Tailoring drug release in bilayer tablets through droplet deposition modeling and injection molding.

This study explores the innovative production of personalized bilayer tablets, integrating two advanced manufacturing techniques: Droplet Deposition Modeling (DDM) and Injection Molding (IM). Unlike traditional methods limited to customizing dense bilayer medicines, our approach uses Additive Manufacturing (AM) to effectively adjust drug release profiles. Focusing on Caffeine and Paracetamol, we found successful processing for both DDM and IM using Caffeine formulation. The high viscosity of Paracetamol formulation posed challenges during DDM processing. Integrating Paracetamol formulation for the over-molding process proved effective, demonstrating IM's versatility in handling complex formulations. Varying infill percentages in DDM tablets led to distinct porosities affecting diverse drug release profiles in DDM-fabricated tablets. In contrast, tablets with high-density structures formed through the over-molding process displayed slower and more uniform release patterns. Combining DDM and IM techniques allows for overcoming the inherent limitations of each technique independently, enabling the production of bilayer tablets with customizable drug release profiles. The study's results offer promising insights into the future of personalized medicine, suggesting new pathways for the development of customized oral dosage forms.

A comparison of droplet deposition modelling, fused filament fabrication, and injection moulding for the production of oral dosage forms containing hydrochlorothiazide.

Additive manufacturing (AM) possesses a transformative potential to revolutionize personalized medicine fabrication. Fused filament fabrication (FFF), an advanced AM technique, enables the development of tailored medicines with customizable dosages and controlled release properties. Nevertheless, filament prerequisites impose material limitations and present considerable challenges, necessitating a comprehensive evaluation of mechanical, rheological, and thermal characteristics to circumvent complications during the FFF process. Droplet deposition modeling (DDM), an innovative AM approach derived from injection molding (IM) technology, processes granulate feedstock to facilitate the production of personalized medicines. This study delves into the effects of FFF, DDM, and IM techniques on the release profiles of Hydrochlorothiazide, a widely employed drug for hypertension and edema treatment. By varying infill density, the investigation assesses the manufactured tablets using DDM and FFF methods. Our findings show that tablets made with FFF and DDM with identical infill densities had distinct microstructures, resulting in variable drug release profiles. Decreasing the infill densities resulted in higher sample porosity, leading to an accelerated drug release rate. A comparative analysis of drug release profiles from DDM and IM fabricated tablets demonstrated notable differences, despite DDM's origins in injection molding technology. This comprehensive study underscores the significance of not only infill densities but also the choice of manufacturing technique, as both factors can profoundly influence drug release profiles. By shedding light on these considerations, the research contributes to the ongoing advancement of personalized medicine through additive manufacturing technologies.

Hybrid Manufacturing of Oral Solid Dosage Forms via Overprinting of Injection-Molded Tablet Substrates.

Since 3D printing allows for patient-specific dosage forms, it has become a major focus in pharmaceutical research. However, it is difficult to scale up drug product manufacturing. Injection molding has been used in conjunction with hot-melt extrusion to mass produce drug products, but making tailored solid dosage forms with this technology is neither cost-effective nor simple. This study explored the use of a combination of fused filament fabrication and injection molding to create patient-specific solid dosage forms. A tablet fixation and location template was used to overprint directly on injection-molded tablet bases, and theophylline was combined with polycaprolactone and Kollidon® VA64 via hot-melt extrusion to produce the filament. Dynamic mechanical analysis was used to evaluate the brittleness of the filament, and differential scanning calorimetry was used to analyze the thermal results. The results showed that theophylline had a flow promoting effect on the polymer blend and that overprinted tablets were manufactured faster than 3D-printed tablets. Drug release studies also showed that overprinted tablets released faster than injection-molded tablets. This method demonstrates the potential of hybrid manufacturing for the pharmaceutical industry as a means of bridging the gap between personalized dosage forms and mass production.

