Solid-state Analytical Techniques Research Articles

Interrogating the Solid–Solid Phase Transition Behavior of a Molecular Crystal with a Diverse Range of Solid-State Analytical Techniques and Computational Predictions

Interrogating the Solid–Solid Phase Transition Behavior of a Molecular Crystal with a Diverse Range of Solid-State Analytical Techniques and Computational Predictions

Cu and Fe modified Cerium and Zirconium Oxides for the Oxidation of Cyclohexane to KA Oil

AbstractCe and Zr oxides have been tested in the oxidation of cyclohexane to KA oil because of the possibility to tune their crystal structure and redox properties by introducing defects, and of modifying their mechanical and thermal stability. The redox properties of the two oxides, prepared by the inverse microemulsion technique, have been tuned by homogeneously including Cu or Fe (10 % molar) into their structures. These modifications led to very different behaviours in terms of both KA oil productivity and K/A ratios, especially upon undergoing reduction treatment, being the reduced Cu‐modified CeO2 oxide the most active catalyst, able to produce 2.2 mmol of KA oil after 5 hours with 93.2 % selectivity (K/A 2.6). The materials obtained have been characterized by solid state analytical techniques to study their structure, morphologies as well as their bulk and surface chemistry (STEM/EDX, BET, XRD, XPS).

Phase Transitions Involving Channel Hydrates of a New Pharmaceutical Compound.

Hydrates are often used as pharmaceutical active pharmaceutical ingredients (API), especially when anhydrates may not be feasible likely due to physicochemical properties concerns. Pharmaceutical hydrates, whereas water is present as crystal adduct, are feasible for drug products as they do not pose any safety concern. Hydrates can impart many different advantages; therefore, they are quite common and preferred solid forms for numerous pharmaceutical materials on market. However, hydrates may involve various phase transitions, which may impact the stability and processability of drug substance. Phase transitions, which include temperature-induced dehydration and moisture-facilitated rehydration are investigated by different solid-state analytical techniques such as powder x-ray diffraction, thermogravimetric analysis, differential scanning calorimetry, polarized light microscopy, and single-crystal x-ray diffraction. This research investigation focuses on the different phase transition behaviors of a newly discovered pharmaceutical compound with three channel hydrates, two of which confirmed by single-crystal analysis. The retention or rearrangement of crystal structures over the transitions are studied. Hydrate 3 exhibits a characteristic feature of channel hydrate that involves symmetric lattice relaxation.Unlike hydrate 3, hydrate 2 results in a potentially new unit cell upon dehydration due to asymmetric lattice relaxation, which converted back to Hydrate 2 in presence of water, a very unique behavior for a channel hydrate, rarely observed, which entails novelty of this research work. The relationship among crystal forms of different hydrates of this new compound is thus established. The current investigation is a vital part of drug product risk assessment for hydrates to avoid any challenges during manufacturing operations and/or stability studies. This investigation was successfully applied in the present study and can be expanded to other newly discovered APIs in future.

Quantitative analysis of amorphous form in indomethacin binary polymorphic mixtures using infrared spectroscopy analytical techniques combined with chemometrics methods

Pharmaceutical corporations prefer amorphous active pharmaceutical ingredients (APIs) because of their high apparent solubility and bioavailability, which are caused by long-range disorder, large unit surface free energy, and easily wetted particle surfaces. APIs in amorphous form tend to recrystallize into crystalline form during production, transportation, and storage, leading to differences in safety and clinical efficacy, which has been a major obstacle to development of amorphous drugs. In this study, rapid and nondestructive methods for quantitative analysis of amorphous indomethacin (A-INDO) content in A-INDO and γ-indomethacin (γ-INDO) binary mixtures were established based on Attenuated Total Reflection Fourier Transform Infrared spectroscopy (ATR-FTIR) and Near-Infrared spectroscopy (NIR) combined with chemometrics methods. Partial least squares regression (PLSR) was used to establish quantitative analysis models of A-INDO content ranging from 0.000 % to 10.000 % w/w %. A variety of spectral pretreatment methods were used to pretreat the spectral, reducing the influence of inconsistent particle size and uneven mixing, and highlighting the sample component information. The two analytical techniques’ best PLSR models were selected, and the performance of the best models was confirmed by the validation samples. The most effective PLSR model based on ATR-FTIR was Y = 0.99456 X + 0.21526, R2 = 0.99456, the limit of detection (LOD) was 0.714 % and the limit of quantification (LOQ) was 2.164 %. The optimal PLSR model based on NIR was Y = 0.99950 X + 0.07465, R2 = 0.99950, with LOD = 0.246 % and LOQ = 0.747 %. The results showed that the PLSR models established by ATR-FTIR and NIR solid-state analytical techniques combined with stoichiometric method could be used to detect the content of amorphous APIs and to control the production quality of APIs.

