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The aim of this study was to investigate new porous flexible substrates, i.e., solid foams that would serve as a carrier with a high ink absorption potential for inkjet printable pharmaceuticals. Propranolol hydrochloride was used as a model active pharmaceutical ingredient (API). Pharmaceutically approved and edible cellulose derivatives and gums together with different additives were evaluated as a base for the substrate. Different methods for preparation of a solid foam such as freeze-drying, vacuum oven drying and drying at room temperature were explored. Only freeze-drying of the polymeric solutions resulted in the desired porous and flexible, but mechanically stable, soft sponge-like substrates with hydroxypropyl methylcellulose (HPMC)-based solid foams being the most suitable for the use in continuous inkjet printing. The plasticized HPMC foams had a superior absorption capacity and fast penetration speed for the different solvents due to the open cell pore structure and higher porosity as compared to nonplasticized additive-free foams, although, the latter were less hygroscopic. The produced solid foams were well suited for inkjet printing of high volumes of API-containing ink. The inkjet-printed API was immediately released from the dosage forms upon contact with the dissolution medium. This work demonstrates that the fabricated solid foams, based on plasticized HPMC, show a great potential as porous carriers in the fabrication of high dose dosage forms by inkjet printing.

The potential of fused filament fabrication (FFF) for the administration of active pharmaceutical compounds is a recent approach to develop complex and custom-made drug delivery systems (DDSs). However, the FFF technology is characterized by certain limitations, which are associated with the nature of the process, i.e., the required mechanical properties of the feedstock, as well as the thermal stability of the incorporated polymers, excipients and active compounds. Thus, hybrid DDSs have been recently introduced, to overcome these boundaries. The concept of these systems is defined by the effective coupling of FFF with conventional manufacturing technologies, as a novel pathway to expand the available pool of raw materials and pharmaceutical applications of FFF.

The aim of this study was to introduce a fast and reliable differential scanning calorimetry (DSC)-based method to determine the monomolecular loading capacity of drugs with good glass-forming ability in mesoporous silica (MS). The proposed method is based on a solvent-free melting/fusion of drug into the MS during a heat-cool-heat cycle in the DSC. Overloaded drug-MS systems were analyzed in the DSC at different drug ratios (50, 60, 70, 80 and 90% w/w) to quantify the excess drug in the (the fraction not adsorbed to the MS surface). During the first heating, the drug will melt and fuse into the pores of the MS and upon subsequent quench cooling, the drug that is not adsorbed to the surface of the MS will amorphize into a separate phase (as drugs with good glass-forming ability do not crystallize upon quench-cooling from the melt). The drug molecules adsorbed to the MS surface are "immobilized" and will not contribute to a glass transition in the DSC and thus, the excess drug can be quantified simply by determining the change in the heat capacity over the glass transition (ΔCp). Since the ΔCp of overloaded samples decrease linearly with decreasing drug content, the monomolecular loading capacity of the drug in the MS can be determined by extrapolating to zero ΔCp. This value corresponds to the highest drug load at which the drug is monomolecularly adsorbed to the surface of the MS and has no drug-related thermal events (glass transition), i.e. a thermodynamically stable system. Using this method, it was possible to determine the monomolecular loading capacity of four drugs with good glass-forming ability in four different MS. These determinations were in good agreement with the physical stability of the systems during an accelerated stability study, which indicates that the thermoanalytical method enabled fast and reliable determination of the monomolecular loading capacity of drugs in MS.

The purpose of this study was to investigate the applicability of Raman spectroscopy for visualization and quantification of inkjet-printed pharmaceuticals. Haloperidol was used as a model active pharmaceutical ingredient (API), and a printable ink base containing lactic acid and ethanol was developed. Inkjet printing technology was used to apply haloperidol ink onto three different substrates. Custom-made inorganic compacts and dry foam, as well as marketed paracetamol tablets were used as the substrates. Therapeutic personalized doses were printed by using one to ten printing rounds on the substrates. The haloperidol content in the finished dosage forms were determined by high-performance liquid chromatography (HPLC). The distribution of the haloperidol on the dosage forms were visualized using Raman chemical imaging combined with principal components analysis (PCA). Raman spectroscopy combined with modeling by partial least squares (PLS) regression was used for establishment of a quantitative model of the haloperidol content in the printed dosage forms. A good prediction of the haloperidol content was achieved for the inorganic compacts, while a slightly poorer prediction was observed for the paracetamol tablets. It was not possible to quantify haloperidol on the dry foam due to the low and varying density of the substrate. Raman spectroscopy is a useful tool for visualization and quality control of inkjet printed personalized medicine.

