Use of a Plasticizer for Physical Stability Prediction of Amorphous Solid Dispersions

Abstract

Utilizing glycerol as a plasticizer, an accelerated physical stability testing method of amorphous solid dispersions (ASDs) was developed. The influence of glycerol concentration on the glass transition temperature and α-relaxation time (a measure of molecular mobility) of amorphous ketoconazole, celecoxib, and the solid dispersions of each prepared with polyvinylpyrrolidone was investigated. By temperature scaling (T g/T), the effects of glycerol concentration and temperature on the relaxation time were simultaneously evaluated. Glycerol, in a concentration dependent manner, accelerated crystallization in all of the systems without affecting the fragility. In celecoxib-PVP ASDs, the drug crystallization was well coupled to molecular mobility and was essentially unaltered at glycerol concentrations up to 2% w/w. The acceleration in crystallization brought about by glycerol expedited the determination of the coupling between molecular mobility and crystallization. As a result, we were able to predict the physical stability of the unplasticized ASD. This approach is especially useful for ASDs with high polymer content where drug crystallization is extremely slow at the relevant storage temperature.

Enhancement of the Physical Stability of Amorphous Sildenafil in a Binary Mixture, with either a Plasticizing or Antiplasticizing Compound

“…Firstly, the ability to form intermolecular interactions between the drug and the polymer (such as ionic interaction, dipole-dipole interactions or hydrogen bonding) is one of the crucial factors to consider when preparing a stable amorphous solid dispersion (ASD) system [40][41][42][43]. Secondly, the addition of a polymer with a high glass transition temperature (T g ) (well above the T g of the amorphous API) will increase the T g of the system-the so-called antiplasticization effect-which corresponds to the deceleration of the molecular mobility controlling the cold crystallization process at a certain temperature [44,45]. In contrast to the above, a polymer with a low T g (well below the T g of the amorphous l) will decrease the T g of the system-the so-called plasticization effect-which corresponds to the acceleration of the molecular mobility.…”

A Miniaturized Extruder to Prototype Amorphous Solid Dispersions: Selection of Plasticizers for Hot Melt Extrusion

“…Plasticizer selection is a multivariate challenge. Compounds which beneficially lower the melt viscosity and reduce the chemo-mechanical stress of the extrusion processes can impair the physical long-term stability of the product, modulate dissolution behaviour or worsen the downstream processability of a basically promising dispersion system [ 37 , 38 , 39 ]. Therefore, the selection of suitable plasticizers requires the same attention as more established polymer carrier systems [ 4 , 39 ].…”

Effects of Molecular Interactions on Miscibility and Mobility of Ibuprofen in Amorphous Solid Dispersions With Various Polymers

“…While incorporation of a drug with polymers having a higher T g may reduce overall molecular mobility through the antiplasticization effect of the polymer, drug-polymer interactions in ASDs have sometimes been shown to play a more important role than T g in determining drug mobility. 17,18 For example, a recent dielectric spectroscopy study found that stronger specific ionic or hydrogen bonding interactions between certain drugs and polymers induced a larger reduction in drug mobility. 17 Similarly, Kothari et al 52 demonstrated delays in the crystallization of nifedipine in ASDs in the order PVP > HPMCAS > PAA.…”

“…Thus, intermolecular drug-polymer interactions may alter both thermodynamic and kinetic driving forces thereby effectively inhibiting drug crystallization and increasing the physical stability of ASD-based drug formulations. 16,[18][19][20] Correlations between drug-polymer interactions and inhibition or enhancement of dissolution by various mechanisms have also been reported. [21][22][23][24][25] Molecular dynamics (MD) simulation has been demonstrated to be a powerful tool in understanding and perhaps predicting a wide range of thermodynamic and kinetic properties such as solubility, mobility, and dissolution rate in condensed materials containing drugs, polymers, and their mixtures.…”

“…14 Decreasing molecular mobility in ASD formulations is another widely appreciated means of slowing drug crystallization and enhancing the physical stability of the formulation. 1,7,17,18 Global molecular mobility may be reduced by incorporating the drug of interest into polymers having a higher glass transition temperature (T g ), thereby taking advantage of the antiplasticization effect of the polymer. Khougaz and Clas 19 explored the effect of four poly(vinyl pyrrolidone) (PVP) homopolymers of different molecular weight and a PVP/VA copolymer on both the glass transition temperature and the temperature for onset of crystallization (T c ) of a model hydrophobic drug.…”