a build plate. The temperature of the build plate can be controlled and is set so that the polymer hardens. The print head deposits polymer on the build plate in the x–y dimensions, creating one layer of the object to be printed. The build plate then lowers and the next layer is deposited. In this
* Corresponding author. Tel.: +44 2077535863; fax.: +44 20 7753 5942. E-mail address: [email protected] (S. Gaisford).
fashion, an object can be fabricated in three dimensions, and in a matter of minutes. FDM technology has the significant advantages of cost (typical systems cost between £800–2000), the ability to fabricate hollow objects, and the opportunity to print a range of polymers. The printer feedstock is an extruded polymer filament, typically 1.75–3 mm in diameter and one of the prime benefits of FDM 3DP is that it is possible in principle to blend active drug and polymer into a solid dispersion prior to extrusion, so that the printed dosage form is drug loaded. This principle has been demonstrated, for example, to tablets containing fluorescein (Goyanes et al., 2014), 4-aminosalicylate and 5-aminosalicylate (Goyanes et al., 2015) and prednisolone (Skowyra et al., 2015). However, in all of these studies the percentage drug loading is low, because the drugs were loaded by passive diffusion from solution. An alternative method is to incorporate drug into polymer filaments by hot-melt extrusion (HME) processing. HME is a widely used technique in the pharmaceutical industry and is in essence a process of using a rotating screw to pump raw materials at elevated temperatures through a die to generate a product of uniform shape. Today, the interest in HME techniques for pharmaceutical applications is growing rapidly with more than 10 pharmaceutical products including oral dosage forms (e.g. Kaletra [Abbott], Rezulin [Pfizer]), implants (Ozurdex [Alergan]) and medical devices (Nuvaring [Merck]) taken to market in the last 12 years. The number of HME patents issued for pharmaceutical systems has steadily increased since the early 1980s, with ever widening international scope: to date, more than 300 such patents
http://dx.doi.org/10.1016/j.ijpharm.2015.04.069 0378-5173/ ã 2015 Elsevier B.V. All rights reserved.
Please cite this article in press as: A. Goyanes, et al., Effect of geometry on drug release from 3D printed tablets, Int J Pharmaceut (2015), http:// dx.doi.org/10.1016/j.ijpharm.2015.04.069
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Fig. 1. 3D representation of the 3D geometries printed (left to right; cube, pyramid, cylinder, sphere and torus).
have been filed. Several research groups have demonstrated HME processes as a viable method to prepare a wide range of accepted pharmaceutical drug delivery systems, including granules, pellets, transdermal patches, transmucosal films systems and implants (Breitenbach, 2002; Crowley et al., 2007; Fonteyne et al., 2013). The use of HME to produce drug-loaded printable filaments has been shown to be feasible for plastics used for medical devices (Sandler et al., 2014) but has not, to our knowledge, been demonstrated for water soluble polymers suitable for fabricating oral dosage forms. A further potential benefit of FDM 3DP, also currently unexplored, is that the printer can be used to fabricate tablets of any geometry. Pretended donut-shape polymer matrices were evaluated to obtain zero-order drug release (Cheng et al., 1999; Kim, 1999), although the matrices were compacts with holes rather than real torus. The theoretical shape of tablets to obtain a uniform drug release rate from multi holed formulations was also noted but not manufactured/evaluated (Cleave, 1965). Other studies reported the use of parabolic shapes to achieve a zero-order release from a polymeric matrix (Bayomi, 1994), or differences in drug release from triangular, cylindrical and half-spherical tablets of the same formulation (Karasulu and Ertan, 2003). Siepmann et al. (2000) developed a model to predict drug release from matrix tablets of hydroxypropylmethylcellulose. They envisaged that since changing tablet shape can modify drug release rates, the optimal shape to obtain a specific release profile could be calculated. 3DP would be the only suitable method to manufacture tablets of such specific shape with precision and ease, including more elaborate shapes that would be impossible to create by powder compaction, e.g. expandable systems (Klausner et al., 2003) or platforms for improved gastrointestinal transit (Varum et al., 2013). The aims of this work, then, were to (i) produce a filament containing a model drug in a water soluble polymer (polyvinyl alcohol, PVA) suitable for printing into pharmaceutical tablets and (ii) to print tablets in a diverse range of geometries, many not attainable by powder compaction, and to correlate geometric parameters with dissolution behaviour. 2. Materials and methods Polyvinyl alcohol (molecular formula (C2H4O)n) was purchased as an extruded filament (1.75 mm diameter, print temperature 190–220 C, batch No: 2013-10-18, Makerbot Inc., USA). Paracetamol USP grade was obtained from (Sigma–Aldrich, UK). Salts for
