Nanothermal Analysis Research Articles

Nanoscale colocalized thermal and chemical mapping of pharmaceutical powder aerosols

Inhalation of pharmaceutical aerosol formulations is widely used to treat respiratory diseases. Spatially resolved thermal characterization offers promise for better understanding drug release rates from particles; however, this has been an analytical challenge due to the small particle size (from a few micrometers down to nanometers) and the complex composition of the formulations. Here, we employ nano-thermal analysis (nanoTA) to probe the nanothermal domain of a pharmaceutical aerosol formulation containing a mixture of fluticasone propionate (FP), salmeterol xinafoate (SX), and excipient lactose, which is widely used to treat asthma and chronic obstructive pulmonary disease (COPD). Furthermore, atomic force microscopy-infrared spectroscopy (AFM-IR) and AFM force measurements are performed to provide nanochemical and nanomechanical information to complement the nanothermal data. The colocalized thermal and chemical mapping clearly reveals the surface heterogeneity of the drugs in the aerosol particles and demonstrates the contribution of the surface chemical composition to the variation in the thermal properties of the particles. We present a powerful analytical approach for in-depth characterization of thermal/chemical/morphological properties of dry powder inhaler particles at micro- and nanometer scales. This approach can be used to facilitate the comparison between generics and reference inhalation products and further the development of high-performance pharmaceutical formulations.

Nanoscale mechanical and thermal properties of a multilayer polyethylene film with varying densities

Various atomic force microscopy methods for the imaging and measurement of the modulus of polyethylene (PE) layers in a five-layer multilayer film are described. The film includes linear low-density polyethylene (LLDPE) products with densities ranging from 0.940 to 0.912 gm/cm3. Conventional TappingMode AFM phase imaging can reveal the layers but is sensitive to measurement conditions. PeakForce Tapping AFM using quantitative nanomechanics (QNM) mode can resolve all five layers based on at least three different signals – stiffness mapping, penetration, and energy dissipation. In particular, the difference is statistically significant for the modulus and penetration data. This is remarkable considering that the method is sensitive to density differences of only 0.004 density units. Quasistatic AFM indentation was also done using the same probe and peak load. Here we see the effect of time dependence on the mechanical properties, where the slower interaction times yield estimated moduli much closer to the long-time moduli measured in bulk tensile experiments, compared to the value obtained at much higher frequency using PeakForce Tapping AFM. Nano-thermal analysis of the same five-layer film using heated tip technology can also discriminate the layers statistically, based on softening temperature, which shows excellent correlation with bulk properties.

The location of adsorbed water in pigmented epoxy-amine coatings

Pigmentation can exacerbate problematic water uptake into protective paints, leading to detrimental effects such delamination, swelling and plasticization. Potential underlying mechanisms include poor adhesion between the pigment and binder, the formation of hygroscopic interphase regions close to the pigment particles, and internal stress. Here, we demonstrate the use of nanoscale chemical mapping using AFM-IR and nanothermal analysis to investigate the contribution of these mechanisms directly for model coatings based on diglycidyl ether of bisphenol-A (DGEBA) cross-linked with triethylenetetramine (TETA). Whilst moisture uptake increases in the presence of a microscale silica matting agent, no chemical interphase could be detected close to the wax-coated particles. Instead, nanothermal analysis reveals attenuated thermal expansion of the polymeric binder and raised Tg values, supporting favourable polymer-pigment interaction and an increase in internal stress in the polymeric network. This is confirmed by mapping water distributions directly using AFM-IR, where no accumulation at the intact pigment-polymer interface/interphase is detected. Finally, further evidence is provided by bulk thermal analysis, where increased plasticization and desorption enthalpies demonstrate that water sorption into the bulk polymer binder increases as a function of added pigment volume concentrations.

Glass Transition Temperatures of Individual Submicrometer Atmospheric Particles: Direct Measurement via Heated Atomic Force Microscopy Probe.

