X-ray diffraction method of identifying batches of pharmaceutical products

FIELD: physics.

SUBSTANCE: sample is irradiated with monochromatic X-ray radiation; the diffraction pattern from the sample is recorded in form of a profile of intensity of the diffraction X-ray radiation at different diffraction angles; diffraction peaks are selected; characteristics of the selected diffraction peaks are compared with similar characteristics of reference samples, from where phase composition of the analysed sample is determined; wherein for analysis, a series of samples is collected from each batch of the pharmaceutical product, said samples being in solid form and having packaging; each sample of the series with an intact structure is scanned without breaching the packaging; diffraction peaks corresponding to the packaging material are selected on the diffraction pattern; the range of angles for analysing the diffracted radiation is set, within which diffraction peaks for the material of each sample are selected, from which, using statistical methods, the identity of the corresponding series of samples, one of which is the reference, to one batch of the pharmaceutical product is established, and by selecting a standard series of the pharmaceutical product of a given manufacturer as the reference series, the authenticity of the pharmaceutical product is determined, wherein the wavelength of the monochromatic X-ray radiation is selected based on characteristics of the packaging material.

EFFECT: possibility of rapid analysis during investigation, identification and authentication of batches of pharmaceutical products in packaging.

10 cl, 12 dwg

The invention relates to the field of physics, namely to the study and analysis of materials, and can be used mainly for production control and detection of counterfeit and/or counterfeit pharmaceuticals.

Technology for the production of pharmaceutical products provides control in real time the quality and quantity of raw materials, process parameters processing on each of the stages of product from initial raw materials to the packaging of the product, characteristics of work equipment and the comparison of the current monitoring data with regulatory requirements for pharmaceuticals. Due to the possible variability of the controlled parameters may be some differences, including the acceptable standards in the pharmaceutical composition of the product over long time period of its production, however, the composition of the pharmaceutical agents in a separate batches of such product, including tablets and Packed, produced in the neighboring time points, almost the same.

A well-known problem of identifying substandard, fake, counterfeit and adulterated pharmaceuticals (medicinal) products, which are characterized by the violation of qualitative and/or quantitative composition up to the absence of AK is positive component, the presence of impurities, poor cleaning of components, etc. that causes not only damage to the original product manufacturer, but often poses a threat to the health of the consumer. While counterfeits usually are packing, also imitating the original with a high degree of similarity, and introduced thereby misleading the consumer.

To identify pharmaceutical products can be used x-ray diffraction method, allowing to selectively conduct nondestructive materials research, analyze their phase composition with high precision, and control of structural and phase differences of the same component in different patterns and their changes over time. Based on these studies created a database /library of diffraction patterns of drugs and their components used for their identification, and synthesis of new drugs /for example, WO 2004092727, JP 2002320474/. However, when using this method on the results of the identification and establishment of authenticity (authenticity of origin) pharmaceutical (medicinal) products affected by the factor complexity of the composition of these funds, because in addition to the active ingredients it contains fillers (in particular, microcrystalline cellulose, starch, flavorings, high is Molekulyarnye connection and others), giving different diffraction spectra. The composition of the shell of the tablet includes, as a rule, film-forming polymers, plasticizers, pigments, dyes, sweeteners. Conditions for forming tablets and the composition of its membrane in production is driven by the requirements of the pharmacokinetic properties of the active component and regulated standards, but in the process of applying the coating on the pill possible partial destruction of the material of the tablets due to the impact of the large mass of material processed at the same time. A significant portion of these products further worked up in the process of applying the wrappers and packaging in blisters (paper, plastic, foil), which may lead to a partial change of the crystal structure of components, the appearance of bulk defects, etc. which, in combination with possible changes in production technology leads to ambiguity diffraction pattern from a sample and/or its unplayable for pharmaceutical products of the same type.

