Seven polymorphic modifications of doxazosin mesylate, designed as forms A, D, E, F, G, H, I, and the amorphous state were
studied by thermal methods (TG and DSC), temperature resolved X-ray powder diffractometry, hot stage and scanning electron
microscopy and by FT-IR spectroscopy. Amorphous form was obtained either by fast evaporation of the solvent or by fast cooling
of the melt in the DSC. Polymorphs A and F were found to be stable in the temperature range from room temperature to their
melting points at 277.9 and 276.5C, respectively. Form G, which melts at 270.8C, was found to be hygroscopic. Polymorph
D undergoes irreversible solid–liquid–solid phase transition at 235.5C to polymorph I which melts at 274.9C. Form H, which
melts at 258.0C, was found to be unstable at high temperatures. DSC examinations revealed that form H is irreversibly transformed
to polymorph F during heating above the temperature of about 240C. The amorphous state was found to be stable at room temperature
but when heating above the glass transition (Tg=144.1C) it crystallizes at 221.6C, what leads into a mixture of polymorphic forms. The new polymorphic form designed as
E was identified in the mixture. The polymorph E is converted by heating to the more stable form F. The solubilities at 25C
for forms A, and F in methanol are 3.5 and 7.7 mg mL−1and in water they are 3.8 and 6.2 mg mL−1, respectively.
Authors:Valentina Martena, Roberta Censi, Ela Hoti, Ledjan Malaj, and Piera Di Martino
crystalline form are poorly water soluble, the potential to transform them into an amorphousstate is regarded with interest because of the advantageous biopharmaceutical properties that might thus be obtained. An amorphous phase may be deliberately formed to
Authors:E. Marti, E. Kaisersberger, and E. Moukhina
heat capacity or the specific heat is for any crystalline, partially amorphous
or completely amorphous substance or material a significant thermodynamic
property. The glass transition may be regarded as the melting point of amorphous
substances and materials, a transition property of an outstanding technical
importance. A crucial point is the fact that the presence of a glass transition
is an unequivocal proof of an amorphous content of a material. Furthermore,
the change of the specific heat at the glass transition temperature enables
the quantitative determination of the amorphicity on a relative or absolute
level of any substance or material. The absolute determination of the amorphicity
affords a calibration with a reference corresponding to the material under
investigation. The crystallinity for this reference substance must be known
from the preparation and or by any independent analytical method.
literature data for the specific heat and the glass transition of polystyrene
were collected and evaluated. Data were found for the specific heat in literature
from 10 to 470 K. The data were unified for each of the reported temperature
in a mean value and the corresponding standard deviation was determined. An
excellent conformity was found in the glassy state of polystyrene with standard
deviations lower than 0.7%. The standard deviations above the glass transition
were considerably higher.
All these literature data were transferred
for each of the literature sets separately into linear specific heat functions
in the vicinity of the glass transition. One set of our measurements performed
with the DSC 204 and with polystyrene SRM 705a as sample material was additionally
integrated in the mean of these functions for the glassy state and the liquid
amorphous state respectively. The addition of our results gave practically
no change of the mean coefficients and only a decrease of the standard deviations.
In such a way, the data with the best statistical base for the specific heat
of polystyrene are listed in this paper ( ‘Conclusions’).
The glass transition as a transition in and out of a non-equilibrium
state, the glassy state, is sensitive to all kind of influences such as thermal
and mechanical treatments as well as to the selected experimental conditions.
Therefore, certain standardized conditions procedures must be fulfilled to
get reproducible data. The literature data for the glass transition temperature
were also used to get a mean value. However, two values were omitted for the
formation of the mean, because the authors reported values, which were too
low on the base of impurities present. The mean value of the glass transition
for polystyrene is according to the literature 3692 K. A mean value
of 3702 K was extrapolated for an infinite molecular mass.
The DSC and TMDSC measurements for the three thermodynamic properties
reported in this paper, namely the specific heat, the glass transition temperature
and the corresponding change of the specific heat gave results without significant
differences compared with the literature values.
is a rather ideal polymer together with sapphire as calibration substance
to elucidate and validate the DSC and TMDSC procedures for the determination
of the specific heat and the glass transition.
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.
Authors:D. Giron, P. Remy, S. Thomas, and E. Vilette
The amorphous state of solids is characterized by a higher chemical and physical reactivity and a hygroscopic behaviour. Furthermore processing of amorphous powders is often difficult, because of the instability. Fast crystallizations, precipitations and milling favour the formation of the amorphous state. Galenical processes like granulation, drying, lyophilization, mixing, may also induce amorphous regions in the drug products.
Thermal analysis methods are well-established techniques in research laboratories of pharmaceutical industry. The robustness
and sensitivity of instrumentation, the introduction of automation and of reliable software according to the industrial needs
widened considerably the areas of applications in the last decade. Calibration of instruments and validation of results follow
the state of the art of cGMP as for other analytical techniques. Thermal analysis techniques are especially useful for the
study of the behavior of the poly-phasic systems drug substances and excipients and find a unique place for new delivery systems.
Since change of temperature and moisture occur by processing and storage, changes of the solid state may have a considerable
effect on activity, toxicity and stability of compounds. Current requirements of the International Conference of Harmonisation
for the characterization and the quantitation of polymorphism in new entities re-enforce the position of thermal analysis
techniques. This challenging task needs the use of complementary methods. Combined techniques and microcalorimetry demonstrate
their advantages. This article reviews the current use of thermal analysis and combined techniques in research and development
and in production. The advantage of commercially coupled techniques to thermogravimetry is emphasized with some examples.
that the amorphousstate is more accurately described as multiple states of aggregation characteristic of this distribution of minima on the hypersurface. This means that the dipole response to the external electric field cannot be described in terms of
to grain size of 0.1–0.3 mm. The chemical composition of glasses was controlled by X-ray fluorescence spectroscopy using ARL Advant ‘XP spectrometer. Chemical composition of the examined glasses was presented in Table 1 . Amorphousstate of the
Modern thermal analysis, microcalorimetry and new emerging combined techniques which deliver calorimetric, microscopic and
spectroscopic data offer a powerful analytical battery for the study of pharmaceuticals. These techniques are very useful
in all steps of development of new drug products as well as methods for quality control in production. The characterization
of raw materials enables to understand the relationships between polymorphs, solvates and hydrates and to choose the proper
development of new drug products with very small amount of material in a very short time. Information on stability, purity
is valuable for new entities as well as for marketed drug substances from different suppliers. Excipients which vary from
single organic or inorganic entity to complexes matrixes or polymers need to be characterized and properly controlled. The
thermodynamic phase-diagrams are the basis of the studies of drug-excipients interactions. They are very useful for the development
of new delivery systems. A great number of new formulations need proper knowledge of the behaviour of the glass transition
temperature of the components. Semi-liquid systems, interactions in aqueous media are also successfully studied by these techniques.
Authors:T. Shakhtshneider, F. Danède, F. Capet, J. Willart, M. Descamps, L. Paccou, E. Surov, E. Boldyreva, and V. Boldyrev
The effect of cryogenic grinding on the indomethacin (IMC) and its mixtures with polyvinylpyrrolidone (PVP) was studied by
powder X-ray diffraction and differential scanning calorimetry. Cryoground mixtures were shown to form glass solutions. PVP
inhibits the crystallization of IMC from the amorphous state: the crystallization temperature of IMC in the mixtures with
PVP increases, and the amorphous state is preserved longer on storage. The mixtures were characterized by Raman spectroscopy.
Dissolution of the IMC in the cryoground mixtures is higher as compared to the pure form, also after a prolonged storage.