Evaluation of Different Polymers in 3D Printing Technologies

Abstract

Various polymers have been investigated for 3D printing (3DP) technologies including fused deposition model, selective laser sintering, semi-solid extrusion, stereolithography and ink jet printing. The effects of additives such as plasticizing polymers/solubilizers on FDM 3DP have also been investigated. Kollidon® VA 64, Soluplus®, Kollidon® SR, Kollicoat® IR and others have been examined in pure and with plasticizing drugs or solubilizers to overcome the FDM processing conditions. The appropriate recommendations have been made to select the optimized compositions for 3DP formulation dosages. Compatibilities of polymers with other technologies requiring less stringent printing conditions, have also been evaluated. Preference of one over the other in 3DP technology could be based on the choice of excipients to yield the desired immediate or modified release profile of formulation dosages.

Introduction

Innovative 3DP technologies to design personalized medicines have become a new paradigm in the pharmaceutical industry.1 The recent launch of antiepileptic drug Spritam® by Aprecia in 2015, has created immense interest in the rapidly growing 3DP segment to cater to patients requiring special personalized medications for long term care or life cycle management. There remain, however, several hurdles to overcome to bring innovative molecules faster to market and make them accessible to a larger patient population.2

The pharmaceutical industry remains committed and continues to adopt 3DP platforms for personalized medicines to address the needs in certain therapeutic areas by developing formulations in early phase clinical studies as the frontline therapy. The future of customized 3DP oral medicines for immediate and controlled release dosages from their first in human (FIH) clinical development to medical care, appears to be promising.3 In recent years, 3DP has drawn tremendous interest not only in oral tablets but also in areas of medical devices and transdermal drug delivery.4-9

Several 3D printing technologies are available to design and manufacture oral dosage tablets. The most commonly used are: fused deposition modeling (FDM), selective laser sintering (SLS, stereolithography (SLA), semi-solid extrusion (SSE), and ink jet printing technologies.10 The requirements for critical excipient attributes are different for each of the individual 3DP technologies,11 with some 3DP technologies requiring polymers with good flexibility and mechanical strengths, but others may require different strategies like laser sintering or heating or cold extrusion or ink jet printing.12

This manuscript will focus on pharmaceutically accepted excipients, especially, those approved in drug products. Different polymers and solubilizers will be the focus with special interest on utilities in 3DP by FDM technology. The properties of polymers will be examined with the aim of understanding their wider acceptability in 3DP. The effects of plasticizers on the flexibility of filaments and the mechanical strengths for fabricating 3DP tablets, will also be discussed. This study will also evaluate other 3DP formulation technologies with reference to identifying the appropriate polymers for development of immediate and modified release dosages.

Materials and Methods

Kollidon® 12 PF, 17 PF, 25, 30 and 90F, and Kollidon® SR, Kollidon® VA 64, Soluplus®, Kollicoat® IR, Kollicoat® Protect, Kollicoat® MAE 100P were obtained from BASF (Florham Park, NJ). Kolliphor® P 188 & P 407, Kollisolv® PEG 400, PEG 1500, Kolliphor® HS 15, Kolliphor® RH 40 amongst others were also obtained from BASF (Florham Park, NJ). Hot melt extrusion was carried out using a PolyLab OS 16 mm (Thermo Fisher) having the screw diameter with variable lengths of 40 D and nozzle diameter of 3 mm. A gravimetric dosing system Brabender (DDSR 20) or mini Twin Type MT with liquid dosing system Brabender screw configuration of TS extruder, was used for extrusion of filaments.

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For the determination of the glass transition temperatures (Tg) DSC (Differential Scanning Calorimetry) studies were performed using a Q2000 (TA Instrument, USA). DSC scans were recorded at a heating rate of 20 K/min in the second heating run. All measurements were analyzed in a 2-bar pressurized pan except for Kolliphor® P 407 and Kolliphor® RH 40, which were tested in an open pan. The drying conditions of polymers and plasticizers had to be adjusted for every single sample to ensure complete drying (drying above Tg) without decomposition. The vacuum drying temperature varied from 140°C to 200°C.

The degradation temperature was analyzed by Thermo Gravimetric Analysis (TGA) using a Netzsch STA 409 C/CD instrument (USA). TGA scans were recorded at a heating rate of 5 K/min up to 450°C (air atmosphere).

Results and Discussion

Fused Deposition Model 3D Printing

Structures of polymers and solubilizers/plasticizers for 3D printing

There are two components in 3DP technology. The main element is the melt extrusion at the processing temperatures that typically reach at > 100 °C. The extruded cooled filaments are then subjected to heating and melting during printing through a nozzle at much higher temperatures than used in extrusion. The twice exposure of some of the polymers at higher temperatures could lead to degradation and a change of the mechanical properties, but others can overcome these challenges. Thus, polymers with the desired critical attributes are required in 3DP.11 Polymers lacking the mechanical strength, could bend because of high flexibility when pushed through gear under the stress during 3D printing. The well-known polymers often compatible to hot melt extrusion at fairly high temperatures, may not adopt the stress in 3DP due to their brittleness without any additional reagents. In those cases, plasticizers and/or solubilizers are often used to improve the flexibility for 3D printing. The difference between glass transition temperatures (Tg) or melting temperature (Tm) and degradation temperature (Tdeg) serves as an indication of the 3D printing range, which is defined as the temperature range within which 3D printing can be performed from a stability point of view, as shown in Figure 2A for polymers and Figure 2B for plasticizers. We evaluated several polymers in FDM to identify such characteristics with certain plasticizers and made recommendations to select the appropriate polymers. The utilities of polymers reported in the literature have also been reviewed and discussed with an aim at understanding their structural compatibilities with FDM 3DP technology.