Modulation of Solid-State Chemical Stability of Gabapentin by Pyridinecarboxylic Acid.

Gabapentin (GBP) is an anticonvulsant drug with poor chemical stability that is particularly sensitive to heat and mechanical stress, which can lead to intramolecular lactamization. The purpose of this study was to enhance the chemical stability of GBP by cocrystallization with organic acids. Two novel multicomponent crystals, GBP-2,6-pyridinedicarboxylic acid salt (GBP-2,6PDA salt) and GBP-2,5-pyridinedicarboxylic acid cocrystal (GBP-2,5PDA cocrystal) were synthesized and characterized by various solid-state analytical techniques. The degradation behavior of GBP, GBP-2,6PDA salt and GBP-2,5PDA cocrystals were evaluated under thermal and mechanical stresses. Under thermal and mechanical stresses, GBP-2,5PDA cocrystals were found to undergo severer degradation than GBP-2,6PDA salt and neat GBP. GBP-2,6PDA salt exhibited superior chemical stability compared to the others. Furthermore, the crystal structure revealed that the order of atomic distance between the carboxyl group (C7) and amino group (N12) of GBP is as follows: GBP-2,5PDA cocrystal < GBP < GBP-2,6PDA salt, which is consistent with the chemical stability of GBP in different solid forms. Therefore, we believe that the distance between C7 and N12, the reaction active sites leading to dehydrative condensation of GBP, is a key factor determining the chemical stability of GBP in the solid state. These results provide a potential method to improve the chemical stability of GBP during the manufacturing process and storage.

Mechanochemical synthesis of six Cu(II) complexes with selected thiols, their physicochemical characterization and interaction with DNA

• Some Cu(II)-thiolates have been synthesized in the solid state. • The complexes are stable and exhibit spectroscopic features similar to those in the Type 1 site. • Cu(II)-mercaptosuccinic acid and Cu(II)- n -acetylcysteine cause extensive degradation, whereas Cu(II)-penicillamine and Cu(II)-glutathione significantly degraded the DNA. • Cu(II)-cysteine appears to form an adduct with the DNA. • Docking of Cu(II)-cysteine with thioredoxine reductase suggests that the complex has the potential to inhibit the activity of the enzyme. Cysteine together with histidine (His 2 Cys) has been identified as one of the ligands in Type 1 copper protein active sites, and Cu-S(Cys) interaction determines their unique spectroscopic features. This work reports the synthesis of model Cu(II)-thiolates, which could mimic the Type 1 sites. The Cu(II)-complexes with l -cysteine, n -acetylcysteine, l -glutathione, l -penicillamine, mercaptosuccinic acid and dl -dithiothreitol were synthesized by solvent-free mechanochemical methods. The complexes were found to be of the ML 2 type as revealed by solid-state analytical techniques including FT-IR (ATR) spectroscopy, Raman spectroscopy, electronic absorption spectroscopy (diffuse reflectance), powder X-ray diffraction and desorption electrospray ionization mass spectrometry. These compounds are difficult, in some cases impossible, to isolate from solution because of rapid oxidation of thiols to disulfides and reduction of Cu(II) to Cu(I) or Cu(0). However, in the solid state these complexes were found to be highly stable and exhibited spectroscopic features similar to those in the Type 1 site. Interaction of the complexes with genomic DNA isolated from human blood was studied by electrophoresis, which showed that Cu(II)-mercaptosuccinic acid and Cu(II)- n -acetylcysteine caused extensive degradation, whereas Cu(II)-penicillamine amd Cu(II)-glutathione significantly degraded the DNA. Cu(II)-cysteine appears to form DNA adducts. Docking of Cu(II)-cysteine with thioredoxine reductase suggests that the complex has the potential to inhibit the activity of the enzyme.

