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.     

不同结晶度的乙二醇及其水溶液玻璃化转变与焓松弛

为了考察晶体成分对无定形成分玻璃化转变和结构松弛行为的影响,利用差示扫描量热法(DSC),结合低温显微技术,研究了乙二醇(EG)及其50％水溶液在不同结晶度时的玻璃化转变和焓松弛行为.采用等温结晶方法控制骤冷的部分结晶玻璃体中的晶体份额.DSC结果表明,对于部分结晶的EG,只有单一的玻璃化转变过程,而对于50％EG,当结晶度不同时,不同程度地表现出两次玻璃化转变（无定形相Ⅰ和无定形相Ⅱ）.相Ⅰ的玻璃化转变温度和完全无定形态的含水EG的玻璃化转变温度相一致;相Ⅱ的玻璃化转变温度要比此温度约高6 ℃.低温显微观察结果印证了DSC实验结果.DSC等温退火的实验和KWW(Kohlrausch-Williams-Watts)衰变函数分析结果表明,EG无定形和50％EG中的两种无定形有不同的焓松弛行为.     

Multivariable structural characterization of semicrystalline polymer blends by small‐angle light scattering

A new multi‐variable‐measurement approach for characterizing and correlating the nanoscale and microscale morphology of crystal‐amorphous polymer blends with melt‐phase behavior is described. A vertical small‐angle light scattering (SALS) instrument optimized for examining the scattering and light transmitted from structures ranging from 0.5 to 50 μm, thereby spanning the size range characteristic of the initial‐to‐late stages of thermal‐phase transitions (e.g., melt‐phase separation and crystallization) in crystal‐amorphous polymer blends, was constructed. The SALS instrument was interfaced with differential scanning calorimetry (DSC), and simultaneous SALS/DSC/transmission measurements were performed. We show that the measurement of transmitted light and SALS under H_V (cross‐polarized) optical alignments during melting can be used to reliably measure the thermodynamic (e.g., crystal melting and melt‐phase separation temperatures) and structural variables (e.g., crystalline fraction within the superstructures and volume fraction of superstructures) necessary for describing the multiphase behavior of crystal‐amorphous blends in one combined measurement. We also evaluate the orientation correlations of crystalline volume elements within the superstructures. Our results indicate that simultaneous measurement of transmitted light can provide a reliable estimate of the total scattering from density and orientation fluctuations and the melt‐phase separation temperature of polymer blends. For solution‐cast poly(?‐caprolactone)/poly(D,L‐lactic acid) blends, our multivariable measurements during melting provide the parameters necessary to generate a crystal–liquid and liquid–liquid phase diagram and characterize the solid‐state morphology. This opens up the challenge to explore use of our vertical SALS instrument as a rapid and convenient method for developing structure–property relationships for crystal‐amorphous polymer blends. © 2002 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 40: 2714–2727, 2002     

Glass transition and enthalpy relaxation of ethylene glycol and its aqueous solution

Differential scanning calorimetry (DSC) and cryomicroscopy were employed to investigate the glass transition and enthalpy relaxation behaviors of ethylene glycol (EG) and its aqueous solution (50% EG) with different crystallization percent. Isothermal crystallization method was used in devitrification region to get different crystallinity after samples quenched below glass transition temperature. The DSC thermograms upon warming showed that the pure EG has a single glass transition, while the 50% EG solution has two if the solution crystallized partially. It is believed that the lower temperature transition represents the glass transition of bulk amorphous phase of EG aqueous solution glass state, while the higher one is related to ice inclusions, whose mobility is restricted by ice crystal. Cryomicroscopic observation indicated that the EG crystal has regular shape while the ice crystal in 50% EG aqueous solution glass matrix has no regular surface. Isothermal annealing experiments at temperatures lower than T_g were also conducted on these amorphous samples in DSC, and the results showed that both the two amorphous phases presented in 50% EG experience enthalpy relaxation. The relaxation process of restricted amorphous phase is more sensitive to annealing temperature.     

