Determination of concentration

(54)

PATENT INVENTOR INVENTOR'S OFFICE NAME

Ägrovision AB, Ideon 223 70 Lund SE

Peter Egelberg, Lund SE

AWAPATENT AB

Concentration determination of one component in a mixture of at least two components

CALLED PUBLICATIONS: - - SUMMARY:

(56) (57)

An apparatus for determining the concentration of a first component in a mixture of at least two components having different absorption properties in the IR region has image recording means (3,24) arranged to image the mixture by means of IR radiation to provide at least one image. It further has image processing means (6.26) which, by means of intensity values ​​for pixels in the image representing the mixture, determine the concentration of the first component of the mixture.

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The numbers in brackets indicate international identification code, INID code. Letters in clamps indicate international document code.

512 098

XJAWAPATENT

Office / Administrator

Malmö / Cecilia Perklev / CH

AGROVISION AB

Application no. Reference

2980570

Field of the Invention

The present invention relates to a device for determining the concentration of a first component in a mixture of at least two components having different absorption properties in the IR range.

Background of the Invention

In the manufacture of drugs, an active substance is often mixed with an inactive substance to obtain sufficient volume of the drug and to obtain suitable properties of the drug. The substances are often in the form of powder consisting of a variety of particles. Furthermore, normally large volumes of powder are mixed to produce a very large number of doses of the drug. It is then of utmost importance that the mixture be homogeneous so that the concentration of the active substance is the same in all doses, for example in all tablets prepared from the mixture.

Today, there is a tendency for the active substance to become increasingly potent and, consequently, when mixing, an ever smaller volume of active substance needs to be mixed into the inactive substance. This makes it more difficult to achieve a homogeneous mixture. Furthermore, it is problematic to preserve the homogeneity of the mixtures since powdered mixtures tend to layer.

A further problem related to homogeneity is the manufacture of divisible tablets. Some tablets are provided with a notch indicating that these tablets may be split so that the user can take half a dose of the drug. For such tablets, the manufacturer must be able to guarantee that the concentration of the active substance is the desired one not only in the tablet as a whole but also in each tablet half.

The homogeneity of a powder mixture can be monitored by sampling the mixture at different times. If the concentration of the active substance is the desired in each sample, it is assumed that the mixture is homogeneous and that the concentration in all doses produced is correct. In tablet manufacturing, a sample of tablets is removed from the production line and the concentration is determined in them. If correct, all tablets are assumed to have the correct concentration. The concentration of the active substance in powders and tablets is often determined by any wet chemical or dry chemical method.

An alternative way of determining homogeneity in tablets is described in US 5,504,332. According to this patent, an NIR reflection spectrum is obtained for a drug tablet whose homogeneity is to be determined. This spectrum is then compared with an index (a recognition index) that has been determined from spectra for previously analyzed, acceptable tablets to determine if the homogeneity of the tablet in question is acceptable.

One disadvantage of this method is that it is slow because you have to record a full spectrum for each tablet. Furthermore, it is not possible to determine how the active substance is distributed in the tablet. Nor can the method be used to study particles of the size present in powder.

Also in other areas of the industry there is a need to monitor the homogeneity of mixtures by measuring the concentration of a component in the mixture. Summary of the Invention

It is therefore an object of the present invention to provide an improved device for determining the concentration of a first component in a mixture of at least two components.

This object is achieved with a device having the features set out in claim 1. Preferred embodiments of the device are set forth in the subclaims of claim 1.

More specifically, the invention relates to a device of the type described initially, which is characterized by image recording means arranged to image the mixture by means of IR radiation to produce at least one image, on the basis of which it is possible to determine the concentration of the first component of the mixture. .

This device is thus based on the idea that images and image analysis can be used instead of spectrum and spectrum analysis, to determine the concentration in a mixture. The advantage of this is that it goes much faster and is much easier to register an image than to record a spectrum that requires the light to be spectrally divided. This, in turn, makes it possible to analyze all tablets during manufacture, which provides a much higher level of safety than random checks.

An image also contains location information. Thus, the image of the mixture can provide information on how the constituent components and in particular the active component are distributed in the mixture.

The image recording means may be any means which are sensitive to IR radiation and which makes it possible to create a two-dimensional IR image. For example, they may include a line sensor which provides an image by scanning. They can record one or more images of the mixture, for example, images based on IR30 radiation of different wavelengths.

The image recording means may be arranged to perform the imaging by means of IR radiation reflected from the mixture or transmitted through the mixture. A combination of these alternatives can sometimes be advantageous.

