Date of Award

5-2012

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Program

Pharmaceutical Sciences

Research Advisor

James R. Johnson, Ph.D.

Committee

Hassan Almoazen, Ph.D William Mclaughlin, Ph.D Arthur B. Straughn, Ph.D George C. Wood, Ph.D

Abstract

Cellulose Acetate (CA) is a polymer extensively used in pharmaceutical applications. Because of the hydrophobic nature and good film properties of CA, it is a good polymer candidate for sustained release matrix tablets. Sustained release matrix tablets of cellulose acetate can be prepared by direct compression or wet granulation methods. However, previous studies showed that a large amount of CA was required to achieve the desired sustained release profile for a sparingly soluble drug and it was difficult to formulate a highly water soluble drug by using CA as the retarding agent. Some studies concluded that CA is very sensitive to the solubility of the drug and it is not suitable for retarding the release for highly water soluble drugs.

There are two aims in our study. One is to modify the physical characteristic of the CA by using a co-processing technique and increase the capacity of cellulose acetate to control the drug release rate. The other is to modulate the drug release rate from the hydrophobic sustained release tablets and apply these formulation strategies to reduce the burst release and enhance the final release.

Three different process methods including heat treatment, wet granulation and spray drying were used to prepare the co-processed excipients with CA, plasticizer and inert excipient. The physical, flow and compaction properties of the co-processed excipients were evaluated. All the co-processed excipients prepared in this study all showed good flow characteristic. The spray dried process produced high porous particles with large surface area. These particles required the least energy for plastic deformation during compression and formed the tablets with highest mechanical strength. The wet granulated excipients showed moderate plastic deformation capacity and resulting tablets with acceptable tensile strength. The heat treated excipients required more energy to deform under compression pressure than the other two methods and the resulting tablets have poor mechanical properties. For all preparation methods, addition of 10% plasticizer increases the plasticity of the final excipient and decreases the tablet tensile strength. The tablets containing hydrophilic plasticizer showed better tensile strength than the hydrophobic plasticizer. The tensile strength of the tablets increased at low plasticizer concentration and the reverse effect was observed on higher plasticizer concentration. Both wet granulated and spray dried excipients showed desired flowability and acceptable compactability which makes them good excipient candidates for direct compression formulation.

The sustained release characteristic of the co-processed excipients were evaluated by a freely water soluble drug propranolol hydrochloride. The spray dried co-processed excipients demonstrated slower drug release profile than the excipients prepared by the other two processing methods. The surface morphology and initial water penetration study found the spray dried co-processed excipient can form a continuous film like structure on the tablet surface which can effectively prevent water penetration and drug diffusion. The drug release rate from the matrix tablets containing the novel spray dried excipients can be decreased by increasing the hydrophobicity of the plasticizer and plasticizer concentration. The drug release rate from the matrix was affected by the compression force but not the pH of the dissolution medium. Based on porosity results and drug release mechanism study, addition of plasticizer to the co-processed excipients showed a decrease in the drug release rate due to three reasons: a) decrease in the porosity of the tablet; b) decrease in the effective diffusion coefficient; c) assist in maintaining tablet structure during dissolution.

Three different types of pore formers were tried to modulate drug release characteristics from the plastic inert matrix. With the help of pore formers lactose and Starch1500®, both observed improved final release as well as increased burst release. When a small amount of hydrophilic polymer pore former was incorporated into the formulation, it showed a limited burst release initially and complete release at final stage. The optical microscopy results revealed the initial gel formation on the tablet surface with development of a swollen porous structure in the matrix network during dissolution. The drug release rate from this swellable porous matrix system is independent with the type and the particle size of hydrophilic polymer and the pH of dissolution medium. The drug release rate increased when the hydrophilic polymer concentration was less than 5%. Further increase of the hydrophilic polymer concentration to 10% did not further increase the drug release rate. The low viscosity grade hydrophilic polymer resulted in rapid burst release and incomplete final release, while middle to high viscosity grades of hydrophilic polymer avoided these problems. The drug release is controlled by both drug diffusion and polymer relaxation. The Fickian diffusion is the dominant release mechanism at the initial stage and the polymer relaxation becomes dominant thereafter.

The spray dried co-processed excipient and the swollen porous matrix system were used to develop the sustained release matrix formulation for three different drugs with different solubility. The optimized formulations for these three drugs either meet the USP specifications or have similar dissolution profile to the commercial product. For a freely water soluble drug propranolol hydrochloride, a roller compaction method was applied to reduce the initial burst release. The tablets prepared by the roller compacted granules showed suppressed burst release and complete final release. For the sparingly water soluble drug theophylline, incorporating 10% hydrophilic polymer can successfully reduce the burst release as well as improve the final release. Two successful sustained release formulations of the poorly water soluble drug glipizide were obtained by using the plasticized co-processed excipient. Both of them have similar dissolution profile as the commercial product Gluctrol XL®. But the formulation prepared with lactose as pore former showed a large variation in dissolution profile while another formulation prepared with both lactose and hydrophilic polymer as pore formers exhibited less variation in dissolution profile and a higher f2 value.

In conclusion, the spray dried co-processed plasticized cellulose acetate developed in this study exhibits good physical and mechanical properties. It can be used alone or combined with hydrophilic polymers to control the release rate of the drugs with different solubility.

DOI

10.21007/etd.cghs.2012.0382

Comments

One year embargo expired May 2013

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