DSC Screening of Potential Prochlorperazine-Excipient Interactions in Preformulation Studies

Differential scanning calorimetry was used to examine the thermal behaviour of mixtures of the drug prochlorperazine with standard excipients, to assess potential interactions, and of mixtures with cyclodextrins, to investigate inclusion complexation which could increase the photostability of the drug. For most of the excipients (magnesium stearate, stearic acid, Explotab^®, Ac-Di-Sol^®, Encompress^® and Ludipress^®, lactose and Starch 1500) disappearance or broadening of the melting endotherm of the drug indicated interactions. Lubritab^® was the only 'inert' excipient tested. Mixtures of prochlorperazine and the cyclodextrins gave incomplete inclusion complexation as shown by only partial disappearance of the melting endotherm of the drug.     

Detection of compatibility of some rubber blends by DSC

The compatibility of some technically important polymer blends, namely BR/NR, NR/NBR and CR/NBR, has been investigated using the DSC method. In addition, dynamic mechanical measurements have been carried out for the NR/NBR blends over the frequency range of 10^–4 Hz –200 Hz and temperatures ranging from –70 to +70°C.The results obtained show that the three rubber blends are not compatible over the entire composition range as proven by the DSC and mechanical measurements. By analyzing the heat capacity increases at the glass transitions of the separate phases in the NR/BR blend, it was possible to suggest the presence of a limited compatibility at the boundaries of the two phases.By comparing this work with prior measurements, it was possible to conclude that the calorimetric method is a more efficient tool for the study of compatibility of polymer blends when compared to ultrasonic and viscosity methods.Furthermore, it was found that polymers that show compatibility when measured with an ultrasonic method could behave compatible, semicompatible or incompatible when analyzed by DSC. On the other hand, blends that show incompatibility by the ultrasonic method are always incompatible by the DSC method.Dedicated to Professor Wunderlich on the occasion of his 65th birthdayWe are grateful to Prof. Dr. W. Pechhold for stimulating and promoting this work and thanks due to colleagues at the Department of Applied Physics and Section of Calorimetry, Ulm University for their valuable help. Thanks are also extended to Alexander von Humboldt Foundation for supporting the residence of A. A. Yehia in Ulm, which gave the starting impulse to this work. A. Mansour. would like to thank the USAID for supplying the PL-DSC to the Chemistry Dept., Cairo University.     

丁基橡胶阻尼材料相容性的DSC与DMA研究

高聚物力学阻尼材料是一种能消除振动和噪声以聚合物为基质的功能材料。当聚合物处于玻璃化转变温度(Tg)区域时,其链段运动不能完全跟上振动的速度而产生分子链内摩擦,吸收一部分振动能,再以“热”的形式而耗散,这样就起到减少振幅或降低振幅的作用。     

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.     

DSC study of radiostability of 1,4-dihydropyridine derivatives

The effect of sterilisation by irradiation has been studied for the seven most often used in medicine derivatives of 1,4-dihydropyridine (nifedipine, nisoldipine, nicardipine, nitrendipine, nimodipine, felodipine and amlodipine). The sterilisation was performed for the compounds in the solid phase with an electron beam of the energy 10 MeV, at room temperature, using the irradiation doses from 20 to 400 kGy. The effects of the irradiation were studied by the methods SEM, DSC, XRD and TLC. The sterilisation with doses 20-100 kGy was found to cause no changes in the physico-chemical properties of the compounds, while the irradiation with higher doses (200-400 kGy) was found to induce changes in the colour, DSC spectrum and TLC picture. As follows from the TLC results, the main product of radiolysis of the compounds studied was a pyridine nitrozoderivative, which indicates the same mechanism of decomposition as in the process of photodegradation. The results prove that the 1,4-dihydropyridine derivatives being highly sensitive to visible and UV radiation are generally resistant to ionising radiation and thus can be subjected to sterilisation by irradiation. This revised version was published online in July 2006 with corrections to the Cover Date.     

Rapid, practical and predictive excipient compatibility screening using isothermal microcalorimetry

Conditions for conducting excipient compatibility studies via isothermal microcalorimetry were explored using model reactions. The resulting recommended procedure for rapid and practical screening consisted of using binary mixtures (100 mg of each component), the addition of 20% (w/w) water, and monitoring the mixture at 50°C for 3 days using an isothermal microcalorimeter. The correlation between calorimetric excipient compatibility results and formulation stability was investigated for two developmental drugs. A comparison of calorimetric results to actual formulation stability suggested that it was possible to predict relative stability within functional classes. However, caution should be exercised in such predictions, because apparent reaction enthalpies were found to vary three-fold among excipients in the same functional class. Based on these observations, a two-step procedure is suggested for efficient development of stable formulations. First, excipient compatibility screening should be conducted using a rapid calorimetric technique. The calorimetric results are then used to evaluate relative risk of incompatibility for each excipient within a particular functional class. The calorimetric data and the functional requirements of the dosage form are then integrated in developing a limited number of model formulations that are likely to succeed from both a performance and a stability perspective. The second step of the process is to conduct traditional HPLC-based accelerated stability studies on the limited number of model formulations.     

