Characterization and compatibility study of desloratadine

Desloratadine (DL) is a selective antagonist of the histamine H₁ receptor, which has been widely used to treat allergic symptoms, and stands out from other drugs in this therapeutic class because it does not cause sedative effects. In the present study, the physico-chemical properties of DL were fully characterized using six analytical techniques such as Differential Scanning Calorimetry (DSC), Thermogravimetric analysis (TG/DTG), Fourier transform infrared spectroscopy (FT-IR), Raman spectroscopy, Powder X-ray diffraction (PXRD), and scanning electron microscopy (SEM). The DSC curve shows a sharp endothermic event at 158.4 °C, and the TG/DTG curve presents two decomposition events between 178.4 and 451.9 °C. A compatibility study involving DL and nine pharmaceutical excipients generally used in pharmaceutical formulations was performed. Physical binary mixtures of DL with each excipient were prepared in a 1:1 (w/w) ratio. After preparation, the samples were analyzed immediately and the results reveal solid-state interaction with anhydrous lactose, microcrystalline cellulose, magnesium stearate, and stearic acid.     

Application of TA and Kinetic Study to Compatibility and Stability Problems in Some Commercial Drugs. Remarks on statistical data

A thermal analysis and kinetic study on decomposition processes of some commercial drugs have been carried out to find their thermal stability. DSC/TG curves of some commercial drugs were compared with those of their active components, the excipients, the active component/excipient and the excipient/excipient mixtures. A kinetic study was carried out using both isothermal and dynamic TG curves. Both active components and commercial drugs tested show a first order decomposition mechanism. The kinetic data showed that excipients cause a decrease of the kinetic stability of the active components. Statistical analysis allowed us to select reliable kinetic parameters related to decomposition processes. This procedure showed that the values obtained by extrapolation,outside the temperature range where the processes occurred must be used with caution. Indeed half-time and shelf-time values, commonly used at room temperature, seemed to be unrealistic. This revised version was published online in July 2006 with corrections to the Cover Date.     

Application of thermal analysis to the study of antituberculosis drugs–excipient compatibility

First-line drugs (rifampicin, RIF; isoniazid, INH; ethambutol, ETA; and pyrazinamide, PZA) recommended in conventional treatment of tuberculosis were analyzed in 1:1 w/w binary mixtures with microcrystalline cellulose MC 101 (CEL) and lactose supertab^® (LAC) by differential scanning calorimetry (DSC), thermogravimetry (TG), differential thermal analysis (DTA), and Fourier transformed infrared analysis (FTIR) as part of development of fixed dose combination (FDC) tablets. Evidence of interaction between drug and pharmaceutical excipients was supposed when peaks disappearance or shifting were observed on DTA and DSC curves, as well as decreasing of decomposition temperature onset and TG profiles, comparing to pure species data submitted to the same conditions. LAC was showed to interact with RIF (absence of drug fusion and recrystallization events on DSC/DTA curves); INH (thermal events of the mixtures different from those observed for drug and excipient pure in DSC/DTA curves); PZA (decrease on drug fusion peak in DSC/DTA curves), and ETA (shift on drug onset fusion and absence of pure LAC events on DSC/DTA curves). In all cases, an important decrease on the temperature of drug decomposition was verified for the mixtures (TG analysis). However, FTIR analysis showed good correlation between theoretical and experimental drug-LAC spectra except for INH–LAC mixture, evidencing high incompatibility between these two species and suggesting that those interactions with PZA and RIF were thermally induced. No evidence of incompatibilities in CEL mixtures was observed to any of the four-studied drugs.     

tudy on compatibility of imatinib mesylate with pharmaceutical excipients

Differential scanning calorimetry and thermogravimetric analysis with the support of X-ray powder diffraction and infrared spectroscopy were used as screening techniques for the compatibility testing of imatinib mesylate, with following excipients: magnesium stearate, polyvinylpyrrolidone, microcrystalline cellulose. In order to maximize the probability of interactions 1:1 (by mass) drug: excipient binary mixtures were analysed and compared to individual components. Additionally an influence of storage at temperatures of 25 and 40°C on physico-chemical stability on drug – excipient binary mixtures was investigated. The largest visible changes were observed in the DSC curves of imatinib mesylate – magnesium stearate mixtures.     

