Measurement chamber extension for spectrophotometric characterization of sterile liquids in polymer containers by NIR or Raman spectrophotometric method.
By using NIR or Raman spectroscopy and specific optical elements in drug packaging, the challenges of component identification and quantitative analysis in drug packaging have been solved, achieving a combination of sterility and accuracy and simplifying batch quality control.
Patent Information
- Authority / Receiving Office
- JP · JP
- Patent Type
- Patents
- Current Assignee / Owner
- AINA ANALYTICS GMBH
- Filing Date
- 2021-07-09
- Publication Date
- 2026-06-25
Smart Images
Figure 0007880047000001 
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Abstract
Description
Technical Field
[0001] The present invention relates to the identification and / or quantification of active pharmaceutical ingredients (APIs), excipients, and possible admixtures, and / or their contaminants, and to the quantification / detection / verification of the physical properties (aggregation, particle size, etc.) of such pharmaceuticals in a liquid state within a sterile package, particularly within an infusion bag or within a syringe within a sterile package.
[0002] The incorrect production or storage of pharmaceuticals can lead to the loss of the intended effect or even harm to the organisms to which the pharmaceuticals are applied.
[0003] Therefore, the control of their quality and / or identity immediately before applying the pharmaceuticals is of utmost importance. Such control of quality and / or identity can be carried out by evaluating, for example, spectroscopic measurements of pharmaceuticals that often exist as sterile solutions within polymer containers held inside sterile packages, such as infusion bags or disposable syringes.
[0004] Typically, samples of batches of pharmaceuticals are taken and analyzed, resulting in the destruction of the samples / batches. Since the batch number for individually produced infusion bags, pumps, or syringes is often n = 1, it is not possible to determine the quality of the formulation before batch release. Furthermore, these techniques often require an analytical laboratory and skilled highly specialized personnel to evaluate the analysis results, such as spectra or chromatograms. Japanese Patent Publication No. 10-078396 discloses a spectroscopic measurement and analysis apparatus. Japanese Patent Publication No. 2006-098276 discloses a water quality measuring instrument and a sample container used therein. Japanese Patent Publication No. 2008-002849 discloses an analytical apparatus and a container.
Summary of the Invention
[0005] <000……此处原文标签缺失部分内容,推测可能是完整标签 ,但无法确定。若按完整标签处理,翻译如下: In order not to impair the integrity and thus the sterility of the original solution and its container, the measurement chamber extension according to claim 1 and the method according to claim 21 are proposed.
[0006] In particular, the chemical components in a liquid can be identified or further quantified using the information gathered by measuring the transmission or transmission reflectance of a measuring light beam (sample beam) of an NIR spectrophotometer or Raman spectrophotometer, directed to pass through a polymer container containing a drug active ingredient in a dissolved state, suspension, or emulsion, whether in an infusion bag or a syringe in a sterile package, and optionally by measurements in the reverse direction of transmission reflectance.
[0007] The measurement principle used can be based on transflection (the optical path that passes through the package and returns in the opposite direction) or transmission (the sample beam passing through the package (liquid) only once).
[0008] Based on the individual shapes and sizes of the containers (primary and / or secondary), and the relationship between these containers and the product itself (including their properties regarding materials, transparency, printing, and, of course, individual spatial behavior, especially with respect to pumps or infusion bags with flexible container walls), the best area for measurement is determined. The optimal parameters for this area are as follows: 1. Light can pass through the container, and the loss of light intensity is minimized by individual holders (e.g., holders equipped with diffuse mirrors or waveguides). 2. The distance between different containers and products is minimized, thereby allowing the shortest possible path of light to be used (e.g., plastic bags / trays for secondary packaging). 3. Minimal influence on the spectrum from the container itself (e.g., different materials, layers, transparency, layer thickness) is ensured. 4. The light beam is focused onto the liquid, that is, into the cylinder of the syringe inside the package (container). 5. Liquid products are typically presented with a repeatable layer thickness corresponding to the diameter of the syringe cylinder, thereby enabling robust and repeatable measurements. 6. Liquid products are typically presented with a reproducible layer thickness corresponding to the distance between the measurement window and the mirror and mirror fixing member (when reflectance mode is used), or the distance between the measurement window and the liquid layer formed by the bag orientation member and the outer contour (when transmission mode is used).