Differential Scanning Calorimetry Evaluates Relative Proportions and Strength of Acid-Sites in Catalytic Materials and Adsorbents Alumina and Amorphous Silica-Alumina

Abstract

Differential scanning calorimetry (DSC) is employed to evaluate the relative proportions and strength of acid-sites in gammaalumina and amorphous silica-alumina through presorption of tri-ethylamine (TEA) followed by its thermal desorption in the DSC equipment. From the data obtained, total acid-sites in silica-alumina is found to be 2.3 times as large as those present in gamma-alumina, and 5–5% of total acidity in alumina is of Bronsted type whereas in silica-alumina this type comprises 28.9%' The Bronsted acidity strength in alumina and silica-alumina is identical although greatly different in quantity. Lewis acidity in silica-alumina is significantly stronger than that in alumina.     

Feasibility of using isothermal microcalorimetry to evaluate the physical stability of amorphous nifedipine and phenobarbital

Feasibility of microcalorimetry to evaluate the physical stability of amorphous drugs was studied. Amorphous forms of nifedipine and phenobarbital were prepared by melting and subsequent cooling in a differential scanning calorimetry (DSC) sample pan, and their heats of crystallization were monitored by isothermal microcalorimetry. The time required for 10% of the amorphous drug to crystallize (t₉₀), a direct measure of the crystallization rate, could be obtained from a single microcalorimetric trace of the amorphous nifedipine or phenobarbital. The t₉₀ values were also determined by conventional storage studies in which the heat of crystallization was determined by DSC. The t₉₀ values obtained by microcalorimetry were consistent with those obtained by DSC, within experimental error, indicating that microcalorimetry is a useful method for evaluating the physical stability of amorphous drugs.     

Thermal analysis of poly(2-methylpentamethylene terephthalamide)

Poly(2-methylpentamethylene terephthalamide) (Nylon M5T) is a new high temperature aromatic polyamide developed by Hoechst Celanese. In this paper thermal properties of Nylon M5T chips, as well as as-spun and drawn fibers were studied by DSC, DMA, hot stage microscopy and WAXS.T _g of the fully amorphous Nylon M5T is 143°C when measured by DSC;T _g increases with crystallinity to 151°C. The temperature dependence of the solid and melt specific heat capacities has also been determined. The heat capacity increase at the glass transition of the amorphous polymer is 103.9 J °C^–1 mol^–1.T _g by DMA for the as-spun fiber is 155°C, for a drawn fiber is 180°C. Three secondary transitions were observed by DMA in addition to the glass transition. These correspond to a local mode relaxation of the methylene groups at –120°C, onset of rotation of the amide-groups at –65°C and the onset of the rotation of the phenylenegroups (at 63°C). The crystallinity of Nylon M5T strongly depends on the rate of cooling from the melt. The isothermal crystallization data are melt temperature dependent: two-dimensional crystallization takes place when the samples are crystallized from higher melt temperatures, and this phase changes into a spherulitic structure during cooling to room temperature. Spherulitic crystallization occurs when lower melt temperatures are used. This polymer has three crystal forms as indicated by DSC, DMA and WAXS data. The crystal to crystal transitions are clearly visible when amorphous samples are heated in the DSC, or the DMA curves of as-spun fibers are recorded. It is experimentally shown that a considerable melting of the lower temperature crystal forms takes place during the crystal to crystal transitions. The equilibrium melting point as measured by the Hoffman-Weeks method, has been determined to be 339°C.Dedicated to Professor Bernhard Wunderlich on the occasion of his 65th birthday     

Techniques of differential scanning calorimetry for quantification of low contents of amorphous phases

Differential scanning calorimetry (DSC) is one of the most frequently used techniques for analyzing small concentrations of amorphous phases in a crystalline matrix. In recent years novel enhanced DSC approaches have been intensively looked for to improve parameters such as sensitivity, accuracy, and detection limit of the technique. Low levels of amorphous phases can be quantitatively determined in DSC by measuring the heat capacity change associated with the glass transition. In this short review the potentials provided by the HyperDSC and StepScan DSC techniques are discussed. Examples illustrate the advantages and disadvantages of the techniques and compare their abilities to detect small glass transitions and determine low contents of amorphous phases in samples which are mostly crystalline.     

Quantification of drug amorphous fraction by DSC

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.     

