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Printing pharmaceuticals by inkjet technology: Proof of concept for stand-alone and continuous in-line printing on orodispersible films
Journal of Manufacturing Processes 35 (2018) 205–215
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Journal of Manufacturing Processes journal homepage: www.elsevier.com/locate/manpro
Printing pharmaceuticals by inkjet technology: Proof of concept for standalone and continuous in-line printing on orodispersible films
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Yasmin Thabet , Rok Sibanc, Joerg Breitkreutz Heinrich Heine University Duesseldorf, Universitaetsstrasse 1, 40225, Duesseldorf, Germany
A R T I C LE I N FO
A B S T R A C T
Keywords: Continuous in-line inkjet printing Continuous manufacturing of orodispersible films Technology transfer
Orodispersible films (ODFs) are promising dosage forms for special patient populations like paediatrics or elderly persons. By printing active pharmaceutical ingredients (APIs) onto orodispersible films, the flexibility of drug dosing is increased and therefore provides potential for personalized medicines. Until now, only small-scale experiments have been conducted, where continuous jetting was performed,but no continuous ODF production was realized. This study deals with the technology transfer from a small-scale inkjet printing system to a pilotscale process by incorporating the same print head assembly into a continuous ODF production process. ODFs made from hydroxypropylcellulose were non-continuously printed multiple times with test ink containing a blue colorant as model drug and were compared to continuously printed ODFs. To identify optimal manufacturing conditions, parameter settings like firing frequencies, resolution, voltage, etc. were varied and these effects were analysed by UV–Vis spectroscopy, image analysis and light microscopy. During continuous production, a linear correlation between firing frequency (100 to 600 Hz) and deposited colourant content could be observed (R = 0.999) as well as for the applied voltage (90–110 V) and the ink content (R = 0.998). A minor impact of the distance between the print head and the substrate was observed. By increasing the natural resolution (50 dpi) of the print head, the deposited ink amount could be doubled. A transfer from the non-continuous production (1 layer of 1 cm × 2 cm with a resolution of 750 dpi × 750 dpi) to the continuous production (corresponding to 380 Hz firing frequency on 6 cm2 ODF) was successfully performed. Furthermore, image analysis was proven as useful tool for process analytical technology (PAT) of the continuously printed ODFs. The continuous ODF production with direct printing enabled various printing concepts, which may serve for individualized dosing in personalized medicine treatment in the near future.
1. Introduction Orodispersible films (ODF) are thin strips of one or more layers of water-soluble polymers, which rapidly disintegrate when placed onto the tongue [1]. Due to the ingredients of this dosage form and also the mode of application, ODFs have been discussed in literature before as potential dosage forms for the elderly or paediatric population [1–3]. Furthermore, this dosage form provides potential applications in the field of individualized dosing, which gained popularity most recently [4]. The most common manufacturing technique is the solvent casting method [5], where the active pharmaceutical ingredient (API) is dissolved or dispersed in a polymer solution, which is cast onto an intermediate liner. After drying the wet film, a flexible and thin orodispersible film is obtained as the final product. Whereas the formulation development and academic often work non-continuously using film-casting benches [6] in a small-scale production, industry
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produces the ODFs in a continuous set-up, where the dried films are coiled up onto jumbo rolls directly after production [7]. To increase the dosing flexibility for individualized medicines [8–10] and to minimize the API waste, printing on orodispersible films has been discussed before. Janssen et al. printed ODFs with a flexographic printer, which is a contact printing technology [11]. A noncontact method is the inkjet printing technology, which recently gained popularity not only in pharmaceutical applications. It has been reported that this technology is also feasible to print metal-inks and produce solar cells, sensors or memory devices [12,13]. In the pharmaceutical area, inkjet printing has not only been discovered to print onto edible substrates [10] but was also utilized for printing microneedle systems [14], biomolecules and cell-based systems [15,16] or inhalable particles [17]. One of the main advantages of printing an API onto an edible substrate is the easy processing of poorly soluble drugs [18,19]. Due to the aqueous water solubility of the film former, poorly soluble APIs are
Corresponding author. E-mail addresses: [email protected], [email protected] (Y. Thabet), [email protected] (R. Sibanc), [email protected] (J. Breitkreutz).
https://doi.org/10.1016/j.jmapro.2018.07.018 Received 9 November 2017; Received in revised form 23 June 2018; Accepted 23 July 2018 1526-6125/ © 2018 The Society of Manufacturing Engineers. Published by Elsevier Ltd. All rights reserved.
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film was redirected to a print head assembly to enable direct printing by inkjet. The print head assembly allows a precise rotation of the print head (rotation angle can be adjusted from 0 to 180 °) to increase the natural resolution of the print head. The film was coiled up onto a jumbo roll directly after production. After printing onto the films, they were cut into a sample size of 6 cm2 (2 cm × 3 cm).
only feasible to be incorporated into ODFs in form of a suspension, which might be quite challenging concerning the homogeneity of the casting solution. Inkjet printing is a possibility to overcome this issue. Buanz et al. compared ODFs prepared by the solvent casting method with printed ODFs and described better film characteristics for the printed films [20]. To our best knowledge, ODF inkjet printing was only performed non-continuously by printing small amounts of substrates like paper or ODFs until now. This study provides for the first time data of an in-line inkjet printing of continuously produced ODFs. For that purpose, a continuous film coating machine was modified by expanding the conveying unit until the dried ODFs reach a top-mounted print head assembly. This implies several differences between the continuous printing process and the non-continuous production. Whereas the noncontinuous production enables multiple-layer printings on a defined area [21,22], during the continuous manufacturing only one printing step is feasible, because the print head is fixed to the coating machine and the printing velocity is determined by the speed of the intermediate liner of the film coater. Therefore, the effects of several parameter settings (e.g. firing frequencies, applied voltage and pulse shape, printing velocity and resolution) on the printed film should be investigated during continuous manufacturing and optimal production settings should be identified and evaluated. Furthermore, the continuously produced films should be compared to printed films by an industrial inkjet printer using the same print head. This enables the utilization of the non-continuous production as small-scale setup for formulation development in first experimental trials and later the transfer to the large-scale production process. Due to limited quality control methods for the continuous production of printed films, image analysis was employed as a new potential tool for in-line quality control as a process analytical technology (PAT).
3.2. Ink-jet printing 3.2.1. Non-continuous printing Non-continuous printing was performed using a PIXDRO LP 50 printer (Meyer Burger, The Netherlands) equipped with a Spectra S Class SE print head (Fujifilm, USA). This print head features 128 linearly arranged nozzles with an average diameter of 30 μm. Following printing parameters were set: on both piezo elements voltages of 90 V were applied, a pulse shape was defined as 1 μs – 12 μs – 1 μs, the print head temperature was 30 °C. The printing was conducted with a step size and a quality factor of 1. On each film, a rectangle (1 cm × 2 cm) was printed, setting the resolution to 750 dpi x 750 dpi. One to seven layers were printed onto the film. After printing the film, each layer was dried for at least half an hour to ensure complete drying of the ink. 3.2.2. Continuous printing Continuous printing was performed using a modified PIXDRO JS 20 jetting station (Meyer Burger, The Netherlands) equipped with the same Spectra S Class SE print head (Fujifilm, USA) as mentioned above. Following basic parameters were set: 90 V on both piezo elements, a printing frequency of 200 Hz, a pulse shape of 1 μs – 4 μs – 1 μs, the print head temperature was 30 °C. The velocity of the film moving below the print head was set to 125 mm/min. The distance between the print head nozzles and the substrate was set to 3 mm. To investigate the influence of the parameter setting on the printed substrates, the following parameters were varied: firing frequency, height of the print head, velocity of the substrate, adjusted voltage to the piezo elements and the pulse shape. Furthermore, the angle of the print head was varied.
2. Materials Film solutions were produced using 15% (m/m) hydroxypropylcellulose (HPC, Klucel, JXF Ashland, USA) and a mixture of ethanol/distilled water (50:50 m/m). Ethanol of analytical grade was purchased from VWR, Germany, and the distilled water was freshly produced shortly before use. Spectra XL 30 ink was utilized (Dimatix, USA) as ink solution consisting of polypropylene glycol, propylene carbonate and blue millijet dye 28 colorant.
3.3. Ink properties 3.3.1. Viscosity analysis The dynamic viscosity of the blue test ink was determined using the rotational viscosimeter Kinexus (Malvern, UK) utilizing a cone-plate setting (1°). Measurements were performed at 25 °C at a shear rate of 1000 s−1. The shear rate was chosen due to literature reports of high shear rates occurring within the print heads. Each sample was measured in triplicate. The mean and standard deviation were calculated.
3. Methods 3.1. Orodispersible film preparation 3.1.1. Non-continuous production ODFs were produced in the non-continuous production mode using the film applicator Coatmaster 510 (Erichsen, Germany) at a casting velocity of 360 mm/min at 30 °C temperature setting for the vacuum plate. The casting was performed with a wet film thickness (WFT) of 400 μm on a silicon coated polyamide–polyethylene foil (Sidamil 50/ 50, Amcor, Melbourne, Australia). After the printing process, specimens of a sample size of 6 cm2 (2 cm x 3 cm) were cut from the dried film material.
3.3.2. Surface tension The surface tension was measured using a K100 tensiometer (Krüss, Germany) utilizing a Wilhelmy plate at ambient conditions. The surface tension was measured at 10 points. Each sample was measured three times. The mean and standard deviation were calculated. 3.4. Morphological properties The morphological properties were investigated via light microscopy (Leica Microsystems, Germany) and scanning electron microscopy (G2 Pro, Phenom, The Netherlands). Furthermore, a sample of 1 cm2 (1 cm × 1 cm) was scanned using an Epson Perfection V800 Photo scanner (Epson, Japan) and visually inspected.
