Semi-batch reactions offer several advantages over traditional batch reactions, such as greater selectivity of products, gradual addition of reactants for better process control, and the ability to isolate product as it is formed.

Polymerizations are often done in semi-batch mode because it offers the ability to carefully control the composition of the product in order to create high-performance materials with fine-tuned custom properties.

However, one significant challenge of semi-batch reactions is that the concentrations of the reactants constantly change, in both relative and absolute senses. If uncontrolled, this variation in the concentrations of reactants can easily result in unwanted properties in the product. So, this reaction mode requires continuous real-time monitoring of the concentrations of the reactants. Simply adding the reactants in the correct ratios is insufficient.

Additionally, batch-to-batch consistency is essential for high-performance materials with finely tailored properties. In many manufacturing plants, the same process equipment must be capable of producing a wide variety of high-performance materials, so the process-control method must be both precise and flexible.

Raman spectroscopy offers several advantages for real-time process monitoring of semi-batch polymerizations. It can identify bands specific to particular functional groups, such as the vinyl and alkyl moieties common to polymerization monomers, and it offers both easy sample interfacing and fiber optic coupling of the probe to the base unit for flexible placement of the base unit relative to the process line.

In this experiment, a semi-batch polymerization reaction was carried out using three proprietary monomers, designated monomers A, B, and C. A schematic of the system is shown in Figure 1.

A Raman analyzer was used to deliver and collect 785 nm near-infrared radiation from a laser. A non-contact optic was used to perform the analysis through a pressure- and temperature-rated sapphire viewport in the wall of the reactor. Each sample acquisition consisted of 60 s of illumination of the reactor contents using 125 mW of laser radiation, followed by a 20 s pause. Five to seven data points from each monomer were used to generate quantitative Raman data for real-time process control.

In this reaction, a vinyl functional group in each of the three monomers changes to an alkyl group during the polymerization. Raman spectroscopy is sensitive to this, whereas traditional infrared spectroscopy is much less so. Chemometric modeling in this case was based on the Raman signal for the vinyl region in all monomers, the C–H wag in monomers A and B, and the lactone region in monomer C.

Raman spectroscopy was demonstrated to be a simple, accurate, and effective method of process analysis for the purpose of real-time monitoring and control of a semi-batch polymerization. Raman data were able to be used for real-time feedback control of the process to maintain ideal process conditions in a closed-loop reaction system and to produce a highly consistent product between batches, ensuring consistent quality of sensitive high-performance materials.

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Semi-batch reactions offer several advantages over traditional batch reactions, such as greater selectivity of products, gradual addition of reactants for better process control, and the ability to isolate product as it is formed. 

Monitoring and Control of a Semi-Batch  Polymerization with Raman Spectroscopy

In this application note, we study a nicotine patch to reveal the active pharmaceutical ingredient (API) as well as the polymer layers encapsulating it via confocal Raman microscopy.

A transdermal patch is a method of drug delivery through the skin into the bloodstream. The patch, shown in Figure 1(a), contains a drug that absorbs into the skin when attached, releasing a consistent and controlled amount of medication into the body. One of the most common uses for transdermal patches is to help combat nicotine addiction. Nicotine replacement therapy releases small amounts of nicotine throughout the day, without the additional harmful components of cigarettes.


An RMS1000 Raman microscope, equipped with a 785-nm laser, was used to measure a 3D Raman map of the transdermal nicotine patch. The nicotine patch was purchased from a pharmacy. The RMS1000 can acquire 3D Raman maps thanks to its confocal pinhole. The pinhole acts as a spatial filter in the axial (Z) direction by blocking the Raman scatter from above and below the focal plane and is essential for 3D mapping. Without the pinhole, there is no axial spatial filtering, and Raman scatter from the entire axial volume of the sample would be collected with no axial resolution.

The transdermal patch analyzed contained nicotine as the active ingredient surrounded by polymers. By carrying out a Raman 3D map we can visualize the different material layers present in patch, Figure 1(b). The 3D Raman map, shown in Figure 1(c), reveals that the patch contains 6 layers; the spectrum of each layer can be extracted and analyzed for identification. The outer layers of the patch, layers 1 and 6, shown in red, can be identified as poly(ethylene terephthalate) (PET) using the KnowItAll Raman Database. The 3D map is colored based on peaks specific to the material identified; for example for the layers of PET the peak at 1293 cm-1 was selected.


Layer 2 can be identified as PET/polyisobutylene, and layers 3 and 5, which surround the API, were determined to be polyethylene (PE). Finally, in the middle of the polymers is a thick layer of the API, nicotine, embedded in polymer reservoir (ethylene).

This application note demonstrated how the RMS1000 Raman microscope can be used for 3D mapping of a transdermal patch. The API, in this case nicotine, can be visualized as can the surrounding polymers responsible for protecting and ensuring API release. In this way confocal Raman microscopy is a useful technique for pharmaceutical laboratories to conduct quality control on their products, ensuring they have been produced correctly without contaminants, and help monitor the stability of adhesive layers

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Analysis of Transdermal Patch Layers  via Confocal Raman MicroscopyAnalysis of Transdermal Patch Layers  via Confocal Raman Microscopy

Sample digestion with the Milestone ultraWAVE takes around one hour including cool-down time.

