In this study, a comparison of different methods to predict drug-polymer solubility was carried out on binary systems consisting of five model drugs (paracetamol, chloramphenicol, celecoxib, indomethacin, and felodipine) and polyvinylpyrrolidone/vinyl acetate copolymers (PVP/VA) of different monomer weight ratios. The drug-polymer solubility at 25 °C was predicted using the Flory-Huggins model, from data obtained at elevated temperature using thermal analysis methods based on the recrystallization of a supersaturated amorphous solid dispersion and two variations of the melting point depression method. These predictions were compared with the solubility in the low molecular weight liquid analogues of the PVP/VA copolymer (N-vinylpyrrolidone and vinyl acetate). The predicted solubilities at 25 °C varied considerably depending on the method used. However, the three thermal analysis methods ranked the predicted solubilities in the same order, except for the felodipine-PVP system. Furthermore, the magnitude of the predicted solubilities from the recrystallization method and melting point depression method correlated well with the estimates based on the solubility in the liquid analogues, which suggests that this method can be used as an initial screening tool if a liquid analogue is available. The learnings of this important comparative study provided general guidance for the selection of the most suitable method(s) for the screening of drug-polymer solubility.
The aim of this paper was to evaluate physical stability of solid dispersions in respect to the drug, tadalafil (Td), in vinylpyrrolidone and vinyl acetate block copolymer (PVP-VA). Nine solid dispersions of Td in PVP-VA (Td/PVP-VA) varied in terms of quantitative composition (1:9-9:1, w/w) were successfully produced by spray-drying. Their amorphous nature, supersaturated character and molecular level of mixing (a solid solution structure) were subsequently confirmed using DSC, PXRD, SEM and calculation of Hansen total solubility parameters. Due to thermal degradation of both components before the melting point of Td
Liquid
crystalline (LC) materials and their nonmedical applications
have been known for decades, especially in the production of displays;
however, the pharmaceutical implications of the LC state are inadequately
appreciated, and the misunderstanding of experimental data is leading
to possible errors, especially in relation to the physical stability
of medicines. The aim of this work was to study LC phases of itraconazole
(ITZ), an azole antifungal active molecule, and for the first time,
to generate full thermodynamic phase diagrams for ITZ/polymer systems,
taking into account isotropic and anisotropic phases that this drug
can form. It was found that supercooled ITZ does not form an amorphous
but a vitrified smectic (vSm) phase with a glass transition temperature
of 59.35 °C (determined using a 10 °C/min heating rate),
as is evident from X-ray diffraction and thermomicroscopic (PLM) experiments.
Two endothermic LC events with the onset temperature values for a
smectic to nematic transition of 73.2 ± 0.4 °C and a nematic
to isotropic transformation at 90.4 ± 0.35 °C and enthalpies
of transition of 416 ± 34 J/mol and 842 ± 10 J/mol, respectively,
were recorded. For the binary supercooled mixtures, PLM and differential
scanning calorimetry showed a phase separation with birefringent vSm
persistent over a wide polymer range, as noticed especially for the
hypromellose acetate succinate (HAS) systems. Both, smectic and nematic,
phases were detected for the supercooled ITZ/HAS and ITZ/methacrylic
acid–ethyl acrylate copolymer (EUD) mixtures, while geometric
restrictions inhibited the smectic formation in the ITZ/poly(acrylic
acid) (CAR) systems. The Flory–Huggins lattice theory coupled
with the Maier–Saupe–McMillan approach to model anisotropic
ordering of molecules was successfully utilized to create phase diagrams
for all ITZ/polymer mixtures. It was concluded that in a supercooled
ITR/polymer mix, if ITZ is present in a LC phase, immiscibility as
a result of molecule anisotropy is afforded. This study shows that
the LC nature of ITZ cannot be disregarded when designing stable formulations
containing this molecule.
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