Use of DSC and TG for identification and quantification of the dosage form

Thermal analysis techniques, DSC and TG can advantageously be used in quality control of drug products.The methods are commonly used in preformulation for the study of polymorphism and for the study of the interactions drug substance-excipients, since these physical interactions can be the basis of the dosage form performance.For routine control of the drug products, DSC and TG methods which are quick, which require only few mg of the samples and which are automated, are very attractive for routine analysis of drug products. A single scan can give several qualitative and quantitative informations.DSC offer analytical possibilities only if the drug substance and the excipients do not have physical interactions or limited interactions (e.g. eutectic behaviour). About twenty marketed products have been analyzed by DSC and TG. In most of them identification of drug substance is easy. Several excipients could be identified in a tablet. Quantitations are demonstrated for some drug substances and excipients. DSC purity calculations have been applied to acetyl salicylic acid, paracetamol, cimetidine, pindolol, ibuprofen.     

Study of the polymorphic behaviour of some local anesthetic drugs

The local anesthetic drug tetracaine hydrochloride is described in the Europ. Pharmacopea with a melting point of 148°C or with a range of 134 to 147°C due to the melting points of two other forms. The polymorphic behaviour of tetracaine hydrochloride has been studied by using thermal treatments, storage at 92% r.h., crystallizations and equilibrations with saturated solutions. Samples were characterized by X-ray diffraction, IR, thermal analysis and elemental analysis. Since some findings were difficult to interpret, temperature resolved X-ray diffraction was used additionally for the understanding of the thermal behaviour of tetracaine hydrochloride. In this study the polymorphic behaviour of some other local anesthetic drugs is compared. Ten different forms of tetracaine hydrochloride: six anhydrous crystalline forms, an amorphous form, a hemihydrate, a monohydrate and a tetrahydrate were identified. The relationships between all forms are given. The heating curve of the commercial form 1 is very dependent on the heating rate. This anhydrous form 1 is the thermodynamic stable modification at ambient temperature. The form 2 is reversibly enantiotrope to form 1. The four other modifications called 3, 4, 5 and 6 are monotropes of form 1. Only forms 1 and 5 are stable at ambient temperature. Form 1 is hygroscopic only at high humidity level of 92% r.h., form 5 is hygroscopic at 61% r.h. Both transform into the monohy-drate. No polymorphic forms of tetracaine base, dibucaine hydrochloride, procaine hydrochloride or prilocaine hydrochloride were found. The commercial form of bupivacaine hydrochloride is a monohydrate. Thermal treatment at 200°C gives one anhydrous form. As demonstrated by temperature resolved X-ray diffraction two other forms are detected by heating and cooling processes between 100 and 170°C. Equilibrations and crystallization experiments show that solvates are easily obtained in different solvents. Temperature resolved X-ray diffraction is a very efficient tool as a support to DSC for the identification of the transition processes and interpretation of thermal events and thermodynamic relationships. Equilibration experiments are very adequate to find out the thermodynamically stable form at ambient temperature (solvent mediated transitions).     

Thermal decomposition kinetics and compatibility studies of primaquine under isothermal and non-isothermal conditions

Primaquine (PQ) is the drug of choice for the radical cure of Plasmodium vivax malaria, and currently being administered in solid dosage form. In this study, the compatibility studies were carried out using differential scanning calorimetry (DSC), thermogravimetry (TG), and fourier transformed infrared (FT-IR). Non-isothermal and isothermal methods were employed to investigate kinetic parameters under nitrogen and air atmospheres using TG. The DSC investigations obtained by physical mixtures showed slight alterations in the melting temperatures of PQ with some excipients. The FT-IR confirmed the possible interactions obtained by DSC for the physical mixtures with PQ and lactose, magnesium stearate and mannitol. The results showed that the thermal decomposition followed a zero order kinetic in both atmospheres in non-isothermal method. The activation energy in both methods using nitrogen atmosphere was similar, and in air atmosphere the activation energy decreased.     