Drug-excipient compatibility studies by physico-chemical techniques; The case of Indomethacin

This work exemplifies a general method of studying the drug excipient interactions, with the aim of predicting rapidly and inexpensively the long term stability of their mixtures. We study the physico-chemical properties of a drug (indomethacin) in the solid state and in different combinations with several excipients (PVP=polyvinylpyrrolidone, MGST=magnesium stearate, Avicel^©). We compare the properties of pure compounds (untreated, or moisture/temperature conditioned) with those of binary mixtures drug:excipient which underwent the same treatment. The purpose is to find indications of interactions within the mixtures, which means a potential incompatibility of the excipient. Both morphological and thermal properties are sensitive to interactions which leave mostly unmodified the IR spectra and the X-rays patterns. In particular, we find that indomethacin does interact with PVP and MGST, but is certainly compatible with Avicel^©.     

Investigation of the Compatibility of a Multi-Component TN Liquid Crystal Mixture and a Multi-Component Cholesteric Liquid Crystal Mixture by DSC

The phase transition curves of a multi-component TN liquid crystal mixture (TN 88-1) and a multi-component cholesteric liquid crystal mixture (Ch 88-2) were plotted by using a differential scanning calorimeter. The phase transition temperature and phase transition heat were obtained from the DSC curves. The results show that the components of TN 88-1 are compatible and they can form a stable mixture with CB 15 chiral liquid crystal. The components of Ch 88-2 are not compatible and Poly (MMA-BMA) can greatly improve their compatibility. This revised version was published online in July 2006 with corrections to the Cover Date.     

DSC investigations of amalgam formation in Bi-Sn-Hg system doped with indium

Differential scanning calorimetric (DSC) measurements have been carried out on Bi-Sn based amalgam precursors to be used in compact fluorescent lamps (CFLs) to study the changes in melting and solidifying behaviour caused by In dopant. The phase and elemental compositions of the samples have been characterized by using X-ray diffraction (XRD) and scanning electron microscopy-energy dispersive X-ray analysis (SEM-EDX), respectively. One of the endothermic peaks of the liquid amalgam formation shifted from 121°C to 112 and 105°C, with increasing content of 2.5 and 4.8 mass% In of samples, respectively.     

Determination of crystalline content gradients in cold-drawn poly-L-lactic acid films by DSC

Poly-L-lactic acid (PLLA) is a semi-crystalline, optically active, biodegradable, and biocompatible polymer that has been utilized extensively in biomedical applications as an implantable artificial cell scaffold material. In its crystalline form, PLLA is piezoelectric and it has been implicated in the enhancement of electromechanically induced osteogenesis in vivo. In its amorphous state, however, PLLA does not exhibit piezoelectricity. By uniaxially cold-drawing the polymer, PLLA can be endowed with varying degrees of piezoelectricity. It is important to understand the crystalline architecture of drawn PLLA so that the osteogenic potential imparted by piezoelectricity, if any, can be differentiated from the effects of sample crystallinity. In our work we investigate the induced crystallinity for samples of drawn PLLA at draw ratios between 1.0 and 5.5 by differential scanning calorimetry (DSC). As long-range molecular ordering occurs along the draw axis, we observe an increase in the average percent crystallinity up to a draw ratio of 5.0 and a slight decrease at a draw ratio of 5.5. More importantly, we observe significant heterogeneity in the crystalline content along the draw axis of standard dumbbells cut from PLLA and cold-drawn to representative draw ratios of 2.5 and 4.0. On average, the highest percent crystallinity occurs nearest the dumbbell center, but the maximum crystallinity is independent of draw ratio. Therefore, the draw ratio should not be considered a semi-quantitative estimate of localized PLLA crystallinity and point-to-point analysis of crystallinity in PLLA samples is required for constructing scaffolds with enhanced cell growth properties. This revised version was published online in July 2006 with corrections to the Cover Date.     

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.     

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.     

Interaction study between pefloxacin mesilate and some diluents using DSC supported with isothermal method

The present investigation was carried out to screen compatibility of some diluents with pefloxacin mesilate using differential scanning calorimetry (DSC), isothermal stability studies, along with stability studies in liquid state and to assign relative ranking to diluents. Compatibility was predicted with MCC101, MCC102, DCP anhydrous, Emcompress, while melting endotherm of drug was lost in admixtures of dextrose anhydrous, Pearlitol, Lactopress spray dried, Lactochem fine powder and Lycatab indicating possibility of interaction. Enthalpy changes were used for relative ranking of diluents.     

