Exploring Applications of Plant-Derived Polymers in Fused Deposition Modeling of Oral Pharmaceutical Tablets

INTRODUCTION

Additive manufacturing or 3D printing technology refers to the fabrication of three-dimensional objects from computer-aided designs (CAD) by adding layers of material on top of each other successively. In oral pharmacotherapy, this technology presents a paradigm shift from the current “one size fits all” approach. The 3D printing technology will allow the manufacture of solid dosage forms with different dose strengths, combinations of different medicaments or drug release profiles. To achieve these properties, the 3D printing technology will work by altering the size, shape and fill level of the tablet directly, which cannot be attained easily with conventional manufacturing methods. Fused deposition modeling (FDM) is one of the most investigated 3D printing technologies for oral tablets. While synthetic oil-based materials such as polyvinylpyrrolidone, polyvinyl alcohol, and polylactic acid are commonly employed in FDM formulations, there is currently limited information on the applicability of safer and more sustainable plant-based alternatives. The purpose of this study was to evaluate the suitability of modified starches in 3D printing of immediate and controlled release tablets containing a model active pharmaceutical ingredient (API) via FDM technology.

OBJECTIVES

The aim of this study was to evaluate the suitability of modified starches in 3D printing of tablets containing different model active pharmaceutical ingredient (API) via FDM technology.

MATERIALS AND METHODS

Diprophylline was used as the primary model API. Prior to FDM printing of the tablets, filaments were prepared via hot melt extrusion (HME) using a twin-screw extruder fitted with a 2.6 mm die orifice. NEOSORB® P 100 C sorbitol and PEARLITOL® 100 SD mannitol were included as plasticizers in the formulations while stearic acid was utilized as lubricant. LYCOAT® RS 720 pregelatinized hydroxypropyl pea starch was used as the polymer matrix in Formulation 1 (F1) while a combination of PREGEFLO® PI 10 pregelatinized potato starch and hydroxypropyl methylcellulose (HPMC K4M) were used in Formulation 2 (F2) to achieve immediate release and controlled release profile respectively with diprophylline. F2 was found to be suitable for a wider range of APIs namely theophylline anhydrous, caffeine anhydrous, and indomethacin in both extrudability and printability and hence were subsequently printed to match their daily dosage of 125 mg, 100 mg, and 75 mg respectively. Critical HME process parameters such as screw speed and barrel temperature were pre-set as detailed in table 1.

Figure 1 shows photos of the tablets of formula 1 and 2 containing different APIs obtained by FDM.

Figure 1. Photos of the tablets of formula 1 and 2 containing different APIs obtained by FDM.

A mixture design approach was used to vary formulation components to investigate effects of plasticizer ratio, starch and stearic acid concentration on filament properties and tablet printability. Flat cylindrical tablets were printed from optimized formulations on a benchtop 3D printer using the parameters stated in table 1. Tablet dimensions were adjusted according to the target drug load by weight. Dissolution studies was performed with USP Apparatus 1 for indomethacin while the remaining model APIs were conducted with USP Apparatus 2 for both immediate (F1) and controlled-release (F2) tablets for 1-hour and 12-hours duration, respectively. Simulated gastric fluid (SGF pH 1.2) was employed for the immediate release dissolution analysis while a 2-stage dissolution starting with pH 1.2 for the first two hours followed by pH transition to an intestinal composition of pH 6.8 was used for the controlled release dissolution test. The in vitro drug release assay was measured via UV spectrophotometry for all the dissolution runs (diprophylline and theophylline at 272 nm, caffeine at 245 nm and indomethacin at 320 nm). Tablets were also assessed for their stability by storing them in heat-sealed aluminium pouches under two conditions (25°C / 60% relative humidity and 40°C / 75% relative humidity) for at least one month.

RESULTS

Sorbitol had a stronger plasticizer effect than mannitol, and optimal ratios of sorbitol to mannitol were found for immediate and controlled release formulations to create the balance between filament brittleness and pliability. Stearic acid had some impact on filament brittleness even at low concentrations as a lubricant and anti-tacking agent. Formulations with high starch content but low HPMC concentration yielded brittle filaments which were not suitable for further processing. Formulations devoid of starch on the other hand were not extrudable. Optimized filament formulations could be extruded continuously and be used for FDM 3D printing.

Figures 2 and 3 present the release kinetics of diprophylline from formula 1 and formula 2.

Figure 2. Dissolution profile of Formulation 1 diprophylline tablets tested using USP Apparatus 2 in SGF pH 1.2 media without enzymes. Error bars represent standard deviation. (n=3)

Figure 3. Dissolution profile of Formulation 2 diprophylline tablets tested using USP Apparatus 2 in SGF-SIF pH transition media without enzymes. Error bars represent standard deviation. (n=3)

Up to 84.2 % of the API was released by 30 minutes in the diprophylline immediate release formulation (F1, fig. 2) while 74.7 % of the API was released by 8 hours in the diprophylline controlled release formulation (F2, fig. 3). A similar controlled release profile was also observed for the theophylline (fig. 4) and caffeine (fig. 5) tablets using F2.

Figure 5. Dissolution profile of Formulation 2 caffeine anhydrous tablets tested using USP Apparatus 2 in SGF-SIF pH transition media without enzymes. Error bars represent standard deviation. (n=3)

The immediate and controlled release tablets showed the typical matrix erosion and matrix swelling, respectively. On the contrary, the Indomethacin tablets in F2 matrix disintegrated within the first 2 hours, followed by a sharp stepwise increase in API dissolution after pH transition (see fig. 6).

Figure 6. Dissolution profile of Formulation 2 indomethacin tablets tested using USP Apparatus 1 in SGF-SIF pH transition media without enzymes. Error bars represent standard deviation. (n=3)

The dissolution increase can be attributed to a combination of two factors: (a) increased surface area due to prior disintegration of the tablet in the acid stage, and (b) improved indomethacin solubility at higher pH (fig. 6).

The observations from HME and dissolution runs showed that filament properties and printed tablets dissolution behavior are highly dependent on API physicochemical properties such as solubility and miscibility with the excipients when the API load is sufficiently high, for example 20 % in this study. This had resulted in different nature and extent of API-matrix interaction during HME and dissolution. Stability studies conducted for diprophylline tablets showed no change to their dissolution profiles after 1 month of storage (fig. 7).

Figure 7. Dissolution profile comparison of Formulation 2 diprophylline tablets after 1 month stability at 25°C / 60% RH and 40°C / 75% RH, tested using USP Apparatus 2 in SGF-SIF pH transition media without enzymes. Error bars represent standard deviation. (n=3)

CONCLUSION

Modified starches were demonstrated to be useful for HME and FDM 3D printing. We have successfully developed two formulation prototypes based on hydroxypropyl starch and pregelatinized starch/HPMC in combination with sorbitol (plasticizer) which yielded extrudable filaments with good printability capable of achieving immediate release and controlled release when printed into tablets with the model BCS Class 1 APIs. Plant-based polymers could prove to be useful and safer alternatives to conventional polymers used in additive manufacturing of oral tablets.

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