Mohammed Al-Sharabi's affiliation was incorrect at the time of publishing. The updated affiliation appears below.

The use of inkjet printing for pharmaceutical manufacturing is gaining interest for production of personalized dosage forms tailored to specific patients. As part of the manufacturing, it is imperative to ensure that the correct dose is printed. The aim of this study was to use inkjet printing for manufacturing of personalized dosage forms combined with the use of near-infrared (NIR) and Raman spectroscopy as complementary analytical techniques for active pharmaceutical ingredient (API) quantification of the inkjet-printed dosage forms. Three APIs, propranolol (0.5–4.1 mg), montelukast (2.1–12.1 mg), and haloperidol (0.6–4.1 mg) were inkjet printed in 1 cm2 areas on a porous substrate. The printed doses were non-destructively analyzed by transmission NIR and Raman spectroscopy (both transmission and backscatter). X-ray computed microtomography (μ-CT) analysis was undertaken for porosity measurements of the substrate. The API content was confirmed using high-performance liquid chromatography (HPLC), and the content in the dosage forms was modeled from the NIR and Raman spectra using partial least squares regression (PLS). HPLC analysis revealed a linear correlation of the number of layers printed to the API content. The resulting PLS models for both NIR and Raman had R2 values between 0.95 and 0.99. The best predictive model was obtained using NIR, followed by Raman spectroscopy. μ-CT revealed the substrate to be highly porous and optimal for inkjet printing. In conclusion, NIR and Raman spectroscopic techniques could be used complementary as fast API quantification tools for inkjet-printed medicines.

The main purpose of this work was to investigate the printability of different grades of ethylene vinyl acetate (EVA) copolymers as new feedstock material for fused-deposition modeling (FDM™)-based 3D printing technology in fabrication of custom-made T-shaped intrauterine systems (IUS) and subcutaneous rods (SR). The goal was to select an EVA grade with optimal properties, namely vinyl acetate content, melting index, flexural modulus, for 3D printing of implantable prototypes with the drug incorporated within the entire matrix of the medical devices. Indomethacin was used as a model drug in this study. Out of the twelve tested grades of the EVA five were printable. One of them showed superior print quality and was further investigated by printing drug-loaded filaments, containing 5% and 15% indomethacin. The feedstock filaments were fabricated by hot-melt extrusion (HME) below the melting point of the drug substance and the IUS and SR were successfully printed at the temperature above the melting point of the drug. As a result, the drug substance in the printed prototypes showed to be at least partly amorphous, while the drug in the corresponding HME filaments was crystalline. This difference affected the drug release profiles from the filaments and printed prototype products: faster release from the prototypes over 30days in the in vitro tests. To conclude, this study indicates that certain grades of EVA were applicable feedstock material for 3D printing to produce drug-loaded implantable prototypes.

Development of new product design principles is crucial for obtaining pharmaceutical products with controlled functionality. Four different molds were designed using a computer-aided design (CAD) software and 3D printed with polylactic acid (PLA). A hydroxypropyl methylcellulose (HPMC) and polyethylene glycol (PEG)-based formulation containing indomethacin as the active pharmaceutical ingredient (API) was casted into the molds. Each mold produced a tablet that was designed to disintegrate into a defined number of sections (2, 4, and 6). This was achieved by incorporating break lines (regions that were significantly thinner than the remainder of the tablet) to control the disintegration process. Disintegration and drug release from these designed tablets was contrasted with a casted tablet without break lines. Disintegration studies confirmed that the casted tablets disintegrated according to their design. Drug-release studies meanwhile demonstrated that tablets with a greater number of sections released the API at a faster rate than those with fewer sections; for example, the 6-sectioned tablet released the API at twice the rate of the tablet without any break lines. It is expected that by using this concept, it would be possible to produce tablets with a designed disintegration profile, which could potentially allow the tailoring of the drug release.

