Critical Appraisal of Kinetic Calculation Methods Applied to Overlapping Multistep Reactions.

Thermal decomposition of solids often includes simultaneous occurrence of the overlapping processes with unequal contributions in a specific physical quantity variation during the overall reaction (e.g., the opposite effects of decomposition and evaporation on the caloric signal). Kinetic analysis for such reactions is not a straightforward, while the applicability of common kinetic calculation methods to the particular complex processes has to be justified. This study focused on the critical analysis of the available kinetic calculation methods applied to the mathematically simulated thermogravimetry (TG) and differential scanning calorimetry (DSC) data. Comparing the calculated kinetic parameters with true kinetic parameters (used to simulate the thermoanalytical curves), some caveats in the application of the Kissinger, isoconversional Friedman, Vyazovkin and Flynn-Wall-Ozawa methods, mathematical and kinetic deconvolution approaches and formal kinetic description were highlighted. The model-fitting approach using simultaneously TG and DSC data was found to be the most useful for the complex processes assumed in the study.

MCR-ALS analysis of IR spectroscopy and XRD for the investigation of ibuprofen - nicotinamide cocrystal formation.

To improve aqueous solubility, a poorly water-soluble active ingredient is classically combined with a conformer to form cocrystals. Hot melt extrusion is one preparation method for the formation of cocrystal solids. The aim of our study was to determine the optimal temperature conditions for the formation of ibuprofen and nicotinamide cocrystals using real-time infrared (IR) and X-ray diffraction (XRD) measurements. IR spectra and XRD patterns were subjected to multivariate curve resolution alternating least squares (MCR-ALS) analysis and decomposed into several components. Each component was descriptive of a specific step in the formation of the cocrystal. Cocrystal formation was followed by a separation phase between amorphous ibuprofen and crystalline nicotinamide. Our results suggest that, when using the hot melt exclusion method, careful consideration should be made towards optimizing processing temperatures in order to prevent amorphization and promote control over the process of cocrystal formation.

Structural and energetic aspects of a new bupropion hydrochloride polymorph.

Crystalline bupropion hydrochloride [(±)1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1-propanone hydrochloride], recently characterized as form 1, was found to undergo, upon storage at RT within months, a solid-solid conversion to a new polymorphic form, hereafter named form 2, containing a markedly different molecular conformer in the solid state. This new form, available only as a polycrystalline material, has been fully characterized using structural X-ray powder diffraction methods, coupled to thermoanalytical analyses. The relative stability of the two crystalline phases (forms 1 and 2) was compared by quantum mechanics calculations including density functional methods specific for solid state molecular systems. Bupropion hydrochloride form 2 crystallizes in the orthorhombic space group Pbca with Z=8, a=27.2853(5)Å, b=8.7184(3)Å, c=12.0422(3)Å, V=2864.7(1)ų, as centrosymmetric dimers, thanks to the presence of N-H…Cl interactions, and µ2-bridging chloride ions, each connected to two protonated amine moieties.

Determination of the melting temperature, heat of fusion, and purity analysis of different samples of zidovudine (AZT) using DSC / Determinação da temperatura de fusão, calor de fusão e pureza análise de diferentes amostras de zidovudina (AZT) por DSC

The determination of chemical purity, melting range, and variation of enthalpy in the process of characterizing medicines is one of the principal requirements evaluated in quality control of the pharmaceutical industry. In this study, the method of purity determination using DSC was outlined, as well as the application of this technique for the evaluation of commercial samples of zidovudine (AZT) (raw material) supplied by different laboratories. To this end, samples from six different laboratories (A, B, C, D, E, and F) and the standard reference (R) from the United States Pharmacopeia (USP) were analyzed. The DSC curves were obtained in the temperature range of 25 to 200 ºC under the dynamic atmosphere of N2 (50 mL min-1), heating rate of β=2 ºC min-1, using an Al capsule containing approximately 2 mg of sample material. The results demonstrated that the standard reference presented a proportion of 99.83 percent whereas the AZT samples presented a variation ranging from 97.59 to 99.54 percent. In addition, the standard reference was found to present a temperature of onset of melting point of 122.80 ºC. Regarding the samples of active agents provided by the different laboratories, a variation ranging from 118.70 to 122.87 ºC was measured. In terms of ΔHm, the samples presented an average value of 31.12 kJ mol-1.