Precise determination of low level sucrose amorphism by microcalorimetry

The DSC curve of freeze-dried amorphous sucrose shows the glass transition, the crystallization and the melting (just before decomposition) of the sample. Sucrose crystallization occurs below 100°C: this phenomenon can therefore be observed with the microcalorimeter Setaram Micro-DSC used in the scanning mode. Mixtures of amorphous and crystalline sucrose in known proportions were used to calibrate the instrument. Low level amorphism (down to about 0.5%) could be detected and quantitatively evaluated on the basis of the crystallization enthalpies determined. The calibration curve obtained can be applied to determine the degree of amorphism in milled sucrose. A simple gravimetric method, based on the desorption of water induced by recrystallization of the amorphous layer can be used to obtain similar data more rapidly. This simple method is particularly useful for controlling the amorphism on line during a process, and is also briefly described.     

Comparison of the glass transition temperature and fragility parameter of isomalto-olygomer predicted by molecular dynamics simulations with those measured by differential scanning calorimetry

The purpose of this study is to examine whether molecular dynamics (MD) simulations using a commercially available software for personal computers can estimate the glass transition temperature (Tg) of amorphous systems containing pharmaceutically-relevant excipients. MD simulations were carried out with an amorphous matrix model constructed from isomaltoheptaose, and the Tg estimated from the calculated density versus temperature profile was compared with the Tg measured by differential scanning calorimetry (DSC) for freeze-dried isomalto-oligomer having an average molecular weight close to that of isomaltoheptaose. The Tg values determined by DSC were lower by 10 to 20 K than those extrapolated from the Tg values estimated by MD simulation. Fragility parameter was estimated to be 56 and 51 from MD simulation and from DSC measurement, respectively. Thus, the results suggest that MD simulation can provide approximate estimates for the Tg and fragility parameter of amorphous formulations. However, a reduction of the cooling rate, achievable by sufficiently elongating the simulation duration, is necessary for more accurate estimation.     

Study on degrees of mesomorphic zone of polymerII. Determination of the degree of mesomorphic zone of eucommia ulmoides gum and natural rubber by dynamic mechanical thermal analysis and differential scanning calorimetry

In a foregoing article, a new method based on dynamic mechanical thermal analysis(DMTA)for determining the degrees of crystallinity of the natural rubber (NR) and the eucommia ulmoides (EU) gum, with different crosslink densities, has been established. In order to verify the effectiveness of this method, in the present paper, the degrees of crystallinity of NR and EU gum with different crosslink densities will be determined by differential scanning calorimetry (DSC). The results indicate that the degrees of crystallinity determined by DMTA are much higher than those of DSC. This is because the degree of crystallinity determined by DMTA involves not only the ratio of the crystalline zone, but also the ratio of the mesomorphic zone, while the degree of crystallinity tested by DSC includes only the ratio of the crystalline zone. So, the degree of crystallinity, the degree of mesomorphic zone and the degree of amorphous zone of NR and EU gums with different crosslink densities can be quantitatively determined by the combination of DMTA and DSC. The results show that the degree of crystallinity, the degree of mesomorphic zone and the degree of amorphous zone of NR (crystallized at −25 °C for 12 h) and EU gum are 33%, 53%, 14% and 34%, 54%, 13%, respectively. For NR, increasing the crosslink density or decreasing the induced time will decrease the degree of crystallinity and the degree of mesomorphic zone simultaneously, but will increase the degree of amorphous zones. For EU gum, increasing the crosslink density will decrease the degree of crystallinity and increase the degree of amorphous zone, but keep the degree of mesomorphic zone invariably consistent within the critical crystallization point, which is approximately 55%. At the end of the paper, the impact of crystallization on the mechanical properties of EU gum and NR is discussed as well.     

