WO2007098392A2

WO2007098392A2 - Method and system for chemical specific spectral analysis

Info

Publication number: WO2007098392A2
Application number: PCT/US2007/062294
Authority: WO
Inventors: Dwight Sherod Walker
Original assignee: Glaxo Group Limited
Priority date: 2006-02-21
Filing date: 2007-02-16
Publication date: 2007-08-30
Also published as: EP1987333A2; WO2007098392A3; JP2009533652A

Abstract

A method for chemical specific spectral analysis of a pharmaceutical composition (100) comprising the steps of transmitting light having a wavelength in the range of 800 - 2500 nm to a pharmaceutical composition, whereby the pharmaceutical composition interacts with the transmitted light, the interaction including the emission of a first light, directing the first light to a first multi-optical element (14) adapted to selectively pass a predetermined first fraction of the first light to pass there through, the first light fraction corresponding to the absorbance spectrum of an active contained in the pharmaceutical composition, and directing the first light fraction to a first NIR camera (16a) adapted to receive the first light fraction and provide a first NIR image of the pharmaceutical composition.

Description

Method and System for Chemical Specific Spectral Analysis

FIELD OF THE PRESENT INVENTION

The present invention relates to the field of spectroscopic analysis of pharmaceutical compositions. More specifically, the invention relates to a method and system for chemical specific spectral analysis of particulate pharmaceutical compositions.

BACKGROUND OF THE INVENTION

Beginning in the early 1970's, it was found that certain pharmaceutical compositions could be administered in dry-powder form directly to the lungs by inhalation through the mouth or inspiration through the nose. This process allows the pharmaceutical composition to bypass the digestive system, and in some instances, allows smaller doses to be used to achieve the same desired results as orally ingested pharmaceutical composition.

Various metered dose powdered inhalers ("MDPI") or nebulizers that provide inhalable mists of pharmaceutical compositions are known in the art. Illustrative is the devices disclosed in U.S. Pat. Nos. 3,507,277; 4, 147 ,166 and 5,577,497.

Most of the prior art MDPI devices employ powdered or particulate pharmaceutical compositions that are contained in a gelatin capsule. The capsules are typically pierced and a metered dose of the powdered pharmaceutical composition is withdrawn by partial vacuum, forced inspiration of the user or by centrifugal force. As is well known in the art, a number of MDPI devices employ a foil blister strip.

The foil blister strip includes a plurality of individual, sealed blisters (or pockets) that encase the powdered medicine. The blisters are similarly pierced during operation to release the metered dose of powdered pharmaceutical composition.

As will be appreciated by one having ordinary skill in the art, the provision of an accurate dose of a pharmaceutical composition in each capsule or blister is imperative. Indeed, the U.S. Government mandates 100% inspection of MDPI formulations to ensure that the formulations contain the proper amount of prescribed active substance or drug.

It would also be advantageous to know the location of actives in a particulate pharmaceutical composition. As will be appreciated by one having ordinary skill in the art, knowing the location of actives in a particulate pharmaceutical composition would provide valuable insight into the homogeneity of the composition during blending and, most importantly, the dispersion characteristics of the active(s) during aerosolization, i.e. administration via inhalation through the mouth or inspiration through the nasal passages.

Various technologies have been employed to analyze pharmaceutical compositions. A well known technique that is often employed is spectroscopic analysis. The absorption of light by a fluid or other substance (e.g., active), as a function of wavelength, forms the basis of spectroscopic analysis. The analysis can take place in a number of spectral ranges, ranging from the ultraviolet and visible range where molecules absorb light due to electronic transitions, to the infra-red range where light absorption corresponds to vibrational transitions. By way of example, it is well known that in the near infra-red (NIR) region, absorption corresponds to vibrational transitions in the bonds between hydrogen atoms and the rest of the molecule (referred to as X-H bonds). The exact wavelength at which these X-H bonds adsorb light depends on the structure of the molecule. This forms the basis of NIR analysis, as different molecules, such as aromatics, aliphatics and olefins, have different absorption spectra.

A number of devices have been, and continue to be, employed for spectral analysis of samples. The devices are typically employed to measure the reflection, transmission, fluorescence or the light scattering from "on-line" samples. Illustrative are the "on-line" devices disclosed in U.S. Pat. Nos. 5,044,755 and 5,442,437. A drawback of conventional spectroscopic systems and methods employing same is that most systems are not capable of determining the location of selective actives in a particulate pharmaceutical composition, particularly, a particulate pharmaceutical composition dispersed in a plume or mist. Further, most systems require samples to be collected from remote, inaccessible, or hazardous environments, and/or require extensive sampling that is time consuming and prohibitively costly. A further drawback is that detection of minute amounts of trace elements, including the active ingredient or drug(s), is often difficult or not possible.