There is a method of identifying substances, including the production of the diffraction pattern of the sample material, an iterative procedure for comparing registered and analytical profiles of diffraction from the sample, the determination of the magnitude of their differences on the measurement of the intensity of the lines registered in the data and analytical spectra of diffraction and the identification of substances with the magnitude of the differences is smaller than the specified parameter and recalculate the analytical profile of diffraction in excess of a predetermined parameter /US 2007263770/. The known method does not have sufficient information content and reliability of identification of multicomponent compounds with possible defects structural component due to the complexity of modeling and calculation of their analytical profiles of diffraction, which makes little perspective using well-known way to determine subtle differences in the compositions of pharmaceutical products for their identification (authentication).

There is a method of x-ray diffraction analysis of materials involving the irradiation of a sample of unknown composition monochromatic x-rays, recording the diffraction pattern from the sample, the determination and analysis of profile records for measuring the intensity of x-ray diffraction peaks and angles of diffraction with visualization of the comparison of the position of the diffraction peaks and the angles of diffraction with similar characteristics from a sample of material of known structure and composition stored in the database /JP 8043327/. When matching same diffraction peaks corresponding component of the material is identified, the peak diffraction is deducted from the account profile and then carried out an iterative procedure for recognizing the component material for the remaining peaks of diffraction on the reduced profile record. The known method allow you to plug the et to conduct a qualitative analysis of materials containing crystals or powders (crystallites) of the active ingredients, using reference databases. However, the known method has insufficient information regarding multicomponent materials with a possible violation of the crystal structure, impurities or defects that appear in the diffraction pattern as halos near the peaks or areas blurred reflection, but almost can't be recreated. As a consequence, the results of the identification of materials, components, pharmaceutical products, not robust enough to identify them due account of uncontrolled technological factors, furthermore, the method cannot provide rapid analysis of identity different batches of pharmaceutical products in tablet form and in packages.

There is a method of x-ray diffraction analysis of materials, providing screening diffraction patterns of a number of standard powder samples by powder diffraction using a diffractometer Bruker AXS D8 Advance /US6327334/. Flat powder samples, which were selected examples of zeolites of the two brands, was irradiated with a powerful x-rays generated by the x-ray tube at a voltage of 40 kV and current of 40 mA, continuously scanned at an angle of incidence of the x-ray beam about ASEC 3,6° and spectra were recorded diffraction (diffraction) in the angle range of θ=5°-40° entry of the peaks of the intensity of diffracted x-ray radiation at the respective angles of diffraction. For processing of diffraction patterns to identify samples used multivariate statistical analysis such as principal component method, which allows to represent significant factors for diffraction patterns are the initial signs - intensity lines of the x-ray spectrum of the sample material, in the form of a linear combination of independent new features in a multidimensional vector space and display them in the form of clusters characterizing homogeneous objects with a high mutual correlation, presenting them in the form of a set of points in the projection on the coordinate plane. Each point of a cluster corresponds to the sample average of the main components for each sample measurement sample, and border cluster - variance principal components associated with variations in the properties of correlated samples in the sample. Spatial separation of the clusters corresponding to the different main components, said phase composition of the studied material. The method allowed to determine the elemental composition of the samples and to identify impurities in comparison with a library of similar characteristics from the reference samples of zeolites with a given ratio of components. Mathematical processing of the diffraction patterns implemented in the software of the x-ray diffractometer brücke AXS D8 Advance, effective for step-by-step control of the phase composition of the materials when they are received, the analysis of patent medicines and the like, but is not known to the application of the method for non-destructive analysis of pharmaceutical products multicomponent composition and violations structures with a package.

There is a method of x-ray diffraction analysis of materials, including the irradiation of a sample with monochromatic x-rays, recording the diffraction pattern from a sample in the shape of the intensity profile of the diffracted radiation at different angles of diffraction, a diffraction peak picker, a comparison of the characteristics of the selected diffraction peaks with similar characteristics of the reference samples, which is judged on the phase composition of the studied sample, selected as the closest analogue of the claimed invention.