The digestion of heavy crude oil samples prior to trace metal analysis by inductively coupled plasma–optical emission spectrometry (ICP-OES) has traditionally been performed by dry ashing in a muffle furnace. The oil is burned off over a burner prior to ashing in a muffle furnace. The process takes several hours and requires continual operator attention. Loss of sample and cross contamination can occur due to foaming and splashing. Volatile analytes are lost and cannot be measured. While closed-vessel microwave digestion offers several advantages over dry ashing, a maximum sample weight of ~0.2 g is considered too small for representative analysis. Single Reaction Chamber (SRC) microwave digestion, however, can digest higher sample weights, enabling microwave digestion to be applied to the sample preparation of heavy oils.

Milestone’s ultraWAVE SRC benchtop digestion system can digest up to 5 heavy oil samples at a time, at up to 300 oC and 199 bar pressure. Its high temperature and pressure capability enables the complete digestion of heavy oils, which makes sample introduction to the ICP-OES instrument easier and more routine. The ultraWAVE can digest 0.75 g of heavy oil (up to 5 samples simultaneously)—more than 3x higher sample weight than traditional closed-vessel digestion systems. Samples are simply digested in disposable glass vials; unlike dry ashing, there are no crucibles to clean.


The system is fully automated: the sample is weighed into a vial, and 10 mL HNO

 is added and loaded into the ultraWAVE. Its walk away operation means labor costs are significantly reduced over dry ashing. The reaction chamber is pre-pressurized with N2, which eliminates cross contamination of loss of volatiles.

Sample digestion with the Milestone ultraWAVE takes around one hour including cool-down time. The digestion of heavy oils in the amounts described was sufficient for the application, with increased sample throughput and reduced labor costs compared to dry ashing. Risk of contamination and loss of volatile elements is eliminated, and the superior digestion quality allows for easier analysis by ICP-OES.

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Sample Preparation of Heavy Crude Oil v2

This application note describes a correlative Raman–scanning electron microscope (SEM) investigation of a lithium-ion battery cathode before and after hundreds of charge cycles. The technique provides an exceptionally detailed chemical and structural analysis of degradation processes on the nanoscale.

Lithium-ion battery technology is the key enabler of the current revolution in transportation and energy. Improving the performance of Li-ion cells is among the highest priorities in contemporary research and a detailed understanding of how charging cycles affect their electrodes is crucial. In the following, we use correlative Raman imaging and scanning electron (RISE) microscopy to visualize changes in molecular composition and the formation of grain fractures.

The investigated lithium nickel manganese cobalt oxide (Li-NMC) cell was subjected to 400 charge cycles, leading to a 40% loss of capacity. Changes in performance are often a result of inhomogeneous degradation in battery electrodes. Local deterioration of microstructure in a Li-NMC battery electrode subjected to fast charging and long-term cycling was studied using a WITec/Tescan RISE microscopy system. This instrument allows samples to be automatically transferred from one measuring position to the other within a common vacuum chamber, enabling the correlation of Raman and SEM data, streamlining the experimental workflow and drastically improving ease of use. Cross sections were created for imaging with the integrated focused ion beam.

Cross section of an uncycled cathode (a). Particles embedded in amorphous carbon (red) contain uniformly distributed lithium nickel cobalt manganese oxide (blue). Cross section of a cycled and rapidly charged cathode (b). Compared to the uncycled cathode, the particles appear inhomogeneous. Changes in peak positions and peak width indicate variance of Li-NMC composition. One particle (bottom left) shows a completely different composition, including a spectrum (blue) identical to the Li-NMC spectrum of the uncycled electrode. RISE image of a particle of a cycled cathode that reveals changes in Li-NMC composition and substantial structural degradation (c).

In the RISE image of the uncycled cathode (a) its particles appear to consist of uniform lithium nickel cobalt manganese oxide. Rapid cycling induced significant changes in lithiation of the particles as indicated by changes in the Raman spectra (green) (b). The Raman data reveals local variations even at the single-particle level. In b, one particle is characterized by two spectra, one of which corresponds to the Li-NMC spectrum of the native electrode, indicating that this particle might not have participated in the cycling process. Lorentzian fitting of the spectral peak positions of another particle also shows a high level of inhomogeneity and degradation in the form of cracks (c).

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This application note describes a correlative Raman–scanning electron microscope (SEM) investigation of a lithium-ion battery cathode before and after hundreds of charge cycles. The technique provides an exceptionally detailed chemical and structural analysis of degradation processes on the nanoscale.


Correlative Raman Imaging for Battery Research

Using an automated FT-IR reflection sampling accessory, the surface of a polymer-coated aluminum film was analyzed. Spectral results were used to investigate chemical uniformity across the sample area.