It would thus be desirable to provide an optical analysis method and system that is capable of determining the location of selective actives in particulate pharmaceutical compositions.

It is therefore an object of the present invention to provide a cost effective, reliable means of determining the location of selective actives in particulate pharmaceutical compositions. It is another object of the invention to provide an optical analysis method and system for determining the presence and location of trace amounts of an active in a particulate pharmaceutical composition.

It is another object of the invention to provide an optical analysis method and system for determining the amount of an active contained in a particulate pharmaceutical composition.

It is another object of the present invention to provide an optical analysis method and system for determining the location and/or amount of selective actives in aerosolized particulate pharmaceutical compositions. It is yet another object of the invention to provide an optical analysis system for performing chemical specific spectral analysis of particulate pharmaceutical compositions.

SUMMARY OF THE INVENTION

In accordance with the above objects and those that will be mentioned and will become apparent below, in one embodiment, the method for chemical specific spectral analysis of a pharmaceutical composition generally comprises the steps of (i) providing a particulate pharmaceutical composition having at least a first active, the first active having a first absorbance spectrum; (ii) transmitting light having a wavelength in the range of approximately 800 - 2600 nm to the pharmaceutical composition, whereby the pharmaceutical composition interacts with the transmitted light, the interaction including the emission of a first light; (iii) directing the first light to a first multi-optical element, the first multi-optical element being adapted to selectively pass a predetermined first fraction of the first light therethrough, the first light fraction corresponding to the first absorbance spectrum of the first active; and (iv) directing the first light fraction to a first NIR camera adapted to provide a first NIR image of the pharmaceutical composition.

In one embodiment of the invention, the wavelength of the transmitted light is in the range of approximately 1100 - 2400 nm.

In another embodiment, the wavelength of the transmitted light is in the range of approximately 1600 - 2300 nm. Preferably, the first NIR image comprises a NIR image of the pharmaceutical composition after interaction with the transmitted light.

Preferably, the first NIR image reflects the location of the first active in the pharmaceutical composition. Preferably, the pharmaceutical composition comprises an aerosolized particulate pharmaceutical composition.

In one embodiment of the invention, the first multi-optical element is further adapted to isolate and redirect a second fraction of the first light. In a preferred embodiment of the invention, the second light fraction is directed to a second NIR camera adapted to provide a second NIR image of the pharmaceutical composition after interaction with the transmitted light.

In one embodiment of the invention, a white light camera is also provided. The white light camera is positioned and adapted to provide a white light image of the pharmaceutical composition.

In one embodiment of the invention, the pharmaceutical composition includes a second active having a second absorbance spectrum.

In a preferred embodiment of the invention, the first light is directed to a second multi-optical element adapted to selectively pass a predetermined third fraction of the first light therethrough, the third light fraction corresponding to the second absorbance spectrum.

In a preferred embodiment of the invention, the third light fraction is directed to a third NIR camera adapted to provide a third NIR image of the pharmaceutical sample.

Preferably, the third NIR image reflects the location of the second active in the pharmaceutical composition.

In accordance with one embodiment of the invention, the optical analysis system generally comprises (i) at least one energy source adapted to provide light having a wavelength in the range of approximately 800 - 2500 nm; (ii) a first multi-optical element adapted to selectively pass a predetermined first fraction of the light therethrough, the first light fraction corresponding to the absorbance spectrum of at least one active; and (iii) at least a first NIR camera adapted to receive the first light fraction and provide a first NIR image.

In one embodiment of the invention, the energy source is adapted to provide light having a wavelength in the range of approximately 1100 - 2400 nm. In another embodiment, the energy source is adapted to provide light having a wavelength in the range of approximately 1600 - 2300 nm.

In one embodiment of the invention, the first multi-optical element is further adapted to isolate and redirect a second fraction of the first light. In one embodiment of the invention, the system includes a second NIR camera adapted to receive the second light fraction and provide a second NIR image.

In one embodiment of the invention, the system includes a white light camera adapted to provide a white light image.

