Authors:F. Giordano, G. Bruni, and G. P. Bettinetti
Differential scanning calorimetry DSC has been applied to the analysis of drugcyclodextrin binary systems in order to gain experimental evidence of the interaction and determine the stoichiometry of the inclusion compound. Two model systems, paracetamolbetacyclodextrin and vinburnineg-ammacyclodextrin were tested through the comparison of thermal behaviors of interacted and non-interacted mixtures containing excess drug. DSC allowed a confirmation of both interaction and stoichiometry of the inclusion compounds.
Authors:V. Berbenni, C. Milanese, G. Bruni, and A. Marini
The thermal decomposition of gallium nitrate hydrate (Ga(NO3)3·xH2O) to gallium oxide has been studied by TG/DTG and DSC measurements performed at different heating rates. It is concluded that 8 water molecules are present in the hydrate compound. The anhydrous gallium nitrate does not form at any temperature as the reaction consists of coupled dehydration/decomposition processes that occur with a mechanism dependent on heating rate. TG measurements performed with isothermal steps (between 31 and 115°C) indicate that Ga(OH)2NO3 forms in the first stage of the reaction. Such a compound undergoes further decomposition to Ga(OH)3 and Ga(NO3)O, compounds that then decompose respectively to Ga(OH)O and finally to Ga2O3 and directly to Ga2O3. Diffuse reflectance Fourier transform IR spectroscopy (DRIFTIR) has been of help in assessing that the reaction consists of parallel dehydration/decomposition processes.
Authors:A. Marini, V. Berbenni, G. Bruni, A. Maggioni, and M. Villa
The heat capacity calibration ‘constants’ of a commercial MTDSC system (TA 3100) were determined in a variety of experimental
conditions. For a given modulation frequency, the calibration constants are the same within a few percents for different temperatures,
and over a wide range of modulation amplitudes and scan rates. This variation decreases below 1% if hidden instrumental constraints
are taken into account, which are related with the capability of the control system to achieve the desired temperature program.
On the other hand, the calibration constant changes substantially with the period, and takes anomalously high values for the
short modulation periods (20+40 s). Rules to optimize the accuracy of the system are given.
Authors:A. Marini, V. Berbenni, G. Bruni, R. Riccardi, and M. Villa
The thermodynamics of β-cyclodextrin dehydration is investigated, by parallel DSC/TG experiments, on both fully and partially
hydrated samples. The apparent dehydration enthalpies per mole of water are impossibly high and this fact suggests that another
phenomenon, in addition to the rupture of the β-cyclodextrin/H2O hydrogen bonds, contributes to the peak area. All the experimental evidence agrees with an ‘interaction model’ which assumes
that deydration is accompanied by a slow and reversible rearrangement of the β-cyclodextrin structure.
Authors:V. Berbenni, A. Marini, G. Bruni, A. Maggioni, and P. Cogliati
A physico-chemical characterization of dipyridamole (C24H40N8O4), a widely used anti-aggregating agent, has been performed by using a combination of thermoanalytical (DSC) and spectroscopic
(XRPD and FT-IR/PAS) techniques. A solid state transition, already reported in literature, has been ascribed to the breaking
of an intramolecular H-bonds network. The rupture of a network of intermolecular H-bonds is thought to accompany the fusion.
The solid state transition has been shown to be reversible provided the sample has not undergone melting.
Mechanical milling and thermal annealing have been shown to decrease melting temperature and enthalpy. The effect brought
about by mechanical and thermal treatment on the solid state transition is different. In the milled samples the transition
peak shifts towards lower temperatures and its enthalpy suggests that all intramolecular H-bonds have been transformed into
Authors:A. Marini, V. Berbenni, G. Bruni, M. Villa, and A. Orlandi
GV150526A is a novel 2-carboxyindole derivative, recently synthesized by GlaxoWellcome, which is used in treatment or prevention
of CNS disorders resulting from neurotoxic damage. It has been prepared in three forms, F1, F2 and F3, having significantly
different hydration/dehydration behavior and/or diffraction patterns. Here, we extend the thermal analysis of these polymorphs
above 200C, where all forms are fully dehydrated and the main thermal phenomena are decomposition and melting. Simultaneous
TG/DSC measurements have been repeated in wet and dry nitrogen atmospheres over a wide range of heating rates. Form F3 displays
a qualitatively different behavior relative to F1 and F2. This fact is interpreted as an evidence of a mechanism of decomposition
which sets F3 apart from F1 andF2. The thermal data are summarized by simple heuristic equations and few ‘apparent’enthalpies.
