International Journal of Pharmaceutics (v.494, #2)

Foreword: SI printing pharmaceuticals by A. Buanz; S. Gaisford; S. Hilton (553).

Inkjet printing for pharmaceutics – A review of research and manufacturing by Ronan Daly; Tomás S. Harrington; Graham D. Martin; Ian M. Hutchings (554-567).
Display OmittedGlobal regulatory, manufacturing and consumer trends are driving a need for change in current pharmaceutical sector business models, with a specific focus on the inherently expensive research costs, high-risk capital-intensive scale-up and the traditional centralised batch manufacturing paradigm. New technologies, such as inkjet printing, are being explored to radically transform pharmaceutical production processing and the end-to-end supply chain. This review provides a brief summary of inkjet printing technologies and their current applications in manufacturing before examining the business context driving the exploration of inkjet printing in the pharmaceutical sector. We then examine the trends reported in the literature for pharmaceutical printing, followed by the scientific considerations and challenges facing the adoption of this technology. We demonstrate that research activities are highly diverse, targeting a broad range of pharmaceutical types and printing systems. To mitigate this complexity we show that by categorising findings in terms of targeted business models and Active Pharmaceutical Ingredient (API) chemistry we have a more coherent approach to comparing research findings and can drive efficient translation of a chosen drug to inkjet manufacturing.
Keywords: Inkjet; Drop-on-demand; Continuous inkjet; Pharmaceutical printing; Continuous manufacturing;

Personalised dosing: Printing a dose of one’s own medicine by Mustafa Alomari; Fatima H. Mohamed; Abdul W. Basit; Simon Gaisford (568-577).
Display OmittedInk-jet printing is a versatile, precise and relatively inexpensive method of depositing small volumes of solutions with remarkable accuracy and repeatability. Although developed primarily as a technology for image reproduction, its areas of application have expanded significantly in recent years. It is particularly suited to the manufacture of low dose medicines or to short production runs and so offers a potential manufacturing solution for the paradigm of personalised medicines. This review discusses the technical and clinical aspects of ink-jet printing that must be considered in order for the technology to become widely adopted in the pharmaceutical arena and considers applications in the literature.
Keywords: Ink-jet printing; Pharmaceutical; Narrow therapeutic index; Personalised medicine; Piezoelectric printer;

Perspective: Concepts of printing technologies for oral film formulations by Maren Preis; Joerg Breitkreutz; Niklas Sandler (578-584).
Display OmittedDifferent types of printing methods have recently attracted interest as emerging technologies for fabrication of drug delivery systems. If printing is combined with different oral film manufacturing technologies such as solvent casting and other techniques, multifunctional structures can be created to enable further complexity and high level of sophistication. This review paper intends to provide profound understanding and future perspectives for the potential use of printing technologies in the preparation of oral film formulations as novel drug delivery systems. The described concepts include advanced multi-layer coatings, stacked systems, and integrated bioactive multi-compartments, which comprise of integrated combinations of diverse materials to form sophisticated bio-functional constructs. The advanced systems enable tailored dosing for individual drug therapy, easy and safe manufacturing of high-potent drugs, development and manufacturing of fixed-dose combinations and product tracking for anti-counterfeiting strategies.
Keywords: Printing; Flexography; Inkjet; Oral film preparations; Personalized medicine;

Printing technologies for biomolecule and cell-based applications by Petri Ihalainen; Anni Määttänen; Niklas Sandler (585-592).
Display OmittedBiomolecules, such as enzymes, proteins and other biomacromolecules (polynucleotides, polypeptides, polysaccharides and DNA) that are immobilized on solid surfaces are relevant to many areas of science and technology. These functionalized surfaces have applications in biosensors, chromatography, diagnostic immunoassays, cell culturing, DNA microarrays and other analytical techniques. Printing technologies offer opportunities in this context. The main interests in printing biomolecules are in immobilizing them on surfaces for sensors and catalysts or for controlled delivery of protein-based drugs. Recently, there have been significant developments in the use of inkjet printing for dispensing of proteins, biomacromolecules and cells. This review discusses the use of roll-to-roll and inkjet printing technologies in manufacturing of biomolecule and cell-based applications.
Keywords: Printing; Enzymes; Proteins; Biomacromolecules; Inkjet; Roll-to-roll printing;