The phase (solid, semisolid, or liquid) of atmospheric aerosols is central to their ability to take up water or undergo heterogeneous reactions. In recent years, the unexpected prevalence of viscous organic particles has been shown through field measurements and global atmospheric modeling. The aerosol phase has been predicted using glass transition temperatures (Tg), which were estimated based on molecular weight, oxygen:carbon ratio, and chemical formulae of organic species present in atmospheric particles via studies of bulk materials. However, at the most important sizes for cloud nucleation (∼50-500 nm), particles are complex mixtures of numerous organic species, inorganic salts, and water with substantial particle-to-particle variability. To date, direct measurements of Tg have not been feasible for individual atmospheric particles. Herein, nanothermal analysis (NanoTA), which uses a resistively heated atomic force microscopy (AFM) probe, is combined with AFM photothermal infrared (AFM-PTIR) spectroscopy to determine the Tg and composition of individual particles down to 76 nm in diameter at ambient temperature and pressure. Laboratory-generated proxies for organic aerosol (sucrose, ouabain, raffinose, and maltoheptaose) had similar Tg values to bulk Tg values measured with differential scanning calorimetry (DSC) and the Tg predictions used in atmospheric models. Laboratory-generated phase-separated particles and ambient particles were analyzed with NanoTA + AFM-PTIR showing intraparticle variation in composition and Tg. These results demonstrate the potential for NanoTA + AFM-PTIR to increase our understanding of viscosity within submicrometer atmospheric particles with complex phases, morphologies, and compositions, which will enable improved modeling of aerosol impacts on clouds and climate.

Advanced structural characterisation of pharmaceuticals using nano-thermal analysis (nano-TA).

The production of drug delivery systems fabricated at the nano scale comes with the challenges of identifying reliable characterisation tools, especially for solid dosage forms. A full understanding of physicochemical properties of solid-state systems at a high spatial resolution is essential to monitor their manufacturability, processability, performance (dissolution) and stability. Nano-thermal analysis (nano-TA), a hybrid of atomic force microscopy (AFM) and thermal analysis, has emerged as a solution to address the need for complete characterisation of samples with surface heterogeneity. Nano-TA provides not only physical information using conventional AFM but also the thermal behaviour of these systems as an additional chemical dimension. In this review, the principles and techniques of nano-TA are discussed with emphasis on recent pharmaceutical applications. Building on nano-TA, the combination of this approach with infrared spectroscopic analysis is briefly introduced. The challenges and considerations for future development of nano-TA characterisation are also outlined.

Nano-Thermal Analysis of Defect-Induced Surface Pre-Melting in 2D Tellurium.

Thermal properties, such as thermal conductivity, heat capacity, and melting temperature, influence the efficiency and stability of two-dimensional (2D) material applications. However, existing studies on thermal characteristics—except for thermal conductivity—are insufficient for 2D materials. Here, we investigated the melting temperature of 2D Tellurium (2D Te) using the nano-thermal analysis technique and found anomalous behavior that occurs before the melting temperature is reached. The theoretical calculations present surface pre-melting in 2D Te and Raman scattering measurements suggest that defects in 2D Te accelerate surface pre-melting. Understanding the pre-melting surface characteristics of 2D Te will provide valuable information for practical applications.

In vitro drug release from acetylated high amylose starch-zein films for oral colon-specific drug delivery

This study describes the preparation of free films of zein with and without acetylated high amylose maize starch (HAS) and their corresponding coated tablets as a novel approach to colonic drug delivery. We hypothesise that the embedding of a digestible starch component within the inert zein would allow the film to remain intact until the large intestine is reached. Free films of zein alone and starch/zein were prepared and characterized. SEM and AFM images of film surface showed that films were morphologically inhomogeneous, particularly at lower HAS/Zein ratios; however, nanothermal analysis data suggested that these differences in appearance within the same film are not compositional differences. Moreover, FT-IR could detect no molecular interaction between the two polymers. Paracetamol tablets were coated with HAS/Zein aqueous based coatings of different compositions to a TWG of 20%. Drug release from zein alone and 1:5 HAS/Zein coated tablets under upper gastrointestinal conditions (pH 1.2, pH 6.8 with pepsin and pancreatin included) was very similar (for example approximately 12% and 14% of the drug was released, respectively, after 6 h in a sequential in vitro test), suggesting that release in this region is limited and is not influenced by the presence of HAS in the ratio to zein under study. Studies using an in vitro colon model showed that under simulated colonic conditions, the drug release was significantly (p < 0.05) more rapid from 1:5 HAS/Zein, compared to the zein alone coating formulation. These data therefore support the potential use of zein-starch mixed films for colonic targeting purposes.