[0009] The NIR or Raman instrument, the (optional) sterile package for the sample, and the optical elements are positioned to ensure one or more of the conditions described above.
[0010] For example, different types of holders or combinations thereof can be used to position the syringe or infusion bag to be measured. These may include, for instance, plastic and / or metal holders housing electronic devices for identity recognition of each part and for automatically ensuring the correct positioning of the parts via software solutions. These holders are manufactured individually according to the specific type of syringe and, consequently, the optimal position required for the corresponding package holder. Since infusion bags are typically standardized, the holders for each infusion bag in each product line from each manufacturer are typically easy to design and therefore fairly universal.
[0011] Regarding product lines from different manufacturers, it has been observed that a given manufacturer typically uses polymer materials of the same or nearly identical composition, even for different drug compounds (APIs). Therefore, since the signals generated by polymer packages (infusion bag walls, syringe cylinders, cartridge cylinders) are always the same, the identity of a product or its potential contaminants can be determined with high reliability by simply comparing measurement data (e.g., spectra or their derivatives) of different products (infusion bags containing liquids, suspensions, or semi-solids, each containing the API of interest to be monitored), without knowing the spectral data of the polymer package. Thus, a simple and reliable method is provided for monitoring erroneous misfiling, as well as contamination or the improper substitution of drug solutions with admixtures in pre-filled polymer packages. The proposed method advantageously does not impair the sterility of the pre-filled syringes, pumps, cartridges, etc., being measured.
[0012] Thus, the present invention describes the identification, quantification, and distinction of packaging materials (plastic bags or syringes and syringe packaging), solvents and active pharmaceutical ingredients, and unwanted solutes (admixtures and / or contaminants) using NIR and Raman spectral characteristics.
[0013] Advantageously, it can identify incorrect misfiling, as well as improper substitution of drug solutions due to contamination or admixture. It can also detect a more accurate concentration of a given substance in a bag or syringe. [Brief explanation of the drawing]
[0014] [Figure 1] One embodiment of the proposed measurement chamber extension 10, connected to a commercially available NIR spectrophotometer 1 or Raman spectrophotometer 1, is shown.
[0015] [Figure 2]Schematically shows an exploded view of the proposed measurement chamber extension 10 in its relationship to the NIR spectrophotometer 1 or the Raman spectrophotometer 1.
[0016] [Figure 3] Shows a vertical cross-section (B - B' in Fig. 4) of the measurement chamber extension 10 fitted to a suitable spectrophotometer.
[0017] [Figure 4] Shows a horizontal cross-section (A - A' in Fig. 3) at the level of the syringe 3 within the sterile package 4.
[0018] [Figure 5] Is a view of the bottom of the outer fitting surface 8 of the proposed measurement chamber extension, i.e., shows the measurement chamber extension as seen from the spectrophotometer.
[0019] [Figure 6] Shows different views of the container holder 7 with a light guide channel inserted into the opening of the outer fitting surface 8 of the light-shielding box 9.
[0020] [Figure 7] Shows different views of the container holder 7.
[0021] [Figure 8] Shows a cross-sectional view (hash area) of the container holder 7. In the figure, the horizontal lines indicate the cross-section.
[0022] [Figure 9] Shows an embodiment of the measurement chamber extension configured for measurement in an infusion bag.
[0023] [Figure 10] Shows the NIR spectra of a directly measured aqueous API solution in infusion bags of the same manufacturer (Fresenius Kabi, Freeflex+) both having the same polyolefin.
[0024] [Figure 11] This shows the intrinsic NIR spectrum of Lucentis® containing 2.3 mg of the monoclonal antibody ranibizumab in a disposable plastic syringe, ready for injection.
[0025] A complete and implementable disclosure of the invention, including the best mode, is described in more detail in another part of the specification, including references to the accompanying drawings.