Application of additive manufacturing techniques (3D printing) for mass-customized products has boomed in the recent years. In pharmaceutical industry and research, the interest has grown particularly with the future scenario of more personalized medicinal products. Understanding a broad range of material properties and process behavior of the drug-excipient combinations is necessary for successful 3D printing of dosage forms. This commentary reviews recent 3D-printing studies by fused deposition modeling (FDM) technique in pharmaceutical sciences, extending into the fields of polymer processing and rapid prototyping, where more in-depth studies on the feedstock material properties, modeling, and simulation of the FDM process have been performed. A case study of a model oral dosage form from custom-prepared indomethacin-polycaprolactone feedstock filament was used as an example in the pharmaceutical context. The printability was assessed in the different process steps: preparation of customized filaments for FDM, filament feeding, deposition, and solidification. These were linked with the rheological, thermal, and mechanical properties and their characterization, relevant for understanding the printability of drug products by FDM.

The 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.

The aim of this study is to explore hot melt extrusion (HME) as a solvent-free drug loading technique for preparation of stable amorphous solid dispersions using mesoporous silica (PSi). Ibuprofen and carvedilol were used as poorly soluble active pharmaceutical ingredients (APIs). Due to the high friction of an API:PSi mixture below the loading limit of the API, it was necessary to add the polymer Soluplus® (SOL) in order to enable the extrusion process. As a result, the APIs were distributed between the PSi and SOL phase after HME. Due to its higher affinity to PSi, ibuprofen was mainly adsorbed into the PSi, whereas carvedilol was mainly found in the SOL phase. Intrinsic dissolution rate was highest for HME formulations, containing PSi, compared to pure crystalline (amorphous) APIs and HME formulations without PSi. HME is a feasible solvent-free drug loading technique for preparation of PSi-based amorphous solid dispersions.

The main goal of the present study was to evaluate applicability of the different model substrates, namely orodispersible films (ODFs), porous copy paper sheets, and water impermeable transparency films (TFs) in preparation of the inkjet-printed drug-delivery systems. Rasagiline mesylate (RM) was used as a low-dose active pharmaceutical ingredient (API). Flexible doses of the drug in a single unit were obtained by printing several subsequent layers on top of the already printed ones, using an off-the-shelf consumer thermal inkjet (TIJ) printer. The produced drug-delivery systems were subjected to microscopic and chemical analysis together with solid-state characterization and content uniformity studies. The results revealed that RM recrystallized on the surface of ODFs and TFs, and the printed crystals were arranged in lines. No drug crystals were detected after printing on the surface of the copy paper due to absorption of the ink into the matrix of the substrate. The best linear correlation between the dose of the drug and the number of the printing layers was obtained for the porous copy paper. The other two substrates showed poor linearity and unacceptable standard deviations of the printed drug substance due to limited absorption of the API ink into the carrier. The shear stress between the substrate, the print head, and the paper feeding rollers caused smearing of the drug that had been surface-deposited during the earlier printing cycles. In conclusion, this study indicates that the edible substrates with absorption properties similar to copy paper are favorable for successful preparation of drug-delivery systems by TIJ printers.

We combined conventional inkjet printing technology with flexographic printing to fabricate drug delivery systems with accurate doses and tailored drug release. Riboflavin sodium phosphate (RSP) and propranolol hydrochloride (PH) were used as water-soluble model drugs. Three different paper substrates: A (uncoated woodfree paper), B (triple-coated inkjet paper) and C (double-coated sheet fed offset paper) were used as porous model carriers for drug delivery. Active pharmaceutical ingredient (API) containing solutions were printed onto 1 cm × 1 cm substrate areas using an inkjet printer. The printed APIs were coated with water insoluble polymeric films of different thickness using flexographic printing. All substrates were characterized with respect to wettability, surface roughness, air permeability, and cell toxicity. In addition, content uniformity and release profiles of the produced solid dosage forms before and after coating were studied. The substrates were nontoxic for the human cell line assayed. Substrate B was smoothest and least porous. The properties of substrates B and C were similar, whereas those of substrate A differed significantly from those of B, C. The release kinetics of both printed APIs was slowest from substrate B before and after coating with the water insoluble polymer film, following by substrate C, whereas substrate A showed the fastest release. The release rate decreased with increasing polymer coating film thickness. The printed solid dosage forms showed excellent content uniformity. So, combining the two printing technologies allowed fabricating controlled-release oral dosage forms that are challenging to produce using a single technique. The approach opens up new perspectives in the manufacture of flexible doses and tailored drug-delivery systems.