3.1.2. Continuous production Continuous film manufacturing was conducted using the coating machine TGM-K-1.4 (Optimags, Dr. Zimmermann, Germany). Films were cast (12 cm coating width) onto an intermediate liner PPQ 76677 (100 μm silicone coated, Huhtamaki, Finland). A pump conveyed the polymer solution through a coating knife, where the WFT was adjusted to 400 μm (Fig. 1). The coating velocity was set to 125 mm/min and the wet films were dried at 60 °C (first heating element) and 80 °C (second heating element) ca. 6.5 min. After passing the 80 cm long drying channel, the dry
3.5. Content uniformity 3.5.1. UV–Vis Due to the complex ink composition and the information lack of absolute quantities of the single ingredients by the ink manufacturer, 206
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Fig. 1. Schematic view of the continuous coating machine (Optimags Dr. Zimmermann, Germany) modified by an external print head assembly for ink jetting.
image, but only causing a longer printing time. The printing can be observed and controlled via a stroboscopic camera, which allows drop volume calculations and enables the observation of each printing nozzle. Furthermore, the quality of the printed image can be monitored post-printing by a camera system. In contrast, during the continuous printing process, there is no opportunity to analyse the drop shape in the set-up of our casting machine. Moreover, the ink load is controlled via the firing frequency of the print head. Only one printing step is possible with one print head assembly because the substrate is coiled up directly after printing. For the ink development the observation of the print head nozzles during jetting is quite important. Therefore, the following results evaluate the possibility to utilize the LP 50 printers as small-scale devices for ink development and first experiments, and later scale up the printing process to a continuous printing using the jetting station JS 20 of the LP 50 printer family. Image analysis has been employed as a quality control tool for the continuous inkjet printing to evaluate the quality of the printing.
the quantitative determination of the printed ink was performed via UV–Vis analysis with a UV–Vis-photometer Spekol 1100 (Analytik Jena, Germany) at a wavelength of 630 nm. The content was calculated as amount of printed colorant (ink/film). An absorption of the drug-free film at 630 nm was excluded before executing the experiments. A calibration curve was measured each day before sample measurements. The calibration curves revealed a coefficient of determination (R2) above 0.99. Each measurement was performed in triplicate. The mean and standard deviation were calculated. 3.5.2. Image analysis Printed films were scanned using a standard computer scanner Perfection V800 Photo (Epson, Japan). Scanning was performed at resolution of 2400 dpi and 48-bit colour depth (16 bit per colour channel) with disabled automatic image corrections. Films printed with varying frequencies used also for UV-VIS method were scanned and analysed. Image analysis was performed using an OpenCV based Python script (Python software foundation, USA). For the analysis a rectangle area enclosing the films was manually selected for each case. The raw RGB pixel values were transformed to absorbance as -log10 (R/B), where R is the red colour channel, and B is the blue colour channel. The red channel was chosen as the blue ink has the strongest absorption in red. The blue channel was chosen as a background reference. The sum of absorbance values of all pixels (Asum) was calculated for each film and used in further analysis.
4.1. Ink properties The dynamic viscosity of the blue test ink was found to be 14.20 ± 0.16 mPa*s and a surface tension of 35.61 ± 0.027 mN/m was measured, which is in accordance to the requirements of the print head manufacturer (8–20 mPa*s and 24–36 mN/m) for the utilized Spectra S Class print head [25].
3.6. Mechanical properties
4.2. Non-continuous film production
Mechanical properties were investigated with the Texture Analyser (Ta-XTplus, Stable Microsystems, UK) according to the method of Preis et al. [23]. To evaluate the results, the elongation to break and the puncture strength was calculated of 6 samples per batch. The mean and standard deviation were calculated.
All produced drug-free films were flexible and transparent showing no precipitations or air bubbles. After the film casting with the Erichsen film applicator, a film of a size of approx. 20 cm x 30 cm is obtained. The complete film was further printed using the LP 50 printer. After the printing process, films were cut into sample sizes of 2 cm x 3 cm (6 cm2).
3.7. Disintegration time 4.3. Non-continuous printing The disintegration time of the ODFs was determined utilizing an automated disintegration tester (Pharma Test Apparatebau, Hainburg, Germany) adapted for film formulations according to Preis et al. [24]. 6 film specimens were measured per batch. The mean and standard deviation were calculated.
The multiple layer printing of orodispersible films was successfully performed. Seven layers can be printed without destroying the integrity of the film. After printing, each film remains flexible and stable after removing it from the intermediate liner. Microscopic images showed that with increasing printed layers the intensity of the blue ink increases. The boundary area between ink and film can be distinguished more clearly with increasing layers. Fig. 2 displays the photometric analysis of the printed films and the evaluation of the results. Fig. 2A shows the number of printed layers on the x-axis versus the ink load per film sample (6 cm2) on the y-axis. A linear correlation could be observed (R= 0.999). The first printed layer revealed an ink content of 3.5 μg ink per film sample (Fig. 2B). On average 4.32 ± 0.76 μg ink was printed per layer. Knowing the
4. Results and discussion Non-continuous inkjet printing has been often described in the pharmaceutical field recently [10,14,16]. However, non-continuous and continuous inkjet printing show some major differences. When printing with the LP 50, the applied ink amount is controlled via the resolution of the artwork programmed by the user. Printing with a single or with multiple nozzles is feasible without losing quality of the 207
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Fig. 2. A: Non-continuously printed films with 1–7 layers, n=3, mean ± SD, B: mean ink amount per printed layer, n=3 C: correlation between the calculated ink amount per sample and the actual measured one [μg], D: calculated and measured ink amount/ film sample per layer.
the ink formulation, a gel-like texture was obtained after drying. This resulted in a lower puncture strength which is more pronounced the more layers and the more ink is applied onto the film. This texture also explains the higher elongation to break with increasing ink amount. The more layers are printed, the higher is the elongation of the film before rupturing. Higher elongation to break can lead to incorrect dosing of the film because when the film is coiled up or stamped to the sample size, mechanical forces are applied to the films. Depending on the force and the flexibility of the film, the film can be stretched which leads to an incorrect dosing. Therefore, elongation and puncture strength are major quality attributes for the film production. The results show that a multiple printing has a huge impact on the mechanical properties of the film. This leads to the conclusion, that the ink formulation and the number of printed layers should be carefully selected. All printed films disintegrated within less than 15 s and fulfill therefore the requirements of the European Pharmacopoeia [26]. No significant influence of the printed layers on the disintegration time could be determined.
resolution of the printed image (750 dpi x 750 dpi) and the adjustment range for the drop size of the print head (25–30 pl), the amount of printed ink can be calculated. This enables the correlation of the measured ink content versus the calculated ink amount considering the 7 printed layers (Fig. 2C, D). It can be seen, that the first printed layers contain less ink than initially calculated. With increasing layers, the deviation between measured and calculated values decreases. These results confirm that precise inkjet printing is feasible even when printing several layers. A saturation of the printed ink while printing multiple layers as described in literature [21,22], could not be observed. Fig. 3 shows the mechanical properties of the printed films expressed as elongation to break and puncture strength. It can be seen, that with increasing ink layers, the puncture strength decreases. Due to
4.4. Continuous film production Major differences between continuous and non-continuous film production have been described in literature before [6]. Apart from the viscosity of the casting solution, the wet film thickness, the velocity of the intermediate liner and the drying temperature are critical process parameters for continuous film production. This leads to a limited opportunity of production setting variations for the subsequent printing process. As the print head is fixed to the continuous film coater, the printing velocity is controlled by the speed of the intermediate liner, which moves under the print head. The printing velocity is a critical production parameter and should be varied to find the optimal settings for the continuous printing. Therefore, the velocity of the intermediate
Fig. 3. Mechanical properties of non-continuously printed films with 1–7 layers. Black symbols represent the puncture strengths of the films and grey symbols the elongation to break; n= 6, mean ± SD. 208
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absorbance values by UV–Vis analysis and the absorbance by image analysis. A linear correlation with a correlation coefficient of R=0.997 was obtained. This proves the feasibility of utilizing the image analysis as tool for ink colourant determination as model drug. Fig. 7 shows the image analysis of a film sample printed with 200 Hz on the left and 400 Hz on the right. The upper pictures exemplarily show the coloured scale which enabled the quantitative analysis of the ink via the absorbance of the sum of the pixels. Lower pictures display the absorbance via the width of the films. These diagrams allow conclusions of the operational reliability of the nozzles. On the 200 Hz film, an unstable nozzle and a failing nozzle can be seen on the left side of the film. These nozzles can be detected in the absorbance profile below as well. The intensity of the absorbance decreases due to missing or irregular colour of the printed line. The image analysis tool is a promising tool to determine the ink content after production but is limited to coloured inks or light absorbing drug substances. Furthermore, it is assumed that the printed ink is uniform; if not, the image analysis leads to inaccurate contents because only the colourant and not the API is detected. Nevertheless, it can be helpful in future to perform the image analysis in-line with a camera to detect failing nozzles. The results for the mechanical properties of the films printed with different firing frequencies are in-line to the results for the films printed with multiple layers, which were described before. Higher ink load at higher firing frequencies led to higher elongation to break of the films (15.3 ± 1.2% at 50 Hz and 22.7 ± 1.7% at 500 Hz). The puncture strength reveals the opposite effect (0.5 ± 0.02 N/mm2 at 50 Hz versus 0.17 ± 0.02 N/mm2 at 600 Hz), which was also observed for the noncontinuous printing. However, for continuous printing it was found less pronounced, probably because of the lower ink load.
liner was varied from 50 mm/min to 200 mm/min. Lower velocities led to brittle films, whereas for higher velocities, the time within the drying channel of the film coater was too short, which led to wet films after passing the drying channel. All films cast within these parameter settings led to dry and flexible films with smooth surfaces, which could be printed directly after production. 4.5. Continuous printing Several parameter settings influence the printing quality during continuous production. Beside the firing frequency (varied from 5 to 600 Hz), which determines the applied ink, the printing velocity is of crucial importance. To ensure a dry and still flexible film, velocity was varied from 50 mm/min to 200 mm/min. At a velocity of 50 mm/min the film is still flexible enough to be coiled up and at 200 mm/min the film is just dry after passing the drying channel. Furthermore, the applied voltage has a high influence on the printing process. The drop shape is also dependent on the voltage. The utilized print head features two piezo elements, which control the jetted ink amount by applying variable voltages on the piezo elements. Therefore, the voltage can be varied from 70 to 120 V for both piezo elements. Moreover, the pulse shape parameters were changed, and the shape of the printed drops analysed. The assembly of the print head within the continuous production line allows a precise rotation of the print head holder so that the resolution of the printer can be increased by altering the angle of the print head. To investigate the effects of the resolution on the formed and printed drops and the amount of ink, the angle of the print head was varied from 0 ° to 60 °. In addition to that, the influence of the distance of the print head to the substrate was analysed. Due to the experience of previous experiments, following parameters were chosen as basic printing parameters: 90 V, 1 μs – 4 μs – 1 μs for the pulse shape, 30 °C as temperature within the print head, 3 mm distance to the substrate, 0° print head angle and a printing velocity of 125 mm/min. These basic parameters were kept constant while varying one of the printing parameters as described before.
