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.

     

Application of chemometrically processed thermogravimetric data for identification of baclofen-excipient interactions

Studies are constantly being conducted on the elaboration of efficient methods to confirm the compatibility of active pharmaceutical ingredients (APIs) and excipients, since medicinal products, apart from their APIs, also contain numerous excipients that not only have important functions in pharmaceutical preparations but can also initiate or participate in interactions with drug substances, which eventually lead to a decline in drug quality. With this in mind, research was undertaken to evaluate two of the most often applied pattern recognition methods, hierarchical cluster analysis (HCA) and principal component analysis (PCA), as supporting techniques in the identification of potential physicochemical interactions that may occur during the preformulation of solid dosage forms. The investigation performed with the use of baclofen and selected excipients has shown that with thermogravimetric analysis, HCA and PCA fulfill their role as supporting techniques in the interpretation of the data obtained. Based on these methods, it is possible to detect incompatibilities between baclofen and excipients, and the data obtained concur strongly with the results of differential scanning calorimetry and IR spectrometry analyses.     

The Usefulness of X-ray Diffraction and Thermal Analysis to Study Dietary Supplements Containing Iron

X-ray powder diffraction (XRPD) and thermal analysis (differential scanning calorimetry/derivative of thermogravimetry (DSC/DTG)) are solid-state techniques that can be successfully used to identify and quantify various chemical compounds in polycrystalline mixtures, such as dietary supplements or drugs. In this work, 31 dietary supplements available on the Polish market that contain iron compounds, namely iron gluconate, fumarate, bisglycinate, citrate and pyrophosphate, were evaluated. The aim of the work was to identify iron compounds declared by the manufacturer as food supplements and to try to verify compliance with the manufacturer’s claims. Studies performed by X-ray and thermal analysis confirmed that crystalline iron compounds (iron (II) gluconate, iron (II) fumarate), declared by the manufacturers, were present in the investigated dietary supplements. Iron (II) bisglycinate proved to be semi-crystalline. However, depending on the composition of the formulation, it was possible to identify this compound in the tested supplements. For amorphous iron compounds (iron (III) citrate and iron (III) pyrophosphate), the diffraction pattern does not have characteristic diffraction lines. Food supplements containing crystalline iron compounds have a melting point close to the melting point of pure iron compounds. The presence of excipients was found to affect the shapes and positions of the endothermic peaks significantly. Widening of endothermic peaks and changes in their position were observed, as well as exothermic peaks indicating crystallization of amorphous compounds. Weight loss was determined for all dietary supplements tested. Analysis of the DTG curves showed that the thermal decomposition of most food supplements takes place in several steps. The results obtained by a combination of both simple, relatively fast and reliable XRPD and DSC/DTG methods are helpful in determining phase composition, pharmaceutical abnormalities or by detecting the presence of the correct polymorphic form.     

Preparation and Characterization of the Hybrids Containing Silica Nanoparticles by Sol-Gel Crosslinking Process

The organic/inorganic hybrid nanomaterials containing silica nanoparticles are synthesized by sol-gel crosslinking process. The tetraethoxysilane (TEOS) and γ-aminopropyltriethoxylsilane as coupling agents are used as a precursor. The 2,4,6-tri [(2-epihydrin-3-bimethyl-ammonium)propyl]-1,3,5-triazine chloride (Tri-EBAC) as crosslinking agent is used to form covalent bonds among the inorganic nanoparticles. The chemical and morphological structures of the organic/inorganic hybrid are characterized with FTIR spectra, ²⁹Si-NMR, x-ray diffraction (XRD), differential scanning calorimetry (DSC), scanning electron microscopy (SEM) and atomic force microscope (AFM). The results show that the organic/inorganic hybrid forms covalent bond between the inorganic nanoparticle and Tri-EBAC. The network organic/inorganic hybrid can form good film with even nanometer particles. The network organic/inorganic hybrids nanomaterial not only exhibits the thermal properties of inorganic compounds, but also exhibits the thermal properties of organic polymer.     

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 of trioxsalen with excipients by DSC,DTA, and FTIR

Psoralens are widely used for the treatment of psoriasis. Trioxsalen is a drug prescribed low-dose, belonging to the group of substituted psoralen. The aim of this study was to evaluate the compatibility of trioxsalen with pharmaceutical excipients used in the solid forms by analytical techniques. Binary mixtures between the trioxsalen and pharmaceutical excipients (namely, magnesium stearate, α-lactose, microcrystalline cellulose 102, pregelatinized starch, mannitol, sodium lauryl sulfate, sodium starch glycolate, and croscarmellose sodium) were examined. The trioxsalen–sodium lauryl sulfate mixture displayed some physical interaction based on the DTA and DSC results, but the FTIR study ruled out any chemical change.     