Monitoring Drug Crystallization in Percutaneous Penetration Using Localized Nanothermal Analysis and Photothermal Microspectroscopy.

Drug crystallization on and in the skin has been reported following application of topical or transdermal formulations. This study explored novel probe-based approaches including localized nanothermal analysis (nano-TA) and photothermal microspectroscopy (PTMS) to investigate and locate drug crystals in the stratum corneum (SC) of porcine skin following application of simple ibuprofen (IBU) formulations. We also conducted in vitro skin permeation studies and tape stripping. The detection of drug crystals in the SC on tape strips was confirmed using localized nano-TA, based on the melting temperature of IBU. The melting of IBU was also evident as indicated by a double transition and confirmed the presence of drug crystals in the SC. The single point scans of PTMS on the tape strips allowed collection of the photothermal FTIR spectra of IBU, confirming the existence of drug crystals in the skin. The combined methods also indicated that drug crystallized in the SC at a depth of ∼4-7 μm. Future studies will examine the potential of these techniques to probe crystallization of other commonly used actives in topical and transdermal formulations.

AFM nanomechanical mapping and nanothermal analysis reveal enhanced crystallization at the surface of a semicrystalline polymer

We used atomic force microscopy (AFM) nanomechanical mapping to image the surface of a semicrystalline polymer, specifically polymorphic isotactic poly (1-butene) (iPB), to determine the mechanical properties of a surface layer, and compared this to the properties in the bulk. The measured Young's modulus of the surface layer as a function of annealing time at room temperature was found to be higher than that of the bulk, indicating a more rapid transformation from form II to I polymorphs and an enhanced movement of polymer chain segments at the surface relative to the bulk for this polymer. Plate-like crystals were found at the surface and, as the annealing temperature increased from 70 to 110 °C, evidence of a surface layer was found that increased in thickness from ∼30 to ∼130 nm, respectively. After removing this layer, the morphology found in the bulk was markedly different. We also used AFM nanothermal analysis to determine the local melting point (Tm) and found, that the melting point, Tm, of the crystals at the surface was higher than that of the bulk, in keeping with the modulus measurements. The nanomechanical and nanothermal properties and the morphology at the surface suggest an enhanced movement of polymer chain segments at the surface and therefore, an enhanced crystallization at the surface.

Nano-thermal imaging of the stratum corneum and its potential use for understanding of the mechanism of skin penetration enhancer

Nano-thermal analysis (nano-TA) is a localised thermal technique which maps a surface in terms of thermal transitions by combining atomic force microscopy with the use of thermal probes, allowing a spatial resolution of sub–100nm. In this communication, we describe the application of a localised nano-TA approach, transition temperature microscopy (TTM), to investigate the thermotropic properties of porcine stratum corneum (PSC) as a function of depth and the influence of penetration enhancer on the nano-thermal properties of PSC. The investigations were conducted on PSC removed using tape strips. The transition temperature of PSC recorded at ∼220°C was ascribed to protein denaturation/degradation. A decrease in the transition temperature was observed with an increase of skin depth. ‘Transition depression’ was observed when PSC was treated with propylene glycol, suggesting its water extraction effect on SC protein and a drop in the biomechanical properties of the SC. TTM has the potential to be extended to on in situ investigations of various penetration enhancers.

The application of novel nano-thermal and imaging techniques for monitoring drug microstructure and distribution within PLGA microspheres

Poly (d,l-lactic-co-glycolic) acid (PLGA) based microspheres have been extensively used as controlled drug release systems. However, the burst effect has been a persistent issue associated with such systems, especially for those prepared by the double emulsion technique. An effective approach to preventing the burst effect and achieving a more ideal drug release profile is to improve the drug distribution within the polymeric matrix. Therefore, it is of great importance to establish a rapid and robust tool for screening and optimizing the drug distribution during pre-formulation. Transition Temperature Microscopy (TTM), a novel nano-thermal and imaging technique, is an extension of nano-thermal analysis (nano-TA) whereby a transition temperature is detected at a localized region of a sample and then designated a color based on a particular temperature/color palette, finally resulting in a coded map based on transition temperatures detected by carrying out a series of nanoTA measurements across the surface of the sample. In this study, we investigate the feasibility of applying the aforementioned technique combined with other thermal, imaging and structural techniques for monitoring the drug microstructure and spatial distribution within bovine serum albumin (BSA) loaded and nimodipine loaded PLGA microspheres, with a view to better predicting the in vitro drug release performance.