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.     

A study of PBT/PC blends by modulated DSC and conventional DSC

Two poly(butylene terephthalate)/polycarbonate (PBT/PC) blends with different formulations were analyzed by modulated DSC (MDSC) and conventional DSC to determine differences in crystallization behavior. A significant difference (30°C in cold crystallization temperature) between the two samples was detectable by MDSC while no significant difference was seen by conventional DSC. That indicatesthe total heat flow from MDSC is not always equivalent to the heat flow from conventional DSC as we have assumed or seen before. The reason has not been fully understood, but may be related to unusual nucleation and crystallization induced by modulation. Alternative conventional DSC methods were developed and compared to the MDSC results.Dedicated to Professor Bernhard Wunderlich on the occasion of his 65th birthdayThe authors like to thank Drs. Bernhard Wunderlich and Robert Gallucci for helpful discussion, David Shaker and Mary Parsonage for some DSC experiments. Technical support from TA Instruments is also greatly appreciated.     

Raman spectroscopic and DSC studies of diglycine-perchlorate (DGPCl)

Single crystals of diglycine perchlorate (DGPCl) and deuterated diglycine perchlorate (DDGPCl) are synthesized and studied using differential scanning calorimetry (DSC) and Raman spectroscopy. DSC data indicated that both DGPCl and DDGPCl undergo a reversible first-order phase transition (solid-solid) at −11.5 °C and −9.3 °C, respectively. The Raman spectra of DGPCl and DDGPCl obtained at ambient temperature are analyzed to infer on the strength of hydrogen bonding in this compound relative to the parent compounds. The occurrence of NH stretching frequency at higher value in DGPCl in comparison with glycine suggests presence of a weak N–H?O hydrogen bond in DGPCl than in glycine. The lower isotropic melting temperature of DGPCl as compared to that of glycine is understood on the basis of the relative strength of hydrogen bonding in these compounds.     

Thermal phenomena studies for dicumyl peroxide at various concentrations by DSC

Information about the kinetics and thermal decomposition of dicumyl peroxide (DCPO) is required for safety concerns, due to its wide applications and accident cases. To understand the inherent hazards during DCPO manufacturing, we selected various concentrations in different stages and analyzed them by differential scanning calorimetry (DSC). We evaluated thermokinetic parameters to set up a simple, but comprehensive kinetic model, with various tests conducted at heating rates of 2, 4, 6 and 10°C min^-1 . Subsequently, we established a more efficient, resource-effective, and cost-effective model of safety evaluation for DCPO with different concentrations, according to thermokinetic parameters, such as activation energy E_a is 125.35 kJ mol^-1 , frequency factor k₀ is 3.124·10 ¹² s^-1 , reaction order n is 0.9 and heat of decomposition ΔH is 750.52 J g^-1 for DCPO 99 mass%.     

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.     

Mixing method influence on compatibility and polymorphism studies by DSC and statistical analysis

Most of the pharmaceutical products are formulated as solid dosage form, which may present drug–excipient interactions that lead to changes in the chemical nature of the drug, such as solubility and bioavailability and may compromise its safety and effectiveness. Differential scanning calorimetry (DSC) is a widely used method for the rapid evaluation of the drug-excipient compatibility and the stability of the mixture formed; however, there is no consensus on the preparation methods of the drug–excipient mixtures. The aim of this study was to investigate the influence of the mixing method on the drug–excipient compatibility studies by means of DSC analysis, using tenofovir disoproxil fumarate as a drug model. Statistical analysis revealed significant differences in the heat of fusion of the drug in the mixtures prepared by several mixing methods. Vortex Mixer with a Pop-Off Cup used for 3 min proved to be very satisfactory for these studies. A polymorphic transition was observed in the mixture prepared with the mortar and pestle. Therefore, this method should be avoided since it may induce errors in the interpretation of DSC results. In this way, the mixing method used to prepare a mixture for studies of interactions between the API and the excipients in a pharmaceutical formulation has a great influence on the results and it must be chosen carefully.     

TG and DSC studies on plaster residues as recycled material

The aim of the present work is to study plaster residues produced in industries in Goiás State (Brazil). The study analyzes the trituration and dehydrating processes of the plaster and compares its chemical, mechanical and physical characteristics to the natural plaster samples aiming its possible recycling. Plaster samples were submitted to X-ray diffraction, infrared spectroscopy, thermogravimetric (TG) and differential scanning calorimetry (DSC) analyses. By the comparison of the results obtained for both samples it was observed that they have similar chemical characteristics. No reason was found against the use of recycled plaster.