Mass Customization of Polylactic Acid (PLA) Parts via a Hybrid Manufacturing Process.

Mass customization is the development of items tailored to specific customers, but produced at low unit cost in high-volume. In this context, hybrid manufacturing (HM) combines fused deposition modeling (FDM) and injection molding (IM) to fabricate a single personalized part with minimum manufacturing cost. In this technique, inserts with different physical features are first FDM-fabricated and then IM-overmolded. This study investigated the effect of hybrid FDM-IM production technology, FDM insert geometry on mechanical properties, and micro-structural evolution of Polylactic Acid (PLA) samples. The findings indicated a comparable tensile properties of FDM-IM samples (68.38 MPa) to IM batch (68.95 MPa), emphasizing the potential of HM in the manufacturing industry. Maximum tensile stress of FDM-IM specimens shows an upward trend due to the increased infill density of preforms. In addition, overmolding interface direction results in a big gap for the maximum tensile strengths between half-length series specimens (12.99 MPa to 19.09 MPa) and half-thickness series specimens (53.83 MPa to 59.92 MPa). Furthermore, four joint configurations resulted in different mechanical performances of finished specimens, in which the female cube sample exhibits the highest tensile stress (68.38 MPa), while the batch with male T joint shows a lower value in maximum tensile strength (59.51 MPa), exhibiting a similar tensile performance with the half-thickness 75% batch without joint configuration. This study lays the groundwork for using HM to produce bespoke and mechanically improved parts over FDM alone.

Hybrid Manufacturing of Acrylonitrile Butadiene Styrene (ABS) via the Combination of Material Extrusion Additive Manufacturing and Injection Molding.

Acrylonitrile Butadiene Styrene (ABS) is a common thermoplastic polymer that has been widely employed in the manufacturing industry due to its impact resistance, tensile strength, and rigidity. Additive manufacturing (AM) is a promising manufacturing technique being used to manufacture products with complex geometries, but it is a slow process producing mechanically inferior products when compared to traditional production processes like injection molding (IM). Thus, our hybrid manufacturing (HM) process combining materials extrusion AM and IM to create a single article was investigated in this study, in which eleven batches of specimens were made and extensively tested. These include the AM, IM, and hybrid manufactured (HYM) samples, in which the HYM samples were made by inserting AM substrates into the IM tool and were varied in infill density of AM preforms and geometries. The HYM samples outperformed AM parts in terms of mechanical performance while retaining customizability dependent on the HYM processing parameters, and the best mechanical performance for HYM samples was found to be comparable to that of IM samples, implying that the overmolding process in HM had primarily improved the mechanical performance of AM products. This work leads to a deeper knowledge of applications to confirm the optimal component fabrication in high design flexibility and mass production.

Additive Manufacturing of Personalized Pharmaceutical Dosage Forms via Stereolithography.

The introduction of three-dimensional printing (3DP) has created exciting possibilities for the fabrication of dosage forms, paving the way for personalized medicine. In this study, oral dosage forms of two drug concentrations, namely 2.50% and 5.00%, were fabricated via stereolithography (SLA) using a novel photopolymerizable resin formulation based on a monomer mixture that, to date, has not been reported in the literature, with paracetamol and aspirin selected as model drugs. In order to produce the dosage forms, the ratio of poly(ethylene glycol) diacrylate (PEGDA) to poly(caprolactone) triol was varied with diphenyl(2,4,6-trimethylbenzoyl)phosphine oxide (Irgacure TPO) utilized as the photoinitiator. The fabrication of 28 dosages in one print process was possible and the printed dosage forms were characterized for their drug release properties. It was established that both drugs displayed a sustained release over a 24-h period. The physical properties were also investigated, illustrating that SLA affords accurate printing of dosages with some statistically significant differences observed from the targeted dimensional range, indicating an area for future process improvement. The work presented in this paper demonstrates that SLA has the ability to produce small, individualized batches which may be tailored to meet patients' specific needs or provide for the localized production of pharmaceutical dosage forms.

