Crystallization of chiral compounds 3. 3-phenoxypropane-1,2-diol and 3-(2-halophenoxy)propane-1,2-diols

Specific features of melting of crystalline samples of 3-(2-R-phenoxy)propane-1,2-diols with different enantiomeric compositions were studied by differential scanning calorimetry. The melting points and enthalpies of melting for the racemate and individual stereoisomers were determined. Binary phase diagrams were constructed. The entropy of mixing of individual enantiomers in the liquid phase and the free energy of formation of the racemic compound were calculated. The thermochemical data indicate that the racemates are formed upon the crystallization of phenoxy-and 2-fluorophenoxy-containing compounds, while crystallization of the chloro-, bromo-, and iodo-substituted analogs would form racemic conglomerates. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 2, pp. 225—232, February, 2006.     

Structural and optical isomers of nonamethoxy cyclotriveratrylene: separation and physical characterization

The paper concerns the structural and optical isomers of nonamethoxy-tribenzocyclononene (compound 1). In the first part of the paper it is shown that 1 exists in two structural isomers: a rigid crown (c-1) with C3 symmetry and a flexible saddle (s-1) with C1 symmetry. The latter, not previously known, can be prepared from the as-synthesized c-1 by quenching a hot solution (or the melt) followed by HPLC separation. The crown/saddle equilibrium, isomerization kinetics, and associated thermodynamic parameters in various organic solvents are reported. Carbon-13 MAS NMR, X-ray diffraction, and differential scanning calorimetry (DSC) of polycrystalline c-1 and s-1 racemates are also reported. The different melting points of the isomers and their rapid isomerization in the melt result in unconventional DSC thermograms involving multiple endothermic and exothermic transitions. The second part of the paper concerns the chiral properties of 1. Both the saddle and crown isomers are structurally chiral, but due to the fast pseudorotation of s-1 in solution, it cannot be separated into its enantiomers. Those of c-1 were separated by HPLC using a chiral column. Their X-ray structure and melting points differ considerably from those of the racemate. This and their fast racemization in the melt lead to complex DSC thermograms with multiple transitions. Solutions of the neat enantiomers exhibit a relatively small specific optical rotation. In the UV they show circular dichroism for the B1u and B2u transitions, with the latter exhibiting a clear couplet structure. Infrared and vibrational circular dichroism spectra of the enantiomers in solution are reported. Comparison of these spectra with quantum mechanical simulations provides unambiguous identification of the enantiomers.     

Thermal and X-ray analysis of racemic bupivacaine hydrochloride

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.     

Synthesis and thermal stability of cubic ZnO in the salt nanocomposites

Cubic zinc oxide (rs-ZnO), metastable under normal conditions, was synthesized from the wurtzite modification (w-ZnO) at 7.7 GPa and ∼800 K in the form of nanoparticles isolated in the NaCl matrix. The phase transition rs-ZnO → w-ZnO in nanocrystalline zinc oxide under ambient pressure was experimentally studied for the first time by using differential scanning calorimetry and high-temperature X-ray diffraction analysis. It was shown that the transition occurs in the temperature range from 370 to 430 K and its enthalpy at 400 K is −10.2 ± 0.5 kJ mol⁻¹.     

Discrimination of thermally treated low density polyethylenes using DSC and principal component analysis

The potential for differential scanning calorimetry (DSC) as a tool for the discrimination of forensic polymer specimens is investigated for a series of commercial low density polyethylene (LDPE) samples. Variation in the melting temperatures of ‘as received’ samples was found to be too small for its use in sample discrimination. The melting behaviour of thermally treated samples, quenched from the melt in liquid nitrogen followed by annealing at temperatures below the melting temperature, showed promise in discrimination potential. The application of principal component analysis to aid discrimination demonstrated the necessity in using a controlled thermal history to aid the discrimination process. The clustering of the LDPEs based on the factors selected demonstrated the potential of DSC for the discrimination of forensic LDPE samples.     

