Compatibility Studies of Multicomponent Tablet Formulations. DSC and experimental mixture design

An experimental mixture design was applied to a differential scanning calorimetry (DSC) study performed to evaluate naproxen compatibility in tablet formulations consisting of four classic excipients (sorbitol, sodium carboxymethylcellulose, poly(ethylene glycol) 20000 and Veegum) each in adequate concentration ranges accounting for the relevant values actually used in pharmaceutical formulations. Twenty-seven different tablets were obtained from as many mixtures prepared according to the experimental design plan and analyzed in a random order by DSC. Statistical evaluation of experimental data enabled correlation of both enthalpy and onset temperature variations of drug melting endotherm (selected as responses indicative of the presence of drug-excipient interactions) with the mixture composition. Variance analysis (Anova) confirmed the reliability of the postulated polynomial model in providing adequate prediction of true system behaviour. This revised version was published online in August 2006 with corrections to the Cover Date.     

Non isothermal heat capacities and chemical reactions using a modulated DSC

An evaluation of measurements of heat capacities by modulated differential scanning calorimetry, MDSC is presented. Heat capacities were obtained from 130 to 550 K by a non isothermal technique in which a periodic modulation was added to the linear heating rate. Effects of amplitude and period of modulation, sample weight, sample type, pan type, and cell imbalance are described. Results are compared with those obtained using the isothermal technique. Heat capacity could be measured well into the decomposition region and separated from the non reversing signal due to chemical reaction (degradation), thus allowing a precise detection of onsets of the thermal degradation. This additional information will aid in the interpretation of the degradation chemistry, a field vital for the petroleum-industry.Dedicated to Professor Bernhard Wunderlich on the occasion of his 65th birthdayPart of this paper was presented at the 23rd Conference of the North American Thermal Analysis Society, Toronto, Canada, September 25–28, 1994.The author (MVN) acknowledges the experimental assistance provided by J. Balogh of Exxon Research and Engineering Company, Linden. Helpful discussions with A. Boller of the University of Tennessee at Knoxville, Dr. Y. Jin, General Electrical, and Dr. S. Sauerbrunn formerly of TA Instruments are also acknowledged.     

Preformulation compatibility studies of etamsylate and fluconazole drugs with lactose by DSC

Chemical compatibility of two drugs, namely, etamsylate and fluconazole was studied with lactose as excipient, employing differential scanning calorimetry (DSC) and X-ray diffraction (XRD) techniques. The DSC patterns recorded for the mixtures of both the drugs with the common excipient (lactose) indicated that fluconazole as well as etamsylate were incompatible with lactose at high temperatures. X-ray diffraction patterns recorded for pure drugs and lactose and the mixtures of individual drugs with lactose prepared at room temperature by intimate grinding of the components revealed incompatibility of both the drugs with lactose also at room temperature. This revised version was published online in July 2006 with corrections to the Cover Date.     

Stability and compatibility study on enalapril maleate using thermoanalytical techniques

This paper demonstrates the application of thermal analysis in compatibility and stability studies between an ACE inhibitor (enalapril maleate) and excipients. The results have helped to elucidate the reason of a stability problem observed during the storage of enalapril maleate tablets. Incompatibility between enalapril maleate and colloidal silicon dioxide was detected. Besides, it was confirmed that the reaction between enalapril maleate and NaHCO₃ increases the thermal stability of the drug. This study supports the importance of using thermoanalytical methods in the development of pharmaceuticals.     

DSC study of the association of ethanol with human serum albumin

Human serum albumin unfolding in ethanol/water mixtures was studied by use of differential scanning calorimetry. Ethanol-induced changes in DSC curves of defatted and non-defatted albumin were markedly different. In the presence of ethanol, bimodal denaturation transition for fatty acid free albumin was observed while that for albumin containing endogenous fatty acids was single and more sharpen than in aqueous solution. Ethanol was found to decrease the thermal stability of albumin due to the binding to the unfolded state to a higher degree than to the native state, thus favouring unfolding. The binding with different affinities has been suggested depending on ethanol concentration range.     