Analysis of Zoledronic Acid and Its Related Substances by Ion-Pair RP-LC

A simple high-performance liquid chromatographic method – ion-pair reversed- phase high performance liquid chromatography (RPIC) has been developed and employed for the analysis of zoledronic acid and its related substances in bulk material and commercial dosage forms. The mobile phase was a mixture of methanol (20%) and 5 mmol L^–1 phosphate buffer (80%) containing 6 mmol L^–1 tetrabutylammonium bromide, adjusted to pH 7.0 with sodium hydroxide. C₈ column was used as the stationary phase. The chromatographic conditions were optimized. The active ingredient – zoledronic acid was successfully separated from its related substances, including remained imidazol-1-yiacetic acid in the synthesis of zoledronic acid and other possible impurities of oxidation and decomposition. The excipients did not interfere with the determination of zoledronic acid in commercial dosage formulations. The method was rapid, simple, accurate and reproducible. It was not only successfully employed for the assay of zoledronic acid in bulk material and pharmaceutical dosage forms but also for the determination of its related substances.     

Discrimination of thermally treated low density polyethylenes using DSC and principal component analysis

The potential for differential scanning calorimetry (DSC) as a tool for the discrimination of forensic polymer specimens is investigated for a series of commercial low density polyethylene (LDPE) samples. Variation in the melting temperatures of ‘as received’ samples was found to be too small for its use in sample discrimination. The melting behaviour of thermally treated samples, quenched from the melt in liquid nitrogen followed by annealing at temperatures below the melting temperature, showed promise in discrimination potential. The application of principal component analysis to aid discrimination demonstrated the necessity in using a controlled thermal history to aid the discrimination process. The clustering of the LDPEs based on the factors selected demonstrated the potential of DSC for the discrimination of forensic LDPE samples.     

Thermotropic phase behaviour of mixed liposomes of archaeal diether and conventional diester lipids

During preformulation studies of pharmaceutical solid dosage forms, thermal analysis techniques are very useful to detect physical or chemical incompatibilities between the drug and adjuvants of interest that might interfere with efficacy and safety of the final drug product. Differential scanning calorimetry (DSC) and thermogravimetry (TG) are useful tools for this purpose. The aim of this study was to investigate the thermoanalytical behavior of olanzapine (OLZ) when mixed with several excipients commonly used in solid dosage forms such as microcrystalline cellulose, croscarmellose, dicalcium phosphate dihydrate (DCPD), lactose, magnesium stearate, and povidone. Following DSC and TG analyses, powder X-ray diffraction tests were carried out. Thermoanalytical methods showed evidence of interaction between OLZ and magnesium stearate, lactose, and povidone. These results can be useful during the selection of excipients for pharmaceutical formulation development.     

Effect of Molecular Mass on the Melting Temperature,Enthalpy and Entropy of Hydroxy-Terminated PEO

This paper studies the effect of molecular mass on the melting temperature, enthalpy and entropy of hydroxy-terminated poly(ethylene oxide) (PEO). It aims to correlate the thermal behaviour of PEO polymers and their variation of molecular mass (MW). Samples ranging from 1500 to 200,000 isothermally treated at 373 K during 10 min, were investigated using DSC and Hot Stage Microscopy (HSM). On the basis of DSC and HSM results, melting temperatures were determined, and melting enthalpies and entropies were calculated. Considering the melting temperatures, it was found that the maximum or critical value of MW was found around 4000, and then these remain almost constant. This behaviour was interpreted assuming that lower MW fractions (MW<4000) crystallize in the form of extended chains and higher MW fractions (MW>4000), as folded chains. The melting enthalpies showed a scattering effect at least up to MW 35,000. It was difficult to obtain any relationship between melting enthalpies in J g^–1 and MW. These variations seem to be of statistical nature. Corrected enthalpy data on a molar basis (kJ mol^–1) exhibited a linear relationship with MW. Considering the solid—liquid equilibrium, the melting entropies (in kJ mol^–1) were calculated. These values were more negative as compared with molar enthalpy increases. It was explained because the changes in melting temperatures are much smaller than those observed in the enthalpy values. Linear relationship between enthalpies andentropies as a function of MW was deduced.This revised version was published online in November 2005 with corrections to the Cover Date.     

