Solid dispersions of the antidiabetic drug glibenclamide and polyethylene glycol 4000 (macrogol 4000) were prepared by the
melting method in order to increase the solubility of this poorly water-soluble compound. The temperature/composition phase
diagram of the components was analyzed by hot-stage microscopy and differential scanning calorimetry, showing a monotectic.
Polarized light hot stage microscopy and X-ray-powder diffraction confirmed, that glibenclamide is mainly present in a non-crystalline
state after melting and solidifying of a 10% (w/w) mixture, which results in an enhanced solubility compared to physical mixtures. The solubility and dissolution rate of the
drug increases clearly with decreasing drug/polymer ratio. Moreover, it was observed for the first time that a drug could
crystallize as whiskers at the surface of aged solid dispersion particles. Besides relaxation phenomena, this crystallization
mechanism may be responsible for a deterioration of liberation properties and bioavailability of solid dispersion based drug
products with increasing storage time.
The binary systems of urea with polyethylene glycols 6000 and 4000 show inclusion compounds with higher melting points than
the two components (m.p. 143 and 142.5°C resp.). From the melt unstable forms crystallize beside the stable crystal modifications. These have also
been identified by FTIR microscopy and X-ray powder diffractometry. The phase diagrams are uncommon in so far as the inclusion
compounds do not form eutectics but monotectics with both components. The inclusion compounds of the two polyethylene glycols
with urea are isomorphous and form a series of mixed crystals following the Roozeboom I type of diagram.
Crystal polymorphs of pramocaine hydrochloride (PRCNC) and pramocaine (PRCN) free base were produced and characterized by
means of thermomicroscopy, differential scanning calorimetry (DSC), FTIR- and FT-Raman-spectroscopy as well as X-ray-powder
diffractometry. The relative thermodynamic stabilities of all forms were determined and are represented in semi-schematic
energy/temperature diagrams. PRCN, which is a viscous liquid at room temperature and insoluble in water, was found to exist
in two different crystal forms with the melting points 23.5C (mod. I) and 12.5C (mod. II). The water-soluble PRCNC crystallizes
in three different crystal modifications. Mod. II is the thermodynamically stable form at room temperature and is present
in commercial products. This form is obtained by crystallization from solvents and transforms on heating at about 95C into
the high temperature form mod. I which melts at 171.0C. Both compounds show conformational polymorphism with forms of low
Authors:A. Schmidt, V. Niederwanger, and U. Griesser
Two polymorphic forms, a dioxane solvate and the amorphous form of the local anaesthetic drug prilocaine hydrochloride (N-(2-methylphenyl)-2-propylamino
monohydrochloride, PRCHC) were characterized by thermal analysis (hot stage microscopy, differential scanning calorimetry,
thermogravimetry), vibrational spectroscopy (FTIR, FT-Raman-spectroscopy), powder X-ray diffractometry and water vapor sorption
analysis. The formation and thermodynamic stability of the different solid phases is described and presented in a flow chart
and an energy temperature diagram, respectively. Mod. I (m.p. 169C) is the thermodynamically stable form at room temperature and present in commercial products. This form crystallizes
from all tested solvents except 1,4-dioxane which gives a solvate with half a mole of 1,4-dioxane per mole PRCHC. Mod. II
occurs only on desolvation of the dioxane solvate and shows a lower melting point (165.5C) than mod. I and a lower heat
of fusion. Thus, according to the heat of fusion rule, mod. II is the thermodynamically less stable form in the entire temperature
range (monotropism) but kinetically stable for at least a year. Freeze-drying of an aqueous solution leads to the amorphous
form. On heating and in moist air amorphous PRCHC exclusively crystallizes to the stable mod. I. PRCHC exemplifies that certain
metastable polymorphic forms are only accessible via a specific solvate, but not via any other crystallization path. Since
no crystallization from 1,4-dioxane was performed in earlier solid-state studies of this compound, PRCHC was to this date
rated as monomorphic.
