Basel Arafat

Emergence of 3D Printed Dosage Forms: Opportunities and Challenges

The recent introduction of the first FDA approved 3D-printed drug has fuelled interest in 3D printing technology, which is set to revolutionize healthcare. Since its initial use, this rapid prototyping (RP) technology has evolved to such an extent that it is currently being used in a wide range of applications including in tissue engineering, dentistry, construction, automotive and aerospace. However, in the pharmaceutical industry this technology is still in its infancy and its potential yet to be fully explored. This paper presents various 3D printing technologies such as stereolithographic, powder based, selective laser sintering, fused deposition modelling and semi-solid extrusion 3D printing. It also provides a comprehensive review of previous attempts at using 3D printing technologies on the manufacturing dosage forms with a particular focus on oral tablets. Their advantages particularly with adaptability in the pharmaceutical field have been highlighted, which enables the preparation of dosage forms with complex designs and geometries, multiple actives and tailored release profiles. An insight into the technical challenges facing the different 3D printing technologies such as the formulation and processing parameters is provided. Light is also shed on the different regulatory challenges that need to be overcome for 3D printing to fulfil its real potential in the pharmaceutical industry.

Adaptation of pharmaceutical excipients to FDM 3D printing for the fabrication of patient-tailored immediate release tablets

This work aims to employ fused deposition modelling 3D printing to fabricate immediate release pharmaceutical tablets with several model drugs. It investigates the addition of non-melting filler to methacrylic matrix to facilitate FDM 3D printing and explore the impact of (i) the nature of filler, (ii) compatibility with the gears of the 3D printer and iii) polymer: filler ratio on the 3D printing process. Amongst the investigated fillers in this work, directly compressible lactose, spray-dried lactose and microcrystalline cellulose showed a level of degradation at 135°C whilst talc and TCP allowed consistent flow of the filament and a successful 3D printing of the tablet. A specially developed universal filament based on pharmaceutically approved methacrylic polymer (Eudragit EPO) and thermally stable filler, TCP (tribasic calcium phosphate) was optimised. Four model drugs with different physicochemical properties were included into ready-to-use mechanically stable tablets with immediate release properties. Following the two thermal processes (hot melt extrusion (HME) and fused deposition modelling (FDM) 3D printing), drug contents were 94.22%, 88.53%, 96.51% and 93.04% for 5-ASA, captopril, theophylline and prednisolone respectively. XRPD indicated that a fraction of 5-ASA, theophylline and prednisolone remained crystalline whilst captopril was in amorphous form. By combining the advantages of thermally stable pharmaceutically approved polymers and fillers, this unique approach provides a low cost production method for on demand manufacturing of individualised dosage forms.

Channelled tablets: An innovative approach to accelerating drug release from 3D printed tablets

Abstract Conventional immediate release dosage forms involve compressing the powder with a disintegrating agent that enables rapid disintegration and dissolution upon oral ingestion. Among 3D printing technologies, the fused deposition modelling (FDM) 3D printing technique has a considerable potential for patient‐specific dosage forms. However, the use of FDM 3D printing in tablet manufacturing requires a large portion of polymer, which slows down drug release through erosion and diffusion mechanisms. In this study, we demonstrate for the first time the use of a novel design approach of caplets with perforated channels to accelerate drug release from 3D printed tablets. This strategy has been implemented using a caplet design with perforating channels of increasing width (0.2, 0.4, 0.6, 0.8 or 1.0 mm) and variable length, and alignment (parallel or at right angle to tablet long axis). Hydrochlorothiazide (BCS class IV drug) was chosen as the model drug as enhanced dissolution rate is vital to guarantee oral bioavailability. The inclusion of channels exhibited an increase in the surface area/volume ratio, however, the release pattern was also influenced by the width and the length of the channel. A channel width was ≥ 0.6 mm deemed critical to meet the USP criteria of immediate release products. Shorter multiple channels (8.6 mm) were more efficient at accelerating drug release than longer channels (18.2 mm) despite having comparable surface area/mass ratio. This behaviour may be linked to the reduced flow resistance within the channels and the faster fragmentation during dissolution of these tablets. In conclusion, the width and length of the channel should be carefully considered in addition to surface area/mass when optimizing drug release from 3D printed designs. The incorporation of short channels can be adopted in the designs of dosage forms, implants or stents to enhance the release rate of eluting drug from polymer‐rich structures. Graphical abstract Figure. No Caption available.

A study of the effects of sodium halides on the performance of air-jet and vibrating-mesh nebulizers.

The influence of sodium halide electrolytes on aerosols generated from the Aeroneb Pro vibrating mesh nebulizer and the Sidestream air-jet nebulizer has been evaluated. Fluids with a range of concentrations of Na halides (i.e. NaF, NaCl, NaBr and NaI) were used as nebulizer solutions and their effect on aerosol properties such as total aerosol output, fine particle fraction (FPF), volume median diameter (VMD) and predicted regional airway deposition were investigated. For both nebulizers, the inclusion of electrolyte significantly enhanced the aerosol properties compared with HPLC grade (deionized) water. Aerosol output, FPF and aerosol fraction less than 2.15 μm were directly proportional to electrolyte concentration. Furthermore, the proportion of aerosols that are likely to deposit in the oropharyngeal region, and the VMD of the droplets were inversely related to the electrolyte concentration for both nebulizers. In general, the inclusion of electrolytes had a greater impact on the aerosol properties of the vibrating-mesh nebulizer. In the Aeroneb Pro, NaI 2.0% (w/v) was the optimum solution as it generated the highest aerosol output, FPF and output fraction below 2.15 μm with the lowest VMD and minimal predicted oropharyngeal deposition. This was attributed to the polarizing ability of iodide ions present in the largest quantity at the air-water interface. This study has shown that the Aeroneb Pro vibrating-mesh device demonstrated greatly enhanced aerosol properties when halides were included in the nebulizer solutions.