The advantage of using reflected radiation is that you get better location information so that you, for example

512 098 can determine the distribution of the component of interest in a tablet or the like where the particles in the mixture are compressed into a unit. The disadvantage is that the reflected radiation only provides information about the particles to a certain depth of penetration. IR radiation transmitted through a mixture provides information on particles at all depths of the mixture. In contrast, it provides poorer position information because the transmitted light is scattered by the particles it encounters.

To obtain clear differences between the two components, it is advisable to record the image of the mixture by means of radiation of one or more wavelengths where there is a large difference between the absorption properties of the components. For this purpose, the image recording means preferably include a filter for selecting at least one wavelength at which the components have different absorption characteristics. Selection of the appropriate wavelength (s) is made individually for each specific substance to be monitored. In this way, a monochromatic representation of the mixture is achieved.

Alternatively, the image recording means may comprise at least two filters for performing the imaging by means of IR radiation from two different wavelength ranges to provide an image of the mixture in IR color in the same manner as conventional red, green and blue light color images.

The IR radiation is advantageously constituted by NIR radiation since biologically active substances included in, among other drugs, usually have characteristic absorption properties in the NIR region.

An electronic image is made up of a large number of pixels, each with one or more intensity values. In an IR image, each pixel has at least one IR intensity value that provides a measure of the intensity of the IR radiation that has hit the corresponding point on a sensor in the image recording means. With the knowledge of the absorption properties of the components included in the depicted mixture for the current IR wavelengths, it is then possible to determine which pixels represent the various components and thus the concentration thereof. The apparatus therefore conveniently comprises imaging means 5 which are arranged to determine, by means of intensity values ​​for pixels in the image of the mixture, the concentration of the first component of the mixture. The image processing means may advantageously comprise an appropriately programmed computer. For example, if the image of the mixture is monochromatic, the computer can determine the concentration of the component of interest using threshold values ​​for the intensity values. If the image is in IR color, the IR color can instead be used for concentration determination.

The device is also advantageously arranged to determine from the image of the mixture the distribution of the first component of the mixture. This can also be done with a suitably programmed computer.

The device can be used to determine the concentration of a component in a variety of mixtures.

For example, the mixture may consist of a plurality of particles suspended in a liquid or a gas. It can also consist of a single particle containing different substances. It may further consist of drops of a first component of an emulsion.

In an advantageous embodiment, the device is used to determine the concentration of the first component of a mixture in the form of an ointment on a carrier, for example a patch. It is becoming more and more common to dose drugs as an ointment on a patch. So far, it has only been possible to analyze the concentration of the active substance in the sample of the ointment prior to application to the patch, but with the invention it is possible to easily determine both the concentration and the distribution of the active substance on each patch. This is advantageous for the later in the manufacturing process you can perform the quality control

512 098 the greater reliability is obtained. In addition, from the image of the patch with the ointment, the extent of the ointment on the patch, its thickness and other interesting parameters can be determined.

In an advantageous embodiment, the device can be used to determine the concentration of the first component of the mixture when it is in the form of separate particles, i.e. particles which are free from each other, such as in a powder. The particles can be analyzed on a carrier in the form of a patch, tape or anything else that the particles can adhere to, or when they are spread on any surface. This embodiment may be relevant during manufacture prior to blending into tablets or for control of a finished drug when applied to the patient via a patch. For this purpose, the apparatus conveniently comprises image processing means arranged in the image to identify pixels representing each of the particles and to determine, on the basis of the intensity of the pixels, which of the components each particle belongs to. Every particle

I can be mapped using one or more pixels and | thus, by determining whether the intensity values ​​for these pixels correspond to the radiation expected from one or the other component, it is possible to determine whether the particle belongs to one or the other of the component. By, for example, the image processing means, for example, calculating how many particles or pixels belong to one and the second component, the concentration of the first component can be determined.

In another advantageous embodiment, the device is used to determine the concentration of the first component of the mixture when in the form of a tablet. Here, the tablet is to be given a wide interpretation and includes, for example, granules, pellets, capsules, dragees ['and all other dosage forms in which a plurality / particles are combined into one unit. The tablet can fl fl -i ... ^: -.---- ^^ --- 3 ^ 2932570. ^

512 098 is analyzed as it is or when packaged in an IR transparent package.

In order for the concentration of the first component to be determined in a tablet, the device 5 conveniently comprises image processing means which are arranged to identify in the image pixels that represent the tablet and to determine on the basis of the intensity of the pixels the concentration of the first component of the tablet. By studying the position in the image for image 10 points representing the first component, it is also possible to determine the distribution thereof in the tablet.