preparing buffer dissolution media were purchased from VWR International Ltd., Poole, UK. 2.1. Preparation of PVA filament loaded with drug The commercial PVA filament (38 g) was cut into small pieces (2 mm) using a Pharma 11 Varicut Pelletizer (Thermo Fisher Scientific, UK) and mixed with paracetamol (2 g, 5% drug w/w) for 10 min in a Turbula1 T2F shaker–mixer (Glen Mills Inc., USA). The mixture was extruded using a single-screw filament extruder, FilaBot1 hot melt extruder (Filabot, USA) at 180 C through a 1.75 mm diameter nozzle (screw speed 35 rpm). The extruded filaments obtained were protected from light and kept in a vacuum desiccator until printing. The drug-loading of the filaments was determined by HPLC analysis. 2.2. Printing of paracetamol dosage forms Tablets were fabricated with the drug-loaded filament using a standard fused-deposition modelling 3D printer, MakerBot Replicator 2X Desktop 3D printer (MakerBot Inc., USA). The templates used to print the tablets were designed with AutoCAD 20141 (Autodesk Inc., USA) and exported as a stereolithography (.stl) file into MakerWare v. 2.4.1 (MakerBot Inc., USA). The .stl format encodes only the surface data of the object to be printed and requires the thickness of the surface to be defined in order to print the desired object. The printer settings were as follows: standard resolution with the raft option deactivated and an extrusion temperature of 180 C, speed while extruding (90 mm/s), speed while travelling (150 mm/s), number of shells (2) and layer height (0.20 mm). The infill percentage was 100% in order to produce tablets of high density. The selected 3D geometries were cube, pyramid, cylinder, sphere and torus (Fig. 1). The sizes of the shapes were varied using the scale function of the software to fabricate tablets of constant surface area (275 mm2), surface area/volume ratio (1:1) or weight (500 mg), Tables 1–3. In all cases, however, the ratio of the length, width and height of each shape was kept constant. 2.3. Scanning electron microscopy (SEM) Surface and cross-section images of the filaments were taken with an SEM (JSM-840A Scanning Microscope, JEOL GmbH, Eching,
Table 1 Physical parameters for tablets with similar surface areas. Shape
Surface area (mm2)
Volume (mm3)
SA/V ratio
Weight (mg)
Density (mg/mm3)
Cube Pyramid Cylinder Sphere Torus
287.9 2.1 270.4 0.4 268.5 3.9 280.8 1.4 266.8 1.0
332.3 3.6 231.3 0.5 314.4 6.5 442.3 3.2 266.4 1.9
0.866 0.003 1.169 0.001 0.854 0.005 0.634 0.002 1.002 0.004
268.2 15.7 187.5 3.9 355.3 23.7 505.3 36.0 276.0 19.6
0.81 0.05 0.81 0.02 1.13 0.05 1.14 0.08 1.04 0.08
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Table 2 Physical parameters for tablets with similar surface/volume ratios. Shape
Surface area (mm2)
Volume (mm3)
SA/V ratio
Weight (mg)
Density (mg/mm3)
Cube Pyramid Cylinder Sphere Torus
212.1 2.2 356.1 2.7 200.8 3.2 111.5 1.2 266.8 1.0
210.1 3.3 353.7 5.2 202.3 4.0 110.7 1.9 266.4 1.9
1.009 0.005 1.007 0.008 0.992 0.004 1.007 0.006 1.002 0.004
186.9 19.3 451.2 12.0 197.6 4.0 98.5 0.9 276.0 19.6
0.89 0.11 1.28 0.05 0.97 0.18 0.89 0.05 1.04 0.08
Germany). All samples for SEM testing were coated with carbon (30–40 nm).
the eluent was screened at a wavelength of 247 nm. All measurements were made in duplicate.
2.4. Thermal analysis
2.7. Dissolution testing
Filaments were characterised with differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). DSC measurements were performed with a Q2000 DSC (TA instruments, Waters, LLC, USA) at a heating rate of 10 C/min. Calibration for cell constant and enthalpy was performed with indium (Tm = 156.6 C, DHf = 28.71 J/g) according to the manufacturer instructions. Nitrogen was used as a purge gas with a flow rate of 50 mL/min for all the experiments. Data were collected with TA Advantage software for Q series (version 2.8.394), and analysed using TA Instruments Universal analysis 2000. All melting temperatures are reported as extrapolated onset unless otherwise stated. TA aluminium pans and lids (TZero) were used with an average sample mass of 8–10 mg. For TGA analysis, samples were heated at 10 C/min in open aluminium pans with a Discovery TGA (TA instruments, Waters, LLC, USA). Nitrogen was used as a purge gas with a flow rate of 25 mL/min. Data collection and analysis were performed using TA Instruments Trios software and % mass loss and/or onset temperature were calculated.