BRIEF DESCRIPTION OF THE DRAWINGS

Further features and advantages will become apparent from the following and more particular description of the preferred embodiments of the invention, as illustrated in the accompanying drawings, and in which like referenced characters generally refer to the same parts or elements throughout the views, and in which:

FIGURE 1 is a schematic illustration of one embodiment of a chemical specific optical analysis system, according to the invention;

FIGURE 2 is a graph of intensity versus wavelength, illustrating one embodiment of the energy provided by the energy source of the invention to illuminate a pharmaceutical sample;

FIGURE 3 is a graph of intensity versus wavelength, illustrating the energy (i.e., light) emitted from a pharmaceutical composition after illumination by the energy source of the invention;

FIGURE 4 is a schematic illustration of an image provided by a white light camera, according to the invention;

FIGURE 5 is a schematic illustration of an image provided by a NIR camera after receipt of a wavelength specific light fraction, according to the invention;

FIGURE 6 is a schematic illustration of an image provided by a NIR camera after receipt of a reflected light fraction, according to the invention; FIGURE 7 is a schematic illustration of another embodiment of a chemical specific optical analysis system, according to the invention;

FIGURE 8 is a schematic illustration of another embodiment of a chemical specific optical analysis system, according to the invention; and

FIGURE 9 is a schematic illustration of yet another embodiment of a chemical specific optical analysis system, according to the invention. DETAILED DESCRIPTION OF THE INVENTION

Before describing the present invention in detail, it is to be understood that this invention is not limited to particularly exemplified materials, methods or structures as such may, of course, vary. Thus, although a number of materials and methods similar or equivalent to those described herein can be used in the practice of the present invention, the preferred materials and methods are described herein.

It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments of the invention only and is not intended to be limiting.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one having ordinary skill in the art to which the invention pertains.

Further, all publications, patents and patent applications cited herein, whether supra or infra, are hereby incorporated by reference in their entirety.

Finally, as used in this specification and the appended claims, the singular forms "a", "an" and "the" include plural referents unless the content clearly dictates otherwise.

Definitions

The term "pharmaceutical composition", as used herein, is meant to mean and include any compound or composition of matter which, when administered to an organism (human or animal) induces a desired pharmacologic and/or physiologic effect by local and/or systemic action. The term therefore encompasses those compounds or chemicals and mixtures thereof (which may include other materials, such as a carrier) that are traditionally regarded as actives or drugs, as well as biopharmaceuticals, including molecules such as peptides, hormones, nucleic acids, gene constructs and the like.

The terms "particulate pharmaceutical composition" and "powdered pharmaceutical composition", as used herein, are meant to mean and include pharmaceutical compositions that substantially comprises minute, separate solid particles. As is well known in the art, "particulate pharmaceutical compositions" are typically in a dry state.

The "pharmaceutical compositions" and "particulate pharmaceutical compositions", alone or in combination with other actives (or agents), typically include one or more added materials, such as carriers, vehicles and/or excipients. "Carriers," "vehicles" and "excipients" generally refer to substantially inert materials that are nontoxic and do not interact with other components of the composition in a deleterious manner. These materials can be used to increase the amount of solids in particulate pharmaceutical compositions.

Examples of carriers include water, fluorocarbons, silicone, gelatin, waxes, and like materials. Examples of normally employed "excipients," include pharmaceutical grades of carbohydrates including monosaccharides, disaccharides, cyclodextrins, and polysaccharides (e.g., dextrose, sucrose, lactose, raffinose, mannitol, sorbitol, inositol, dextrins, and maltodextrins); starch; cellulose; salts (e.g., sodium or calcium phosphates, calcium sulfate, magnesium sulfate); citric acid; tartaric acid; glycine; low, medium or high molecular weight polyethylene glycols (PEG's); pluronics; surfactants; and combinations thereof.

The term "plume", as used herein, is meant to mean and include a gaseous mixture or mist containing a "pharmaceutical composition" or "particulate pharmaceutical composition", i.e. a "pharmaceutical composition" or "particulate pharmaceutical composition" separated in strata by a gas, e.g., atmospheric air.

The terms "light fraction" and "light signal" are used interchangeably herein and mean a segment of transmitted or emitted energy, e.g. light.

The term "interacts", as used herein, means the interaction by and between a pharmaceutical composition and transmitted energy, particularly light, including, without limitation, the absorption, reflection and/or emission of light and/or fractions thereof by the pharmaceutical composition.

The present invention substantially reduces or eliminates the disadvantages and drawbacks associated with conventional spectroscopic methods and systems. As discussed in detail below, the optical analysis system of the invention generally includes at least one energy source adapted to provide energy, preferably light, a multi-optical element adapted to selectively pass a predetermined fraction of light therethrough and at least one NIR camera adapted to receive the fraction of light and provide an image of the pharmaceutical composition.

As will be appreciated by one having ordinary skill in the art, the optical analysis systems of the invention can be readily employed in conjunction with a multitude of "online" and "off-line" qualitative and quantitative assessments of particulate pharmaceutical compositions. Potential applications thus include, for example, the following: • Blending operations and blenders associated therewith to assess homogeneity of pharmaceutical compositions;

• Aerosolization studies to determine the dispersion characteristics of actives contained in pharmaceutical compositions; and • Bulk density studies of pharmaceutical compositions.