[0026] The following detailed description will refer to the accompanying drawings, which form part of the present invention and illustrate specific embodiments and features of the invention as examples. It should be understood that other embodiments may be used and structural or logical modifications may be made without departing from the scope of the invention. Therefore, the following detailed description should not be construed as limiting, and the scope of the invention is defined by the appended claims. [Modes for carrying out the invention]
[0027] When used in conjunction with the term “equipped with” in the claims and / or specification, the use of the words “a” or “an” may mean “one,” but is not inconsistent with the meanings of “one or more,” “at least one,” and “one or more.”
[0028] The use of the term “or” in the claims is used to mean “and / or” unless it is expressly indicated that it refers only to substitutes, or that the substitutes are not mutually exclusive; however, this disclosure supports the definitions that refer only to substitutes and “and / or”.
[0029] When used herein (above and below) and in the claims, the words “comprise” (and any form of “comprise,” such as “comprise” and “comprises”), “have” (and any form of “have,” such as “have” and “has”), “include” (and any form of “include,” such as “includes” and “include”), or “contain” (and any form of “contains,” such as “contains” and “contain”) are comprehensive or open-ended and do not exclude additional, unmentioned elements or method steps.
[0030] As used herein, the term “semi-solid” includes gels, pastes, or lotions (which are of higher viscosity than typical physiological (aqueous) solutions, and therefore most often two-phase systems, solid / liquid, or liquid / liquid). The term is used in accordance with its general understanding by those skilled in the art in pharmaceutical and / or food technology.
[0031] Furthermore, it should be noted that the term "solution" as used herein is not limited to aqueous solutions but also relates to other solvents, such as oils. Therefore, liquid compositions that can be measured using the proposed measurement chamber extension may include, for example, multi-component / multi-phase solutions and dispersions.
[0032] According to one embodiment, a measurement chamber extension for an NIR spectrophotometer or Raman spectrophotometer is proposed. It is adapted for the corresponding spectrophotometric characterization of sterile liquids in polymer containers, such as infusion bags or disposable syringes wrapped in sterile packaging. The measurement chamber extension is: - Adapter having an adapter opening; -Container holder; and - Equipped with optical elements selected from mirrors and waveguides, The adapter is configured to cover the measurement chamber of the NIR spectrophotometer or the Raman spectrophotometer in a light-shielding manner, and the adapter opening is positioned to surround the measurement window of the selected spectrophotometer, providing exposure of the liquid to the measurement light beam emitted from the measurement chamber of the spectrophotometer through the measurement window; The container holder is configured such that the optical element is placed adjacent to the polymer container containing the liquid, and that the optical element can provide lossless transmission or transmission reflection of the measurement light beam from the optical element to the detector of a selected spectrophotometer, optionally through a measurement window in the reverse direction. The container holder has a clamp configured to hold a tubular section of the polymer container, enabling reproducible measurement conditions.
[0033] Advantageously, by comparing the newly collected NIR spectra with known alternatively analyzed NIR spectra of the same sample type (packaging, excipients, APIs), it becomes possible to qualitatively and at least semi-quantitatively detect the chemical and / or physical properties of the sample dissolved or suspended in the liquid inside the container. In this way, it becomes possible to identify the incorrect composition or substandard quality of the liquid, or its contamination by unwanted substances.
[0034] According to one embodiment, the container holder comprises a support structure for an optical element, the support structure comprising a channel whose width is adapted to match the width of the measurement window of a corresponding spectrophotometer (NIR or Raman spectrophotometer).
[0035] Advantageously, this allows the sample beam to pass through the package, syringe, and, for example, the package for recording the NIR spectrum of the transmitted and reflected light, without intensity loss (particularly with respect to transmission and reflection).
[0036] According to one embodiment, the optical element comprises a mirror with a gold layer, or at least an optical fiber or waveguide.
[0037] Advantageously, gold reflects more than 95 percent of incident radiation with wavelengths above 700 nm. Therefore, channels and mirrors can be coated with a gold layer or another reflective coating. Thus, the light being measured is transmitted and reflected light. The gold layer can be deposited by vacuum deposition or plating, both of which are galvanic and electroless, as well as by other suitable additive manufacturing techniques. Advantageously, optical waveguides or fibers may be selected to provide lossless guidance over at least a short distance (typically 10 or tens of centimeters) for coupling from the polymer package to the photodetector or into the measuring chamber of the corresponding spectrophotometer (NIR or Raman spectrophotometer), as relevant herein.