The objective of the invention is to provide a rapid analysis in the study, identification and authentication of the parties of pharmaceutical products in packages.

The problem is solved by the fact that in the method of x-ray diffraction analysis of materials, including the irradiation of a sample with monochromatic x-rays, recording the diffraction pattern from a sample in the shape of the intensity profile of the diffracted x-rays at different angles of diffraction, the allocation of p the Cove diffraction, comparison of the characteristics of the selected diffraction peaks with similar characteristics of the reference samples, which is judged on the phase composition of the studied sample, in accordance with the invention, for the analysis of each batch of a pharmaceutical product selected sample series in solid form, with packaging, each sample series with undisturbed structure scan without disturbing the packaging, to produce the diffraction pattern diffraction peaks, corresponding to the packing material, specify the range of angles studies of the diffracted radiation, within which produce diffraction peaks for the material of each sample for which statistical methods establish the identity of the relevant series of samples, one of which is a reference to one party pharmaceutical product, and selecting the reference series of the pharmaceutical product specified manufacturer as a reference series are judging the authenticity of a pharmaceutical product, in this case, the wavelength of the monochromatic x-ray radiation is chosen based on the characteristics of the packing material.

In addition, as the sample pharmaceutical product choose his solid form in the form of compressed tablets.

In addition, as the sample pharmaceutical product choose his solid form in the form tabled is, with the shell.

In addition, as the sample pharmaceutical product choose its solid form as a powder.

In addition, the packaging of the sample is made of paper.

In addition, the packaging of the sample is made in the form of a plastic blister.

In addition, the packaging of the sample made in the form of blisters, laminated foil.

In addition, as the peaks of diffraction select line x-ray diffraction pattern corresponding to the active ingredients and excipients in the pharmaceutical composition of the product.

In addition, characteristics of the pharmaceutical product specified manufacturer is determined on the basis of a library of reference spectra of diffraction.

In addition, x-ray diffraction analysis is carried out with the use of the software product, including methods of multidimensional statistical analysis, including principal component method, in accordance with which a comparison of the characteristics of the series of samples is performed by mapping clusters characterizing the sample mean and sample variance of the principal components of the sample material.

The technical result of the invention is to provide a rapid analysis of the phase composition of solid samples through packaging the diffraction patterns and identification of pharmaceutical products in batches, supply various producer who mi, including the identification of counterfeit products, as well as reduce the time of control of the technological characteristics of the production of the pharmaceutical product and characteristics of the raw materials used and the product packaging.

The invention is illustrated figure 1-10 are: 1 - the fragment pattern of the original drug "Theraflu" (curve 1 is the spectrum of paracetamol, curve 2 is the spectrum of sucrose); 2 - fragment pattern counterfeit drug "Theraflu" (curve 1 is the spectrum of paracetamol, curve 2 is the spectrum of sucrose), 3 - diffraction spectra of standard paper packaging "Aspirin", produced by different manufacturers, 4 pattern paper packaging of the drug Parasol"received from the smooth side of the packaging (curve 1) and its grooved side (curve 2), 5 is a pattern blister packs of medication "Flemoxin" (product packaging in the Netherlands under license in Russia)made of thin aluminum (food) foil, 6 - pattern plastic PVC packaging products "Flemoxin Solutab" (party of two manufacturers and packaging of the drug "Flameclaw", produced by the Netherlands, made of biodegradable plastic, 7 - diffractogram tablets "Ascarina" - unpackaged (1), in PVC blister (2), blister foil wrapped with layers is Noah foil is 0.260 μm (3) (wavelength irradiation of λ=2,2597 μm, the exposure time of 240 s), Fig - diffractogram tablets "Ascarina" - unpackaged (1), in PVC blister (2), blister foil wrapped thick 0,175 μm (3) (wavelength radiation λ=0,7093 μm, the exposure time of 2400 s)Fig.9 - diffraction spectrum of the drug "raw materials" and strategema dipyrone from the reference database figure 10 - results of the mathematical analysis of the diffraction patterns of the two parties tablets of Aspirin", pressed from the same material phase composition and with different granulometric characteristics, 11 - results of the mathematical analysis of diffraction patterns two batches of tablets of Aspirin", pressed from the material of the same phase and particle size distribution using presses of various types, Fig - average results identification of tablets of Aspirin" in the packaging of batches of different manufacturers.