Differential scanning calorimetry (DSC) of semicrystalline polymers

Differential scanning calorimetry (DSC) is an effective analytical tool to characterize the physical properties of a polymer. DSC enables determination of melting, crystallization, and mesomorphic transition temperatures, and the corresponding enthalpy and entropy changes, and characterization of glass transition and other effects that show either changes in heat capacity or a latent heat. Calorimetry takes a special place among other methods. In addition to its simplicity and universality, the energy characteristics (heat capacity C _P and its integral over temperature T—enthalpy H), measured via calorimetry, have a clear physical meaning even though sometimes interpretation may be difficult. With introduction of differential scanning calorimeters (DSC) in the early 1960s calorimetry became a standard tool in polymer science. The advantage of DSC compared with other calorimetric techniques lies in the broad dynamic range regarding heating and cooling rates, including isothermal and temperature-modulated operation. Today 12 orders of magnitude in scanning rate can be covered by combining different types of DSCs. Rates as low as 1 μK s⁻¹ are possible and at the other extreme heating and cooling at 1 MK s⁻¹ and higher is possible. The broad dynamic range is especially of interest for semicrystalline polymers because they are commonly far from equilibrium and phase transitions are strongly time (rate) dependent. Nevertheless, there are still several unsolved problems regarding calorimetry of polymers. I try to address a few of these, for example determination of baseline heat capacity, which is related to the problem of crystallinity determination by DSC, or the occurrence of multiple melting peaks. Possible solutions by using advanced calorimetric techniques, for example fast scanning and high frequency AC (temperature-modulated) calorimetry are discussed.     

Multiple Melting Endotherms of Syndiotactic Polystyrene in β Crystalline Form

Multiple melting behaviors have been studied extensively. Syndiotactic polyStyrene(SPS), in 6 crystalline form exhibited such phenomena. It was suggested that arecrystallization process occurred since it has been clarified that no other modificationswere observed during the DSC heating scanl. In this study, a series of SPS samples in 0form were prepared by cooling from the melt at various cooling ratesl and the factors thatinfluence the multiple melting behavior of SPS in 0 form were exam…     

Discovery of a solid solution of enantiomers in a racemate-forming system by seeding

A racemic liquid of opposite enantiomers usually crystallizes as a racemic compound (racemate), rarely as a conglomerate, and even more rarely as a solid solution. We discovered a Type II solid solution (mixed crystal) of the enantiomers of the chiral drug tazofelone (TZF) by seeding its racemic liquid with enantiomerically pure crystals (enantiomorphs). Without seeding, the racemic liquid crystallized as a racemic compound. The crystal structure of this solid solution resembles that of the enantiomorph but has static disorder arising from the random substitution of enantiomers. This solid solution is a kinetic product of crystallization made possible by its faster growth rate compared to that of the competing racemate (by 4- to 40-fold between 80 and 146 degrees C). The free energy of the solid solution continuously varies with the enantiomeric composition between those of the conglomerate and the racemates. The existence of the TZF solid solution explains the absence of eutectic melting between crystals of different enantiomeric compositions. The ability of TZF to simultaneously form racemate and solid solution originates from its conformational flexibility. Similar solid solutions of enantiomers may exist in other systems and may be discovered in similar ways. The study demonstrates the use of cross-nucleation for discovering and engineering crystalline materials to optimize physical properties.     

A modulated dsc study on the strain-induced βα-transformation in a β-form isotactic polypropylene

The mechanical strain-induced βα-transition of a β-phase isotactic polypropylene (β-iPP) was studied by modulated differential scanning calorimetry (MDSC). Samples were taken after tensile fracture of a double notched specimen from its process and plastic zones, respectively, and the related calorimetric response was compared to that of the bulk material. In contrast to conventional DSC results, it was found that the βα-transformation was not completed in the process zone. Furthermore, the melting of the α-iPP showed both non-reversing and reversing characteristics, whereas the melting of the β-phase proved to be a reversing process. Therefore, it was recommended to consider the conversion grade of the βα-transformation by the relative change in the melt flux of the reversing β-melting peak. This work was supported by the German Science Foundation (DFG-Ka 1202/4-1).     

