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At the JASIS 2024 "New Technology Presentation," we jointly presented with Tech Analysis Co., Ltd. on the topic "Case Study of Analyzing Moisture-Proof Packaging of Pharmaceuticals Using Raman Spectroscopy." We introduced a case where model formulations packaged in a humidity-controlled environment were set up, and the physical property changes of the model formulations were analyzed and evaluated in real-time using Raman spectroscopy.

• Raman Spectrophotometer

• Accurate and reproducible measurements are possible • Disposable probes for batch use in case of high costs • Can be sterilized by autoclave, SIP, EtO, or gamma radiation • Compatible with standard Pg13.5 ports • Specifications such as probe length can be customized

• Raman Spectrophotometer

In the pharmaceutical industry, there are active pharmaceutical ingredients with multiple crystal structures, which are said to influence various physicochemical properties such as solubility, depending on the intellectual property rights of the drug and polymorphism. Furthermore, it is known to affect the bioavailability of drugs, making it one of the most important tasks for originator, generic, and pharmaceutical companies, where crystal forms and impurities are often selected as Critical Quality Attributes (CQA). In industrial crystallization, the goal is to separate impurities and control the crystal structure and particle size distribution of the product crystals; however, many phenomena remain unclear despite the operation and examination of inline analytical techniques such as FBRM, FT-IR, near-infrared, and Raman spectroscopy. Raman spectroscopy is known to have a distinct advantage over other inline analytical techniques in that it can quantitatively monitor crystal transitions. This paper presents the practical applicability and usefulness of low-frequency Raman spectroscopy by equipping a Raman spectrometer with a low-frequency Raman module, which has recently been commercialized and enables the measurement of low-frequency Raman spectra, to conduct real-time observation of crystal transitions using CBZIII form as a model formulation.

• Spectroscopic Analysis Equipment

The stability testing guidelines state that stability tests, which determine the shelf life of formulations and storage conditions for pharmaceuticals under various environmental factors such as temperature, humidity, and light, are necessary tests for drug approval applications. Therefore, using Raman spectroscopy, which allows for non-contact measurements and is used for identifying polymorphs similar to powder X-ray diffraction, we focused on one of the environmental factors, "humidity," and analyzed and evaluated the crystal transition from hydrate to anhydrous form of caffeine, a model formulation, under humidity conditions using Raman spectra. This demonstrated that Raman spectroscopy is effective for observing the crystal forms of active pharmaceutical ingredients under humid conditions.

• Analytical Equipment and Devices
• Spectroscopic Analysis Equipment

In the analysis of pharmaceutical tablets and capsules, it can be difficult to easily obtain information about the physical state and components of the active pharmaceutical ingredient inside the tablet or capsule due to interference from the tablet coating or capsule material. In this study, commercially available coated drugs and capsules filled with active pharmaceutical ingredients of different raw materials were used as model formulations. By employing forward scattering (transmission) Raman spectroscopy, we demonstrate that it is possible to reduce surface interference caused by the coating of the tablet or capsule and analyze and evaluate the components.

• Spectroscopic Analysis Equipment

A newly developed forward scattering (transmission) unit was connected to an existing Raman spectrometer, and using model formulations, the practicality and usefulness of the forward scattering unit were demonstrated. The forward scattering unit (from Horiba, Kyoto) is connected to the ALL-IN-ONE Raman spectrometer (Marqmetrix, Seattle, USA) via fiber optics. The measurement conditions included a spectral resolution of 6 cm-1, an excitation laser wavelength of 785 nm, a single accumulation, and an exposure time of 3 seconds. The sample is simply placed on the standard sample stage, eliminating the need for sample positioning or height adjustments. The company also provides holders compatible with different dosage forms, including glass containers and powdered samples, in addition to the tablets and capsules used in this study. It should be noted that while this experiment was conducted by connecting the forward scattering unit to the Marqmetrix ALL-IN-ONE for sample measurement, the unit can be connected and used with any Raman spectrometer that has fiber connection ports for the excitation laser and Raman scattered light (for example, Raman spectrometers from Wasatch Photonics).

• Spectroscopic Analysis Equipment

In May 2014, Japan's membership in PIC/S was approved, leading to the consideration of operational verification tests for all pharmaceutical raw materials used in formulations as required by PIC/S. Furthermore, in 2019, the Raman spectral measurement method was included in the seventeenth revision of the Japanese Pharmacopoeia, second supplement, increasing expectations for Raman spectroscopy. This analytical method has become widely used, ranging from the evaluation of the crystal forms of active pharmaceutical ingredients and research and development of crystallization reactions to quality control measures such as the assessment of content uniformity of active ingredients in formulations and raw material acceptance testing. As its use has expanded, issues have emerged, such as the spectral shifts of fluorescent substances like cellulose and herbal raw materials. In recent years, cases of counterfeit pharmaceuticals have come to light, raising questions about the scientific validation of testing methods and the minimization of human error in pharmaceutical quality control. Therefore, using crystalline cellulose with fluorescent properties as a model raw material, we report the results of constructing a discrimination model using a portable Raman spectrometer and scientifically validating the variability of the discrimination model and test results.