Compatibility study between indomethacin and excipients in their physical mixtures

Thermal analysis is a routine method for analysis of drugs and substances of pharmaceutical interest. Thermogravimetry/derivative thermogravimetry (TG/DTG) and differential scanning calorimetry (DSC) are thermoanalytical methods which offer important information about the physical and chemical properties of drugs (purity, stability, phase transition, polymorphism, compatibility, kinetic analysis, etc.). This work exemplifies a general method of studying the drug-excipient interactions with the aim of predicting rapidly and inexpensively the long thermal stability of their mixtures. The TG/DTG and DSC were used as screening techniques for assessing the compatibility between indomethacin (IND) and its physical associations as binary mixtures with some common excipients. Based on their frequent use in preformulations eleven different excipients: corn starch, microcrystalline cellulose (PH 101; PH 102), colloidal silicon dioxide, lactose (monohydrate and anhydre), polyvinilpyrrolidone K30, magnesium stearate, talc, stearic acid, and manitol were blended with IND. The samples were prepared by mixing the analyte and excipients in a proportion of 1:1 (w:w). In order to investigate the possible interactions between the components, the thermal curves of IND and each selected excipient were compared with those of their 1:1 (w/w) physical mixtures. FT-IR spectroscopy and X-ray powder diffraction were used as complementary techniques to adequately implement and assist in interpretation of thermal results. On the basis of thermal results, confirmed by FT-IR and X-ray analyses, a possible interaction was found between IND with polyvinylpyrrolidone K30, magnesium stearate, and stearic acid.     

DSC and physico-chemical properties of a substituted pyridoquinoline and its interaction study with excipients

The 4,6-bis[2′(diethylamino)ethoxy]2,8,10-trimethylpyrido[3,2-g]quinoline (BG 637) is one of the compound from the pyrido[3,2-g] quinolines family. This compound had in vitro activity against the resistant cells and can reverse the multidrug resistance developed during the chemotherapeutic treatments. To characterize BG 637, techniques such as differential scanning calorimetry (DSC), Fourier transform infrared spectrometer (FTIR), ultra violet spectrophotometry (UV), gas chromatography coupled with mass spectrometry (GC/MS), nuclear magnetic resonance (NMR) and X-ray powder diffraction (XRPD) were used. Several of them were also used to show the stability of the drug during various storage conditions. DSC, FTIR and UV were used as screening techniques for assessing the compatibility of BG 637 with several commonly used pharmaceutical excipients. We compared the properties of the pure drug with those of binary mixture drug/excipient. Studied excipients were lactose monohydrate, microcrystalline cellulose, polyvinylpyrrolidone, sodium croscarmellose and magnesium stearate. Melting temperature and enthalpy of BG 637 in binary mixtures were similar to theoretical values. These results showed that BG 637 is a very stable compound and compatible with several pharmaceutical excipients.     

Physicochemical characterization of dipeptidyl peptidase-4 inhibitor alogliptin in physical mixtures with excipients

Alogliptin (ALG) is a hypoglycemic drug used in diabetes which inhibits the enzyme dipeptidyl peptidase-4 (DPP-4), preventing the degradation of incretins, stimulating insulin secretion. The physicochemical characteristics of ALG were evaluated by differential scanning calorimetry (DSC), thermogravimetry (TG) and scanning electron microscopy equipped with energy-dispersive X-ray spectrometer (SEM/EDS). The compatibility studies were carried out between ALG and excipients (physical mixtures, 1:1) using DSC, TG, diffuse reflectance Fourier transform infrared spectroscopy (FTIR), X-ray powder diffraction (XRPD) and hot-stage microscopy. ALG presented purity near to 99%, melted in the range of 179.4–187.2 °C, followed by decomposition which started in 198.0 °C. SEM/EMS analysis of ALG presented irregular crystals and traces of impurities as copper and lead. DSC investigations obtained by physical mixtures showed minor alterations in the melting ranges of ALG with mannitol, magnesium stearate and commercial tablets. Solubilization of ALG in the fused excipient was observed by hot-stage microscopy between mannitol and ALG, and in tablets. The interaction observed in the mixture with magnesium stearate is due to the melting of the excipient and drug separately, first the excipient and then the drug. FTIR showed additional bands related to the excipients. XRPD proved that ALG has a crystal form and no alterations in the ALG profile were observed after the mixtures. ALG was compatible with all excipients tested. These results were important to understand the characteristics, stability and compatibility of the drug, and proved to be useful in preformulation studies.

