Pressure Gauge Plunger for Semi-Solid Mass Extrusion 3D Printing Platforms

Abstract

The pressure gauge plunger for 3D printing platforms is applicable in various 3D printing fields (tissue bioprinting as well as food, pharmaceutical and ceramic industries). Its usefulness is based on its ability to continuously control the applied pressure throughout the entire printing process thanks to the plunger mechanism. It therefore allows improved quality and on-the-spot detection of errors, allowing corrective actions to be applied during the process. Using a stress gauge, the pressure values ​​exerted by the printing platform components on the plunger (and thus on the extruded mass) are obtained. This continuous control allows profiling of the printed semi-solid mass, allows the most suitable printing parameters to be set on-the-spot, and even allows the process to be fully automated.

Description

[Technical Field]

[0001] The present invention is in the area of ​​3D printing of semi-solid masses. [Background technology]

[0002] 3D printing is currently playing a crucial role in small-scale industrial production in various fields, such as pharmaceutical technology and the production of pharmaceutical dosage forms, due to its versatility. This technology has developed with the goal of reducing the long timeframes and enormous costs involved in drug development and manufacturing (Jamroz et al., 2018). In the field of pharmaceutical technology, three technologies for 3D printing stand out: fused deposition modeling (FDM), direct extrusion, and gel extrusion (semi-solid extrusion, or SSE). In the latter, a semi-solid material (gel or paste) is forced through an orifice, syringe plunger, or worm screw by compressed air pressure. In the pharmaceutical industry, it is important to guarantee the mass uniformity (Monograph 2.9.5., Royal Spanish Pharmacopeia) and content uniformity (Monograph 2.9.6., Royal Spanish Pharmacopeia) of all produced pharmaceutical dosage forms, thereby complying with the pharmacopeia requirements of different regulatory authorities (e.g., AEMPS, EMA, FDA). In 3D printing, the amount of active ingredient is determined by the extrusion volume, which, together with the control of the printing pressure, ensures that the exact amount of material, and therefore the dose of active ingredient, is dispensed in each production batch of pharmaceutical dosage forms (Zidan et al., 2019). Among the technologies for 3D printing with solid materials, there is a system for preparing pharmaceutical compositions that allows for monitoring the pressure in the printing device (US Patent Application Publication No. 2020338009).

[0003] Currently, the state-of-the-art technology of semi-solid mass extrusion does not allow this control, and this is considered a significant challenge as pressure is a critical parameter in the printing process ( Zidan et al., 2019 ).

[0004] References Jamroz W, Szafraniec J, Kurek M, Jachowicz R. 3D printing in pharmaceutical and medical applications. Pharm Res. 2018;35(9):1-22. Zidan A, Alayoubi A, Coburn J, Asfari S, Ghammraoui B, Cruz CN et al. "Extrudability analysis of drug-loaded pastes for 3D printing of modified release tablets." Int J Pharm [Internet]. 2019;554(November 2018):292-301. Available from: https: / / doi.org / 10.1016 / j.ijpharm.2018.11.025. Agencia Espanola de Medicamentos y Productos Sanitarios [Spanish Drug and Health Products Agency]. Monograph 2.9.5. Uniformity of mass of single-dose preparations [Uniformity of mass of single-dose preparations]. Royal Spanish Pharmacopeia. 2008 Spanish Drug and Health Products Agency. Monograph 2.9.6. Uniformity of content of single-dose preparations. Royal Spanish Pharmacopeia. 2008 Summary of the Invention

[0005] In the pharmaceutical industry and dosage form manufacturing, mass uniformity is fundamental to ensure uniformity of the dose of the main active ingredient in each printed dosage form.

[0006] The semi-solid mass used in 3D printing with SSE technology passes through a nozzle and exhibits specific behavior depending on its hydrodynamic properties, resulting in linear flow only within a given pressure range. In the case of printing dosage forms, non-linear flow results in dosage errors.