[0038] According to one embodiment, the container holder comprises a receptacle formed by a channel along with a mirror.
[0039] Advantageously, such holders are adapted to reproducibly hold the containers.
[0040] According to one embodiment, the surface of the channel is also covered with a gold layer.
[0041] Advantageously, the signal-to-noise ratio can be improved. Mirrors can be made from materials such as gold, Spectralon (PTFE), or aluminum, which can provide a highly reflective surface for light in the relevant wavelength range (for both NIR and Raman spectrophotometric methods).
[0042] According to one embodiment, the container holder is placed in a light-shielding box, and this light-shielding box has a lid adapted to close the light-shielding box in a light-shielding manner.
[0043] In this case as well, the signal-to-noise ratio is improved, and consequently, the accuracy of the measurement increases. A more compact design can be achieved. The optical guide may comprise a hollow channel, or a waveguide, or a bundle of waveguides. For example, the optical guide may have a lateral recess, and the mirror may be positioned on the side of the optical guide furthest from the entrance of the sample beam (i.e., furthest from the opening into which the optical guide is fitted into the box). The opening may even be located on the lid of the box.
[0044] According to one embodiment, the optical element is fixed to the lid. According to one embodiment, the optical element may be positioned on the lid so as to hold the circular portion of the polymer container near the channel opening.
[0045] For example, the optical element may be connected to the lid by an elastic element, such as a spring or a sponge-like material. Advantageously, by closing the lid, the optical element is pressed against a syringe in a polymer container, such as a package. This may be used to simplify the design of the measurement chamber expansion and optimize the measurement process.
[0046] According to one embodiment, the gold layer on the surface of the channel fuses with the gold layer of the mirror, and the mirror becomes integrated with the channel.
[0047] The mirror, together with the optical guide, may thus form a receptacle, or package holder. Advantageously, the orientation of the optical element, such as the mirror, relative to the optical guide remains constant throughout all measurements, which allows for the establishment of standardized and reproducible measurement conditions.
[0048] According to one embodiment, the optical element is a mirror, particularly a diffuse mirror.
[0049] Advantageously, this allows a representative signal, consisting of light transmitted and reflected through the liquid in the syringe, to be collected by an optical guide and analyzed with an NIR spectrophotometer or Raman spectrophotometer.
[0050] According to one embodiment, the gold layer of the diffusion mirror surrounds a plurality of mirrors, each mirror having a flat polygonal surface, and the plurality of mirrors are arranged as a corrugated surface of the mirror.
[0051] Advantageously, gold reflects over 95 percent of incident radiation with wavelengths above 700 nm. Its wave-like structure allows for complete collection of even refracted stray light within the container. Advantageously, even finely dispersed (suspended) particles can be measured.
[0052] According to one embodiment, multiple mirrors with rough or smooth mirror surfaces can be arranged to consist of an optimized mirror or simply a single smooth or rough mirror. These surfaces are covered at least partially with a gold layer.
[0053] Advantageously, the shown shape, i.e., the three-dimensional structure of the rough surface, allows for nearly perfect diffuse reflection of the incident light, i.e., the sample beam after it has passed through the package, syringe wall, and liquid.
[0054] According to one embodiment, the rough mirror surface has a roughness in the range of 20 μm to 1000 μm.
[0055] Advantageously, roughness in the range of 20 μm to 1000 μm allows for perfect diffuse reflection without signal loss, and consequently, a high signal-to-noise ratio.
[0056] According to one embodiment, the optical element is a waveguide rather than a mirror.
[0057] Advantageously, waveguides typically allow lossless guidance of light to and from a liquid layer within a polymer container.
[0058] According to one embodiment, on the measurement window of the spectrophotometer, the first waveguide is positioned to guide the measurement light from the light source of the spectrophotometer to the liquid in the polymer container and then to an optical element, i.e., the second waveguide. The second waveguide is configured to guide the measurement light, after passing through a layer of liquid in the polymer container having a specified thickness, from the polymer container to the photodetector of the spectrophotometer.