     

FTIR, XRD, and DSC analysis of the rosemary extract effect on polyethylene structure and biodegradability

The purpose of this research study was evaluation of the utility of two common multivariate techniques, agglomerative cluster analysis (CA) and principal component analysis (PCA), as supplementary means of detecting incompatibilities, which can occur between active pharmaceutical ingredients and excipients at the preformulation stage of a solid dosage form. For the detection of incompatibilities between atenolol (beta blocker) and selected excipients (mannitol, lactose, starch, methylcellulose, β-cyclodextrin, meglumine, chitosan, polyvinylpyrrolidone and magnesium stearate), the thermogravimetry (TG), differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FTIR) were chosen. The results have shown that compatibility between atenolol and an excipient can be identified in a CA dendrogram by two large clusters, from which one groups an excipient and physical mixtures with a high concentration of the excipient. Another cluster encompasses atenolol and mixtures with a high content of the drug. In the PCA plot, all samples are located along the first principal component axis (PC1), beginning from a single component located with the most negative PC1 value, through mixtures with gradually varying concentration of both ingredients, till the second component located close to the most positive PC1 values. The results have shown that CA and PCA fulfil their role as supporting techniques in the interpretation of the data acquired from the TG curves, and the obtained data are compatible with the results of DSC and FTIR analyses.     

Paracetamol-propyphenazone interaction and formulation difficulties associated with eutectic formation in combination solid dosage forms

Polymorphic behaviours of paracetamol and propyphenazone and interaction between these two compounds were investigated using differential scanning calorimetry (DSC), X-ray powder diffraction and Fourier transform-infrared (FT-IR)-spectroscopy. Binary mixtures containing various ratios of the compounds were prepared as physical and fused mixtures and analysed by DSC to study their thermal behaviours. Phase diagrams obtained from the melting endotherms of the binary mixtures demonstrated formation of an eutectic mixture at a paracetamol-propyphenazone combination of about 35:65 (w/w) with an eutectic temperature of 56 degrees C. The FT-IR spectroscopy revealed no chemical interaction due to eutectic formation, and a lower degree of crystallinity of the eutectic mixture than individual substances was observed by X-ray powder diffraction analysis. The DSC and X-ray powder diffraction data demonstrated a polymorphic change in propyphenazone as a result of melting of the compound. Tablets, containing both paracetamol and propyphenazone in a combination formulation and prepared using standard wet granulation technology, were found to have physical instability when packed in either polyvinylchloride// aluminium or polyvinylchloride/polyvinyldienechloride// aluminium blisters and stored for one month at 40 degrees C with either 75% relative humidity or without any humidity control. The instability of the tablets was more apparent under the high humidity condition.     

Lactose as a low molecular weight carrier of solid dispersions for carbamazepine and ethenzamide

Solid dispersions of carbamazepine or ethenzamide were prepared by melting and rapid cooling with liquid nitrogen using lactose as a carrier. The physical characteristics of these solid dispersions were investigated by powder X-ray diffraction, differential scanning calorimetry, and dissolution rate analysis. The degree of crystallinity of the drugs in solid dispersions decreased with decreases in the molar ratio of the drugs to lactose. Fourier-transform infrared (FT-IR) analysis demonstrated the presence of intermolecular hydrogen bonds between the primary amide group of carbamazepine and lactose. Dissolution studies indicated that the dissolution rate was markedly increased in solid dispersions compared with physical mixtures and pure drugs. These results indicated that lactose is useful as a carrier for the production of solid dispersions of drugs having a primary amide group in their structures.     

