Analysis apparatus including a microwave device and use thereof

Abstract

The invention relates to a method for analysing and controlling environmental conditions for the pharmaceutical, cosmetic and biochemical industries, among others. The method is based on implementing a portable, autonomous apparatus, incorporating a novel microwave device designed to detect quality deviations of substances that are potentially sensitive to environmental constraints experienced during a given period of time.

Description

[0001] ANALYSIS APPARATUS COMPRISING A MICROWAVE DEVICE AND ITS APPLICATION

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to an apparatus for the online and real-time analysis of the qualitative deviation of substances potentially sensitive to environmental constraints experienced during a given period, and more particularly to a portable, autonomous apparatus, comprising a microwave device capable of determining, measuring and qualifying a qualitative deviation.

[0004] The invention applies in particular to the non-destructive testing of medicinal products or similar.

[0005] PREVIOUS ART

[0006] The control of environmental conditions is essential for the chemical, biochemical, pharmaceutical, cosmetic or food industry, as several environmental factors, including temperature, humidity and light, can have an impact on the quality of the substances used and marketed. For such purposes, various devices or apparatuses are known that can detect the quality deviation of a variety of materials and active substances.

[0007] For example, mastering the detection of temperature variations experienced by drugs is essential to ensure production quality and their safety during administration to patients. By accurately tracking and controlling temperature throughout the manufacturing process and supply chain, manufacturers can prevent potential degradation of active ingredients or drugs, ensure their efficacy and safety, and thus offer better quality pharmaceutical products for patients.

[0008] In the field of research, various solutions have been proposed to analyze the qualitative gap of drugs. However, these solutions encounter limitations and drawbacks, particularly when it comes to ensuring non-invasive, automatic use and easy and reliable handling.

[0009] Some techniques require specific facilities, such as clean rooms for mass spectrometers or controlled environments for NMR equipment, which may restrict their use in certain mobility and supply chain contexts.

[0010] Other techniques may require extended analysis times, which can be cumbersome, especially when rapid analysis is required, such as for real-time quality checks or emergency situations.

[0011] Such techniques require extensive expertise for their implementation and interpretation of the results. Specialized training is often required for the personnel involved to properly handle the instruments and analyze the data obtained.

[0012] One of the most widespread techniques in this context is High Pressure Liquid Chromatography (HPLC), a technique commonly used to analyze the chemical composition of active drug substances. However, it can be time-consuming and require sophisticated equipment. In addition, it may not detect alterations or structural defects that may affect the quality of said active drug substances. The present invention aims precisely to overcome the above-mentioned drawbacks and many others, by providing a portable analysis apparatus incorporating a device based on the microwave principle, offering several additional advantages.

[0013] BRIEF DESCRIPTION OF THE INVENTION

[0014] The present invention consists of a novel apparatus incorporating a microwave device for detecting the qualitative deviation of a variety of materials, active substances, including chemical, biochemical or pharmaceutical products, using a rapid, if not real-time, and portable online analysis approach. By implementing it, the invention aims to control the quality of such potentially sensitive substances that have suffered a damaging qualitative impact caused by variations in their environment, such as temperature during transportation or storage.

[0015] Expressed in other words, the present invention has as its first object a portable and autonomous apparatus for the online analysis, in real time, of the qualitative deviation of substances potentially sensitive to environmental constraints undergone during a given period (TO to Tx), comprising a planar microwave sensor cooperating with several constituent units (b to e) as defined by the following claims 1.

[0016] The invention also relates to a method for analyzing said qualitative difference by means of the aforementioned apparatus as defined by claims 7 and following.

[0017] BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1: Schematic representation of the device according to the invention

[0019] Figure 2.1: Top plan view of the microwave sensor

[0020] Figure 2.2: Cross-sectional view of the sensor and its arrangement relative to the material under analysis

[0021] Figure 3: Definition of the microwave quality factor of the material under analysis

[0022] Figure 4: Inference (prediction) models of temperature and duration of exposure to this temperature as a function of the measurable factor of microwave quality of the material under analysis exposed to qualitative degradation due to temperature variation

[0023] Figure 5: Preferred embodiment of the present invention.