Application of DSC and NIRS to study the compatibility of metronidazole with different pharmaceutical excipients

The purpose of the present work was to study the compatibility of metronidazole with different pharmaceutical excipients (hydroxypropyl methylcellulose, poly(ethylene oxide), microcrystalline cellulose, dicalcium phosphate dihydrate, and anhydrous dicalcium phosphate) using differential scanning calorimetry and diffuse reflectance spectroscopy. Dicalcium phosphate dihydrate was the only excipient that showed interaction with metronidazole even before storage. Changes referring to a possible transition to dihydrate form were observed in the thermal curves of anhydrous dicalcium phosphate after four weeks of storage. Although dicalcium phosphate dihydrate can be replaced by the anhydrous form in pharmaceutical formulations, the observed transition might negatively influence the stability of dosage forms.     

Comparative DSC study of human and bovine serum albumin

The thermal denaturation process of bovine and human both fatty acid containing and fatty acid free albumins in aqueous solution was studied by use of differential scanning calorimetry. Human serum albumins were found to be more stable than their bovine counterparts. Fatty acid free albumins were characterized as generally less stable, more susceptible to aggregation, their unfolding endothermic transition was less cooperative and with the smaller degree of reversibility. Deconvolution analysis with using a non-two-state model with two component transitions showed essential differences in the thermodynamic parameters between all studied albumins, particularly regarding the high-temperature component transition.     

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.     

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.     

Comparative study of specific heat capacities of some vegetable oils obtained by DSC and microwave oven

Summary TG and DSC analyses were carried out in this work to evaluate the changes in the denaturation of human hair keratin submitted to different chemical effects. Hair bleaching and chlorinating treatments caused changes in the denaturation temperatures and denaturation enthalpies of hair keratin. Bleached hair and hair kept in a chlorinated solution presented a lower denaturation enthalpy and a higher denaturation temperature compared to the control hair sample. The TG and DSC analyses allowed to quantify the degradation level of hair fibers after the chemical treatments. AFM was also utilized to characterize the morphological alterations in the hair fiber surfaces caused by the chlorinating and bleaching treatments.     

Interaction between bovine serum albumin and Indo-1 using fluorescence spectroscopic method

This work attempts to calculate the binding-site number using fluorescence spectroscopic method with bovine serum albumin (BSA) and Indo-1 as protein and ligand models, respectively. The method for calculating the binding-site number in BSA for Indo-1 was developed based on the relationships between changes in Indo-1 fluorescence intensity and the analytical concentration of BSA. The interaction between BSA with Indo-1 was investigated comprehensively using fluorescence techniques as well as fluorescence resonance energy transfer, and the thermodynamic parameters were calculated according to the effect of enthalpy on temperature. Three binding sites in BSA for Indo-1 were revealed, and the distances from Trp212 in BSA to the three binding sites were 2.93, 2.57 and 2.40 nm, respectively. It was also proven that Indo-1 embedded into the three hydrophobic cavities of BSA by hydrophobic association. This paper provides a reference on calculating the binding-site number in proteins for ligands and studying their interactions by fluorescence spectroscopic methods. In fluorescent quenching experiments, fluorescence changes were automatically recorded in real time by combining the Microlab 500 Series Dispenser and PTI fluorescence apparatus. __________ Translated from Chemical Journal of Chinese Universities, 2007, 28(2): 227–233 [译自: 高等学校化学学报]     

A method for quantifying the unstable and highly polar drug nafamostat mesilate in human plasma with optimized solid-phase extraction and ESI-MS detection: more accurate evaluation for pharmacokinetic study