Authors:G. Bruni, L. Amici, V. Berbenni, A. Marini, and A. Orlandi
This paper is the first one of a research project aimed to find and optimize methods by which drug-excipient compatibility
can be reliably and quickly assessed.
A number of experimental techniques (simultaneous TG-DSC, FT-IR spectroscopy, X-ray powder diffraction, scanning electron
microscopy) have been used to investigate the compatibility between a novel tricyclic β-lactam antibiotic developed by GlaxoWellcome
(now GlaxoSmithKline), GV118819x, and some commonly used excipients (poly(vinylpyrrolidone), magnesium stearate and α-lactose).
Binary mixtures of two different compositions have been analyzed: drug:excipient=80:20 and 20:80 (mass/mass). Both qualitative
and quantitative interaction indicators have been identified. It is shown that simultaneous thermal analysis is the best suited
technique in the search of interaction indicators. With a proper selection of experimental conditions it is able to reveal
the thermal changes brought about by the early stages of interaction, i.e. those occurring during the measurement on physical
mixtures not previously annealed under stress conditions. Such an ability is discussed, in particular, with respect to the
role of the water vapour, which has been found to be a critical parameter for all our systems.
Authors:G. Bruni, V. Berbenni, C. Milanese, A. Girella, P. Cofrancesco, G. Bellazzi, and A. Marini
In this work the solid-state characterization of anhydrous D-mannitol has been performed: α and β modifications can be distinguished only by XRPD and FTIR as they show melting temperature
and enthalpy that are the same within the standard deviation. The understanding of the thermal behaviour of the δ form (obtained
by re-crystallization in acetone) has required XRPD experiments performed at variable temperature. This form during heating
undergoes a solid phase transition to α modification. By cooling a melted sample, under a wide range of experimental conditions,
a very fast crystallization occurs. Independently of the starting crystal form (β or δ form), the re-crystallization of D-mannitol from melt always leads to α form.
Authors:G. Bruni, C. Milanese, V. Berbenni, F. Sartor, M. Villa, and A. Marini
The thermodynamic properties of a new antidepressant drug are studied from room temperature to 200 °C. In this range, the
sample neither decompose, nor has a significant reactivity with water. When slowly heating a “fresh” sample, we may observe
the following phenomena (in the order): melting of a form (F1, ~170 °C), crystallization of a structurally different form
(F2), and melting of F2 (~180 °C). In no circumstances, the direct transition from F1 to F2 can be observed. On the other
hand, F2 reverts to F1 upon cooling below ~130 °C. A glassy phase is formed upon cooling from above 180 °C, as confirmed by
X-ray analysis and the appearance of a glass transition when reheating. The “reversible” (e.g., melting) and “irreversible”
(e.g., glass formation) contributions to the measured enthalpies are estimated with temperature-modulated DSC measurements,
resulting into a consistent description of thermodynamics of the forms, their melting and their kinetics of transformation.
Authors:Giovanna Bruni, C. Milanese, G. Bellazzi, V. Berbenni, P. Cofrancesco, A. Marini, and M. Villa
The processes of production of drugs and dosage forms in the solid state often cause unwanted transformation of portions of
the substances into amorphous state, with significant changes of properties such as stability and bio-availability. When this
amorphous fraction is of the order of a few percent, it usually goes unnoticed, but it should be accurately determined within
a quality control system. In this work, we consider a model drug, perphenazine, where partial amorphisation may be induced
by standard mechanical treatments.
We show that Differential Scanning Calorimetry (DSC) leads to consistent estimations of the amorphous fractions induced by
the treatment. Furthermore, DSC also yields the expected amounts of amorphous perphenazine when analysing known mixtures of
perfectly crystalline samples (untreated) and partially amorphous samples (treated). We show that even amorphous fractions
of the order of 1% are accurately estimated by our method.