Extraction and RP-HPLC determination of taxol in rat plasma, cell culture and quality control samples

A rapid, sensitive, selective and validated reverse phase high-performance liquid chromatography (RP-HPLC) method for the estimation of paclitaxel in micro-sample of rat plasma and in culture of cancer cells was performed in this study. The mobile phase consisted of an optimized mixture of methanol:water: trifluroacetic acid (80: 20: 0.1, v/v/v). Column elution at a flow rate of 1 mL/minute with UV detection at 225 nm at room temperature was used. The RP-HPLC method was successfully applied for the determination of paclitaxel in plasma samples and in culture of cancer cells with nano-quantity of estimation. The validation studies were performed in accordance with the International Conference on Harmonization (ICH) guidelines. The intra- and inter-day precision showed that the coefficients of variation ranged from 1.07% to 4.27% at different levels of concentrations. To the best of our knowledge, this study also reported for the first time the optimization of different solvents for effective extraction of paclitaxel wherein tert.-butyl methyl ether (TBME): diethyl ether (DEE) in 50: 50 v/v composition was found most efficient with extraction efficiency ranging between 77.99% and 91.74% and between 76.14 and 93.66% in the plasma and cell culture, respectively. This proposed method was successfully applied to study the pharmacokinetics of paclitaxel and the influence of verapamil and all-trans retinoic acid (atRA) on paclitaxel pharmacokinetics in rat models. This proposed method might emerge as a valuable aid in the laboratory monitoring of paclitaxel in a variety of in vitro as well as in vivo scenarios.

Tablet fragmentation without a disintegrant: A novel design approach for accelerating disintegration and drug release from 3D printed cellulosic tablets

&NA; Fused deposition modelling (FDM) 3D printing has shown the most immediate potential for on‐demand dose personalisation to suit particular patients needs. However, FDM 3D printing often involves employing a relatively large molecular weight thermoplastic polymer and results in extended release pattern. It is therefore essential to fast‐track drug release from the 3D printed objects. This work employed an innovative design approach of tablets with unique built‐in gaps (Gaplets) with the aim of accelerating drug release. The novel tablet design is composed of 9 repeating units (blocks) connected with 3 bridges to allow the generation of 8 gaps. The impact of size of the block, the number of bridges and the spacing between different blocks was investigated. Increasing the inter‐block space reduced mechanical resistance of the unit, however, tablets continued to meet pharmacopeial standards for friability. Upon introduction into gastric medium, the 1mm spaces gaplet broke into mini‐structures within 4min and met the USP criteria of immediate release products (86.7% drug release at 30min). Real‐time ultraviolet (UV) imaging indicated that the cellulosic matrix expanded due to swelling of hydroxypropyl cellulose (HPC) upon introduction to the dissolution medium. This was followed by a steady erosion of the polymeric matrix at a rate of 8&mgr;m/min. The design approach was more efficient than a comparison conventional formulation approach of adding disintegrants to accelerate tablet disintegration and drug release. This work provides a novel example where computer‐aided design was instrumental at modifying the performance of solid dosage forms. Such an example may serve as the foundation for a new generation of dosage forms with complicated geometric structures to achieve functionality that is usually achieved by a sophisticated formulation approach. Graphical abstract: Symbol. No Caption available.

Tailored on demand anti-coagulant dosing: An in vitro and in vivo evaluation of 3D printed purpose-designed oral dosage forms

Graphical abstract Figure. No caption available. Abstract Coumarin therapy has been associated with high levels of inter‐ and intra‐individual variation in the required dose to reach a therapeutic anticoagulation outcome. Therefore, a dynamic system that is able to achieve accurate delivery of a warfarin dose is of significant importance. Here we assess the ability of 3D printing to fabricate and deliver tailored individualised precision dosing using in‐vitro and in‐vivo models. Sodium warfarin loaded filaments were compounded using hot melt extrusion (HME) and further fabricated via fused deposition modelling (FDM) 3D printing to produce capsular‐ovoid‐shaped dosage forms loaded at 200 or 400 &mgr;g dose. The solid dosage forms and comparator warfarin aqueous solutions were administered by oral gavage to Sprague–Dawley rats. A novel UV imaging approach indicated that the erosion of the methacrylate matrix was at a rate of 16.4 and 15.2 &mgr;m/min for horizontal and vertical planes respectively. In vivo, 3D printed forms were as proportionately effective as their comparative solution form in doubling plasma exposure following a doubling of warfarin dose (184% versus 192% respectively). The 3D printed ovoids showed a lower Cmax of warfarin (1.51 and 3.33 mg/mL versus 2.5 and 6.44 mg/mL) and a longer Tmax (6 and 3.7 versus 4 and 1.5 h) in comparison to liquid formulation. This work demonstrates for the first time in vivo, the potential of FDM 3D printing to produce a tailored specific dosage form and to accurately titrate coumarin dose response to an individual patient.