[0007] To solve this problem, we designed a plunger that can be adapted to syringe-type cylindrical dispensers of different volumes and can measure the applied pressure throughout the printing process to ensure that the correct amount of semi-solid material is dispensed by microextrusion or semi-solid extrusion (SSE) in the 3D printing platform.

[0008] The plunger that is the subject of this invention is equipped with a strain gauge that can continuously measure the pressure that the printing platform engine applies to it to obtain the desired three-dimensional form, and therefore the pressure that is applied to the extruded mass throughout the process.

[0009] The present invention, i.e., plunger measurement instrumentation, provides a series of advantages which are outlined below. Allows continuous hydrodynamic profiling of each mass used, thus allowing adjustment of printing parameters before printing begins Ensures consistent flow of semi-solid mass through the syringe nozzle of the dispensing cylinder, thus ensuring accurate extrusion volume and therefore dosage Using the printing platform's personalized firmware, continuous control of the process can be achieved and corrections can be made during the process. It makes it possible to detect possible printing errors such as the presence of air inside the mass, which can cause errors in the flow (sudden drop in printing pressure) or solidification inside the nozzle (sudden increase in printing pressure), so that some of these errors can destroy the recorded 3D morphology and guarantee the design quality during the printing process of each dosage form in every batch produced.

[0010] For all the reasons explained above, the present invention has direct applications in the field of 3D printing, not only in the pharmaceutical industry but also in tissue bioprinting and especially in the food, pharmaceutical (sic) and ceramic industries, where a uniform dose is required for each batch and between production batches when semi-solid masses are used.

[0011] To complement the description given herein and to help achieve a better understanding of the nature of the invention, a series of figures are attached as an integral part of said description, for illustrative purposes only and without showing any limitations, and are as follows: [Brief explanation of the drawings]

[0012] [Figure 1]Perspective view of a pressure gauge plunger for a 3D printing platform, showing the different parts of the instrumented plunger: the movable cylinder (1), the central cylinder (2), the flap (3) for fastening to the 3D platform, the screw (4) for adapting the invention to any syringe plunger or dispensing cylinder, the circular opening (5) for the fastening system between the movable cylinder (1) and the central cylinder (2), the pressure sensor connector (6), and the oval opening (12) for the fastening system between the movable cylinder (1) and the central cylinder (2). [Figure 2] A perspective view of a preferred embodiment of the present invention adapted to accommodate a syringe used in a 3D printing platform. The elements shown in this figure are the movable cylinder (1), the central cylinder (2), the flap (3) for fastening to the 3D platform, the pressure sensor connector (6), the screw (7) for the fastening system between the movable cylinder (1) and the central cylinder (2), and the syringe (8) used in the 3D printing platform. [Figure 3] Longitudinal section of the central cylinder. The elements shown in this figure are the central cylinder (2), the circular opening (5) for the fastening system between the movable cylinder (1) and the central cylinder (2), the pressure sensor connector (6), the connecting cable to the extensometer (9), the receptacle on the central cylinder for the movable cylinder (10), and the extensometer (11). [Figure 4] Graphical representation of the distribution of data points obtained using the present invention during the 3D printing of over 100 pharmaceutical dosage forms. Detected pressure (N.cm-2) (sic) is shown on the Y-axis against time (seconds) on the X-axis. Extrusion start point (13), feed rate correction and pressure rise point (14), air detection and sudden pressure drop point (15) and extrusion stop point (16). [Figure 5] Results of a comparative study on the printing of two batches of dosage forms according to the requirements of the Royal Spanish Pharmacopeia. DETAILED DESCRIPTION OF THE INVENTION

[0013] The plunger (FIG. 1), the subject of the present invention, consists of four essential parts: the movable cylinder (1), the central cylinder (2), the pressure sensor (11) and the threaded fixing area (4).

[0014] In a preferred embodiment (Figure 2), the central cylinder (2) and the movable cylinder (1) are connected via a fastening system using screws (7). The movable cylinder has tabs (3) that allow a plunger to be connected to the rails of a 3D printing platform, which applies pressure to the movable cylinder. At the end of the central cylinder, there is a set of 6-10 screws (4) that allow the invention to be adapted to any syringe plunger or dispensing cylinder, such as a cartridge pre-filled with a major active ingredient or other substance.