Screw Configuration and Processing conditions in 3DP

Comparison of Tg or Tm performed by DSC with Tdeg performed by TGA of pure polymers
Comparison of Tg or Tm performed by DSC with Tdeg performed by TGA of pure plasticizers

We have evaluated polymers under special extrusion processing conditions. The following screw configurations were used for processing of polymers alone and in binary mixtures with the appropriate plasticizers, as shown in Figure 3.

All extrusion trials were performed at 200 rpm at a constant throughput of 1.0 kg/hour. The extruded filaments with a length of approx. 0.4m were cooled on a metal plate, and the temperature profiles were adjusted accordingly to the corresponding polymer’s properties as listed below.

The following criteria for extruded filaments are optimally required for 3DP

  1. Appearance: Visual assessment
  2. Tackiness: Less tacky when tested with fingers
  3. Flexibility: Measured by manual bent until it breaks (score: 1-10; 1 being highly flexible and 10 being brittle)
  4. Winding on a spool: 8 cm and 10 cm diameter spools as a measure of flexibility of filaments
  5. Mechanical strength of extruded fi laments to withstand stress during printing

Polymers were used in binary combinations with the appropriate plasticizers in varying amounts to select the best blends and to define the optimum concentration range. For example, plasticizers such as Kollisolv PEG 400, PEG 1500, Kolliphor P 188, RH 40, HS 15 were used at the respective amounts with the corresponding polymers. These amounts were varied between 2.5 wt% and 20 wt%, as shown in Table 1.

Illustration of screw configurations in melt extrusion

All compositions were systematically evaluated and the results of those with the desired properties were further explored. For example, the optimized Kollicoat® IR formulations containing 10.0 to 17.5% Kollisolv® PEG 400, and 5.0% Kolliphor® RH 40, were evaluated. The extrusion temperature was 170 °C, below the melting temperature of Kollicoat® IR (ca. 209 °C), by using 17.5% Kollisolv® PEG 400 or 5.0% Kolliphor® RH 40. The extruded filaments were flexible as evident by winding around the spool, indicative of the desired mechanical strength as shown in Table 2.

Polymers with selected plasticizers for the extrusion

Kollicoat® IR, is a graft copolymer comprised of 25% polyethylene glycol and 75% polyvinyl alcohol. It is inherently flexible and used in instant release coatings, and most recently has been used as a peroxide free binder (Fussnegger et al.).13 It has a significantly high melting temperature. In our investigation, it was used with the appropriate amounts of Kollisolv® PEG 400 and Kolliphor® RH 40 as the plasticizers to mitigate the extrusion at lower temperatures and to generate the flexible fi laments. The list of excipients could be exhaustive given the understanding of physicochemical properties of known polymers suited for extrusion at higher temperatures. For example, Solanki et al. used Kollicoat® IR with Kollidon® VA 64 and HPMC as the plasticizers to mitigate the extrusion conditions and overcome the FDM 3D printing challenges.14 Obviously, Kollicoat® IR pure was not suited for extrusion due to high melt viscosity and temperature, nor it could withstand the stress exerted by the drive gear during printing. On the other hand, Kollicoat® IR in a 1:1 binary mixture with Kollidon® VA 64 or HPMC 15 cP, and with addition of 10% haloperidol, overcame these challenges and resulted in 3DP tablets. The authors concluded that the inclusion of haloperidol plasticized the Kollicoat® IR, making it amenable for extrusion and 3D printing.

Kollicoat® IR filament properties derived from selected plasticizers
Kollidon® SR filament properties derived from selected plasticizers

Kempin et al. studied the Kollicoat® IR with 5% pantoprazole in FDM 3DP.15 The authors also observed that Kollicoat® IR without a plasticizer was extruded at 142-145 °C and the filaments were thin and discolored. The higher melt viscosity also caused the frequent blockage of nozzle by solids. It was also true with Kollicoat® IR in our experiment in which the melt viscosity reached very high and required a relatively large amount of plasticizer to overcome the extrusion and yield the fi laments for spooling with the optimum mechanical strength. Likewise, with addition of 10% haloperidol, Kollicoat® IR was easily extruded to fi laments suitable for 3D printing tablets due to plasticizing effect of drug. 14
Kollidon® SR, a co-processed excipient, is comprised of 80% polyvinyl acetate and about 20% povidone 30. It is widely used as a directly compressible excipient for controlled release tablets and pellets.16 We evaluated this excipient to understand its feasibility in melt extrusion and investigated its compatibility in 3DP application. Kollidon® SR possesses a glass transition temperature (Tg) of about 39 °C due to the large amount of polyvinyl acetate. It has been successfully extruded at 150-160 °C. It was investigated with interest in development of extruded filaments suited for 3D printing. The compositions of Kollidon® SR with the plasticizers and processing parameters are shown in Table 3.

The following observations can be made from screening of Kollidon® SR with different amounts of plasticizers/solubilizers:

  1. Kollidon® SR with 7.5% Kolliphor® P 188 or 5.0-10.0% Kollisolv® PEG 400 were extruded successfully at 160 °C with low torque (60 Nm), and the fi laments were flexible with little or no tackiness. Further investigation is needed to prove the stability of these filaments under storage or any cold flow.
  2. Kollisolv® PEG 400 is relatively more compatible to extrusion of Kollidon® SR and may be used as a preferred plasticizer during process

There are no other relevant studies reported with Kollidon® SR 3DP by FDM, so a direct comparison with other polymers and/or plasticizing agents, is difficult. However, this excipient has been used in other 3DP by ink jet technology, which will be subject of discussion in later part of the manuscript.