[0059] Advantageously, the design of the measurement chamber extension can be greatly simplified. The polymer container containing the liquid having the active pharmaceutical component (whether in the form of a solution or suspension / emulsion thereof) only needs to be isolated in a light-shielding manner, for example, in a light-shielding box, and the two end surfaces of the first and second waveguides (i.e., optical elements) should be aligned with respect to each other so as to contain a layer of liquid (of a specified thickness) consisting of the two polymer walls of the polymer container surrounding the polymer container and the liquid itself in the gap formed between the two ends.
[0060] According to one embodiment, the polymer container is a disposable syringe.
[0061] Currently, many drugs are sold in pre-filled, disposable syringes, and their quality is controllable. Typically, disposable syringes are made from certain well-characterized polymer materials (due to the thorough regulation of primary and secondary packaging, and the fact that only qualified suppliers can be used by pharmaceutical companies), thus simplifying the analysis of measurement data.
[0062] According to one embodiment, the optical guide comprises a channel, for example, a tube flange, the end of which is shaped to form a tongue-like portion, which forms a receptacle, or contact portion, for fitting and holding the cylinder of a syringe in an orientation perpendicular to the central axis of the tube flange, the surface of which the tongue-like portion is oriented toward the tube flange is a corrugated surface with a mirror, and the cylinder of the syringe can be positioned on the receptacle in the optical path of the sample beam.
[0063] Advantageously, a flanged pipe (tube flange) surrounds the light guide channel, which is also coated with a reflective layer, such as a gold layer. The light guide channel terminates at the surface of a corrugated mirror, thus allowing the sample beam to pass through the syringe and the liquid contained therein to a diffusion mirror, and then the diffused and reflected (transmitted reflected) light is adapted to be guided from the diffusion mirror to the detection unit of an NIR spectrophotometer or Raman spectrophotometer, or through a second light guide channel to a transmission detector.
[0064] According to one embodiment, the disposable syringe is enclosed, or wrapped, in a sterile package.
[0065] Such sterile packaging typically consists of polymer foil. These materials are known and specified by the manufacturer. Therefore, corresponding measurements can be verified using a properly fitted database.
[0066] According to one embodiment, the opening of the adapter is fitted to accommodate the corner of the infusion bag.
[0067] As is evident from element 40 in Figure 9, the adapter is provided with a hole (channel), which may also be covered by a mirror surface or lead to a light guide channel to a transmission detector. The shape of the adapter can be triangular, but it can be individually adapted to the shape (other shapes are also available) of the infusion bag or pump in question. As shown, the material of the mirror surface may be, for example, aluminum, Spectralon (sintered PTFE), or gold. Advantageously, the corners of the infusion bag can be compressed (tightened) until only a thin layer of liquid remains. Furthermore, the liquid can be completely shut out from these corners to obtain a spectrum of only the polymer material of the bag. Thus, the identification or quantification of signals belonging to pure substances (and solvents, excipients, etc.) is facilitated.
[0068] According to one embodiment, the measurement chamber extension described above comprises an adapter having an opening configured for measuring the liquid in an infusion bag, the measurement chamber extension further comprises a bag orientation member, the outer contour of the bag orientation member being configured to fit the inner contour of the adapter opening over most of the length of the outer contour when the bag orientation member is at least partially inserted into the adapter opening, the bag orientation member being configured to fit the inner contour of the adapter opening over most of the length of the outer contour. The bag orientation member may be equipped with a clamp to ensure an optimal and repeatable passage. This can be either two separate parts, one above and one below the liquid container, or a single clamp comprising both of these parts, to guide the light.
[0069] Advantageously, the outermost rim of the corner can be protected from ambient light because it fits into the space formed by the adapter's opening and the bag orientation member. The shorter portion of the outer contour fits the inner contour of the base plate's opening, while the rest of the bag is kept far away from the measurement path.
[0070] According to one embodiment, a corresponding pair of permanent magnets is positioned at or near the fitting edge of the adapter opening and the bag orientation member.
