Document Type
Dissertation
Date of Award
5-31-2018
Degree Name
Doctor of Philosophy in Chemical Engineering - (Ph.D.)
Department
Chemical and Materials Engineering
First Advisor
Rajesh N. Dave
Second Advisor
Ecevit Atalay Bilgili
Third Advisor
Xiaoyang Xu
Fourth Advisor
S. Basuray
Fifth Advisor
Zafar Iqbal
Abstract
Polymer strip films have been recently established as a robust platform for delivery of poorly water-soluble drugs via slurry casting, in particular using stable drug nanosuspensions. In this dissertation, a simpler, economically feasible, and robust method to directly incorporate dry micronized poorly water-soluble drug is introduced. As a major novelty, simultaneous surface modification using hydrophilic silica along with micronization is done using fluid energy mill (FEM) in order to reduce the hydrophobicity and agglomeration of poorly water-solube drug powder. When micronized coated drug powders are used, films exhibit improved appearance (thickness uniformity, visible lumps), better drug content uniformity (relative standard deviation), fast and immediate drug release, and enhanced mechanical properties (tensile strength, elongation percentage), regardless of the polymer solution viscosity or mixer type.
As a major contribution, release mechanisms of poorly water-soluble drugs from thicker hydroxypropyl methylcellulose (HPMC) films are investigated, including assessing thickness above which they exhibit zero-order drug release. Films thicker than 1000 µm are formed by either stacking two or more layers of ~500 μm, or forming a monolithic thick film. Compared to monolithic thick films, stacked films requir simpler manufacturing process and result in better critical quality attributes. As thickness increased from 100 μm to 2000 μm, the release mechanism changes from Fickian diffusion to zero-order release for films 1000 μm, confirmed by the diffusional power law exponent (n) in the model. Whereas the percentage drug release varies linearly with the sample surface area, and for fixed sample diameter, film sample thickness. Furthermore, the impact of the type and amount of super-disintegrant (SDI) and film thickness is investigated. Percentage reduction in disintegration time (DT) is a strong function of SDI amount while thinner films naturally disintegrate faster. Films with either higher SDI concentrations (>9%) or films under 80 μm, exhibite fast DT (<180s, Ph. Eur.). All thin films (50-60 μm) exhibite immediate release (>80% in 10 min), adequate mechanical properties and achieve good content uniformity, except for those with the lowest amount of SDI, attributed to insufficient viscosity along with thickness non-uniformity due to the SDI. While thicker films have controlled release and carry significant drug amount, thinner films present a potential platform for pediatric population, so it is important to evaluate the feasibility of strip film to delivery low dose of poorly water-soluble drug. In this study, films loaded with as low as 0.3 mg/cm2, prepared with micronized coated and nano-size particles illurstrate good content uniformity, excellent mechanical properties, and fast dissolution.
NJIT research for the past few years reveals that films formed via aqueous slurry casting may have advantages over solution cast films for poorly water soluble drugs at higher drug loadings (>20 wt%). In this study, slurry casting with micronized coated drug particles demonstrates that this approach can be used to prepare thin films with enhanced critical quality attributes (CQAs) of high drug loading films such as drug content uniformity, smooth film appearance, desired mechanical properties, and fast dissolution. The major weakness of solution casting is that drug recrystallization occurs during drying causing the instability of particle size and shape leading to poor drug content uniformity, brittle films, and slowdown of dissolution at high drug loading products (>20 wt%).
These results establish the feasibility of directly incorporating surface modified-micronized poorly water-soluble drug powders in the film manufacturing to produce diversitified films, such as fast disintegrated and sustained release films, and low and high (3 wt%-50 wt%) drug loaded films with good content uniformity.
Recommended Citation
Zhang, Lu, "Micronized dry drug powder-loaded polymer films for delivery of poorly water soluble drugs" (2018). Dissertations. 1902.
https://digitalcommons.njit.edu/dissertations/1902