The method is carried out using the software-based x-ray diffractometer, including the x-ray source, the camera sample with a sample holder, a detector of x-ray diffraction radiation and the system of registration of diffraction spectra with the software-oriented complex processing of measurement results. From each batch of a pharmaceutical product selected a representative number of samples in cellular packages. The way the pharmaceutical product packaging (paper, film and/or foil blister) is placed in the sample holder without disturbing the packaging, and the sample may be from a index a pill, a tablet with a film coating or compressed tablet. The sample holder is put into rotation, is directed to the sample beam of monochromatic x-rays and scans the sample. Using the detector of the x-ray diffraction radiation (in particular, position-sensitive), record the intensity distribution of the diffracted radiation as a function of diffraction angle (diffraction pattern of the sample) and the background spectrum of the scattered x-ray radiation ("Compton substrate"), due to the presence of impurity amorphous substances present in the material of the tablet, its shell and its packaging, isotropic scattering x-rays. To produce the diffraction pattern intensity peaks corresponding to the diffraction of x-rays by the atoms of the crystal lattice under certain angles of incidence of the beam on the sample, and determine the position of the diffraction peaks corresponding to the package. Specify the range of angles (2θ=20°-70°), within which define the most intense line of the spectrum and identify them by comparison with the spectrum of a reference sample with a known composition and structure on the position of the peaks dip the options and angles of diffraction. Comparison of the diffraction patterns and the processing of results of measurements performed using the multivariate statistical analysis, including principal component (PCA), according to the original program, with identification of the most intense spectral lines (principal components), which define the basic components of the sample material, describing them in such quantities as mathematical expectation (the sample mean) and sample variance. However, depending on the packaging and if the blister foil wavelength x-ray radiation source is reduced (compared to the case with paper/plastic packaging) to increase the depth of radiation penetration into the packing material, considering the exponential attenuation of x-ray radiation, thereby increasing the resolution of the peaks in the diffraction pattern.

To identify the samples to one party product investigate a series of samples, for example 10 tablets in each series. One of the series is considered the reference, the diffraction characteristics of the samples of this series make reference database including instrumental parameters (wavelength of x-ray radiation, the angular spacing, exposure), and the diffraction characteristics of the sample material (the relative intensity of diffraction peaks and the corner position (in the range of angles 2θ), processing options diffraction spectrum and magnitude of measurement errors.

For a more visual representation of the homogeneous series of samples for the identification of batches of pharmaceutical products used principal component method and the mathematical characteristics of the cluster center of the cluster, the variance of the cluster, the standard deviation and the radius of the cluster), which are homogeneous objects of the same spectral lines of the diffraction of the samples, corresponding, in particular, at least one current active substance in the pharmaceutical composition of the product. Clusters can be graphically represented in the projections on the axes of principal components, so convenient for additional selective production control in the production and analysis of deviations in the processing modes of the product.

When establishing the authenticity of pharmaceutical products and separation of genuine products manufacturers from generics as a reference using the reference spectra of diffraction from libraries (databases) reference characteristics of pharmaceutical products (medicines, substances, ingredients), created by the respective manufacturers of pharmaceutical products or measured in parallel with the study sample to ensure identical measurement conditions. In effect has the value of 5%deviation of the content of the ingredients of a medicinal product from the established standard number of samples can be considered identical (belonging to one party product) or authentic, if the correlation coefficient lies in the range (0,95-0,99). Given the nature of the samples and the objectives of the study can further be defined by such characteristics and packaging of pharmaceutical (medicinal) products (paper, plastic and foil), which are considered as witnesses of their identity or possible forgery/falsification. Identity marking packaging of pharmaceutical products is beyond the scope of this method.