[0071] Advantageously, small niobium magnets, for example, may be inserted in adjacent sections to enable self-fitting between the bag orientation member and the adapter opening. These magnets can be inserted coplanar with the outer surface to further enable light-shielding fitting.
[0072] According to one embodiment, the thickness of the layer of liquid or (nano)particle suspension in a polymer container, such as a bag or syringe, can be adjusted between 0.2 mm and 5.1 mm, preferably between 0.5 mm and 2.1 mm.
[0073] Advantageously, it is possible to achieve an optimal and reproducible layer thickness for transmission-reflected or transmission-based measurements.
[0074] According to one embodiment, the position of the optical element can be stabilized by a fixing (or holding) member. This allows for stabilization in the horizontal plane and the vertical direction, and therefore, a specified layer thickness can be achieved.
[0075] Advantageously, this allows for the standardization of measurement conditions.
[0076] According to one embodiment, the holding or fixing member and the bag orientation member each comprise at least one magnet from a pair of permanent magnets for stabilizing the optical element in or within the channel, and the channel is dimensioned to surround, i.e., to fit snugly with, the outer dimensions and shape of an optical element, such as a circular mirror.
[0077] Advantageously, the reproducibility of the measurements can be further improved.
[0078] According to one embodiment, a method is proposed for the analysis of liquids or semi-solids in polymer containers by NIR spectroscopy. The polymer container is selected from infusion bags and syringes. The syringe, infusion bag, or pump may optionally be enclosed in sterile packaging. Thus, pharmaceutically or otherwise biologically effective substances, or substances used as excipients, dissolved or suspended (dispersed) in the liquid can be measured without extra sampling, i.e., without unpacking or opening the polymer container, i.e., while maintaining the sterility of the original liquid. Based on the use of the measurement chamber expansion unit described above, this method is: - The step of holding the circular portion of the polymer container with a receptacle; - The step of arranging an optical element adjacent to the surface of a polymer container; - The step of directing the measurement light beam toward the optical element and analyzing the transmitted or transmitted and reflected light with an NIR spectrophotometer or Raman spectrophotometer; - A step of comparing the signal generated by transmitted or transmitted and reflected light with a dataset stored in a database containing NIR spectra or Raman spectra of similar or identical samples; and -The process includes steps of determining the identity of a solute dissolved in a liquid, and / or detecting admixtures or contaminants in the liquid, and / or detecting the concentration of the active pharmaceutical ingredient or its contaminants, at least semi-quantitatively, and / or determining the physical properties (e.g., particle size, particle aggregation) of the solute dissolved in the liquid or particles dispersed per unit volume of liquid, and / or detecting admixtures or contaminants in the liquid or dispersion, respectively.
[0079] Advantageously, the above method allows for the qualitative and at least semi-quantitative determination of the physical or chemical parameters of a liquid or semi-solid contained within a polymer container (infusion bag or disposable syringe), and any associated contaminants or foreign matter accidentally contained (e.g., admixtures, decomposition products of the intended substance, etc.). Furthermore, if the liquid comprises a dispersion of suspended (nano) particles, the homogeneity of the dispersion can be evaluated. In addition, quantitative determination of the active drug component, verification of the drug quality of the product in the polymer container, and acquisition of its physical properties (e.g., particle size, presence of aggregation, etc.) can be performed.
[0080] According to one embodiment, the sample beam is 4,000 cm². -1 ~12,500cm -1 It provides light within the wavenumber range.
[0081] Advantageously, the spectral characteristics within the indicated wavelength range can be used to distinguish various drug substances (APIs and excipients), associated contaminants, and physical properties (e.g., particle size, aggregation, etc.).
[0082] According to one embodiment, the proposed method comprises repeated measurements with different sample beams having different wavelengths. These sample beams are directed toward a reflective mirror at the same angle, but can also be directed toward a reflective mirror at different angles. For example, different incident angles can be selected for the same wavelength. Different wavelengths can be advantageously directed (transmitted and reflected) by a diffuse mirror at different incident angles.
[0083] One advantage is that it allows for improved measurement accuracy.