[0024] With regard to each of the figures mentioned above, the nature and, where relevant, the interaction and function of the constituent elements of each of the modules or portions of the apparatus according to the invention are specified in detail. This list is an integral part of the description and supports the explanation of its operation.

[0025] DETAILED DESCRIPTION OF THE INVENTION

[0026] According to the invention, the portable and autonomous apparatus for the online analysis, in real time, of the qualitative deviation of substances potentially sensitive to environmental constraints undergone during a given period (from TO to Tx), firstly comprises: a. a planar microwave sensor (2 fig.l) arranged on a disc made of metallic material (1 fig.2.1) having etched therein a coupling of a network of hexagonal ring resonators (2 fig.2.1), which disc is printed on the upper face of a magneto-dielectric substrate (9 fig.2.1), the other face comprising a layer of a printed metallic material (1 fig.2.2) forming a ground plane (4 fig.2.2); said microwave sensor being connected to two microwave ports (4,5 fig.2.1) symmetrical allowing to simultaneously carry out the functions of excitation and transmission of electromagnetic waves; said network of hexagonal resonators being arranged to create a concentrated near electromagnetic field resulting from the electromagnetic coupling between the adjacent hexagonal edges of the resonators (2 fig.2.1), oriented perpendicular to the plane (6 fig.2.2) of the substance under analysis (1 fig-i); a fixing mechanism (3 fig.l) of the substance under analysis arranged within the zone of creation of the electromagnetic field (5 fig. 2.2) of said sensor.

[0027] The apparatus according to the invention is characterized by a device defined by a new topology of a planar microwave sensor (2 fig. 1), based on a coupling of three split hexagonal ring resonators (2 fig. 2) etched within a disc (1 fig. 2) manufactured by a stack of metallo-dielectric layers, which disc is made of a metallic material printed on a magnetodielectric substrate (1 fig. 3) having on the other face a layer of a printed metallic material and forming a ground plane (4 fig. 3).

[0028] The said sensor is connected to two symmetrical microwave excitation ports (4,5 fig.3) allowing to simultaneously perform the functions of excitation and transmission of electromagnetic waves. This network of hexagonal resonators is adapted to create a very concentrated near electromagnetic field, resulting from the coupling between the adjacent hexagonal edges of the resonators (2 fig.2). This near electromagnetic field will be concentrated and oriented perpendicular to the plane of the resonators (2 fig.2) respectively perpendicular to the plane (6fig.3) of the substance under analysis (1 fig.l) and thus, will penetrate the substance under analysis.

[0029] The analysis apparatus according to the invention further comprises b. a unit (8 fig.l) for generating and measuring electromagnetic waves for exciting said sensor; c. a calculation unit (9 fig.l) capable of executing an inference model recognizing the qualitative deviation of the substance under analysis based on the electromagnetic wave measurements; d. a transmission unit (10 fig.l) of the inference data; and e. a power supply unit (11 fig.l) incorporating a battery ensuring the autonomy of the device.

[0030] The invention also relates to a method for online, real-time analysis of the qualitative deviation of substances potentially sensitive to environmental constraints experienced over a given period, implemented using the apparatus described above.

[0031] By its implementation, said apparatus is capable of measuring in real time the microwave quality factor of the material under analysis, determined according to the invention by the difference between the frequency peaks of the transmission coefficient between ports 1 and ports 2 (x) of the sensor for the case of a reference material, i.e. at T0, and for the case of the same material at Tx (x = predefined time units) presenting a potential for permanent qualitative degradation caused by temperature variations or other environmental constraints in the past. The difference is represented schematically by the coefficient Quw as illustrated in Figure 4.According to a particular embodiment, said apparatus is provided with a mathematical model as illustrated by Figure 5, previously calibrated to perform an inference function recognizing the variation in temperature or any other environmental constraint, having impacted the quality of the material under analysis as a function of the shift in microwave quality Quw.

