Pharmaceutical raw materials may be fed into a mixing device, such as a blender, where the drug is mixed with other ingredients, generally non-pharmaceutically-active components known as excipients, in order to form a dosage form such as a tablet or capsule. During this process, the drug is mixed with suitable excipients such as dextrin, lactose, salt, polymers, celluloses, stearic acid, talc, or other inactive ingredients. The dosage unit can then be packaged as is, or it may be further modified into a more convenient form for administration to a patient, such as a capsule or tablet. A hopper may be used to feed the pharmaceutical raw material into the blender. A tableting or encapsulating machine may be used to form the capsule or tablet dosage form. Hoppers can also be used to feed the pharmaceutical raw material (which may be in the form of a granulate or dry blend) into a tableting/encapsulating machine.
When blending a product in a blender it is useful to know the homogeneity of the blended product in order to know when to end the blending process. Specifically, with regard to pharmaceutical products, it is important to be able to determine the homogeneity of the blended product with some precision in order to ensure that the proper dosage of the active drug is delivered to the patient and physical characteristics, such as dissolution, are consistent.
Vibrations that occur during the manufacturing process may cause stratification of the granules within the hopper prior to preparation of the dosage form. Stratification is localized areas of differing drug potencies, and may occur even though the composition within a localized area is itself homogeneous. Stratification may be related to varying particle size. A consequence of stratification may be a dosage form being prepared with an inaccurate dosage (e.g., a sub-potent or a super-potent product). Accordingly, the mixing of pharmaceutical compositions is a crucial step in processing an active drug into a dosage form.
Generally, the homogeneity of a pharmaceutical composition refers to the distribution of the active drug in the pharmaceutical composition, and the potency of a pharmaceutical composition refers to the amount of the active component in the pharmaceutical composition. Traditionally, the determination of the homogeneity and/or potency of a pharmaceutical mixture have been time consuming. In addition, traditional methods measure the homogeneity and potency only of the active component within a pharmaceutical composition and give no information concerning the homogeneity of the non-active components.
It is also important to determine the concentration of the other, non-active components within the pharmaceutical mixture. The concentration of the non-active components in a pharmaceutical mixture is important because it determines the physical properties of the mixture. For example, disintegrants affect the rate of dissolution of a tablet in a recipient's stomach. If the disintegrant is not homogeneously distributed in the pharmaceutical mixture, then the resulting tablets may not dissolve at a uniform rate, thereby potentially resulting in quality, dosing and bioavailability problems. Thus, it is important to measure the homogeneity of all the components of a pharmaceutical mixture because the dispersion of certain components may ultimately affect the physical properties of the final form of the pharmaceutical composition.
Additionally, as noted above, stratification may be associated with uneven distribution of particle size. The result may be quality, dosing and bioavailability problems.
Pharmaceutical products are typically mixed in a blender. Conventional blenders include, among others, “V”-blenders, ribbon blenders, and vertical blenders. According to one method for determining the homogeneity of a blended pharmaceutical product, a technician must stop the blender, remove samples of the blended product from various locations in the blender, and assay those samples in a laboratory using a technique such as ultra-violet (UV) spectroscopy or High Performance Liquid Chromatography (HPLC) analysis. While the samples are taken to the laboratory and analyzed, the blending process is put on hold. The analysis determines the potency of the product at each of the various locations. If the potency of each of the samples is the same (i.e., within statistical limits), then the mixture is determined to be homogeneous, and the blending process may end. However, neither UV nor HPLC analysis establishes the concentration of the non-active components of the mixture. If the potency is not the same for each of the samples, the blender is run again for a period and the testing is repeated.
Infrared spectroscopy is a technique which is based upon the vibrations of the atoms of a molecule. Transmitting radiation through a sample generates a spectrum determining what portion of the incident radiation is absorbed by the sample at a particular energy.
Infrared spectroscopy is a technique which is based upon the vibrational changes of the atoms of a molecule. In accordance with infrared spectroscopy, an infrared spectrum is generated by transmitting infrared radiation through a sample of an organic compound and determining what portion of the incident radiation are absorbed by the sample. An infrared spectrum is a plot of absorbence (or transmittance) against wave number, wavelength, or frequency. Infrared radiation (IR) may be roughly divided into three wavelength bands: near-infrared radiation, mid-infrared radiation, and far-infrared radiation. Near-infrared radiation (NIR) is radiation having a wavelength between about 750 nm and about 3000 nm. Mid-infrared radiation (MIR) is radiation having a wavelength between about 3000 and about 10,000 nm. Far-infrared radiation (FIR) is radiation having a wavelength between about 10,000 nm and about 1000 μm (1000 μm being the beginning of the microwave region). The desired range may be chosen to suit the analysis being performed.
In general, spectrometers (e.g., a spectrophotometer) can be divided into two classes: transmittance spectrometers and reflectance spectrometers. In a transmittance spectrometer, light having a desired narrow band of wavelengths is directed onto a sample, and a detector detects the light which was transmitted through the sample. In contrast, in a reflectance spectrometer, light having a narrow band of wavelengths is directed onto a sample and one or more detectors detect the light which was reflected from the sample. Depending upon its design, a spectrometer may, or may not, be used as both a transmittance and a reflectance spectrometer.
A variety of different types of spectrometers are known in the art such as grating spectrometers, FT (Fourier transformation) spectrometers, Hadamard transformation spectrometers, AOTF (Acousto Optic Tunable Filter) spectrometers, diode array spectrometers, filter-type spectrometers, scanning dispersive spectrometers, and nondispersive spectrometers.
