Tablet Printing
Batches of tablets were printed following the method outlined in Fig. 2. Examples of printed tablets are shown in Fig. 3.
In vitro Drug Dissolution
Dissolution data from the paracetamol tablets (Fig. 4) showed that the different tablet geometries with different height but similar dimension and total weight and dose (Tables IV and V) gave distinct release profiles. For the paracetamol mesh tablets, more than 70% of the drug was released within the first 15 min. In contrast, only 25 and 12% of the drug was released in the same period from the ring and the solid paracetamol tablets, respectively. This indicates that the tablet surface area showed an influence on drug release. Apart from surface area exposed to solution, the drug release is also impacted by the inclusion of the disintegrant, NaCCS, which rapidly absorbs water and swells leading to rapid disintegration. For the mesh tablets with the increased surface means that water absorption takes place more rapidly than for the ring and solid tablets (Fig. 4).
The drug release from the 3D printed tablets correlates with the SA/V ratios, the higher the SA/V ratio value, the faster the drug release (Table II). This trend has also been reported by other researches (10,11,29). Goyanes et al. showed the effects of SA/V ratios of different geometries on paracetamol release from tablets prepared by hot melt extrusion (HME) (11). Also in the same study, the authors showed that the drug release was independent of the surface area (11). Research done by Yi et al. demonstrated that the drug release from polylactic-co-glycolic acid/polycaprolactone/5-fluorouracil (PLGA/PCL/5-FU) patches was dependent on the changes of SA produced by geometric modifications (12). The authors then concluded that the tendency of slowing drug release corresponded to a decrease in the SA/V ratio (12). Furthermore, Gökçe et al. studied the influence of tablet SA/V ratio of two different geometries (cylinder and hexagonal) of the lipophilic matrix tablets of metronidazole prepared by Cutina HR (hydrogenated castor oil) (10). They found that the tablets with the highest release rates for both geometric shapes reflecting the highest surface area and the lowest SA/V ratio (10). Kyobula et al. showed that hot melt 3D inkjet printing can be used to manufacture complex and variable honeycomb geometry tablets for the controlled loading and release of the drug fenofibrate. In this case, the surface area and wettability of the tablet were shown to influence to the observed sustained drug release profiles (5). Hence, as can reasonably be expected, we can conclude that the tablet geometry and surface area generally have an effect on drug release behaviour and are parameters that can be manipulated to control drug release, even in formulations with additives such as a swellable disintegrant, as here. The higher the SA and SA/V ratio values, the faster the drug release is from the 3D printed tablets (Fig. 4 and Table II).
Table II Paracetamol 3D Printed Tablet’s Dimensions for Different Geometries of Similar Total Weight and Increased Surface Area and SA/V Ratios The demonstrated ability to use a single unmodified formulation to achieve defined release profiles presents opportunities to optimise or personalise medicines during formulation development and in clinical use. For example, relatively straightforward personalization of medicines would be possible for individuals with different metabolism rates due to their genetic makeup (26) for certain drugs and hence could address issues where people who metabolise drugs slowly may accumulate a toxic level of a drug in the body or in others who process a drug quickly and never have high enough drug concentrations to be effective.
Drug Release Kinetics
To further understand the drug release mechanisms displayed by the different geometries, the modes of release of paracetamol over 12 h at a buffer pH 6.8 was modelled using zero-order, first-order, Higuchi and Korsmeyer–Peppas models (30,31). According to fitted r2 values, the mesh and ring tablets were best fitted by the first-order equation (i.e. log cumulative percentage of drug remaining is proportional to the time) (32) and the solid tablets were best fitted by the Higuchi model (i.e. cumulative percentage drug release versus square root of time) (32) with r2 values of 0.77, 0.97 and 0.99, respectively (Table III). The equation reveals n values (as in Eq. (2)) of 0.25 for mesh tablets, 0.44 for ring tablets and 0.56 for solid tablets.
$$ {M}_t/{M}_{\infty }={Kt}^n $$
(2)
Table III Fitting Experimental Release Data, from the In Vitro Release of 3D Printed Paracetamol Tablets to Zero-order, First-order, Higuchi and Korsmeyer-Peppas Kinetic Equations at a Buffer Condition (pH 6.8–12 h) where Mt/M∞ is the fraction of drug released at time t, K is the release rate constant and the release exponent (32,33).
The above results suggest that the drug is released primarily by Fickian diffusion through a gel layer formed by the amylose in the added starch. Amylose is known to absorb water, swell and then form a gel layer (34). The drug release from the mesh tablets was faster than the drug release from the other geometries (ring and solid). This is, we propose, related to the larger surface area (mesh>ring>solid) and the more easily disrupted geometry of the mesh tablets where the chance to form a stable gel layer, and hence, retard drug release is inhibited. The disintegrants (the amylopectin (insoluble component found in the starch that can absorb water, swell and act as disintegrant) and NaCCS)) work to weaken and disrupt the formed gel layer in the mesh tablets. In case of ring and solid tablets, the geometry is more compact with a smaller surface area and less exposure to the dissolution medium than mesh tablets, so the disintegration rate is reduced, and there is an increased time to form a gel layer and hence retardation of drug release (solid>ring>mesh).