Quantitative analysis of binary mixtures of entecavir using solid-state analytical techniques with chemometric methods

Entecavir (ETV), a guanosine analogue, can be rapidly phosphorylated to the active intracellular triphosphate form that inhibits replication of the hepatitis B virus (HBV). This work aims to develop useful methods to quantify the content of ETV-A in ETV-H and ETV-A binary mixtures. The integral enthalpy value of the phase transformation in the DSC thermogram was selected to quantify the content of ETV-A in binary mixture. Different ranges (full spectrum and partial spectrum) of the PXRD and ATR-FTIR data versus ETV-A content were used to develop partial least squares (PLS) calibration curves with different pre-processing algorithms including multiplicative scatter correction (MSC), standard normal variate (SNV), wavelet transform (WT) or their combinations. The standard curve obtained for the DSC technique is Y = 100.455 + 7.255X, R2 = 0.997, in the ETV-A contents range of 0–100% w/w% in binary mixtures. Limit of detection (LOD) of ETV-A was 0.909% and limit of quantitation (LOQ) is 2.755%. The best correction models for PXRD and ATR-FTIR techniques, in the ETV-A contents range of 0–100% w/w% in binary mixtures, were Y = 0.346 + 0.999X, R2 = 0.999 in the 2θ range of 4-6° with 14-34° and Y = 0.767 + 0.991X, R2 = 0.991 in the range of 3500–2500 cm−1 with 2000–400 cm−1 pretreated by MSC + WT, respectively. Limit of detection (LOD) of ETV-A was 1.394% and limit of quantitation (LOQ) was 4.224% for PXRD technique. LOD and LOQ for ATR-FTIR technique were 9.124% and 27.648%. The results show that DSC, PXRD and ATR-FTIR techniques are precise and accurate, and could be used for the measurement of ETV-A content in the binary mixtures.

Ciprofloxacin salts with benzoic acid derivatives: structural aspects, solid-state properties and solubility performance

In this work, three new pharmaceutical hydrated salts of ciprofloxacin with selected derivatives of benzoic acid were obtained and systematically investigated by several solid-state analytical techniques.

Thermoset materials characterization by thermal desorption or pyrolysis based gas chromatography-mass spectrometry methods

Thermoset materials characterization is often limited to solid state analytical techniques such as IR, NMR, DSC, TGA and mechanical testing. Alternatively, their off-gassing behavior can also be evaluated using GC based techniques such as TD-GC-MS, allowing this method to be applied to thermoset materials analyses such as identification, aging characterization, and formulation optimization. As an overview, common thermoset materials were evaluated by analyzing their gaseous degradation products via TGA-based pyrolysis and subsequent TD-GC-MS for the identification of representative volatile signatures. It is thereby possible to distinguish different classes of phenolic materials or cured epoxy resins, as well as their amine or anhydride curatives. Additionally, this method enabled quantification of a volatile fragment (bisphenol A, BPA) which is associated with oxidation of epoxy/amine thermoset materials. The amount of evolved BPA increased linearly with aging time and this trend exhibits linear Arrhenius behavior over the temperature range (80–125 °C) studied, in agreement with oxidation sensitivies based on oxygen consumption data. Further, TD-GC-MS was used to explore how off-gassing of residual anhydride curative from an epoxy/anhydride material depends on formulation stoichiometry. Even in formulations that theoretically contained enough epoxy to consume all anhydride (1:1 stoichiometry), an imperfect final cure state resulted in residual anhydride which could evolve from the material. For such materials, a slightly epoxy-rich formulation is required to ensure that the material contains no residual unreacted anhydride. Analysis of volatiles generated by thermal exposure is an attractive characterization approach enabling compositional analysis as well as complementary diagnostics for materials degradation.

Ultrasonic-Assisted Synthesis, Characterization, and Application of a Metal–Organic Framework: A Green General Chemistry Laboratory Project

An instructional research-like multiweek laboratory project for a second-semester introductory general chemistry laboratory course has been developed. The ultrasonic-assisted synthesis method using low cost commercial ultrasonic cleaners has the convenience of running multiple students’ reactions simultaneously. Taking advantage of short reaction time, the green metal–organic framework project has been developed to facilitate experimental synthesis, characterization, and application of a porous material and debriefing of results during a normal laboratory period (about 3 h/class). This project provides the opportunity for instructors to introduce students to the Twelve Principles of Green Chemistry, the environmental impact of chemistry, modern solid-state analytical techniques, and a research-like experience of materials science.

English

English

Investigating the effects of amphipathic gastrointestinal compounds on the solution behaviour of salt and free base forms of clofazimine: An in vitro evaluation

