Siro Toscani

In vitro and in vivo evaluation of carbamazepine-PEG 6000 solid dispersions

The present work extended previous physico-chemical investigations on the effects of solid dispersion on the solubility, the dissolution rate and the pharmacokinetic profile of carbamazepine. Solubility studies showed a linear increase in carbamazepine solubility with the increase of PEG 6000 concentration. There is no marked difference between physical mixtures and solid dispersions for the enhancement of carbamazepine solubility by PEG 6000. Less than 60% of pure carbamazepine was dissolved in 90 min. Physical mixtures (carbamazepine phase III) and solid dispersions (carbamazepine phase II) dissolution rates were higher in comparison of the parent drug. The dissolution of carbamazepine phase III was more pronounced than that evoked by the phase II. The dissolution profiles indicated that the percentage of the drug dissolved was dependent on the proportion of PEG 6000. In solid dispersions there was a remarkable enhancement in the dissolution rates of the drug in the vicinity of the eutectic composition as compared with those of corresponding physical mixtures. Hence, the optimum value for the solid dispersion was 80.5+/-1.7% of carbamazepine having dissolved within the first 10 min compared to 40+/-1% for the corresponding physical mixtures of the same composition. Statistical analysis of pharmacokinetic parameters confirmed that the carbamazepine:PEG 6000 binary systems displayed higher bioavailability of the drug than the pure carbamazepine. The area under the curve (AUC) values highlighted the evidence that only slight differences in the bioavailability of the drug occur between physical mixtures and solid dispersions prepared at the 80:20 and 50:50 drug:carrier compositions. However, the mean normalized plasma concentrations showed that standard error deviations are rather wide intervals for pure drug and physical mixtures in comparison to solid dispersions. One additional interesting point to consider is the disappearance of the multiple peaks on the individual kinetic curves of the 50:50 solid dispersion composition. Furthermore, our investigations have highlighted the interest of solid dispersions prepared at <<near>>-eutectic composition as our preliminary data show that the plasma concentration (C(5h)) of the drug for the 15:85 dispersed sample containing 150 mg of carbamazepine is not significantly different from that obtained for the 50:50 dispersed sample containing 300 mg of the drug.

Solid-state studies on C60 solvates grown from n-heptane

Crystallographic and thermodynamic experiments show that crystalline C60 obtained by slow evaporation of solutions in n-heptane is a C60, n-heptane 1:1 solvate. Its lattice is hexagonal, Laue class 6/mmm, with a = 10.00(4) A and c = 10.16(1) A. No transition is observed at temperatures higher than 100 K, and desolvation into fcc C60 occurs at about 360 K with ΔH = +43.5 J g−1, close to the sublimation enthalpy for pure n-heptane. Another binary compound, presumably a polymorph of the former, is sometimes obtained by rapid evaporation of toluene + n-heptane mixtures. Its lattice is orthorhombic, Immm, with a = 10.07 A, b = 10.22 A and c = 48.9 A.

A magnetic-suspension apparatus to measure densities of liquids as a function of temperature at pressures up to 100 MPa Application to n-heptane

A densimeter designed for high-pressure work has been constructed. Densities of liquids have been measured with an accuracy of 0.2 per cent through the determination of the buoyancy of a magnetic float immersed in the samples. Thanks to a microbalance, a dynamic method is used to measure the total downward force of the magnetic-suspension system and of the floating buoy. The density of n-heptane has been determined from 298.15 to 373.15 K at pressures up to 100 MPa. Our results are compared with those previously published.

C60CCl4 phase diagram: polythermal behaviour of solvates C60, 12 CCl4 and C60, 2 CCl4

Abstract Polythermal investigation of the C 60 CCl 4 system resulted in two phase diagrams. The stable one involves two solvates with 1:12 and 1:2 molar ratios, respectively. A metastable diagram, only showing the 1:2 solvate, has been observed. C 60 , 12 CCl 4 and C 60 , 2 CCl 4 decompose peritectically at 299 and 402 K, with ΔH = 15.2 and 61 J g −1 , respectively. C 60 , 12 CCl 4 is formed with a positive excess volume while C 60 , 2 CCl 4 does so with a negative one. The desolvation enthalpy for C 60 , 2CCl 4 and sublimation enthalpy for pure CCl 4 are close.

Polymorphism of Sulfanilamide: (II) Stability Hierarchy of α-, β- and γ- Forms from Energy Calculations by the Atom-Atom Potential Method and from the Construction of the p, T Phase Diagram

AbstractPurpose. Sulfanilamide trimorphism was chosen as a model system for comparison between stability hierarchies obtained from lattice-energy calculations with those deduced from the relative locations of the sublimation curves of polymorphs in the sulfanilamide p, T diagram. Methods. The atom-atom potential (AAP) method was used for lattice-energy calculations. The p, T diagram was constructed by using crystallographic and thermodynamic data for α-, β-, and γ- forms, and by assigning the temperatures of the experimentally observed phase transitions to triple points involving the vapour phase. Results. The hierarchy obtained with the AAP method (Eα ≥ Eγ>> Eβ) differs only slightly from that deduced from the positions of the sublimation curves (pγ > pα > pβ) in the p, T diagram at room temperature. No stable phase region was found for form α. Thus it is really monotropic. Conclusions. Provided enthalpy and volume changes at the transitions are accurate enough, it is possible to draw a p, T diagram that accounts for the stability hierarchy of polymorphs.

Thermodynamic Study of Sulfanilamide Polymorphism: (I) Monotropy of the α-Variety

AbstractPurpose. Sulfanilamide was chosen as a model compound in order to gain insights on the stability hierarchy of drug polymorphs from structural and thermodynamic criteria. Despite numerous studies, disagreements remained on the reported enthalpies associated with the mutual interconvertions of the α-, β-, and γ-forms of sulfanilamide. Therefore, the unambiguous determination of these enthalpies was the purpose of this work. Methods. Samples, free of solvent inclusions and made of only one form, were prepared, and analyzed combining X-ray powder diffraction and Differential Scanning Calorimetry (DSC). Results. The enthalpy values associated with the α- to γ- and β- to γ-transitions were found to be + 10.2 and + 10.9 J g−1, respectively. The calculated enthalpy of the β- to α-transition is consistent with the experimental one ( + 1 J g−1). Conclusions. The monotropy of the α-form was ascertained over the explored temperature range at ordinary pressure.

Fullerene C70, toluene 1:1 solvate: structural and thermodynamic evidences

Abstract X-ray diffraction and thermodynamic measurements show that crystalline fullerene C70 obtained from toluene solutions is a C70, toluene 1:1 solvate. Its structure is orthorhombic with space group Pbca (a = 21.075 A, b = 32.990 A, c = 10.844 A). The evolution of this solvate towards the face-centred cubic and hexagonal phases of pure C70 is described and a hierarchy of relative stabilities of these latter phase is tentatively proposed.

PHASE EQUILIBRIA IN THE C60-SULPHUR SYSTEM

Abstract A study of the C 60 –S system in the 220–773 K range revealed the existence of only one molecular compound, monoclinic C 60 ·2S 8 , that melts peritectically at 543 K (Δ π H =+54 J g −1 ). Although C 60 ·2S 8 forms with a negative excess volume, the enthalpy associated with its desulphuration is close to that of the sublimation of pure sulphur. The molar fractions of the peritectic and eutectic liquids were found to be x S 8 =0.988 (543 K) and 0.992 (385 K), respectively.