The inventive method was validated using a diffractometer "DEFRA", manufactured by CJSC "Scientific instruments", Saint-Petersburg. For research in the instrument uses x-ray optical scheme of Brega-Brentano, as an x-ray source - weight fine-focus tube BSV-33 with the anode of Cr-ka (2.2897 nm), the voltage of the tube 25 kV, a current of 5 mA, the focal spot size of 1.2×3 mm, the detector has a curved position-sensitive detector with a range of simultaneous recording of 55°, the angular range 2θ=20-70°, exposure time 300 C. Calibration of the detector was performed by external standard.

During validation of the method was established to identify pharmaceutical products belonging to a single party, identify differences in the production of various manufacturers was analyzed material the packaging for its range, and set the influence of the characteristics of the raw material and its processing technology on a range of product samples when it is received.

1. Identification of the samples of pharmaceutical products.

To test the principal identification of batches of the pharmaceutical product from different manufacturers were conducted product research as such, without packaging. Together with the North-Western Centre of the Russian Federation for quality control of medicines conducted a study drug "Theraflu".

As the sample chose the original (reference) and counterfeit (investigational) drugs in the form of pressed pellets in the shell containing flavorings (diffraction spectra are shown respectively in figures 1 and 2, the line spectrum is approximated by gaussianly). The study samples was carried out by a known method of "comparison of fingerprints using variance analysis and the application of two criteria:

A) the Criterion for the comparison of the amplitude ranges of the spectra of the original sample and adulterated sample.

It is established that a statistically significant level of difference between the original product and the counterfeit was 15% with a statistical error of less than 2%. The ratio of the maximum amplitudes in the spectra of I_paracetamolI_sucrose well 0,089 for the original sample and of 0.066 for adulterated sample, which indicates the underestimation of the number of active components in the composition of the product is counterfeit.

B) criterion relational comparison of the integrated areas of the diffraction maxima of paracetamol (the main active ingredient - paracetamol - curve 1 in figure 1 and 2) and sucrose (basic excipient is sucrose curve 2 in figure 1 and 2)which shows the overestimation of the number of fillers to the detriment of the pharmaceutical activity of the drug.

It is established that a statistically significant level of difference between the original and counterfeit drugs "Theraflu" was 26% with a statistical error of less than 2%. The obtained result allows us to conclude about the differences in qualitative and quantitative composition of the studied samples.

2. Study samples of pharmaceutical products of different manufacturers.

To assess the identity and stability characteristics of pharmaceuticals in samples of products from different manufacturers have conducted studies of the drug Aspirin (generic name "Acetylsalicylic acid" in the name of the active components) from a number of manufacturers of pharmaceutical products distributed on the territory of the Russian Federation initiated the development of Ekaterinburg, Perm, Khabarovsk, Russia, and Bayer, Germany). Of the products of these manufacturers to study selected several series of packages with samples (in each series of 10 CT in paper packaging). On the x-ray diffractometer "DEFRA" for the studied series of samples obtained from 80 diffraction patterns. The diffraction patterns were sampled values of the intensity of the diffracted radiation at specific points in the range of angles 2θ for each sample was determined by the sample mean, sample variance, mutual variance of two samples and calculated the cross-correlation coefficients of the sample spectra, %, between rows of registered parameters, the results are shown in the Table.

The results show a high degree of homogeneity of the samples within the same packaging (blisters) for the production of each of the manufacturers, the correlation coefficient is close to 100%. Comparison of product series of the same manufacturer, made in Ekaterinburg is Urga and Perm, also shows a fairly high correlation coefficient is on average 94%-96% with minor variance, which indicates stable as a drug with a possible small change in particle size distribution component in the production cycle. However, comparing the series of product from different manufacturers shows a significant reduction of the correlation coefficient to 81% (average for the products of the company Bayer and company Ekaterinburg) and the increase in the variance of the analyzed parameters. Such a significant drop in the value of the correlation coefficient may indicate a variety of factors - the difference in concentrations of the active substance, lattice strain components, the change in the ratio of fillers. However, in all cases, the magnitude of the correlation coefficient defined by the ratio of the intensity of the spectral lines of x-ray radiation, indicates the similarity or difference of the drugs. When access to Bank data reference physical characteristics of the pharmaceutical (medicinal) products from different manufacturers, you can Refine the conclusions about the cause of the differences of the compared indicators and identify counterfeit pharmaceutical products.

