Date of Award
Ph.D. in Pharmaceutical Sciences
Michael A. Repka
Samir A. Ross
This research work exhibited the new outlook of hot melt extrusion technology for orally disintegrating tablet, fast disintegration films and fixed dose combinations. Previous research demonstrated these applications by conventional formulation techniques which has inherent shortcoming of use of large amount of solvent and batch size manufacturing. This present work addressed some of the unique challenges which could provide patients ease of administration and reduce dosing frequencies, and moreover, mitigate the manufacturing challenges. For orally disintegrating tablet study, 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 0.1 N 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. Additionally, melt extrusion provided peculiar advantages for oral fast disintegrating film development. Modified starch with glycerol was used as a polymer matrix for melt extrusion. Sweetening and saliva-simulating agents were incorporated to improve palatability and lower the disintegration time of film formulations. A standard screw configuration was applied, and the last zone of the barrel was opened to discharge water vapors, which helped to manufacture non-sticky, clear, and uniform films. The film formulations demonstrated rapid disintegration times (6–11 s) and more than 95% dissolution in 5 min. In addition, the films had characteristic mechanical properties that were helpful in handling and storage. An animal model was employed to determine the taste masking of melt-extruded films. The lead film formulation was subjected to a human panel for evaluation of extent of taste masking and disintegration. The novel double extrusion approach was utilized for the development of fixed dose combination. For this study, carbamazepine and caffeine citrate were selected as model drugs, and hydroxypropyl methyl cellulose (HPMC), hydroxy propyl cellulose (HPC) and poly ethylene oxide (PEO) were as polymeric carriers. Standard screw design was used for first extrusion and modified screw design for second extrusion. Two step dissolution was performed on extrudated formulations which demonstrated significantly different release profile compared to single extrudated formulations. The solid-state characterizations confirmed the presence of drug in an amorphous form and could not find any chemical interaction. In addition, the FTIR-chemical imaging results shothe uniform distribution of drugs in double extrudated formulations.
Pimparade, Manjeet Bhagwan, "Patient Friendly Formulations Utilizing Hot Melt Extrusion Technology" (2017). Electronic Theses and Dissertations. 1495.