4.5.2. Variation of the print head angle The variation of the print head angle results in a higher resolution of the printed image. The natural resolution of the Spectra S Class print head is 50 dpi. By setting the angle of the print head to 45°, the resolution can be increased to 71 dpi. Fig. 8 displays scans and microscopic images of printed films at different angles of the print head. The higher the pre-set angle, the closer are the resulting lines. At an angle of 60 °, the printed lines are merging, which can be seen in the scan as blue dots. The printed image gets an irregular shape. The closer printed lines result in a higher ink amount on the orodispersible film which can be seen in Fig. 9A. With increasing angle, the deposited ink also increases. A sinusoidal shape of the curve can be observed. An angle of 60 ° doubles the printed ink amount (1.6 ± 0.09 μg vs. 3.2 ± 0.16 μg).
4.5.1. Variation of the firing frequency Fig. 4 shows scans and microscopic images from orodispersible films printed with different firing frequencies. Firing with 5 and 10 Hz at a printing velocity of 125 mm/min led to individual drops on the substrate. With increasing firing frequency up to 50 Hz the single drops merge to a printed line. At 100 Hz an unstable line was printed consisting of liquid bulges connected by ridges. This phenomenon has been described in literature before [27]. With further increasing firing frequencies, the unstable lines become thicker and get closer together. The higher the firing frequencies of the print head, the higher is the ink amount per film sample (Fig. 5). A linear correlation between the firing frequency and the printed ink amount (R=0.994) could be shown. Because of this, the visual appearance of the printed lines (bulges connected by ridges) can be neglected. The focus of the printing during the continuous film production is to apply a defined volume and API amount onto the ODF and not to print perfectly shaped lines. The quality of the printed lines could therefore be neglected within the first experiments, as long as the printed API amount shows a linear correlation to the firing frequencies. For the continuous printing, there is still a lack of PAT and quality controls. Printing with the LP 50 printer enables drop shape analysis and control of the printed drops after image printing. Image analysis is one potential tool to verify the printing quality of the continuous printing process. After printing, the films can be scanned or monitored by a camera and the ink absorbance enables analysis of content and a nozzle observation so that failing nozzles can be detected. These assumptions could be confirmed by the performed image analysis (Fig. 6). A linear correlation (R= 0.999) between the firing frequencies during printing and the colouring depths of the pixels could be seen in Fig. 6A. Fig. 6B displays the correlation between the obtained
4.5.3. Variation of the printing velocity The printing velocity is controlled via the speed of the intermediate liner of the ODF. The higher the speed of the intermediate liner, the lower is the printed ink amount (Fig. 9B). The intensity of the liquid bulges decreases until at 200 mm/min an almost stable line is printed. But higher printing velocity also means less drying time for the ODF. This can lead to higher drying temperature settings to obtain a dry film after passing the drying channel. Higher drying temperatures may lead to lower tensile strength or the formation of air bubbles due to fast solvent evaporation. High air bubble quantities within the film result in an uneven surface of the film, which may complicate the printing process and the content uniformity. Therefore, printing at lower intermediate liner velocities is highly recommended. 4.5.4. Variation of the voltage The Spectra S Class print head is equipped with two piezo elements which can be separately controlled. By applying a certain voltage on the elements, a drop is forced out of the print head nozzle. Fig. 9C shows the impact of the applied voltage on the printed ink amount. With increasing voltage, the deposited ink also increases. It could be shown, 209
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Fig. 4. Scans and microscopic images from orodispersible films printed with blue ink printing with various firing frequencies. Scale bars increased for better visualization.
4.5.5. Variation of the print head distance The setup of the print head within the continuous production line also allows a precise adjustment of the print head distance. By increasing the distance between nozzle plate and substrate, the droplet has higher fly times and this can affect the drop shape and size. Fig. 9D displays the effect of the print head distance on the amount of printed ink. No distinct effect can be observed by changing the distance. Therefore, the distance seems to be no major quality factor during continuous printing concerning the applied drop volume. 4.5.6. Variation of the pulse shape Settings of the pulse shape of the print head have a crucial impact on the drop shape and size. The pulse shape is highly dependent on the used print head. The spectra print head has a quite simple pulse shape. Basic settings for the performed printing were 90 V and 1 μs – 4 μs – 1 μs. This means that it lasts 1 μs until the voltage is fully applied, then hold for 4 μs and need 1 μs to decrease. Beside the applied voltage, the correct settings for the pulse shape are essential to obtain optimal droplets. The pulse shape was varied for the rising time from 1 μs to 10 μs, for the dwell time from 4 μs to 20 μs and for the falling time from 1 μs to 10 μs. The effects were observed utilizing light microscopic images of the printed lines. Following observations could be made for the rising time: Changing the settings from 1 to 4 μs, no significant influence on the printed lines could be observed. Further increasing to 10 μs led to some single nozzle failings and therefore missing lines. The shape of the printed lines of the operating nozzles was not affected by the faster
Fig. 5. Deposited ink amount per film sample at different firing frequencies, n=3, mean ± SD.
that there is a linear correlation between the applied voltage and the resulting ink drop volume (R=0.998). Fig. 10 confirms these results. The intensity of the ink and of the printed lines increase from 90 to 110 V. By applying too low voltages, no reproducible drops can be formed as displayed in Fig. 10 (for 70 V).
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Fig. 6. Results of the image analysis; A: correlation of the utilized firing frequency of the print head and the sum of the absorbance of the pixels, n= 3, mean; B: correlation between the absorbance of different firing frequencies obtained by UV–Vis measurements and the sum of the absorbance of the pixels, n=3, mean.
Fig. 7. Image analysis of 200 Hz and 400 Hz printed films. Lower pictures show the absorbance via the width of the film. n= 3, mean.
process allows accurate printing of even electronics [12,13]. To print precise electronical structures, various parameter settings have to be chosen. These parameter settings are highly dependent on the utilized print head assembly and the ink formulation. Furthermore, the characteristics of the substrates (contact angle, porosity, etc.) have to be taken into account. These facts result in a very complex process. For the LP 50 printer, analytical technologies provide process control, e.g. with the help of the stroboscopic camera, which enables the observation of the nozzle plate. The picture or geometric form, which should be printed can be designed by the printer’s software. Printing with one or only a few nozzles is feasible without altering the quality of the printed picture and only prolonging the printing time. The quality of the
rising times. Higher effects could be observed by changing the dwell times. With higher dwell times (above 15 μs) the quality of the printed lines decreases dramatically and at dwell times of 20 μs almost no nozzle printed reproducible droplets anymore. The falling time also had a crucial impact. At falling times of 4 μs the printed lines became irregular. By further increasing the falling time (10 μs) no line could be printed anymore.
4.6. Comparison and transfer non-continuous to continuous printing Inkjet printing is a very precise printing process, where small droplets are placed onto variable substrates. The high precision of the 211
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Fig. 8. Scans and microscopic images from orodispersible films printed with blue ink at various print head angles. Scale bars increased for better visualization.
reproducible. This has to be guaranteed and can be controlled by the camera systems of the LP 50 printer. In contrast to this kind of printing process, the printing during a continuous ODF production differs. The applied ink amount is controlled via the firing frequency of the print head and is not programmed in advance. Therefore, a reproducible
printed image is highly dependent on the drop shape of the droplets. When the droplet leaves the nozzle plate, a cycle has to be formed until the droplet meets the substrate. Otherwise, no precise dot will be printed. For pharmaceutical applications, the formation of a perfect drop is not necessary as long as the applied drug amount is
Fig. 9. Effects of different parameter settings on the ink load of the film sample; A: print head angle, B: intermediate liner velocity, C: applied voltage to the print head and D: print head distance to the substrate, n=3, mean ± SD. 212
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Fig. 10. Scans and microscopic images of printed orodispersible films with blue ink at different voltage settings. Scale bars increased for better visualization.
which was proven to be feasible as off-line application within this article. Furthermore, a Raman probe or NIR probe could be utilized as PAT tool, not only enabling the control of the jetting of single nozzles, but also to directly quantify the printed drug amount without needing a coloration of the ink. A further challenge of printing during continuous production is the short drying time of the ink, which is caused by the limited ability to adjust the velocity of the substrate (due to the ODF manufacturing) and the short way between the mounted print head and the coiling machine. This could be overcome by incorporating further drying units (e.g. IR lamps or heating elements). Moreover, further research has to be undertaken concerning the development of printable inks. Especially new, non-toxic polymers enabling a precise adjustment of dynamic viscosities and surface tensions, while staying stable during the printing process without clogging the small print head nozzles would be desirable.