Melting behaviour and evolved gas analysis of xylose

Two enantiomeric forms of xylose were identified as α-D-xylopyranose and α-L-xylopyranose by powder diffraction. Their melting behaviour was studied with conventional DSC and StepScan DSC method, the decomposition was studied with TG and evolved gases were analyzed with combined TG-FTIR technique. The measurements were performed at different heating rates. The decomposition of xylose samples took place in four steps and the main evolved gases were H₂O, CO₂ and furans. The initial temperature of TG measurements and the onset and peak temperatures of DSC measurements were moved to higher temperatures as heating rates were increased. The decomposition of L-xylose started at slightly higher temperatures than that of D-xylose and L-xylose melted at higher temperatures than D-xylose. The differences were more obvious at low heating rates. There were also differences in the melting temperatures among different samples of the same sugar. The StepScan measurements showed that the kinetic part of melting was considerable. The melting of xylose was anomalous because, besides the melting, also partial thermal decomposition and mutarotation occurred. The melting points are affected by both the method of determination and the origin and quality of samples. Melting point analysis with a standardized method appears to be a good measure of the quality of crystalline xylose. However, the melting point alone cannot be used for the identification of xylose samples in all cases.     

Stability studies on nifedipine tablets using thermogravimetry and differential scanning calorimetry

A new formulation of nifedipine tablets was prepared. 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. There is no evidence of interaction between nifedipine and excipients or degradation products. High performance liquid chromatography (HPLC) was used in the dosage of nifedipine tablets before and after acclimatized exposure. Results show that DSC and TG offer important data for a more detailed assessment of the stability of a pharmaceutical formulation.     

Compatibility study of tobramycin and pharmaceutical excipients using differential scanning calorimetry,FTIR, DRX,and HPLC

Differential scanning calorimetry (DSC), isothermal stress testing–Fourier transform infrared spectroscopy (IST–FTIR), isothermal stress testing–high-performance liquid chromatography, and powder X-ray diffraction (PDRX) were used as screening techniques for assessing the compatibility of tobramycin with some currently employed ophthalmic excipients. In the first phase of the study, DSC was used as a tool to detect any interaction. The absolute value of the difference between the enthalpy of the pure tobramycin melting peak and that of its melting peak in the different analyzed mixtures was chosen as a parameter of the drug–excipient interaction degree. DSC results demonstrated that benzalkonium chloride, monobasic sodium phosphate, boric acid, edetate disodium, sodium metabisulfite, thimerosal, and potassium sorbate interact with tobramycin. Taking into account these results, it could be suggested that some of the changes observed in the IST–FTIR spectra of binary blends of tobramycin and some of the excipients would account for a possible interaction between the mixture component. In this study, PDRX did not provide much information, since only tobramycin–thimerosal interactions could be detected. DSC and IST–FTIR are suitable and simple methods for the detection of potential incompatibilities between active pharmaceutical ingredient (API) and excipients.

     

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.     

Crystallisation and melting behaviour of fish oil measured by DSC

Fish oil which is characterised by important amounts of poly-unsaturated ω-3 fatty acids attach increasing importance within functional foods. Recently attention is directed on physical methods that allow fast and relatively easy the identification and discrimination of oils. DSC measurements yield in information on thermal effects, characterised by changes in enthalpy and their temperature range such as melting and crystallisation. The aim of the investigation presented here was to take DSC curves in the temperature range +20 to ?40°C on several fish oils and fish oil capsules to visualise the crystallisation and melting behaviour and to compare transition temperatures and enthalpies.     

Application of differential scanning calorimetry in food research and food quality assurance

Differential scanning calorimetry (DSC) is the most widely used thermal analytical technique in food research and it has a great utility in quality assurance of food. Proteins are the most studied food components by thermal analysis including studies on conformation changes of food proteins as affected by various environmental factors, thermal denaturation of tissue proteins, food enzymes and enzyme preparations for the food industry, as well as effects of various additives on their thermal properties. Freezing-induced denaturation of food proteins and the effect of cryoprotectants are also monitored by DSC. Polymer characterization based on DSC of polysaccharides, gelatinization behaviour of starches and interaction of starch with other food components can be determined, and phase transitions during baking processes can be studied by DSC. Studies on crystallization and melting behaviour of fats observed by DSC indicate changes in lipid composition or help characterizing products. Thermal oxidative decomposition of edible oils examined by DSC can be used for predicting oil stability. Using DSC in the freezing range has a great potential for measuring and modelling frozen food thermal properties, and to estimate the state of water in foods and food ingredients. Research in food microbiology utilizes DSC in better understanding thermoadaptive mechanisms or heat killing of food-borne microorganisms. Isothermic microcalorimetric techniques provide informative data regarding microbial growth and microbial metabolism.     