In an advantageous embodiment, the image processing means are arranged to determine whether the tablet has a desired composition. It can apply to both the concentration of the first component and its distribution. The device then includes a sorting mechanism which is arranged to sort out the tablet under the influence of the image processing means if it does not have the desired composition. In this way, a fully automated quality control is obtained, which ensures that only those tablets that meet the set quality requirements are passed on in production.

In many of the applications where it is desired to determine the concentration of a first component of a mixture, it is also interesting to determine other parameters, sauce of size and shape. Therefore, the device is advantageously arranged to determine a size parameter and / or a shape parameter for the mixture. The device may contain special software for this purpose. The size parameter may be, for example, the size of a particle or a tablet, or the spread of the mixture on a carrier. The shape parameter may be, for example, the shape of a tablet or a particle. The size and shape parameters can in turn be used to determine volume and mass through correlation.

The device is particularly suitable for concentration determination when the first component is a biological iz

512 098 active substance, preferably a pharmacologically active substance.

In a second aspect of the invention, this relates to a device for determining the distribution of a first component in a mixture of at least two components having different absorption properties in the IR region, the image recording means being arranged to image the mixture by means of IR radiation to provide of at least one image, on the basis of which it is possible to determine the concentration of said first component in the mixture. The advantages of this aspect of the device are shown above.

Brief description of the drawings

The present invention will now be described by way of example with reference to the accompanying drawings, in which Fig. 1 shows schematically a first example of how a device according to the invention can be realized; and Fig. 2 schematically shows a second example of how a device according to the invention can be realized.

Description of a preferred embodiment

Figure 1 shows a device for determining the concentration of a biologically active substance in drug tablets containing a mixture of the active substance and an inactive substance. In this example, the tablets 1 are placed in rows of five tablets on a running band 2. The device comprises an image recording means in the form of an NIR camera 3, a lighting 4, a trigger unit 5, a computer 6 and a sorting mechanism 7.

The NIR camera 1 is a CCD camera equipped with a NIR filter, which transmits NIR radiation of a desired wavelength. The NIR camera captures an image of each row of tablets 1 passing through its field of view. In this example, it records the NIR radiation reflected from the tablets. If transmitted radiation is to be registered

512 098 requires the camera to be positioned so that it can receive radiation passed through the tablets.

The lighting 4 consists of a broadband lamp with a strong emission in the NIR area.

The trigger unit 5 consists of a sensor that detects when a new row of tablets passes in front of it and sends a signal to the NIR camera 3 via the computer 6 that the NIR camera should take a picture.

The removal mechanism 7 consists of a displaceable arm which, with suppression, lifts up and removes tablets 1 which the computer 6 is deemed to have undesirable composition.

The computer 6, which is connected to the NIR camera 3 illumination 4, the trigger unit 5 and the pick-up mechanism 7, includes software for realizing image processing means.

The device operates as follows. The tablets 1 on the band 2 are illuminated with NIR radiation from the illumination 4. When the trigger unit 5 detects that a new row of tablets 1 passes in front of it, it triggers the camera 3 to take a picture of the tablets in that row. The image is transferred to the computer 6, which identifies which pixels in the image correspond to the tablets. This can be done, for example, by using thresholds that separate the tablets from the background. The computer then determines, using the intensity values ​​of the pixels, which pixels in each tablet correspond to the biologically active substance and which correspond to the inactive substance. This is also done with the help of threshold values.

When this is done, the computer can determine both the concentration of the active substance in the tablet and the distribution thereof.

The concentration and distribution of each of the tablets in the image are compared with predetermined quality requirements. If any tablet does not meet the quality requirements, the computer signals to the removal mechanism 7 that the defective tablet should be removed, which

512 098 also occurs when the tablet in question passes the pick-off mechanism.

Figure 2 shows how a device according to the invention can be constructed in case the concentration of a biologically active substance is to be determined in a mixture in the form of a powder from which a sample is to be taken. The powder, which consists of a very large number of particles 20, is transported in a channel 21. In the channel there is a cyclone chamber 22, in which the particles are swirled around in air. Through the cyclone chamber, a plastic tape 23 is moved onto which certain particles become stuck. The plastic tape 23 is passed by a camera 24 while illuminated with NIR light from a lamp 25. The camera takes pictures at such frequency that each particle is included in an image.

The images are then processed in a computer 26 which is coupled to the camera 24, the computer determining which particles belong to which component. By counting the number of particles of each component, the computer can determine whether the mixture has the desired concentration. In this embodiment, neither triggering means nor removal mechanism is required. Determination of concentration takes place in reflected light, but can of course be just as easily done in transmitted light. The device can, for example, be used to control a tablet manufacturing process so that tablets are made of the powder only when it has the correct composition.

512 098