Inkjet printing of transdermal microneedles for the delivery of anticancer agents by Md Jasim Uddin; Nicolaos Scoutaris; Pavlos Klepetsanis; Babur Chowdhry; Mark R. Prausnitz; Dennis Douroumis (593-602).
Display OmittedA novel inkjet printing technology is introduced as a process to coat metal microneedle arrays with three anticancer agents 5-fluororacil, curcumin and cisplatin for transdermal delivery. The hydrophilic graft copolymer Soluplus® was used as a drug carrier and the coating formulations consisted of drug–polymer solutions at various ratios. A piezoelectric dispenser jetted microdroplets on the microneedle surface to develop uniform, accurate and reproducible coating layers without any material losses. Inkjet printing was found to depend on the nozzle size, the applied voltage (mV) and the duration of the pulse (μs). The drug release rates were determined in vitro using Franz type diffusion cells with dermatomed porcine skin. The drug release rates depended on the drug–polymer ratio, the drug lipophilicity and the skin thickness. All drugs presented increased release profiles (750 μm skin thickness), which were retarded for 900 μm skin thickness. Soluplus assisted the drug release especially for the water insoluble curcumin and cisplatin due to its solubilizing capacity. Inkjet printing has been shown to be an effective technology for coating of metal microneedles which can then be used for further transdermal drug delivery applications.
Keywords: Inkjet printing; Microneedles; Release; Transdermal delivery; Anticancer drugs;

Fabrication of drug-loaded edible carrier substrates from nanosuspensions by flexographic printing by Mirja Palo; Ruzica Kolakovic; Timo Laaksonen; Anni Määttänen; Natalja Genina; Jarno Salonen; Jouko Peltonen; Niklas Sandler (603-610).
Display OmittedThe main goal of the current work was to investigate the possible use of flexographic printing for the conversion of nanosuspensions into solid dosage forms. Aqueous nanosuspensions of indomethacin (IND) and itraconazole (ITR) with Poloxamer 407 as the stabilizer agent were prepared by wet ball-milling. The nanosuspensions were flexographically printed on three different substrates, including two commercially available edible substrates. The printed formulations were characterized with X-ray diffractometry (XRD) and scanning electron microscopy (SEM). In addition, dissolution studies for the printed IND and ITR formulations were conducted. The mean particle size of milled nanosuspensions of IND and ITR was 422.6 ± 7.7 nm and 698.1 ± 14.0 nm, respectively. The SEM imaging showed even distribution of nanosuspensions on the substrates after printing without any evident agglomeration. The printed formulations contained drug at least partially in crystalline form. The drug dissolution rate from the prepared formulations was improved compared to the pure drug. The drug release from the preparations on edible substrates was slightly slower due to the incorporation of the drug particles into the substrate matrix. In conclusion, the results indicated that flexographic printing can be considered as a promising fabrication method of solid nanoparticulate systems with enhanced dissolution behavior.
Keywords: Ball-milling; Nanoparticles; Flexographic printing; Indomethacin; Itraconazole;

Ink-jet printing versus solvent casting to prepare oral films: Effect on mechanical properties and physical stability by Asma B.M. Buanz; Claudia C. Belaunde; Nina Soutari; Catherine Tuleu; Mine Orlu Gul; Simon Gaisford (611-618).
Display OmittedThe aim of this work was to compare and contrast the mechanical properties and physical stabilities of oral films prepared with either thermal ink-jet printing (TIJP) or solvent casting (SC). Clonidine hydrochloride was selected as a model drug because of its low therapeutic dose and films were prepared using cellulose polymers. Mechanical testing showed that the printed films had Young’s moduli and tensile strength values similar to the free film, while casted films were significantly more brittle. The drug also appeared to crystallize out of casted films during stress testing whereas printed films remained unchanged. The dissolution behavior of printed and cast films were similar, because of the rapid disintegration of the polymer. The conclusion is that printing resulted in a better film than casting because the drug resided on the film, rather than in the film where it could exert a plasticizing effect.
Keywords: Thermal ink-jet printing; Oral films; Clonidine; Dynamic mechanical analysis; Critical humidity;

Taste masked thin films printed by jet dispensing by Nikolaos Scoutaris; Martin Snowden; Dennis Douroumis (619-622).
Display OmittedTaste masking of bitter active substances is an emerging area in the pharmaceutical industry especially for paediatric/geriatric medications. In this study we introduce the use of jet dispensing as a taste masking technology by printing mucosal thin films of three model bitter substances, Cetirizine HCl, Diphenylhydramine HCl and Ibuprofen. The process was used to dispense aqueous drugs/polymer solutions at very high speed where eventually the drugs were embedded in the polymer matrix. The in vivo evaluation of jet-dispensed mucosal films showed excellent taste masking for drug loadings from 20 to 40%. Jet dispensing was proved to make uniform, accurate and reproducible thin films with excellent content uniformity.
Keywords: Jet dispensing; Printing; Taste masking; Water insoluble drugs;