Soluplus® is a graft copolymer of vinylcaprolactam and vinyl acetate on polyethylene glycol 6000 (57/30/13). It has a Tg of 70 °C, thus ideally suited for melt extrusion.17 It is a surface-active polymer with a critical micelle concentration (CMC) of 8 ppm (8 mg/liter) and a hydrophilic lipophilic balance (HLB) of 14. So far it has been approved in several drug products globally.18

Soluplus® filament properties derived from selected plasticizers

We investigated Soluplus® to assess its feasibility in 3D printing. Since it has been used in the extrusion for many insoluble drugs, our aim was to understand the polymer’s characteristics in FDM 3DP. To test this, Soluplus® was extruded at 150 °C under a lower torque (25-50 Nm) with the plasticizers like Kollisolv® PEG 400, PEG 1500 and Kolliphor® P 188. The extruded filaments were robust, non-tacky and transparent, and possess an excellent flexibility with the desired strength suited for FDM 3DP. The binary compositions of Soluplus® with the plasticizers are shown in Table 4.

The following observations were drawn from the screening of Soluplus® with varied amounts of plasticizers.

With addition of 5.0% Kollisolv® PEG 400 in Soluplus® blend, the melt viscosity was lowered as compared to those containing 10.0-15.0% of PEG 1500 or P 188. The resulting filaments were soft, thin, and were flattened during cooling on an air chilled belt. It was not obvious whether the extrusion at lower temperature will improve the robustness of the filaments. It is however our understanding that the lower extrusion temperatures and/or lower amounts of PEG 400 in the blend could overcome these challenges and may yield more robust filaments. Kollisolv® PEG 400 might represent the preferred plasticizer for Soluplus® at an amount much lower than 5.0% for improving the filaments.

Soluplus® has been studied in FDM 3D printing already. In a recent study, Alhijjaj et al. evaluated Soluplus® in felodipine solid dispersions with varying amounts of plasticizers/solubilizers including polysorbate 80, polyethylene glycol (PEG) and polyethylene oxide (PEO).19 The compositions of the placebo formulations (F1) and with drug (F2),solubility parameters and processing parameters are shown in Table 5.

Soluplus® formulation composition and processing with felodipine and polymers/plasticizers

It is obvious that the solubility parameters (δ) of felodipine, Soluplus® and the processing aids were all within < 7.0, suggesting the drug will be fully miscible in the solid dispersions, as confi rmed by differential scanning calorimetry (DSC) and x-ray powder diffraction (XPRD) techniques. Soluplus® alone was not found to be well suited for 3D printing but on combination with the processing aids, it improved the 3D printability of the blend. For instance, using Soluplus® blends with one of the plasticizers, filaments were successfully extruded at 120 °C, and felodipine 3D transparent discs (or tablets) were printed at 150 °C; the printing time was about 25 sec for each disc. The diameter and thickness of each printed disc were 12 mm and 0.6 mm, respectively. The extended drug dissolution also supports that Soluplus® prevented precipitation and maintained supersaturation for over 6 hours. Kojo and Terukina studied Soluplus® with Kolliphor® P 407 in FDM 3D printing of clarithromycin tablets and found that in vitro release of drug was 80% in 1 - 6 hours depending upon the composition of formulations.20 PVP K12 and Kollidon® VA 64 have also been investigated in the binary blends with pantoprazole in FDM 3DP, as shown in Table 6.15 A flow chart recommending the optimum processing conditions for 3D printing was proposed by authors. Accordingly, the polymers with processing temperatures below 100 °C were ideally suited for 3D printing but those with higher extrusion temperatures > 100°C, were excluded. Those excluded, however, can be re-processed to 3D printing with the appropriate plasticizers. As noted earlier by Alhijjaj et al.,19 Kempin et al. also observed that

PVP K 12 and Kollidon® VA 64 were brittle, less flexible, and hence, posed the challenges during printing through a heated nozzle.15 They were however extruded and successfully 3D printed into tablets with the desired amount of plasticizer. Both polymers with 10-35% TEC were extruded at temperatures significantly lower than 100°C, yielding printable filaments with the desired mechanical strengths for 3DP tablets. For example, PVP K 12 blends with TEC 15% or higher, yielded the pantoprazole immediate release tablets with complete dissolution in less than 30 min. Likewise, Kollidon® VA 64 with 25% TEC in the binary blend, was successfully extruded, and the resulting filaments were fabricated into immediate release 3D tablets at much lower temperature (ca. 85 °C) due to inherent flexibility and mechanical strength.

Polymers used with pantoprazole and triethyl citrate as a plasticizer in 3D printing

Kollicoat® IR, a PEG grafted polyvinyl alcohol (PEG-PVA) copolymer was also used alone in 3D printing but not successfully. It required much higher extrusion temperature (ca. 142-145 °C) which caused degradation of the drug pantoprazole sodium. Due to its thermosensitivity Kollicoat® IR extruded filaments were not suited for 3D printing of thermo-labile drug like pantoprazole, as shown in Table 6. Kolliphor® P 407, an A-B-A triblock copolymer comprised of polypropylene oxide at the center and polyethylene oxide at both ends, has been used as a solubilizer and gelling agent.21 It is a low melting solid with melting point of 52 °C and a CMC of 0.004%. Kolliphor® P 407 (Poloxamer 407) can be extruded easily without any plasticizers. It was also evident that the extruded fi laments can be fabricated to 3D pantoprazole printed tablets. Taken collectively, the data in Table 6, suggests that Kollicoat® IR, PVP K12 and Kollidon® VA 64 when used alone were not highly suitable for 3DP. On the other hand, when TEC used as a plasticizer, both PVP K12 and Kollidon® VA 64 were easily extrudable and successfully fabricated into tablets at slightly higher temperatures than extrusion. The higher temperature difference between nozzle and printable surface facilitated the rapid cooling and solidification of tablets during 3 D printing. With an exception of Poloxamer 407, the dissolution of all 3D printed tablets was faster at pH 6.8 at 37 °C, and all achieved complete release within 30-40 min, whereas, the Poloxamer 407 tablets gelled and took over 2 hours for complete dissolution.