Dissolution profiles were obtained using a USP-II apparatus (Model PTWS, Pharmatest, Germany). In each assay, the tablets were placed at the bottom of the vessel in phosphate buffer pH 6.8 (0.05 M, 900 mL) under constant paddle stirring (50 rpm) at 37 C. During the dissolution test, samples of paracetamol were automatically removed and filtered through 10 mm filters and drug concentration was determined using an in-line UV spectrophotometer (Cecil 2020, Cecil Instruments Ltd., Cambridge, UK) operated at the wavelength of maximum absorbance of the drug in phosphate buffer (243 nm). Data were processed using Icalis software (Icalis Data Systems Ltd., Berkshire, UK). Tests were conducted in triplicate under sink conditions. Data are reported throughout as mean standard deviation.
2.5. Characterisation of tablet morphology The physical dimensions of the tablets were measured using a digital calliper. Pictures of the tablets were taken with a Nikon CoolpixS6150 with the macro option of the menu. The surface areas and volumes of the tablets were calculated based on these dimensions. The surface area to volume ratio was obtained by dividing these values. 2.6. Determination of drug loading A tablet or a section of drug-loaded strand (approx. 0.3 g) was placed in a volumetric flask with deionized water (1 L) with magnetic stirring until complete dissolution (3 h). Samples of solution were then filtered through 0.45 mm filters (Millipore Ltd., Ireland) and the concentration of drug determined with HPLC (Hewlett Packard 1050 Series HPLC system, Agilent Technologies, UK). The validated high performance liquid chromatographic assay entailed injecting 20 mL samples for analysis using a mobile phase, consisting of methanol (15%) and water (85%), through a Luna 5 mm C8 column, 25 4.6 cm (Phenomenex, UK) maintained at 40 C. The mobile phase was pumped at a flow rate of 1 mL/min and
3. Results and discussion Firstly, it was possible to prepare drug-loaded filaments by HME that were suitable for 3D printing. The drug loading percentage was 3.95% w/w 0.01 and the mechanical behaviour of the extruded filament did not appear to be significantly different from the commercial product, indicating paracetamol did not plasticise the polymer. Higher drug-loading percentages may require the addition of plasticizing agents to give a filament with suitable flexibility and softening temperature for printing. The single screw extruder used in this study was designed to produce filaments from pelletized feedstock, and so blending PVA pellets with powdered drug led to a lower drug encapsulation percentage than expected (5% w/w), probably because the fine powder adhered to the container during the mixing process and to the walls of the barrel of the HME. It would be possible to obtain higher drug loading by obtaining mixtures of drug and polymer of similar particle size. Nevertheless, filament extruder appears to be a cheap alternative to the twin-screw HME apparatus typically used to manufacture pharmaceutical products. Secondly, it was possible to fabricate all of the shapes by 3DP with the paracetamol loaded filament, Fig. 2. Five shapes were printed; four compact geometries with different edges and surfaces (cube, pyramid, cylinder and sphere) and one with a hole in the middle (torus). Manufacture of such complex and intricate shapes by powder compaction would be extremely challenging and so the study immediately suggests that 3DP offers a route of manufacture of dosage forms of novel geometries not
Table 3 Physical parameters for tablets with similar weights. Shape
Surface area (mm2)
Volume (mm3)
SA/V ratio
Weight (mg)
Density (mg/mm3)
Cube Pyramid Cylinder Sphere Torus
341.4 0.5 393.0 15.2 335.0 15.7 280.8 1.4 387.0 3.0
429.2 1.0 406.2 23.4 438.3 29.3 442.3 3.2 479.5 4.3
0.795 0.001 0.968 0.019 0.765 0.016 0.634 0.002 0.807 0.001
477.9 11.9 494.8 16.6 480.0 11.0 505.3 36.0 509.9 29.0
1.11 0.03 1.22 0.03 1.10 0.06 1.14 0.08 1.06 0.05
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previously possible. FDM appears as versatile approach suitable for manufacturing multiple drugs e.g. fluorescein (Goyanes et al., 2014), aminosalicylates (Goyanes et al., 2015) and herein paracetamol. As found in previous studies, 3D printed PVA tablets were not friable and so easy to handle (Goyanes et al., 2014, 2015). DSC and TGA analyses of the pure substances and extruded filament were performed in order to understand how the drug was incorporated in the polymer (Figs. 3–5). It is apparent that paracetamol raw material melts around 168 C (Fig. 3), indicative of form I while PVA shows a glass transition around 135 C and melting between 175 and 200 C (Fig. 4). Significant degradation of PVA is seen above 260 C, but the printhead temperature used during tablet fabrication is 180 C. The DSC data of the paracetamol-loaded PVA filament shows no evidence of melting around 168 C, indicating that the drug is molecularly dispersed within the polymer matrix as a solid solution. A glass transition is seen in both samples containing PVA, but the transition temperature remains the same whether the drug is present or not, suggesting paracetamol does not exert a plasticising effect. TGA data suggests
Power / arbitrary units
Fig. 2. Images of the 3DP fabricated tablets at constant (A) surface area, (B) surface area/volume ratio and (C) mass (scale bar in cm).