Preformulation studies on grewia gum as a formulation excipient

Grewia gum is a naturally occurring polysaccharide which has potential as a pharmaceutical excipient. Differential scanning calorimetry and Fourier transform infrared (FT-IR) spectroscopy techniques were used to examine the thermal and molecular behaviours, respectively, of mixtures of grewia gum with cimetidine, ibuprofen or standard excipients, to assess potential interactions. No disappearance or broadening of the melting endotherm was seen with cimetidine or ibuprofen. Similarly, there was no interaction between grewia gum and the standard excipients tested. The results obtained using thermal analyses were supported by FT-IR analysis of the material mixtures. Grewia gum is an inert natural polymer which can be used alone or in combination with other excipients in the formulation of pharmaceutical dosage forms.     

Comparative study of DSC pattern, colour and texture of shrimps during heating

Fish oil which is characterised by important amounts of poly-unsaturated ω-3 fatty acids attach increasing importance within functional foods. Recently attention is directed on physical methods that allow fast and relatively easy the identification and discrimination of oils. DSC measurements yield in information on thermal effects, characterised by changes in enthalpy and their temperature range such as melting and crystallisation. The aim of the investigation presented here was to take DSC curves in the temperature range +20 to −40°C on several fish oils and fish oil capsules to visualise the crystallisation and melting behaviour and to compare transition temperatures and enthalpies.     

Thermal characterization of antimicrobial drug ornidazole and its compatibility in a solid pharmaceutical product

The ornidazole drug substance presents melt at approximately 90 °C (∆T = 85–98 °C), which is critical for its use on pharmaceutical manufacturing process. This work aimed the thermal characterization of ornidazole raw-material synthesized by three different manufacturers from India, China, and Italy, using the thermoanalytical techniques of DTA, DSC, and TG, besides the verification of its stability and compatibility as a solid pharmaceutical product by the analysis of its binary mixtures (BM) with excipients and a tablet formulation. The characterization includes the thermal decomposition kinetic investigation by Ozawa model using Arrhenius equation and drug purity determination by Van’t Hoff equation. The DSC purity determination and precision were compared with results from UV–Vis spectrophotometric and liquid chromatography, showing an adequate correlation before being recommended as a general method for purity assay. The drug raw-materials presented similar quality and zero-order kinetic behavior, besides showing differences on thermal stability. The drug presented compatibility with the tested excipients since the BM studied presented melting at the same temperature range as the drug and a decomposition temperature similar to the drug for two of the BM, and at a higher temperature for the others three of the BM evaluated, which presented excipients with higher molecular structure, capable of spatial coating on the small drug molecule promoting a physical interaction pharmaceutical acceptable. The tablet was processed by wet granulation and compressed under normal conditions of pressure and temperature, maintaining the physical properties of solid drug approving the manufacturing process used. In this study, the thermal analysis was used with success as an alternative method to characterize, quantify, and perform a preformulation study.     

Solid-state mechanical properties of crystalline drugs and excipients

Thermal mechanical analysis (TMA) of crystalline drugs and excipients in their pre-melt temperature range performed in this study corroborate their newly found linear dielectric conductivity properties with temperature. TMA of crystalline active pharmacy ingredients (APIs) or excipients shows softening at 30–100 °C below the calorimetric melting phase transition, which is also observed by dielectric analysis (DEA). Acetophenetidin melts at 135 °C as measured calorimetrically by DSC, but softens under a low mechanical stress at 95 °C. At this pre-melting temperature, the crystals collapse under the applied load, and the TMA probe shows rapid displacement. The mechanical properties yield a softening structure and cause a dimensionally slow disintegration resulting in a sharp dimensional change at the melting point. In order to incorporate these findings into a structure–property relationship, several United States Pharmacopeia (USP) melting-point standard drugs were evaluated by TMA, DSC, and DEA, and compared to the USP standard melt temperatures. The USP standard melt temperature for vanillin (80 °C) [1], acetophenetidin (135 °C) [2], and caffeine (235 °C) [3] are easily verified calorimetrically via DSC. The combined thermal analysis techniques allow for a wide variety of the newly discovered physical properties of drugs and excipients.     