Reference will now be made in detail to presently preferred embodiments of the invention, one or more examples of which are illustrated in the accompanying figures. As indicated above, repeat use of reference characters herein and in the figures is intended to represent same or analogous features or elements of the invention. Referring first to Fig. 1, there is shown one embodiment of a "transmission" optical analysis system (designated generally 10) of the invention. As illustrated in Fig. 1, the system 10 includes at least one energy source 12 that is adapted to provide NIR light having a wavelength in the range of at least approximately 800 - 2500 nm, more preferably, in the range of approximately 1100 - 2400 nm, even more preferably, in the range of approximately 1600 - 2300 nm. Additionally, in another embodiment, the light may have a wavelength in the range of from approximately 1700 - 2600 nm. As illustrated in Fig. 1, the light is transmitted to a pharmaceutical sample 101, which, in this instance, is dispersed in a plume 100 (hereinafter "sample plume"). Preferably, the pharmaceutical sample 101 comprises a particulate pharmaceutical composition having at least one active 102.

In a preferred embodiment of the invention, the optical analysis system 10 also includes at least one multi-optical element (MOE) 14, i.e. a wavelength-specific light filter. As is known in the art, MOEs can be designed to selectively pass a predetermined fraction of light, which, according to the invention, corresponds to the absorbance spectrum of at least one active (i.e. target element). An MOE can also be employed as a light re-direction device, i.e. beam splitter. Further details of MOEs are set forth in U.S. Pat. Nos. 6,529,276 and 6,198,531, which are incorporated by reference herein in their entirety. In addition to the above, an example of an instrument that may be used for multivariate optical computing is Spectrlnline Processware made commercially available by Ometric Corporation located in Columbia, South Carolina.

In an alternative embodiment (not shown), the system 10 includes a series of optical filters, such as a dichroic, bandpass and long pass filter, that are similarly designed to selectively pass a predetermined fraction of light that corresponds to a target absorbance spectrum therethrough. The number of filters employed in the series is based on the desired spectral resolution and optical density of the sample or active of interest.

Referring back to Fig. 1, the optical analytical system 10 further includes at least one, preferably, two NIR cameras 16a, 16b and at least one conventional white light camera 18. NIR camera 16a is adapted to receive the predetermined fraction of light (or first light signal), designated 24, that is transmitted through MOE 14 and provide a first NIR image of the pharmaceutical sample 101. NIR camera 16b is adapted to receive the fraction of light (or second light signal), designated 26, that is reflected off MOE 14 and provide a second NIR image of the pharmaceutical sample 101. The white light camera 18 is adapted and positioned to provide a simple "white light" image of the sample plume 100.

As will be appreciated by one having ordinary skill in the art, various conventional NIR and white light cameras can be employed within the scope of the invention. Illustrative are the NIR camera manufactured by FLIR Systems, Inc., under the trade name Alpha NIR and white light camera manufactured by Hitachi, Model No. HV-C20.

Similarly, one having ordinary skill in the art will appreciate that energy source 12 can comprise various suitable energy sources, including energy sources employed in known spectroscopy methods. For example, energy source 12 can comprise a broad band light source, such as a lamp, filament, LED or other device that provides multi-wavelength light substantially over the visible and near visible light spectrum. As an example, a 5 W broad band light source can be used.

According to the invention, the pharmaceutical composition 101 interacts with the light provided by energy source 12, when transmitted thereto. As indicated above, the term "interacts", as used herein, means and includes, without limitation, the absorption, reflection and/or emission of light and/or fractions thereof by the pharmaceutical composition 101.

Thus, in one embodiment of the invention, the light provided by the energy source 12 interacts (or excites) the pharmaceutical composition 101, whereby light is emitted therefrom. Energy source 12 can thus comprise a laser, lamp or other electrical source. As will be appreciated by one having ordinary skill in the art, two or more energy sources (shown in phantom and designated 13a and 13b) can also be employed to provide the desired light. In a preferred embodiment, energy source 12 comprises a lamp. As illustrated in Fig. 1, the energy source, i.e. lamp 12, is preferably disposed proximate sample plume 100.

According to the invention, the optical system 10 can additionally include processing means, shown in phantom and designated 19, such a microprocessor or computer that is in communication with the energy source 12 and cameras 16a, 16b, 18 to control the optical system 10 and, if desired, display one or more images provided by cameras 16a, 16b, 18.

