HK1146117B - Thermography based system and method for detecting counterfeit drugs - Google Patents

Description

Thermography-based system and method for detecting counterfeit drugs

Technical Field

The present invention relates generally to the field of counterfeit detection systems. In particular, the field relates to systems and methods for detecting counterfeit products of pharmaceutical products. More particularly, the present invention relates to thermography-based systems and methods for detecting counterfeit of pharmaceutical products operating in the MWIR or LWIR range.

Background

The pharmaceutical industry is a billion yuan international business area. However, similar to many industries, many products of the pharmaceutical industry are sacrificial to counterfeiters who make rejected or fake counterfeit products and sell them at a fraction of their actual market price. Globally, the percentage of counterfeit drugs is high enough to seriously impact the revenue of major pharmaceutical companies. Even more serious is the potential health risks involved for counterfeit drug consumers.

In addition to infringement of intellectual property rights and violation of other governmental laws, the Federal Drug Administration (FDA) has not proposed a comprehensive solution to the counterfeiting problem of the pharmaceutical industry.

Many attempts have been made in the prior art to solve the problem of counterfeit drugs, however, each of the prior art solutions has drawbacks associated with it. Some prior art uses RFID and bar codes to read packaging labels to determine the authenticity of the content contained therein. However, this does not necessarily provide accurate results since the product itself is not analyzed directly.

The prior art has developed drug identification programs based on the concept of spectral signatures. Each drug has a unique spectral signature (or fingerprint) determined by its molecular composition. Infrared spectroscopy is used to determine whether the molecular composition of a sample product is the same as the known spectral characteristics of an authentic product. Infrared spectroscopy is a subset of spectroscopy that involves the infrared region of the electromagnetic spectrum. Infrared spectroscopy exploits the principle that molecules have a specific frequency at which they rotate or oscillate relative to discrete energy levels.

U.S. Pat. No. 6,395,538 relates to the fields of bio-manufacturing and infrared spectroscopy, and more particularly to quality monitoring and control of biological materials, for example, in bioactive pharmaceutical compositions. Fourier transform infrared spectroscopy is used to monitor the production of biomolecules and to collect specific markers qualitatively and quantitatively for biomolecules at different stages of the bio-manufacturing process. As described herein, U.S. patent No. 6,395,538 is directed to a spectroscopy-based system and does not involve a commercial level of counterfeit drugs, and therefore the system is not directed to overcoming difficulties such as determining the authenticity of a plurality of pharmaceutical products contained in a sealed package.

U.S. Pat. No. 6,853,447 pertains to the screening and identification of materials, such as pharmaceutical or food products being packaged in an automated machine. The invention uses an array of imaging spectrometers. The system of U.S. Pat. No. 6,853,447 performs spectroscopy in the near IR and short IR spectra. Spectroscopy examines the IR reflection from the product, or more specifically the spectral distribution of the reflection in the frequency domain, in contrast to thermography, which detects the level of IR emission from an object and the distribution of IR emission from an object. The spectral determination of us patent No. 6,853,447 only allows inspection of the outer surface of the product without involving the product body. Thus, when applying the spectroscopy of U.S. Pat. No. 6,853,447, each drug must be inspected separately outside its container. This makes handling problematic when the drug is in a liquid state. Additionally, many capsules are coated with a thin layer of, for example, gelatin, which prevents the near IR detector device from determining the authenticity of the drug. Moreover, such methods are expensive to utilize on a commercial scale due to the amount of time required for each inspection.

U.S. patent No. 6,771,369 relates to the verification and identification of packaged medicaments in a retail setting. The chemical analysis and verification system preferably uses visual (Vis) and Near Infrared (NIR) spectroscopy to analyze and identify the contents of the filled prescription vials by measuring the chemical characteristics of the project (chemical signature). Other variations, such as various forms of optical spectroscopy, UV-Vis-NIR, infrared or Raman spectroscopy, may also be used. Similar to the system of U.S. Pat. No. 6,853,447, the system of U.S. Pat. No. 6,771,369, produced by the same company, only performs detection in the near IR spectrum and the short wave IR spectrum. As mentioned above, the operations in these spectra only allow the detection of the outer surface of the product, and therefore each drug must be inspected separately outside the container. On a commercial scale, such a limitation is a serious impediment to the efficiency of counterfeit detection. Moreover, checking the liquid drug becomes problematic. Additionally, as mentioned above, many capsules are coated with a thin layer of, for example, gelatin, which prevents the detector device from determining the authenticity of the medicament.

U.S. Pat. No. 7,126,685 describes light absorption spectroscopy, the method comprising providing a container (e.g., a vial containing a sample); rotating the container; directing a light beam comprising one or more wavelengths consisting of visible wavelengths, infrared wavelengths, and ultraviolet wavelengths; and measuring a characteristic of the light beam after the light beam passes through the container. U.S. Pat. No. 7,126,685 does not relate to the detection of counterfeit drugs, let alone on a commercial scale, and therefore does not provide a solution to the counterfeiting problem of the aforementioned industry.

In the prior art, the development of IR techniques for the detection of counterfeit drugs has been entirely limited to the field of spectroscopy, particularly near IR. Near IR spectroscopy is limited in its detection capabilities because it is limited by surface (e.g., drug coatings, external packaging, etc.) reflections. In spectroscopy, the molecular structure of a drug is measured in the frequency domain, and the characteristic curvature is analyzed with the corresponding features to determine the authenticity of the drug.

Thermography is an infrared imaging method in which radiation emitted from an object is detected based on the temperature of different locations through the subject and an image is produced from the radiation. In passive thermography, an image of the emitted radiation of an object is acquired at a steady state temperature. In active thermography, a heat pulse is applied to the object to change its temperature, and a plurality of images are acquired during the entire temperature cycle from the moment of applying the temperature heat pulse until the sample drug reaches the ambient temperature and for a predetermined period of time.

Thermography measures the distribution of the emission from the object and it works only in mid-wavelength IR (MWIR between 3-5.4 microns) and long-wavelength IR (LWIR between 8-14 microns). This is in contrast to spectroscopy which involves spectral distribution of the reflection from objects mostly in NIR (near IR) and SWIR (short wavelength IR). The inventors have found that the use of thermography allows for deep inspection of the object, i.e. well beyond the outer surface of the surrounding container and object.

Although heat-based systems (especially in the field of thermography) are well developed in fields such as military/security systems, non-destructive testing, and medical imaging, such systems have never been suggested for use in detecting counterfeit products, especially in the pharmaceutical industry.