[0084] According to one embodiment, the database used to analyze the acquired spectra comprises datasets belonging to different sample types, including a typical product range (see also European Pharmacopoeia 2.2.40). Typically, these materials comprise organic polymers such as PE, PP, PVC, and PMMA. Furthermore, the spectrophotometer software, or similar software, used is adapted to extract the information of interest (e.g., absorbance at a specific wavelength linked to the API content) from the currently measured NIR spectrum.
[0085] Advantageously, this makes it possible to extract from spectral data information that can be used to reliably identify or quantify substances dissolved or suspended in a liquid, or to quantify the physical parameters of a composition contained in a syringe.
[0086] According to one embodiment, software stored in an NIR spectrophotometer or a Raman spectrophotometer, or stored in a computerized system used to control each spectrophotometer, is adapted to extract from the measured NIR or Raman spectrum the corresponding spectrum belonging to a material comprising a sterile package of a polymer container or syringe.
[0087] Advantageously, spectral data belonging to the target parameter can be extracted and evaluated with high reliability.
[0088] Each of the embodiments described above may be combined with any other embodiment or combination of embodiments unless otherwise explicitly indicated.
[0089] For the purposes of this explanation, Figure 1 shows only one embodiment adapted for use with a commercially available spectrophotometer (e.g., an NIR or Raman spectrophotometer), for example, provided by Bruker or Jasco, PerkinElmer, Shimadzu, Metrohm or Varian. The measurement chamber extension 10 is connected to the NIR spectrophotometer 1 or Raman spectrophotometer 1 using an adapter 11 that fits into the opening of the measurement chamber 20.
[0090] Figure 2 shows that the measurement chamber extension 10 includes a light-shielding box 9, and that before connecting the measurement chamber extension 10 to the measurement chamber 20 of the NIR spectrophotometer or Raman spectrophotometer 1, the open lid 8 is ready to receive the sterile package 4 containing the syringe 3' and hold it in the inner package holder 6. It is shown that the light-shielding box 9 is positioned directly above the measurement chamber 20 so that the measurement (sample) beam of the NIR spectrophotometer or Raman spectrophotometer 1 can enter (along a vertical line) into the optical guide 6, which is shown as the light guide channel 6 of the package holder 7.
[0091] Figure 3 shows how the sterile package 4, equipped with a syringe, is held by an internal package holder 6 precisely in the center of the sample beam (red) of an NIR spectrophotometer 1 or Raman spectrophotometer 1 (not shown), which is connected in a light-shielding manner (via an adapter 11).
[0092] As can be seen in Figure 4, in order to enable the measurement chamber extension 10 to be light-shielded and fitted to the NIR spectrophotometer 1 or Raman spectrophotometer 1, the box 9 of the illustrated embodiment must be closed by the lid 8.
[0093] Figure 5 is a view of the measurement chamber extension 10 from below, i.e., from the side of the spectrophotometer. The wall of the box 9 having a circular opening 88 for receiving the optical guide 6 is shown. The four slits of the circular recess 86 ensure the correct position and, consequently, the correct orientation of the optical guide 6 inside the light-shielding box 9. Advantageously, the shape and size of the optical guide 6 can be adapted to different enclosures (packages 4) of different syringes 3.
[0094] Among the different diagrams of the optical guide 6, there is a combination of the optical guide and the mirror 5, both of which comprise a package holder 7. Figure 6A shows the outside of the package holder 7 with the optical guide 6, with the optical guide, in this case the channel 6, visible. Figure 6B shows the optical guide 6 with the mirror 5, in this case the diffusion mirror 5. The diffusion mirror 5 has a corrugated, rough mirror surface. The tongue-shaped portion 66 of the optical guide 7 is adapted to hold the tubular portion 3a of the syringe 3 in a sterile container 3, for example, a sterile package 4. As shown, the inner surface 66 of the optical guide 6 is covered with a gold layer, which is fused with the gold layer of the corrugated mirror 5 inside the optical guide 6. As also shown in the vertical cross-sectional views in Figure 6C and Figure 6D, the combined optical guide 6 / package holder 7 comprises a mouth-shaped receptacle 13 or holder 13 with a tongue-shaped contact portion 66. In the illustrated embodiment, the inside of the contact portion 66, which is oriented toward the spectrophotometer 1, is provided with a corrugated mirror surface 5. Advantageously, the corrugated structure of the mirror surface 5 allows for both diffuse reflection and secure gripping of the syringe 3 encased in the sterile package 4.