jetting of the nozzles is essential to enable a precise dosing of the ink. Whereas the non-continuous printing is feasible with one nozzle, almost all nozzles have to jet during the continuous ODF printing. Otherwise, only small ink amounts would be applied. Similar to the LP 50 printing process, for a pharmaceutical application within a continuous ODF production process, the shape of the droplet and the visual appearance of the printed lines has only an inferior standing as long as the printed volume is reproducible and controlled by the applied production setting. As settings of crucial importance were found: applied voltage, firing frequency and print head angle. The pulse shape was found to play indeed an important role to enable a jetting and a constant shape of the droplet but was further found to be robust to small variations regarding the applied ink amount. Furthermore, the distance of the print head to the substrate led to only small variations in applied drug amount despite the distance is very important for the shape of the applied droplet (circular dot or irregular shaped dot). The non-continuous printing allows precise multiple layer printings, which result in higher ink loads on the ODF. However, multiple printing cycles cause long processing times because the printed layer has to dry before the next printing step could be performed. In contrast to this non-continuous printing, the continuous printing of orodispersible films can be conducted quite fast and the film can be coiled up directly after printing. The continuous process limits the ink load on the film because only one layer can be printed with one print head. Due to the limited drying time before the film is coiled up, it was found that the maximum frequency of 1000 Hz is applicable, still ensuring complete drying of the ink. The non-continuous printing can be quite useful for the ink development and the finding of the optimal parameter setting for the print head. The obtained data from the tested Spectra XL 30 ink reveal that a firing frequency of 380 Hz during continuous printing is necessary to print the same ink amount as one layer (1 cm × 2 cm) printed noncontinuously. These data enable the possibility to utilize the LP 50 printer as a small-scale device for the development and later transfer of the process to the continuous production line. Nevertheless, some technical challenges have to be overcome. To enable a better process control, a PAT tool is needed, to observe the single nozzles and the jetting of the nozzles. This could be realized by a high-speed camera and the simultaneously ongoing image analysis,
4.7. Continuous inkjet printing for various printing concepts In literature, several printing concepts have been discussed before [28]. Beside of the precise and flexible dosing, one of the main advantages of printing APIs is the potential of producing lower drug waste by centered printing. While cutting the jumbo- or daughter-rolls into the specified sample size, API waste occurs [29], which can be quite hazardous and cost intensive, depending on the used API. By centered printing, the waste can be significantly reduced. The previous described results enabled the finding of the optimal production settings for the continuous printing. Fig. 11 displays the implemented printing concepts printed utilizing the JS 20 within a continuous production process utilizing the basic parameter settings described before. Symmetric and asymmetric lines enable a high dosing flexibility by cutting the films. Central surface printing or dots are advantageous for high potent or expensive drugs to increase the safety during production and minimize the API waste. Complete printing can be utilized to obtain higher drug loads or to produce fixed-dose combinations. It was feasible to print the previously proposed printing concepts during continuous film production. Each film dried during the prescribed drying time and stayed flexible despite the printing. 213
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Fig. 11. Implemented printing concepts utilizing the JS 20 during continuous manufacturing.
5. Conclusion
[8] Alomari M, Mohamed F, Basit A, Gaisford S. Personalised dosing: Printing a dose of one’s own medicine. Int J Pharm 2015;494:568–77. [9] Pardeike J, Strohmeier DM, Schrödl N, Voura C, Gruber M, Khinast JG, et al. Nanosuspensions as advanced printing ink for accurate dosing of poorly soluble drugs in personalized medicines. Int J Pharm 2011;420:93–100. [10] Sandler N, Määttänen A, Ihalainen P, Kronberg L, Meierjohann A, Viitala T, et al. Inkjet printing of drug substances and use of porous substrates-towards individualized dosing. J Pharm Sci 2011;100:3386–95. [11] Janssen E, Schliephacke R, Breitenbach A, Breitkreutz J. Drug-printing by flexographic printing technology–a new manufacturing process for orodispersible films. Int J Pharm 2013;441:818–25. [12] Tekin E, Smith P, Schubert U. Inkjet printing as a deposition and patterning tool for polymers and inorganic particles. Soft Matter 2008;4:703. [13] Singh M, Haverinen H, Dhagat P, Jabbour G. Inkjet printing-process and its applications. Adv Mater 2010;22:673–85. [14] Uddin M, Scoutaris N, Klepetsanis P, Chowdhry B, Prausnitz M, Douroumis D. Inkjet printing of transdermal microneedles for the delivery of anticancer agents. Int J Pharm 2015;494:593–602. [15] Ihalainen P, Määttänen A, Sandler N. Printing technologies for biomolecule and cell-based applications. Int J Pharm 2015;494:585–92. [16] Delaney J, Smith P, Schubert U. Inkjet printing of proteins. Soft Matter 2009;5:4866. [17] Sharma G, Mueannoom W, Buanz ABM, Taylor KMG, Gaisford S. In vitro characterisation of terbutaline sulphate particles prepared by thermal ink-jet spray freeze drying. Int J Pharm 2013;447:165–70. [18] Raijada D, Genina N, Fors D, Wisaeus E, Peltonen J, Rantanen J, et al. A step toward development of printable dosage forms for poorly soluble drugs. J Pharm Sci 2013;02:3694–704. [19] Scoutaris N, Alexander M, Gellert P, Roberts C. Inkjet printing as a novel medicine formulation technique. J Control Release 2011;156:179–85. [20] Buanz ABM, Belaunde C, Soutari N, Tuleu C, Gul M, Gaisford S. Ink-jet printing versus solvent casting to prepare oral films: effect on mechanical properties and physical stability. Int J Pharm 2015;494:611–8. [21] Wickström H, Palo M, Rijckaert K, Kolakovic R, Nyman JO, Määttänen A, et al. Improvement of dissolution rate of indomethacin by inkjet printing. Eur J Pharm Sci 2015;75:91–100. [22] Buanz ABM, Saunders MH, Basit AW, Gaisford S. Preparation of personalized-dose salbutamol sulphate oral films with thermal ink-jet printing. Pharm Res 2011;28:2386. [23] Preis M, Knop K, Breitkreutz J. Mechanical strength test for orodispersible and buccal films. Int J Pharm 2014;461:22–9. [24] Preis M, Gronkowsky D, Grytzan D, Breitkreutz J. Comparative study on novel test systems to determine disintegration time of orodispersible films. J Pharm Pharmacol 2014;66:1102–11. [25] Dimatix. Data sheet SE-128 AA. 2017 Accessed 06 November 2017 https://www. fujifilmusa.com/shared/bin/PDS00009.pdf. [26] Orodispersible tablets. European directorate for the quality of medicines & healthcare. Strasbourg, France: EDQM); 2017. [27] Duineveld PC. The stability of ink-jet printed lines of liquid with zero receding contact angle on a homogeneous substrate. J Fluid Mech 2003;477:175. [28] Preis M, Breitkreutz J, Sandler N. Perspective: concepts of printing technologies for oral film formulations. Int J Pharm 2015;494:578–84. [29] Jansen J, Horstmann M. Gut abschneiden - Feindosierung in oralen Filmen.
A multilayer printing utilizing a non-continuous inkjet printing system is feasible, when required drying times are exactly followed. With increasing layers up to 7 layers the printed ink amount remains constant, but a major impact of the number of printed layers on the mechanical properties could be observed. The continuous printing enables a direct API printing during production with a subsequent packaging of the product. Optimal production settings for the continuous printing could be found by analysing variations of critical process parameters like firing frequency, print head angle, applied voltage and pulse shape. A quality control system after production was successfully employed utilizing image analysis. Transfer from noncontinuous to continuous printing was performed and demonstrated by continuous printing of various different printing concepts. Acknowledgements The authors are grateful to Stefan Stich who provided his help for the construction of the print head holder and its assembly in the continuous production line. Furthermore, the authors want to thank Wouter Brok from Meyer Burger (Eindhoven, The Netherlands) who provided his help and knowledge for the integration of the print head into the continuous film coating machine from Optimags. This work was partially supported by the Alexander von Humboldt Foundation. References [1] Slavkova M, Breitkreutz J. Orodispersible drug formulations for children and elderly. Eur J Pharm Sci 2015;75:2–9. [2] Borges AF, Silva C, Coelho JF, Simões S. Oral films: current status and future perspectives: I—galenical development and quality attributes. J Control Release 2015;206:1–19. [3] Liew K, Tan JTF, Peh K. Characterization of oral disintegrating film containing donepezil for alzheimer disease. AAPS PharmSciTech 2012;13:134–42. [4] Visser JC, Woerdenbag HJ, Crediet S, Gerrits E, Lesschen MA, Hinrichs WLJ, et al. Orodispersible films in individualized pharmacotherapy: The development of a formulation for pharmacy preparations. Int J Pharm 2015;478:155–63. [5] Dixit R, Puthli S. Oral strip technology: overview and future potential. J Control Release 2009;139:94–107. [6] Thabet Y, Breitkreutz J. Orodispersible films: product transfer from lab-scale to continuous manufacturing. Int J Pharm 2018;535:285–92. [7] Hoffmann EM, Breitenbach A, Breitkreutz J. Advances in orodispersible films for drug delivery. Expert Opin Drug Deliv 2011;8:299–316.
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Slovenia in 2014 and finished his Master at the same faculty in 2007. His main research topics are simulations of pharmaceutical processes and process analytical technologies.
TechnoPharm 2014;4:306–13. Yasmin Thabet studied pharmacy at the Heinrich Heine University Duesseldorf, Germany and received the license as a pharmacist in 2013. Since 2014 she is working as scientific assistant at the Institute of Pharmaceutics and Biopharmaceutics, University Duesseldorf, Germany focusing on her PhD thesis: Continuous manufacturing of orodispersible films as combination products.
Jörg Breitkreutz is a pharmacist by training and finished his PhD in 1996 at the Institute for Pharmaceutical Technology and Biopharmaceutics in Münster under supervision of Prof. Gröning. From 1996 to 1997 he joined Thiemann Arzneimittel GmbH in Waltrop, Germany, and from 1997 to 2004 the University of Münster to work on his habilitation on paediatric drug formulations. In 2004 he became professor for pharmaceutical technology at the Heinrich-Heine-University in Düsseldorf, Germany. Since 2010 he is the president of the International Association of Pharmaceutical Technology (APV). His research focuses on paediatric drug formulations, orphan drugs and process analytical technologies.