It is therefore an object of the present invention to provide a method and system for determining the authenticity of a pharmaceutical product, which overcomes the disadvantages associated with the prior art.

It is another object of the present invention to provide a method and system for determining the authenticity of pharmaceutical products by thermography, i.e. by an IR imaging system operating in MWIR or LWIR spectroscopy.

It is an additional object of the present invention to provide a method and system for determining the authenticity of a pharmaceutical product by passive or active thermography.

It is another object of the present invention to provide a method and system that can inspect pharmaceutical products in depth and determine counterfeits.

It is another object of the present invention to provide a method and system that can inspect and determine the counterfeiting of a pharmaceutical product even from outside the package of the pharmaceutical product without the need to open the package.

It is another object of the present invention to provide a method and system that can inspect and determine the counterfeiting of a plurality of pharmaceutical products packaged together without the need to open the package.

It is another object of the present invention to provide a method and system that can inspect and determine the counterfeiting of pharmaceutical products from outside the multilayer package.

It is another object of the present invention to provide a method and system that can inspect and determine counterfeiting of liquid drugs from outside their containers.

It is another object of the present invention to provide a method and system that enables the manufacturer of a pharmaceutical product to design unique features for products that are difficult to counterfeit and that can be easily verified.

Additional objects and advantages of the invention will become apparent as the description proceeds.

Disclosure of Invention

The present invention relates to a thermographic IR system for determining the authenticity of a pharmaceutical product, comprising: (a) a thermographic IR device for: (a.1) acquiring, under predetermined controlled conditions, authenticity features of an authentic pharmaceutical product, said authenticity features comprising at least one thermographic image of said authentic product, each said image describing the distribution of IR radiation in the MWIR or LWIR spectrum on said product as a function of temperature and emissivity; (a.2) storing said acquired authenticity signature in a memory; and (a.3) for a tested pharmaceutical product corresponding to said authentic product and whose authenticity is suspected, acquiring test features under the same predetermined controlled conditions, said test features also comprising at least one thermographic image of said tested product, each said image describing the distribution of the IR radiation in the MWIR or LWIR spectrum on said tested product as a function of temperature and emissivity; and (b) a comparison unit for making a comparison between the authenticity signature and the test signature.

Preferably, said predetermined controlled conditions comprise a definition of a temperature variation signal, which in turn comprises a rate of temperature variation applied to the product, and a duration of time during which said temperature variation occurs.

Preferably, a respective image of each of the authenticity feature and the test feature is acquired at a particular time during or after the temperature change signal.

Preferably, a comparison is made between the selected single images from each of the authentic and test features.

Preferably, a comparison is made between respective two images from the real and test features, wherein each of the images in turn reflects a mathematical operation performed on the respective image or images acquired at a particular time during or after the temperature change signal.

Preferably, said predetermined controlled conditions further comprise a definition of the type of heat source used to influence said temperature variation.

Preferably, said predetermined controlled conditions further comprise a definition of a profile of said temperature variation.

Preferably, the predetermined controlled conditions further comprise a definition of the distance to the heat or cooling source.

Preferably, the predetermined controlled condition further comprises a definition of capturing a feature image in the LWIR, MWIR, or both.

Preferably, the predetermined controlled conditions further comprise the definition of one or more filters, each filter limiting the image capture to a spectral range.

In one embodiment, the pharmaceutical product is a solid drug.

In another embodiment, the pharmaceutical product is a liquid medication.

Preferably, each of the authentic and corresponding test signatures comprises one or more thermographic images of the product packaging.

Preferably, the authentic and corresponding test characteristics of the product are obtained with or without the package containing the pharmaceutical product itself.

In one embodiment, the solid pharmaceutical product is a pill packaged in a carton package.

In another embodiment, the solid pharmaceutical product is a pill packaged in an aluminum or plastic package.

In another embodiment, the solid pharmaceutical product is a pill packaged in one or more aluminum or plastic packages, which in turn are included in a carton package, and wherein the conditions include acquiring images from outside the carton package.

In another embodiment, the liquid medicant is contained within a container, and wherein the conditions include acquiring images from outside the container package.

Preferably, the memory comprises a remote database or a local database, wherein the database contains a plurality of authenticity signatures for one or more pharmaceutical products.

In one embodiment, the memory includes a remote database, and wherein the comparison is performed remotely at the location of the remote database.

In one embodiment of the invention, the comparison unit comprises image processing means for automatic comparison between the images, and wherein the authenticity is determined when a similarity above a predetermined threshold is found.

Preferably, the comparison unit comprises a display for displaying the real image together with the corresponding test image for visual comparison by an operator.

In another embodiment, the system further comprises a signal generator for generating said temperature change signal.

According to various embodiments of the invention, the temperature variation is performed by one or more of the following ways:

an oven;

microwave;

an IR lamp;

a laser beam;

cooling by gas expansion;

a thermoelectric cooler;

and (4) ultrasonic waves.

According to various embodiments of the invention, the temperature variation is performed in one or more of the following forms:

a dirac function;

a step function;

a rectangular function;

a sawtooth function; and

a periodic function.

In an embodiment of the invention, the thermographic IR device comprises: (a) a thermographic 2D focal plane array for detecting IR radiation energy in the MWIR and LWIR ranges; (b) an optical assembly for focusing the radiation on the focal plane array; and (c) a controller for operating the focal plane array and for converting analog output of the array into a digital high resolution image.

In an embodiment of the invention, the real and test features further relate to images reflecting 2D radiation from the drug in one or more of the ranges 5.4-8 μm and 14-20 μm.

In an embodiment of the invention, the conditions comprise the use of one or more IR polarizers.

In an embodiment of the invention, the authentic drug product is intentionally designed to introduce a distinctive authentic signature when operated in conjunction with the system of the invention.

In an embodiment of the invention, said design of said authentic product comprises one or more coating or edible materials.

In an embodiment of the invention, the edible material is a bubble added to the product in a specific pattern.

In another embodiment, the authenticity verification is extended to include also verification that the storage conditions of the pharmaceutical product are fulfilled during the life of the pharmaceutical product, wherein the product is coated with an edible film which changes its emissivity and form when exposed to harmful storage conditions and by this change also changes its authenticity characteristics.

In another embodiment of the invention, the pharmaceutical product is contained in a package, which in turn comprises an internal heating element, and wherein the temperature change signal is provided to the element to influence the temperature change.

