A new program for DSC purity analysis

DSC purity determinations have become very popular today [3]. The latest edition of the Mettler software package for thermal analysis, TA72.S GraphWare, now comprises a powerful purity evaluation program. It is based on the simultaneous calculation of the mole ratio of the sum of the eutectic impurities, the melting point of the pure component, the melting point of the substance present and the linearization term. The portion of the melting curve investigated is selected appropriately.Experience has shown, that the applied heating rate is a very important parameter which influences the duration of the measurement and also the possible exposure to elevated temperature where decomposition can become a problem and last but not least the accuracy of the calculated impurity value.

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Zusammenfassung Die DSC-Reinheitsbestimmung ist heute eine weit verbreitete Methode, die mit einer einzigen Messung und unter Verwendung geeigneter Auswerteprogramme eine Bestimmung der absoluten eutektischen Reinheit einer Probe zulÄsst. Gleichzeitig können weitere thermodynamische Daten bestimmt werden, wie Schmelzpunkt der Probensubstanz und der reinen Hauptkomponente und die Schmelzenthalpie der Probe.Durch experimentelle Befunde konnte gezeigt werden, dass die Wahl der Aufheizrate kritisch ist in bezug auf die Genauigkeit und die Signifikanz der ermittelten Daten.

     

Use of DSC robotic systems in pharmaceutical analysis

DSC is extremely valuable for analysis of pharmaceuticals. The introduction of robotic systems with data acquisition and processing makes it very competitive to other methods in the field of purity determination or solid state characterization of raw materials. Some applications are also possible to dosage forms. Applications of DSC robotics with statistical results are given.

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Zusammenfassung Zur Analyse von Arzneimitteln ist DSC außerst wertvoll. Die Einführung von Robotersystemen mit Datenaquisition und -aufarbeitung macht dieses Verfahren auf dem Gebiet der Reinheitsuntersuchung und Feststoffcharakterisierung der Rohmaterialien konkurrenzfähig im. Vergleich zu anderen Methoden. Einige Varianten lassen sich auch auf fertige Präparate anwenden. Es wird die Anwendung von computerisierten DSC-Systemen einschließlich statistischen Ergebnissen gegeben.

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Many thanks to Mrs C. Goldbronn and Mr P. Piechon for their technical assistance.     

Dynamic DSC purity analysis studies of two component doped systems

Up to the present time, the accuracy and precision of dynamic DSC purity analysis measurements have been tested by using simple binary systems as models. For the most part, pure organic substances have served as host and eutectic-forming low level dopant. As a first step in considering whether the DSC method can be applied to multicomponent impure substances, the simple ternary model system, phenacetin doped with benzamide and p-aminobenzoic acid, has been studied. Separately, the two dopants form well defined eutectics with the host melting at 370 K (benzamide dopant) and 385 K (p-aminobenzoic acid dopant). When the two dopants are combined, a third eutectic melting at 353 K is produced. Evidence is presented confirming the fact that in the range 100-98.5 mole % purity, the total DSC measured impurity is the sum of the two individual dopant levels, and is independent of their relative proportions.     

Broad range purity analysis by melting point depression using a singular feature common to all DSC purity scans

DSC purity assay by melting point between has had a limited range of less than several percent impurities. Step-mode heating techniques have increased the range to 6–8%. However, empirical corrections were used to linearize the purity slope of the van't Hoff plot, temperatures vs. reciprocal of fraction melted (1/F).A unique feature common to all dynamic purity scans has been discovered which matches a point on the non-linear van't Hoff plot to the heating rate. This point, or reciprocal of the melt fraction (1/F), occurs where the melting rate has attained maximum acceleration. The melting rate at this point is used as a tangential straight line projection from the curve to become a function of mole % impurity. The melting rate at maximum acceleration is independent of reference material, heating rate, sample size, thermal conductivity, or specific heat.Phenacetin, spiked with 50 mole % benzamide, has been measured to ±2 mole % at heating rate of 5 and 10°C min^?1; the restriction on upper detection limits is adequate resolution between preliminary eutectic events and the final melt. Impurities in indium, with a reported purity of 99.9999%, have been measured at 4 × 10^?5 mole % by this technique.     

A DSC compositional analysis of some binary organic mixtures of pharmaceutical significance

A DSC compositional analysis of 3 model binary systems of pharmaceutical significance has been conducted. Mixtures of known selected composition for each of the systems 3,5-dinitrobenzoic acid/benzoic acid, paracetamol/4-aminobenzoic acid and acetylsalicylic/salicylic acid were prepared and analyzed by DSC. The respective compositions derived from applications of the van't Hoff equation were correlated with the corresponding theoretical values and with the corresponding fusion temperatures and fusion enthalpies, obtained from the relevant DSC profiles. Linear correlations were found to exist between the theoretical compositions, fusion temperatures and fusion enthalpies for each of these systems and it is apparent that with suitable calibration procedures, the DSC compositional analysis method can be applied to determine the purity at the 90–95 mole% level. This level is of considerable interest in drug stability studies and has real significance in purity assays of commercial pharmaceutical preparations.     