Rheology as a tool for evaluation of melt processability of innovative dosage forms by Johanna Aho; Johan P. Boetker; Stefania Baldursdottir; Jukka Rantanen (623-642).
Display OmittedFuture manufacturing of pharmaceuticals will involve innovative use of polymeric excipients. Hot melt extrusion (HME) is an already established manufacturing technique and several products based on HME are on the market. Additionally, processing based on, e.g., HME or three dimensional (3D) printing, will have an increasingly important role when designing products for flexible dosing, since dosage forms based on compacting of a given powder mixture do not enable manufacturing of optimal pharmaceutical products for personalized treatments. The melt processability of polymers and API–polymer mixtures is highly dependent on the rheological properties of these systems, and rheological measurements should be considered as a more central part of the material characterization tool box when selecting suitable candidates for melt processing by, e.g., HME or 3D printing. The polymer processing industry offers established platforms, methods, and models for rheological characterization, and they can often be readily applied in the field of pharmaceutical manufacturing. Thoroughly measured and calculated rheological parameters together with thermal and mechanical material data are needed for the process simulations which are also becoming increasingly important. The authors aim to give an overview to the basics of rheology and summarize examples of the studies where rheology has been utilized in setting up or evaluating extrusion processes. Furthermore, examples of different experimental set-ups available for rheological measurements are presented, discussing each of their typical application area, advantages and limitations.
Keywords: Rheology; Rheometry; Hot melt extrusion; 3D printing; Process design; Polymers;

3D printing of tablets containing multiple drugs with defined release profiles by Shaban A. Khaled; Jonathan C. Burley; Morgan R. Alexander; Jing Yang; Clive J. Roberts (643-650).
Display OmittedWe have employed three-dimensional (3D) extrusion-based printing as a medicine manufacturing technique for the production of multi-active tablets with well-defined and separate controlled release profiles for three different drugs. This ‘polypill’ made by a 3D additive manufacture technique demonstrates that complex medication regimes can be combined in a single tablet and that it is viable to formulate and ‘dial up’ this single tablet for the particular needs of an individual. The tablets used to illustrate this concept incorporate an osmotic pump with the drug captopril and sustained release compartments with the drugs nifedipine and glipizide. This combination of medicines could potentially be used to treat diabetics suffering from hypertension. The room temperature extrusion process used to print the formulations used excipients commonly employed in the pharmaceutical industry. Attenuated Total Reflectance Fourier Transform Infrared Spectroscopy (ATR-FTIR) and X-ray powder diffraction (XRPD) were used to assess drug–excipient interaction. The printed formulations were evaluated for drug release using USP dissolution testing. We found that the captopril portion showed the intended zero order drug release of an osmotic pump and noted that the nifedipine and glipizide portions showed either first order release or Korsmeyer–Peppas release kinetics dependent upon the active/excipient ratio used.
Keywords: 3D printing; Multi-active tablets; Osmotic pump; Sustained release; Personalised medicine;

Display OmittedThe cost of 3D printing has reduced dramatically over the last few years and is now within reach of many scientific laboratories. This work presents an example of how 3D printing can be applied to the development of custom laboratory equipment that is specifically adapted for use with the novel brain tissue clearing technique, CLARITY. A simple, freely available online software tool was used, along with consumer-grade equipment, to produce a brain slicing chamber and a combined antibody staining and imaging chamber. Using standard 3D printers we were able to produce research-grade parts in an iterative manner at a fraction of the cost of commercial equipment. 3D printing provides a reproducible, flexible, simple and cost-effective method for researchers to produce the equipment needed to quickly adopt new methods.
Keywords: 3D printing; Additive manufacturing; Optical clearing; CLARITY;

Effect of geometry on drug release from 3D printed tablets by Alvaro Goyanes; Pamela Robles Martinez; Asma Buanz; Abdul W. Basit; Simon Gaisford (657-663).
Display OmittedThe aim of this work was to explore the feasibility of combining hot melt extrusion (HME) with 3D printing (3DP) technology, with a view to producing different shaped tablets which would be otherwise difficult to produce using traditional methods. A filament extruder was used to obtain approx. 4% paracetamol loaded filaments of polyvinyl alcohol with characteristics suitable for use in fused-deposition modelling 3DP. Five different tablet geometries were successfully 3D-printed—cube, pyramid, cylinder, sphere and torus. The printing process did not affect the stability of the drug. Drug release from the tablets was not dependent on the surface area but instead on surface area to volume ratio, indicating the influence that geometrical shape has on drug release. An erosion-mediated process controlled drug release. This work has demonstrated the potential of 3DP to manufacture tablet shapes of different geometries, many of which would be challenging to manufacture by powder compaction.
Keywords: 3D printing; Controlled-release; Fused deposition modeling; PVA; paracetamol; Hot melt extrusion;