Selection of excipients for dispersible tablets of itraconazole through the application of thermal techniques and Raman spectroscopy

For the development of dispersible tablets of itraconazole (ITR), techniques of thermal, Raman spectroscopy, and isothermal stress testing (IST) were used to assess the compatibility of ITR with selected excipients. Initially, differential scanning calorimeter (DSC) was used to evaluate the compatibility. Raman spectrum of drug–excipient mixture was also compared with that of pure drug and excipient. Compatibility of excipients defined in the prototype formula was tested using IST. Based on the DSC results alone, PEG-4000 was found to exhibit interaction with ITR. However, the results of Raman and IST studies showed that all the excipients used in the formula were compatible with ITR. Overall, compatibility of excipients with ITR was successfully evaluated using the combination of DSC, Raman spectroscopy, and IST techniques.     

Flow-through microdispenser for interfacing micro-HPLC to Raman and mid-IR spectroscopic detection

A flow-through microdispenser has been coupled to a micro HPLC separation system and used as a solvent elimination interface for Fourier transform infrared (FTIR) and Raman spectroscopic detection of the separated compounds. Using the microdispenser picoliter sized droplets can be generated and deposited on an appropriate target placed on a computerized x, y-stage. Evaporation of volatile solvent and buffer is rapid and allows analysis of the obtained dry deposits by various techniques. Due to the destruction free character of Raman and FTIR spectroscopy they can be applied sequentially to interrogate the same deposit. In the reported application five phenolic acids typically present in wine have been separated on a C-18 column technique using a mixture of water, methanol and acetic acid as mobile phase. For spectrum acquisition infrared and Raman microscopes have been used. The spectra recorded from the dried deposits of the separated compounds agreed well with the reference spectra of corresponding components.     

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.     

Application of DSC, IST, and FTIR study in the compatibility testing of nateglinide with different pharmaceutical excipients

Experiments were done to assess the compatibility of nateglinide (NTG) with selected excipients in the development of immediate release tablets of NTG by thermal and isothermal stress testing (IST) techniques. To evaluate the drug excipient compatibility, different techniques such as differential scanning calorimetric (DSC) study, infrared (IR) spectrophotometric study, and IST were adopted. The results of DSC study showed that magnesium stearate exhibited some interaction with NTG. However, the results of IR and IST studies showed that all the excipients used in the formula were compatible with NTG. The optimized formulation developed using the compatible excipients were found to be stable after 3 months of accelerated stability studies (40 ± 2 °C and 75 ± 5% RH). Overall, compatibility of excipients with NTG was successfully evaluated using the combination of thermal and IST methods and the formulations developed using the compatible excipients was found to be stable.     

Determination of St. John's wort components in dietary supplements and functional foods by liquid chromatography

St. John's wort (Hypericum perforatum L.) preparations, a top-selling botanical dietary supplement used primarily as an antidepressant, has recently been used as an ingredient in some food products sold as functional foods. A rapid extraction technique followed by a liquid chromatographic (LC) method was developed to determine 4 characteristic bioactive compounds (pseudohypericin, hypericin, hyperforin, and adhyperforin) from St. John's wort in dietary supplements and functional foods to which it was added. Solid samples, including dried leaf/flower mixture, dietary supplement capsules, tea bags, puff and snack bar, were extracted with methanol by sonication. Noncarbonated, fruit-flavored drinks were centrifuged and mixed with methanol. Compounds were then determined by isocratic, reversed-phase LC with UV detection at 2 wavelengths and further identified or confirmed by photodiode array spectra and LC/mass spectrometry. Within-laboratory method variations (% RSD) were satisfactory. Very low amounts, if any, of the 4 components were found in drink and puff samples, and none was found in the snack bar. The methods developed provide a useful means for the determination of St. John's wort components in dietary supplements and functional foods.     

Compatibility studies between captopril and pharmaceutical excipients used in tablets formulations

Captopril (CAP) was the first commercially available angiotensine-converting enzyme (ACE) inhibitor. In the anti-hypertensive therapy is considered the selected drug has to be therapeutically effective together with reduced toxicity. CAP is an antihypertensive drug currently being administered in tablet form. In order to investigate the possible interactions between CAP and excipients in tablets formulations, differential scanning calorimetry (DSC) and thermogravimetric (TG) analysis completed by X-ray powder diffraction (XRPD) and Fourier transform infrared spectroscopy (FTIR) were used for compatibility studies. A possible drug-excipient interaction was observed with magnesium stearate by DSC technique.     