Flexibility and mechanical properties of Kollidon® VA 64 filaments can be enhanced by addition of HPMC or HPMCAS as a polymeric plasticizer. These binary blends were used in fabrication of 3D printed tablets containing 10% haloperidol.14 Kollidon® VA 64, though it is ideally extruded at 150°C or above, the fi laments without plasticizers were brittle and could not withstand the 3D printing stress. The drug release was complete from 1:1 Kollidon® VA 64 and HPMC 3DP tablets irrespective of pH at 1.2 or 6.8. Kempin et al. also studied Kollidon® VA 64 with HPMC 1:1 mixture and found that extruded filaments were flexible and possessed an optimal mechanical strength for printing.15 The fabricated tablets with 10% drug loading with 60% and 100% infill showed complete drug release at pH 2 in 45 min and 120 min, respectively. The authors also observed that Kollicoat® IR with haloperidol or with Kollidon® VA 64, was easily extrudable as well as suited for printing tablets, further supporting that drug behaved as a plasticizer. This is in contrast to finding by Kempin et al., wherein pantoprazole did not plasticize Kollicoat® IR, and hence, did not give the appropriate fi laments for 3DP.15 It can be argued that the plasticizing agents such as APIs or excipients (e.g. haloperidol or Kollidon® VA 64), alike improved the mechanical properties of Kollicoat® IR for 3D printing. A striking similarity was also evident with HPMC or HPMCAS in Kollidon® VA64, which showed signifi cant improvements in processability and fabrication of FDM 3D printing of the Copovidone tablets.14

Nukula et al. also studied Kollidon® VA 64 with HPMC in design of FDM 3DP egglets containing water soluble metformin as a model drug.22 Kollidon® VA 64/HPMC (1:1) fi laments possessed higher mechanical strength but were too brittle for reproducible printing. On the other hand, Solanki et al. were able to produce 3DP tablet with 10% haloperidol, suggesting that the successful 3D printing was dependent on the amount of plasticizing drug/substrate used.14 Kollicoat® IR with 10% sorbitol produced weak fi laments with low hardness <130 N making them unacceptable for printing but with polyvinyl alcohol, it produced FDM 3DP tablets since the filaments were flexible and possessed good mechanical strength. It further supports the earlier findings of Solanki et al.14 Nukula et al. finding, however, demonstrates that Kollicoat IR is compatible with polyvinyl alcohol and can produce the flexible filaments for 3D printing. With Kollicoat® Protect, which is, derived from co-processing of Kollicoat® IR with polyvinyl alcohol (6:4) and used as a moisture barrier coating polymer, it can be argued that this excipient could yield the desired flexible filaments with the optimum strength for 3DP. Further investigation is warranted to establish the utility of Kollicoat® Protect in FDM 3DP to overcome the challenge in abuse deterrent opioid formulations.22

Fuenmayor et al. also investigated Kollidon® VA 64 in 3DP in combination with solubilizers and/or polymers.23 The authors used Kolliphor® P 188, PCL and PEO in binary blends to print out the desired 3DP tablets. Addition of Kolliphor® P188 improved the processability of Kollidon® VA64 in melt extrusion at temperatures between 150-160 °C, and yielded 3DP tablets, while Kollidon VA 64 alone did not yield the suited filaments for 3DP. This is consistent with the findings by Solanki et al. and Kempin et al.14-15 Table 7 shows the compositions of Kollidon® VA 64 with other polymers as plasticizers (F1-F5), and the processing torque used in the investigation. Interestingly, the addition of polymers in Kollidon® VA 64 reduced the torque and allowed the extrusion at temperatures between 140 °C and 150 °C.

The authors evaluated the mechanical strength by stiff ness of the filaments. The stiff ness of Kollidon® VA 64 decreased by 69% with addition of 10% Kolliphor® P 188, making it more flexible for 3D printing. Addition of 10% PEO and PCL also significantly decreased the filament stiffness by 66% and 48%, respectively, making them more adoptable to 3DP. Kollidon® VA64 was over 200 times stiffer than PCL (306 N/m) and maintained a constant stiffness with an onset temperature of 68.7 °C.

Composition of Kollidon® VA64 with different plasticizers/polymers and processing torques

Kollidon® VA 64 blends containing 5% caffeine as a model drug with different amounts of PCL and PEO were used as shown in Table 8 (F1-F3). These formulations were evaluated for drug release from 3DP tablets and compared with directly compressed (DC) tablets (F4-F5). The extrusion was carried out at temperature of 140 °C with throughput of 0.4 kg/hour and screw speed of 80 rpm. The diameter of filament was 1.75 mm.

In summarizing, the wider utilities of Kollidon® VA 64 in FDM 3D printing cannot be underestimated. It is a unique polymer, hydrophilic and freely soluble in aqueous and organic solvents. It is comprised of 60% of vinyl pyrrolidone and 40% vinyl acetate in the copolymer. Figure 4 shows that Kollidon® VA 64 is a high functional polymer and widely compatible with many other polymers in hot melt extrusion to yield filaments with excellent mechanical strengths in FDM 3DP technology.

