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Pharmaceutical quality control: using thermal stage microscopy.

Polarized light microscopes are now optimized to offer extreme resolution of pharmaceutical products. When coupled with the latest thermal stages, pharmaceutical scientists are able to determine particle size, locate contaminants and determine lyophilization parameters quickly and accurately.


Thermal microscopy requires adding a heating/cooling stage to a microscope, usually in conjunction with other analytical methods such as differential scanning calorimetry, gravimetric analysis, IR, Raman, humidity studies and X-ray diffraction. Using a thermal stage with a polarized light microscope is the preferred method because it offers the scientist the advantage of directly observing phase transitions. Also, being able to insert a full-wave plate is critical, as some of the solid-state transitions can only be seen in polarized light.

Lower-powered microscope objectives can be of moderate quality, such as achromats, as lower magnifications are typically used. For higher magnification (200X and 500X), higher quality objectives are used, such as long-working distance fluorites. Most thermal stages have a required working distance, from the top of the lid window down to the sample, and is usually anywhere from 4.5mm to 6mm. Long-working distance objectives meet this requirement and also protect the optics from the relatively high temperatures (as high as 400[degrees]C) typically required.


Nikon's Eclipse polarizing microscopes are known for their ability to produce brighter, clearer, and higher contrast images. The LV100 POL (figure 1), available in diascopic and episcopic microscope illumination types, offers a completely reengineered base for even easier operation. It also features an exclusive high-intensity halogen light source, which delivers brighter images, lower power consumption and less heat generation--thereby reducing the chance of heat-induced focus drift. The high intensity 50W halogen light source incorporates a fly-eye lens design that outputs more light than a 100W lamp. The greater brightness is achieved by optimizing the lamp filament size and optically expanding the size of the light source within the pupil illumination fulfillment.

The reversed-type quadruple nosepiece of Nikon's Eclipse provides more space at the front of the stage to make handling specimen slides fast and easy. The increased objective lengths and longer working distances provide more space around the nosepiece to exchange specimens or oil the slide. The stage is large-sized, pre-adjusted and click-stops in 45[degrees] increments, making it extremely accurate and easy to rotate. Because the stage is designed to be supported from the bottom of the microscope near the optical axis and incorporates steel cross roller guides, it is twice as stable and durable as conventional stages.


The ability to resolve your specimen under the microscope is of critical importance and leads to accurate particle sizing as well as determination of contaminants. Essentially, the greater the numerical aperture, the greater the resolving power, Nikon's CFI 60 (chromatic aberration-free infinity) system, the infinity optics system, is designed for such advanced I needs. Designed to meet the most advanced imaging requirements, the CFI 60 objectives represent the perfection of Nikon's optical technology. A 60mm parfocal distance and a much larger barrel diameter allows these objectives to offer increased brightness and the highest possible combination of working distance and numerical aperture (for light-gathering ability). Designed to correct lateral and axial chromatic aberrations over the entire field of view, these objectives produce images that are crisp, flat and clear with high contrast and high resolution

Within the realm of formulation, The LV100N research polarizing microscope, the multi-purpose AZ100 Multizoom upright zoom microscope, covering a wide range of magnifications, and Nikon's top of the range high zoom SMZ25 and SMZ18 stereomicroscopes, in particular, can be used to study a wide range of properties. In tablets, capsules, creams, pastes and gels, the way in which a drug compound is combined with excipients can be critical to the performance of the active ingredient. The formulation must also be fully characterized to ensure product efficacy and patient safety and lack of susceptibility to microbial contamination. This wide range of Nikon microscopes, when coupled with the wide range of Linkam thermal stage technical capabilities, offers the end-user a full arsenal of thermal microscopy opportunities.


Of critical importance is the configuration of the pharmaceutical freeze-dry microscope, necessary to determine lyophilization parameters. Necessary components for the standard freeze-dry microscopy lab include a Nikon LV100 polarized-light microscope, a liquid-nitrogen-cooled thermal stage--Linkam FDCS196 (figure 2), a vacuum pump and an imaging system. The optimal polarized-light microscope system includes a strong light source, a Bertrand lens, proper working distance objectives, and polarizer/analyzer. Polarized-light microscopy allows researchers to visualize critical temperature. It also allows them to determine if their sample is crystalline or partially crystalline based on the birefringence of anisotropic crystals within the frozen matrix.

An ideal thermal stage for lyophilization studies possesses these key capabilities:

* Temperature range of -196[degrees]C to 125[degrees]C

* Temperature stability less than 0.1[degrees]C

* Temperature accuracy of 0.01[degrees]C

* X-Y sample manipulation functionality

* Vacuum tight sample chamber to 10-3 mbar

* Silver heating block (ensuring high thermal conductivity)

With these components, formulators can determine the critical temperature before lyophilization begins, saving time and money associated with trial and error freeze dry attempts. Formulators can predict how their products will react under different thermal conditions and pinpoint the critical temperature so they can get their formulations right the first time.


Nikon's CFI 60 objectives offer the longest working distances and highest numerical apertures. These critical features lead to superior optical performance with edge-to-edge flat images. When coupled with Linkam thermal stages, an unrivaled, high precision thermal microscope system offers the pharmaceutical industry the strongest range of imaging possibilities.
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Title Annotation:QUALITY
Author:McGinn, Jeff
Publication:Pharmaceutical Processing
Date:Apr 1, 2015
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