The operation of optical system 10 will now be described in detail. In one embodiment of the invention, a sample plume 100 having a dispersed (or aerosolized) particulate pharmaceutical composition 101 containing a first active 102 is provided. A MOE 14 is also provided having a "fingerprint" corresponding to the absorbance spectrum of the first (or target) active 102, i.e. only allows a predetermined fraction of light corresponding to the absorbance spectrum of the target active 102 to pass. As discussed in detail below, in the noted embodiment, MOE 14 is also adapted and positioned to re-direct a reflected fraction of light.

The sample plume 100 having a pharmaceutical composition 101 dispersed therein is placed (or provided) between the energy source 12 and the MOE 14. NIR light having a wavelength in the range of approximately 800 - 2500 nm, such as illustrated in Fig. 2 and designated generally 30, is provided by energy source 12 and transmitted to (designated generally 20) and through sample plume 100.

In another embodiment, NIR light having a wavelength in the range of approximately 1100 - 2400 nm is provided by energy source 12. In yet another embodiment, NIR light having a wavelength in the range of approximately 1600 - 2300 nm is provided by energy source 12.

According to the invention, the pharmaceutical sample 101 interacts with the transmitted light, the interaction including the emission of light from the pharmaceutical sample 101 (designated generally 22). The emitted light 22 is directed to MOE 14. As will be appreciated by one having ordinary skill in the art, the emitted light 22 would have a second wavelength, such as illustrated in Fig. 3 and designated generally 32.

As illustrated in Fig. 1, a fraction of the emitted light 22 or first light signal 24, which corresponds to the absorbance spectrum of the target active 102, passes through MOE 14 to NIR camera 16a. A fraction of the emitted light 22, i.e. light that does not correspond to the absorbance spectrum of the target active 102, is reflected off of MOE 14. The reflected light fraction or second light signal 26 is directed to NIR camera 16b.

In the illustrated embodiment, as well as all embodiments illustrated and discussed herein, light to and from the pharmaceutical sample 101 or sample plume 100 is shown as being transmitted over air. It should be understood, however, that other light transmitting media, such as fiber optic elements, can also be employed to transmit light to and from a pharmaceutical sample or sample plume, as well as to the MOE and NIR cameras of the invention.

Referring now to Figs. 4-6, the images provided by the white light camera 18 and NIR cameras 16a, 16b will now be discussed. Referring first to Fig. 4, there is shown an illustration of a non-magnified image, designated generally 40a, that can be provided by the white light camera 18. The non-magnified image 40a would thus substantially comprise that which can be seen with the naked eye. As is known in the art, the image can also be magnified. Referring now to Fig. 5, the image provided by the NIR camera 16a that receives the first light signal 24, i.e., light fraction or signal 24 that passes through MOE 14, designated generally 40b, would include dark areas or spots 42 reflecting the location(s) of the target active 102.

Referring now to Fig. 6, the image provided by NIR camera 16b that receives the reflected second light signal 26, designated generally 40c, would include bright areas or spots 44 that also reflect the location(s) of the target active 102. The image 40c provided by the NIR camera 16b that receives the reflected light signal 26 would thus be a substantially negative image of the image 40b provided by NIR camera 16a that receives the first light signal 24. As will be appreciated by one having ordinary skill in the art, the noted images

40b, 40c can be combined, by, for example, a processor 19, to provide a composite NIR image of the pharmaceutical sample 101.

In additional envisioned embodiments of the invention, multiple MOEs and NIR cameras can be employed to detect and display the location of multiple actives in non- dispersed and dispersed particulate pharmaceutical compositions.

Referring now to Fig. 7, there is shown another embodiment of a "transmission" optical analysis system (designated generally 11) of the invention. As illustrated in Fig. 7, the system 11 similarly includes at least one energy source 12 that is adapted to provide NIR light having a wavelength in the range of approximately 800 - 2500 nm, more preferably, in the range of approximately 1100 - 2400 nm, even more preferably, in the range of approximately 1600 - 2300 nm, and at least one multi-optical element (MOE) 14.

The optical analytical system 11 further includes one NIR camera 16a and at least one conventional white light camera 18. In this embodiment, the NIR camera 16a is adapted to receive the predetermined fraction of light, designated 23, that is transmitted through MOE 14 (designated 21) and through the sample plume 100, and provide a NIR image of the pharmaceutical sample 101. The white light camera 18 is similarly adapted and positioned to provide a simple "white light" image of the sample plume 100. Energy source 12 can similarly comprise various suitable energy sources, such as a broad band light source, e.g., a lamp, filament or LED, or other device that provides multi- wavelength light substantially over the visible and near visible light spectrum.

In the embodiment illustrated in Fig. 7, two or more energy sources can similarly be employed to provide the desired light. In a preferred embodiment, energy source 12 comprises a lamp. As illustrated in

Fig. 7, the energy source, i.e. lamp 12, is preferably disposed proximate MOE 14.

