Date of Award
Doctor of Philosophy in Pharmaceutical Sciences
Biomedical and Pharmaceutical Sciences
Serpil M. Kislalioglu
With the advent of combinatorial chemistry and high throughput screening of drug molecules, poorly water soluble molecules have been entering the development stage as new drug candidates. The poor aqueous solubility of these molecules is one of the limiting factors for them to succeed as a new drug product. This had led to converting these drugs in most cases are crystalline to amorphous solid dispersion with use of amorphous polymers to improve the solubility.
Although amorphous solid dispersion of a poorly water drug can improve the solubility, careful selection of polymer is a necessity in order to stabilize the high energy nature of the amorphous solid dispersion. Miscibility of a drug and a polymer is important. With specific interaction between the drug and the polymer, the dispersion can remain miscible much longer. Another factor that needs to be considered when formulating an amorphous solid dispersion is the amount of drug that is incorporated into the polymer. Over saturating the polymer with the drug can cause instability of the dispersion and crystallization may occur which will lead to reduced solubility.
In this work, effects of processing method, polymer selection and the drug concentrations for the preparation of amorphous solid dispersion as well as prediction of drug-polymer miscibility have been studied. Hot melt extrusion (HME), rotary evaporation (Rot) and spray drying (SD) processing methods used in the study with Eudragit E 100 (EPO), HPMCAS LF and PVPVA 64 polymers. Drug concentration was another factor that was explored.
The objective of this dissertation were: (1) to prepare amorphous solid dispersion of nifedipine with polymers (2) to characterize the solid dispersions (3) to determine the factors which contributes to successful amorphous solid dispersion (4) to evaluate prediction methods used to study drug and polymer miscibility and solubility (5) to use a thermodynamic prediction model to determine solubility of nifedipine at room temperature.
In the first manuscript, amorphous solid dispersions of nifedipine and polymers were prepared. Physical and chemical characterizations of the solid dispersions indicated solid dispersions prepared with EPO polymer were unstable although intrinsic dissolution rates (IDR) of those samples had higher rates than those prepared with HPMCAS LF or PVPVA 64 polymers. The instability was explained by the lack of specific hydrogen bond interaction while the high IDR was explained by the low glass transition temperature (Tg) of the polymer. With lower Tg, molecular mobility would be higher and therefore the drug could dissolve at a faster rate. ANOVA analysis of factorial design showed all factors (process, polymer and drug concentration) affected the IDR. Further optimization of experiments may be necessary to determine the dominant factor for improving IDR.
In the second manuscript, we have calculated three different ways to calculate the Flory-Huggins interaction parameter, χ. Although using melting point depression approach and solubility parameter of a drug and a polymer are common to estimate the miscibility of the two, there were assumptions that needed to be addressed. We have modified the melting point depression approach by calculating a better estimate of volume fractions needed to calculate the interaction parameter.
In the third manuscript, we have taken a recently published thermodynamic prediction model, which can estimate the stable drug concentration that can be incorporated into an amorphous solid dispersion at room temperature, to predict the solubility of nifedipine with EPO, HPMCAS LF and PVPVA 64 polymers in amorphous solid dispersions prepared by HME, Rot and SD processes. The predictions showed less stable nifedipine concentration could be incorporated into HME processed solid dispersions than samples prepared by Rot or SD processes. Overall, nifedipine-PVPVA 64 solid dispersion prepared by SD method was predicted to incorporate nifedipine concentration up to 30 % w/w.
Tominaga, Kaoru, "Effect of Manufacturing Methods Used in the Stability of Amorphous Solid Solutions and Predictions to Test them" (2013). Open Access Dissertations. Paper 41.