3. The analysis of the spectra of the packaging of pharmaceutical products.

In cases where the coefficient correl is tion between the characteristics of the samples is high, research and compare the diffraction pattern of the packaging of the drug. For modern pharmaceutical products use paper packaging and blister sealing tablets product in aluminum foil or in a plastic PVC-sheath - to improve their security.

3 shows the diffraction spectra of standard paper packaging CT "Aspirin" two different manufacturers (psysun Novosibirsk region, curve 1 and Perm curve 2). The amplitude of the intensity of diffraction peaks substantially (2 times) vary in size, and their average correlation coefficient is 92.3%, which indicates different origins parties of the samples.

4 shows the diffraction pattern paper packaging of the drug Parasol," the producer company hirbet received from the smooth side of the packaging (curve 1) and its grooved side (curve 2). Differences in the amplitude spectra and the shape of spectral lines indicates some influence of the surface structure of the packaging for its range, with a correlation coefficient spectra of diffraction is 94,8%.

Figure 5 presents the diffraction pattern blister packages Flemoxin made of thin aluminum (food) foil. On the territory of the Russian Federation distribute originaldisplay, packaged as a manufacturer and distributor of the same product. Figure 5 curve 1 describes the original packaging of the product "Flemoxin Solutab" production company, Astellas Pharma Europe B.V. (Astellas Pharma Europe B.V.), the Netherlands, and curve 2 - packaging of the same name of product manufactured by Yamanouchi, the Netherlands made by a company CJSC ORTAT, Kostroma, under license. Differences in the amplitudes of the spectral lines of blisters already allow you to pre-separate batches of the same name product description packaging reflecting the influence of production conditions, in addition to analyzing the actual pharmaceutical product.

Figure 6 shows the results of a study of plastic PVC packaging, namely pattern plastic packaging products "Flemoxin Solutab" (original packaging company Astellas curve 1 and packaging company CJSC OROTATE curve 2) and packaging of the drug "Flameclaw", produced by the Netherlands, made of plastic, biodegradable under the action of bacteria and fungi in the environment, curve 3. Standard plastic packaging in the diffraction pattern characterized by the two-halo (curves 1 and 2), but biodegradable materials in the diffraction pattern characterized by the presence of strong lines and therefore easily distinguishable from other packages.

