Direct Powder Extrusion of Paracetamol Loaded Mixtures for 3D Printed Pharmaceutics for Personalized Medicine via Low Temperature Thermal Processing

Three-dimensional printed drug development is nowadays an active area in the pharmaceutical industry, where the search for an appropriate edible carrier that permits the thermal processing of the mixture at temperature levels that are safe for the drug is an important field of study. Here, potato starch and hydroxypropyl cellulose based mixtures loaded with paracetamol up to 50% in weight were processed by hot melt extrusion at 85 °C to test their suitability to be thermally processed.

The extruded mixtures were tested by liquid chromatography to analyze their release curves and were thermally characterized. The drug recovery was observed to be highly dependent on the initial moisture level of the mixture, the samples being prepared with an addition of water at a ratio of 3% in weight proportional to the starch amount, highly soluble and easy to extrude. The release curves showed a slow and steady drug liberation compared to a commercially available paracetamol tablet, reaching the 100% of recovery at 60 min.

The samples aged for 6 weeks showed slower drug release curves compared to fresh samples, this effect being attributable to the loss of moisture. The paracetamol loaded mixture in powder form was used to print pills with different sizes and geometries in a fused deposition modelling three-dimensional printer modified with a commercially available powder extrusion head, showing the potential of this formulation for use in personalized medicine.

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Introduction

Medication adherence is crucial to achieve a properly successful therapy and the discontinuationMendibil, X.; Tena, G.; Duque, A.; Uranga, N.; Campanero, M.Á.; Alonso, J. Direct Powder Extrusion of Paracetamol Loaded Mixtures for 3D Printed Pharmaceutics for Personalized Medicine via Low Temperature Thermal Processing. Pharmaceutics 2021, 13, 907. of the treatment involves high economic costs and several thousands of premature deaths each year [1,2,3,4]. It is estimated that up to 50% of medicines are not used as prescribed; this misuse can happen for diverse reasons: confusion caused by polypharmacy, misunderstanding of the treatment, lack of health knowledge, poor palatability, etc. [5,6]. Lately, 3D Printed (3DP) drugs have drawn attention as an alternative to improve the adherence to treatment, improving the organoleptic characteristics and facilitating identification by using different shapes and colors [7,8,9]. The use of 3D printing allows the personalization of the oral forms (3DP pills) not only to improve adherence, but to customize the drug dosage, which is of great interest in the definition of the prescription for adults and is critical in pediatrics [10,11,12,13].

Different 3D printing technologies have been described in the literature to prepare 3DP pills [14,15,16,17]. Fused deposition modelling (FDM) and Semi Solid Extrusion (SSE) are the most straightforward technologies to prepare different mixtures and combinations of drugs and excipients, where the active pharmaceutical ingredient (API) is directly blended with or impregnated in the excipient/carrier to subsequently be processed. Seoane-Viaño et al. [18] did a thorough review of SSE, highlighting the numerous applications this technology has and discussing some of its drawbacks: post-printing drying process, complete solvent evaporation, risk of material collapse and loss of shape. On the contrary, FDM does not show those post processing problems, but it is limited by the low number of Food and Drug Administration (FDA) approved thermoplastic polymers and the thermal degradation the drug undergoes during the process [14,19,20]. Nevertheless, FDM has become one of the most popular 3D printing technologies, offering consumer level use at reduced investment [21,22]. The filament extrusion is the most extended FDM printing technique and there are commercially available solutions that upgrade the printer head to allow processing polymers in pellet and powder form [23], avoiding the need of filament production and reducing in this way the thermal stress of the deposited material.

Most of the found literature, where the FDM is used to prepare 3DP pills, applies the loaded filament approach; some authors use the impregnation method, where the drug is added to a preexisting polymer filament [24,25], but the most settled method is the preparation of the loaded filament by thermal processing. In this procedure, the drug loaded filament is manufactured by hot melt extrusion to later be fed into the 3D printer and be heated again. For example, Đuranović et al. [26] processed paracetamol loaded filaments based on poly(ε-caprolactone) (PCL) and poly ether oxide (PEO) polymers. They succeeded in extruding filaments and printing with drug loads up to 48% wt at 130 °C but their polymer–drug blends underwent two thermal processes, and although the processing temperature was under the melting point of the paracetamol, their samples showed yellowish discoloration, indicating some degradation or oxidation of the components. Gorkem Buyukgoz et al. [27] extruded filament based on Hydroxypropyl Cellulose (HPC) loaded with Griseofulvin at 140 °C to subsequently 3D print it at 170 °C. Other examples of drug loaded filament preparation to feed the 3D printer can be found in [28,29,30,31,32].

By contrast, Goyanes et al. [23] used a FDM modified printer to directly 3D print from powder form, avoiding in this way the need of filament preparation. They tested different molecular weight (Mw) HPC loaded with 35% itraconazole and successfully printed pills processing the blends at 170 °C. Ong et al. [33], following the work made by Goyanes, also tested the direct printing of powder mixtures of different HPC grades loaded with PEO and tramadol as API, achieving successful 3DP pills processed at 170 °C. The use of modified 3D printers to directly print the drug and excipient in powder form, reducing in this way the thermal stress on the API, seems to be the appropriate process chain to success in 3DP drug development. The search of suitable edible low temperature processing excipients to reduce the need of high temperatures in the printer nozzle is the next step to foster the research in this area. The main drawback in the 3DP drug development is the need of an appropriate drug carrier that allows the thermal processing of the mixture, and that meets the requirements of being edible, processable at low temperature and with customizable solubility to control the release curve.

In this regard, starch and HPC arise as interesting excipients as they can be processed at low temperatures and are widely used in pharma technology to prepare pharmaceutical formulations and are also extensively used in cosmetics and food products. The Guar gum (Gg) is used as binder and disintegrant in solid dosages and in low percentages can ease the thermal processing of the mixture of excipients [34,35].

Paracetamol is authorized to be used to alleviate mild to moderate pain caused by headaches, toothache, sprain or strains. This drug is available in different dosage oral solid forms such as tables, capsules, suspensions. The active dose ranges from 300 mg to 1000 mg. Direct compression is the most common method used for tableting production [36]. The direct compression is a pharmaceutical operation limited to relatively low drug loading tablet production due to the mechanical properties of some active pharmacological ingredient compromising compression characteristics. For paracetamol tables, only 30–40% wt of the active can be accommodated. This can cause patient non-compliance due to the large tablets [36]. Moreover, the crystals of paracetamol display low flowability and poor compression ability, and when such crystals are compressed into tablets, they show massive elastic deformation under pressure and a tendency to cause problems with tablets, such as chipping, capping, stress cracking, lamination, ticking and picking [37].

The present paper studies the suitability of different formulations, based on starch and HPC with different proportions of acetaminophen (paracetamol), to be processed at a low temperature by hot melt extrusion, searching the compliance to be printed in an FDM 3D printer. The different drug excipient mixtures were thermally processed, with different quantities of Gg, by hot melt extrusion (HME). The dissolution rates and drug release curves of each combination were measured, and the samples were thermally characterized to ensure that the API did not undergo thermal degradation. Finally, 3DP pills were obtained directly from powder form to show the potential of those starch/HPC based mixtures to be processed by means of FDM 3D printing at low temperatures.

Mendibil, X.; Tena, G.; Duque, A.; Uranga, N.; Campanero, M.Á.; Alonso, J. Direct Powder Extrusion of Paracetamol Loaded Mixtures for 3D Printed Pharmaceutics for Personalized Medicine via Low Temperature Thermal Processing. Pharmaceutics 2021, 13, 907. https://www.mdpi.com/1999-4923/13/6/907/htm