In another embodiment of the invention, the temperature recording device is a 1-pixel measurement device.

Drawings

In the drawings:

FIG. 1 illustrates a block diagram schematically showing the components of a first embodiment of the system of the present invention;

FIG. 2 illustrates a schematic view of a cooling detector used in a first embodiment of the present invention;

figure 3 shows images of five tablets, four of which are true and one of which is false, as acquired by a standard CCD camera.

Figure 4 shows a two-dimensional thermographic image of the tablet of figure 3 as obtained by the apparatus of the present invention at t ═ 1 second after the application of the cooling pulse;

figure 5 shows a two-dimensional thermographic image of the tablet of figure 3 as obtained by the apparatus of the present invention at t-10 seconds after the application of the cooling pulse;

figure 6 shows a two-dimensional thermographic image of the tablet of figure 3 as obtained by the apparatus of the present invention at t-15 seconds after the application of the cooling pulse;

FIG. 7a shows an InSb cooled prototype apparatus used to test the present invention;

FIG. 7b shows a comparison between two empty aluminum packages of a true West Lily pill and a false West Lily pill as obtained by the device of FIG. 7 a;

FIG. 7c shows a comparison between two empty carton packages of real and fake West pills as obtained by the device of FIG. 7 a;

FIG. 7d shows a comparison between two real and fake Lei's pills as obtained by a CCD (VIS) camera;

FIG. 7e shows a comparison between the two real and fake real Leishi pills of FIG. 7d as obtained by the device;

fig. 7f shows a comparison between two genuine and fake aluminum packages comprising a true and fake fusi pill, respectively, as obtained by a ccd (vis) camera;

FIG. 7g shows a comparison between two true and false aluminum packages comprising the West Lishi pill of FIG. 7f as obtained by the device;

FIG. 7h shows a comparison between two real and fake cartons including aluminum packages that in turn each include real and fake Li-;

FIG. 7i shows a comparison between the two real and fake carton packages of FIG. 7f including aluminum packages that in turn each include a real and fake Li-;

FIG. 8a shows a comparison between two real and two fake chocolate pills, respectively, as obtained by the uncooled device;

FIG. 8b shows two true images and two false images of the West Lishi pill of FIG. 8a as obtained by a CCD (VIS) camera;

FIG. 8c shows a comparison between two fully packaged (carton and aluminum) real Saili pills and two fully packaged pseudo-Saili pills, respectively, as obtained by the uncooled apparatus;

fig. 9a shows images of a true and a false filled liquid methadone container as obtained by a ccd (vis) camera;

fig. 9b shows the same container of fig. 9a as seen respectively through the cooled InSb device of the present invention.

Detailed Description

There is currently no complete solution to the problems associated with counterfeit drugs. The present invention provides a new method and system for determining the authenticity of a pharmaceutical product using a thermography based system. The system can determine counterfeiting even without removing the product from its cover, package or container.

The term "drug" as used herein refers to any form of medication (e.g., tablets, capsules, or solutions), and is used interchangeably herein with the term "medication".

According to an embodiment of the present invention, thermographic characteristics of a sample of each of a plurality of authentic pharmaceutical products are initially acquired and stored in a database. The initially acquired features are referred to below as "true features" of the drug. Thermographic features are thermographic (i.e., in the LWIR or MWIR range) two-dimensional views of the drug product, which are acquired under controlled specific product conditions. Such specific conditions may be, for example, a 2D response of the drug to a heating (or cooling) signal over time, a response after a specific predetermined time after the initial signal, etc. The form of the heating or cooling signal is predetermined, but may vary (which may be, by way of example only, a square pulse, a sawtooth signal, etc.). Also, as will be detailed, the response may be limited to specific wavelengths in the LWIR or MWIR range, which may use polarization, etc. In any event, the inventors have found that such responses are very unique to the composition and structure of the drug and are difficult to mimic.

As mentioned, the MWIR and LWIR ranges are conventionally referred to in the art as ranges between 3-5.4 microns and 8-14 microns, respectively. The limitation stems from the fact that the atmosphere typically absorbs IR between the ranges (i.e., between 5.4-8 microns). However, the invention may also use the ranges described below: a VLWIR range of 5.4-8 microns, and even 14-20 microns, and with various detectors also sensitive in the ranges described later. Thus, the use of MWIR and LWIR throughout this application should not be considered limiting of its scope to exclude the 5.4-8 micron and/or 14-20 micron ranges.

According to the present invention, the characteristics of the pharmaceutical product in any given market, the authenticity of which is suspected, are compared with the authenticity characteristics to verify whether it is authentic. And under substantially the same conditions as used in acquiring the true features.

For example, a feature may be displayed as one or a series of visual images of a drug, and may be quantified by a value for comparison with a corresponding sample drug, as described below. Because the pseudodrug is assumed to comprise a different molecular composition (and sometimes structure) than the authentic drug, the MWIR or LWIR emissions, for example, as a function of time (i.e., characteristic) of the authentic drug are different than those of the pseudodrug.

The inventors of the present invention have found that after providing a heating or cooling signal (herein, for simplicity, these two terms are simply referred to as "heating signal") to a counterfeit product, the use of a thermography system for detecting counterfeit products in MWIR and LWIR spectra, in particular, but not by way of limitation, has significant advantages over prior art counterfeit drug detection systems that utilize spectroscopic apparatus and methods. For example, as mentioned above, the prior art uses detection systems in the near wavelength infrared (NIR) spectrum, which is based on reflection from the product, and thus enables inspection of only the outer surface of the drug. Such prior art spectroscopy-based systems are often difficult to thread through a drug container, cover or package (all of which terms will be referred to hereinafter as "package"), and in any event require the package to be opened. On the other hand, the thermographic MWIR or LWIR detection system of the present invention allows for the detection of internal molecular changes of the drug, which bypass the coating of the packaging that may be present on the surface of the capsule (or on any other form of drug). In other words, the MWIR and LWIR detection systems of the present invention pass through the package of the drug, thus eliminating the need to open the package. Even when the medicament is contained in the entire container or even in the entire crate or carton, the operator of the system is allowed to determine the authenticity of the medicament in a single procedure, thereby greatly increasing the efficiency of the detection process on a commercial scale. Furthermore, by allowing the drug to remain in the container, the process for detecting the authenticity of the liquid drug is far more practical than that provided by procedures performed using prior art spectroscopy-based systems.

The use of a thermographic system allows the detected features to be displayed in the form of images in which the variations in temperature and radiation emission are clearly shown. This allows for a greater ability to distinguish drugs on a visual scale.