Compatibility of sildenafil citrate and pharmaceutical excipients by thermal analysis and LC–UV

The evaluation of sildenafil citrate (SC), the best-selling drug for treatment of impotence, for compatibility with various excipients was investigated using thermal and isothermal stress testing. Differential scanning calorimetry (DSC), hot-stage microscopy (HSM) and liquid chromatography (LC) with ultraviolet detection were successfully employed to investigate the compatibility between SC and various excipients commonly used in solid form in the pharmaceutical industry. The studies were performed using 1:1 (m/m) drug/excipient physical mixtures and samples were stored under accelerated stability conditions (40 °C at 75% relative humidity). All excipients tested (such as colloidal silicon dioxide, croscarmellose sodium, lactose, mannitol and sucrose) showed potential incompatibilities by DSC and LC analysis after accelerated stability testing. However, some incompatibilities were not detected by the DSC method and were observed only when LC analysis was performed. HSM was able to differentiate active pharmaceutical ingredient degradation from solubilisation, supporting the interpretation of DSC in excipients where thermal events either overlapped or disappeared. The combination of both the analytical techniques (DSC and LC) and use of a stability chamber is extremely helpful in detecting incompatibilities and providing more robust and accurate approaches for pre-formulation studies.     

Compatibility studies between nebicapone,a novel COMT inhibitor,and excipients using stepwise isothermal high sensitivity DSC method

Study of excipients incompatibility with drugs in an early phase of pharmaceutical development is still a persistent difficulty within the pharmaceutical industry. We examine here the compatibility between an experimental drug (nebicapone) and common excipients using differential scanning calorimetry (DSC), high sensitivity DSC (HSDSC) and a conventional heat stress test. The results obtained indicate that nebicapone may be compatible with lactose monohydrate and sodium croscarmellose but is incompatible with magnesium stearate. This study concludes that HSDSC, in stepwise isothermal mode, may be used as a potential tool for detecting excipient incompatibilities.     

A dynamical study of the melting behavior of polypivalolactone single crystals by the X-ray diffraction method

Wide-angle and small-angle X-ray diffraction patterns of polypivalolactone single crystals were recorded as a function of temperature while heating at a constant rate. Long periods were found to increase abruptly at a certain temperature, while the degree of crystallinity decreased up to that temperature and then recovered on further heating, to an extent depending on the rate of heating. Multiple endotherms were observed in DSC measurements. The temperature at which the first endotherm peak was observed corresponded exactly to the temperature of the long period jump mentioned above. From these data, it is concluded that the original lamellar crystals melt at each peak temperature in the DSC thermogram and new lamellae are produced by subsequent crystallization. Multiple endotherms in the DSC thermogram are thus considered to represent repeated melt-recrystallization processes.     

胆甾液晶／聚合物多组分体系的结构与性能研究（Ⅲ）──ChN／poly（MMA－CO－BMA）混合体系的形态结构

应用Ｘ射线衍射、偏光显微镜及电子显微镜研究了胆甾液晶与甲基丙烯酸甲酯（ＭＭＡ）─甲基丙烯酸丁酯（ＢＭＡ）无规共聚物共混体系的形态结构。研究了体系的结晶态及液晶态的行为和共聚物含量及组成对光学织构的影响。     

Covalent grafting of ethylene glycol and glycerol into brucite

Layered brucite was synthesized at room temperature and, after characterization, was reacted in a closed flask with either ethylene glycol or glycerol. Powder X-ray diffraction patterns have shown that new compounds with interlayer expansions were obtained. New bands attributed to grafting of ethylene glycol and glycerol into the interlayer surface of brucite were detected by FTIR. XPS spectroscopy and thermal analyses (TG/DSC) have shown that nearly all of the hydroxide groups of the layers were replaced by either ethylene glycol or glycerol through Mg-O-C bonds.     

