The federal state budget educational institution of higher education russian presidential academy of

• Название: The federal state budget educational institution of higher education russian presidential academy of
• Дата: 27.06.2021
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Results and discussion

3.1. Optimization of materials for extrusion-based 3D printing

The extrusion behavior of selected polymers was optimized and tested for their capability to build the layer-by-layer 3D design shell. From the literature review, it was found that ethylcellulose, HPMC, PVP, and cellulose acetate were employed in semisolid extrusion-based (PAM) 3D printing technique [9], [22] and very well reported as a polymer of choice for the design and development of controlled/sustained release pharmaceutical products [23], [24]. Ethylcellulose, HPMC, and PVP were tested and exhibited variability in the paste properties. Table 1 shows the behavior of ethylcellulose, HPMC, and PVP with a particular solvent/combination of solvents. The consistency and the rheological behavior of these polymers made them difficult to extrude through the printer nozzle and to form a layer-by-layer structure. It was observed that during the printing process these materials showed extrusion inability and spreading of material at the base. This is due to variation in the viscoelastic characteristics such as elastic deformation, flow behavior, and relaxation behavior of the material during the printing process. Based on the desirability of physical characteristics and rheological behavior during the extrusion process, cellulose acetate has been optimized as the material of choice to build a circular structure of layer-by-layer geometry with immediate drying to support the printing of the second layer over it. Various mixtures of polymer, filler, and plasticizer were screened initially. However, most of the compositions tested were failed to exhibit uniform extrusion through the printing nozzle due to higher viscosity or less consistency. The different compositions of polymer (cellulose acetate) were 20 %, 40 %, and 60 % with corresponding filler (D’mannitol) concentration 65 %, 45 %, and 25 % respectively. The concentration (15 %) of plasticizer (PEG 6000) was kept constant in all the compositions for the development of a controlled release shell. The composition with a lower amount of filler was required a higher pressure for the extrusion of material whereas compositions with a higher amount of filler extruded rapidly due to low viscosity at a very low applied pressure for extrusion. The paste formed from high viscosity grade polymers like HPMC resulted in a clear transparent gel which is not fabricating layer by layer design. Similarly, the paste formed from low viscosity grade HPMC resulted in a low viscous gel at lower concentration and higher concentrations were forming a viscous gel but exhibiting extrusion problem as it was spread over the substrate without solidifying. The paste formed from ethylcellulose composition also showed structural deformity upon extrusion. Therefore, based on the extrusion behavior, layer-by-layer deposition, and structural building ability, an optimized composition of cellulose acetate in a specific ratio of chosen solvent was used for the design of a 3D printed shell . The paste obtained was used immediately for 3D printing to avoid chances of solvent evaporation before the initiation of the printing process.

The selection of the solvent has also been optimized as the printing process requires a solvent that helps in the extrusion process and should be ready to evaporate after extruding through the printing nozzle from the surface of the printed layers. It should allow the complete drying of the first layer before the deposition of the subsequent layer. Among the various solvents tested water, ethanol and IPA showed material insolubility and formed an insoluble mass whereas acetone exhibited a better solubility profile for the material composition and resulted in a homogenous paste formation. Indeed, acetone being a highly evaporative solvent, result in rapid drying of the paste before extrusion. To overcome this issue, a combination of the solvent mixture was used to minimize the rate of evaporation of solvent during the extrusion process. A combination of acetone and water formed a granular mass whereas a combination of acetone and IPA resulted in a gummy mass. However, the combination of acetone, ethanol, and DMSO was optimized as a solvent choice for the 3D printing of the cellulose acetate shell as it formed extrudable and non-spreadable paste.

The composition of extrusion paste also consisted of D’mannitol as filler which plays a significant role in the flow behavior of the paste. The high amount of filler leads to an increase in the flow of the paste. The increase in the flow of the paste ultimately leads to less requirement of the applied extrusion pressure. The amount of filler also affected the rigidity (hardness) and surface smoothness of the printed layer. The addition of a high amount of filler leads to a less rigid and comparatively less smooth surface of the printed layers. Moreover, different grades of PEG (polyethylene glycols) were evaluated as a plasticizer to improve the physical appearance of the printed design. Among the different tested grades of PEG (such as 4000, 6000, and 8000), PEG 6000 was optimized as a desirable plasticizer. It exhibited a better plasticizing effect. The plasticizer also imparted viscoelastic properties to the paste which helps in uniform extrusion through the printing nozzles. PEG is considered as one of the most efficient plasticizers in polymer-based drug delivery application and an increase in the molecular weight of PEG exhibited better plasticizing efficiency.

Printing pressure and speed

The influence of printing pressure on the extrusion behavior (flow rate) of the feed material has been investigated by applying the variable printing pressure in a range of 50–70 PSI (illustrated in Fig. 2). Similarly, the influence of the printing speed on the flow rate of the feed material has been investigated by applying the variable printing speed in a range of 2−6 mm/sec (illustrated in Fig. 2). The impact of printing pressure and printing speed has been demonstrated by layer printing. The process of layer printing illustrated three types of extrusion behavior. Firstly, the line thickness was greater than the size of the nozzle and it was bloated and fails to achieve the structural fineness. It was also dragging the line by the tip of the nozzle due to over extrusion. The second behavior showed a broken printed line and is not continuous because the printing speed was more than the rate of extrusion of material, and consider as under extrusion. Also, observed that the line was continuous but the thickness remains smaller than the size of the nozzle because of dragging and stretching of the layer under extrusion conditions. The third situation demonstrated a line of uniform or slightly larger thickness with respect to the size of the nozzle which was considered as optimum extrusion. Shafiei and coworkers also interpreted the viscous behavior of the materials and their corresponding impact on the applied pressure which is an expression of “non-extrudability”