Fig. 1 shows in block diagram form the general structure of a first embodiment of a thermographic IR system 100 of the present invention. System 100 includes a heat source 110 for heating (or cooling) sample drug 102 to a modified temperature, thereby changing its IR emission in the MWIR or LWIR range. The system 100 further comprises a thermographic arrangement 120 for detecting radiation emitted from the drug 102. The detection may be continuous or may be performed for some predetermined period starting from the moment the temperature heat pulse has been applied. The detection conditions should be as consistent as possible with the conditions under which the actual features stored in the database 130 have been collected. The thermographic arrangement 120 includes one or more IR array detectors 122 (also commonly referred to in the art as "focal plane arrays") for sensing and converting IR radiation energy in the MWIR and LWIR ranges into images. These arrays are well known in the art and are used in, for example, night vision thermal systems. The optics 124 focus the radiation on the two-dimensional array 122. The optical device may include one or more lenses, filters, and/or polarizers. The controller 126 operates the array 122. The controller also receives analog signals from the detector array 122 that describe the thermographic emission from the drug 102. The controller 126 also converts the signals from the array into a digital high resolution 2D current product image 140. A 2D image 140 of the radiation emission from the drug 102 is displayed on the display unit 132. As mentioned, the database 130 stores a plurality of authentic characteristics of a number of authentic drugs. The stored features may be generally represented as images. In one embodiment of the invention, the controller 126 extracts 129 the true features 140' of the drug 102 (as previously acquired from the true drug) from the database 130 and displays it alongside the current image 140 for visual inspection. It should be noted that the characteristic levels of IR emission are displayed in various colors on the display unit 132 to emphasize the varying spatial emissions from the product. As described above, it has been found that there is a very clear visual distinction between images 140 of genuine and fake drugs of all general drugs that have been tested by the inventors. It should be mentioned once more that the present features are obtained under the same controlled conditions as the real features. In any case, the actual features in the database 130 and the conditions under which they were collected can be readily defined to reflect and emphasize such differences. Some options for changing such conditions will be described in detail later. Alternatively, instead of visual inspection and comparison of the images on the screen 132, the comparison may be performed automatically by the image processing unit 128. The image processing unit 128 determines a correlation factor between the current feature and the stored true features from the database 130 and evaluates whether the correlation factor is above a predetermined threshold. After this evaluation, the image processing unit 128 establishes a conclusion as to whether the sample 102 is real or false, and the conclusion 104 may be displayed on the display unit 132 or notified to the user in any other conventional manner.

In another option, the drug being tested (suspected) may be compared to a reference drug known to be authentic (rather than pre-stored signatures in a database). In a similar manner to the previously described processing, the comparison may be made by visual inspection or automatically by applying image processing algorithms.

The database 130 may be located in various locations. In one embodiment, the database 130 is located in the testing device. In another embodiment, the database 130 is maintained in a secure manner at a secure location and relevant real features are extracted therefrom by the testing device via the internet (or any other communication, such as cellular technology). In another embodiment, the database 130 is maintained in a secure manner, the image 140 is transmitted to the secure location via the internet, and a comparison is made in the secure location, which in turn transmits a yes/no result regarding the authenticity of the product to the testing device. As mentioned, in another option, images locally extracted from physical ("master") products known to be certainly authentic are compared.

The heat source 110 is preferably controlled by the signal generator 105. The heat source 110 and signal generator 105 together mimic the same conditions under which the true characteristics of the drug 102 have been collected. For example, the heat source 110 may be an oven, microwave, IR lamp, laser beam, etc. for heating (or cooling, e.g., by gas expansion) a single medicament (e.g., a capsule), or its entire container. The thermal signal 107 from the generator 105 may be a dirac function, a step function, a rectangular function, a periodic function, a sawtooth function, and any other specified function. It is important to note that the response of the drug to heat is different depending on the type of heat applied to the drug (e.g., oven, microwave, etc.) and the type of thermal signal as provided from the generator 105. Thus, if desired, more than one heat source and combination of thermal signals 107 may be used in order to obtain more comprehensive characteristics of the sample drug 102. Also, a number of features that reflect changes in emission from the drug over time or in response to polarization or filtering may also be used. Of course, in this case, the database needs to store a number of real features for comparison as a function of signal form of time, wavelength, polarization, heat source type, etc.

In one embodiment, the IR temperature recording device 120 may include both cooled and uncooled detectors. The cooled detector is capable of detecting infrared radiation energy in the MWIR (3 μm-5.4 μm) range. For example, the detector array comprises 320 × 256 individual elements of about 30 μm size per pixel, or alternatively 640 × 512 individual elements of about 15 μm pitch (pitch) size. In this case, the array may be made of InSb (indium antimonide) or MCT (mercury cadmium telluride), and operated at freezing temperatures. Also, the detector array may be connected to a Focal Plane Processor (FPP) array (not shown in the figures) by indium bumps (Indiumbumps) and may be illuminated from the backside. The uncooled detector is an electro-optical component that converts infrared radiation energy in the LWIR (8-14 μm) range. Uncooled detectors are fabricated with detector arrays mounted in vacuum dewars. For example, the non-cooled detector array comprises 320 × 256 individual elements of 20-30 μm size per pixel, or alternatively 640 × 512 individual elements of 20-30 μm pitch size. The array is made of VOx (vanadium oxide) or amorphous silicon and operates at about room temperature.

It should be understood that alternative cooled and uncooled IR detectors having different capabilities and configurations may be used for the purposes of the present invention. For example, LWIR (8 μm-12 μm) array detectors may be optionally cooled from MCT or QWIP (Quantum well Infrared photodetector) sensors.

Although not a necessary requirement, in one embodiment the filter/optics may comprise a set of filters, for example in the form of filter wheels (see fig. 2), as is well known in the art. The wheel may comprise a set of narrow band filters and/or IR polarizers, preferably from MWIR to LWIR. Alternatively, any optical device capable of changing the spectral transmission characteristics at high frequencies may be used.

FIG. 2 shows the components of the cooled thermographic array detector 122 in schematic form. The array detector 122 includes a focal plane array 150 and an electronic interface board 156. Vacuum chamber 152 is shown coupled to a chiller 154. In an alternative case, when a non-cooled detector is used, the assembly does not include the cooler 154. However, to maintain the focal plane array at a stable temperature, a thermoelectric cooler (TEC) may be provided instead. When the object emits IR radiation, as represented by arrow 158, it is filtered by filter 160 and impinges on focal plane array 150 in the desired wavelength.

