Electronic Theses and Dissertations

Date of Award

1-1-2012

Document Type

Dissertation

Degree Name

Ph.D. in Pharmaceutical Sciences

Department

Biomolecular Sciences

First Advisor

Michael A. Repka

Second Advisor

John O'Haver

Third Advisor

Seongbong Jo

Relational Format

dissertation/thesis

Abstract

Polymers have indispensable role in pharmaceutical formulation development. Polymer choice is a critical factor to obtain the desired drug-release profile during formulation development for HME (Hot melt extrusion). Many commercially available, pharmaceutical-grade polymers can be used in HME formulations. The suitable polymer choice facilitates processing in the extruder. When choosing a polymer to use in a formulation, processing conditions and processing attributes of the active pharmaceutical ingredients (APIs) should be considered. The physicochemical and the mechanisms of drug release from drug delivery systems prepared by utilizing HME with various polymeric carriers were investigated. Amorphous forms of API can have as much as 10-1600 fold higher solubility than their crystalline forms. HME technology is extensively been used to convert crystalline form to amorphous form of drug with increased solubility with polymeric matrices as carriers. Efavirenz (EFZ) and Carbamazepine (CBZ) are crystalline lipophilic model drugs used in the studies. These are class II drugs (low solubility, high permeability) according to the BCS guidance by the FDA. Various polymers for example cellulose ethers (HEC, HPC and HPMC), hypermellose ester derivatives (HPMCAS and HPMCP) and acrylic polymer (Eudragit® EPO) with pH dependant solubility were examined for suitability as solubility enhancers for EFZ and processability in melt extrusion processes. To determine suitable polymeric carrier, different tools like solubility parameter calculation, Thermogravimetric analysis (TGA), Differential scanning calorimetry (DSC) and Dissolution were employed. The physicochemical characteristics of the extruded formulations were compared to the respective physical mixtures to examine the effect of the extrusion process. Furthermore, HME formulations were evaluated for drug polymer interaction utilizing Fourier transform infrared spectroscopy (FTIR). Sugar alcohols were used as carriers in solid dispersions, since it is known that glass formation is common in many polyhydroxy substances, presumably due to their strong hydrogen bonding which may prevent re-crystallization of the amorphous form of drug molecules. Furthermore, they possess the advantage of high thermal stability and absence of browning reactions. The sugar alcohols (Mannitol, Sorbitol, and Xylitol) investigated in this study proved to be very effective in forming solid dispersions and enhancing solubility of CBZ form III. Xylitol exhibited good processability. Chlorpheniramine Maleate (CLPM) and Diltiazem Hydrochloride (DTZ) were used as a model API to design a sustained release pellet formulations utilizing EthocelTM (EC). EC is also studied as matrix former with lipophillic processing aids (Stearic acid, Tristearin and Trimyristin) for HME sustained release pellets. The purpose of this project was to study the effect various levels of processing aid with Ethyl cellulose matrices utilizing melt extrusion techniques. All of the processing aids decreased the Tg of EthocelTM, which facilitated the extrusion process. With addition of Stearic acid (10%w/w), the Tg of the EC matrix decreased from 132.6±2.5°C to 125.4±1.7°C. FTIR spectra of extruded pellets of EC with lipophillic processing aids indicated band shift when compared to the spectra of pure EC suggesting intermolecular interaction between EC and lipophillic processing aids.

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