In the present study, thin-coating as a potential method for improving flow properties of cohesive ibuprofen powder was introduced. Briefly, the technique was based on the successive deposition of ultrasound-assisted fine polymer mist onto the surface of the powdered active pharmaceutical ingredient (API), producing individual particles with a hydrophilic thin-coat. A 0.15% m/V aqueous solution of hydroxypropyl methylcellulose (HPMC) was used. Particle size and surface analysis revealed a decrease in the cohesiveness of ibuprofen powder and an increase in the homogeneity of particle surfaces as a result of polymer treatment. Superficial changes caused a substantial improvement on the flowing characteristics of coated substance over uncoated. The enhancement in flow rate proceeded as the uniformity of the HPMC layer increased. In conclusion, the proposed technique is a simple and effective method that can be used as a continuous process to modify API particle surface properties, which in turn improve the handling of poorly flowable powder.

The goal of the present study was to fabricate drug-containing T-shaped prototypes of intrauterine system (IUS) with the drug incorporated within the entire backbone of the medical device using 3-dimensional (3D) printing technique, based on fused deposition modeling (FDM™). Indomethacin was used as a model drug to prepare drug-loaded poly(e-caprolactone)-based filaments with 3 different drug contents, namely 5%, 15%, and 30%, by hot-melt extrusion. The filaments were further used to 3D print IUS. The results showed that the morphology and drug solid-state properties of the filaments and 3D prototypes were dependent on the amount of drug loading. The drug release profiles from the printed devices were faster than from the corresponding filaments due to a lower degree of the drug crystallinity in IUS in addition to the differences in the external/internal structure and geometry between the products. Diffusion of the drug from the polymer was the predominant mechanism of drug release, whereas poly(e-caprolactone) biodegradation had a minor effect. This study shows that 3D printing is an applicable method in the production of drug-containing IUS and can open new ways in the fabrication of controlled release implantable devices.

The aim of this study was to prepare printable inks of the poorly water soluble drug indomethacin (IMC), fabricate printed systems with flexible doses and investigate the effect of ink excipients on the printability, dissolution rate and the solid state properties of the drug. A piezoelectric inkjet printer was used to print 1×1cm(2) squares onto a paper substrate and an impermeable transparency film. l-arginine (ARG) and polyvinylpyrrolidone (PVP) were used as additional formulation excipients. Accurately dosed samples were generated as a result of the ink and droplet formation optimization. Increased dissolution rate was obtained for all formulations. The formulation with IMC and ARG printed on transparency film resulted in a co-amorphous system. The solid state characteristics of the printed drug on porous paper substrates were not possible to determine due to strong interference from the spectra of the carrier substrate. Yet, the samples retained their yellow color after 6months of storage at room temperature and after drying at elevated temperature in a vacuum oven. This suggests that the samples remained either in a dissolved or an amorphous form. Based on the results from this study a formulation guidance for inkjet printing of poorly soluble drugs is also proposed.

The aim of the study was to investigate applicability of near infra-red (NIR) hyperspectral imaging technique in quality control of printed personalised dosage forms. Inkjet printing technology was utilized to fabricate escalating doses of an active pharmaceutical ingredient (API). A solution containing anhydrous theophylline as the model drug was developed as a printable formulation. Single units solid dosage forms (SDFs) were prepared by jetting the solution onto 1 cm × 1 cm areas on carrier substrate with multiple printing passes. It was found that the number of printing passes was in excellent correlation ( R 2 = 0.9994) with the amount of the dispensed drug (μg cm −2 ) based on the UV calibration plot. The API dose escalation was approximately 7.5 μg cm −2 for each printing pass concluding that inkjet printing technology can optimally provide solutions to accurate deposition of active substances with a potential for personalized dosing. Principal component analysis (PCA) was carried out in order to visualize the trends in the hyperspectral data. Subsequently, a quantitative partial least squares (PLS) regression model was created. NIR hyperspectral imaging proved ( R 2 = 0.9767) to be a reliable, rapid and non-destructive method to optimize quality control of these planar printed dosage forms.