Liquid chromatographic determination of fluvastatin and its enantiomers in blood plasma by automated solid-phase extraction

Summary Liquid chromatographic methods for determination of fluvastatin, as racemate and asseparated enantiomers, are described. Fluvastatin is an anticholesterolemic agent that inhibits the rate limiting enzyme in cholesterol biosynthesis. The sample clean-up was fully automated, using solid-phase extraction. Plasma samples were injected onto disposable C2 cartridges, connected on-line with the analytical column. After washing, the analytes were eluted and transferred to a C8-analytical column for racemate determination or to a Chiralcel OD-R column for enantiomer separation. Analytes were monitored by fluorescence detection after post-column exposure of the eluate to UV light, which enhanced the sensitivity 20-fold for fluvastatin and 10-fold for the enantiomers. Absolute recoveries were >90% both for the recemate and enantiomers. Limits of quantitation were 0.5 nM for the racemente and 1 nM for enantiomers, using 200 μL plasma sample. Presented at the 21^st ISC held in Stuttgart, Germany, 15^th–20^th September, 1996     

Effect of 4 mass% Ag addition on the thermal behavior of the Cu-9 mass% Al alloy

The effect of 4 mass% Ag addition on the thermal behavior of the Cu-9 mass% Al alloy was studied using differential scanning calorimetry (DSC), optical microscopy (OM), scanning electron microscopy (SEM), energy dispersive X-ray analysis (EDX) and X-ray diffractometry (XRD). The results showed that the presence of silver causes (Cu)-α+(α+g1)→ (Cu)-α+β transformation to occur in two stages. In the first one, part of the produced b phase combines with the precipitated Ag to give a silver-rich phase and in the second one the transformation is completed. The formation of this silver-rich phase seems to be enhanced at very low cooling rates. This revised version was published online in August 2006 with corrections to the Cover Date.     

Molar-mass dependence of apparent relaxation time in melting region of poly(oxytetramethylene)glycol

Melting behaviours of poly(oxytetramethylene)glycols (POTMGs) with different molar masses were investigated by temperature-modulated differential scanning calorimetry (TMDSC) and relaxation times within the melting range were estimated from the modulation-frequency dependence of phase angle δ. An Arrhenius plot of the relaxation times exhibited a plateau in the lower melting peak region of POTMGs with molar masses of 1400, 1000 and 650. This plot was compared with the standard DSC curve. The apparent activation energy was estimated from the relaxation time in the upper and lower sides of a melting temperature region: slight dependence on the molar mass was observed for the former region whereas the maximum value was obtained for a molar mass 1400 for the latter region.     

Thermal Behavior of Hexogen Phlegmatized with Montan Waxes

Hexogen can be used pressed only if its crystals are covered by some polymeric material [1], either natural or artificial. Montan waxes, as natural polymeric materials, were used for the phlegmatization. The melting process of seven types of waxes was analyzed by differential scanning calorimetry. The thermal decomposition processes of hexogens and phlegmatized hexogens were investigated by dynamic differential scanning calorimetry and dynamic thermogravimetric analyses. Kinetic parameters of the decomposition processes of hexogens were evaluated by using data obtained from differential scanning calorimetric curves. This revised version was published online in August 2006 with corrections to the Cover Date.     

Water behaviour in processed cheese spreads

The behaviour of water in two processed cheese spreads, either standard or cream-enriched, was studied by differential scanning calorimetry (DSC) in the −50 to 45 °C temperature range as a function of controlled dehydration. The results were analyzed and related to cheese microstructures observed by environmental scanning electron microscopy (ESEM). Water freezing and subsequent ice melting were found to be dependent on the cheese composition in hydrophilic components and on water confinement within the micro-domains delimited by the fat droplets. Both cheeses exhibited partial water freezing from supercooling state while ice nucleation process was shown to be tightly affected by water connectivity within the cheese matrices.     

On the thermal behaviour of acetylphenyl-hydroxyaceticacid-4-nitrobenzyl esters

The 4-nitrobenzyl ester of acetylphenylhydroxyacetic acid differs in its melting behaviour from other nitrobenzyl esters of phenylhydroxyacetic or acetylphenylhydroxyacetic acids, the racemate having a higher melting point than the enantiomers. By means of thermal analysis, IR spectroscopy and X-ray diffractometry the ester can be shown to occur in two crystalline modifications. In the process of solidification of the molten mass, at first a modification of higher energy is formed, obviously being caused by an excess of one enantiomer, which is then exothermally rearranged in the lattice of the racemate.     

