Development of laminate-based, prefabricated dosage forms - Formulation, processing and characterization

Bo Zhou, Purdue University

Abstract

Film tablet is a novel dosage form developed from the work presented in this thesis. It has similar appearance as traditional tablet dosage forms, but significant advantages that can improve the efficiency of pharmaceutical research and development, as well as manufacturing. It is assembled from single-layer strip films, which are also relatively new to the industry. They are composite systems with API particles/molecules embedded in thin polymer film matrices, which provides a configuration that is effective at maintaining small particles in a non-agglomerated form. Chapter 1 focuses on the impact of film formulation on drug release rate from strip films. To understand the macroscopic behavior of the films, this research also covered microscopic level characterization including the drug particle size distribution in the matrix and microscopic topographical/chemical relationship. Film strips made from hydroxypropylmethylcellulose (HPMC) and sodium alginate (SA) containing dispersed griseofulvin microparticles were prepared by film casting. Several factors from the film formulation and processing were varied to understand their effect on the drug release rate. Analysis of particle size distribution within the films was conducted by using Coherent anti-Stokes Raman scattering (CARS). The microscopic structural-chemical relationship of mixed polymers was studied using Atomic Force Microscopy (AFM). The drug particle size distribution within the film was effectively evaluated using CARS showing the majority of the API particles had a size of less than 5 microns under the film formation conditions employed. The dissolution rate of the drug was dramatically enhanced by the polymer matrices compared to the non dispersed drug. Effects of formulation and processing factors on dissolution rate were also evaluated. Enhanced dissolution rate was obtained with decreased molecular weight of the polymer, reduced film thickness as well as elevated drying temperature. Composite films made from HPMC and SA can also be used to fine tune performance, in this case, by changing the proportion of each polymer composition. Its micron-scale spinodal microstructure was evidenced by AFM. As a conclusion, particle-laden polymer strip films can effectively prevent the agglomeration of micron or sub-micron sized drug particles. Formulation and processing conditions of the films can be changed to engineer the drug release rates. CARS and AFM are effective tools to assist in analyzing the films' microstructure. Chapter 2 is a collaborative work with Ms. Maria Elisa Luque, focuses on the impact of film formulation and processing conditions on the products' pharmaceutical and engineering properties. The factors explored were drug/polymer ratio, plasticizer level and ratio organic cosolvent/water. A half response surface design for five factors was constructed. Two additional factors were introduced, including wet film thickness and drying temperature. The model drug used was Griseofulvin and polymer was hydroxypropylmethylcellulose. As a critical liquid handling property during manufacturing process, viscosity of the film suspension was evaluated before casting. Dry film thickness was determined at different areas of the film at 25°C. Particle size distribution was obtained by microscopy and image analysis. Disintegration time was determined by applying a visual-based method (Int. J. Pharm., 368: 98–102, 2009) with multiple replicates. Tensile strength and elasticity were determined according to ASTM method. The results showed that parameters selected in this study for measuring both formulation and processing conditions were shown to influence almost every property of the strip films in both engineering and pharmaceutical aspects. Within the ranges employed, there was no significant difference in the particle sizes obtained. For disintegration time, the most relevant linear factors were plasticize content, solvent/water ratio and drying temperature. These factors were all negatively related to the film disintegration time. For tensile strength, the most important linear factors were drug/polymer and solvent/water ratios. Chapter 3 focuses on mechanistic and mathematical modeling of drug release from polymer film matrix. There has been a great deal of effort on modeling the process of drug release from polymeric matrices. However, the question remains as to a better understanding of the dissolution of poorly soluble drug from a polymer matrix, which is a common situation for today's pharmaceutical development. The mathematical model assumes two processes during the drug release: one is the hydration of the polymer, the other is the diffusion of the drug through the hydrated polymer, leading to a steady state for drug diffusion. The model was successful in describing the experimental drug release profiles from our novel dosage forms. Chapter 4 focuses on using multiple layers of film, each with a specific performance function, to design and assemble "tablet" dosage forms, with full strength and controllable pharmaceutical performance. It overcomes 3 major limitations of single-layer strip films as the final pharmaceutical dosage form: 1) Limited dose of API (~10 mg per film). 2) Limited to dissolution in mouth. 3) Limited to molecularly dispersed API in gel. This work presents a method for making tablets that have similar look and feel as conventional tablets, prepared in a completely different and advantageous manner. Different pharmaceutical functions (disintegrant, solubilizer, pH control, etc.) can be readily incorporated into the multi-layer assembled tablet. Through a priori design, one can effectively control the pharmaceutical performance of the tablets. Using different molecular weight of polymer but the same basic film forming process. Dissolution rate can be made similar, faster or slower than a reference product.

Degree

Ph.D.

Advisors

Pinal, Purdue University.

Subject Area

Pharmacy sciences

COinS