PVA-paracetamol filament
PVA filament
50
100
150
200
250
Temperature / oC Fig. 4. DSC thermal traces for PVA and PVA-paracetamol filaments. The PVA melts between 175 and 200 C.
100
Power / arbitrary units
PVA
Mass loss / %
80 PVA-paracetamol
60 40 20 Paracetamol
0
80
100
120
140
160
180
200
220
240
o
Temperature / C Fig. 3. DSC thermal trace for paracetamol raw material, showing melt of the stable form I at 168 C.
50
100
150
200
250
300
o
Temperature / C Fig. 5. TGA thermal traces for paracetamol raw material and PVA and PVAparacetamol filaments.
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Fig. 6. SEM images of the surface and cross-section of; (Top) PVA filament, (middle) PVA-paracetamol filament and (bottom) a section of a printed geometry (in this case from the torus).
that PVA is stable until 260 C, consistent with the DSC data, while paracetamol degrades significantly above 200 C (Fig. 5). When paracetamol is incorporated into the PVA, no appreciable mass loss is seen, suggesting the polymer is stabilising the drug. The drug loading of the printed tablets was 3.78% 0.01, similar to that of the filament, which indicates little degradation of the drug occurred during printing, consistent with the thermal stability of paracetamol above its melting point seen by DSC. Electron micrographs show little evidence of paracetamol crystallites within the polymer filaments (Fig. 6), also consistent with the DSC data. Images of the cross-section of a printed torus clearly show the individual strands deposited by the printer (Fig. 6). The 3D printed strands are ca. 100 mm in diameter, consistent with the
nozzle diameter of the printhead, and there is some evidence of fusion of strands, leading to the strength of the tablet noted earlier. This observation also suggests that the surface areas calculated in Tables 1–3 may in reality be slightly larger than expected. Dissolution tests confirm that geometry plays an important role in defining drug release profiles, Fig. 7. When the surface area of the tablets was kept constant, drug release rates were in the following order (fastest first); pyramid > torus > cube > sphere and cylinder. The time to 90% release (t90) varied from just under 2 h (pyramid) to nearly 12 h (sphere and cylinder). This order matches the surface area/volume ratio order of the tablets, with the pyramid having the highest value (1.169) and the sphere the lowest (0.634). Reynolds et al. (2002) noted the same trend, tablets with
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Constant Surface Area 100
Drug Released (%)
80
60
40
Pyramid Torus Cube Sphere Cylinder
20
0 0
60
120
180
240
300
360
420
480
540
600
Time (Min) Constant Surface Area/Volume ratio 100
Drug Released (%)
80
60
40
Cube Sphere Torus Cylinder Pyramid
20
0 0
60
120
180
240
300
360
420
480
540
600
Time (Min)
Constant Weight 100
Drug Released (%)
80
60
area to volume ratio) and noted that (i) tablets with a high aspect ratio had fastest dissolution and (ii) for tablets of different volume, smaller tablets had faster dissolution rates, because their surface area to volume ratio is highest. They suggest that either aspect ratio or surface area to volume ratio would be suitable parameters with which to predict and achieve defined release kinetics. Studies performed with discrete element method (DEM) modelling have similarly suggested that drug release profiles from swelling tablets is independent of tablet shape and directly related to the surface area/volume ratio (SA/V) (Kimber et al., 2013). When tablets were prepared with a constant surface area/ volume ratio, the order of drug release rates was (fastest first); sphere and cube > torus > cylinder > pyramid. In line with the observations above, less differentiation was seen in the t90 values, with most shapes having a value between 2 and 3 h. Notably, only the pyramid gave noticeably slower release (9 h). The fact that dissolution profiles were not identical, however, suggests that in the case of the PVA matrix used here erosion plays a role in defining release kinetics. Drug release rate from water soluble and swellable polymers is governed by the relative contribution of two mechanisms, drug diffusion and polymer dissolution (surface erosion) (Reynolds et al., 2002). The predominance of one or other mechanism depends on different factors such drug solubility and nature of the excipients. Some previous work on the influence of tablet shape used HPMC (to