Having the capability to map several spots of a solid sample via FT-IR analysis is useful to investigate uniformity of new chemical formulations and effects of processing parameters. By incorporating automated sampling, more consistent and reliable results may be obtained because the sample is not removed from the accessory between measurements for area analysis. Additionally, automation improves productivity by freeing time to accomplish other tasks and reducing the possibility of user error.

PIKE Technologies’ XY Autosampler diffuse/specular reflection accessory was used to automate mid infrared spectral mapping of a polymer-coated aluminum foil surface.


The XY Autosampler fits into the sample compartment of most commercial FT-IR instruments. Its precision XY stage accepts a sample plate with a microtiter plate footprint (85 × 128 mm). Sixteen scans were co-added using a resolution of 4 cm

For this investigation, a custom clamshell sampling plate ensured foil flatness during the measurements. Eighteen points were analyzed on the sample, which was 65 x 128 mm. Data presented were baseline corrected.

The optical layout of the XY Autosampler is based upon a precision ellipsoidal collection mirror that condenses the beam onto the sample with a power of approximately 3x. A typical 9-mm beam size results in roughly a 3-mm spot on the sample. The beam strikes the sample at a 30° angle of incidence.

Specular reflection sampling in the mid infrared is a useful technique for measuring thin coatings on reflective substrates and analyzing of bulk materials. In the case of a relatively thin film on a reflective substrate, like the polymer-coated foil sample measured here, the specular reflection experiment may be thought of as a “double-pass transmission” measurement because the beam passes through the coating, reflects off the substrate, and once again passes through the coating.


For samples with coating thickness in micrometers, results are very sensitive when using specular reflection accessories with angles of incidence at near normal (10

Typically, the resulting IR spectrum of a coating on a reflective substrate collected via specular reflection sampling is easily searchable in a spectral database library because it appears similar to a transmission spectrum. For the spectra collected here, a high-quality database match was found against a styrene-acrylic polymer coating. This match quality was consistent across the macro-mapping area.

A subset of the data is presented here for presentation clarity (Figure 1). Upon a closer inspection of the fingerprint region, there are some small differences as a function of position (upper versus lower area of the sample foil) in the spectral band shapes and band ratios at 1180, 1160, 1120, and 1100 cm

. This would suggest that either the chemical composition of the coating was slightly different in these areas or that processing conditions could be responsible.

In addition to measuring individual samples by diffuse reflection, the XY Autosampler also offers a versatile platform for mapping the surface of a one-piece solid by specular/diffuse reflection to evaluate chemical uniformity across a sample.

Automated Macro-Mapping a  Coating via Reflection Sampling

Thermotropic liquid crystal polymers (TLCP) are injection molded and undergo spontaneous ordering while flowing through the mold. The degree of orientation depends on the distance from the injection point, the depth into the material, and other factors. Since the orientation changes the physical properties of the product, it is important to control the degree of anisotropy. This application note demonstrates using ATR to examine the changes in surface orientation as a function of the distance from the injection point or gate.

Samples of the TLCP were cut down the centerline of the mold, 15 mm apart, and cleaned using Alconox™ in an ultrasonic bath to remove surface contaminants.

Infrared spectra were collected on an FT-IR spectrometer equipped with the Seagull variable angle reflection accessory with its ATR rotator (Figure 1), ZnSe ATR crystal, and KRS-5 wire grid polarizer set to s-polarization. The Seagull was used at a 55° incident angle. The spectrometer collected data at 4 cm

 resolution, signal averaged over 32 scans.

A background was collected from the clean ATR crystal. Each sample was oriented on the ATR rotator so its cut edges corresponded to the 0° and 90° setting. Sample spectra were collected at 0°, 45°, and 90°.

Figure 2 shows the data collected from the sample farthest (60 mm) from the gate. The band at 1500 cm

 shows the most striking change. It is much weaker at the 0° position than at the 90° position. This band is due to the skeletal vibration of the benzene and naphthalene rings in the TLCP, which are oriented relative to the polymer chain axes. The band at 1730 cm

, on the other hand, shows very little change.

Pirnia and Sung (1) developed a methodology using the dichroic ratios to calculate the orientation function for polymers and determined that the orientation was the highest on the surface, well beyond the gate. The spectra measured here were processed using the methods developed by Pirnia et al. The orientation function (Figure 3) shows the surfaces of the samples become more oriented further from the gate, comparable to the 0.77–0.88 reported.

The orientation of injection-molded polymers can be analyzed by ATR dichromism. Using a variable angle ATR accessory like the Seagull and its ATR rotator, the incident angle can be optimized for a given sample and the orientation axis can be determined.

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This application note demonstrates using ATR to examine the changes in surface orientation as a function of the distance from the injection point or gate.


The Application Notebook 02-01-2022

Monitoring and Control of a Semi-Batch Polymerization with Raman Spectroscopy

Analysis of Transdermal Patch Layers via Confocal Raman MicroscopyAnalysis of Transdermal Patch Layers via Confocal Raman Microscopy

Sample Preparation of Heavy Crude Oil v2

Correlative Raman Imaging for Battery Research

Automated Macro-Mapping a Coating via Reflection Sampling

Characterization of Surface Orientation of a Molded Polymer by FTIR-ATR