Drug-Polymer Solubility Determination: A New Thermodynamic Model Free from Lattice Theory Assumptions.

PURPOSE: Traditional methods for estimating drug-polymer solubility either require fast dissolution in the polymeric matrix, rapid re-crystallization kinetics from supersaturated states or derive from regular solution theories. In this work, we present a new method for determining drug solubility, purely based on thermodynamic considerations, that uses only experimental data from DSC for calculations. METHODS: The new thermodynamic model presented combines DSC analysis and application of Hess's law to determine free energies of conversion of binary mixtures to amorphous solid dispersions, free energies of mixing as well as solubility as a function of temperature. The model drug indomethacin and polymers HPMCAS LF, PVP K29/32 and Eudragit EPO were used in these studies. RESULTS: Free energies were calculated as a function of temperature, for different drug-polymer compositions and the results show that HPMCAS LF solid dispersion with high drug content are less thermodynamically favorable compared to other polymer systems. Solubility of indomethacin in HPMCAS LF, PVP K29/32 and Eudragit EPO was 24, 55 and 56% w/w, respectively, at 25°C. CONCLUSIONS: The thermodynamic model presented has great advantages over traditional methods. It does not require estimation of any interaction parameters, it is almost assumption-free and uses only thermal data for calculations.

Fructans from oat and rye: composition and effects on membrane stability during drying.

Fructans have been implicated in the abiotic stress tolerance of many plant species, including grasses and cereals. To elucidate the possibility that cereal fructans may stabilize cellular membranes during dehydration, we used liposomes as a model system and isolated fructans from oat (Avena sativa) and rye (Secale cereale). Fructans were fractionated by preparative size exclusion chromatography into five defined size classes (degree of polymerization (DP) 3 to 7) and two size classes containing high DP fructans (DP>7 short and long). They were characterized by high performance liquid chromatography (HPLC) and matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS). The effects of the fructans on liposome stability during drying and rehydration were assessed as the ability of the sugars to prevent leakage of a soluble marker from liposomes and liposome fusion. Both species contain highly complex mixtures of fructans, with a DP up to 17. The two DP>7 fractions from both species were unable to protect liposomes, while the fractions containing smaller fructans were protective to different degrees. Protection showed an optimum at DP 4 and the DP 3, 4, and 5 fractions from oat were more protective than all other fractions from both species. In addition, we found evidence for synergistic effects in membrane stabilization in mixtures of low DP with DP>7 fructans. The data indicate that cereal fructans have the ability to stabilize membranes under stress conditions and that there are size and species dependent differences between the fructans. In addition, mixtures of fructans, as they occur in living cells may have protective properties that differ significantly from those of the purified fractions.

Monosaccharide composition, chain length and linkage type influence the interactions of oligosaccharides with dry phosphatidylcholine membranes.

Sugars play an important role in the desiccation tolerance of most anhydrobiotic organisms and disaccharides have been extensively investigated for their ability to stabilize model membranes in the dry state. Much less is known about the ability of oligosaccharides to protect dry membranes. However, it has been shown that different structural families of oligosaccharides have different efficacies to interact with and protect membranes during drying. Here, we have compared three families of linear oligosaccharides (fructans, malto-oligosaccharides, manno-oligosaccharides) for their chain-length dependent lyoprotective effect on egg phosphatidylcholine liposomes. We found increased protection with chain length for the fructans, a moderate decrease in protection with chain length for malto-oligosaccharides, and a strong decrease for manno-oligosaccharides. Using Fourier-transform infrared spectroscopy and differential scanning calorimetry, we show that the degree of lyoprotection of the different sugars is closely related to their influence on the gel to liquid-crystalline phase behavior of the dry membranes and to the extent of H-bonding to different groups (C=O, P=O, choline) in the lipids. Possible structural characteristics of the different oligosaccharides that may determine the extent to which they are able to interact with and protect membranes are discussed.

Low amounts of sucrose are sufficient to depress the phase transition temperature of dry phosphatidylcholine, but not for lyoprotection of liposomes.

Disaccharides such as sucrose and trehalose play an important role in stabilizing cellular structures during dehydration. In fact, most organisms that are able to survive desiccation accumulate high concentrations of sugars in their cells. The mechanisms involved in the stabilization of cellular membranes in the dry state have been investigated using model membranes, such as phosphatidylcholine liposomes. It has been proposed that the lyoprotection of liposomes depends on the depression of the gel to liquid-crystalline phase transition temperature (T(m)) of the dry membranes below ambient and on the prevention of membrane fusion by sugar glass formation, because both lead to leakage of soluble content from the liposomes. Since fusion is prevented at lower sugar/lipid mass ratios than leakage, it has been assumed that more sugar is needed to depress T(m) than to prevent fusion. Here, we show that this is not the case. In air-dried egg phosphatidylcholine liposomes, T(m) is depressed by >60 degrees C at sucrose/lipid mass ratios 10-fold lower than those needed to depress fusion to below 20%. In fact, T(m) is significantly reduced at mass ratios where no bulk sugar glass phase is detectable by Fourier transform infrared spectroscopy or differential scanning calorimetry. A detailed analysis of the interactions of sucrose with the P=O, C=O, and choline groups of the lipid and a comparison to published data on water binding to phospholipids suggests that T(m) is reduced by sucrose through a "water replacement" mechanism. However, the sucrose/lipid mass ratios necessary to prevent leakage exceed those necessary to prevent both phase transitions and membrane fusion. We hypothesize that kinetic phenomena during dehydration and rehydration may be responsible for this discrepancy.

Thermal study of simple amino-alcohol solutions.

Widely regarded as the most promising approach to long-term cryopreservation of organs for transplantation, vitrification is a process where liquid is transformed into a disordered solid state free from crystals, known as the amorphous state. The vitreous state is obtained by rapid cooling to cryogenic temperatures in the presence of antifreeze substances called cryoprotectants, such as polyalcohols, which are known to be very good vitrification agents. This work reports on the thermal properties of a new class of compounds, the amino-alcohols, studied for its similarity to the structure of the equivalent polyalcohols. We studied by differential scanning calorimetry the glass-forming tendency and stability of the amorphous state for de-ionized water solutions containing 2-amino-1-ethanol and 3-amino-1-propanol at the concentrations of 35%, 40%, 43%, and 45% (w/w). A comparison is made with previous results obtained by Mehl [Cryobiology 27 (1990) 687-688] on the same compounds under different experimental conditions. The results are also compared with those obtained by Boutron [Cryobiology 30 (1993) 87-97] for the corresponding dialcohols. A further comparison is made with a few results obtained for the 1-amino-2-propanol and the 2-amino-1-propanol tested under the same conditions.