A determinação da pureza química, a faixa de fusão e a variação de entalpia envolvida no processo de caracterização de fármacos é um dos principais requisitos avaliados no controle de qualidade em indústrias farmacêuticas. Neste trabalho é feita uma breve abordagem sobre o método de determinação de pureza utilizando DSC, assim como a aplicação desta técnica para avaliação de amostras comerciais de zidovudina (AZT) (matéria-prima) fornecida por diferentes laboratórios. Para tal, foram analisadas amostras de seis diferentes laboratórios (A,B,C,D,E e F) e a substância química de referência (R) da United States Pharmacopeia (USP). As curvas DSC foram obtidas na faixa de temperatura entre 25 a 200 ºC, sob atmosfera dinâmica de N2 (50 mL min-1), β=2 ºC min-1, utilizando cápsula de Al contendo aproximadamente 2 mg de amostra. De acordo com os resultados, pode-se observar que a substância química de referência apresentou teor igual a 99,83 por cento e que as amostras de AZT apresentaram uma faixa de variação entre 97,59 e 99,54 por cento. Pode-se verificar, ainda, que a substância química de referência apresentou uma temperatura onset de fusão igual a 122,80 ºC. Para as amostras dos princípios ativos fornecidos pelos diferentes laboratórios, pode-se verificar uma faixa de variação entre 118,70 e 122,87 ºC. No que se refere ao ΔHm, as amostras apresentaram valor médio de 31,12 kJ.mol-1.

Terpenes in propylene glycol as skin-penetration enhancers: permeation and partition of haloperidol, Fourier transform infrared spectroscopy, and differential scanning calorimetry.

The respective alcoholic terpenes carvacrol, linalool, and alpha-terpineol were used at 5% w/v in propylene glycol (PG) to increase the in vitro permeation of haloperidol (HP) through human skin. The possible enhancement mechanism was then elucidated with HP-stratum corneum (SC) binding studies, Fourier transform infrared spectroscopy, and differential scanning calorimetry. The greatest increase in the permeation of HP was achieved with linalool followed by carvacrol and terpineol. HP permeation with linalool was predicted to reach a therapeutic plasma concentration and therapeutic daily-permeated amounts. Carvacrol increased lag time, which was attributed to slow redistribution of the enhancer within SC. Carvacrol increased the partition of the drug to the pulverized SC. Pure PG extracted lipids from SC but less than that achieved by the terpenes in PG. Terpenes extracted lipids to a similar extent. An increase in bilayer cohesion in the remaining lipids present in the SC could be attributed to the alignment of terpenes within the lipid bilayer. The higher permeation with linalool was attributed to its molecular orientation within the lipid bilayer. Terpenes showed different rates of SC dehydration but did not change the percentages of secondary structures of keratin.

Crystallization and transitions of sulfamerazine polymorphs.

A bulk powder of sulfamerazine polymorph II in a narrow distribution of particle size was prepared for the first time. The two known sulfamerazine polymorphs, I and II, were physically characterized by optical microscopy, powder X-ray diffractometry, differential scanning calorimetry, carbon-13 solid-state nuclear magnetic resonance spectroscopy, and measurements of aqueous solubility and density. The thermodynamics and kinetics of the transition between the polymorphs was examined under various pharmaceutically relevant conditions, such as heating, cooling, milling, compaction, and contact with solvents. The two polymorphs were found to be enantiotropes with slow kinetics of interconversion. The thermodynamic transition temperature lies between 51 and 54 degrees C, with polymorph II stable at lower temperatures. Ostwald's Rule of Stages explains the crystallization of the polymorphs from various solvents and may account for the delay in the discovery of polymorph II.

Investigation of protein/carbohydrate interactions in the dried state. 1. Calorimetric studies.

Isoperibol calorimetry was used to evaluate protein/carbohydrate interactions after freeze drying. rh-DNase, rh-GH, rh-MetGH, and rh-IGF-I were freeze dried with either mannitol, sucrose, trehalose, or dextran at concentrations ranging from 0% to 100% (w/w). Enthalpies of solution for both freeze-dried and physical mixtures were measured in water at 25 degrees C. Differential scanning calorimetry was used to monitor changes in the melting or crystallization temperatures of the lyoprotectants. Linear relationships between enthalpies of solution and the percentage of protein in the formulations were observed for all physical mixtures. In contrast, nonlinear relationships between the enthalpies of solution and protein content were observed for the freeze-dried mixtures. Mannitol-containing mixtures were characterized by negative deviation from linearity, while positive deviations were detected for mixtures containing sucrose or trehalose. Using DSC, sucrose was found to be amorphous at low and not detected at high protein content in the freeze-dried mixtures. Melting of mannitol was observed through almost all of the protein concentration range examined. Two melting endotherms, however, were observed for mannitol at most protein/mannitol ratios, indicating the presence of protein/mannitol interactions. This work suggests that direct interactions occur between proteins and carbohydrates in lyophilized mixtures.

Thermodynamics of conformational ordering of iota-carrageenan in KCl solutions using high-sensitivity differential scanning calorimetry.

Thermodynamic properties of aqueous solutions of iota-carrageenan as affected by KCl (0.15-1.2 M) or iota-carrageenan (0.5-6 mg/mL) content were studied by high-sensitivity differential scanning calorimetry. The polysaccharide was found to undergo two consecutive cooperative conformational transitions, which can be represented by the scheme: [H2]2<-->2H2<-->4C where C is the random coil, H2 is the double helix, and [H2]2 is the double helix dimer. The first transition follows by the "all or none" mechanism. The profile of the second transition resembles that of a second-order phase transition. The parameter sigma (of order 1), estimated for this latter transition, suggests that the stacking effect in helices of iota-carrageenan is rather small. The cooperativity of the transition is mainly defined by the loop factor. Free energies of both transitions at 273 K were calculated as a function of salt concentration. These experimental data were found to agree with Manning's theory.