Atomic Force Microscopy Thermally-Assisted Microsampling with Atmospheric Pressure Temperature Ramped Thermal Desorption/Ionization-Mass Spectrometry Analysis.

The use of atomic force microscopy controlled nanothermal analysis probes for reproducible spatially resolved thermally assisted sampling of micrometer-sized areas (ca. 11 × 17 μm wide × 2.4 μm deep) from relatively low number-average molecular weight (Mn < 3000) polydisperse thin films of poly(2-vinylpyridine) (P2VP) is presented. Following sampling, the nanothermal analysis probes were moved up from the surface and the probe temperature ramped to liberate the sampled materials into the gas phase for atmospheric pressure chemical ionization and mass spectrometric analysis. The procedure and mechanism for material pickup, the sampling reproducibility and sampling size are discussed, and the oligomer distribution information available from slow temperature ramps versus ballistic temperature jumps is presented. For the Mn = 970 P2VP, the Mn and polydispersity index determined from the mass spectrometric data were in line with both the label values from the sample supplier and the value calculated from the simple infusion of a solution of polymer into the commercial atmospheric pressure chemical ionization source on this mass spectrometer. With a P2VP sample of higher Mn (Mn = 2070 and 2970), intact oligomers were still observed (as high as m/z 2793 corresponding to the 26-mer), but a significant abundance of thermolysis products were also observed. In addition, the capability for confident identification of the individual oligomers by slowly ramping the probe temperature and collecting data-dependent tandem mass spectra was also demonstrated. The material type limits to the current sampling and analysis approach as well as possible improvements in nanothermal analysis probe design to enable smaller area sampling and to enable controlled temperature ramps beyond the present upper limit of about 415 °C are also discussed.

Molecularly controlled epoxy network nanostructures

Epoxy thermosets continue to be used in a variety of coatings, adhesives, and structural composites. Nanostructural heterogeneities have been proposed to determine the physical properties of these materials, but the presence and origin of these features is disputed. Here, we combine nano-chemical imaging and nano-thermal analysis to establish a connection between internal crosslinking and the appearance of nanoscale chemical heterogeneities in epoxy resins. Deflection of an AFM probe is used as a local sensor to detect photothermal expansion in response to infrared excitation, and nanoscale lateral variations are detected in response to illumination at wavenumbers associated with crosslinking. Furthermore, these heterogeneous chemical features correspond to an increased range of local thermal transitions, and only arise within highly cross-linked resins; lightly cross-linked specimens are found to be homogeneous.

Nano-Localized Thermal Analysis and Mapping of Surface and Sub-Surface Thermal Properties Using Scanning Thermal Microscopy (SThM).

Determining and acting on thermo-physical properties at the nanoscale is essential for understanding/managing heat distribution in micro/nanostructured materials and miniaturized devices. Adequate thermal nano-characterization techniques are required to address thermal issues compromising device performance. Scanning thermal microscopy (SThM) is a probing and acting technique based on atomic force microscopy using a nano-probe designed to act as a thermometer and resistive heater, achieving high spatial resolution. Enabling direct observation and mapping of thermal properties such as thermal conductivity, SThM is becoming a powerful tool with a critical role in several fields, from material science to device thermal management. We present an overview of the different thermal probes, followed by the contribution of SThM in three currently significant research topics. First, in thermal conductivity contrast studies of graphene monolayers deposited on different substrates, SThM proves itself a reliable technique to clarify the intriguing thermal properties of graphene, which is considered an important contributor to improve the performance of downscaled devices and materials. Second, SThM's ability to perform sub-surface imaging is highlighted by thermal conductivity contrast analysis of polymeric composites. Finally, an approach to induce and study local structural transitions in ferromagnetic shape memory alloy Ni-Mn-Ga thin films using localized nano-thermal analysis is presented.