Rok Šibanc is a postdoc researcher at Institute of Pharmaceutics and Biopharmaceutics at Heinrich Heine University Düsseldorf since October 2015 working on a research project involving pellet coating. He completed his PhD at Pharmacy at University of Ljubljana,
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Printing pharmaceuticals by inkjet technology: Proof of concept for standalone and continuous in-line printing on orodispersible films
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Yasmin Thabet , Rok Sibanc, Joerg Breitkreutz Heinrich Heine University Duesseldorf, Universitaetsstrasse 1, 40225, Duesseldorf, Germany
A R T I C LE I N FO
A B S T R A C T
Keywords: Continuous in-line inkjet printing Continuous manufacturing of orodispersible films Technology transfer
Orodispersible films (ODFs) are promising dosage forms for special patient populations like paediatrics or elderly persons. By printing active pharmaceutical ingredients (APIs) onto orodispersible films, the flexibility of drug dosing is increased and therefore provides potential for personalized medicines. Until now, only small-scale experiments have been conducted, where continuous jetting was performed,but no continuous ODF production was realized. This study deals with the technology transfer from a small-scale inkjet printing system to a pilotscale process by incorporating the same print head assembly into a continuous ODF production process. ODFs made from hydroxypropylcellulose were non-continuously printed multiple times with test ink containing a blue colorant as model drug and were compared to continuously printed ODFs. To identify optimal manufacturing conditions, parameter settings like firing frequencies, resolution, voltage, etc. were varied and these effects were analysed by UV–Vis spectroscopy, image analysis and light microscopy. During continuous production, a linear correlation between firing frequency (100 to 600 Hz) and deposited colourant content could be observed (R = 0.999) as well as for the applied voltage (90–110 V) and the ink content (R = 0.998). A minor impact of the distance between the print head and the substrate was observed. By increasing the natural resolution (50 dpi) of the print head, the deposited ink amount could be doubled. A transfer from the non-continuous production (1 layer of 1 cm × 2 cm with a resolution of 750 dpi × 750 dpi) to the continuous production (corresponding to 380 Hz firing frequency on 6 cm2 ODF) was successfully performed. Furthermore, image analysis was proven as useful tool for process analytical technology (PAT) of the continuously printed ODFs. The continuous ODF production with direct printing enabled various printing concepts, which may serve for individualized dosing in personalized medicine treatment in the near future.
1. Introduction Orodispersible films (ODF) are thin strips of one or more layers of water-soluble polymers, which rapidly disintegrate when placed onto the tongue [1]. Due to the ingredients of this dosage form and also the mode of application, ODFs have been discussed in literature before as potential dosage forms for the elderly or paediatric population [1–3]. Furthermore, this dosage form provides potential applications in the field of individualized dosing, which gained popularity most recently [4]. The most common manufacturing technique is the solvent casting method [5], where the active pharmaceutical ingredient (API) is dissolved or dispersed in a polymer solution, which is cast onto an intermediate liner. After drying the wet film, a flexible and thin orodispersible film is obtained as the final product. Whereas the formulation development and academic often work non-continuously using film-casting benches [6] in a small-scale production, industry
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produces the ODFs in a continuous set-up, where the dried films are coiled up onto jumbo rolls directly after production [7]. To increase the dosing flexibility for individualized medicines [8–10] and to minimize the API waste, printing on orodispersible films has been discussed before. Janssen et al. printed ODFs with a flexographic printer, which is a contact printing technology [11]. A noncontact method is the inkjet printing technology, which recently gained popularity not only in pharmaceutical applications. It has been reported that this technology is also feasible to print metal-inks and produce solar cells, sensors or memory devices [12,13]. In the pharmaceutical area, inkjet printing has not only been discovered to print onto edible substrates [10] but was also utilized for printing microneedle systems [14], biomolecules and cell-based systems [15,16] or inhalable particles [17]. One of the main advantages of printing an API onto an edible substrate is the easy processing of poorly soluble drugs [18,19]. Due to the aqueous water solubility of the film former, poorly soluble APIs are
Corresponding author. E-mail addresses: [email protected], [email protected] (Y. Thabet), [email protected] (R. Sibanc), [email protected] (J. Breitkreutz).
https://doi.org/10.1016/j.jmapro.2018.07.018 Received 9 November 2017; Received in revised form 23 June 2018; Accepted 23 July 2018 1526-6125/ © 2018 The Society of Manufacturing Engineers. Published by Elsevier Ltd. All rights reserved.
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film was redirected to a print head assembly to enable direct printing by inkjet. The print head assembly allows a precise rotation of the print head (rotation angle can be adjusted from 0 to 180 °) to increase the natural resolution of the print head. The film was coiled up onto a jumbo roll directly after production. After printing onto the films, they were cut into a sample size of 6 cm2 (2 cm × 3 cm).
only feasible to be incorporated into ODFs in form of a suspension, which might be quite challenging concerning the homogeneity of the casting solution. Inkjet printing is a possibility to overcome this issue. Buanz et al. compared ODFs prepared by the solvent casting method with printed ODFs and described better film characteristics for the printed films [20]. To our best knowledge, ODF inkjet printing was only performed non-continuously by printing small amounts of substrates like paper or ODFs until now. This study provides for the first time data of an in-line inkjet printing of continuously produced ODFs. For that purpose, a continuous film coating machine was modified by expanding the conveying unit until the dried ODFs reach a top-mounted print head assembly. This implies several differences between the continuous printing process and the non-continuous production. Whereas the noncontinuous production enables multiple-layer printings on a defined area [21,22], during the continuous manufacturing only one printing step is feasible, because the print head is fixed to the coating machine and the printing velocity is determined by the speed of the intermediate liner of the film coater. Therefore, the effects of several parameter settings (e.g. firing frequencies, applied voltage and pulse shape, printing velocity and resolution) on the printed film should be investigated during continuous manufacturing and optimal production settings should be identified and evaluated. Furthermore, the continuously produced films should be compared to printed films by an industrial inkjet printer using the same print head. This enables the utilization of the non-continuous production as small-scale setup for formulation development in first experimental trials and later the transfer to the large-scale production process. Due to limited quality control methods for the continuous production of printed films, image analysis was employed as a new potential tool for in-line quality control as a process analytical technology (PAT).
3.2. Ink-jet printing 3.2.1. Non-continuous printing Non-continuous printing was performed using a PIXDRO LP 50 printer (Meyer Burger, The Netherlands) equipped with a Spectra S Class SE print head (Fujifilm, USA). This print head features 128 linearly arranged nozzles with an average diameter of 30 μm. Following printing parameters were set: on both piezo elements voltages of 90 V were applied, a pulse shape was defined as 1 μs – 12 μs – 1 μs, the print head temperature was 30 °C. The printing was conducted with a step size and a quality factor of 1. On each film, a rectangle (1 cm × 2 cm) was printed, setting the resolution to 750 dpi x 750 dpi. One to seven layers were printed onto the film. After printing the film, each layer was dried for at least half an hour to ensure complete drying of the ink. 3.2.2. Continuous printing Continuous printing was performed using a modified PIXDRO JS 20 jetting station (Meyer Burger, The Netherlands) equipped with the same Spectra S Class SE print head (Fujifilm, USA) as mentioned above. Following basic parameters were set: 90 V on both piezo elements, a printing frequency of 200 Hz, a pulse shape of 1 μs – 4 μs – 1 μs, the print head temperature was 30 °C. The velocity of the film moving below the print head was set to 125 mm/min. The distance between the print head nozzles and the substrate was set to 3 mm. To investigate the influence of the parameter setting on the printed substrates, the following parameters were varied: firing frequency, height of the print head, velocity of the substrate, adjusted voltage to the piezo elements and the pulse shape. Furthermore, the angle of the print head was varied.
2. Materials Film solutions were produced using 15% (m/m) hydroxypropylcellulose (HPC, Klucel, JXF Ashland, USA) and a mixture of ethanol/distilled water (50:50 m/m). Ethanol of analytical grade was purchased from VWR, Germany, and the distilled water was freshly produced shortly before use. Spectra XL 30 ink was utilized (Dimatix, USA) as ink solution consisting of polypropylene glycol, propylene carbonate and blue millijet dye 28 colorant.
3.3. Ink properties 3.3.1. Viscosity analysis The dynamic viscosity of the blue test ink was determined using the rotational viscosimeter Kinexus (Malvern, UK) utilizing a cone-plate setting (1°). Measurements were performed at 25 °C at a shear rate of 1000 s−1. The shear rate was chosen due to literature reports of high shear rates occurring within the print heads. Each sample was measured in triplicate. The mean and standard deviation were calculated.
3. Methods 3.1. Orodispersible film preparation 3.1.1. Non-continuous production ODFs were produced in the non-continuous production mode using the film applicator Coatmaster 510 (Erichsen, Germany) at a casting velocity of 360 mm/min at 30 °C temperature setting for the vacuum plate. The casting was performed with a wet film thickness (WFT) of 400 μm on a silicon coated polyamide–polyethylene foil (Sidamil 50/ 50, Amcor, Melbourne, Australia). After the printing process, specimens of a sample size of 6 cm2 (2 cm x 3 cm) were cut from the dried film material.
3.3.2. Surface tension The surface tension was measured using a K100 tensiometer (Krüss, Germany) utilizing a Wilhelmy plate at ambient conditions. The surface tension was measured at 10 points. Each sample was measured three times. The mean and standard deviation were calculated. 3.4. Morphological properties The morphological properties were investigated via light microscopy (Leica Microsystems, Germany) and scanning electron microscopy (G2 Pro, Phenom, The Netherlands). Furthermore, a sample of 1 cm2 (1 cm × 1 cm) was scanned using an Epson Perfection V800 Photo scanner (Epson, Japan) and visually inspected.