[0015] In a preferred embodiment, the plunger is adapted to a syringe (8) containing the semi-solid mass (gel or paste) to be extruded during the printing process. In this embodiment, the two main parts of the invention (1) and (2) are connected using a screw (7). The opening (5) of the central cylinder is circular and has the same diameter as the screw (7), while the opening (12) of the movable cylinder has an oval shape; both parts remain attached but unfixed, allowing the movable cylinder (1) to descend within the receptacle of the central cylinder (10) when the printing platform applies pressure to the cylinders. This connection allows movement between both parts in the range of 0.1 to 0.95 mm, which makes it possible to vary the pressure applied to the extruded mass.

[0016] At the bottom of the central cylinder (2), a disposable syringe plunger (7) is firmly connected to the screw (4), which makes contact with the mass to be extruded inside the syringe. As the movable cylinder descends in the central cylinder's receptacle (10), pressure is applied to its base, which is detected by a force gauge (11) attached to said base.

[0017] The sensor is based on the piezoresistive effect, which is the property of certain materials to change their normal resistance when exposed to a certain pressure, so that greater pressure means less electrical resistance. The calibration is calibrated to a pressure range where a linear response is obtained using a standard set of weight and repeat measurements to establish the relationship between the recorded voltage and the applied pressure.

[0018] The sensor is connected via a male 2-pin hook connector (6) to an electrical resistance circuit, which, together with a plate with an Arduino®-type microcontroller, allows for the continuous recording of data that can be stored for later interpretation thanks to web software created for that purpose. This software is able to overcome certain pre-established pressure limits and apply adjustments by sending commands to vary the feed rate via the API (Application Programming Interface) of a server integrated into the printing platform, thereby obtaining a constant pressure and a linear printing flow.

[0019] By means of the present invention, it is possible to prepare an orally disintegrating pharmaceutical dosage form of very reduced size (4.0 mm x 1.5 mm) and weighing only 25 mg, which meets the requirements proposed by the Royal Spanish Pharmacopeia, namely, uniformity of mass of single-dose formulations (Monograph 2.9.5., Royal Spanish Pharmacopeia) and uniformity of content of single-dose formulations (Monograph 2.9.6., Royal Spanish Pharmacopeia).

[0020] Mass uniformity tests comparing the standard printing process (without the pressure gauge plunger) with the improved printing process with the pressure gauge plunger demonstrated that the necessary requirements were met in the second case, which does not occur in the absence of pressure control in the extrusion process (Figure 5).

[0021] In another embodiment of the invention, the adjustment between the movable cylinder (1) and the central part (2) is done via a threaded set tab that allows both parts to stay together but remain unattached.

[0022] In another embodiment of the present invention, the printer firmware can be directly modified to provide direct feedback on pressure and subsequently self-adjust to correct the feed rate during the printing process.

Claims

1. A pressure gauge plunger for a 3D printer in semi-solid mass extrusion, characterized by a movable cylinder, a central cylinder, a fixation system between the cylinders that keeps both parts together but does not fix them, a pressure sensor, and a bottom end that is attached to a receptacle for receiving the material to be extruded, wherein the pressure sensor is a strain gauge located between the movable cylinder and the central cylinder that allows continuous recording of extrusion pressure data.

2. 2. The pressure gauge plunger of claim 1, wherein the inter-cylinder fixing system is implemented via two openings of different shapes and a fixing screw.

3. 3. The pressure gauge plunger of claim 2, which is attachable to both a syringe plunger and a printing cartridge pre-filled with material via a fastening system using a set of 6-10 screws and a set of grooves for inserting the syringe or the cartridge pre-filled with material for printing.

4. 4. A 3D printing process for pharmaceutical tablets, characterized in that it uses a pressure gauge plunger according to any one of claims 1 to 3, for continuously recording the extrusion pressure data and monitoring the quality control of the printed mass.

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