Comonomer Distribution in Polyethylenes Analysed by DSC After Thermal Fractionation

Ethylene copolymers exhibit a broad range of comonomer distributions. Thermal fractionation was performed on different grades of copolymers in a differential scanning calorimeter (DSC). Subsequent melting scans of fractionated polyethylenes provided a series of endothermic peaks each corresponding to a particular branch density. The DSC melting peak temperature and the area under each fraction were used to determine the branch density for each melting peak in the thermal fractionated polyethylenes. High-density polyethylene (HDPE) showed no branches whereas linear low-density polyethylenes (LLDPE) exhibited a broad range of comonomer distributions. The distributions depended on the catalyst and comonomer type and whether the polymerisation was performed in the liquid or gas phase. The DSC curves contrast the very broad range of branching in Ziegler—Natta polymers, particularly those formed in the liquid phase, with those formed by single-site catalysts. The metallocene or single-site catalysed polymers showed, as expected, a narrower distribution of branching, but broader than sometimes described. The ultra low-density polyethylenes (ULDPE) can be regarded as partially melted at room temperature thus fractionation of ULDPE should continue to sub-ambient temperatures. The thermal fractionation is shown to be useful for determining the crystallisation behaviour of polyethylene blends.This revised version was published online in November 2005 with corrections to the Cover Date.     

Thermal characterization of polyethylene glycols applied in the pharmaceutical technology using differential scanning calorimetry and hot stage microscopy

In the present study, the effect of the molecular weight and thermal treatments on commercial polyethylene glycols (PEG) samples used in the pharmaceutical processing technology, has been analyzed using DSC and HSM. The molecular weight of these polymers range from 1500 to 200000. Thermal investigations on the melting behavior of original PEG samples (as received from the manufacturer) showed only one single melting DSC endotherm effect before 373 K. This fact was associated to the presence of only one type of polymeric chain. Using standard conditions, PEG samples were solidified from the melt at 373 K, either by flash cooling (using liquid nitrogen and an ice bath) and by slow cooling, soaked and by slow cooling at room temperature. They were further studied by DSC. It was found that after cooling, PEG with molecular weight 1500 and 15000 showed DSC thermograms with a single endothermic peak. However, thermograms for PEG 4000 and 6000 produced a splitted melting endotherm. This fact was attributed to the presence of two types of chains, that are the folded and extended chains.Ageing time influences also the shape of the DSC endothermal effects. It was concluded that the endotherms obtained after heating these PEG indicate that the thermal history determine the structure (extended or folded chain type forms) and the degree of crystallinity, as evidenced by changes in heat of fusion values, melting points and structures after crystallization. The relationships between melting enthalpies and melting points, as deduced from DSC diagrams, with molecular weight of the polymers are also presented.     

Isothermal crystallisation kinetics of poly(3-hydroxybutyrate) using step-scan DSC

The crystallisation kinetics, melting behaviour and morphology, of bacterial poly(3-hydoxybutyrate) (PHB) have been investigated by using differential scanning calorimetry (DSC), step-scan DSC (SDSC), wide angle X-ray diffraction (WAXRD) and hot stage polarised optical microscopy (HSPOM). DSC imparted isothermal crystallisation thermal history. The subsequent melting behaviour revealed that all PHB materials experienced secondary crystallisation during heating and the extent of secondary crystallisation varied depending on the crystallisation temperature. PHB samples were found to exhibit double melting behaviour due to melting of SDSC scan-induced secondary crystals, while considerable secondary crystallisation or annealing took place under the modulated heating conditions. The overall melting behaviour was rationalised in terms of recrystallisation and/or annealing of crystals. Interestingly, the PHB materials analysed by SDSC showed a broad exotherm before the melting peak in the non-reversing curve and a multiple melting peak reversing curve, verifying that the melting-recrystallisation and remelting process was operative. HSOM studies supported the conclusions from DSC that the radial growth rate of the PHB spherulites was significantly varied upon the crystallisation conditions. One form of crystals was shown by WAXRD from isothermally crystallised PHB.