Interactions between hydrophobic drugs and endogenous gastrointestinal substances have the potential to manipulate drug concentration in the human gastrointestinal system, and thus likely play an important role in determining the rate of absorption for hydrophobic drugs. The effects of phospholipids, bile salts and digestive proteins on the solution behaviour of clofazimine in biorelevant media was demonstrated here using dissolution experiments and solid state analytical techniques. Clofazimine is a hydrophobic, anti-mycobacterial agent with virtually no detectable water solubility in its free base form. Salt forms of the drug offer improved aqueous solubility but are unstable in solutions at low pH (pH 1.6) or high pH (pH 6.5). At low pH and high chloride ion concentrations, CFZ in solution experiences a high driving force to crystallize from solution as a hydrochloride salt, which is insoluble, while at high pH CFZ does not dissolve to any extent. In this study, it is demonstrated that amphipathic compounds present in the gastric and intestinal systems can overcome the instability experienced by CFZ at these pH values. This is done by encapsulation of the hydrophobic drug in mixed bile salt phospholipid micelles in both the gastric and intestinal fluid, and by the drug actively binding with the digestive enzyme pepsin in the gastric system. Pepsin binds and solubilises the drug at even relatively low concentration (0.1 mg/mL). When pepsin concentration is increased in the gastric media, a corresponding increase in the solution stability of CFZ is observed.

Design of spray dried ternary solid dispersions comprising itraconazole, soluplus and HPMCP: Effect of constituent compositions

A range of 17 ternary formulations of itraconazole (ITZ), HPMCP and Soluplus have been manufactured using spray drying. These amorphous solid dispersions (ASDs) were very stable against crystallisation and ITZ was found to be amorphous in all formulations after one year at 40°C/75% RH. A number of solid state analytical techniques including PXRD, DSC, small angle X-ray scattering, FTIR and solid state NMR were used to characterise the physicochemical properties of the ASDs following processing and storage and to assess any interactions between components. Microtrac laser scattering analysis revealed a relationship between polymer levels and particle size distribution (PSD). Dissolution studies indicated that higher Soluplus content in the formulation resulted in higher concentrations of ITZ in acidic media.

Incorporation of Transition‐Metal‐Ion Guests (Co 2+ , Ni 2+ , Cu 2+ , Zn 2+ ) into the Ti 2 ‐Containing 18‐Tungsto‐2‐arsenate(III) Monolacunary Host

The Ti2-containing 18-tungsto-2-arsenate(III) host [(TiIVO)2(α-AsIIIW9O33)2]14– is rationally functionalized by incorporation of various 3d metal ions resulting in [MII(H2O)(TiIVO)2(α-AsIIIW9O33)2]12– (M = Co, Ni, Cu, Zn), and these four derivatives are characterized by a multitude of solution and solid-state analytical techniques.

Synthesis and Characterization of New 3-(4-Arylpiperazin-1-yl)-2-hydroxypropyl 4-Propoxybenzoates and Their Hydrochloride Salts.

Five new 3-(4-arylpiperazin-1-yl)-2-hydroxypropyl 4-propoxybenzoates were designed and synthesized as potential dual antihypertensive agents. The compounds were prepared as free bases and subsequently transformed to hydrochloride salts. The position of protonation of nitrogen atoms in the piperazine ring of hydrochloride salts was determined by means of 13C-CP/MAS and 15N-CP/MAS NMR and IR spectroscopy. Using these solid-state analytical techniques, it was found that both nitrogen atoms were protonated when excess hydrogen chloride was used for preparation of salts. On the other hand, when the equimolar amount of hydrogen chloride was used, piperazine nitrogen substituted by aryl was protonated.

Low temperature decomposition of U(IV) and Th(IV) oxalates to nanograined oxide powders

Oxalate precipitation is a powerful technique for actinide oxide preparation at either laboratory or industrial scales. In this study we focus on the low temperature decomposition of Th(C2O4)2⋅2H2O and (N2H5)2U2(C2O4)5⋅nH2O into nanograined ThO2 and UO2 powders, which will be used later as precursors for the generation of materials emulating the nuclear fuel high burn up structure (HBS). The evolution with temperature of the nanoparticles properties has been investigated using several solid state analytical techniques (transmission and scanning electron microscopy, room and high temperature powder X-ray diffraction, Raman spectroscopy, thermogravimetry). Oxide powders with a high degree of crystallinity and grain size from ∼10nm were prepared. Their purity was examined with special focus on the presence of carbonates. It was found that carbonate content in the final powder did not exceed 3.4wt.%, for the powder treated at 600°C for 1h.