Optical birefringence and molecular orientation of electrospun polycaprolactone fibers by polarizing-interference microscopy

The potential of polarizing-interference Pluta microscope for determination of optical birefringence of individual nanofibers formed by electrospinning was shown. This technique can be applied for measurements of fiber birefringence, practically at diameter above 300 nm. The molecular orientation of individual polycaprolactone (PCL) nanofibers was determined from birefringence assuming the same orientation of both phases, crystal and amorphous. The molecular orientation was determined using DSC crystallinity, crystal intrinsic birefringence calculated for the first time for PCL from bond polarizabilities as well as estimated value of amorphous intrinsic birefringence. Our results indicate that the birefringence and thus molecular orientation are strongly inhomogeneous along the nanofibers, reflecting a complex nature of forces acting during electrospinning process. The average molecular orientation is weak if any, being dependent together with fiber thickness and crystallinity on electrospinning parameters, like applied voltage, concentration and type of solvent. The obtained results indicate that the average molecular orientation displays similar dependence on applied voltage as fiber diameter. Relatively low melting temperature of electrospun nanofibers suggests low crystal size and/or high concentration of defects in crystals. This observation corresponds with low crystallinity and molecular orientation, indicating together relatively low degree of crystal ordering due to high rate of cooling and solvent evaporation during electrospinning, limiting thus crystallization process.     

CO和H2在非晶态合金Ni-B、Co-B催化剂上的吸附及其作用的TPD-MS研究

ＣＯ和Ｈ_２在非晶态合金Ｎｉ－Ｂ、Ｃｏ－Ｂ催化剂上的吸附及其作用的ＴＰＤ－ＭＳ研究张菊,郑小明,周烈华（杭州大学催化研究所,杭州,３１００２８）关键词非晶态Ｎｉ（Ｃｏ）－Ｂ合金,Ｈ_２、ＣＯ吸附,ＴＰＤ－ＭＳ非晶态合金作为一种新型催化材料在加氢反应中表...     

Estimation of physical stability of amorphous solid dispersion using differential scanning calorimetry

The physical stability of amorphous drug in solid dispersion was estimated using differential scanning calorimetry (DSC). Tolbutamide (TB) and flurbiprofen (FBP) were selected as insoluble drugs in water. Polyvinylpyrrolidone (PVP) was selected as a polymer for solid dispersion. Solid dispersions of various ratios of TB or FBP and PVP-K25 were prepared by solvent evaporation method and the induction period of crystallization from amorphous drug in solid dispersion was measured by DSC. Compared with FBP, the induction period of crystallization from TB was delayed by an addition of PVP. The improvement of the physical stability by the addition of PVP-K25 was estimated from the activation energy of diffusion of drug molecules and the interfacial free energy between drug crystal and supercooled liquid of drug in solid dispersion. From thses results, the hindrance of the diffusivity of the drug molecule might be mainly affected the delay of the induction period of crystallization of TB and FBP.     

广角X-射线衍射对PET结晶度的研究

应用广角X-射线衍射(WAXD)来测定高聚物的结晶度可以分为相对法(CCI、ICI)与绝对法(HWM、CPRM、Ruland)两大类,但长期以来在文献上这些方法得出的结果往往差别很大,而且WAXD与其它的方法,如DSC、ρ、NMR、IR等往往也不相一致。本文就此两问题进行了系统的研究,不仅对WAXD与DSC、ρ测定结晶度的可靠性进行了讨论,更对WAXD的各种方法中,2θ应选的范围、是否应作校正、非晶散射如何扣除、相对法自身之间的关系、各种绝对法之间的关系、相对法与绝对法的关系等进行了仔细的研究。结论是:WAXD在可靠性与重复性方面优于DSC与ρ法,而且是其它方法的根据;绝对法优于相对法,各种绝对法有利有弊,而非晶散射的合理分离是最为关键的问题。     

Smart stability-indicating spectrophotometric methods for determination of binary mixtures without prior separation

Ratio subtraction and isosbestic point methods are 2 innovating spectrophotometric methods used to determine vincamine in the presence of its acid degradation product and a mixture of cinnarizine (CN) and nicergoline (NIC). Linear correlations were obtained in the concentration range from 8-40 microg/mL for vincamine (I), 6-22 microg/mL for CN (II), and 6-36 microg/mL for NIC (III), with mean accuracies 99.72 +/- 0.917% for I, 99.91 +/- 0.703% for II, and 99.58 +/- 0.847 and 99.83 +/- 1.039% for III. The ratio subtraction method was utilized for the analysis of laboratory-prepared mixtures containing different ratios of vincamine and its degradation product, and it was valid in the presence of up to 80% degradation product. CN and NIC in synthetic mixtures were analyzed by the 2 proposed methods with the total content of the mixture determined at their respective isosbestic points of 270.2 and 235.8 nm, and the content of CN was determined by the ratio subtraction method. The proposed method was validated and found to be suitable as a stability-indicating assay method for vincamine in pharmaceutical formulations. The standard addition technique was applied to validate the results and to ensure the specificity of the proposed methods.     