Crystallization kinetics of poly(vinylidene fluoride)/MMT,SiO<Subscript>2</Subscript>, CaCO<Subscript>3</Subscript>, or PTFE nanocomposite by differential scanning calorimeter

The nonisothermal crystallization kinetics of poly(vinylidene fluoride) (PVDF) in PVDF/MMT, SiO₂, CaCO₃, or PTFE composites was investigated through differential scanning calorimetry measurements. The enhanced nucleation of PVDF in its nanocomposites with four types of nanoparticle, and their impact on the crystallization kinetics and melting behaviors were discussed. The modified Avrami method and combined Ozawa–Avrami approaches successfully described the primary crystallization of PVDF in nanocomposite samples under the nonisothermal crystallization process. The activation energy was determined according to the Friedman method and it was quite fit with the results of the analysis according to the modified Avrami model and a combined Ozawa–Avrami model.     

Structural characterization,thermal investigation,and liquid crystalline behavior of 4-[(4-chlorobenzyl)oxy]-3,4′-dichloroazobenzene

Using the Williamson method, a new dye 4-[(4-chlorobenzyl)oxy]-3,4′-dichloroazobenzene (CODA) with liquid crystalline properties was synthesized. The structure and the thermal behavior of CODA were investigated by means of nuclear magnetic resonance, X-ray diffraction, differential scanning calorimetry, and light polarized optical microscopy techniques. The thermophysical processes were monitored by heating–cooling cycles, but the formation of liquid crystal phases were exhibited only for small values of the cooling rates. For the first heating–cooling cycle, the melting and the solidification processes, thus the characteristic temperatures, are shifted to higher values when compared to the following cycles.     

Effect of phalloidin on filaments polymerized from heart muscle ADP-actin monomers

The effect of phalloidin on filaments polymerized from ADP-actin monomers of the heart muscle was investigated with differential scanning calorimetry. Heart muscle contains α-skeletal and α-cardiac actin isoforms. In the absence of phalloidin the melting temperature was 55°C for the α-cardiac actin isoform and 58°C for the α-skeletal one when the filaments were generated from ADP-actin monomers. After the binding of phalloidin the melting temperature was isoform independent (85.5°C). We concluded that phalloidin stabilized the actin filaments of α-skeletal and α-cardiac actin isoforms to the same extent when they were polymerized from ADP-actin monomers.     

Physicochemical characterization of nicergoline and cabergoline in its amorphous state

Formulation of poorly water-soluble crystalline drugs into their more soluble amorphous form is a common approach for improving their bioavailability. In this study, the amorphous forms of nicergoline (NIC) and cabergoline (CAB) were obtained by different methods (melting and precipitation under solvent evaporation). The physicochemical characteristics of the samples were determined by HPLC, differential scanning calorimetry (DSC), thermogravimetry, and X-ray powder diffractometry. The physical stability of the amorphous forms was investigated by DSC by considering how the onset temperature and the enthalpy content at the glass transition vary with aging time and temperature. Using the Kohlrausch–Williams–Watts equation on the data obtained from the experiments, the “mean molecular relaxation time constant” (τ) was estimated. This parameter was used to understand the stability of NIC and CAB in their glassy state at different temperatures, and results showed that their stability is adequate to enable the formulation of these drugs into solid dosage forms.     

Entropy driven binding of the alkaloid chelerythrine to polyadenylic acid leads to spontaneous self-assembled structure formation

The binding thermodynamics and interaction of the putative anticancer alkaloid chelerythrine with polyadenylic acid were investigated by isothermal titration calorimetry, absorption and fluorescence spectroscopy, circular dichroism, differential scanning calorimetry and thermal melting experiments. The equilibrium binding constant was evaluated to be of the order of 10⁷ M⁻¹. Strong positive entropic and favorable enthalpic contributions to the binding were revealed. The binding affinity was enhanced within (10 to 100) mM Na⁺ concentration. Circular dichroism spectra confirmed that the increase in entropy change was caused by a strong conformational change in the RNA polynucleotide. Absorption and circular dichroism melting studies revealed that chelerythrine binding induced self-assembled duplex structure formation in poly(A) molecules resulting in a cooperative melting profile. This was further confirmed from differential scanning calorimetry data. The intercalation binding of the alkaloid involved strong energy transfer from the polynucleotide bases to the bound alkaloid molecules. The remarkably high entropy driven binding of the alkaloid induced spontaneous self-assembled structure formation in poly(A) and the associated binding affinity is the highest so far reported for a small molecule binding to poly(A).