Technological quality determination of pharmaceutical disintegrant by DSC cooling and DSC photovisual

A number of disintegrants are available on the market. They improve tablets’ disintegration. The objective of this work is the comparison of the technological quality parameters of disintegrants using different analytical techniques. Three batches of disintegrants and their binary mixtures (water:disintegrants) were investigated. Cooling experiments were used from –30 up to 200°C. The data obtained showed calorimetric differences between the samples. In the binary mixtures water showed different crystallization behaviour from the one found in the literature. According to the results DSC technique helped the quality control of different disintegrants.     

Application of DSC for the determination of purity of organic semiconductors

DSC method was developed for the analysis of organic and inorganic substances. Beside the common method short method is applied. Comparison of these two methods for the determination of purity on standard samples like indium, benzil, caffeine showed good similarity of the results so it allowed to use a short method for the determination of the amount of impurity in semiconductors such as bis(ethylenedithio)tetrathiofulvalen and tetrathiotetracene. These compounds are unstable and begin to decompose some times during melting.

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Zusammenfassung Für die Analyse von organischen und anorganischen Substanzen wurde ein DSC-Verfahren entwickelt. Neben dem herkömmlichen wurde auch ein Kurzverfahren angewendet. Der Vergleich der Ergebnisse der zwei Verfahren bei der Reinheitsbestimmung von Standardproben, wie z.B. Indium, Biphenyl und Koffein zeigte eine gute übereinstimmung. Das Kurzverfahren kann somit gut zur Bestimmung des Verunreinigungsgrades von Halbleitern wie z.B. Bis-(äthylendithio)-tetrathiofulvalen und Tetrathiotetrazen genutzt werden. Diese Verbindungen zeigen nämlich während des Schmelzens mitunter Zersetzungserscheinungen.

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Chiral capillary electrophoretic analysis of the enantiomeric purity of a pharmaceutical compound using sulfated beta-cyclodextrin

A practical chiral capillary electrophoresis method using randomly sulfated beta-cyclodextrin was developed for the quantitative determination of the chiral purity of a pharmaceutical compound. A systematic method development approach was conducted by modifying selected parameters such as the concentration of the chiral selectors, buffer pH, organic modifiers, buffer concentrations and type, temperature and applied voltage. The results of the investigation permitted an improved understanding of the separation mechanism. Two facile strategies for the reversal of the enantiomer elution order are also described. The optimized method was validated in terms of variability of the chiral selector, linearity, sensitivity, accuracy, recovery, ruggedness, and precision.     

Approach to method development and validation in capillary electrophoresis for enantiomeric purity testing of active basic pharmaceutical ingredients

A chiral capillary electrophoresis system allowing the determination of the enantiomeric purity of an investigational new drug was developed using a generic method development approach for basic analytes. The method was optimized in terms of type and concentration of both cyclodextrin (CD) and electrolyte, buffer pH, temperature, voltage, and rinsing procedure. Optimal chiral separation of the analyte was obtained using an electrolyte with 2.5% carboxymethyl-beta-CD in 25 mM NaH2PO4 (pH 4.0). Interchanging the inlet and outlet vials after each run improved the method's precision. To assure the method's suitability for the control of enantiomeric impurities in pharmaceutical quality control, its specificity, linearity, precision, accuracy, and robustness were validated according to the requirements of the International Conference on Harmonization. The usefulness of our generic method development approach for the validation of robustness was demonstrated.     

DSC studies on the polymorphism and pseudopolymorphism of pharmaceutical substances

A complex system including thermoanalytical methods, infrared spectroscopy and X-ray powder diffraction for studying physico-chemical behaviour of binary mixtures is described. This system has been tested by investigating binary mixtures of amphetamine hydrochloride salts.These studies have proved that among the selected compounds the primary and secondary amine hydrochloride salts exhibit conglomerate forming tendency, while the tertiary amine hydrochloride salts form molecular compounds (racemates). For thep-fluoro amphetamine hydrochloride the existence of two polymorphic modifications has been detected.The authors are grateful to D. Kozma (Department of Organic Chemical Technology) for the thermoanalytical data of compound III, to Prof. E. Fogassy for the fruitful discussion.     

A DSC study of some biomaterials relevant to pharmaceutical industry

The present investigation concerns with thermal analysis of biomaterials such as Chitosan, Xanthan gum, Guar gum Pectin, Karaya gum, Sodium alginate, and Psyllium husk mucilage. The DSC curve of the natural polymers showed its specific endothermic peaks and ΔH _f values, and these will be helpful in determining the fitness of the polymers with active drug. The drug and natural polymer compatibility study is now one of the recognized methods for preformulation step in pharmaceutical drug development. All the natural polymers showed endothermic peak below 150 °C, and this make them suitable with a wide class of therapeutic drugs.     