Certain difficulties may cause and ertificate pharmaceutical products, Packed in blisters, laminated foil. Studies of the feasibility of the method performed further on the diffractometer "DEFRA" weight fine-focus tube BSV-33 with the anode SG-ka (2.2897 nm), when the voltage of the tube 25 kV, a current of 3 mA, the focal spot size of 1.2×3 mm, for registration of the diffracted radiation is applied curved position-sensitive detector with simultaneous recording of the spectra in the range of angles of 55°, the x-ray tube and detector installed at an angle of 20° relative to the sample plane. The detector has been calibrated by an external standard (Al₂About₃). Time shooting tablets without packaging with 240 tablets in PVC-blister - 2400 with tablets in a blister, laminated foil - 2400 C. as the sample selected tablet "Askofen", giving a powerful, well-defined peaks in the diffraction pattern intensity in a predetermined range of angles registration of the spectrum. Figure 7 shows the registered diffraction pattern tablets "Ascarina" - without packaging (curve 1), in PVC blister (curve 2), in blister foil wrapped with foil thickness is 0.260 μm (curve 3) (wavelength radiation λ=2,2597 μm, the exposure time of 240 s). From Fig.7 shows that the diffraction peaks of the material of the drug can registrirovatsa through PVC blister, and through the laminated foil blister card, changing the amplitude of the peak is about without displacement of the diffraction angle. A similar result follows from the analysis Fig, which presents diffraction tablets Ascarina" without packaging (curve 1) and tablets in the blister foil wrapped thick 0,175 μm (curve 2) (exposure time of 2400 s). It is apparent that the amplitude of the diffraction peaks from the active substance is substantially impaired, but their shape is similar to the diffraction peaks tablets without packaging, and the angular position of the peaks does not change. When this amplitude peaks of diffraction when using thinner foil above, which allows a more reliable judgement about the nature of the active component and phase composition of the sample material. This result is equivalent to changing the wavelength of the x-ray radiation to a value of λ=0,7093 microns, providing a higher penetrating ability of the used x-ray radiation. Changing the wavelength of the penetrating x-ray radiation, depending on the thickness and material of the blister can change the diffraction pattern of the studied sample which is determined, in particular, the interatomic distances of the lattice, the order of diffraction and a certain angular range of the output of the diffracted radiation, and therefore requires a comparison with spectra of the reference sample of an adequate database.

Thus, pattern packaging allow you to distinguish between products of different PR the producers, to identify features of the packaging and to clarify the composition and properties of packaging profiles of the diffraction maxima simple and effective way. The analysis package can be effectively used to identify pharmaceutical generic drugs, in which the activity of active substances may be identical to the original (patented) drugs, so that they can replace the original drugs, however, have significantly lower market value.

4. Managing the impact of characteristics of the feedstock on the analysis results.

To study the influence of the characteristics of the feedstock on the results of the analysis were prepared samples of the pharmaceutical product - pressed tablets of Aspirin" (chemical formula C₁₃H₁₆N₃O₄SNa). To do this, as raw material mixture for forming tablets analgin used pieces of material the size of 1-5 mm, with an irregular shape. Selected material to grind in an agate mortar to a powder (particle size of about 40 μm)was placed in special holders and using a diffractometer "DIVREI received pattern of fabricated samples. Comparison of the averaged spectrum of diffraction on powder samples (curve 1) with stratagema (2) of dipyrone from the reference database (PDF#91685) shows an almost unequivocal compliance with the provisions of the peaks of x-ray intensity on the diffraction patterns from the test and reference samples (Fig.9).

Investigation of the influence of particle characteristics on the diffraction pattern of samples is carried out using the method of principal components. Raw materials after grinding was divided into two fractions using a sieve, the powder was filled in the cell and condensed glass plate with four tablets of Aspirin" with each faction powder. Using a diffractometer "DEFRA received the diffraction pattern of the samples. By the method of principal component has processed diffraction and vector feature space has received two spatially separated systems of points (cluster 1 - pills from a small fraction of the granules cluster 2 - for tablets from the coarse fraction of the granules), the coordinates which describe the position of the basic component of matter of each tablet. Each pill has its own coordinates in the feature space within the cluster, which indicates the influence of structural differences of the samples on the diffraction pattern. Figure 10 shows that the tablets of Aspirin", pressed from the material of one phase composition, but with different granulometric characteristics, can be effectively separated using the proposed method. Thus, it is possible to identify possible violations of technology for the pharmaceutical product in the aspect of structure the th inhomogeneity of raw materials.

5. Managing the impact of technological operations.

To study the control of influence of technological operations on the diffraction pattern produced the batch of tablets of Aspirin" from one raw material identical particle size distribution, and the pressing part of the tablets produced on the press got (1), and for the rest of the tablets used press Fette (2). Using a diffractometer "DEFRA received the diffraction pattern of the samples, which were analyzed by the method of principal components, as described above. The results are shown figure 11, which reflects the fact that in the feature space are two groups of points (cluster 1 and cluster 2)characterizing samples of each party. Thus, it is possible to identify the samples produced using different process equipment.