Molecular heterogeneity of ethylene‐propylene rubbers: New insights through advanced crystallization‐based and chromatographic techniques

For a long time ethylene‐propylene rubber (EPR) copolymers with high comonomer contents were believed to be amorphous materials with a random copolymer composition. This is not completely correct as has been shown by temperature rising elution fractionation (TREF) combined with differential scanning calorimetry (DSC), crystallization analysis fractionation (CRYSTAF), and high temperature–high‐performance liquid chromatography (HT‐HPLC). When using only conventional crystallization‐based fractionation methods, the comprehensive compositional analysis of EPR copolymers was impossible due to the fact that large fractions of these copolymers do not crystallize under CRYSTAF conditions. In the present work, HT‐HPLC was used for the separation of the EPR copolymers according to their ethylene and propylene distributions along the polymer chains. These investigations showed the existence of long ethylene sequences in the bulk samples which was further confirmed by DSC. The results on the bulk samples prompted us to conduct preparative fractionations of EPR copolymers having varying ethylene contents using TREF. Surprisingly, significant amounts of crystallizing materials were obtained that were analyzed using a multistep protocol. CRYSTAF and DSC analyses of the TREF fractions revealed the presence of components with large crystallizable sequences that had not been detected by the bulk samples analyses. HT‐HPLC provided a comprehensive separation and characterization of both the amorphous and the crystalline TREF fractions. The TREF fractions eluting at higher temperatures showed the presence of ethylene‐rich copolymers and PE homopolymer. In order to obtain additional structural information on the separated fractions, HT‐HPLC was coupled to Fourier transform‐infrared (FT‐IR) spectroscopy. The FT‐IR data confirmed that the TREF fractions were separated according to the ethylene contents of the eluted samples. Preparative TREF analysis together with a combination of various analytical methods proved to be useful tools in understanding the complex molecular composition of these rubber samples. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2015 , 53, 863–874     

Determining the wax content of crude oils by using differential scanning calorimetry

By the use of differential scanning calorimetry (DSC), a new method to measure the wax content of crude oil has been developed. In this paper, the wax content of a crude oil is proposed and proved to be the Q (total thermal effect of wax precipitation in sample) ratio of the crude oil and its corresponding wax obtained by using standard acetone method, i.e. Q_oil/Q_wax. For the 14 studied crude oils with the wax content ranging from 1 to 27 wt.%, the wax contents determined by the presented method are in good agreement with those determined by standard acetone method, with an absolute average deviation of only 0.82 wt.%. This method has an advantage over reported DSC methods in which the exact dissolution or precipitation enthalpy of wax is a must. It is also found that the wax contents determined by either of the two methods show good linear relationship with the total thermal effect Q_oil, with the correlation coefficients over 0.96. According to the empirical correlations, the wax content of a crude oil can be easily determined by using the DSC total thermal effect Q_oil. In addition and more significantly, the new method can be applied to improve the accuracy in determining the amount of precipitated wax in a waxy crude oil at different temperatures.     

喹哪啶酸合铕/二氧化硅发光材料的溶胶-凝胶法合成与性能

通过红外光谱、紫外可见光谱、荧光光谱和X射线粉末衍射等测试手段,对溶液中合成的喹哪啶酸合铕(Eu-qina)配合物进行了表征,且将溶胶-凝胶法合成出的Eu-qina/SiO2杂化发光材料,与溶液中合成的配合物Eu-qina进行对比.结果表明,配合物Eu-qina中由于喹哪啶酸能有效地将能量传递给Eu3+离子,使Eu3+发出较强的红色特征荧光,而杂化材料Eu-qina/SiO2因SiO2的加入使荧光强度增大.当Eu-qina配合物的掺杂量达到一定值时,Eu-qina/SiO2发较强的红光,并由晶态的Eu-qina转化为非晶态的Eu-qina/SiO2.