A model for thermograms.

Thermograms are curves resulting from thermal analysis and are of great interest in the study of various food and biological products physical properties. A method to separate underlying peaks is proposed, and statistical properties of estimates for some characteristic parameters are derived. The total number of peaks can be estimated with a sequential analysis of the residual plots. For each new peak, a statistical criterion is proposed to check whether it is significantly different from the noise of the recording. As an example, the method is applied to a summer milk fat fusion thermogram.

Glass transition temperatures of dental porcelains determined by DSC measurement.

The differential scanning calorimetry (DSC) curves for three commercial dentin and incisal porcelains fused-to metal were measured using high-temperature DSC. The glass transition temperatures (Tg) were determined from the DSC curves at heating rates of 7-20 degrees C/min, and the activation energy was derived from an Arrhenius plot of negative reciprocal Tg vs. logarithm of heating rate. The Tg of the dental porcelains depended on the content of aluminum oxide, whereas the activation energy depended on the content of sodium oxide. The ultra-low fusing type porcelains had a low activation energy due to the higher content of sodium oxide than the other porcelains.

Tecido adiposo marrom e sua implicacao no desenvolvimento da obesidade / Brown adipose tissue and its implication in the development of the obesity

Pesquisa mostram que o tecido adiposo marrom e essencial ao equilibrio energetico em inumeras especies de animais dissipando, sob forma de calor, o excesso de energia ingerida. Neste estudo nos propomos estudar a implicacao do tecido adiposo marrom no desenvolvimento da obesidade. Foram utilizados ratos, da linhagem WISTAR, mantidos em gaiolas metabolicas, na temperatura de 25oC +- 1oC e 12 horas luz / 12 horas escuridao. Os animais foram divididos em dois grupos, segundo regime a ser submetido: racao controle e dieta tipo "cafeteria. Foi controlado o peso dos animais, o resto-ingesta das dietas ofertadas e analises bioquimicas foram realizadas. Os resultados encontrados neste experimento mostram que o "regime de cafeteria" induziu ao mesmo tempo um ganho de peso e um aumento do tecido adiposo marrom. Uma diminuicao significativa no teor de colesterol plasmatico, foi tambem observado no grupo experimental. Um mau funcionamento ou a nao estimulacao da termogenese no tecido adiposo marrom sao hipotese para explicar os resultados encontrados.

Study of strong to ultratight protein interactions using differential scanning calorimetry.

Data from differential scanning calorimetry (DSC) may be used to estimate very large binding constants that cannot be conveniently measured by more conventional equilibrium techniques. Thermodynamic models have been formulated to describe interacting systems that involve either one thermal transition (protein-ligand) or two thermal transitions (protein-protein) and either 1:1 or higher binding stoichiometry. Methods are described for obtaining binding constants and heats of binding by two different methods: calculation or simulation fitting of data. Extensive DSC data on 2'CMP binding to RNase are presented and analyzed by the two methods. It is found that the methods agree when binding sites are completely saturated, but substantial errors arise in the calculation method when site saturation is incomplete and the transition of liganded molecules overlaps that of unliganded molecules. This arises primarily from an inability to determine TM (i.e., the temperature where concentrations of folded and unfolded protein are equal) under weak-binding conditions. Results from simulation show that the binding constants and heats of binding from the DSC method agree quantitatively with corresponding estimates obtained from equilibrium methods when extrapolated to the same temperature. It was also found from the DSC data that the binding constant decreases with increasing concentration of ligand, which might arise from nonideality effects associated with dimerization of 2'CMP. Simulations show that the DSC method is capable of estimating binding constants for ultratight interactions up to perhaps 10(40) M-1 or higher, while most equilibrium methods fail well below 10(10) M-1. DSC data from the literature on a number of interacting systems (trypsin-soybean trypsin inhibitor, trypsin-ovomucoid, trypsin-pancreatic trypsin inhibitor, chymotrypsin-subtilisin inhibitor, subtilisin BPN-subtilisin inhibitor, RNase S protein-RNase S peptide, avidin-biotin, ovotransferrin-Fe3+, superoxide dismutase-Zn2+, alkaline phosphatase-Zn2+, and assembly of regulatory and catalytic subunits of aspartate transcarbamoylase) were analyzed by simulation fitting or by calculation. Apparent single-site binding constants ranged from ca. 10(5) to 10(20) M-1, while the interaction constant for assembly of aspartate transcarbamoylase was estimated as 10(37) in molarity units. For most of these systems, the DSC interaction constants compared favorably with other literature estimates, for some it did not for reasons unknown, while for still others this represented the first estimate. Simulations show that for proteins having two binding sites for the same ligand within a single cooperative unit, ligand rearrangement will occur spontaneously during a DSC scan as the transition temperature of the unliganded protein is approached.(ABSTRACT TRUNCATED AT 400 WORDS)