Quantitative Determination of Crystallinity of α-Lactose Monohydrate by DSC

In pharmaceutical practice it is important and useful to know the crystallinity of materials and to monitor it during formulation development, production processes and storage. The purpose of this study was to assess the quantitative capability of DSC for determining crystallinity in crystalline/amorphous powder mixtures and to compare the accuracy of the DSC method with that of conventional powder X-ray diffraction. Alpha-lactose monohydrate was chosen as the model material. On the basis of this study it can be concluded, that DSC method can be applied safely for semiquantitative evaluation of the crystallinity of lactose samples consisting of an amorphous content higher than 20%. This revised version was published online in August 2006 with corrections to the Cover Date.     

Thermal behavior and polymorphism in medium–high temperature range of the sulfur containing amino acids <Emphasis Type="SmallCaps">l</Emphasis>-cysteine and <Emphasis Type="SmallCaps">l</Emphasis>-cystine

A thermophysical study of the sulfur containing amino acids l-cysteine and l-cystine has been carried out by differential scanning calorimetry (DSC). Heat capacities of both compounds were measured in the temperature interval from T = 268 K to near their respective melting temperatures. DSC and variable temperature powder X-ray diffraction analysis (PXRD) gave evidence for a solid–solid phase transition close to the melting point only in the l-cysteine sample. DSC experiments show that this solid–solid transition is not reversible in the temperature interval T = 235–485 K and presents a behavior depending on heating temperature, time, and rate. This behavior is also supported by variable-temperature PXRD. The patterns for the commercial samples, at room temperature, are consistent with those simulated for the orthorhombic and hexagonal polymorphic forms from the single-crystal X-ray analysis.     

Thermal characterization of lovastatin in pharmaceutical formulations

Thermogravimetry (TG) and differential scanning calorimetry (DSC) are useful techniques that have been successfully applied in the pharmaceutical industry to reveal important information regarding the physicochemical properties of drug and excipient molecules such as polymorphism, stability, purity, and formulation compatibility among others. In this study, lovastatin was studied by TG, DSC, and other techniques such as Fourier transform infrared spectroscopy, optical microscopy, X-ray diffraction, chromatography, and mass spectrometry. Lovastatin showed melting point at 445 K and thermal stability up to 535 K. It presented morphological polymorphism, which in the drug has the same unit cell, but with different crystal habits. Preservative excipient butylhydroxyanisole (BHA) causes amorphization of lovastatin crystallites and, therefore is incompatible with lovastatin. Degradation by hydrolysis was observed under neutral, acid, and basic conditions. The active degradation product, lovastatin hydroxyacid, was obtained after neutral and basic hydrolysis.     

α-β Phase Re-Transformation Kinetics in Nickel Sulphide

Nickel sulphide (NiS) was characterised using X-ray diffraction, thermal gravimetric analysis (TG) and differential scanning calorimetry (DSC). The 'as received' Millerite, stoichiometric NiS, observed to be slightly nickel deficient, was found to readily decompose in a nitrogen atmosphere at elevated temperatures (450°C max.) to the sulphur deficient Godlevskite, Ni₇S₆. DSC and X-ray measurements demonstrated that the high temperature form of the Godlevskite was readily stabilised at room temperature. The kinetics of the α-β re-transformation in Godlevskite were then investigated using DSC and were observed to be first order. This revised version was published online in July 2006 with corrections to the Cover Date.     

Phase transitions in ternary caesium lead bromide

Phase transitions in ternary caesium lead bromide (CsPbBr₃) were studied by means of DSC, TMA and high temperature X-ray diffraction. The samples were prepared from the solution by water evaporation and from the melt. on the DSC curves as well as on the temperature dependence of the lattice constants of CsPbBr₃ only two effects were found belonging to the earlier published phase transitions at 88 and 130°C and no further effects. Linear thermal expansion coefficient α of individual CsPbBr₃ modifications were calculated from both TMA and high temperature X-ray diffraction. The structural parameters of the room temperature orthorhombic phase were refined and the results are presented. CsPbBr₃ prepared from the solution contained about 10% of CsPb₂Br₅ and so the DSC curve of pure CsPb₂Br₅ was also measured and an effect at a temperature of 68.5°C was found. This revised version was published online in July 2006 with corrections to the Cover Date.