An advanced quantification method was developed with solid-phase extraction (SPE) and mass spectrometry (MS) determination for nafamostat, an unstable and highly polar drug, in human plasma. For unstable drugs with an ester group, the main analytical challenge is how to avoid the ester hydrolysis, and strong acid or alkaline conditions should be excluded during sample preparation. Considering that, we developed a relatively mild method with SPE for sample preparation without strong acid and alkaline treatment, which was optimized with different pHs and salt concentrations in phosphate-buffered saline treatment. The results indicated that pH 5 gave the most efficient extraction and 0.1 M salt concentration enhanced the extraction the most, with a minor effect on MS monitoring. The extraction method effectively avoided drug hydrolysis and achieved good drug enrichment over 82.2%. The linear range of quantification was 1.25–160 ng mL⁻¹. The stability of the drug in sample treatment was fully validated according to the sample processing procedure, including the stability in fresh blood, mobile phase, plasma and acidic methanol, and the results indicated that the drug remained stable during the whole sample preparation. Compared with a previous isotope-labeling method, more accurate and specific quantification of plasma concentration was achieved with liquid chromatography–electrospray ionization MS determination. With use of our method, nafamostat mesilate pharmacokinetics in 30 Chinese healthy volunteers was investigated with three doses via intravenous-drip infusion. The pharmacokinetic parameters were also estimated and compared with those of Japanese volunteers (slightly lower plasma concentration and longer terminal elimination half-life for Chinese volunteers). The difference in the pharmacokinetics may be ascribed to the quantification method, because previous isotope labeling may have overestimated the parent drug.     

DSC and EPR study on AMP.PNP,BeFx and AlF4 containing myosin nucleotide complexes

Differential scanning calorimetry and electron paramagnetic resonance experiments were performed on glycerinated skeletal muscle fibres to study the effect of the binding of nucleotides and nucleotide analogues to myosin. The thermal unfolding of muscle fibres in rigor showed three discrete domain regions with thermal stability of 52.2, 58.8 and 67.8°C. AMP.PNP and ATP plus AlF₃ or BeF₂ affected markedly the transitions, which implies the strong interaction between AMP.PNP or nucleotide analogues and catalytic domain of myosin, and a partial dissociation of heads from actin. ADP.BeFx and states model the transition states of the ATP hydrolysis cycle which precede the powerstroke of the muscle fibres. Spectrum deconvolution on isothiocyanate-labelled fibres in AMP.PNP-state resulted in two populations; 50% of labels was highly ordered with respect to fibre axis, whereas the other 50% of labels was randomly oriented. The myosin heads which showed high degree of order were in the strongly binding ADP-state. The spectra in - and ADP.BeFx state reflected random orientation of labels with increased rotational mobility in comparison with rigor. The results suggest that myosin in muscle fibres in ADP.BeFx state exists in two forms. This revised version was published online in July 2006 with corrections to the Cover Date.     

Thermoanalytical and Microscopic Investigation of Interaction between Paracetamol and Fatty Acid Crystals

The objective of this study was to investigate the possibility of interaction between paracetamol and saturated fatty acids. Although literature is replete with the interaction study of fatty acids with different drugs, few have examined the interaction with NSAIDs. Keeping in view the crystalline nature of paracetamol and fatty acids and to provide the intimate contact between the interacting molecules, crystals of binary mixture of drug with fatty acids were prepared by the solvent evaporation method. These crystals were subjected to FT‐IR, DSC, XRD, optical microscopy, SEM and AFM. DSC and XRD studies were unable to detect any interaction. Some changes were observed in FT‐IR spectrum of a binary mixture of drug with fatty acid. A better probe into interaction was obtained by microscopic techniques, especially atomic force microscopy.     

Observation of multiple phase transitions in some even n-alkanes using a high resolution and super-sensitive DSC

The phase transitions of even n-alkanes, n-C₃₄H₇₀, n-C₃₆H₇₄, n-C₄₀H₈₂ and n-C₄₂H₈₆ with high purity have been measured using a high resolution and super-sensitive DSC. A new transition in the low temperature phase was observed in all the samples in the heating run. The surface freezing phenomenon was observed by thermal measurement for the first time in all the samples both in the heating and in the cooling run. The difference of the thermal behaviors between the heating and cooling run was also observed in all the samples.     