According to the invention, the optical system 11 can similarly include processing means, shown in phantom and designated 19, such a microprocessor or computer that is in communication with the energy source 12 and cameras 16a, 18 to control the optical system 11 and, if desired, display one or more images provided by cameras 16a, 18.

The operation of optical system 11 will now be described in detail. In one embodiment of the invention, a sample plume 100 having a dispersed particulate pharmaceutical composition 101 containing a first active 102 is provided. An MOE 14 having a "fingerprint" corresponding to the absorbance spectrum of the first (or target) active 102 is also provided.

In one embodiment of the invention, NIR light having a wavelength in the range of approximately 800-2500 nm is provided by energy source 12 and transmitted to (designated generally 20) and through MOE 14. In another embodiment, NIR light having a wavelength in the range of approximately 1100 - 2400 nm is provided by energy source 12. In yet another embodiment, NIR light having a wavelength in the range of approximately 1600 - 2300 nm is provided by energy source 12.

The light emitted from MOE 14, designated 21, is directed through the sample plume 100, whereby the pharmaceutical sample 101 interacts with the light emitted from MOE 14; the interaction including the emission of light from the pharmaceutical sample 101. The light emitted from the pharmaceutical sample, designated 23, is then transmitted to NIR camera 16a.

According to the invention, the image provided by the NIR camera 16a that receives the light emitted by the pharmaceutical sample 101, i.e. light signal 23, would be similar to image 40b shown in Fig. 5, having dark areas or spots 42 reflecting the location(s) of the target active 102. The image provided by the white light camera 18 would also be similar to image 40a shown in Fig. 4.

Referring now to Fig. 8, there is shown an embodiment of a "reflectance" optical analysis system (designated generally 50) of the invention. As illustrated in Fig. 8, the system 50 preferably includes two energy sources 13a, 13b, each energy source 13a, 13b being adapted to provide NIR light having a wavelength in the range of approximately 800 - 2500 nm, more preferably, in the range of approximately 1100 - 2400 nm, even more preferably, in the range of approximately 1600 - 2300 nm, and at least one multi-optical element (MOE) 14. As will be appreciated by one having ordinary skill in the art, one energy source can also be employed to illuminate the sample 101.

The optical analytical system 50 further includes at least one, preferably two NIR cameras 16a, 16b and at least one conventional white light camera 18. NIR camera 16a is adapted to receive the predetermined fraction of light or first light signal, designated 29, that is transmitted through MOE 14 and provide a first NIR image of the pharmaceutical sample 101. NIR camera 16b is adapted to receive the fraction of light or second light signal, designated 31, that is reflected off MOE 14 and provide a second NIR image of the pharmaceutical sample 101. The white light camera 18 is similarly adapted and positioned to provide a simple "white light" image of the sample plume 100. Energy sources 13a, 13b can similarly comprise various suitable energy sources, such as a broad band light source, e.g., a lamp, filament or LED, or other device that provides multi-wavelength light substantially over the visible and near visible light spectrum.

In a preferred embodiment, energy sources 13a, 13b comprise lamps. As illustrated in Fig. 7, the energy sources, i.e. lamps 13a, 13b, are preferably disposed proximate the sample plume 100.

According to the invention, the optical system 50 can similarly include processing means, shown in phantom and designated 19, such a microprocessor or computer, that is in communication with the energy sources 13a, 13b and cameras 16a, 16b, 18 to control the optical system 50 and, if desired, display one or more images provided by cameras 16a, 16b, 18.

The operation of optical system 50 will now be described in detail. In one embodiment of the invention, a sample plume 100 having a dispersed particulate pharmaceutical composition 101 containing a first active 102 is provided. An MOE 14 is also provided having a "fingerprint" corresponding to the absorbance spectrum of the first (or target) active 102. MOE 14 is also designed and positioned to re-direct a reflected fraction of light. NIR light in the range of 800 - 2500 wavelengths is provided by each of the energy sources 13a, 13b and transmitted to the sample plume 100 (designated 25a), whereby the pharmaceutical sample interacts with the transmitted light; the interaction including the emission of light by the pharmaceutical sample, designated 27. The emitted light 27 is directed to MOE 14. As illustrated in Fig. 8, a first light signal 29, which corresponds to absorbance spectrum of the target active 102, passes through MOE 14 to NIR camera 16a. The second light signal that is reflected off MOE 14, designated 31, is directed to NIR camera 16b.

According to the invention, the image provided by the NIR camera 16a that receives the first light signal 29 would be similar to image 40b shown in Fig. 5, having dark areas or spots 42 reflecting the location(s) of the target active 102. The image provided by NIR camera 16b that receives the reflected light signal 31 would be similar to image 40c shown in Fig. 6, having bright areas or spots 44 that also reflect the location(s) of the target active 102. The image provided by the white light camera 18 would be similar to image 40a shown in Fig. 4.

