Development of taste masked caffeine citrate formulations utilizing hot melt extrusion technology and in vitro-in vivo evaluations

Abstract

The objective of this study was to develop caffeine citrate orally disintegrating tablet (ODT) formulations utilizing hot-melt extrusion technology and evaluate the ability of the formulation composition to mask the unpleasant bitter taste of the drug using in vitro and in vivo methods. Ethylcellulose, along with a suitable plasticizer, was used as a polymeric carrier. Pore forming agents were incorporated into the extruded matrix to enhance drug release. A modified screw configuration was applied to improve the extrusion processability and to preserve the crystallinity of the API. The milled extrudates were subjected to dissolution testing in an artificial salivary fluid and investigations using e-tongue, to assess the extent of masking of bitter taste of the API. There was an insignificant amount of drug released from the formulation in the salivary medium while over 80% of drug released within 30 min in 0.1N HCl. ODTs were also developed with the extrudate mixed with mannitol and crospovidone. The quality properties such as friability and disintegration time of the ODTs met the USP specifications. The lead extrudate formulations and the ODTs prepared using this formulation were subjected to human gustatory evaluation. The formulations were found to mask the unpleasant taste of caffeine citrate significantly.

Keywords: Ethylcellulose (EC); Hot-melt extrusion; Modified screw design; Pediatric and geriatric; Taste-masking.

Figure 1

Twin screw extruder screws; (a) for high shear, (b) for low shear and its magnified image of the kneading zone.

Figure 2

TGA Thermograms of Mannitol, caffeine citrate and Ethyl cellulose.

Figure 3

DSC Thermograms of extruded formulations and caffeine citrate; (CC2) caffeine citrate with EC/TEC and 3%mannitol, (CC7) 5%mannitol, (CC8) 10%mannitol, (CC9) 15% calcium carbonate, (CC10) 15% magnesium oxide, (CC11) 15%calcium phosphate.

Figure 4

FTIR spectra of extrudates; (CC) caffeine citrate, (CC2) with 3%mannitol, (CC7) with 5%mannitol, (CC8) with 10%mannitol, (CC9) with 15%calcium carbonate, (CC10) with 15% magnesium oxide, (CC11) with 15%calcium phosphate.

Figure 5

Dissolution profiles of caffeine citrate in EC/TEC extrudates (n=3); (a) gastric dissolution profile with mannitol as pore former, control (CC1) caffeine citrate with EC/TEC, (CC2) with 3%mannitol, (CC7) with 5% mannitol, (CC8) with 10% mannitol; (b) gastric dissolution profile with inorganic salts, (CC9) caffeine citrate with EC/TEC and 15%calcium carbonate, (CC10) with 15% magnesium oxide, (CC11) with 15% calcium phosphate.

Figure 6

Salivary dissolution profiles of caffeine citrate in EC/TEC extrudates (n=3); (a) dissolution profile with mannitol: (CC2) with 3% mannitol, (CC7) with 5% mannitol, (CC8) with 10% mannitol; (b) dissolution profile with inorganic salts, (CC9) with 15% calcium carbonate, (CC10) with 15% magnesium oxide, (CC11) with 15% calcium phosphate.

Figure 7

Taste masking evaluation using Astree e-tongue; (a) PCA chart for E-tongue results, (b) bar graph of distance between placebo and formulations.

Figure 8

Schematic diagram of tablet blend characterizations, (F1) CC2 extrudates and polyplasdone XL, (F2) CC2 extrudates and polyplasdone XL-10, (F3) CC9 extrudates and polyplasdone XL, (F4) CC9 extrudates and polyplasdone XL-10, (F5) CC10 extrudates and polyplasdone XL, (F6) CC10 extrudates and polyplasdone XL-10, (F7) CC11 extrudates and polyplasdone XL, (F8) CC11 extrudates and polyplasdone XL-10.

Figure 9

Schematic diagram of ODT characterizations; (F1) CC2 extrudates and polyplasdone XL, (F2) CC2 extrudates and polyplasdone XL-10, (F3) CC9 extrudates and polyplasdone XL, (F4) CC9 extrudates and polyplasdone XL-10, (F5) CC10 extrudates and polyplasdone XL, (F6) CC10 extrudates and polyplasdone XL-10, (F7) CC11 extrudates and polyplasdone XL, (F8) CC11 extrudates and polyplasdone XL-10.

Figure 10

Human taste panel evaluations; PM (CC2): pre extrusion blend caffeine citrate with EC/TEC and 3%mannitol, HME (CC2): hot melt extrudate of CC2, Tablet CC2: ODT of CC2; PM(CC11): pre extrusion blend caffeine citrate with EC/TEC and 15% calcium phosphate, HME(CC11): hot melt extrudate of CC11, Tablet CC11: ODT of CC11.