Compatibility of medroxyprogesterone acetate and pharmaceutical excipients through thermal and spectroscopy techniques

Studies of active drug-excipient compatibility represent an important phase in the preformulation stage of the development of all dosage forms. For the development of conjugation estrogens and medroxyprogesterone acetate (MPA) double-layer tablets, techniques of thermal, isothermal stress testing (IST), and molecular vibrational spectroscopy analysis were performed to access the compatibility. Differential scanning calorimetry (DSC) studies were used as an important and complementary tool during preformulation to determine drug-excipient compatibility. On the basis of DSC results, MPA was found to be compatible with polyethylene glycol 6000. However, the results of Raman and IST studies showed that all the excipients defined in the prototype formula were found to be compatible with MPA. Overall, the compatibility of selected excipients with MPA was successfully evaluated using a combination of thermal and IST methods, and the formulations developed using the compatible excipients were found to be stable.     

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.     

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.     

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.

     

Compatibility study between sitagliptin and pharmaceutical excipients used in solid dosage forms

Differential scanning calorimetry (DSC) is a primary technique for measuring the thermal properties of materials, which reflects the physico-chemical properties of drug substances. In the present study, it is used as a screening technique for assessing the compatibility of sitagliptin with some currently employed pharmaceutical excipients. The influence of processing conditions and their effects (simple blending, co-grinding or kneading) on drug stability was evaluated. Sitagliptin showed a sharp endothermic peak at 212.1 °C with an enthalpy change of 131.5 J g^?1 indicating melting of drug. Facile transformation of dehydrated sitagliptin to monohydrate form was observed in some mixtures, disappearance of sharp melting endothermic peak of sitagliptin was observed in some mixtures. On the basis of DSC results, sitagliptin was found to be compatible with micro crystalline cellulose, croscarmellose, and pregelatinized starch. Some excipient interaction was observed with magnesium stearate, ascorbic acid, and citric acid. X-ray diffractometry and FT-IR were used as supportive tools in interpreting the DSC results. Overall, the excipients selected were compatible with the API and the mixtures are stable within the tested conditions. These results would be useful for formulation development of the film coated tablets of sitaglitptin.     

手性尼莫地平绝对构型的确定和关联

概述了手性1, 4-二氢吡啶类（1, 4-DHPs）钙拮抗剂的立体化学结构及其药效与绝对构型的关系,以及尼莫地平（nimodipine）的多晶型现象。采用单晶X射线衍射与固体和溶液圆二色（ECD）光谱直接关联的方法,对自发拆分获得的一对尼莫地平外消旋聚集体进行了绝对构型确定,首次获得了手性1, 4-DHPs类化合物的固体和溶液ECD光谱图。本方法对确认有机小分子的绝对构型,以及关联系列手性1, 4-DHP衍生物的绝对构型具有重要参考价值,同时提供了有别于常规非手性方法鉴别优势手性药物晶型的有效手段。     

Spectral analysis of pharmaceutical formulations prepared according to ancient recipes in comparison with old museum remains

A study of the composition of the remains of ancient ointments from museums was undertaken to enable understanding of the preparation techniques. Comparison of ancient recipes from different historical periods and spectroscopic characteristics of inorganic and/or organic remains recovered in museum vessels enabled preparation of ancient pharmaceutical–cosmetic formulations. Farmacopea Augustana by Occo was one the most important books studied for the 14 formulations prepared in the laboratory. Three formulations are discussed in detail and raw materials and new preparations were proposed for ozone ageing. The most important micro Raman results are discussed. The spectra of the raw materials lipids, beeswax, and resins are discussed; beeswax and pig suet (axŭngia) Raman spectra were found to be similar, but different from those of the aged oils. SERS was applied to ancient ointments and galbanum and the Raman spectra are reported and discussed for the first time.     

Investigation of sport supplements quality by Raman spectroscopy and principal component analysis

In this work, sport supplements were investigated by Raman spectroscopy. Samples were obtained from health foods shops, gyms and sports centers covering a wide range of available supplement powders. A systematic comparison of Raman spectra of the analyzed supplements allowed identifying the supplement type through the characteristic vibrational modes of carbohydrates and proteins. The protein supplements were identified by Raman bands at 1650, 1250 and 1004 cm⁻¹, while the spectral range between 1200 and 800 cm⁻¹ was useful to identify the carbohydrate supplements. Due to the diversity in composition of sport supplements, a chemometric tool such as principal component analysis (PCA) was employed to assist in the interpretation of Raman spectra, allowing also the identification of compounds present in sport supplements. Especially, the Raman scattering of aromatic and aliphatic amino acids residues contributes to the existence of bands characteristic for the different types of proteins. This kind of information is very important for the quality control of these products, for detecting the presence of fraud or a sample composition in disagreement with the label, thus ensuring the provenance of the supplements.