An investigation into the feasibility of Fused Deposition Modelling for 3D printing oral pharmaceuticals

Fused Deposition Modelling (FDM) is a variant of 3D Printing (3DP) that relies on the melt extrusion of thermoplastic polymers for the fabrication of objects. Using FDM, objects with customised geometries, mass, shapes, and dimensions can be printed on-demand. This customisability makes FDM a robust method for creating patient-tailored, personalised dosage forms. Therefore, the past few years have seen an increase in research demonstrating the use of FDM to produce solid dosage forms. Various research efforts have demonstrated the capacity of FDM to create dosage forms with customised geometries, tailored release profiles, and polypills containing multiple drugs. However, there remains no commercially available products are produced by FDM. This may be due to the absence of a Good Manufacturing Practices (GMP) compliant printer, and thus no approved manufacturing process utilising FDM. Furthermore, reported works describing the use of FDM as a pharmaceutical manufacturing process often employ a trial-and-error approach to arrive at a formulation, with little work demonstrating a thorough understanding of the FDM process and the involved parameter interactions as a whole. Parameters involved in the FDM process can be grouped into three main categories; material parameters (parameters relating to the material being printed), machine parameters (parameters relating to the particular model of printer), and process parameters (parameters are those relating to the particular printing process). The work presented herein describes an investigation into the parameters involved in FDM, and their impact on the perceived quality parameters of 3D printed solid dosage forms, which should help to guide towards a more rational approach towards FDM printable dosage forms. The work conducted herein investigated material properties (melt flow, and mechanical flexibility), and FDM process parameters (printing speed, printing temperature, and infill density) and their impact on perceived quality attributes of the printed dosage forms (filament printability, weight uniformity, dimensional uniformity, reproducibility, drug release rate, printing road width). Furthermore, some process parameter interactions were also identified and discussed

Impact of processing parameters on the quality of pharmaceutical solid dosage forms produced by fused deposition modelling (FDM)

Fused deposition modeling (FDM) 3D printing is being increasingly explored as a direct manufacturing method to product pharmaceutical solid dosage forms. Despite its many advantages as a pharmaceutical formulation tool, it remains restricted to proof-of-concept formulations. The optimization of the printing process in order to achieve adequate precision and printing quality remains to be investigated. Demonstrating a thorough understanding of the process parameters of FDM and their impact on the quality of printed dosage forms is undoubtedly necessary should FDM advance from a proof-of-concept stage to an adapted pharmaceutical manufacturing tool. This article describes the findings of an investigation into a number of critical process parameters of FDM and their impact on quantifiable, pharmaceutically-relevant measures of quality. Polycaprolactone, one of the few polymers which is both suitable for FDM and is a GRAS (generally regarded as safe) material, was used to print internally-exposed grids, allowing examination of both their macroscopic and microstructural reproducibility of FDM. Of the measured quality parameters, dimensional authenticity of the grids was found to poorly match the target dimensions. Weights of the grids were found to significantly vary upon altering printing speed. Printing temperature showed little effect on weight. Weight uniformity per batch was found to lie within acceptable pharmaceutical quality limits. Furthermore, we report observing a microstructural distortion relating to printing temperature which we dub The First Layer Effect (FLE). Principal Component Analysis (PCA) was used to study factor interactions and revealed, among others, the existence of an interaction between weight/dosing accuracy and dimensional authenticity dictating a compromise between the two quality parameters. The Summed Standard Deviation (SSD) is proposed as a method to extract the optimum printing parameters given all the perceived quality parameters and the necessary compromises among them

Development of a Simple Mechanical Screening Method for Predicting the Feedability of a Pharmaceutical FDM 3D Printing Filament

Purpose: The filament-based feeding mechanism employed by the majority of fused deposition modelling (FDM) 3D printers dictates that the materials must have very specific mechanical characteristics. Without a suitable mechanical profile, the filament can cause blockages in the printer. The purpose of this study was to develop a method to screen the mechanical properties of pharmaceutically-relevant, hot-melt extruded filaments to predetermine their suitability for FDM. Methods: A texture analyzer was used to simulate the forces a filament is subjected to inside the printer. The texture analyzer produced a force-distance curve referred to as the flexibility profile. Principal Component Analysis and Correlation Analysis statistical methods were then used to compare the flexibility profiles of commercial filaments to in-house made filaments. Results: Principal component analysis showed clearly separated clustering of filaments that suffer from mechanical defects versus filaments which are suitable for printing. Correlation scores likewise showed significantly greater values with feedable filaments than their mechanically deficient counterparts. Conclusion: The screening method developed in this study showed, with statistical significance and reproducibility, the ability to predetermine the feedability of extruded filaments into an FDM printer

Investigation of the mechanical properties of hot-melt extruded filaments for pharmaceutical applications of FDM