XRPD
XRPD of the pure paracetamol, excipients (PVP K25, NaCCS and starch) and paracetamol formulation powder (powder mixture after tablet ground into powder) was done to investigate any potential changes in physical form of the active on printing (Figs. 5 and 6). The Bragg peaks observed from the pure paracetamol (as received) match the Bragg peaks of paracetamol (calculated) reported in the Cambridge Structural Database (CSD) (Fig. 5).
The results in Fig. 6 show that the paracetamol (non-ground and ground powder) exhibited multiple sharp Bragg peaks in their XRPD patterns related to their crystalline nature. The post-printing XRPD data show the same Bragg peaks for the paracetamol. There was, therefore, no evidence of a change in physical form (form I) for the paracetamol in this formulation fabricated using extrusion-based 3D printing. We believe that a portion of the paracetamol powder could have dissolved after addition a significant quantity of water (4.5 ml) into total paracetamol dry formulae (12 g) (paracetamol solubility 12.78 g/l /20°C) (34) as the whole mixture formed a paste; however, this must have recrystallised back into form I if this had occurred. The XRPD data from Fig. 6 also did not show evidence of incompatibility between the active and the chosen additives (PVP K25 (10% w/w), starch (8.33% w/w) and NaCCS (0.63% w/w)) in the 3D printed tablets.
ATR-FTIR
Infrared spectral data show that the characteristic peak positions remained unchanged from the paracetamol powder to the formulation, indicating that there were no detectable interactions between paracetamol (81% w/w) and the chosen excipients (PVP K25 (10% w/w), starch (8.33% w/w) and NaCCS (0.63% w/w)) in the tablets (Fig. 7).
DSC
DSC analysis was performed to explore potential incompatibility between the active and added excipients and the stability of drug crystallinity after the 3D printing process (grinding, mixing, paste formulation and drying process on a hot plate heated at 80°C). The DSC data from Fig. 8 shows that the pure powder of paracetamol melts at 169.7°C confirming the presence of form I (4,35,36) while the pure powder of PVP K25 shows a glass transition (Tg) around 155°C (4,37). The same figure also shows clear evidence of an endothermal event (melting point) at 169.24°C from the printed paracetamol formulation, indicating that the active is still in a crystalline form, specifically form I. From the above results and discussions, we found that DSC thermogram of paracetamol formulation powder after grinding, blending, printing and post-printing processes with the excipients; starch, PVP K25 and NaCCS did not show significant changes in peak placement apart from the peak depression and reduction caused by the presence of the polymer in the formulation in comparison to the peak obtained from the pure paracetamol powder and again suggesting compatibility of the excipients.
Physical Properties
The 3D printed tablets were evaluated for weight variation, content uniformity, breaking force, friability and tablet dimensions.
Tablet’s Shape and Dimension
Table IV confirms that the tablet dimensions were reproducible and comparable with the designed tablet’s size and dimension and with the tablet size reported in the literature prepared by conventional tableting press machines (38,39,40).
Table IV Individual Paracetamol 3D Printed Tablet’s Dimensions and Their Average, Median, Maximum, Minimum Dimension and Standard Deviation Weight Variation
The paracetamol 3D printed tablets showed an acceptable percentage weight variation (Table V) and, therefore, comply with the USP specification for uncoated tablets (± 7.5% for average weight of tablets 130–324 mg) (41,42). The paracetamol content in the final tablets was also assessed and found to be 103.2 ± 1.1% for the mesh tablets, 104.0 ± 1.1% for the ring tablets and 103.1 ± 1.5% for the solid tablets.
Table V Individual Paracetamol 3D Printed Tablets Weight, Calculated Paracetamol Dose/Tablet, Percentage Deviation, and Their Average, Median, Maximum, Minimum Weight and Standard deviation Breaking Force
Table VI shows the 3D printed tablets breaking forces (kg and N) and the tensile fracture strength. Tensile fracture strength of the paracetamol flat-faced oval tablets was calculated (28). In a conventional tableting press, compression forces can be used to control the physical properties of the final tablet, where a breaking force value of 4 kg is the minimum satisfactory measurement (26,43). Measured breaking force measurements were within the accepted range of 8.69–9.56 kg for the solid tablets but failed to reach the minimum satisfactory value for the mesh and ring tablets (Table VI). It is clear that as compression force is not part of 3D printing process that the same opportunity to manipulate tablet hardness in this way does not exist and rather the formulation composition, solidification/drying process and the type of printer employed are critical factors. Clearly, further work beyond the scope of this paper is required in this area; however, from a subjective and qualitative assessment, the ring and mesh paracetamol 3D printed tablets appear to be quite robust and are able to tolerate a reasonable amount of rough handling. For example, they could be dropped onto a hard surface from a height of around 15 cm without observable damage. In addition, such tablets could be considered for manufacture close to the patient where traditional wear factors such as chipping, capping and abrasion which normally occurred during manufacturing, packaging and shipping processes are not relevant.
Table VI Individual Paracetamol 3D Printed Tablet’s Breaking Force (kg and N), Tensile Fracture Strength (MPa), and Their Average, Median, Maximum, Minimum Hardness and Standard Deviation Friability
This is a USP test used to determine a tablet resistance to abrasion, capping and chipping occurred during manufacturing, packaging and shipping processes. All paracetamol 3D printed tablets of different geometries showed a satisfactory percentage of weight loss ≤ 1% of the tablet weight (Table VII) and, therefore, the tablets meet USP specifications (44).
Table VII Friability of Different Paracetamol 3D Printed Geometries; Mesh, Ring and Solid Tablets