Delphian provided seminars related to the use of the fiber optic technology for dissolution testing and demonstrated the Rainbow Dynamic Dissolution Monitor® to numerous parties across the pharmaceutical industry.
Our audience included people who did not have UV experience at all, some experience, as well as those who have good experience.
We experienced a good number of technical questions irrespective
of the level of experience of our audience. We have listed below some
frequently asked questions and have provided answers to help you better understand the Rainbow technology.
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I have heard that the Rainbow Dynamic Dissolution Monitor® can cause solarization of the fiber-optic cables, effectively reducing the minimum frequency at which it can measure. Is this true? |
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All fiber optic cables carrying low-UV light are subject to solarization. The more powerful the light at low UV wavelength and the more often the fiber is exposed to the light, the sooner it will become solarized. Solarization causes the fiber to go 'blind' below 220 nm. Since severe background signals from excipients are encountered below 230 nm, the Rainbow is specified to operate in the 235 nm to 390 nm range.
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The Rainbow measures through a wavelength range (235 - 390 nm) during the dissolution test. Isn’t it better to focus the scan at a specified wavelength for more qualified data? |
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The Rainbow uses a diode array to simultaneously measure absorption at 0.8 nm intervals over its entire operating range of wavelengths. This technique allows any wavelength to be chosen before or after the measurement has taken place. This is not possible if a single wavelength is chosen up front. Having the entire spectra allows for a greater wealth of data, enables thorough analysis after the data has been collected, and provides a better means of correcting for turbidity. |
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I have heard that installing UV probes in the hollow paddle shaft requires a complex retrofit of the dissolution bath. Isn’t this prohibitively expensive? |
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The Rainbow UV probes work with just about every bath on the market. In some types of baths, the UV probes may be situated in the hollow paddle shaft, in others the probes may be placed at the USP sampling point. Also, the probes in some bath types may be mounted in a manifold that can be raised almost out of the dissolution medium and lowered just before measurements are taken.
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The Rainbow UV dip probes have an adjustable path opening in which to read the dissolution media. Is it possible for excipients to become lodged in this opening? |
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In choosing the path length, the possible effect of the excipient should be considered. While this scenario is possible, the hydrodynamic flow through the opening makes it unlikely that any particle will stay. The only situation in which this occurs is using a path length of 2mm or less. By employing a larger path length, this problem can be eliminated. |
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Since the Rainbow uses UV to measure dissolution, what happens when the solution becomes overly turbid? Can the Rainbow still “see” in such conditions? |
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As long as enough light can be transmitted through the path length for the spectrometer to remain within its linear range, the Rainbow will be able to take a reading. The Rainbow Dissolution SmartWare® contains a powerful second derivative baseline compensation (patent pending) that can eliminate many of the effects of turbidity. |
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Are your probes stable in low pH environments such as simulated gastric fluid? |
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Rainbow probes are built of high quality stainless steel and utilize quartz mirrors in the tips. This allows them to handle a wide variety of dissolution media without corrosion or degradation. In fact, every batch of probes Delphian receives are tested for 100 hours in 0.1 M HCl to assure quality. |
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How does the Rainbow Dynamic Dissolution Monitor®
system correct for the absorbance of excipients? |
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Nearly all pharmaceutical excipients absorb at wavelengths below 230 nm since they are non-aromatic. Most (about 80%) of pharmaceutical active ingredients contain an aromatic system that has a secondary absorbance peak at wavelengths longer than 250 nm.
Since the excipients are not aromatic, they do not interfere with measurements made above 250 nm. Any absorbance that is observed at wavelengths longer than 250 nm can be attributed to the active component or to scattering by the excipients. Even common colorants do not usually interfere. They may be insoluble, or when soluble, their absorbance occurs in the visible region. |
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How does the Rainbow correct for scattering? |
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Scattering causes an offset to all of the wavelengths in the spectrum. This offset is related to the wavelength being measured and the size of the particle. Scattering is not a true molecular absorbance, but is, instead, a “redirection” of the light by small particulate in the light path.