Selective Laser Sintering 3D Printing

Compositions of caffeine and Kollidon® VA 64 formulation within different plasticizers used in 3DP and direct compression

Kollidon® VA 64 is highly versatile and adoptable to different formulation technologies. It has been used in selective laser sintering (SLS) 3D printing. Fina et al. investigated Kollidon® VA 64 and HPMC in SLS 3DP technology.24 By employing slow and faster laser scanning speeds, the authors fabricated the printlets with faster release characteristics. For instance, Kollidon® VA 64 when used at a laser sintering speed of 300 mm/s, yielded an orally disintegrating tablet (ODT) with disintegration time (Dt) of about 4 seconds. This quick dissolving property was attained due to increased porosity and decreased density as confirmed by X-ray micro-CT analysis. This is yet another novel application of Kollidon® VA 64 in an orally dispersible tablets by selecting the appropriate sintering frequency in 3D laser printing. This work further demonstrates the advantages of selecting the appropriate technologies and/or excipients to create the printed tablets with unique characteristics to achieve the desired release profiles. In this study, the authors fabricated the Kollidon® VA 64 tablets by laser sintering at ultra-faster screening speeds of 100 mm/s, 200 mm/s and 300 mm/s. The latter speed yielded the paracetamol tablets with orally disintegrating properties with disintegration time (ca. 4 seconds); whereas, the tablets with 100 mm/s and 200 mm/s speed were relatively harder and showed the complete release in 60 min and 10 min, respectively. This data suggests that the frequency of sintering speed determines the nature of derived 3 DP tablets because of varied level of porosities in the matrix.24

Semi-Solid Extrusion 3DP Technology

Compatibility of Kollidon® VA64 with other polymers in FDM 3DP

3D printing technology such as semi-solid extrusion (SSE) is used for sensitive APIs to avoid exposure to higher temperatures. This is a pressure driven cold extrusion process requiring the use of a paste of drugs and excipients. That means, the selection of the excipients for this 3D printing technology can be much broader as opposed to thermally driven 3DP technologies such as FDM and SLS. For example, higher molecular weight povidones with higher Tgs, are not suited for melt extrusion in FDM and laser induced SLS technology due to their degradation, but they could be used in SSE as a binder. Khaled et al. used PVP K 25 in SSE for 3D printing of immediate release paracetamol tablets.25 The drug loading was 80% w/w with PVP K 25 in the acceptable tablet. These tablets were disintegrated in 60 seconds with complete dissolution in 5 minutes, demonstrating that SSE printing technology can be used for preparation of immediate release medium to high dosage drugs with much wider choice of excipients. The authors used a syringe cartridge installed into printer head, which was filled in with a semi-solid paste, and pressure extruded layer by layer to yield a desired tablet dimension. The resulting tablets, each weighing 320 mg, were dried for 3 hours at 80 °C. Each printed tablet had the dimension of 14.7 mm length × 7.5 mm width × 5.0 mm height, and an average disintegration time was 61 sec showing >95% dissolution in 15 min. In contrast to FDM 3DP requiring higher extrusion temperatures, SSE opens the door for many active ingredients and/or excipients thermally labile and may have tendencies to degrade on exposure to high temperatures and sintering energy. Kollidon® VA 64, Soluplus®, Kollidon® 25, 30, K90, Kollidon® SR, Kollicoat® IR, Kollicoat® Protect, Kollicoat® MAE 100-55 amongst others will be suited for SSE 3DP. Further work is warranted to support the utilities of these polymers in this 3D printing technology.

Modified Release 3D Printed Tablets

Kollidon® SR has been investigated in the extrusion with plasticizers like PEG 400, Kolliphor® P 188 among others. It is an excellent excipient for modified and controlled release. The properties of Kollidon® SR in 3D printed tablets have yet to be investigated (unpublished). Yang et al. used cellulosic based sustained release excipients such as ethyl cellulose (EC) and HPMC for fabricating the ibuprofen FDM 3DP tablets.26 The extruded filaments were robust and the printed 3D tablets were investigated for drug release profile. EC and HPMC matrix based 3DP tablets with 20% ibuprofen loading achieved the extended release over 24 hours. In contrast, the release was only 50% from the directly compressed mini-tablets because of highly compacted dense matrix. The authors concluded that the sustained release behaviors of ibuprofen can be regulated by adjusting the fill densities and porosities of the EC scaffold with HMPC as a hydrophilic pore former. Can HPMC (or HPMCAS) in Kollidon® SR (PVP/PVAc co-processed) matrix impact the extrusion and influence the extended release characteristics of 3D printed tablets? Wang et al. investigated the impact of HPMC on Kollidon® SR 3DP shell carrier on the sustained release of pseudoephedrine hydrochloride.27 The authors observed that changing the ratios of HPMC in Kollidon® SR fabricated tablets, controlled the drug release, and yielded the dosages from an immediate release core to a controlled release regulating shell. The HPMC controlled the drug release via diffusional pathways formed in the matrix shell. Solanki et al. have demonstrated that HPMC in Kollidon® VA 64 (PVP-PVAc copolymer) acts as a plasticizer and the dissolution properties of tablets were independent of pH.14

Goyanes et al. also investigated the delayed release properties of paracetamol 3DP tablets derived from three different granular hydroxypropyl methylcellulose acetate succinate grades, namely, HPMCAS LG, HPMCAS MG and HPMCAS HG.28 The release properties were dependent upon acetic acid and succinic acid substitutions in HPMCAS and drug release decreased in the order: HPMCAS LG > HPMCAS MG > HPMCAS HG, suggesting that the faster release was with polymers bearing a lower pH-threshold. In earlier studies by Solanki et al. , the authors demonstrated that HPMCAS in Kollidon® VA 64 matrix, delayed the release and the dissolution was pH dependent due to the enteric nature of the polymer.14 The effect of enteric polymer like poly-(methacrylic acid ethyl acrylate) copolymer (Kollicoat® MAE 100-55/Eudragit L 100-55) was investigated by Okwuosa et al.29 The study demonstrates that 3D printed tablets were enteric in nature. It also demonstrates that 3DP is a single step process which could offer an opportunity to alleviate the fluid bed coatings to achieve either sustained or enteric release profile of drugs depending upon the polymers used.