Referring now to Fig. 9, there is shown another embodiment of a "reflectance" optical analysis system (designated generally 52) of the invention. As illustrated in Fig. 9, the system 52 similarly includes two energy sources 13a, 13b, each energy source 13a, 13b preferably providing NIR light having a wavelength in the range of at least approximately 800 - 2500 nm, more preferably, in the range of approximately 1100 - 2400, even more preferably, in the range of approximately 1600 - 2300 nm, and at least one multi-optical element (MOE) 14. The optical analytical system 52 further includes one NIR camera 16a and at least one conventional white light camera 18. In this embodiment, the NIR camera 16a is adapted to receive the fraction of light that is emitted from the pharmaceutical sample 101, designated 27, and provide a NIR image of the sample 101. The white light camera 18 is similarly adapted and positioned to provide a simple "white light" image of the sample plume 100.

Energy sources 13a, 13b can similarly comprise various suitable energy sources, such as a broad band light source, such as a lamp, filament, LED or other device that provides multi-wavelength light substantially over the visible and near visible light spectrum.

In a preferred embodiment, energy sources 13a, 13b comprise lamps. As illustrated in Fig. 9, the energy sources, i.e. lamps 13a, 13b, are preferably disposed proximate the sample plume 100.

According to the invention, the optical system 52 can similarly include processing means, shown in phantom and designated 19, such a microprocessor or computer that is in communication with the energy sources 13a, 13b and cameras 16a, 18 to control the optical system 52 and, if desired, display one or more images provided by cameras 16a, 18.

The operation of optical system 52 will now be described in detail. In one embodiment of the invention, a sample plume 100 having a dispersed particulate pharmaceutical composition 101 containing a first active 102 is provided. An MOE 14 having a "fingerprint" corresponding to the absorbance spectrum of the first (or target) active 102 is also provided.

NIR light in the range of 800-2500 nm is provided by energy sources 13a, 13b and transmitted to the sample plume 100 (designated 25a), whereby the pharmaceutical composition interacts with the transmitted light; the interaction including the emission of light by the pharmaceutical composition. The light emitted by the pharmaceutical sample 101 is similarly directed to MOE 14. Light signal 29, which corresponds to the absorbance spectrum of the target active, passes through MOE 14 and is directed to NIR camera 16a.

According to the invention, the image provided by NIR camera 16a would be similar to image 40b shown in Fig. 5, having dark areas or spots or spots 42 reflecting the location(s) of the target active 102. The image provided by the white light camera 18 would also be similar to image 40a shown in Fig. 4.

EXAMPLES The following examples are given to enable those skilled in the art to more clearly understand and practice the present invention. They should not be considered as limiting the scope of the invention, but merely as being illustrated as representative thereof.

Example 1 A particulate pharmaceutical composition comprising 250 meg fluticasone propionate, 50 meg salmeterol and the balance sucrose is provided. A multi-optical element (MOE) having a fingerprint corresponding to the absorbance spectrum of fluticasone propionate is also provided.

NIR light having a wavelength in the range of approximately 800 - 2500 nm is transmitted to an aerosolized sample of the pharmaceutical composition, whereby the pharmaceutical composition interacts with the transmitted light; the interaction including the emission of light by the pharmaceutical composition. The light emitted by the composition is directed to the MOE. A portion of the emitted light that corresponds to the absorption spectrum of the fluticasone propionate is transmitted through the MOE and directed to a NIR camera, whereby the NIR camera provides an image reflecting the location of the fluticasone propionate in the aerosolized sample.

From the foregoing description, one having ordinary skill in the art can readily ascertain that the optical analysis system of the invention provides numerous advantages. Among the advantages are the following: • Cost effective, reliable and accurate means for determining the location and/or amount of selective actives in a particulate pharmaceutical composition; • Means for detecting trace amounts of selective actives in particulate pharmaceutical compositions; and • Means for determining the location and/or amount of selective actives in aerosolized particulate pharmaceutical compositions.

Without departing from the spirit and scope of this invention, one having ordinary skill in the art can make various changes and modifications to the invention to adapt it to various usages and conditions. As such, these changes and modifications are properly, equitably, and intended to be, within the full range of equivalence of the following claims.