In pharmaceutical dosage forms, the particulate we are concerned with arise from film coatings, excipients, and gelatin capsules. The amount of scattering is very often variable depending on the actual dosage formulation. The potential interference can range from a slight, uniform (across all wavelengths) baseline offset, to a sloping offset due to severe turbidity (Tyndall scattering).
Rainbow SmartWare uses two types of calculation methods to correct for the scattering from disintegrating solid dosage formulations. These calculations are the baseline correction method and the second derivative method.
The baseline correction method uses two wavelengths to calculate the amount of drug present in solution. The first wavelength is the peak measurement, and the second wavelength is a baseline measurement, made at a region where the active compound does not absorb, but scattering occurs. The amount of active component is calculated by subtracting the baseline measurement from the peak measurement. This calculation will successfully correct for a non-sloping baseline offset (an offset where the interference is the same at the peak wavelength and the baseline measurement), observed during most dissolution experiments.
The second derivative calculation is useful for a more severe scattering interference. This method first calculates a second derivative of the raw absorbance spectrum. This removes any baseline offsets (as the baseline correction method does), and also removes any baseline slope. This is because the second derivative of a sloping line is zero.
Over the short wavelength range used by the Rainbow Monitor, the effect of Tyndall scattering is a sloping baseline, easily corrected by the second derivative method. The Delphian Technology patent-pending algorithm also increases the observed signal-to-noise ratio (S/N) significantly, when compared to a standard second derivative calculation.
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Is the Rainbow Monitor stable during a 24-hour dissolution test? |
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The Rainbow Monitor is very stable because there are no moving parts in the system. Once the Rainbow Monitor is set up, and passes system suitability, the system collects analytically sound data for at least two days without interruption. (Run times of 45 days have been studied.)
The Zeiss spectrometers used in the Rainbow Monitor are extremely stable. Its body is made of titanium, which has a very low coefficient of expansion. This provides unprecedented wavelength accuracy on the order of + 0.1 nm. The detector is a 256 element Hamamatsu photo diode array (PDA). Unlike lower cost charge coupled device (CCD) detectors, this PDA detector was specifically developed for absorbance measurements.
The high quality deuterium lamp is supplied by Cathodeon. The lamp is internally regulated to guarantee stability. The lamp use indicator allows for regular scheduled lamp changing.
Finally, the Rainbow SmartWare removes any long-term electronic drift. Even if large temperature fluctuations (unlikely in laboratory environment) or slight changes in lamp intensity occur, their effects are automatically corrected in real time by either the baseline correction method or the second derivative method.
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If a hydrodynamic effect is suspected, what can be done? |
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If a hydrodynamic effect is evident for a specific formulation, then there are two ways
to deal with it.
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Validate the apparatus as a whole. The hydrodynamic effect on drug release is reproducible. The release rate with the resident probe will be typically 2-3%
faster when compared with non-resident probes. Since this minor effect is consistent, it is automatically factored into the release specifications when a new
formulation is written. As long as the formulation is always tested using resident probes, the results will be reproducible.
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In a situation where the new method must be exactly matched to an existing method, use a sampling manifold to partially remove the probes from the vessels.
The sampling manifold raises and lowers probes in and out of the USP position. The Rainbow Monitor raises the probes to a point JUST beneath the surface
of the media between sampling measurements. It has been demonstrated that holding the probes in this partially submerged position imparts no significant
release offset onto USP calibrator tablets. The advantage of keeping the probes partially submerged over total removal, is that the probe tips remain in the media,
eliminating the possibility of air bubbles, or fouling due to drying, which may occur if the probes are removed from the media entirely.
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Can the Rainbow analyze a multicomponent formulation? |
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Although multicomponent formulations have been successfully analyzed in a few cases by UV/vis analysis, in general, the answer is no. Remember, this technique has the same
strengths - and lacks most of the weaknesses - of on-line UV detection.
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