Date of Award
Doctor of Philosophy in Chemical Engineering - (Ph.D.)
Chemical, Biological and Pharmaceutical Engineering
Costas G. Gogos
Norman W. Loney
Solid dispersion/solution processes for producing pharmaceutical oral dosages such as hot-met extrusion (HME) have received increasing attention by industry and academe because they can enhance drugs’ solubility and even bioavailability to a great extent by converting drugs from crystalline to amorphous form. HME can be carried out at two process temperature regimes: one where Tprocess > Tm of the drug and the Tg of the polymer (or the Tm for the case of semi-crystalline polymers); the other at Tm > Tprocess > Tg (Tm for the case of semi-crystalline polymer). Processing below the drug’s melting point in the second case has the advantage of reducing potential for degradation.
Broader applications of HME are often limited by two technical challenges. One is that the active pharmaceutical ingredient (API) or the polymer may degrade at the elevated temperatures during extrusion processing. To avoid this problem and yet obtain a well-mixed solid dispersion/solution, HME needs to be carried out in an optimal processing window, where the temperature is kept safely below the degradation temperature but is high enough to enhance API’s dissolution in the polymer. Another challenge is the possible physical instability of the extrudate during its shelf life. The API’s solubility is decreased significantly once the temperature is dropped from the HME processing temperature to room temperature. As a result, the drug may recrystallize from the polymeric matrix. It is rather challenging to experimentally determine the API’s solubility in the polymer and there are only few published articles in this area. In this dissertation, solid dispersions of a model drug acetaminophen (APAP) and a pharmaceutical grade polymer poly(ethylene oxide) (PEO) were prepared by using hot- melt mixing (HMM), a process closely related to HME. APAP’s solubility in PEO at HME processing temperature was measured utilizing a novel rheological characterization technique, hot-stage microscopy and differential scanning calorimetry (DSC). The results from the three methods were consistent and the solubility was found to increase from 14% at 80 ºC to 41% at 140 ºC. A “phase diagram” was constructed based on the experimental data and could be explored to design the HME process and formulation.
The apparent drug solubility at room temperature was estimated to be less than 10% via glass transition temperature (Tg) measurements using DSC and dynamic mechanical thermal analysis (DMTA), scanning electron microscopy (SEM), and X-ray diffraction (XRD). A model using the Flory-Huggins interaction parameter X estimated from the “phase diagram” was utilized to predict the room temperature solubility. The drug’s solubility in the amorphous portion of PEO was estimated to be 11.7% at 300 K. Since PEO is a semi-crystalline polymer with crystallinity of about 80%, the actual solubility is around 2.3%, consistent with apparent solubility estimation.
A new method to determine APAP’s solubility at temperatures below the PEO’s melting temperature was developed by observing the number of spherulitic nuclei, growth rate and the “quality” of the spherulites under polarized optical microscopy (POM). At 30 °C, the solubility was determined to be less than 1 %, while at 50 °C the solubility was 10%. The nucleation constant Kg, fold surface free energy σe and work of chain folding q were calculated using the Hoffman-Lauritzen (HL) theory and it was found that the chain folding of PEO became more difficult in the presence of APAP.
Yang, Min, "Hot-melt mixing of partially miscible active pharmaceutical ingredient-polymer mixtures" (2012). Dissertations. 336.