Thus, in the above-described embodiment for performing the authenticity detection program of the present invention, the active thermography method is performed. In this case, a sample drug is obtained and heated by a heat source 110, which in turn is controlled by a signal generator 105 (which generates, for example, a step function, dirac function, rectangular function, periodic function, etc.). The emitted IR radiation is sampled at least once by the thermographic IR system during at least a portion of the heating and/or relaxation period (i.e. the cooling of the product) in a manner consistent with the conditions maintained when the authentic features were acquired. For example, the drug is heated by the heat pulse for a predetermined period of time until the original temperature of the drug is increased by a predetermined amount to the corrected temperature. The drug is then cooled back to its original temperature. The thermographic arrangement of the present invention samples the emitted radiation during at least a portion of the heating period and/or the cooling period to determine a characteristic of the sample drug. As currently obtained, the characteristics of the drugs are compared visually on a display or automatically by a signal processing unit, the corresponding real characteristics of the drugs being as previously obtained and stored in the database 130.

As noted, the emitted radiation response is a function of time of the sample drug (i.e., either a continuously varying response or radiation after a certain period of time from the moment heating is initiated) and compared to the characteristics of the corresponding real version of the sample drug. A sample is considered authentic if the characteristics of the authentic version of the drug are the same, or at least highly correlated with the sample drug above a predetermined threshold. However, if the characteristics of the actual drugs are not identical and are also not highly correlated with the sample drug above a predetermined threshold, the sample is considered false. If the sample drug is counterfeit, necessary action may be taken depending on the circumstances in which the counterfeit drug is found.

As previously described, in an alternative aspect, the sample drug is cooled by the heat pulse generator for a predetermined time (e.g., a rapid cooling method such as gas expansion) until it reaches a predetermined modified temperature. The response is acquired during the entire pulse, at a specific time after the start of the pulse, or even at some time after the end of the pulse. In a similar way to the above, also in the case of cooling, the real features as well as the features from the currently tested product are obtained under exactly the same controlled conditions (i.e. the same pulses, the same cooling or heating temperature, the same time period, etc.).

In an alternative aspect, to ensure accurate controlled conditions, the drug may be placed on an extended black body (such extended black bodies are known in the art and are manufactured by, for example, CI corporation).

In another alternative aspect, the complete test process is conducted in a temperature-stable and control room that ensures uniform ambient temperature conditions.

In the event that the characteristics of the true version of the sample medication have not been previously recorded and stored in the database, the characteristics of the sample medication are obtained as described herein and stored in the secondary database of the system of the present invention until the true version of the sample medication is obtained, at which time the characteristics of the sample medication are compared thereto.

According to an alternative aspect of the invention, a passive thermography is performed in which the sample is kept at ambient temperature and is not heated or cooled. According to this embodiment, the IR detector system only detects steady state radiation emissions in the MWIR or LWIR spectral wavelengths, and not as a function of time. Thus, the database in this case contains the appropriate temperature profile for the actual drug in the MWIR and/or LWIR spectra for a particular ambient temperature.

In another alternative aspect, a complete test process can be performed in a temperature stabilization and control room that ensures uniform ambient temperature conditions within the room.

In another embodiment, the product package itself (e.g., an aluminum package of pills) may include one or more internal heating elements. The one or more heating elements in this case are activated by providing corresponding internal electrical signals to the one or more heating elements, which in turn heat the drug.

According to the present invention, the manufacturer may add additional secret identification information to the authentic drug during the manufacturing process to further distinguish the authentic drug from the counterfeit drug. For example, an internal barcode in the form of a bubble may be included in the medication by the manufacturer. There are many other possible ways in which additives may be included in a drug that would affect the response in MWIR or LWIR without affecting the medical effectiveness of the drug. While such addition to a drug has no significant effect (if any) on the medical effectiveness of the drug (and therefore, does not require additional regulatory approval by the FDA), it may significantly affect the true characteristics of the drug to the extent that it is difficult to mimic, or form distinguishing features that distinguish from those of a drug known to be fake. It should be noted that a pharmaceutical manufacturer may also include such additives on the pharmaceutical packaging. For example, a pharmaceutical manufacturer may include a portion of a pharmaceutical or packaging having a high emissivity, thermal capacity, etc.

In another aspect of the invention, the invention is capable of determining whether a drug has been exposed to inappropriate thermal conditions during its useful life. In this case, the medicament is coated with an edible sheet that changes its physical properties when exposed to temperatures above some predetermined allowed limit. By way of example only, the medicament may be coated with a thin layer of chocolate and the actual features of the medicament include such a layer. Later, if the drug has been exposed to a temperature above room temperature, the coating melts and it also affects the characteristics of the drug as obtained by the device of the invention (MWIR or LWIR, active or passive radiation, as is often the case). In this way, the device of the invention can not only detect counterfeiting, but also ensure the quality of the drug which may be subjected to inappropriate storage conditions during its lifetime. Moreover, in a similar manner, the device of the present invention may also ensure the quality of the drug and detect that the drug has been manufactured incorrectly while lacking certain ingredients. Such a lack of contribution typically involves a deviation from true features from the MWIR or LWIR 2D emission angle. Thus, for the sake of brevity, quality assurance as described herein will not be distinguished from conventional counterfeits in the present application. In other words, the term "counterfeit" of a drug relates to any deviation of the actual drug composition, whatever the cause of the deviation.

In another embodiment of the invention, although the invention has been described herein with reference to detecting counterfeit drugs, the application of the methods and systems described herein can equally be used to identify other counterfeit products, such as currency, diamonds, food products or other products whose deviation from their authentic "component" material results in a change in their 2D (thermographic) LWIR or MWIR emission time (e.g. after being subjected to some predetermined controlled temperature change), and thus, in one particular embodiment of the invention, the term "drug" in this application can be extended to include such other types of products (although they are not actually drugs).