Physical aging of glassy perfluoropolymers in thin film composite membranes. Part II. Glass transition temperature and the free volume model

Thin film composite (TFC) membranes for gas separation often comprise a thin selective layer of a glassy polymer, which, however, suffers from physical aging, i.e., gas permeance decreases with time. This study aims to provide a mechanistic understanding of the effect of physical aging on permeance reduction in TFC membranes. The Part I study reports gas permeances in two-layer TFC membranes comprising perfluoropolymers of Teflon® AF or Hyflon® AD with thicknesses of 50–400nm. In this Part II study, apparent glass transition temperature (Tg) of thin selective layers was determined in situ over time using a nano-thermal analysis (nano-TA). Physical aging decreases gas permeances and increases apparent Tg, and the rate of changes is more significant for thinner selective layers. For example, N2 permeance decreases from 1000 gpu to 550 gpu while apparent Tg increases from 160°C to 172°C after aging for 2000h in a membrane with 100-nm-thick Teflon AF1600. The measured Tg values are used to derive polymer fractional free volume and physical aging rate. A simplified free volume model is used to successfully correlate the gas permeance reduction with Tg increase during physical aging. Polymers with good stability of permeability should have low physical aging rate and high fractional free volume.

Space-resolved thermal properties of thermoplastics reinforced with carbon nanotubes

Composites comprising biobased poly(lactic acid) (PLA) and polyethylene (Bio-PE) were reinforced with multi-walled carbon nanotubes (MWCNTs). These nanocomposites were analyzed using space-resolved thermal analysis (TA) integrated with atomic force microscopy. The deflection temperature, which indicates thermal-induced expansion and thermal transitions of the composite, was monitored by nanoscale TA (nanoTA) utilizing the displacement of a cantilever in contact with the material. Results were compared to bulk electrical, mechanical and thermal properties. Electrical conductivity was detected at lower MWCNT loadings for PLA than for Bio-PE (at 2.5 vs. 5 mass%). Maximal electrical conductivity of 27 S m−1 for PLA and 0.7 S m−1 for Bio-PE-based samples was reached at 10 mass% MWCNT loading. Tensile behavior combined with thermogravimetric analysis indicated strong MWCNT–Bio-PE interactions, in contrast to PLA. The glass transition and melting temperature measured by differential scanning calorimetry (DSC) were not changed by the increase in MWCNT loading. Increased deflection temperature was registered by bulk heat deflection measurements on Bio-PE, but not for PLA. The thermal transitions obtained by nanoTA at the nanoscale were in the same temperature range as the first transitions observed upon temperature ramp in DSC (e.g., glass transition and melt temperatures of PLA and Bio-PE, respectively). Remarkably, thermal expansion was detected by nanoTA for PLA- and Bio-PE-based composites below electrical percolation threshold as well as an increase in PLA softening temperature. Space-resolved nanothermal analysis revealed thermal phenomena that are otherwise overlooked when bulk methods are applied.

Topographical and Chemical Imaging of a Phase Separated Polymer Using a Combined Atomic Force Microscopy/Infrared Spectroscopy/Mass Spectrometry Platform.

In this paper, the use of a hybrid atomic force microscopy/infrared spectroscopy/mass spectrometry imaging platform was demonstrated for the acquisition and correlation of nanoscale sample surface topography and chemical images based on infrared spectroscopy and mass spectrometry. The infrared chemical imaging component of the system utilized photothermal expansion of the sample at the tip of the atomic force microscopy probe recorded at infrared wave numbers specific to the different surface constituents. The mass spectrometry-based chemical imaging component of the system utilized nanothermal analysis probes for thermolytic surface sampling followed by atmospheric pressure chemical ionization of the gas phase species produced with subsequent mass analysis. The basic instrumental setup, operation, and image correlation procedures are discussed, and the multimodal imaging capability and utility are demonstrated using a phase separated poly(2-vinylpyridine)/poly(methyl methacrylate) polymer thin film. The topography and both the infrared and mass spectral chemical images showed that the valley regions of the thin film surface were comprised primarily of poly(2-vinylpyridine) and hill or plateau regions were primarily poly(methyl methacrylate). The spatial resolution of the mass spectral chemical images was estimated to be 1.6 μm based on the ability to distinguish surface features in those images that were also observed in the topography and infrared images of the same surface.