Mass-customization of oral tablets via the combination of 3D printing and injection molding.

The new frontier of medicine is the personalization of treatment to match a patient's individual needs. Fused-filament fabrication (FFF) offers a platform for the personalization of drug dosage forms, but one of its chief shortcomings compared to other tablet production methods such as dry compression and wet granulation is relatively low throughput. Conversely, injection molding (IM) is a manufacturing technique for the high-volume production of parts, but in which individual part customization is both expensive and slow requiring the modification of expensive mold tooling. Mass-customization is the manufacture of custom products that match the needs of individual consumers but which are produced at the low unit cost associated with high-volume production. We successfully integrated for the first time FFF with IM in a multi-step manufacturing process for the production of custom bilayer tablets loaded with two active pharmaceutical ingredients used in the treatment of cardiovascular disease. The FFF layer was loaded with the diuretic hydrochlorothiazide, while the IM layer was loaded with lovastatin. Infill percentage was varied for the FFF layer as a means to modify drug release. The IM injection pressure was evaluated for its effect on drug release and layer-layer adhesion. The bilayer tablets obtained offered different combinations of drug release profiles, which were governed by a combination of factors, including surface area to volume ratio; IM injection volume penetration into the FFF layer; FFF infill percentage; layer tortuosity and porosity. These different parameters could be utilized to modify the individual release of both drugs from the bilayer tablet. Thus for the first time, we have demonstrated a viable method for the mass-customization of oral tablets which could hasten the rollout of personalized medicine.

Influence of Annealing and Biaxial Expansion on the Properties of Poly(l-Lactic Acid) Medical Tubing.

Poly-l-lactic acid (PLLA) is one of the most common bioabsorbable materials in the medical device field. However, its use in load-bearing applications is limited due to its inferior mechanical properties when compared to many of the competing metal-based permanent and bioabsorbable materials. The objective of this study was to directly compare the influence of both annealing and biaxial expansion processes to improve the material properties of PLLA. Results showed that both annealing and biaxial expansion led to an overall increase in crystallinity and that the crystallites formed during both processes were in the α' and α forms. 2D-WAXS patterns showed that the preferred orientation of crystallites formed during annealing was parallel to the circumferential direction. While biaxial expansion resulted in orientation in both axial and circumferential directions, with relatively equal sized crystals in both directions, Da (112 Å) and Dc (97 Å). The expansion process had the most profound effect on mechanical performance, with a 65% increase in Young's modulus, a 45% increase in maximum tensile stress and an 18-fold increase in strain at maximum load. These results indicate that biaxially expanding PLLA at a temperature above Tcc is possible, due to the high strain rates associated with stretch blow moulding.

The Influence of Low Shear Microbore Extrusion on the Properties of High Molecular Weight Poly(l-Lactic Acid) for Medical Tubing Applications.

Biodegradable polymers play a crucial role in the medical device field, with a broad range of applications such as suturing, drug delivery, tissue engineering, scaffolding, orthopaedics, and fixation devices. Poly-l-lactic acid (PLLA) is one of the most commonly used and investigated biodegradable polymers. The objective of this study was to determine the influence low shear microbore extrusion exerts on the properties of high molecular weight PLLA for medical tubing applications. Results showed that even at low shear rates there was a considerable reduction in molecular weight (Mn = 7-18%) during processing, with a further loss (Mn 11%) associated with resin drying. An increase in melt residence time from ~4 mins to ~6 mins, translated into a 12% greater reduction in molecular weight. The degradation mechanism was determined to be thermal and resulted in a ~22-fold increase in residual monomer. The differences in molecular weight between both batches had no effect on the materials thermal or morphological properties. However, it did affect its mechanical properties, with a significant impact on tensile strength and modulus. Interestingly there was no effect on the elongational proprieties of the tubing. There was also an observed temperature-dependence of mechanical properties below the glass transition temperature.