The thermographic arrangement of the present invention may detect a counterfeit drug by applying one or more of the following techniques:

1. predetermining the temperature change (i.e., minimum to maximum temperature, or vice versa) to be applied to the sample (i.e., to the "main" genuine drug, and to the drug in question);

2. the type of heat source that will be used to affect the temperature change, such as a typical oven, a microwave-based oven, a laser-based heating source, a refrigerator, a thermoelectric cooler, etc.;

3. the profile of the temperature change signal, i.e., spike, sawtooth, step, cyclic, etc.;

4. distance from a heat (cooling) source;

5. the type of detector, i.e., a cooled (MWIR) detector or a non-cooled (LWIR) detector;

6. at two times (e.g. at a predetermined time T)₁And T₂) The option of applying an average of the responses from the samples. It should be noted that the use of other types of mathematical operations is also possible, either in the time domain or in the spatial domain. The analysis in the time domain represents an analysis of several frames obtained in a certain period of time, for example an average of 10 consecutive images. Analysis in the spatial domain means that some image processing algorithm is applied on a single image, for example in order to emphasize the edges of the real and/or tested image. Specific examples for operations in the time domain are an average over time of the frame images, a time-varying STD (standard deviation) of the frame images, a time-varying fourier transform, a low-pass filter in the time domain, or a high-pass filter in the time domain. Specific examples for operations in the spatial domain are FFT (fast fourier transform), wavelet transform, Discrete Fourier Transform (DFT), Discrete Cosine Transform (DCT), low-pass, or high-pass. These are merely examples, and other mathematical operations in the spatial or time domain may be applied;

7. the option of using one or more filters in order to limit the response to a particular optical range;

8. an option to make a comparison between the characteristics of the actual outer package of the pill and the suspected outer package (aluminum or carton or plastic package) or the inner aluminum package of the pill;

9. as mentioned, the authenticity verification made by the system of the present invention includes predetermined conditions applied to the product when obtaining the authenticity and test characteristics. These conditions, although predetermined, are flexible. Thus, if for some reason it is found that the device of the present invention cannot clearly distinguish between a particular genuine drug and a counterfeit drug when a particular condition is applied, the predetermined condition can be easily modified in order to find a more suitable condition. The various parameters that form the possible conditions can vary widely and the fact that suitable conditions can almost certainly be found for each and every drug in the market will lead to a distinctive authenticity feature for the product.

All of the above options may be used in defining the conditions for obtaining the drug characteristics. It should be noted that the conditions may vary from one drug to another in order to find conditions that provide a distinguishing result. Once a counterfeit drug is known, these conditions are specifically determined for each drug to find the conditions that best distinguish between a genuine drug and the given drug known to be counterfeit. Thus, various conditions may be applied to various drugs or various types of drugs. Furthermore, the device may be operable in one of the following modes:

1. an automatic mode in which evaluation is performed by image processing that makes a comparison (correlation) between images of an actual drug and a suspected drug;

2. image processing as in item 1, while certain operations apply to the image, such as high-pass, low-pass, FFT, DFT, DCT, etc.;

3. manual mode, in which the operator of the device makes a comparison visually between the two images. As will be demonstrated by the following examples, operation in such a manual mode provides good results in many actual typical counterfeiting scenarios;

4. in one option, the device may collect features from only the suspected medication and transmit them to a secure location (which maintains a library of features) for comparison. In this case, the comparison is performed at a safe place. After the comparison, securely returning a yes/no result to the device;

5. in another option, the device includes a local database of features therein for various drug types;

6. in another option, a local comparison is made between the signature as obtained from the suspected medication and the signature as obtained from the medication that is physically available to the operator at the same time and known to the operator to be absolutely authentic ("reference medication"). When verification is required, the device first extracts the true features from the reference drug on site, then it extracts the features from the drug being tested, then a comparison is made between the two features and a final conclusion is provided.

In another embodiment of the invention, the MWIR or LWIR array detector 122 is a single pixel "array" (although the term "array" generally refers to multiple sensors and does not refer to the case when only one sensor is used, for simplicity, the invention also uses the term "array" when the array includes only one sensor, i.e., pixel). More specifically, the array includes only one IR sensor. There are three alternative options for operating with the one pixel array, as follows:

a. in obtaining the true features from the medication, the medication (e.g., pill) 102 is in a predetermined fixed position and orientation relative to one pixel array, and the features (i.e., radiation from the medication) are obtained from the one pixel array relative to a predetermined point on the outer surface of the medication 102. In this case, the optical device 124 directs one pixel array toward the predetermined point. In obtaining the test features from the drug product, the drug in question is precisely located in the same position and orientation as defined for the authentic drug, so that a comparison is made with respect to the same points in the two authentic and tested drugs, respectively.

b. In obtaining the true features from the drug, the drug (e.g., pill) is positioned at a predetermined fixed location and orientation relative to one pixel array, and the features (i.e., radiation from the drug) are obtained from the one pixel array relative to the entire drug. In this case, the optical device 124 images the entire drug on one pixel array, so that radiation from the entire drug is measured. In obtaining the test signature from the drug being tested, the drug in question is precisely located in the same position and orientation as defined for the authentic drug, so that a comparison is made with respect to the same orientation in the two authentic and tested drugs.

c. The third alternative is the same as the first option described above. However, the optical device is movable such that it "scans" the drug 102 in such a way that it measures another point on the outer surface of the drug at a time.

It should be noted that the one pixel array embodiment (especially the first two alternatives thereof) is generally simpler and has a lower cost, and is therefore more suitable for use by the end user of a medicament, for example in his home.

It should also be noted that the system of the present invention may in principle be operated in two modes of operation, which are referred to herein as "active" and "passive". In the passive mode, the authenticity signature and the test signature are obtained at ambient temperature without the application of a heating or cooling signal. Typically, in passive mode, the IR radiation is: (a) a function of the emissivity of the object, (b) a function of the selected wavelength band (MWIR or LWIR, etc.), (c) a function of the temperature of the object (planck's equation), and (d) a function of the ambient temperature. Thus, the operation of a passive-mode thermographic system reveals most of the features of the object's surface, rather than its complete internal structure. In the active mode, the authenticity signature and the test signature are obtained after or during application of the heating or cooling signal to the object. In this case, the IR radiation from the product is: (a) a function of the operating wavelength band (MWIR or LWIR, etc.); (b) a function of product temperature (planck's equation); (c) a function of ambient temperature; (d) a function of the emissivity of the object; (e) a function of the thermal conductivity of the object; (f) a function of the thermal capacity of the object; (g) a function of thermal convection of the object; and (h) absorption of the heat pulse due to the molecular structure of the object. Thus, the use of the present invention in the active mode is preferred because it reveals various attributes of the object not revealed when operating in the passive mode. A complete imitation of all said properties in a counterfeit product, which all affect the result of the active mode operation of the inventive system, is not at all possible.