minimise erosion of the tablet) and several models accounting for geometry were developed, but generally these are applicable only to specific formulations (Siepmann et al., 2000, 1999). Drug release profiles from tablets of constant weight were very similar (Fig. 7). Previous studies with 3D printed PVA tablets noted that the drug release was through an erosion-mediated process (Goyanes et al., 2014, 2015), and the erosion may explain why tablets of similar mass show little difference in dissolution profiles. A magnetic resonance imaging based method, used recently to compare the behaviour of different geometries during dissolution studies (Dorozynski et al., 2014), could help to understand the dissolution process involved for these 3D printed formulations. The data do show, however, that it is possible to design a tablet with a controlled-drug release profile (varying over 10 h) by careful selection of shape and/or size. It also worthy to mention that the geometry not only affects the drug dissolution release in vitro but also the transit time in vivo. In expandable oral drug delivery systems (easily swallowed systems that reach a significantly larger size in the stomach due to swelling or unfolding processes), tetrahedron shaped devices remained in the stomach for longer periods of time than other shapes of similar size (Klausner et al., 2003).
40
Torus Pyramid Cube Sphere Cylinder
20
0 0
60
120
180
240
300
360
420
480
540
600
Time (Min) Fig. 7. Paracetamol dissolution profiles from 3DP solid dosage with (top) surface area 275 mm2, (middle) surface area/volume ratio 1 and (bottom) 500 mg mass all in phosphate buffer (pH 6.8).
larger surface area/volume values had faster drug release, in a study of HPMC tablets in a diffusion-controlled release process. Siepmann et al. (1999) studied dissolution rates from tablets of different aspect ratio (height to radius ratio) and volume (surface
4. Conclusions A filament extruder was successfully used to obtain paracetamol-loaded filaments of PVA with appropriate characteristics for use in FDM 3DP. The printer software enabled easy fabrication of tablets with different geometries (cube, pyramid, cylinder, sphere and torus), many of which would be challenging to manufacture by powder compaction, demonstrating the potential of 3DP as a novel manufacturing technology in pharmaceutics. Drug release kinetics from tablets showed no dependence on the surface area but rather on surface are to volume ratio, indicating the influence that geometrical shape has on drug release profile. Tablets of similar mass showed little difference in dissolution profiles that could be explained by the erosion-mediated process that drives the drug dissolution. Fabrication of different shaped objects with 3D printing may modulate drug dissolution profiles and can aid in
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the rational design of new dosage forms with specific pharmacokinetics characteristic or targeted to different sites of the gut. Acknowledgements The authors would like to acknowledge the assistance provided by John Frost to operate the hot melt extruder. Alvaro Goyanes would like to thank Fundación Alfonso Martín Escudero for the post-doctoral fellowship. References Bayomi, M.A., 1994. Geometric approach for zero-order release of drugs dispersed in an inert matrix. Pharm. Res. 11, 914–916. Breitenbach, J., 2002. Melt extrusion: from process to drug delivery technology. Eur. J. Pharm. Biopharm. 54, 107–117. Cheng, K., Zhu, J., Song, X., Sun, L., Zhang, J., 1999. Studies of hydroxypropyl methylcellulose donut-shaped tablets. Drug Dev. Ind. Pharm. 25, 1067–1071. Cleave, J.P., 1965. Some geometrical considerations concerning the design of tablets. J. Pharm. Pharmacol. 17, 698–702. Crowley, M.M., Zhang, F., Repka, M.A., Thumma, S., Upadhye, S.B., Battu, S.K., McGinity, J.W., Martin, C., 2007. Pharmaceutical applications of hot-melt extrusion: part I. Drug Dev. Ind. Pharm. 33, 909–926. Dorozynski, P., Kulinowski, P., Jamroz, W., Juszczyk, E., 2014. Geometry of modified release formulations during dissolution—influence on performance of dosage forms with diclofenac sodium. Int. J. Pharm. 477, 57–63. Fonteyne, M., Vercruysse, J., Diaz, D.C., Gildemyn, D., Vervaet, C., Remon, J.P., De Beer, T., 2013. Real-time assessment of critical quality attributes of a continuous granulation process. Pharm. Dev. Technol. 18, 85–97.
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