3.1.2. Continuous production Continuous film manufacturing was conducted using the coating machine TGM-K-1.4 (Optimags, Dr. Zimmermann, Germany). Films were cast (12 cm coating width) onto an intermediate liner PPQ 76677 (100 μm silicone coated, Huhtamaki, Finland). A pump conveyed the polymer solution through a coating knife, where the WFT was adjusted to 400 μm (Fig. 1). The coating velocity was set to 125 mm/min and the wet films were dried at 60 °C (first heating element) and 80 °C (second heating element) ca. 6.5 min. After passing the 80 cm long drying channel, the dry
3.5. Content uniformity 3.5.1. UV–Vis Due to the complex ink composition and the information lack of absolute quantities of the single ingredients by the ink manufacturer, 206
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Fig. 1. Schematic view of the continuous coating machine (Optimags Dr. Zimmermann, Germany) modified by an external print head assembly for ink jetting.
image, but only causing a longer printing time. The printing can be observed and controlled via a stroboscopic camera, which allows drop volume calculations and enables the observation of each printing nozzle. Furthermore, the quality of the printed image can be monitored post-printing by a camera system. In contrast, during the continuous printing process, there is no opportunity to analyse the drop shape in the set-up of our casting machine. Moreover, the ink load is controlled via the firing frequency of the print head. Only one printing step is possible with one print head assembly because the substrate is coiled up directly after printing. For the ink development the observation of the print head nozzles during jetting is quite important. Therefore, the following results evaluate the possibility to utilize the LP 50 printers as small-scale devices for ink development and first experiments, and later scale up the printing process to a continuous printing using the jetting station JS 20 of the LP 50 printer family. Image analysis has been employed as a quality control tool for the continuous inkjet printing to evaluate the quality of the printing.
the quantitative determination of the printed ink was performed via UV–Vis analysis with a UV–Vis-photometer Spekol 1100 (Analytik Jena, Germany) at a wavelength of 630 nm. The content was calculated as amount of printed colorant (ink/film). An absorption of the drug-free film at 630 nm was excluded before executing the experiments. A calibration curve was measured each day before sample measurements. The calibration curves revealed a coefficient of determination (R2) above 0.99. Each measurement was performed in triplicate. The mean and standard deviation were calculated. 3.5.2. Image analysis Printed films were scanned using a standard computer scanner Perfection V800 Photo (Epson, Japan). Scanning was performed at resolution of 2400 dpi and 48-bit colour depth (16 bit per colour channel) with disabled automatic image corrections. Films printed with varying frequencies used also for UV-VIS method were scanned and analysed. Image analysis was performed using an OpenCV based Python script (Python software foundation, USA). For the analysis a rectangle area enclosing the films was manually selected for each case. The raw RGB pixel values were transformed to absorbance as -log10 (R/B), where R is the red colour channel, and B is the blue colour channel. The red channel was chosen as the blue ink has the strongest absorption in red. The blue channel was chosen as a background reference. The sum of absorbance values of all pixels (Asum) was calculated for each film and used in further analysis.
4.1. Ink properties The dynamic viscosity of the blue test ink was found to be 14.20 ± 0.16 mPa*s and a surface tension of 35.61 ± 0.027 mN/m was measured, which is in accordance to the requirements of the print head manufacturer (8–20 mPa*s and 24–36 mN/m) for the utilized Spectra S Class print head [25].
3.6. Mechanical properties
4.2. Non-continuous film production
Mechanical properties were investigated with the Texture Analyser (Ta-XTplus, Stable Microsystems, UK) according to the method of Preis et al. [23]. To evaluate the results, the elongation to break and the puncture strength was calculated of 6 samples per batch. The mean and standard deviation were calculated.
All produced drug-free films were flexible and transparent showing no precipitations or air bubbles. After the film casting with the Erichsen film applicator, a film of a size of approx. 20 cm x 30 cm is obtained. The complete film was further printed using the LP 50 printer. After the printing process, films were cut into sample sizes of 2 cm x 3 cm (6 cm2).
3.7. Disintegration time 4.3. Non-continuous printing The disintegration time of the ODFs was determined utilizing an automated disintegration tester (Pharma Test Apparatebau, Hainburg, Germany) adapted for film formulations according to Preis et al. [24]. 6 film specimens were measured per batch. The mean and standard deviation were calculated.
The multiple layer printing of orodispersible films was successfully performed. Seven layers can be printed without destroying the integrity of the film. After printing, each film remains flexible and stable after removing it from the intermediate liner. Microscopic images showed that with increasing printed layers the intensity of the blue ink increases. The boundary area between ink and film can be distinguished more clearly with increasing layers. Fig. 2 displays the photometric analysis of the printed films and the evaluation of the results. Fig. 2A shows the number of printed layers on the x-axis versus the ink load per film sample (6 cm2) on the y-axis. A linear correlation could be observed (R= 0.999). The first printed layer revealed an ink content of 3.5 μg ink per film sample (Fig. 2B). On average 4.32 ± 0.76 μg ink was printed per layer. Knowing the
4. Results and discussion Non-continuous inkjet printing has been often described in the pharmaceutical field recently [10,14,16]. However, non-continuous and continuous inkjet printing show some major differences. When printing with the LP 50, the applied ink amount is controlled via the resolution of the artwork programmed by the user. Printing with a single or with multiple nozzles is feasible without losing quality of the 207
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Fig. 2. A: Non-continuously printed films with 1–7 layers, n=3, mean ± SD, B: mean ink amount per printed layer, n=3 C: correlation between the calculated ink amount per sample and the actual measured one [μg], D: calculated and measured ink amount/ film sample per layer.
the ink formulation, a gel-like texture was obtained after drying. This resulted in a lower puncture strength which is more pronounced the more layers and the more ink is applied onto the film. This texture also explains the higher elongation to break with increasing ink amount. The more layers are printed, the higher is the elongation of the film before rupturing. Higher elongation to break can lead to incorrect dosing of the film because when the film is coiled up or stamped to the sample size, mechanical forces are applied to the films. Depending on the force and the flexibility of the film, the film can be stretched which leads to an incorrect dosing. Therefore, elongation and puncture strength are major quality attributes for the film production. The results show that a multiple printing has a huge impact on the mechanical properties of the film. This leads to the conclusion, that the ink formulation and the number of printed layers should be carefully selected. All printed films disintegrated within less than 15 s and fulfill therefore the requirements of the European Pharmacopoeia [26]. No significant influence of the printed layers on the disintegration time could be determined.
resolution of the printed image (750 dpi x 750 dpi) and the adjustment range for the drop size of the print head (25–30 pl), the amount of printed ink can be calculated. This enables the correlation of the measured ink content versus the calculated ink amount considering the 7 printed layers (Fig. 2C, D). It can be seen, that the first printed layers contain less ink than initially calculated. With increasing layers, the deviation between measured and calculated values decreases. These results confirm that precise inkjet printing is feasible even when printing several layers. A saturation of the printed ink while printing multiple layers as described in literature [21,22], could not be observed. Fig. 3 shows the mechanical properties of the printed films expressed as elongation to break and puncture strength. It can be seen, that with increasing ink layers, the puncture strength decreases. Due to
4.4. Continuous film production Major differences between continuous and non-continuous film production have been described in literature before [6]. Apart from the viscosity of the casting solution, the wet film thickness, the velocity of the intermediate liner and the drying temperature are critical process parameters for continuous film production. This leads to a limited opportunity of production setting variations for the subsequent printing process. As the print head is fixed to the continuous film coater, the printing velocity is controlled by the speed of the intermediate liner, which moves under the print head. The printing velocity is a critical production parameter and should be varied to find the optimal settings for the continuous printing. Therefore, the velocity of the intermediate
Fig. 3. Mechanical properties of non-continuously printed films with 1–7 layers. Black symbols represent the puncture strengths of the films and grey symbols the elongation to break; n= 6, mean ± SD. 208
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absorbance values by UV–Vis analysis and the absorbance by image analysis. A linear correlation with a correlation coefficient of R=0.997 was obtained. This proves the feasibility of utilizing the image analysis as tool for ink colourant determination as model drug. Fig. 7 shows the image analysis of a film sample printed with 200 Hz on the left and 400 Hz on the right. The upper pictures exemplarily show the coloured scale which enabled the quantitative analysis of the ink via the absorbance of the sum of the pixels. Lower pictures display the absorbance via the width of the films. These diagrams allow conclusions of the operational reliability of the nozzles. On the 200 Hz film, an unstable nozzle and a failing nozzle can be seen on the left side of the film. These nozzles can be detected in the absorbance profile below as well. The intensity of the absorbance decreases due to missing or irregular colour of the printed line. The image analysis tool is a promising tool to determine the ink content after production but is limited to coloured inks or light absorbing drug substances. Furthermore, it is assumed that the printed ink is uniform; if not, the image analysis leads to inaccurate contents because only the colourant and not the API is detected. Nevertheless, it can be helpful in future to perform the image analysis in-line with a camera to detect failing nozzles. The results for the mechanical properties of the films printed with different firing frequencies are in-line to the results for the films printed with multiple layers, which were described before. Higher ink load at higher firing frequencies led to higher elongation to break of the films (15.3 ± 1.2% at 50 Hz and 22.7 ± 1.7% at 500 Hz). The puncture strength reveals the opposite effect (0.5 ± 0.02 N/mm2 at 50 Hz versus 0.17 ± 0.02 N/mm2 at 600 Hz), which was also observed for the noncontinuous printing. However, for continuous printing it was found less pronounced, probably because of the lower ink load.
liner was varied from 50 mm/min to 200 mm/min. Lower velocities led to brittle films, whereas for higher velocities, the time within the drying channel of the film coater was too short, which led to wet films after passing the drying channel. All films cast within these parameter settings led to dry and flexible films with smooth surfaces, which could be printed directly after production. 4.5. Continuous printing Several parameter settings influence the printing quality during continuous production. Beside the firing frequency (varied from 5 to 600 Hz), which determines the applied ink, the printing velocity is of crucial importance. To ensure a dry and still flexible film, velocity was varied from 50 mm/min to 200 mm/min. At a velocity of 50 mm/min the film is still flexible enough to be coiled up and at 200 mm/min the film is just dry after passing the drying channel. Furthermore, the applied voltage has a high influence on the printing process. The drop shape is also dependent on the voltage. The utilized print head features two piezo elements, which control the jetted ink amount by applying variable voltages on the piezo elements. Therefore, the voltage can be varied from 70 to 120 V for both piezo elements. Moreover, the pulse shape parameters were changed, and the shape of the printed drops analysed. The assembly of the print head within the continuous production line allows a precise rotation of the print head holder so that the resolution of the printer can be increased by altering the angle of the print head. To investigate the effects of the resolution on the formed and printed drops and the amount of ink, the angle of the print head was varied from 0 ° to 60 °. In addition to that, the influence of the distance of the print head to the substrate was analysed. Due to the experience of previous experiments, following parameters were chosen as basic printing parameters: 90 V, 1 μs – 4 μs – 1 μs for the pulse shape, 30 °C as temperature within the print head, 3 mm distance to the substrate, 0° print head angle and a printing velocity of 125 mm/min. These basic parameters were kept constant while varying one of the printing parameters as described before.