Example 1

5 drug samples (tablets) for testing were obtained by active thermography using the system of the present invention. Four tablets are authentic and one tablet is counterfeit. Figure 3 shows images of 5 samples taken from a standard CCD camera. As can be seen, all 5 samples are substantially identical to the human eye in appearance (color, shape, size) and weight. The middle tablet 302 is counterfeit and the surrounding tablets 303 are authentic.

The tablets were placed on an open surface adjusted to 40 ℃. Pulses were applied to cool the tablets from 40 ℃ to 20 ℃. The system of the present invention was used to detect MWIR emissions from each tablet during cooling.

In fig. 5-7, thermographic images of tablets were displayed using a detector array comprising 640 x 512 individual elements. It should be noted that the images in the experiment, as performed, included a display in the form of a color temperature scale, where the lowest temperature was displayed as blue and the highest temperature was displayed as red. The color in this temperature scale changes between two limits for displaying the other temperatures accordingly. Thus, in this experiment, the determination of the pseudodrug is even easier and more distinguishable than in the black and white images provided in the present application. To this end, the present invention supports the use of such color temperature scales for displaying varying MWIR or LWIR temperature emissions.

Fig. 4 shows a two-dimensional thermographic image of the tablets 302, 303 at t 1 second after the cooling pulse is applied. Next, thermographic images of the tablets 302, 303 are taken at 10 seconds (fig. 5) and 15 seconds (fig. 6) as further cooling occurs. Thus, fig. 5-7 show the temperature recording shots as a function of time and the temperature change from 40 ℃ to 20 ℃.

The thermographic image of the fake drug 302 clearly differs from the thermographic image of the genuine drug 303. The thermographic image in the figure shows that the genuine drugs 303 are gradually lighter in appearance until they are barely detectable by the human eye in front of the background as shown (fig. 6). In contrast to fig. 4, the counterfeit drug 302 that has been taken after the first second is darkened in fig. 5, and then slightly lighter near the fifteenth second image of fig. 6.

Example 2

Feasibility tests were performed using an InSb cooled detector. The feasibility test compares between real West Liriods and counterfeit West Liriods (as provided by the pharmaceutical crime check office of the Ministry of health in Israeli).

The laboratory prototype included:

1. a cooled detector in the MWIR region (3 μm-5.4 μm);

2. an optical device;

3. electronic circuitry for acquiring a 2D digital spatial image from the detector output; and

4. an extended black body for applying a heating signal.

The prototype device is shown in fig. 7 a. The device includes electronics 801, a focal plane array 802 in the MWIR range, optics 803, and a black body 804 manufactured by CI. A west li shi packaging 805 is shown placed over the black body 804.

A number of tests were performed. During testing, various samples were placed on the black body 804. In each of the tests, the black body was initially set at 30 ℃. After stabilizing the temperature of the black body at 30 ℃, the temperature of the drug emission was reduced to 15 ℃ every 1 second recorded throughout the temperature change. The order of the 10 images obtained was averaged to provide a single image for each test. The two real images and the counterfeit image are compared.

Fig. 7b shows a comparison between two empty aluminum packages of real and fake sirloin pills as obtained by the device. It can be seen that the images are very easily visually distinguishable.

Fig. 7c shows a comparison between two empty carton packages of real and fake west Li Shi pills, respectively, as obtained by the device. Again, it can be seen that the two images are very easily visually distinguishable.

Fig. 7d shows a comparison between two real and fake lissajous pills as obtained by a ccd (vis) camera. It can be seen that the pills appear substantially identical.

Fig. 7e shows a comparison between the two real and fake fusi pills of fig. 7d as obtained by the device. It can be seen that the two images are very easily visually distinguishable.

Fig. 7f shows a comparison between two genuine and fake aluminum packages comprising a true and fake fusi pill, respectively, as obtained by a ccd (vis) camera. It can be seen that the package containing the pills looks substantially identical.

Fig. 7g shows a comparison between two true and false aluminum packages comprising the west li pill of fig. 7f as obtained by the device. It can be seen that the two images are very easily visually distinguishable.

Fig. 7h shows a comparison between two real and fake cartons comprising aluminium packs, which in turn each comprise real and fake rifles pills, respectively, as obtained by a ccd (vis) camera. It can be seen that the package comprising the aluminium package with the pills looks exactly the same.

Fig. 7i shows a comparison between the two real and fake carton packages of fig. 7f each comprising an aluminium package further comprising a real and a fake riffle pill, respectively, as obtained by the device of the invention. It can be seen that the two images are very easily visually distinguishable.

As mentioned, the above example and several other examples are performed using an average of several images to obtain the features. It should be noted that other mathematical operations may be used as further options to perform the averaging, such as multiplication, integration, differentiation, division, addition, difference, and so on.

Example 3

The results of example 3 were obtained by a device using a non-cooled detector (in the range of 8 μm to 14 μm). These results were obtained for the same samples as used in example 2.

A number of tests were performed. During testing, various samples were placed on black body 804. In each of the tests, the black body was initially set at 30 ℃. After stabilizing the temperature of the black body at 30 ℃, the temperature of the black body decreased to 15 ℃ during the entire temperature change, when the drug emission was recorded (imaged) every 1 second. The order of the 10 images obtained was averaged to provide a single image as the result of each test. The two real images and the counterfeit image are compared.

Fig. 8a shows a comparison between two real and two fake fusi pills, respectively, as obtained by the uncooled device. It can be seen that the genuine image and the counterfeit image are very easily visually distinguishable.

Fig. 8b shows two true images and two false images of the west Li Shi pill of fig. 8a as obtained by a CCD (VIS) camera. It can be seen that all the pill images appear identical.

Fig. 8c shows a comparison between two fully packaged (carton and aluminum) truly siemens pills and two fully packaged pseudosiella pills, respectively, as obtained by the uncooled device. It can be seen that the corresponding real and counterfeit images are very easily visually distinguishable.

It is known in the art that non-cooled detectors are much cheaper than cooled detectors. The inventors have found that the results obtained for both types of detector are essentially the same. In other words, both provide distinguishable results.

In another embodiment, a cooled MWIR detector and an uncooled LWIR detector are used together in the same system. The use of such a multispectral detector may provide a greater range of sensitivity. While such systems are more expensive and complex than single detector systems, multispectral systems are advantageous in certain difficult to distinguish cases.

Example 4

In example 4, a device with InSb (in the range of 3 μm to 5.4 μm) cooling detectors (640 × 512 pixels at 15 μm pitch) was used.