Stereolithography 3D Printing Technology

Sustained release of drugs can also be achieved by cross-linking of polymers within the matrix by stereolithography (SLA) 3D printing technology. For example, Wang et al. investigated the modified release properties of 2 model drugs in PEG based polymers by SLA 3DP technology.30 The two model drugs, 4-amino salicylic acid (4-ASA) and paracetamol, (acetaminophen) were successfully printed in 3D tablets. The degrees of cross-linking of the two polymers during the stereolithography exposure controlled the release profiles of drugs. It was evident that higher amount of polyethylene glycol diacrylate (PEGDA) retarded the dissolution rate while the higher amount of liquid PEG 300 promoted a faster release due to lesser degrees of crosslinking and increased fluidity in the matrix. Taken collectively, this data suggests that drugs susceptible to hydrolysis or thermal degradation, can be alleviated in SLA 3DP to yield more stable tablets unlike in FDM and SLS 3D printing technologies. Further studies are warranted to explore the utilities of PEG based low and high molecular weight polymers such as Kollisolv® PEG 400, PEG 600, PEG 1450, PEG 3350, PEG 8000, and grafted copolymers such as Soluplus®, Kollicoat® IR, and Kollicoat® Protect in SLA 3DP technology.

Ink Jet 3D Printing Technology

Ink jet printing technology has been widely used for depositing films on surfaces. Wimmer-Teubenbacher et al. used the ink jet for printing of sodium picosulfate (SP) oral films derived from cellulosic excipients with and without plasticizers.31 Solubility of drug in the films was investigated by small and wide-angle X-ray scattering, differential scanning calorimetry and polarized light microscopy. The authors concluded that drug in the printed films was completely miscible with no crystals detected by polarized light microscopy, SWAXS and DSC, suggesting cellulosic excipients presumably act as crystallization inhibitors of SP. Acosta-Vélez et al. investigated the compatibility of polyethylene glycol (PEG) in ink jet fi lm printing of a hydrophobic drug.32 Polyethylene glycol and methanol were used in ink jet printing of orally dispersible enalapril maleate (EM) films by Thabeta et al.33 Solvents were relevant for calibrating the drug loading. PEG 400 based ink jet printing yielded films with drug loading of 0.05 mg/6 cm2; while, methanol ink jet printing yielded with loading of 0.5 mg/ film. The authors demonstrated the feasibility of ink jet technology in continuous manufacturing for fi xed dose combination of EM and hydrochlorothiazide (HCT) cellulosic orally dispersible films (ODFs). Ehtezazi et al. used FDM technology to design polyvinyl alcohol based single layered and multilayered fast dissolving oral films with thicknesses of about 200 microns and 300 microns, respectively.34 Each film contained paracetamol or ibuprofen with a nominal drug loading of 15.6 mg per fi lm and in addition polyethylene oxide and a flavor for taste-masking. The disintegration time of these single and multilayered, films were about 42 seconds and 48 seconds, respectively; and they dissolved within 30 min with some exceptions and showed a good content uniformity.

Kollicoat® Protect has been used in ink jet printing as well. Standaert designed the multilayered smooth films comprised of Kollicoat® Protect or HPC with other additives by drop-on-demand (DoD) inkjet 3D printing technology for veterinary use.35 Table 9 shows the characteristics of the ink jet fi lms composed of Kollicoat® Protect and HPC polymers.

It is evident that Kollicoat® Protect ink jet films possessed relatively much higher strength in spite of lower film weight and thickness as compared with HPC ink jet films.

Properties of Kollicoat Protect® and HPC ink jet films

Conclusion

This study sheds light on the understanding of 3DP and the advantages of expediting drug development by selecting the appropriate printing technologies for complex formulations over multi-step conventional technologies. The excipients’ characteristics play on an important role in optimization of 3DP dosages. Polymers such as Kollidon® VA 64, Soluplus®, Kollidon® SR, and Kollicoat® IR, to the extent all form the 3DP tablets, if not in pure but with additional substrates or plasticizing agents. If one excipient is suited for certain 3DP technology, it may not be directly compatible to other technologies due to thermal instability or other challenges. Understandably, more studies are warranted to fully understand the critical material attributes within the scope of stability and compatibility in 3DP technologies to develop innovative and personalized medicines.

As the pharmaceutical industry continues to take interests in developing 3DP drugs in the future, the regulatory requirements warrant a closer scrutiny. With rising interest in the continuous manufacturing, establishing the guiding principles for 3DP is the biggest challenge, due, in part, to incomplete understanding of material and processing attributes for large scale up and commercial manufacturing. The sense of urgency is realized. As a result, FDA has established a manufacturing science program to apply the innovative technologies including 3DP.36 These initiatives will aid in advancing 3DP from early innovative to more realistic fully developed scale up and manufacturing processes.

Various excipients will continue to play an important role in 3DP technologies. As demonstrated, many of the polymeric excipients ideally suited for one 3DP technology, can be adopted in alternative technologies by addition of the appropriate polymers and/or solubilizers acting as plasticizers for immediate and modified released dosages. For others, the full utilities in 3DP remain elusive and must be explored as binary and ternary compositions in 3DP technologies. Selecting this strategy may change the landscape by advancing more innovative 3DP approaches to yield immediate and modified released tablets, orally dispersible tablets and films for humans and animals in the future.