On Fig shows the average results of the study parties tablets of Aspirin" (4 pieces) from different manufacturers, including tablets manufactured by JSC "Irbitsky champarnaud" (cluster 1), JSC "Asharma" (cluster 2), CJSC "moskhimpharmpreparati" (cluster 3) and OJSC "Pharmstandard Leksredstva" (cluster 4). Tablets manufactured by CJSC "moskhimpharmpreparati", prepared from the same raw materials, but on different forging equipment (ORT - cluster 3A and Fette - cluster 3b)also have individual the layout area. Because the field values practically do not overlap, it is possible to determine whether tablets are specific manufacturers. At the same time, it should be noted that if the process of production and raw materials produced by different manufacturers are identical (or as close as possible), possible areas of overlap (in this example, clusters 1 and 2).

The proposed method provides rapid analysis of batches of pharmaceutical products, including drugs, directly in the packaging. In contrast to known methods of identification of the substance based on consistent accounting diffraction spectra recognized active ingredients registered in the diffraction pattern involving databases and conducting iterative procedure of subtraction of the spectra to achieve a minimum level of noise, the inventive method allows using statistical methods of processing of measurement results, to demonstrate the similarities or differences between batches of samples belonging to different quantities of products, in the form of the corresponding cluster, with the correct exception of the influence of background and to evaluate the dispersion characteristics of each series of samples of the product and their various packages. The method can be effectively used in order to control product quality manufacturers of detection technologies the AI production, identification of counterfeit medicines and generics, and when determining the shelf life of pharmaceutical products for use during and after storage and can be used effectively in the activities of enterprises producing and/or selling pharmaceuticals, customs and other regulatory authorities.

1. The method of x-ray diffraction analysis of materials, including the irradiation of a sample with monochromatic x-rays, recording the diffraction pattern from a sample in the shape of the intensity profile of the diffracted x-rays at different angles of diffraction, a diffraction peak picker, a comparison of the characteristics of the selected diffraction peaks with similar characteristics of the reference samples, which is judged on the phase composition of the studied sample, wherein the analysis of each batch of a pharmaceutical product selected sample series in solid form, with packaging, each sample series with undisturbed structure scan without disturbing the packaging, to produce the diffraction pattern diffraction peaks, corresponding to the packing material, specify the range of angles of diffracted radiation research within which produce diffraction peaks for the material of each sample for which statistical methods are installing, the awn of the relevant series of samples, one of which is the reference to one batch of a pharmaceutical product, and selecting the reference series of the pharmaceutical product specified manufacturer as a reference series are judging the authenticity of a pharmaceutical product, in this case, the wavelength of the monochromatic x-ray radiation is chosen based on the characteristics of the packing material.

2. The method according to claim 1, characterized in that as the sample pharmaceutical product choose his solid form in the form of compressed tablets.

3. The method according to claim 1, characterized in that as the sample pharmaceutical product choose its solid form as tablets, which has a shell.

4. The method according to claim 1, characterized in that as the sample pharmaceutical product choose its solid form as a powder.

5. The method according to claim 1, characterized in that the packaging of the sample is made of paper.

6. The method according to claim 1, characterized in that the packaging of the sample is made in the form of a plastic blister.

7. The method according to claim 1, characterized in that the packaging of the sample made in the form of blisters, laminated foil.

8. The method according to claim 1, characterized in that as the peaks of diffraction select line x-ray diffraction pattern corresponding to the active ingredients and excipients in the pharmaceutical composition of the product.

9. The method according to claim 1, distinguished by the different topics what characteristics of the pharmaceutical product specified manufacturer is determined on the basis of a library of reference spectra of diffraction.

10. The method according to claim 1, characterized in that the x-ray diffraction analysis is carried out with the use of the software product, including methods of multidimensional statistical analysis, including principal component method, in accordance with which a comparison of the characteristics of the series of samples is performed by mapping clusters characterizing the sample mean and sample variance of the principal components of the sample material.