Gravimetric analysis of high purity tellurium for purity evaluation

Gravimetric analysis was utilized for purity evaluation of high purity tellurium, which was a raw material of a tellurium standard solution. Using a method in which tellurium was precipitated as elemental tellurium with hydrazinium after dissolution of the high purity tellurium, an avoidable positive error (ca. 0.02%) was observed. It seems that a cause of the positive error is oxidation of the tellurium or occlusion of the solvent during the precipitation. On the other hand, when the precipitated elemental tellurium was further converted into tellurium oxide by heating at 600 °C, the positive error disappeared. Finally, the purity of the starting tellurium was evaluated from the recovery of tellurium oxide with sufficient accuracy for a raw material of a tellurium standard solution (0.017% expanded uncertainty (k = 2)).     

DSC in the Chemical Analysis of Drugs. Determination of diclofenac in pharmaceutical formulations

Differential scanning calorimetry was applied to the determination of diclofenac in three 'Voltaren' formulas. The pharmaceutical products (soluble tablets, suppositories and vials) were selected in order to show that calorimetric analysis is an easy technique to perform and can be competitive with other conventional methods. In the tablets diclofenac (DH) was determined, without any pre-treatment, from the area of the endothermic peak which occurs at about 180°C in the DSC curve obtained in N2 atmosphere. In the analysis of the suppositories and vials, nitrilotriacetic acid (NTA) was added to transform the diclofenac sodium salt (DS) into the thermally active form (DH). In both cases, it was necessary to eliminate the interference of excipient by cyclohexane extraction (suppositories) or by a multistep program for the DSC run (vials). The accuracy of the results and the simplicity of the procedure justify the important role of DSC in the analysis of these drugs and certainly of several other commercial products. This revised version was published online in July 2006 with corrections to the Cover Date.     

Chemometrics in pharmaceutical analysis

Chemometrics is now a well established discipline prompting independent research and development in its own right but, for their continuing success, chemometric developments must be relevant to the real needs of analysis. Pharmaceutical analysis, i.e., physical and chemical assessment of drugs and their dosage forms, needs more formal application of mathematical and statistical methods. The organisation of the laboratory, the development, optimization, assessment and interpretation of methods, and the evaluation of the data produced can all benefit from the application of chemometrics. Here, a selection of the more challenging problems facing the pharmaceutical analyst is presented, the potential for chemometrics is considered and some consequent implications for utilisation, against a background of control and regulation are discussed.     

The role of UHPLC in pharmaceutical development

Pharmaceutical separations can be divided into three categories: high throughput, high productivity, and high resolution. These categories contain specific pharmaceutical applications, each of which has distinct separation goals. Traditionally, these goals have been achieved utilizing conventional HPLC with typical column dimensions and particle sizes. The recent introduction of ultra-HPLC (UHPLC) has provided a new potential for method development and analysis. Pharmaceutical chemists must determine the impact of this emerging technology. UHPLC is achieved by using sub-2 microm particle size column packing at increased linear velocities. In order to utilize this technology, mobile phase viscosity must be minimized or the chromatography system must be redesigned to withstand an increased backpressure. Today, there are many commercially available UHPLC systems capable of exceeding conventional pressure limits of 400 bar. The advantage of UHPLC over conventional HPLC is the capability to increase the speed without sacrificing efficiency. In comparison to traditional HPLC, our research showed that UHPLC can decrease run times up to 7 x. In addition, for high resolution applications, UHPLC achieved significant efficiency advantages over traditional HPLC. This paper will evaluate the potential roles for utilizing UHPLC in the pharmaceutical industry.     

DSC analysis of the anti-HIV agent loviride as a preformulation tool in the development of hot-melt extrudates

Thermal analysis was performed on the anti-HIV agent loviride in order to test its suitability to be processed using hot-melt extrusion. Temperature characteristic parameters of crystallization were determined to quantify the stability of amorphous loviride. The present study has shown that cooling and heating loviride at different rates influenced its thermal stability. At high cooling rates melted loviride did not crystallize during cooling, and formed a glass that recrystallized during reheating. Very low cooling rates resulted in significant decomposition of the drug. The glass transition temperature was found to increase as a function of increasing heating rates and the activation energy for the transition from the glassy to the super-cooled liquid state was relatively high, indicating good stability of the glass. This revised version was published online in July 2006 with corrections to the Cover Date.     

高效液相色谱整体柱在药物分离分析中的应用进展

本文对高效液相整体柱在药物分离分析方面的应用进行了综述.主要介绍了以烷氧基硅烷为主要原料,采用溶胶-凝胶法制备的硅胶整体柱,由于其具有微米级通孔结构和大的比表面积,他们在高效、快速分离小分子物质方面得到广泛地应用.对于聚合物整体柱,主要介绍了包括分子印迹聚合物在内的有机聚合物整体柱在药物分离、生物样品的处理等方面的应用.