The developments in printing technologies allow fabrication of micron-size nano-layered delivery systems to personal specifications. In this study we fabricated layered polymer structures for drug-delivery into a microfluidic channel and aimed to interferometrically assure their topography and adherence to each other. We present a scanning white light interferometer (SWLI) method for quantitative assurance of the topography of the embedded structure. We determined rapidly in non-destructive manner the thickness and roughness of the structures and whether the printed layers containing polymers or/and active pharmaceutical ingredients (API) adhere to each other. This is crucial in order to have predetermined drug release profiles. We also demonstrate non-invasive measurement of a polymer structure in a microfluidic channel. It shown that traceable interferometric 3D microscopy is a viable technique for detailed structural quality assurance of layered drug-delivery systems. The approach can have impact and find use in a much broader setting within and outside life sciences.

The use of three-dimensional (3D) printing technologies is transforming the way that materials are turned into functional devices. We demonstrate in the current study the incorporation of anti-microbial nitrofurantoin in a polymer carrier material and subsequent 3D printing of a model structure, which resulted in an inhibition of biofilm colonization. The approach taken is very promising and can open up new avenues to manufacture functional medical devices in the future.

The primary goal of the current work was to study the applicability of precision inkjet printing in fabrication of personalized doses of active pharmaceutical ingredients (APIs). Loperamide hydrochloride (LOP) and caffeine (CAF) were used as model compounds. Different doses of the drugs in a single dosage unit were produced, using a drop-on-demand inkjet printer by varying printing parameters such as the distance between jetted droplets (drop spacing) and the physical dimensions of the printed dosage forms. The behavior of the formulated printable inks for both APIs was investigated on the model substrates, using different analytical tools. The obtained results showed that printed LOP did not recrystallize on any substrates studied, whereas at least partial recrystallization of printed CAF was observed on all carrier surfaces. Flexible doses of both APIs were easily obtained by adjusting the drop spacing of the depositing inks, and the results were relevant with regards to the theoretical content. Adapting the dose by varying physical dimensions of single dosage units was less successful than the approach in which drop spacing was altered. In conclusion, controlled printing technology, by means of adjusting the distance between jetted droplets, offers a means to fabricate dosage forms with individualized doses.

An ultrasound-assisted powder-coating technique was used to produce a homogeneous powder formulation of a low-dose active pharmaceutical ingredient (API). The powdered particles of microcrystalline cellulose (MCC; Avicel® PH-200) were coated with a 4% m/V aqueous solution of riboflavin sodium phosphate, producing a uniform drug layer on the particle surfaces. It was possible to regulate the amount of API in the treated powder. The thickness of the API layer on the surface of the MCC particles increased near linearly as the number of coating cycles increased, allowing a precise control of the drug content. The tablets (n = 950) prepared from the coated powder showed significantly improved weight and content uniformity in comparison with the reference tablets compressed from a physical binary powder mixture. This was due to the coated formulation remaining uniform during the entire tabletting process, whereas the physical mixture of the powders was subject to segregation. In conclusion, the ultrasound-assisted technique presented here is an effective tool for homogeneous drug coating of powders of irregular particle shape and broad particle size distribution, improving content uniformity of low-dose API in tablets, and consequently, ensuring the safe delivery of a potent active substance to patients.

Processing ionomers is complicated by their ability to exhibit brittle fracture even in the melt state. This work introduces a new strategy for providing ionomers with good flowability, extensibility, and superior strain hardening. Diamineneutralized entangled poly(styrene-co-4-vinylbenzoic acid) ionomers were studied using small-amplitude oscillatory shear and nonlinear uniaxial extension measurements. The parent molecule, poly(styrene-co-4-vinylbenzoic acid), has a molar mass of 85,400 g/mol, well above the entanglement molar mass of polystyrene (13,300 g/mol). Neutralization was performed using "Jeffamine" type diamines with different molar masses. The resulting neutralized ionomers presented relaxation processes similar to entangled polymers but with faster terminal relaxation, suggesting negligible ionic cluster formation and indicating a diluting effect of the introduced diamines. This feature provides the ionomers with good flowability and facilitates their processing. In extensional measurements, these ionomers displayed superior strain hardening compared to the parent molecule, which also proved to be adjustable via changing diamine length. The stress growth curves showed a maximum stress, followed by stress overshoot and steady state at larger strain. The stress maximum and overshoot were correlated with ionic sticker disassociation, as evidenced by phase separation-induced color change during filament stretching. At high stretch rates, the stickers disassociate abruptly to accommodate the strain, so that the sticker disassociation time decreased with increasing stretch rates. Good extensibility (up to Hencky strain 7) was achieved via ionic sticker reassociation and entanglements.