The advent of additive manufacturing techniques, namely Fused Deposition Modeling (FDM), holds many promising prospects for medical applications, from tailored polypills for personalized medicine to patient-specific implants. However, the lack of pharmaceutically-acceptable materials that possess suitable properties for FDM is the main issue standing in the way of turning FDM into a commercially viable process. And although a number of research efforts has demonstrated the feasibility of using blends of pharmaceutically relevant polymers to print pharmaceutical dosage forms, there remains littleto-no investigation into the critical parameters that govern the feasibility of an FDM process. Mechanical properties of the filament used in FDM is one such critical parameter; part of the filament feeding process involves rotating gears pushing the filament into a pinhole slit that leads on to the heating element of the printer. Trial and error attempts at feeding various inhouse prepared filaments to the printer revealed that filaments need to possess specific mechanical properties; filaments which are too brittle will fracture inside the print head causing a blockage, filaments which are too deformable will coil around the conveyer gears without threading into the melting zone. This presentation outlines an in-house developed method to identify the desired mechanical properties for FDM filament: A TA.XT 2 Texture Analyzer fitted with an in-house prepared rig loosely based on the spaghetti flexure rig was used to quantify forces required to deform a number of commercial and in-house filaments. Principal Component Analysis (PCA) was used to sort the data collected from the texture analysis and categorize the various filaments into feedable and non-feedable. The method was then employed to evaluate the feedability of an ibuprofen formulation to verify its suitability as a method to test the mechanical properties of filaments

Personalized Polypills Produced by Fused Deposition Modeling 3D Printing

Personalized medicine in the literature commonly refers to using patient's genetic information to enable therapeutic decisions tailored to an individual patient. Personalized pills containing more than one drug are referred as polypills, which is a term exclusively used in the treatment of cardiovascular diseases (CVD) in the literature, but the usage is expanded to cover a range of pills that combine many medicines to provide a single solid dosage form that allows the patients to self‐administer easily. Polypharmacy is used in the medical literature to describe the co‐administration of multiple medications to patients who may have multiple comorbidities. There are a number of critical process parameters (CPPs) controlling the quality of fused deposition modeling (FDM) 3D printing. Two common methods of preparing drug‐loaded filaments have been reported in the pharmaceutical literature: impregnation and extrusion. It has been widely recognized that FDM 3D printing has unique advantages for fabricating personalized polypills

Dissecting the stability of Atezolizumab with renewable amino acid-based ionic liquids:Colloidal stability and anticancer activity under thermal stress

Monoclonal antibodies (mAbs) have revolutionised the biopharmaceutical market. Being proteinaceous, mAbs are prone to chemical and physical instabilities. Various approaches were attempted to stabilise proteins against degradation factors. Ionic liquids (ILs) and deep eutectic solvents (DESs) have been established as green solvents for ever-increasing pharmaceutical and biopharmaceutical applications. Hence, amino acid (AA)-based ILs, were used for the first time, for mAb stabilisation. Choline (Ch)-based DESs were also utilised for comparison purposes. The prepared ILs and DESs were utilised to stabilise Atezolizumab (Amab, anti-PDL-1 mAb). The formulations of Amab in ILs and DESs were incubated at room temperature, 45 or 55 °C. Following this, the structural stability of Amab was appraised. Interestingly, Ch-Valine retained favourable structural stability of Amab with minimal detected aggregation or degradation as confirmed by UV–visible spectroscopy and protein Mass Spectroscopy. The measured hydrodynamic diameter of Amab in Ch-Valine ranged from 10.40 to 11.65 nm. More interestingly, the anticancer activity of Amab was evaluated, and Ch-Valine was found to be optimum in retaining the activity of Amab when compared to other formulations, including the control Amab sample. Collectively, this study has spotlighted the advantages of adopting the Ch-AA ILs for the structural and functional stabilising of mAbs

Dissecting the stability of Atezolizumab with renewable amino acid-based ionic liquids:Colloidal stability and anticancer activity under thermal stress

Monoclonal antibodies (mAbs) have revolutionised the biopharmaceutical market. Being proteinaceous, mAbs are prone to chemical and physical instabilities. Various approaches were attempted to stabilise proteins against degradation factors. Ionic liquids (ILs) and deep eutectic solvents (DESs) have been established as green solvents for ever-increasing pharmaceutical and biopharmaceutical applications. Hence, amino acid (AA)-based ILs, were used for the first time, for mAb stabilisation. Choline (Ch)-based DESs were also utilised for comparison purposes. The prepared ILs and DESs were utilised to stabilise Atezolizumab (Amab, anti-PDL-1 mAb). The formulations of Amab in ILs and DESs were incubated at room temperature, 45 or 55 °C. Following this, the structural stability of Amab was appraised. Interestingly, Ch-Valine retained favourable structural stability of Amab with minimal detected aggregation or degradation as confirmed by UV–visible spectroscopy and protein Mass Spectroscopy. The measured hydrodynamic diameter of Amab in Ch-Valine ranged from 10.40 to 11.65 nm. More interestingly, the anticancer activity of Amab was evaluated, and Ch-Valine was found to be optimum in retaining the activity of Amab when compared to other formulations, including the control Amab sample. Collectively, this study has spotlighted the advantages of adopting the Ch-AA ILs for the structural and functional stabilising of mAbs