The test was performed with an actual container of methadone drops and another test with a counterfeit container of liquid methadone. During the test, the sample was placed on the black body. In each of the tests, the black body was initially set at 30 ℃. After stabilizing the temperature of the black body at 30 ℃, the temperature of the drug emission was reduced to 15 ℃ every 1 second recorded throughout the temperature change. The order of the 10 images obtained was averaged to provide a single image for each test. The two real images and the counterfeit image are compared.

Fig. 9a shows an image of a real and counterfeit liquid methadone container as obtained by a ccd (vis) camera. The upper container in the image is authentic while the lower is counterfeit. Fig. 9b shows the same respective container as obtained by the device as a result of the experiment as described. As can be seen, these two images of the real container and the counterfeit container are very easily visually distinguishable.

Although some embodiments of the invention have been described by way of illustration, it will be apparent that the invention may be carried out with many modifications, variations and adaptations, and with many equivalents or alternative solutions that fall within the scope of persons skilled in the art, but without exceeding the scope of the claims.

Claims (34)

1. A method for determining the authenticity of a pharmaceutical product, the method comprising the steps of:

(a) acquiring one or more thermographic IR images of the pharmaceutical product at a wavelength or spectrum of wavelengths selected from a medium to ultra-long wave IR spectrum, wherein the medium to ultra-long wave IR is between 3 μ ι η and 20 μ ι η, the pharmaceutical product being cooled to a temperature below ambient temperature;

(b) comparing the acquired one or more images of the drug product or a quantified value derived therefrom with a characteristic of a reference drug, wherein the one or more images of the drug product and the characteristic of a reference drug are acquired under the same predetermined controlled conditions; and

(c) displaying the comparison, whereby the authenticity of the pharmaceutical product can be determined.

2. The method of claim 1, wherein the drug is actively cooled prior to imaging.

3. The method of claim 1 or 2, wherein a cooling source is used to cool the pharmaceutical product.

4. The method of claim 3, comprising cooling the drug for a period of time sufficient to reach the corrected temperature.

5. The method of claim 3, wherein the cooling of the drug comprises applying a cooling pulse to the drug.

6. The method of claim 5, wherein the cooling pulse takes a form selected from a Dirac function, a step function, a rectangular function, a sawtooth function, and a periodic function, or a combination thereof.

7. The method of claim 1, wherein the one or more IR images are acquired at a time during or after the cooling.

8. The method of claim 1, wherein the wavelength or spectrum of wavelengths is selected from 3 μ ι η -5.4 μ ι η and 8 μ ι η -14 μ ι η.

9. The method of claim 1, comprising processing the one or more IR images of the pharmaceutical product into a visual image or a quantified value.

10. The method of claim 9, wherein the processing uses a spatial domain or temporal domain mathematical operation on the IR image of the drug to obtain the visual image or quantitative value.

11. The method of claim 1 or 10, wherein the comparing comprises correlating visual images or quantified values of the acquired one or more IR images of the drug product with characteristics of a reference drug.

12. The method of claim 11, wherein the characteristic of the reference medication comprises a visual image or a quantified value from a database of visual images or quantified values for a plurality of reference medications.

13. The method of claim 1, comprising displaying the comparison.

14. The method of claim 13, wherein the displaying comprises displaying one or more visual images of the drug with one or more images of the reference medication.

15. The method of claim 13, wherein the display comprises a color display of the one or more images of the drug and a color display of the one or more images of the reference medication.

16. The method of claim 13, wherein the database comprises a plurality of characteristics of reference drugs, the plurality of characteristics comprising at least one intentionally introduced distinguishing mark that can be imaged by the thermographic arrangement.

17. The method of claim 16, wherein the distinguishing mark comprises one or more of a coating or edible material in the reference medication or an air bubble contained in the pharmaceutical product.

18. A system for determining the authenticity of a pharmaceutical product, the system comprising:

thermographic infrared means for acquiring one or more thermographic IR images of the pharmaceutical product at a wavelength or spectrum of wavelengths selected from a medium to ultra-long wave IR spectrum, wherein the medium to ultra-long wave IR is between 3 to 20 μ ι η;

a cooling source for cooling the drug to a temperature below ambient temperature; and

a display unit for displaying at least features of the one or more IR images and a reference drug, or for displaying a comparison result between the features of the one or more IR images and a reference drug, wherein the features of the one or more IR images and a predetermined reference drug of the drug are acquired under the same predetermined controlled conditions.

19. The system of claim 18, wherein the wavelength or spectrum of wavelengths is selected from 3-5.4 μ ι η and 8-14 μ ι η.

20. The system of claim 18, wherein the thermographic IR device is configured to acquire one or more IR images at a time during or after the cooling.

21. The system of claim 18, comprising a comparison unit for comparing between said acquired one or more IR images of said drug product and authentic characteristics of a reference drug.

22. The system according to claim 21, wherein said comparing unit comprises a processing unit adapted to receive said one or more acquired IR images from said thermographic IR device and to process said one or more images into a visual image or a quantitative value comparable to said characteristic of a reference drug.

23. The system of claim 18, wherein the display unit is adapted to display one or more visual images or quantified values of both the drug and the reference medication.

24. The system of claim 18, for displaying the one or more IR images of the reference medication.

25. The system according to claim 21, wherein the comparison unit is adapted to process the one or more acquired IR images compared to characteristics of a reference drug.

26. The system of claim 25, wherein the comparison is between the one or more acquired IR images and one or more visual or quantitative images of the reference medication obtained under the same conditions as used for the drug.

27. The system of claim 18, wherein the reference medication is an authentic medication.

28. The system of claim 18, comprising a database of actual characteristics of the reference medication.

29. The system of claim 28, wherein the database comprises a plurality of characteristics of reference drugs, the plurality of characteristics comprising at least one intentionally introduced distinguishing mark that can be imaged by the thermographic arrangement.

30. The system of claim 29, wherein the distinguishing mark comprises one or more of a coating or edible material in the reference medication or an air bubble contained in the pharmaceutical product.

31. The system of claim 28, wherein the database is remote from the thermographic infrared device.

32. The system of claim 21, wherein the comparison unit is remote from the thermographic infrared device.

33. The system of claim 28, comprising a memory carrying the database.

34. The system of claim 18, wherein the cooling source is adapted to apply a cooling pulse on the drug for a period of time sufficient to cool the drug to a modified temperature, and wherein the cooling pulse is applied in a form selected from a dirac function, a step function, a rectangular function, a sawtooth function, and a periodic function, or a combination thereof.