Prototypic corium oxidation and hydrogen release during the Fuel–Coolant Interaction

The article is focused on the hydrogen release by chemical reaction of Fuel and Coolant (FCR) during the molten Fuel–Coolant Interaction (FCI) and its impact on the steam explosion (SE) efficiency. Samples of debris coming from several FCI tests have been characterized by solid-state analytical techniques. Two kinds of tests have been analyzed: (i) Experiments using simulant materials (MISTEE, PREMIX, ECO FCI experiments) and tests using prototypic corium i.e., in the U–Zr–O system (KROTOS experiments). The nonradioactive melts produce during FCI from negligible amounts of hydrogen up to 3.6g per kg of melt. It was found that UO2–ZrO2 melt solidifies during FCI into face-centered (Fm3m) crystal cell forming a U1−xZrxO2+y solid solution. The oxygen over-stoichiometry of the solid solution is the evidence of FCR and release of hydrogen. A method combining chemical analysis by Energy Dispersive X-ray Spectrometry (SEM/EDS) and X-ray Powder Diffraction (XRD) allowed the determination of the oxygen over-stoichiometry y. Therefore, it has been indirectly estimated how much hydrogen was formed during the chemical reaction between hot corium and water. These data are provided for KROTOS KS2, KS4 and KS5 tests performed in the frame of the OECD/NEA Serena phase-2 project. It has been shown that up to i.e., 4.7g of H2 per kg of delivered corium melt can be formed by the reaction stoichiometric or sub-oxidized UO2–ZrO2 melts with water. The oxygen over-stoichiometry of the U1−xZrxO2+y debris (initially x=0.48 for KS2; x=0.35 for KS4; x=0.38 and y=−0.37 for KS5) varied between 0.107⩽y⩽0.167. The hydrogen formation during FCI is primarily linked to the melt composition and secondary to the size of the fragmented melt droplets.

Marine sponge melanin: a new source of an old biopolymer

Various types of melanin have already been found in the majority of organisms, being this biopolymer considered as one of the major pigments present in nature. The presence of this pigment in marine sponges (Phylum Porifera, one of the simplest multicellular organisms) was postulated, but never characterized. In this context this work aims the extraction and characterization of a dark pigment observed in four different marine sponges species (Erylus mamillaris, Erylus discophorus var. deficiens, Pachymatisma johnstonia, Dercitus bucklandi). Characterization of the extracted biopolymer was performed using solid state analytical techniques, due to the characteristic non-solubility of melanin. Therefore, characterization techniques like SEM–EDS, IR, UV–vis, MALDI-MS, elemental analysis and X-ray powder diffraction (XRD) were used to identify the biopolymer. The results showed that the extracted material was obtained with high purity, being identified as melanin. The results also emphasize a large structure variability present in this pigment, showing different structure arrangements and composition depending on its source, which influences the UV behaviour. The structural characterization of this class of pigments is fundamental, allowing a better understanding of melanin properties.

A Process Analytical Technology Based Investigation of the Polymorphic Transformations during the Antisolvent Crystallization of Sodium Benzoate from IPA/Water Mixture

Manufacturing of medicines often requires a crystallization stage. The crystallization method must be designed to produce the desired crystal form with specific shape, size distribution, and polymorphic form. This paper presents the use of process analytical technology (PAT) tools, including focused beam reflectance measurement (FBRM) probe, turbidity meter, and attenuated total reflectance (ATR) UV−vis spectroscopy, for the monitoring and detection of polymorphic transformation during the antisolvent crystallization of sodium benzoate from a propan-2-ol (IPA)/water mixture. A range of solid-state analytical (SSA) techniques including optical microscopy, scanning electron microscope (SEM), X-ray powder diffraction (XRPD), high temperature X-ray powder diffraction (HT-XRPD), solid and solution state nuclear magnetic resonance (SSNMR), infrared (IR) spectroscopy, thermal gravimetric analysis (TGA), and differential scanning calorimetry (DSC) confirmed the formation of a new, previously unreported channel solvate, which transforms into a channel hydrate during the antisolvent crystallization experiments. A combination of DSC and hot stage microscopy (HSM) analyses discovered the formation of a higher melting polymorphic form of sodium benzoate, which also has not yet been reported in the literature. This paper provides an illustrative example how the combination of PAT tools and SSA techniques can lead to the discovery of new polymorphic forms and can provide the conditions under which different forms of the compound sodium benzoate exist so the system can be designed to produce the desired form.

Use of isothermal microcalorimetry in pharmaceutical preformulation studies, Part I. Monitoring crystalline phase transitions

Solid-state transformation kinetics of two crystal forms of a synthetic tetrapeptide was monitored by isothermal microcalorimetry and complementary solid-state analytical techniques. Form B, the crystal form obtained from the synthetic process transformed to Form D upon exposure to higher relative humidity conditions (>60% RH). The transformation occurred rapidly at higher temperature, and relative humidities. An intermediate phase of very low crystallinity (amorphous-like phase) was observed when transformation was slow. Form D was observed to be physically stable at higher relative humidities and thus the preferred crystal form for development. Exposure of Form B to high relative humidity was the only process through which Form D was obtained. Optimal conditions for transformation of Form B to Form D were determined by microcalorimetric experiments and were used for larger scale processing of Form B to Form D.