Stability studies on nifedipine tablets using thermogravimetry and differential scanning calorimetry

A formulation of nifedipine tablets was prepared in the present research. The tablets were conditioned in amber-colored glass containers and placed in a climatized room at 40°C and relative humidity of 75% for 180 days. Differential scanning calorimetry (DSC) and thermogravimetry (TG) were used in order to evaluate the thermal properties of nifedipine, the excipients and two well-known nifedipine degradation products. The results demonstrated that there is no evidence on the interaction between nifedipine and excipients, or degradation products.     

Solid state interaction of steroids with calixarenes. I. A preliminary FTIR and DSC study on 4-en-3-keto-steroids

Both DSC and FTIR studies indicate that co-grinding and co-precipitation cause steroids to interact with calixarenes. This interaction leads to breaking of the crystal lattice of the steroids, dispersion of the steroidal carbonyls in a hydrophobic environment and formation of hydrogen bonds between steroidal and calixarene hydroxyls. This interaction seems to be specific, depending on the structure of the calixarene and of the steroid involved. It is reasonable to assume that inclusion complexes are formed.     

Elucidation of Interaction between Whey Proteins and Proanthocyanidins and Its Protective Effects on Proanthocyanidins during In-Vitro Digestion and Storage

Whey proteins and oligomeric proanthocyanidins have nutritional value and are widely used in combination as food supplements. However, the effect of the interactions between proanthocyanidins and whey proteins on their stability has not been studied in depth. In this work, we aimed to characterize the interactions between β-Lactoglobulin (β-LG) and α-lactalbumin (α-LA) and oligomeric proanthocyanidins, including A1, A2, B1, B2, B3, and C1, using multi-spectroscopic and molecular docking methods. Fluorescence spectroscopic data revealed that all of the oligomeric proanthocyanidins quenched the intrinsic fluorescence of β-LG or α-LA by binding-related fluorescence quenching. Among the six oligomeric proanthocyanidins, A1 showed the strongest affinity for β-LG (K_a = 2.951 (±0.447) × 10⁴ L∙mol⁻¹) and α-LA (K_a = 1.472 (±0.236) × 10⁵ L∙mol⁻¹) at 297 K. β-LG/α-LA and proanthocyanidins can spontaneously form complexes, which are mainly induced by hydrophobic interactions, hydrogen bonds, and van der Waals forces. Fourier-transform infrared spectroscopy (FTIR) and circular dichroism spectroscopy showed that the secondary structures of the proteins were rearranged after binding to oligomeric proanthocyanidins. During in vitro gastrointestinal digestion, the recovery rate of A1 and A2 increased with the addition of WPI by 11.90% and 38.43%, respectively. The addition of WPI (molar ratio of 1:1) increased the retention rate of proanthocyanidins A1, A2, B1, B2, B3, and C1 during storage at room temperature by 14.01%, 23.14%, 30.09%, 62.67%, 47.92%, and 60.56%, respectively. These results are helpful for the promotion of protein–proanthocyanidin complexes as functional food ingredients in the food industry.     

Interaction between PAMAM 4.5 dendrimer, cadmium and bovine serum albumin: a study using equilibrium dialysis, isothermal titration calorimetry, zeta-potential and fluorescence

Binding of Cd²⁺ by PAMAM 4.5 dendrimer was studied by equilibrium dialysis, isothermal titration calorimetry and zeta-potential measurement. The following binding parameters were obtained: n = 23.8 ± 9.5, K_b = 4.7 ± 0.9 × 10³ in water; and n = 41.3 ± 13.4, K_b = 2.1 ± 0.8 × 10³ in 0.15 mol/l phosphate-buffered saline. The location of the bound Cd²⁺ is discussed. The interactions between bovine serum albumin, PAMAM 4.5 dendrimer and cadmium were analyzed using fluorescence and equilibrium dialysis. The competition between Cd²⁺ binding to BSA and PAMAM 4.5 dendrimer was investigated. It is proposed that PAMAM 4.5 dendrimer could be successfully used for extracting Cd²⁺ from aqueous solutions (environmental protection).