• Spectroscopic Analysis Equipment

Probe-type Raman spectrometer. The excitation laser wavelengths can be selected from 532, 633, 785, 830, and 1064 nm. The probe size can be chosen according to the sample's state and measurement purpose. Equipped with a low-frequency Raman module from Coherent, it enables highly accurate and sensitive analysis of crystal polymorphs and cocrystals.

• Analytical Equipment and Devices

By using this sample room, you can easily set up tablet and liquid samples in containers, and you can adjust the laser focus and measurement location in real-time while in a light-shielded state using the probe position adjustment knob. By using the coarse and fine adjustment knobs, you can quickly and accurately move the probe and take measurements.

• Other physicochemical equipment

In 2019, Raman spectroscopy was included in the seventeenth revision of the Japanese Pharmacopoeia as "Raman Spectral Measurement Method." This spectroscopy is known to be effective for the quantitative evaluation of active ingredients in a non-contact and non-destructive manner. In recent years, in addition to reflection methods, there have been numerous reports indicating its effectiveness in transmission methods and in evaluating the polymorphism of active ingredients. While there are reports suggesting that near-infrared spectroscopy is effective for process management, particularly in the quantification of active ingredients, there are also reports indicating that it is difficult to quantitatively evaluate active ingredients that are unevenly dispersed. Therefore, we conducted an evaluation and examination of the practicality of a wide-area Raman probe capable of collecting Raman scattered light from a broad range of areas for the quantitative evaluation of multiple crystal forms of active ingredients.

• Spectroscopic Analysis Equipment

This is an accessory for Raman microscopes that can be easily attached and detached from existing Raman microscopes. It allows for non-contact and non-destructive analysis without the need for sample pretreatment, enabling the measurement of components in organic and inorganic materials, and is suitable for evaluating the crystal forms of trace and minute active pharmaceutical ingredients. It is also possible to assess the dispersion state of components such as active ingredients and excipients that make up tablets and mixed powders through chemical imaging.

• Spectroscopic Analysis Equipment

The TH-RamanProbe system consists of a control unit made up of a laser light source and power supply, and a probe that irradiates the sample with laser light and receives Raman scattered light from the sample. A special notch filter that cuts the excitation laser is built into the probe section. The probe, equipped with a sapphire lens that has high throughput, is available in two types: short focus and long focus, depending on the measurement purpose.

• Analytical Equipment and Devices

The wide-area probe has an effective aperture diameter of 8mm, which is wider than that of a standard probe, allowing for the broad collection of Raman scattered light from samples. Additionally, the working distance (focal length) is 3cm, enabling non-contact measurements in the biopharmaceutical, pharmaceutical, and food sectors, thereby reducing the risk of cross-contamination and foreign matter intrusion during measurement.

• Raman Spectrophotometer
• Other photoanalytical instruments

We handle Raman probes for low wavenumber region measurements manufactured by Coherent (formerly Ondax). Peaks appear in the fingerprint region, which is called 200 to 1800 cm-1, representing the molecular structure of substances, including functional groups, geometric isomers, conformations, hydrogen bonding, and the state of chemical structures. The region below 200 cm-1 is referred to as the low wavenumber region. Peaks that represent structural information, such as the crystal form of compounds, appear, and it is known that in the low wavenumber region, the intensity of Raman scattered light is stronger than that in the fingerprint region. 【Applications of THz-Raman(R) Probe】 - Evaluation of physical properties such as polymorphism of pharmaceutical active ingredients - Evaluation of content uniformity of active ingredients in formulations - Crystal transformation of active ingredients - Co-crystal screening - Evaluation of polymorphism in fats and oils *For more details, please download the PDF or feel free to contact us.

• Analytical Equipment and Devices

We offer the Marqmetrix "Raman Spectrometer (ALL IN ONE)," which is very compact and can be easily moved to measurement locations. The built-in laser has an excitation wavelength of 785nm and an adjustable output ranging from 5 to 450mW. The integrated computer includes 128GB of storage capacity, as well as connectors for USB and internet connectivity. 【Features and Application Areas】 ■ A standard 1/2 inch probe is included ■ Probes of different diameters, such as 1/4 inch and 1/8 inch, can be purchased as options depending on the size and quantity of the reaction vessel or measurement target ■ Quantification of glucose and lactate concentrations in solutions ■ Non-contact measurement of tablets and powders ■ Real-time monitoring of mixing and granulation *For more details, please download the PDF or feel free to contact us.

• Analytical Equipment and Devices