Beneath the Skin: A Review of Current Trends and Future Prospects of Transdermal Drug Delivery Systems

The ideal drug delivery system has a bioavailability comparable to parenteral dosage forms but is as convenient and easy to use for the patient as oral solid dosage forms. In recent years, there has been increased interest in transdermal drug delivery (TDD) as a non-invasive delivery approach that is generally regarded as being easy to administer to more vulnerable age groups, such as paediatric and geriatric patients, while avoiding certain bioavailability concerns that arise from oral drug delivery due to poor absorbability and metabolism concerns. However, despite its many merits, TDD remains restricted to a select few drugs. The physiology of the skin poses a barrier against the feasible delivery of many drugs, limiting its applicability to only those drugs that possess physicochemical properties allowing them to be successfully delivered transdermally. Several techniques have been developed to enhance the transdermal permeability of drugs. Both chemical (e.g., thermal and mechanical) and passive (vesicle, nanoparticle, nanoemulsion, solid dispersion, and nanocrystal) techniques have been investigated to enhance the permeability of drug substances across the skin. Furthermore, hybrid approaches combining chemical penetration enhancement technologies with physical technologies are being intensively researched to improve the skin permeation of drug substances. This review aims to summarize recent trends in TDD approaches and discuss the merits and drawbacks of the various chemical, physical, and hybrid approaches currently being investigated for improving drug permeability across the skin

Effects of porosity on drug release kinetics of swellable and erodible porous pharmaceutical solid dosage forms fabricated by hot melt droplet deposition 3D printing

3D printing has the unique ability to produce porous pharmaceutical solid dosage forms on-demand. Although using porosity to alter drug release kinetics has been proposed in the literature, the effects of porosity on the swellable and erodible porous solid dosage forms have not been explored. This study used a model formulation containing hypromellose acetate succinate (HPMCAS), polyethylene oxide (PEO) and paracetamol and a newly developed hot melt droplet deposition 3D printing method, Arburg plastic free-forming (APF), to examine the porosity effects on in vitro drug release. This is the first study reporting the use of APF on 3D printing porous pharmaceutical tablets. With the unique pellet feeding mechanism of APF, it is important to explore its potential applications in pharmaceutical additive manufacturing. The pores were created by altering the infill percentages (%) of the APF printing between 20 and 100% to generate porous tablets. The printing quality of these porous tablets was examined. The APF printed formulation swelled in pH 1.2 HCl and eroded in pH 6.8 PBS. During the dissolution at pH 1.2, the swelling of the printing pathway led to the gradual decreases in the open pore area and complete closure of pores for the tablets with high infills. In pH 6.8 buffer media, the direct correlation between drug release rate and infills was observed for the tablets printed with infill at and less than 60%. The results revealed that drug release kinetics were controlled by the complex interplay of the porosity and dynamic changes of the tablets caused by swelling and erosion. It also implied the potential impact of fluid hydrodynamics on the in vitro data collection and interpretation of porous solids

Effects of porosity on drug release kinetics of swellable and erodible porous pharmaceutical solid dosage forms fabricated by hot melt droplet deposition 3D printing

3D printing has the unique ability to produce porous pharmaceutical solid dosage forms on-demand. Although using porosity to alter drug release kinetics has been proposed in the literature, the effects of porosity on the swellable and erodible porous solid dosage forms have not been explored. This study used a model formulation containing hypromellose acetate succinate (HPMCAS), polyethylene oxide (PEO) and paracetamol and a newly developed hot melt droplet deposition 3D printing method, Arburg plastic free-forming (APF), to examine the porosity effects on in vitro drug release. This is the first study reporting the use of APF on 3D printing porous pharmaceutical tablets. With the unique pellet feeding mechanism of APF, it is important to explore its potential applications in pharmaceutical additive manufacturing. The pores were created by altering the infill percentages (%) of the APF printing between 20 to 100% to generate porous tablets. The printing quality of these porous tablets were examined. The APF printed formulation swelled in pH 1.2 HCl and eroded in pH 6.8 PBS. During the dissolution at pH 1.2, the swelling of the printing pathway led to the gradual decreases in the open pore area and complete closure of pores for the tablets with high infills. In pH 6.8 buffer media, the direct correlation between drug release rate and infills was observed for the tablets printed with infill at and less than 60%. The results revealed that drug release kinetics were controlled by the complex interplay of the porosity and dynamic changes of the tablets caused by swelling and erosion. It also implied the potential impact of fluid hydrodynamics on the in vitro data collection and interpretation of porous solids