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:Irene Pasquali, R. Bettini, and F. Giordano
This work aims to investigate the thermal behaviour of diclofenac, diclofenac sodium, and NaHCO3 both as single components and binary mixtures. In particular, the melting point and latent heat of fusion binary diagrams
of the diclofenac sodium/diclofenac mixtures at different mole fraction compositions were investigated in order to gain information
about the thermal behaviour of their solid mixtures. A good agreement between liquidus curves, calculated by the Schroeder-Van
Laar equation from fusion enthalpies and temperatures, and the experimental results was found. For all binary compositions,
an endothermic effect at 153�C, probably due to the eutectic fusion, is present.
Authors:Zsuzsanna Éhen, F. Giordano, J. Sztatisz, L. Jicsinszky, and Cs. Novák
Summary Thermoanalytical techniques (TG, DSC) are frequently used in the investigation of the thermal properties of cyclodextrins and their inclusion complexes. However, the above techniques do not provide information on the chemical composition of the evolved fragments upon the thermal decomposition. In this study &-, &- and &-cyclodextrins and 4 methylated and 3 ethylated &-CD derivatives were investigated with a TG-MS combined thermoanalytical technique in order to get information about their fragmentation behaviour. By comparison of the TG/DTA curves, a different thermal behaviour was found for each of the native and the chemically modified cyclodextrins. Except for the water loss profiles and the solid-solid phase transformations, the thermal behaviour of the (investigated) native CDs do not show remarkable differences. However, the chemical modification of the native &-CD resulting in a new compound may change the strength of interactions between host and guest causing differences in the thermal stabilities of the derivatives. The mass spectrometry results supported the observed thermal differences and showed significant alterations in the fragmentation of ethylated and methylated compounds. The investigated natural CDs possess a very similar fragmentation profile, due to the common &-D-glucopyranose building units. In the case of modified CDs characteristic signals of the substituents are present.
Authors:M. Caira, A. Foppoli, M. Sangalli, L. Zema, and F. Giordano
The thermal and structural characteristics of two crystal forms of ambroxol, (trans-((amino-2-dibromo-3,5-benzyl)amino)-4-cyclohexanol), a drug with remarkable mucolytic and expectorant properties marketed
in several drug products, were investigated. Form II (m.p. 92.4C) is obtained by spontaneous cooling from a hot water/ethanol solution while Form I (m.p. 99.5C) slowly separates from the mother liquor. The two forms can be identified by PXRD and DSC analyses. On the basis
of both thermal and structural data the thermodynamic relationship of enantiotropy was deduced. No metastable (Form I)?stable
(Form II) conversion was observed upon storage at ambient conditions. Form I crystallizes in the space group P21/n (alternative setting of P21/c) with Z=8. Form II crystallizes in the space group P21/c with Z=4 and a significantly different crystal packing arrangement from that in Form I. A third crystalline modification, Form III
(space group P21/c with Z=16) was detected on cooling a single crystal of Form I down to -70C. On warming to ambient temperature Form III was found
to revert to Form I. This reversible single crystal to single crystal transition was structurally characterised and found
to involve subtle changes in the types and extent of molecular disorder as well as the hydrogen bonding arrangement.
Authors:R. Bettini, G. Bertolini, E. Frigo, A. Rossi, I. Casini, I. Pasquali, and F. Giordano
The aim of this work was to study the solubility in supercritical CO2 of the hydrated phase of three model drugs, namely theophylline, carbamazepine, and diclofenac sodium, in comparison with
the respective anhydrous form. Possible solid-state modifications, stemming from the interaction with supercritical CO2, were investigated by differential scanning calorimetry, thermogravimetric analysis, hot stage microscopy, Fourier Transform
infrared spectroscopy and Karl-Fischer titrimetry. It was found that all three pharmaceutical hydrates exhibited higher solubility
in supercritical CO2 than the relevant anhydrous phases. In the case of theophylline monohydrate, the instability of the crystal phase at the
experimental temperature adopted has been evidenced. Diclofenac sodium tetrahydrate represents a peculiar case of chemical
interaction with the acid supercritical fluid, mediated by crystal water.
Authors:A. Cvetkovskii, R. Bettini, Lj. Tasic, M. Stupar, I. Casini, A. Rossi, and F. Giordano
The thermal behaviour of binary mixtures between β-cyclodextrin (β-CD) and either carbamazepine polymorphic Form I (CBZ I),
Form III (CBZ III) or dihydrate was investigated in order to assess possible interactions of CBZ solid phases with β-CD. Physical
mixtures and kneaded binaries of β-CD and different CBZ crystal forms were studied by differential scanning calorimetry, thermogravimetric
analysis and hot stage microscopy. The pattern of transition of CBZ Form III into Form I is strongly influenced by β-CD. The
liquid-solid transition is practically absent when anhydrous CBZ/β-CD mixes are tested, as a consequence of an interaction
between β-CD and liquid CBZ that hinders CBZ recrystallisation as Form I occurring after CBZ Form III melting.
Water loss on heating of CBZ dihydrate in the presence of β-CD leads in all cases to the formation of CBZ Form I.
Authors:F. Giordano, A. Rossi, R. Bettini, A. Savioli, A. Gazzaniga, and Cs. Novák
The thermal behavior of binary mixtures of paracetamol and a polymeric excipient (microcrystalline cellulose, hydroxypropylmethylcellulose
and cross-linked poly(vinylpyrrolidone)) was investigated. The physical mixtures, ranging from 50 to 90% by mass of drug,
were submitted to a heating-cooling-heating program in the 35–180C temperature range. Solid-state analysis was performed
by means of differential scanning calorimetry (DSC), hot stage microscopy (HSM), micro-Fourier transformed infrared spectroscopy
(MFTIR), and scanning electron microscopy (SEM).
The polymeric excipients were found to address in a reproducible manner the recrystallization of molten paracetamol within
the binary mixture into Form II or Form III. The degree of crystallinity of paracetamol in the binary mixtures, evaluated
from fusion enthalpies during the first and second heating scans, was influenced by the composition of the mixture, the nature
of the excipient and the thermal history. In particular, DSC on mixtures with cross-linked poly(vinylpyrrolidone) and hydroxypropylmethylcellulose
with drug contents below 65 and75%, respectively, evidenced the presence only of amorphous paracetamol after the cooling phase.
Microcrystalline cellulose was very effective in directing the recrystallization of molten paracetamol as Form II.