4.5.2. Variation of the print head angle The variation of the print head angle results in a higher resolution of the printed image. The natural resolution of the Spectra S Class print head is 50 dpi. By setting the angle of the print head to 45°, the resolution can be increased to 71 dpi. Fig. 8 displays scans and microscopic images of printed films at different angles of the print head. The higher the pre-set angle, the closer are the resulting lines. At an angle of 60 °, the printed lines are merging, which can be seen in the scan as blue dots. The printed image gets an irregular shape. The closer printed lines result in a higher ink amount on the orodispersible film which can be seen in Fig. 9A. With increasing angle, the deposited ink also increases. A sinusoidal shape of the curve can be observed. An angle of 60 ° doubles the printed ink amount (1.6 ± 0.09 μg vs. 3.2 ± 0.16 μg).
4.5.1. Variation of the firing frequency Fig. 4 shows scans and microscopic images from orodispersible films printed with different firing frequencies. Firing with 5 and 10 Hz at a printing velocity of 125 mm/min led to individual drops on the substrate. With increasing firing frequency up to 50 Hz the single drops merge to a printed line. At 100 Hz an unstable line was printed consisting of liquid bulges connected by ridges. This phenomenon has been described in literature before [27]. With further increasing firing frequencies, the unstable lines become thicker and get closer together. The higher the firing frequencies of the print head, the higher is the ink amount per film sample (Fig. 5). A linear correlation between the firing frequency and the printed ink amount (R=0.994) could be shown. Because of this, the visual appearance of the printed lines (bulges connected by ridges) can be neglected. The focus of the printing during the continuous film production is to apply a defined volume and API amount onto the ODF and not to print perfectly shaped lines. The quality of the printed lines could therefore be neglected within the first experiments, as long as the printed API amount shows a linear correlation to the firing frequencies. For the continuous printing, there is still a lack of PAT and quality controls. Printing with the LP 50 printer enables drop shape analysis and control of the printed drops after image printing. Image analysis is one potential tool to verify the printing quality of the continuous printing process. After printing, the films can be scanned or monitored by a camera and the ink absorbance enables analysis of content and a nozzle observation so that failing nozzles can be detected. These assumptions could be confirmed by the performed image analysis (Fig. 6). A linear correlation (R= 0.999) between the firing frequencies during printing and the colouring depths of the pixels could be seen in Fig. 6A. Fig. 6B displays the correlation between the obtained
4.5.3. Variation of the printing velocity The printing velocity is controlled via the speed of the intermediate liner of the ODF. The higher the speed of the intermediate liner, the lower is the printed ink amount (Fig. 9B). The intensity of the liquid bulges decreases until at 200 mm/min an almost stable line is printed. But higher printing velocity also means less drying time for the ODF. This can lead to higher drying temperature settings to obtain a dry film after passing the drying channel. Higher drying temperatures may lead to lower tensile strength or the formation of air bubbles due to fast solvent evaporation. High air bubble quantities within the film result in an uneven surface of the film, which may complicate the printing process and the content uniformity. Therefore, printing at lower intermediate liner velocities is highly recommended. 4.5.4. Variation of the voltage The Spectra S Class print head is equipped with two piezo elements which can be separately controlled. By applying a certain voltage on the elements, a drop is forced out of the print head nozzle. Fig. 9C shows the impact of the applied voltage on the printed ink amount. With increasing voltage, the deposited ink also increases. It could be shown, 209
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Fig. 4. Scans and microscopic images from orodispersible films printed with blue ink printing with various firing frequencies. Scale bars increased for better visualization.
4.5.5. Variation of the print head distance The setup of the print head within the continuous production line also allows a precise adjustment of the print head distance. By increasing the distance between nozzle plate and substrate, the droplet has higher fly times and this can affect the drop shape and size. Fig. 9D displays the effect of the print head distance on the amount of printed ink. No distinct effect can be observed by changing the distance. Therefore, the distance seems to be no major quality factor during continuous printing concerning the applied drop volume. 4.5.6. Variation of the pulse shape Settings of the pulse shape of the print head have a crucial impact on the drop shape and size. The pulse shape is highly dependent on the used print head. The spectra print head has a quite simple pulse shape. Basic settings for the performed printing were 90 V and 1 μs – 4 μs – 1 μs. This means that it lasts 1 μs until the voltage is fully applied, then hold for 4 μs and need 1 μs to decrease. Beside the applied voltage, the correct settings for the pulse shape are essential to obtain optimal droplets. The pulse shape was varied for the rising time from 1 μs to 10 μs, for the dwell time from 4 μs to 20 μs and for the falling time from 1 μs to 10 μs. The effects were observed utilizing light microscopic images of the printed lines. Following observations could be made for the rising time: Changing the settings from 1 to 4 μs, no significant influence on the printed lines could be observed. Further increasing to 10 μs led to some single nozzle failings and therefore missing lines. The shape of the printed lines of the operating nozzles was not affected by the faster
Fig. 5. Deposited ink amount per film sample at different firing frequencies, n=3, mean ± SD.
that there is a linear correlation between the applied voltage and the resulting ink drop volume (R=0.998). Fig. 10 confirms these results. The intensity of the ink and of the printed lines increase from 90 to 110 V. By applying too low voltages, no reproducible drops can be formed as displayed in Fig. 10 (for 70 V).
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Fig. 6. Results of the image analysis; A: correlation of the utilized firing frequency of the print head and the sum of the absorbance of the pixels, n= 3, mean; B: correlation between the absorbance of different firing frequencies obtained by UV–Vis measurements and the sum of the absorbance of the pixels, n=3, mean.
Fig. 7. Image analysis of 200 Hz and 400 Hz printed films. Lower pictures show the absorbance via the width of the film. n= 3, mean.
process allows accurate printing of even electronics [12,13]. To print precise electronical structures, various parameter settings have to be chosen. These parameter settings are highly dependent on the utilized print head assembly and the ink formulation. Furthermore, the characteristics of the substrates (contact angle, porosity, etc.) have to be taken into account. These facts result in a very complex process. For the LP 50 printer, analytical technologies provide process control, e.g. with the help of the stroboscopic camera, which enables the observation of the nozzle plate. The picture or geometric form, which should be printed can be designed by the printer’s software. Printing with one or only a few nozzles is feasible without altering the quality of the printed picture and only prolonging the printing time. The quality of the
rising times. Higher effects could be observed by changing the dwell times. With higher dwell times (above 15 μs) the quality of the printed lines decreases dramatically and at dwell times of 20 μs almost no nozzle printed reproducible droplets anymore. The falling time also had a crucial impact. At falling times of 4 μs the printed lines became irregular. By further increasing the falling time (10 μs) no line could be printed anymore.
4.6. Comparison and transfer non-continuous to continuous printing Inkjet printing is a very precise printing process, where small droplets are placed onto variable substrates. The high precision of the 211
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Fig. 8. Scans and microscopic images from orodispersible films printed with blue ink at various print head angles. Scale bars increased for better visualization.
reproducible. This has to be guaranteed and can be controlled by the camera systems of the LP 50 printer. In contrast to this kind of printing process, the printing during a continuous ODF production differs. The applied ink amount is controlled via the firing frequency of the print head and is not programmed in advance. Therefore, a reproducible
printed image is highly dependent on the drop shape of the droplets. When the droplet leaves the nozzle plate, a cycle has to be formed until the droplet meets the substrate. Otherwise, no precise dot will be printed. For pharmaceutical applications, the formation of a perfect drop is not necessary as long as the applied drug amount is
Fig. 9. Effects of different parameter settings on the ink load of the film sample; A: print head angle, B: intermediate liner velocity, C: applied voltage to the print head and D: print head distance to the substrate, n=3, mean ± SD. 212
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Fig. 10. Scans and microscopic images of printed orodispersible films with blue ink at different voltage settings. Scale bars increased for better visualization.
which was proven to be feasible as off-line application within this article. Furthermore, a Raman probe or NIR probe could be utilized as PAT tool, not only enabling the control of the jetting of single nozzles, but also to directly quantify the printed drug amount without needing a coloration of the ink. A further challenge of printing during continuous production is the short drying time of the ink, which is caused by the limited ability to adjust the velocity of the substrate (due to the ODF manufacturing) and the short way between the mounted print head and the coiling machine. This could be overcome by incorporating further drying units (e.g. IR lamps or heating elements). Moreover, further research has to be undertaken concerning the development of printable inks. Especially new, non-toxic polymers enabling a precise adjustment of dynamic viscosities and surface tensions, while staying stable during the printing process without clogging the small print head nozzles would be desirable.