[0032] Exposure of sensitive active substances to high temperatures during storage or transport can reduce their effectiveness, and most manufacturers recommend storage and transport at a maximum of 27°C. Measuring the recorded instantaneous value of Quw allows identification of all temperatures and durations to which the material has been subjected during transport. The temperature and duration of exposure can directly reflect the degradation of the quality of the material under analysis.

[0033] Advantageously, the implementation of the apparatus comprising the microwave devices described above makes it possible to carry out, among other things, an online analysis, a portable analysis, a non-destructive analysis of the substance or material tested and a real-time analysis.

[0034] First, it reduces costs, making it accessible to small laboratories and limited resources. Furthermore, its ease of use simplifies its handling and the interpretation of the results obtained, allowing for faster and easier analysis. Thanks to its ability to provide near-instantaneous results, it allows for real-time evaluation of samples of the substance under analysis, thus meeting the needs of situations requiring a rapid response. In addition, it offers the possibility of direct sampling, without the need for complex preparation or dilution, which reduces analysis time and minimizes the risk of errors or contamination.

[0035] Finally, its portability makes it easy to use in the field or on the go, expanding analysis possibilities and providing increased flexibility. This innovation exploits the interaction between microwave waves and drugs to obtain information on their electromagnetic properties, representing a significant advance, particularly in the quality analysis of drugs and chemicals. It offers a practical, affordable, and accurate solution.

[0036] In a particular embodiment of the invention, the analysis apparatus comprises mechanical fixing means (x) arranged to ensure the fixing of a medicinal tablet or an equivalent dosage form.

[0037] The operation of said sensor was validated according to a non-limiting experimental mode based on the use of a set of PARACETAMOL® 1000 mg tablets: the chosen tablets underwent qualitative deviations caused by temperature variations from 27°C to 80°C. The temperature variation margin is chosen in a non-limiting manner in order to simulate the conditions of thermal variations within the means of transport under the impact of solar radiation and also within the storage spaces. In fact, in the absence of ventilation or air conditioning systems, temperatures within the means of transport or distribution can reach values ​​close to 89°C. This is generally observed during the stopping of the vehicle and during the loading and unloading operations of the transported products.The said tablet was chosen to represent one or more production batches which will follow the same logistical path from production to final unloading.

[0038] The device is characterized by the possibility of reuse for the analysis of tablets belonging to several production batches. INDUSTRIAL APPLICATION

[0039] The present invention is particularly intended for the chemical, pharmaceutical, agro-industry, agro-food industry and agriculture, this list not being exhaustive.

[0040] REFERENCES

[0041] [1] Said, Mazlina M., Simon Gibbons, Anthony C. Moffat, and Mire Zloh. "Near-infrared spectroscopy (NIRS) and chemometric analysis of Malaysian and UK paracetamol tablets: a spectral database study." International journal of pharmaceutics 415, no. 1-2 (2011): 102-109. [2] R. Bate, R. Tren, K. Hess, and A. Attaran, "Physical and chemical stability of expired fixed dose combination artemether lumefantrine in uncontrolled tropical conditions," Malar. J., vol. 8, no. 1, 2009, doi: 10.1186 / 1475-2875-8-33.

[0042] [3] A. P. Terzyk, G. Rychlicki, S. Biniak, and J. P. tukaszewicz, "New correlations between the composition of the surface layer of carbon and its physicochemical properties exposed while paracetamol is adsorbed at different temperatures and pH," J. Colloid Interface Sci., vol. 257, no. 1, pp. 13-30, 2003, doi: 10.1016 / S0021-9797(02)00032-2.

[0043] [4] Devi, T. A., Aravind Setti, S. Srikanth, Sivaramaiah Nallapeta, Smita C. Pawar, and J. Venkateshwara Rao. "Method development and validation of paracetamol drug by RP-HPLC." Journal of Medical & Allied Sciences 3, no. 1 (2013).