Comparison of fused-filament fabrication to direct compression and injection molding in the manufacture of oral tablets.

Oral tablets are a convenient form to deliver active pharmaceutical ingredients (API) and have a high level of acceptance from clinicians and patients. There is a wide range of excipients available for the fabrication of tablets thereby offering a versatile platform for the delivery of therapeutic agents to the gastrointestinal tract. However, the geometry of tablets is limited by conventional manufacturing processes. This study aimed to compare three manufacturing processes in the production of flat-faced oral tablets using the same formulation composed of a polymer blend and caffeine as a model drug: fused-filament fabrication (FFF), direct compression (DC) and injection molding (IM). Hot-melt extrusion was used to convert a powder blend into feedstock material for FFF and IM processes, while DC was performed on the powder mixture. Tablets were produced with the same dimensions and were characterized for their physical and dissolution properties. There were statistical differences in the physical properties and drug release profiles of the tablets produced by the different manufacturing processes. DC tablets displayed immediate release, IM provided sustained release over 48 h, and FFF tablets displayed both release types depending on the printing parameters. FFF continues to demonstrate high potential as a manufacturing process for the efficient production of personalized oral tablets.

Material Considerations for Fused-Filament Fabrication of Solid Dosage Forms.

Material choice is a fundamental consideration when it comes to designing a solid dosage form. The matrix material will ultimately determine the rate of drug release since the physical properties (solubility, viscosity, and more) of the material control both fluid ingress and disintegration of the dosage form. The bulk properties (powder flow, concentration, and more) of the material should also be considered since these properties will influence the ability of the material to be successfully manufactured. Furthermore, there is a limited number of approved materials for the production of solid dosage forms. The present study details the complications that can arise when adopting pharmaceutical grade polymers for fused-filament fabrication in the production of oral tablets. The paper also presents ways to overcome each issue. Fused-filament fabrication is a hot-melt extrusion-based 3D printing process. The paper describes the problems encountered in fused-filament fabrication with Kollidon® VA64, which is a material that has previously been utilized in direct compression and hot-melt extrusion processes. Formulation and melt-blending strategies were employed to increase the printability of the material. The paper defines for the first time the essential parameter profile required for successful 3D printing and lists several pre-screening tools that should be employed to guide future material formulation for the fused-filament fabrication of solid dosage forms.

The Production of Solid Dosage Forms from Non-Degradable Polymers.

Non-degradable polymers have an important function in medicine. Solid dosage forms for longer term implantation require to be constructed from materials that will not degrade or erode over time and also offer the utmost biocompatibility and biostability. This review details the three most important non-degradable polymers for the production of solid dosage forms - silicone elastomer, ethylene vinyl acetate and thermoplastic polyurethane. The hydrophobic, thermoset silicone elastomer is utilised in the production of a broad range of devices, from urinary catheter tubing for the prevention of biofilm to intravaginal rings used to prevent HIV transmission. Ethylene vinyl acetate, a hydrophobic thermoplastic, is the material of choice of two of the world's leading forms of contraception - Nuvaring® and Implanon®. Thermoplastic polyurethane has such a diverse range of building blocks that this one polymer can be hydrophilic or hydrophobic. Yet, in spite of this versatility, it is only now finding utility in commercialised drug delivery systems. Separately then one polymer has a unique ability that differentiates it from the others and can be applied in a specific drug delivery application; but collectively these polymers provide a rich palette of material and drug delivery options to empower formulation scientists in meeting even the most demanding of unmet clinical needs. Therefore, these polymers have had a long history in controlled release, from the very beginning even, and it is pertinent that this review examines briefly this history while also detailing the state-of-the-art academic studies and inventions exploiting these materials. The paper also outlines the different production methods required to manufacture these solid dosage forms as many of the processes are uncommon to the wider pharmaceutical industry.