Claims

CLAIMS What is Claimed is:

1. A method for chemical specific spectral analysis of a pharmaceutical composition having at least one active, the active having an absorbance spectrum, the method comprising the steps of: transmitting light having a wavelength in the range of approximately 800 - 2500 nm to said pharmaceutical composition, whereby said pharmaceutical composition interacts with said transmitted light, said interaction including the emission of a first light by said pharmaceutical composition; directing said first light to a first multi-optical element, said first multi-optical element being adapted to selectively pass a predetermined first fraction of said first light therethrough, said first light fraction corresponding to said absorbance spectrum of said active; and directing said first light fraction to a first NIR camera, said first NIR camera being adapted to provide a first NIR image of said pharmaceutical sample.

2. The method of Claim 1, wherein said transmitted light has a wavelength in the range of approximately 1100 - 2400 nm.

3. The method of Claim 1, wherein said transmitted light has a wavelength in the range of approximately 1600 - 2300 nm.

4. The method of Claim 1, wherein said first NIR image comprises a NIR image of said pharmaceutical composition after said interaction with said transmitted light.

5. The method of Claim 1, wherein said pharmaceutical composition comprises an aerosolized particulate pharmaceutical composition.

6. The method of Claim 1, wherein said first multi-optical element is further adapted to isolate and redirect a second fraction of said first light.

7. The method of Claim 6, wherein said second light fraction is directed to a second NIR camera, said second NIR camera being adapted to provide a second NIR image of said pharmaceutical sample.

8. The method of Claim 1, wherein a white light camera is provided, said white light camera being positioned and adapted to provide a white light image of said pharmaceutical composition.

9. A method for chemical specific spectral analysis of a pharmaceutical composition, comprising the steps of: providing a particulate pharmaceutical composition having at least a first active, said first active having a first absorbance spectrum; transmitting light having a wavelength in the range of approximately 800 - 2500 nm to said pharmaceutical composition, whereby said pharmaceutical composition interacts with said transmitted light, said interaction including the emission of a first light by said pharmaceutical composition; directing said first light to a first multi-optical element, said first multi-optical element being adapted to selectively pass a predetermined first fraction of said first light therethrough, said first light fraction corresponding to said first absorbance spectrum of said first active; and directing said first light fraction to a first NIR camera, said first NIR camera being adapted to provide a first NIR image of said pharmaceutical composition, said first NIR image reflecting the location of said first active in said pharmaceutical composition.

10. The method of Claim 9, wherein said transmitted light has a wavelength in the range of approximately 1100 - 2400 nm.

11. The method of Claim 9, wherein said transmitted light has a wavelength in the range of approximately 1600 - 2300 nm.

12. The method of Claim 9, wherein said pharmaceutical composition comprises an aerosolized particulate pharmaceutical composition.

13. The method of Claim 9, wherein said first multi-optical element is further adapted to isolate and redirect a second fraction of said first light.

14. The method of Claim 13, wherein said second light fraction is directed to a second NIR camera, said second NIR camera being adapted to provide a second NIR image of said pharmaceutical composition, said second NIR image reflecting said location of said first active in said pharmaceutical composition.

15. The method of Claim 9, wherein a white light camera is provided, said white light camera being positioned and adapted to provide a white light image of said pharmaceutical composition.

16. The method of Claim 9, wherein said pharmaceutical composition includes a second active, said second active having a second absorbance spectrum.

17. The method of Claim 16, wherein said first light is directed to a second multi- optical element, said second multi-optical element being adapted to selectively pass a predetermined third fraction of said first light therethrough, said third light fraction corresponding to said second absorbance spectrum of said second active.

18. The method of Claim 17, wherein said third light fraction is directed to a third NIR camera, said third NIR camera being adapted to provide a third NIR image of said pharmaceutical composition, said third NIR image reflecting the location of said second active in said pharmaceutical composition.

19. An optical analysis system, comprising: an energy source adapted to provide light having a wavelength in the range of 800 - 2500 nm; a first multi-optical element adapted to selectively pass a predetermined first fraction of said energy source light therethrough, said first light fraction corresponding to the absorbance spectrum of at least one active; and at least a first NIR camera adapted to receive said first light fraction and provide a first NIR image.

20. The optical analysis system of Claim 19, wherein said energy source provides light having a wavelength in the range of approximately 1100 - 2400 nm.

21. The optical analysis system of Claim 19, wherein said energy source provides light having a wavelength in the range of approximately 1600 - 2300 nm.

22. The optical analysis system of Claim 19, wherein said first multi-optical element is further adapted to isolate and redirect a second fraction of said first light.

23. The optical analysis system of Claim 22, wherein said system includes a second NIR camera.

24. The optical analysis system of Claim 23, wherein said second NIR camera is adapted to receive said second light fraction and provide a second NIR image.

25. The optical analysis system of Claim 19, wherein said system includes a white light camera, said white light camera being adapted to provide a white light image.