Determination of material extrusion rate

The material extrusion rate was determined at different printing speeds by applying an optimized pressure (60 PSI) and nozzle dimensions (tapered shape nozzle tips of 630 µm). The rate of material extrusion is helpful to determine the drug content uniformity to design a personalized dose pharmaceutical product. The extrusion rate is directly affected by the printing speed as shown in Fig. 3. As the printing speed increases the extrusion rate was found to be linearly increased with a correlation coefficient (R²) value of 0.994. It was observed that an increase in printing speed results in a decrease in the total print time to create a specific design that ultimately in turn increases the extrusion rate to keep the amount of print output constant for the dose uniformity.

 Nozzle size and shape

The influence of nozzle dimension on the flow rate of the feed material has been investigated using the nozzle of variable dimension in a range of 203−840 µm. The nozzles with smaller diameters 203, 280, and 420 µm showed hindered extrusion due to the comparatively larger particle size of the paste material. The nozzle with a larger diameter (840 µm) exhibited a very rapid rate of extrusion which influence the printing process (illustrated in Fig. 2). The extrudability behavior of the paste through different nozzle diameters exhibited a relationship between nozzle diameter and extrusion rate. The extrusion rate increases with an increase in the nozzle diameter. This similar correlation has been observed by Ahmad Zidan et al. in his investigation [28]. Therefore, based on the extrusion behavior of the material, its consistency, and particle size of the material composition, a nozzle diameter of 630 µm was found desirable for extrusion-based 3D printing design for drug delivery application. Moreover, the nozzle diameter was the only significant determinant of the flow behavior of the material rather than its consistency. The result shows that the smallest orifices exhibited the lowest flow which consecutively requires an increase in printing pressure [29], [30].

The selection of a suitable nozzle shape for an optimized printing process was based on the paste flowability and extrudability. The standard blunt shape nozzle tips exhibited problems in the extrusion of the feed materials (illustrated in Fig. 2). This could be due to the applied pressure was not uniformly distributed throughout the nozzle. Moreover, tapered shape nozzle tips provide a comparatively smoother flow of feed materials (illustrated in Fig. 2). The tapered shape nozzle tips decreased friction in the pressure-applied microsyringe (PAM). Another advantage of the tapered shape nozzle tips was the reduction in the clogging of the feed materials. Moreover, a standard blunt shape nozzle tips were used for dispensing fluids and a tapered shape nozzle is ideal for dispensing UV-cure adhesives, gels, and thick pastes . A uniform flow rate was achieved through tapered shape nozzle tips comparatively at lower printing pressure.

Optimization of printed design for extrusion-based 3D printing

The printed layers were optimized at different printing speeds and dimensions of the layers (thickness/width) were measured under wet and dry conditions as shown in Table 3. These measurements were used to fix the printing settings which include the number of layers required to build a complete structure of the shell for drug delivery application. The total printing time and the initial height i.e. offset between the printer tip and the substrate and line spacing (space between strands) were also taken into the consideration in this optimization process.
The different substrates (such as paper, glass, and polystyrene) were investigated to optimize a design for the drug delivery application. Among paper substrate, different types of papers like a paper sheet, copy paper, photocopy paper, uncoated paper, coated paper, pigment coated paper, uncoated wood-free paper, triple-coated inkjet paper, double-coated sheet, icing sheet, and edible icing sheets were used in literature as a substrate to print the 3D design. Apart from paper, different polymer-coated films have also been used as a substrate which includes hydroxypropyl methylcellulose (HPMC) films, hydroxypropyl cellulose (HPC) film, potato starch, starch film, acetate films, clear acetate film, polyethylene terephthalate (PET) film, water non-permeable PET film, polytetrafluoroethylene (PTFE) coated fiberglass film, PTFE films over a clear transparency film, water-impermeable transparency films, and orodispersible films. Among glass, different substrates used were glass coverslips, glass slides, and glass coverslip coated with flutec fluid to increase hydrophobicity [32], [33]. The hydrophilic and hydrophobic nature of the substrate has a significant impact on deposited layer characteristics. It may observe as spreading of the deposited layer, sticking of the printed layer to the substrate, and variability in the layer width/thickness.

It was observed that the substrate of paper and polystyrene exhibited sticking of the printed layer to the substrate whereas glass substrate not exhibited any sticking of the printed layer to the substrate. It is due to the interaction of polystyrene substrate with solvent present in the extruded printing material. 

It has been used to enclose a tablet of immediate-release profile to achieve the aim of a modified drug release profile of an enclosed tablet of propranolol HCl. The detail of this was available in the previous investigation of our research lab [13]. The drug release profile through this 3D printed design system was found to be sustained-release compare to the release profile of the enclosed tablet without the shell. It was observed that the variability in the shell composition has influenced the release profile significantly and internal space between the 3D printed shell wall further helpful in fine modulation of drug release profile to achieve the aim of zero-order drug release kinetics. Also, this novel approach could be helpful in design a delayed-release system, time-dependent drug release system, and gastro-retentive drug delivery systems through further manipulation of this 3D printed controlled release shell composition/components. The result validates the proof-of-concept that the 3D printing technique has potential drug delivery applications by modifying the drug release profile through the printing of pharmaceutical products of specific design and shape.