Browsing by Subject "amorphous"

Now showing 1 - 3 of 3
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    The effect of additives on the molecular mobility, physical stability and dissolution of amorphous solid dispersions
    (2018-01) Fung, Michelle
    Amorphization provides an avenue for improving the oral bioavailability of poorly water-soluble compounds. However, crystallization of the amorphous phase during storage or dissolution could negate the solubility advantage. The objectives were to (i) develop an accelerated testing method for predicting the solid-state physical stability of drugs in amorphous solid dispersions (ASD), (ii) gain a mechanistic understanding of the stabilization in the amorphous state brought about by small molecule excipients, and (iii) investigate the relationship between solid-state properties and dissolution performance of ASDs. Utilizing glycerol as a plasticizer, an accelerated physical stability testing method of ASD was developed. The acceleration in crystallization brought about by glycerol expedited the determination of the coupling between molecular mobility and crystallization. This approach is especially useful for ASDs with high polymer content where drug crystallization is extremely slow at relevant storage temperature. The ability of several organic acids to stabilize an amorphous API, ketoconazole (KTZ), was next investigated. Oxalic (OXA), citric (CIT), tartaric (TAR) and succinic (SUC) acids were chosen based on their relative strengths (pKa values). Coamorphous systems of KTZ with each acid exhibited ionic and/or hydrogen bonding interactions. An increase in the strength of KTZ-acid interactions translated to a reduction in molecular mobility. However, molecular mobility could not completely explain the crystallization propensity of the systems. When in contact with water, coamorphous KTZ-citric and KTZ-tartaric were exceptionally stable while KTZ-succinic and KTZ-oxalic systems crystallized more readily than KTZ. The dissolution performance of the coamorphous systems were compared using the areas under the curve (AUC) obtained from the concentration-time profiles. KTZ-OXA exhibited the highest AUC, while it was about the same for KTZ-TAR and KTZ-CIT and the lowest for KTZ-SUC. Coamorphization with acid caused at least a 2-fold increase in AUC when compared with amorphous KTZ. In ternary KTZ-acid-polyvinylpyrrolidone (PVP) ASDs, the interactions between drug and acid each acid influenced the solid-state stability as well as dissolution performance.
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    Molecular Mobility In Pharmaceutical Glasses: Implications On Physical Stability
    (2016-05) Mehta, Mehak
    Amorphous pharmaceuticals have gained widespread importance due to their advantageous increase in solubility and dissolution rate. However, a major challenge with this approach is the high risk of physicochemical instability in comparison to its crystalline counterparts. The goal of my research was to investigate the correlations between molecular mobility and physical stability in model amorphous systems (both drug substance and solid dispersions), specifically in the glassy state. This will potentially enable development of effective strategies to stabilize amorphous pharmaceuticals. Use of time-temperature, time-aging and time-concentration superposition principle enabled comprehensive characterization of structural relaxation behavior in the glassy state. This was followed by the investigation of correlation between crystallization behavior and different mobility modes in glassy celecoxib and indomethacin. Structural relaxation time correlated well with characteristic crystallization time in the supercooled state. On the other hand, a stronger correlation was observed between the Johari-Goldstein relaxation time and physical instability in the glassy state but not with structural relaxation time. Effect of polymer additive and polymer concentration on the structural relaxation behavior in nifedipine dispersions was investigated. We found that stronger drug-polymer interactions enhanced physical stability by reducing the molecular mobility. With an increase in polymer concentration, the relaxation times were longer indicating a decrease in molecular mobility. The effect of sorbed water on molecular mobility and physical stability in a model amorphous drug and dispersion was also evaluated. Sorbed water, in a concentration dependent manner, increased mobility and accelerated crystallization - attributable to the plasticization effect of water. The extent of coupling between molecular mobility and crystallization time (defined as time for 2.5% crystallization) was found to be unaffected in the range of water content studied ( < 2% w/w). Based on this finding, we have proposed the use of “water sorption” as an accelerated stability approach to predict crystallization in slow crystallizing systems.
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    The Role Of Molecular Mobility And Hydrogen Bonding Interactions On The Physical Stability Of Amorphous Pharmaceuticals
    (2014-09) Kothari, Khushboo
    The physical instability of amorphous pharmaceuticals and our inability to reliably predict their crystallization propensity is a major impediment to their use in solid oral dosage forms. The central goal of this thesis work is to gain a fundamental insight into the roles of (i) specific molecular mobility (global or local) on the observed physical instability (crystallization) in the supercooled as well as glassy states of amorphous pharmaceuticals and (ii) the influence of hydrogen bonding on molecular mobility and thereby the physical stability. Our ultimate objective is to be able to use molecular mobility as a predictor of drug crystallization from complex multi-component solid dispersions. The different modes of molecular motions were comprehensively characterized using broadband dielectric spectroscopy (BDS). Since, BDS is traditionally conducted with film samples, we first validated the use of powder samples for measuring molecular mobility. Crystallization kinetics was monitored by powder X-ray diffractometry using either a laboratory or a synchrotron X-ray source. Physical instability, both above and below Tg in our model systems (griseofulvin, nifedipine and nifedipine-PVP dispersion), increased with a decrease in structural relaxation time. Next, a causal relationship between hydrogen bonding interactions and molecular mobility was established. The higher physical stability in felodipine as compared to nifedipine was attributed to the reduced molecular mobility brought about by the stronger and more extensive hydrogen bonding interactions in the former. In solid dispersions of nifedipine with each PVP, HPMCAS and PAA, the drug-polymer interactions, by modulating molecular mobility, influenced the drug crystallization kinetics. The strength of drug-polymer hydrogen bonding, the structural relaxation time and the crystallization kinetics were rank ordered as: PVP > HPMCAS > PAA. Finally a model derived from the relationship between diffusion and relaxation time was used to predict drug crystallization from solid dispersions. Molecular mobility proved to be an effective predictor of drug crystallization in nifedipine solid dispersions.