[0044] [5] H. Garcia, C. G. Juan, E. Avila-Navarro, E. Bronchalo, and J. M. Sabater-Navarro, "Portable Device Based on Microwave Resonator for Noninvasive Blood Glucose Monitoring," Proc. Annu. Int. Conf. IEEE Eng. Med. Biol. Soc. EMBS, pp. 1115- 1118, 2019, doi: 10.1109 / EMBC.2019.8856934.

Claims

CLAIMS 1. Portable and autonomous device for the online analysis, in real time, of the qualitative deviation of substances potentially sensitive to environmental constraints undergone during a given period, comprising: a) a planar microwave sensor (2 fig.1) arranged on a disc of metallic material (1 fig.2) having etched therein a coupling of a network of hexagonal ring resonators (2 fig.2), which disc is printed on the upper face of a magneto-dielectric substrate (9 fig.2), the other face comprising a layer of a printed metallic material (1 fig.3) forming a ground plane (4 fig.3); said microwave sensor being connected to two microwave ports (4,5 fig.2) symmetrical, allowing the simultaneous performance of the functions of excitation and transmission of electromagnetic waves; said network of hexagonal resonators being arranged to create a concentrated near electromagnetic field resulting from the electromagnetic coupling between the adjacent hexagonal edges of the resonators (2 fig.2), oriented perpendicular to the plane (6 fig.3) of the substance under analysis (1 fig.1); a fixing mechanism (3 fig.1) of the substance under analysis arranged within the zone of creation of the electromagnetic field (5 fig. 3) of said sensor; b) a unit (8 fig.1) for generating and measuring electromagnetic waves of excitation of said sensor; c) a calculation unit (9 fig.1) capable of executing an inference model recognizing the qualitative deviation of the substance under analysis according to the measurements of electromagnetic waves; d) a transmission unit (10 fig.1) of the inference data; and e) a power supply unit (11 fig.1) integrating a battery ensuring the autonomy of the device.

2. Portable apparatus according to claim 1, characterized in that the electromagnetic wave generation unit (8 fig.1) belongs to the microwave domain and is capable of measuring microwave properties in modulus and phase as a function of frequency.

3. Apparatus according to claims 1 and 2, characterized in that it detects the qualitative deviation of the substance under analysis having undergone variations in environmental constraints over a given period, through the measurement of the microwave qualitative deviation factor (7 fig.4) defined by the deviation Quw between the peak of the microwave signal (5 fig.4) of a standard substance or of the substance under analysis at the start of the period (T0), and the microwave signal (6 fig.4) of the substance under analysis at the end of the given period (Tx).

4. Apparatus according to at least one of the preceding claims, characterized in that it comprises a calculation unit (9 fig.1) capable of executing an inference model making it possible to indicate the level of environmental constraints having, during the period concerned, impacted the quality of the substance under analysis.

5. Apparatus according to at least one of the preceding claims, characterized in that it further comprises an inference data transmission unit (10 fig.1) ensuring the transmission of the data collected by the sensor (2 fig.1) to a user platform, allowing the analysis of the results remotely.

6. Apparatus according to at least one of the preceding claims, characterized in that the planar microwave sensors (2 fig. 2) comprise mechanical fixing means (3 fig. 1) arranged to ensure the fixing of the substance under analysis (1 fig. 1) in a solid or compacted form such as a medicinal tablet.

7. Method for online analysis, in real time, of the qualitative deviation of substances potentially sensitive to environmental constraints undergone during an implementation using the apparatus according to one of claims 1 to 6.

8. Method according to claim 7, characterized in that the environmental constraints undergone by the substance under analysis include exposure to high temperatures, extremely low temperatures, exposure to ionizing or non-ionizing radiation, shocks or high pressures, exposure to humidity or chemical contaminants.

9. Method according to claim 7, characterized in that the substance under analysis is chosen from metabolic, chemical or biochemical active ingredients such as human or veterinary medicines, fertilizers, fertilizers or pesticides, food supplements or micronutrients, in particular medicinal tablets.

10. Method according to claim 7 applied to the quality control of the substance under analysis, in particular of drugs during manufacture, during storage, during clinical or preclinical trials, or in the context of pharmacovigilance.

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