Effect of geometry on drug release from 3D printed tablets

Abstract

The aim of this work was to explore the feasibility of combining hot melt extrusion (HME) with 3D printing (3DP) technology, with a view to producing different shaped tablets which would be otherwise difficult to produce using traditional methods. A filament extruder was used to obtain approx. 4% paracetamol loaded filaments of polyvinyl alcohol with characteristics suitable for use in fused-deposition modelling 3DP. Five different tablet geometries were successfully 3D-printed—cube, pyramid, cylinder, sphere and torus. The printing process did not affect the stability of the drug. Drug release from the tablets was not dependent on the surface area but instead on surface area to volume ratio, indicating the influence that geometrical shape has on drug release. An erosion-mediated process controlled drug release. This work has demonstrated the potential of 3DP to manufacture tablet shapes of different geometries, many of which would be challenging to manufacture by powder compaction.

Introduction

The future of medicine design and manufacture is likely to move away from mass production of tablets/capsules of limited dose range towards extemporaneous fabrication of unit dosage forms of any dose, personalised to the patient. The factors driving this change include the development of low dose drugs with narrow therapeutic indices (for instance immunosuppressants and/or blood thinners), the increasing awareness and importance of pharmacogenomics (for instance in the drug sensitivity of cancer sufferers, Kim et al., 2012) and the need to formulate drug combinations. To face this challenge, the pharmaceutical industry needs to evaluate and embrace novel manufacturing technologies. One technology with such potential is 3D printing (3DP).

Of the many types of 3D printer commercially available, fused-deposition modelling (FDM) offers perhaps the most immediate potential to unit dose fabrication. In FDM 3DP an extruded polymer filament is passed through a heated tip. The heat softens the polymer and it is then deposited on a build plate. The temperature of the build plate can be controlled and is set so that the polymer hardens. The print head deposits polymer on the build plate in the x–y dimensions, creating one layer of the object to be printed. The build plate then lowers and the next layer is deposited. In this fashion, an object can be fabricated in three dimensions, and in a matter of minutes. FDM technology has the significant advantages of cost (typical systems cost between £800–2000), the ability to fabricate hollow objects, and the opportunity to print a range of polymers. The printer feedstock is an extruded polymer filament, typically 1.75–3 mm in diameter and one of the prime benefits of FDM 3DP is that it is possible in principle to blend active drug and polymer into a solid dispersion prior to extrusion, so that the printed dosage form is drug loaded. This principle has been demonstrated, for example, to tablets containing fluorescein (Goyanes et al., 2014), 4-aminosalicylate and 5-aminosalicylate (Goyanes et al., 2015) and prednisolone (Skowyra et al., 2015).

However, in all of these studies the percentage drug loading is low, because the drugs were loaded by passive diffusion from solution. An alternative method is to incorporate drug into polymer filaments by hot-melt extrusion (HME) processing. HME is a widely used technique in the pharmaceutical industry and is in essence a process of using a rotating screw to pump raw materials at elevated temperatures through a die to generate a product of uniform shape. Today, the interest in HME techniques for pharmaceutical applications is growing rapidly with more than 10 pharmaceutical products including oral dosage forms (e.g. Kaletra [Abbott], Rezulin [Pfizer]), implants (Ozurdex [Alergan]) and medical devices (Nuvaring [Merck]) taken to market in the last 12 years. The number of HME patents issued for pharmaceutical systems has steadily increased since the early 1980s, with ever widening international scope: to date, more than 300 such patents have been filed. Several research groups have demonstrated HME processes as a viable method to prepare a wide range of accepted pharmaceutical drug delivery systems, including granules, pellets, transdermal patches, transmucosal films systems and implants (Breitenbach, 2002, Crowley et al., 2007, Fonteyne et al., 2013). The use of HME to produce drug-loaded printable filaments has been shown to be feasible for plastics used for medical devices (Sandler et al., 2014) but has not, to our knowledge, been demonstrated for water soluble polymers suitable for fabricating oral dosage forms.

A further potential benefit of FDM 3DP, also currently unexplored, is that the printer can be used to fabricate tablets of any geometry. Pretended donut-shape polymer matrices were evaluated to obtain zero-order drug release (Cheng et al., 1999, Kim, 1999), although the matrices were compacts with holes rather than real torus. The theoretical shape of tablets to obtain a uniform drug release rate from multi holed formulations was also noted but not manufactured/evaluated (Cleave, 1965). Other studies reported the use of parabolic shapes to achieve a zero-order release from a polymeric matrix (Bayomi, 1994), or differences in drug release from triangular, cylindrical and half-spherical tablets of the same formulation (Karasulu and Ertan, 2003). Siepmann et al. (2000) developed a model to predict drug release from matrix tablets of hydroxypropylmethylcellulose. They envisaged that since changing tablet shape can modify drug release rates, the optimal shape to obtain a specific release profile could be calculated. 3DP would be the only suitable method to manufacture tablets of such specific shape with precision and ease, including more elaborate shapes that would be impossible to create by powder compaction, e.g. expandable systems (Klausner et al., 2003) or platforms for improved gastrointestinal transit (Varum et al., 2013).

The aims of this work, then, were to (i) produce a filament containing a model drug in a water soluble polymer (polyvinyl alcohol, PVA) suitable for printing into pharmaceutical tablets and (ii) to print tablets in a diverse range of geometries, many not attainable by powder compaction, and to correlate geometric parameters with dissolution behaviour.