Author Biographies

Shaukat Ali has worked in the pharma industry for over 25 years including 15 years at BASF. His areas of expertise include the controlled release, solid dispersions, lipid based emulsifying systems, liposome drug delivery, and film development technology. He received his PhD in chemistry from the City University of New York, and postdoctoral training from the University of Minnesota and Cornell University. He is the editor-in-chief of Journal Analytical and Pharmaceutical Research and serves as a member of the editorial advisory board of several pharmaceutical journals including the American Pharmaceutical Review. He also serves as a panel of expert in the USP expert committees for General Chapters-Physical Analysis, Continuous Manufacturing and Excipient Performance <1059>. He has published over 45 articles in the scientific journals and is the inventor in 14 US Patents

After his apprenticeship as laboratory chemist, Matthias Karl worked in the quality control at Schaper & Brümmer GmbH. Following his first professional experience he has studied pharmaceutical technology at the University of Applied Science in Lippe. After his studies, he worked in the analytical chemistry department at Grünenthal GmbH and as project manager for preclinical development at Trommsdorff Arzneimittel GmbH & Co. KG. He joined BASF in 2009 as engineer for the development of pharmaceutical excipients. His expertise includes the solid dispersions, solubilizers, and the development of excipients for solid drug formulations.

Karl Kolter joined BASF SE in 1993 after having worked for 7 years at Knoll AG in Ludwigshafen. He has been responsible for R&D of pharmaceutical excipients, drug formulations and formulation development of vitamins, carotenoids and enzymes for human and animal nutrition. His work on innovative excipients has already resulted in a number of new products in the Kollicoat® and Kollidon® ranges, e.g. Kollicoat® IR, Kollicoat® Smartseal 30D, Kollidon® SR, Ludiflash® and Soluplus®. Karl Kolter obtained his Ph.D. in Pharmaceutical Chemistry at the University of Mainz, Germany. He has published more than 150 articles and posters and is inventor of 150 patents.

