Printable Medicines: A Microdosing Device For Producing Personalized Medicines - Pharmaceutical Technology

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PharmTech Europe

Printable Medicines: A Microdosing Device For Producing Personalized Medicines
The authors describe a new method for the production of personalised medicines involving the direct printing of drug solutions or suspensions containing APIs and excipients onto edible paper carrier materials utilising ultra-precise microdrop printing technology. The approach allows ultra-precise dosing of the API according to the specific requirements of each individual patient and is suited for highly active low-dose drugs.

Pharmaceutical Technology Europe
Volume 23, Issue 1

Our approach to producing personalised drugs

Figure 1: Schematic of the set–up.
The method for producing personalised, individually-dosed drugs involves using an inkjettype printing technique where all of the API and related excipients required by a specific patient are directly printed onto an edible substrate of a special paper carrier. Figure 1 shows the general principle of this approach.

After printing, the paper strip may be dried and online process analysers used to verify the dosing in real time, e.g., by using UV-Vis, NIR or Raman spectroscopy. For product safety reasons, as well as to prevent counterfeiting, a 2D matrix code including the drug and patient information, with up to 200 million characters per centimetre, can be printed on the paper strip. The printed paper carrier is subsequently rolled up to minimise the size of the dosage form, and then cut and inserted into a hard gelatin capsule for oral administration. The production steps for a capsule (printing, drying, controlling, rolling and inserting in a capsule) can occur within a few seconds.

One prerequisite for the successful application of the technique is the choice of an appropriate paper carrier material and a suitable solvent, depending on the properties of the API. High solubility of the API in the solvent is preferred to ensure high API concentrations for a faster dosing process, as well as to minimise the amount of paper substrate needed. Alternatively, suspensions of API particles in an anti-solvent can be printed. The paper carrier must not interact with the API and should be highly digestible. A paper grade with high penetration volume for fluid uptake is required to print multiple API formulations onto one paper strip.

Currently, different solvents are used to prepare the drug solutions, depending on the solubility of the APIs, e.g., deionised water, ethanol or isopropanol. Additionally propylene glycol is added to the formulations to stabilise the dosing process and to inhibit recrystallisation of the dissolved API at the printer head. Alternative solvents and anti-solvents will be evaluated in the future.

The printing apparatus for manufacturing the medication comprises a dropondemand technology for dosing, which is based on the piezo-electric effect. This technique is adapted from inkjet printing and is used to eject a predefined amount of a drug solution or suspension onto the carrier substrate.

Figure 2: Principle of the microdrop printing device using the piezoelectric effect.
A microdrop printing device from Microdrop Technologies GmbH (Germany) has been used for the experiments.3 This system consists of a fluid container, a flexible tube connecting the container with a capillary and a drop-generating electric element. The end of the capillary is formed as an orifice, where specific amounts of fluid are ejected. The capillary of the microdosing device is surrounded by a piezoelectric element, which is deformed when an electric voltage pulse is applied. This deformation leads to a compression of the capillary and, subsequently, to the ejection of a fluid droplet with an exactly defined volume (Figure 2). Dropondemand technology enables the generation of single droplets in the range of 30–500 pl. The formation of one single droplet takes about 200 s and the maximum drop rate can be set to 2000 Hz.3,4 The volume of the droplets depends on the electric voltage pulse level, the geometry of the nozzle and fluid properties, such as surface tension, dynamic viscosity and contact angle.

Droplets of different fluids were analysed with a video camera and image analytical tools, which showed that the size of an ejected water droplet (surface tension of 72.75 mN/m and viscosity of 1 mPa∙s) is about 80 m for a nozzle with a diameter of 70 m. Ethanol droplets with a considerably lower surface tension of 22.55 mN/m and a similar viscosity of 1.2 mPa∙s have a size of 65 m. The ejection velocity for most liquids is approximately 1 m/s.

Temperature adjustment elements are installed for heating or cooling the fluid container and the capillary, and for equilibrating the fluid flow properties before ejection; thus, constant printing conditions are guaranteed. The printing of larger amounts of the drug solution/suspension is realised by ejecting a defined number of droplets. The final dosage of the medication can be calculated from the concentration of the liquid, the droplet size and the number of droplets. This printing method provides an efficient way of manufacturing drugs with target dosages in the range of 1–20 mg of API.

The drying of the printed paper strip after completion of the dosing process will be performed using IR-dryers or air dryers. Heat-sensitive drugs should not be exposed to temperatures exceeding 50 C, which can be compensated by an elongated drying time. To control the quality of the final dosage form and the performance of the process, the application of an NIR or UV–Vissensor is envisioned to be an appropriate tool to measure API content on the paper strip and to ensure that the amount of residual solvent does not exceed a predefined value.

The benefits and drawbacks

Major advantages of the technique include the fact that most steps downstream of the API synthesis can be eliminated. In fact, after the final purification and/or crystallisation, the drug solution or suspension, including further printing additives, can be filled in cartridges. Alternatively, in case of limited drug stability in solution, a dry powder can be provided with an appropriate solvent in a twocompartment container. These prepacked drug containers are delivered to pharmacies or care providers, effectively eliminating most steps in association with powder processing, such as blending, milling, sieving, granulation, compaction and coating of solid forms.

Potential limitations of the technique may involve the production of high-dose dosage forms because of the limited capacity of paper substrates for fluid uptake and the solubility limit of many APIs, which may prevent the dosing of highly concentrated formulations. However, solvent optimisation could offer a solution. Furthermore, the actual setup is not intended for the mass production of dosage forms with a high throughput, such as seen in conventional tablet presses.

Table 1: Main advantages and limitations of the presented microdosing technique for the preparation of personalised oral dosage forms.
The main advantages and limitations of the presented technique for the production of personalised drugs are listed in Table 1.


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