jetting of the nozzles is essential to enable a precise dosing of the ink. Whereas the non-continuous printing is feasible with one nozzle, almost all nozzles have to jet during the continuous ODF printing. Otherwise, only small ink amounts would be applied. Similar to the LP 50 printing process, for a pharmaceutical application within a continuous ODF production process, the shape of the droplet and the visual appearance of the printed lines has only an inferior standing as long as the printed volume is reproducible and controlled by the applied production setting. As settings of crucial importance were found: applied voltage, firing frequency and print head angle. The pulse shape was found to play indeed an important role to enable a jetting and a constant shape of the droplet but was further found to be robust to small variations regarding the applied ink amount. Furthermore, the distance of the print head to the substrate led to only small variations in applied drug amount despite the distance is very important for the shape of the applied droplet (circular dot or irregular shaped dot). The non-continuous printing allows precise multiple layer printings, which result in higher ink loads on the ODF. However, multiple printing cycles cause long processing times because the printed layer has to dry before the next printing step could be performed. In contrast to this non-continuous printing, the continuous printing of orodispersible films can be conducted quite fast and the film can be coiled up directly after printing. The continuous process limits the ink load on the film because only one layer can be printed with one print head. Due to the limited drying time before the film is coiled up, it was found that the maximum frequency of 1000 Hz is applicable, still ensuring complete drying of the ink. The non-continuous printing can be quite useful for the ink development and the finding of the optimal parameter setting for the print head. The obtained data from the tested Spectra XL 30 ink reveal that a firing frequency of 380 Hz during continuous printing is necessary to print the same ink amount as one layer (1 cm × 2 cm) printed noncontinuously. These data enable the possibility to utilize the LP 50 printer as a small-scale device for the development and later transfer of the process to the continuous production line. Nevertheless, some technical challenges have to be overcome. To enable a better process control, a PAT tool is needed, to observe the single nozzles and the jetting of the nozzles. This could be realized by a high-speed camera and the simultaneously ongoing image analysis,
4.7. Continuous inkjet printing for various printing concepts In literature, several printing concepts have been discussed before [28]. Beside of the precise and flexible dosing, one of the main advantages of printing APIs is the potential of producing lower drug waste by centered printing. While cutting the jumbo- or daughter-rolls into the specified sample size, API waste occurs [29], which can be quite hazardous and cost intensive, depending on the used API. By centered printing, the waste can be significantly reduced. The previous described results enabled the finding of the optimal production settings for the continuous printing. Fig. 11 displays the implemented printing concepts printed utilizing the JS 20 within a continuous production process utilizing the basic parameter settings described before. Symmetric and asymmetric lines enable a high dosing flexibility by cutting the films. Central surface printing or dots are advantageous for high potent or expensive drugs to increase the safety during production and minimize the API waste. Complete printing can be utilized to obtain higher drug loads or to produce fixed-dose combinations. It was feasible to print the previously proposed printing concepts during continuous film production. Each film dried during the prescribed drying time and stayed flexible despite the printing. 213
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Fig. 11. Implemented printing concepts utilizing the JS 20 during continuous manufacturing.
5. Conclusion
[8] Alomari M, Mohamed F, Basit A, Gaisford S. Personalised dosing: Printing a dose of one’s own medicine. Int J Pharm 2015;494:568–77. [9] Pardeike J, Strohmeier DM, Schrödl N, Voura C, Gruber M, Khinast JG, et al. Nanosuspensions as advanced printing ink for accurate dosing of poorly soluble drugs in personalized medicines. Int J Pharm 2011;420:93–100. [10] Sandler N, Määttänen A, Ihalainen P, Kronberg L, Meierjohann A, Viitala T, et al. Inkjet printing of drug substances and use of porous substrates-towards individualized dosing. J Pharm Sci 2011;100:3386–95. [11] Janssen E, Schliephacke R, Breitenbach A, Breitkreutz J. Drug-printing by flexographic printing technology–a new manufacturing process for orodispersible films. Int J Pharm 2013;441:818–25. [12] Tekin E, Smith P, Schubert U. Inkjet printing as a deposition and patterning tool for polymers and inorganic particles. Soft Matter 2008;4:703. [13] Singh M, Haverinen H, Dhagat P, Jabbour G. Inkjet printing-process and its applications. Adv Mater 2010;22:673–85. [14] Uddin M, Scoutaris N, Klepetsanis P, Chowdhry B, Prausnitz M, Douroumis D. Inkjet printing of transdermal microneedles for the delivery of anticancer agents. Int J Pharm 2015;494:593–602. [15] Ihalainen P, Määttänen A, Sandler N. Printing technologies for biomolecule and cell-based applications. Int J Pharm 2015;494:585–92. [16] Delaney J, Smith P, Schubert U. Inkjet printing of proteins. Soft Matter 2009;5:4866. [17] Sharma G, Mueannoom W, Buanz ABM, Taylor KMG, Gaisford S. In vitro characterisation of terbutaline sulphate particles prepared by thermal ink-jet spray freeze drying. Int J Pharm 2013;447:165–70. [18] Raijada D, Genina N, Fors D, Wisaeus E, Peltonen J, Rantanen J, et al. A step toward development of printable dosage forms for poorly soluble drugs. J Pharm Sci 2013;02:3694–704. [19] Scoutaris N, Alexander M, Gellert P, Roberts C. Inkjet printing as a novel medicine formulation technique. J Control Release 2011;156:179–85. [20] Buanz ABM, Belaunde C, Soutari N, Tuleu C, Gul M, Gaisford S. Ink-jet printing versus solvent casting to prepare oral films: effect on mechanical properties and physical stability. Int J Pharm 2015;494:611–8. [21] Wickström H, Palo M, Rijckaert K, Kolakovic R, Nyman JO, Määttänen A, et al. Improvement of dissolution rate of indomethacin by inkjet printing. Eur J Pharm Sci 2015;75:91–100. [22] Buanz ABM, Saunders MH, Basit AW, Gaisford S. Preparation of personalized-dose salbutamol sulphate oral films with thermal ink-jet printing. Pharm Res 2011;28:2386. [23] Preis M, Knop K, Breitkreutz J. Mechanical strength test for orodispersible and buccal films. Int J Pharm 2014;461:22–9. [24] Preis M, Gronkowsky D, Grytzan D, Breitkreutz J. Comparative study on novel test systems to determine disintegration time of orodispersible films. J Pharm Pharmacol 2014;66:1102–11. [25] Dimatix. Data sheet SE-128 AA. 2017 Accessed 06 November 2017 https://www. fujifilmusa.com/shared/bin/PDS00009.pdf. [26] Orodispersible tablets. European directorate for the quality of medicines & healthcare. Strasbourg, France: EDQM); 2017. [27] Duineveld PC. The stability of ink-jet printed lines of liquid with zero receding contact angle on a homogeneous substrate. J Fluid Mech 2003;477:175. [28] Preis M, Breitkreutz J, Sandler N. Perspective: concepts of printing technologies for oral film formulations. Int J Pharm 2015;494:578–84. [29] Jansen J, Horstmann M. Gut abschneiden - Feindosierung in oralen Filmen.
A multilayer printing utilizing a non-continuous inkjet printing system is feasible, when required drying times are exactly followed. With increasing layers up to 7 layers the printed ink amount remains constant, but a major impact of the number of printed layers on the mechanical properties could be observed. The continuous printing enables a direct API printing during production with a subsequent packaging of the product. Optimal production settings for the continuous printing could be found by analysing variations of critical process parameters like firing frequency, print head angle, applied voltage and pulse shape. A quality control system after production was successfully employed utilizing image analysis. Transfer from noncontinuous to continuous printing was performed and demonstrated by continuous printing of various different printing concepts. Acknowledgements The authors are grateful to Stefan Stich who provided his help for the construction of the print head holder and its assembly in the continuous production line. Furthermore, the authors want to thank Wouter Brok from Meyer Burger (Eindhoven, The Netherlands) who provided his help and knowledge for the integration of the print head into the continuous film coating machine from Optimags. This work was partially supported by the Alexander von Humboldt Foundation. References [1] Slavkova M, Breitkreutz J. Orodispersible drug formulations for children and elderly. Eur J Pharm Sci 2015;75:2–9. [2] Borges AF, Silva C, Coelho JF, Simões S. Oral films: current status and future perspectives: I—galenical development and quality attributes. J Control Release 2015;206:1–19. [3] Liew K, Tan JTF, Peh K. Characterization of oral disintegrating film containing donepezil for alzheimer disease. AAPS PharmSciTech 2012;13:134–42. [4] Visser JC, Woerdenbag HJ, Crediet S, Gerrits E, Lesschen MA, Hinrichs WLJ, et al. Orodispersible films in individualized pharmacotherapy: The development of a formulation for pharmacy preparations. Int J Pharm 2015;478:155–63. [5] Dixit R, Puthli S. Oral strip technology: overview and future potential. J Control Release 2009;139:94–107. [6] Thabet Y, Breitkreutz J. Orodispersible films: product transfer from lab-scale to continuous manufacturing. Int J Pharm 2018;535:285–92. [7] Hoffmann EM, Breitenbach A, Breitkreutz J. Advances in orodispersible films for drug delivery. Expert Opin Drug Deliv 2011;8:299–316.
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Slovenia in 2014 and finished his Master at the same faculty in 2007. His main research topics are simulations of pharmaceutical processes and process analytical technologies.
TechnoPharm 2014;4:306–13. Yasmin Thabet studied pharmacy at the Heinrich Heine University Duesseldorf, Germany and received the license as a pharmacist in 2013. Since 2014 she is working as scientific assistant at the Institute of Pharmaceutics and Biopharmaceutics, University Duesseldorf, Germany focusing on her PhD thesis: Continuous manufacturing of orodispersible films as combination products.
Jörg Breitkreutz is a pharmacist by training and finished his PhD in 1996 at the Institute for Pharmaceutical Technology and Biopharmaceutics in Münster under supervision of Prof. Gröning. From 1996 to 1997 he joined Thiemann Arzneimittel GmbH in Waltrop, Germany, and from 1997 to 2004 the University of Münster to work on his habilitation on paediatric drug formulations. In 2004 he became professor for pharmaceutical technology at the Heinrich-Heine-University in Düsseldorf, Germany. Since 2010 he is the president of the International Association of Pharmaceutical Technology (APV). His research focuses on paediatric drug formulations, orphan drugs and process analytical technologies.
Rok Šibanc is a postdoc researcher at Institute of Pharmaceutics and Biopharmaceutics at Heinrich Heine University Düsseldorf since October 2015 working on a research project involving pellet coating. He completed his PhD at Pharmacy at University of Ljubljana,
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