References

  1. M. Alomari, F. H. Mohamed, A. W. Basit, and S. Gaisford, Personalized dosing: printing a dose of one’s own medicine. Int. J. Pharm.2015, 494, 568–577.
  2. G. F. Acosta-Vélez, and B. M. Wu, 3D Pharming: Direct Printing of Personalized Pharmaceutical Tablets, Polymer Sciences, 2016, 2, 1:3 DOI: 10.4172/2471-9935.100011
  3. S. J. Trenfield, A. Awad, A. Goyanes, S. Gaisford, and A. W. Basit, 3D Printing pharmaceuticals: drug development to frontline care, Trends Pharmacol. Sci., 2018, 39, 440-451.
  4. N. Sandler, Printing of medical devices, Arh. Farm. 2016; 66/Special Issue, 11th Central European Symposium on Pharmaceutical Technology, Sept. 22-24, 2016, Belgrade, Serbia.
  5. D. Douroumis, 3D printing of pharmaceutical and medical applications: A new era, Pharm. Res. 2019, 36: 42; https://doi.org/10.1007/s11095-019-2575-x
  6. S. Lamichhane, S. Bashyal, T. Keum, G. Noh, J. E. Seo, R. Bastola, J. Choi, D. H. Sohn, and S. Lee, Complex formulations, simple techniques: Can 3D printing technology be the Midas touch in pharmaceutical industry? Asian J. Pharm. Sci., available online 14 February 2019; doi.org/10.1016/j.ajps.2018.11.008
  7. S. N. Economidoua, D. A. Lamproua, D. Douroumisb, 3D printing applications for transdermal drug delivery, Int. J. Pharm. 2018, 544, 415-424.
  8. A. E. Allen, C. O’Mahony, M. Cronin, T. O’Mahony, A. C. Moore, and A. M. Crean, Dissolvable microneedle fabrication using piezoelectric dispensing technology, Int. J. Pharm., 2016, 500, 1-10
  9. C. P. P. Perea, S. N. Economidoua, G. Lall, C. Ziraud, J. S. Boateng, B. D. Alexander, D. A. Lamprou, and D. Douroumis, 3D printed microneedles for insulin skin delivery, Int. J. Pharm., 2018, 544, 425-432
  10. Z. Rahman, S. F. Barakh Ali, T. Ozkan, N. A. Charoo, I. K. Reddy and M. A. Khan, Additive manufacturing with 3D printing: Progress from bench to bedside, The AAPS Journal, 2018, 20, 101; DOI: 10.1208/s12248-018-0225-6
  11. T. Huang, S. Wang, and K. He, (editors), 2015, Quality control for fused deposition modeling based additive manufacturing: current research and future trends. In reliability systems engineering (ICRSE), First International Conference 2015, Beijing: IEEE.
  12. F. A Maulvi, M. J Shah, B. S Solanki, A. S Patel, T. G Soni, and D. O Shah, Application of 3D printing technology in the development of novel drug delivery systems, Int. J. Drug Dev., 2017, 9, 44-49.
  13. B. Fussnegger, V. Tawde, A. Chivate, K. Kolter and S. Ali, Kollicoat® IR: Minimizing the Risks for Oxidative Degradation of Drugs, J. Anal. Pharm. Res., 2016, 2 (3); DOI: 10.15406/japlr.2016.02.00020.
  14. N. G. Solanki, M. Tahsin, A. V. Shah, A.T.M. Serajuddin, Formulation of 3D printed tablet for rapid drug release by fused deposition modeling: Screening polymers for drug release, drug-polymer miscibility and printability, J. Pharm. Sci., 2018, 107, 390-401
  15. W. Kempin, V. Domsta, G. Grathoff, I. Brecht, B. Semmling, S. Tillmann, W. Weitschies, and A. Seidlitz, Immediate release 3D-printed tablets produced via fused deposition modeling of a thermo-Sensitive Drug, Pharm. Res., 2018, 35, 124.
  16. V. Bühler, Kollidon® Polyvinylpyrrolidone excipients for the pharmaceutical industry, 9th revised edition, March 2008
  17. K. Kolter, M. Karl, and A. Gryczke, Hot melt extrusion with BASF pharma polymers, Extrusion Compendium, 2nd Edition, BASF October 2012.
  18. S. Ali, N. Langley, D. Djuric, and K. Kolter, Eye on Excipients, Tablets & Capsules, October 2010, 8 (7).
  19. M. Alhijjaj, P. Belton, and S. Qi, An investigation into the use of polymer blends to improve the printability of and regulate drug release from pharmaceutical solid dispersions prepared via fused deposition modeling (FDM) 3D printing, Eur. J. Pharm. Biopharm., 2016, 108, 111-125.
  20. K. Kojo and T. Terukina, 3D Printing of hot-melt extruded clarithromycin formulations using Soluplus® and Kolliphor® P407, AAPS Pharma Sci 360, Washington DC, Nov. 4-7, 2018, Poster T1330-11-086.
  21. G. Dumortier, J. L. Grossiord, F. Agnely, and J. C. Chaumeil, A review of poloxamer 407 Pharmaceutical and Pharmacological Characteristics, Pharm. Res., 2006, 23, 2709-2228.
  22. P. K. Nukala, S. Palekar, M. Patki, and K. Patel, Abuse deterrent immediate release eggshaped tablet (Egglets) using 3D printing technology: Quality by design to optimize drug release and extraction, AAPS PharmSciTech, 2019, 20:80; DOI: 10.1208/s12249-019-1298-y
  23. E. Fuenmayor, M. Forde, A. V. Healy, D. M. Devine, J. G. Lyons, C. McConville, and I. Major, Material considerations for fused-filament fabrication of solid dosage forms, Pharmaceutics, 2018, 10, 44; doi:10.3390/pharmaceutics10020044
  24. F. Fina, C. M. Madla, A. Goyanes, J. Zhang, S. Gaisforda, and A. W. Basit, Fabricating 3D printed orally disintegrating printlets using selective laser sintering. Int. J. Pharm., 2018, 541, 101-107.
  25. S. A. Khaled, M. R. Alexander, R. D. Wildman, M. J. Wallace, S. Sharpe, J. Yoo, and C. J. Roberts, 3D extrusion printing of high drug loading immediate release paracetamol tablets, Int. J. Pharm., 2018, 538, 223-230.
  26. Y. Yang, H. Wang, H. Li, Z. Ou, and G. Yang, 3D printed tablets with internal scaffold structure using ethyl cellulose to achieve sustained ibuprofen release, Eur. J. Pharm. Sci., 2018, 115, 11-18.
  27. C. C. Wang, M. R. Tejwani, W. J. Roach, J. L. Kay, J. Yoo, D. C. Monkhouse, and T. J. Pryor, Development of near zero-order release dosage forms using three-dimensional printing (3-DP™) Technology, Drug Dev. Indus. Pharm, 2006, 32, 367-376.
  28. A. Goyanes, F. Fina, A. Martorana, D. Sedough, S. Gaisford, and A. W. Basit, Development of modified release 3D printed tablets (printlets) with pharmaceutical excipients using additive manufacturing, Int. J. Pharm., 2017, 527, 21-30.
  29. T. C. Okwuosa), D. Stefaniak, B. Arafat, A. Isreb, K. W. Wan and M. A. Alhnan, A lower temperature FDM 3D printing for the manufacturer of patient-specific immediate release tablets, Pharm. Res., 2016, 33, 2704-2712.
  30. J. Wang, A. Goyanes, S. Gaisford, and A. W. Basit, Stereolithographic (SLA) 3D printing of oral modified-release dosage forms, Int. J. Pharm., 2016, 503, 207-212.
  31. M. Wimmer-Teubenbacher, C. Planchette, H. Pichler, D. Markl, W.K. Hsiao, A. Paudela, and S. Stegemannd, Pharmaceutical-grade oral films as substrates for printed medicine, Int. J. Pharm., 2018, 547, 169-180.
  32. G. F. Acosta-Vélez, T. Z. Zhu, C. S. Linsley, and B. M. Wu, Photocurable poly-(ethylene glycol) as a bioink for the inkjet 3D pharming of hydrophobic drugs, Int. J. Pharm. 2018, 546, 145-153.
  33. Y. Thabet, D. Lunter, and J. Breitkreutz, Continuous inkjet printing of enalapril maleate onto orodispersible film formulations, Int. J. Pharm., 2018, 546, 180-187
  34. T. Ehtezazi, M. Algellay, Y. Islam, M. Roberts, N. M. Dempster, and S. D. Sarker, The application of 3D printing in the formulation of multilayered fast dissolving oral films, J. Pharm. Sci., 2018, 107, 1075-1085.
  35. S. Standaert, Inkjet printed personalized multilayered dosage forms for veterinary use. Master’s thesis, 2017-2018; Ghent University and Abo Akademi
  36. J. Markarian, FDA and the emerging technology of 3D printing, Pharm. Tech, 2016, 40.
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  • BASF Extends Offer Period for Pronova BioPharma

    BASF is extending its offer period to acquire all of the issued and outstanding shares of Pronova BioPharma ASA, Lysaker, Norway, for NOK 12.50 per share in cash until January 18, 2013, 16:30 CET.

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