Authors:U. Griesser, M. Szelagiewicz, U. Hofmeier, C. Pitt, and S. Cianferani
In order to determine the applicability of vapor pressure studies on polymorphic modifications, pairs of enantiotropically related modifications of caffeine, theophylline and carbamazepine were investigated. The studies were performed over a wide temperature range (71 to 191°C) and accordingly over a wide vapor pressure range (0.02 to 400 Pa) using an automatic instrument constructed on the basis of the gas saturation principle. This instrument enables an analytical determination of the main component and the impurities present by the chromatographic separation of the substances transported in the gas flow. Therefore, the real partial pressure of the main component can be measured. Due to the high precision of the applied method it was possible to determine partial pressure curves and the thermodynamic transition temperature — the point at which the vapor pressure of two crystal polymorphs is equal. The thermodynamic transition temperatures of caffeine and theophylline were determined to be 136 and 232°C, respectively. These values are in agreement with experimental or calculated values derived from DSC investigations but are more reliable. Vapor pressure measurements of carbamazepine are only meaningful in the low temperature range due to its decomposition at high temperatures. The thermodynamics, advantages and limits of vapor pressure determinations of polymorphic modifications are discussed.
Authors:U. Griesser, D. Weigand, J. Rollinger, M. Haddow, and E. Gstrein
Five crystal polymorphs of the herbicide metazachlor (MTZC) were characterized by means of hot stage microscopy, differential
scanning calorimetry, IR- and Raman spectroscopy as well as X-ray powder diffractometry. Modification (mod.) I, II and III
can be crystallized from solvents and the melt, respectively, whereas the unstable mod. IV and V crystallize exclusively from
the super-cooled melt. Based on the results of thermal analysis and solvent mediated transformation studies, the thermodynamic
relationships among the polymorphic phases of metazachlor were evaluated and displayed in a semi-schematic energy/temperature-diagram.
At room temperature, mod. III (Tfus =76C, ΔfusHIII =26.6 kJ mol-1) is the thermodynamically stable form, followed by mod. II (Tfus =80C, ΔfusHII =23.0 kJ mol-1) and mod. I (Tfus =83C, ΔfusHII=19.7 kJ mol-1). These forms are enantiotropically related showing thermodynamic transition points at ~55C (Ttrs, III/II), ~60C (Ttrs, III/I) and ~63C (Ttrs, II/I). Thus mod. I is the thermodynamically stable form above 63C, mod. III below 55C and mod. II in a small window between
these temperatures. Mod. IV (Tfus =72-74C, ΔfusHII =18.7 kJ mol-1) and mod. V (Tfus =65C) are monotropically related to each other as well as to all other forms. The metastable mod. I and II show a high kinetic
stability. They crystallize from solvents, and thus these forms can be present in commercial samples. Since metazachlor is
used as an aqueous suspension, the use of the metastable forms is not advisable because of a potential transformation to mod.
III. This may result in problematic formulations, due to caking and aggregation.
Authors:A. Sykuła-Zając, E. Łodyga-Chruścińska, B. Pałecz, R. E. Dinnebier, U. J. Griesser, and V. Niederwanger
An amide-type local anesthetic drug, bupivacaine hydrochloride (BupiHCl), in the form of racemate is listed in the European and American pharmacopoeias and continues to be used in medicine. Thermal and X-ray analysis of commercial BupiHCl monohydrate was performed by differential scanning calorimetry with thermogravimetry, hot stage microscopy, and X-ray diffraction. Endothermic dehydration occurs at the temperature range of 73–130 °C for DSC–TG 111 (Setaram) and at 83–150 °C for DSC 404 (Netzsch). Both curves at 2 and 10 °C min−1 clearly reflect phase transformation of anhydrous Form I into II before reaching the melting point. A well-defined exothermic phase transition of BupiHCl was detected at a lower heating rate. Temperature-resolved X-ray diffraction in conjunction with DSC led to determining a similarity between the obtained thermal events. Microscopic investigation also confirmed the above-mentioned transformations.