Heat-resistant organic molecular layer as a joint interface for metal reduction on plastics surfaces

Heat-resistant organic molecular layers have been fabricated by triazine-based silane coupling agent for metal reduction on plastic surfaces using adsorption method. These molecular layers were used as an interfacial layer between polyamide (PA6) and metal solution to reduce Ag+ ion to Ag0. The interfacial behaviors of triazine molecular layer at the interfaces between PA6 and Ag solution were investigated using quartz crystal microbalance (QCM). The kinetics of molecular adsorption on PA6 was investigated by using triazine-based silane coupling agent solutions at different pH and concentration. X-ray photoelectron spectroscopy (XPS), atomic force microscope (AFM), and local nano thermal analysis were employed to characterize the surfaces and interfaces. The nano thermal analysis results show that molecular layers of triazine-based silane coupling agent greatly improved heat resistance of PA6 resin from 170°C up to 230°C. This research developed an in-depth insight for molecular behaviors of triazine-based silane coupling agent at the PA6 and Ag solution interfaces and should be of significant value for interfacial research between plastics and metal solution in plating industry.

Linking atomic force microscopy with nanothermal analysis to assess microspatial distribution of material characteristics in young soils

AbstractCoupling of atomic force microscopy (AFM) with nanothermal analysis (nTA) has the potential to assess material characteristics in soils on the lower µm‐scale, but has been shown to require additional characteristics for clear distinction of materials. The objective of this study was to evaluate to which extent the combination of AFM‐nTA with AFM adhesion force analysis and structural features allows distinction of organic materials in soils. Using soil samples from a chronosequence from the Damma Glacier forefield, Switzerland, as example, we tested a grid analysis approach for assessing distribution of adhesion forces and nanothermal characteristics. This approach was compared with an approach involving pre‐selection of structural features of interest via morphological criteria. Only three types of nanothermograms were distinguished in the soil samples based on different thermal expansion‐compression characteristics and phase transition temperatures. Combined evaluation of nanothermal characteristics, adhesion forces and morphological characteristics allowed distinction of a larger set of materials than using nanothermal analysis, adhesion force distribution or morphological characteristics separately. Part of the analyzed features showed a combination of characteristics similar to that of fresh bacterial cells which we analyzed as a potential reference material. Their stronger occurrence in the regions of interest of older samples than in those of younger samples may underline their relevance in soil development. Achieving the long‐term objective of identification of materials still requires more information on reference materials, understanding the impact of mixed layering of materials on thermal profiles and the assessment of variability of the characteristics within and between different material groups.

Miscibility of Itraconazole-Hydroxypropyl Methylcellulose Blends: Insights with High Resolution Analytical Methodologies.

Drug-polymer miscibility is considered to be a prerequisite to achieve an optimally performing amorphous solid dispersion (ASD). Unfortunately, it can be challenging to evaluate drug-polymer miscibility experimentally. The aim of this study was to investigate the miscibility of ASDs of itraconazole (ITZ) and hydroxypropyl methylcellulose (HPMC) using a variety of analytical approaches. The phase behavior of ITZ-HPMC films prepared by solvent evaporation was studied before and after heating. Conventional methodology for miscibility determination, that is, differential scanning calorimetry (DSC), was used in conjunction with emerging analytical techniques, such as fluorescence spectroscopy, fluorescence imaging, and atomic force microscopy coupled with nanoscale infrared spectroscopy and nanothermal analysis (AFM-nanoIR-nanoTA). DSC results showed a single glass transition event for systems with 10% to 50% drug loading, suggesting that the ASDs were miscible, whereas phase separation was observed for all of the films based on the other techniques. The AFM-coupled techniques indicated that the phase separation occurred at the submicron scale. When the films were heated, it was observed that the ASD components underwent mixing. The results provide new insights into the phase behavior of itraconazole-HPMC dispersions and suggest that the emerging analytical techniques discussed herein are promising for the characterization of miscibility and microstructure in drug-polymer systems. The observed differences in the phase behavior in films prepared by solvent evaporation before and after heating also have implications for processing routes and suggest that spray drying/solvent evaporation and hot melt extrusion/melt mixing can result in ASDs with varying extent of miscibility between the drug and the polymer.