Filter-type spectrometers, for example, utilize a light source to provide continuous radiation (e.g. tungsten filament lamp) to illuminate a rotating opaque disk, wherein the disk includes a number of narrow bandpass optical filters. The disk is then rotated so that each of the narrow bandpass filters passes between the light source and the sample. An encoder indicates which optical filter is presently under the light source. The filters filter the light from the light source so that only a narrow selected wavelength range passes through the filter to the sample. Optical detectors are positioned to detect light which either is reflected by the sample (to obtain a reflectance spectra) or is transmitted through the sample (to generate a transmittance spectra). The amount of detected light is then measured, which provides an indication of the amount of absorbence of the light by the substance under analysis.
Diode source spectrometers use infrared emitting diodes (IREDs) as sources of near infrared radiation. A plurality of (for example, eight) IREDs are arranged over a sample work surface to be illuminated for quantitative analysis. Infrared radiation having a narrow bandwidth (e.g. 30–50 nm) emitted from each IRED impinges upon an accompanying optical filter. Each optical filter is a narrow bandpass filter which passes IR radiation at a different wavelength. IR radiation passing through the sample is detected by a detector (such as a silicon photodetector). The amount of detected light is then measured, which provides an indication of the amount of the substance under analysis, based upon absorbence of the light.
Acousto Optical Turnable Filter spectrometers utilize an RF signal to generate acoustic waves in a TeO2 crystal. A light source transmits a beam of light through the crystal, and the interaction between the crystal and the RF signal splits the beam of light into three beams: a center beam of unaltered white light and two beams of monochromatic and orthogonally polarized light. A sample is placed in the path of one of the monochromatic beam detectors, which are positioned to detect light which either is reflected by the sample (to obtain a reflectance spectra) or is transmitted through the sample (to generate a transmittance spectra). The wavelength of the light source is incremented across a wavelength band of interest by varying the RF frequency. The amount of detected light is then measured, which provides an indication of the amount of absorbence of the light by the substance under analysis.
In an ATR (attenuated total reflectance) spectrometer, radiant energy incident on an internal surface of a high refractive index transparent material is totally reflected. When an infrared absorbing material is in optical contact with the totally internally reflecting surface, the intensity of the internally reflected radiation is diminished for those wavelengths or energies where the material absorbs energy. Since an internal reflecting surface is essentially a perfect mirror, the attenuation of this reflected intensity by a material on its surface provides a means of producing all absolution spectrum of the material. Such spectra are called internal reflection spectra or attenuated total reflection (ATR) spectra. An ATR spectrometer, as described herein, refers to any type of spectrometer (e.g., grating, FT, AOTF, filter) which includes, as a component part, an ATR crystal.
The material with the high index of refraction that is used to create internal reflection is called an internal reflection element (IRE) or an ATR crystal. The attenuation of the internally reflected radiation results from the penetration of the electromagnetic radiation field into the matter in contact with the reflection surface. This field was described by N. J. Hayrick (1965) as an evanescent wave. It is the interaction of this field with the matter in contact with the IRE interface that results in attenuation of the internal reflection.
In granting monochromator spectrometers, a light source transmits a beam of light through an entrance slit and onto a diffraction grating (the dispersive element) to disperse the light beam into a plurality of beams of different wavelengths (i.e., a dispersed spectrum). The dispersed light is then reflected back through an exit slit onto a detector. By selectively altering the path of the dispersed spectrum relative to the exit slit, the wavelength of the light directed to the detector can be varied. The amount of detected light is then measured, which provides an indication of the amount of absorbence of the light by the substance under analysis. The width of the entrance and exit slits can be varied to compensate for any variation of the source energy with wave number.
Detectors used in spectroscopy generally fall into two classes, photographic detectors, in which radiation impinges upon an unexposed photographic film, and electronic detectors, in which the radiation impinges upon a detector and is converted into an electrical signal. Electronic detectors provide the advantage of increased speed and accuracy, as well as the ability to convert the spectral data into an electronic format, which can be displayed, processed, and/or stored. Examples of electronic detectors include photomultiplier tubes and photodetectors. Photomultiplier tubes are quite sensitive, but are relatively large and expensive. Photodetectors provide the advantage of reduced size and cost. Some examples of photodetectors are pin diode detectors, charge coupled device detectors, and charge injection device detectors.
U.S. Pat. No. 5,946,088, which is incorporated by reference herein, purportedly describes an apparatus for mixing compositions into a homogeneous mixture using a blender and detecting on-line the homogeneity and potency of the mixture using a spectrometer. In a preferred embodiment, a “V”-blender is described, which mixes compositions, such as powders or liquids, in a “V”-shaped container by rotating the container about a horizontal axis of rotation. Two support shafts, which connect to the container along its axis of rotation, support the container and drive the rotation of the container about the axis. The wall of the container includes a single aperture at the location in the wall intersecting the axis of rotation of the container. One of the support shafts connects to the container precisely at the point of the aperture and forms a seal for the aperture. The support shaft forming the seal for the aperture is hollow with a transparent window covering its end where it contacts the aperture. A detection means, which includes a fiber optic bundle for detecting the spectroscopic characteristics of the composition mixture is rotatably mounted through the inside of the hollow support shaft. At one end, the optical fibers abut against the transparent window on the inside of the hollow support shaft. At the other end, at a location remote from the “V”-blender, the fibers attach to a spectroscopic means. Thus, the spectrometer and fiber optic bundle remain stationary, while the support shaft and the transparent widow, rotate relative to them. This apparatus, with the fiber optic, bundle threaded through the rotating hollow support shaft, enables the spectrometer to acquire spectroscopic information about the composition mixture while the container is rotating about its axis, and thus, while the product is being blended.
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