[0095] Figure 7 shows a view from below the inner syringe holder (A) in which the optical guide and (corrugated mirror) are directly visible, a front view (B), a side view (C), and a top view of the optical guide 6. According to one embodiment, the optical guide 6, which has a tongue-shaped portion 66, i.e., a corrugated surface on the inside of the package holder, can be manufactured, for example, from polystyrene by injection molding. It can also be manufactured from glass, or for example, aluminum. Its surface can be coated with a gold layer, for example, by electroless (barrel) plating or by vapor deposition.
[0096] Figure 8A shows a horizontal cross-section passing through the optical guide 6 at the level of the mouth-shaped receptacle 7 directly below the tongue-shaped contact portion 66, i.e., the upper portion of the cross-sections in Figures 8B and 8C. Figure 8B is a vertical cross-section in the front view arrangement of the optical guide 6, while Figure 8C is a cross-section in the side view arrangement. Indicator symbol 66 indicates the inner surface of the optical guide 6. Figure 8D shows the lower portion of the cross-sections in Figures 8B and 8C.
[0097] An advantage of the presented embodiment is that the proposed measurement chamber extension 10 can be combined with all commercially available NIR spectrophotometers 1 once its outer contour is appropriately fitted to the outer contour of the measurement chamber 20 of the spectrophotometer 1. In this specification, “appropriately” means a fit that maintains light-shielding conditions and ensures that the sample beam is directed into the optical guide 6 inside the box 9 for transmission or transmission reflectance measurements of the liquid 2 in the syringe 3' inside the sterile package 4.
[0098] Figure 9, in particular, shows one embodiment of the extension 10 that can be combined with both an NIR spectrophotometer 1 and a Raman spectrophotometer 1. The infusion bag 3 is held by a receptacle 13 of a container holder 7 in at least one tubular section 3a. The edge of the bag 3 is aligned with the corresponding opening of the adapter 11 by a bag orientation member 40. The adapter 11 is connected in a light-shielded manner to the measurement chamber 20 of the corresponding spectrophotometer 1. The measurement light beam (e.g., NIR) or the corresponding laser beam (Raman spectrophotometry) enters the adapter 11 and reaches (is directed to) an optical element 5 (here, a mirror) held by a corresponding fixing member 15 (or stabilizing member 15). The stabilizing member 15 ensures direct physical contact between the optical element and the outer wall of the bag 3 (or syringe package 4) at corner 3b. The distance of the front surface of the optical element to the optical window of the measurement chamber 20, along with the thickness of at least two layers of polymer material, defines the length (layer thickness) of the measurement light path in the liquid 2 containing the target API. The measurement light beam is guided by a light guide channel 6. The channel wall is made of or coated with a reflective material. To give a few examples, suitable materials are, for example, aluminum, gold, and Spectralon. Advantageously, the mirror, i.e., its three-dimensional shape, mating contour 41, and surface structure, i.e., roughness, can be adjusted during its manufacture to suit the current measurement conditions, for example, by CAD-assisted 3D printing (an additive manufacturing technique that allows for easy and rapid adaptation to a given spectrophotometer and packaging of a sterile solution of the API (e.g., syringe 3, infusion pump 3 or cartridge of such, infusion bag 3)).
[0099] Figure 10A shows physiological saline, i.e., 0.9% NaCl in water (orange line), compared to 5% glucose solution "Glucosteril 500" in water (green). Glucosteril 500 is a 5% glucose monohydrate solution according to the European Pharmacopoeia. Both spectra are shown as acquired (original spectral data with no data processing / pretreatment). As is clear, the quality achieved directly from the infusion bag by the proposed measurement chamber expansion is good. By directly comparing the acquired spectra, the influence of the ubiquitous water band (approximately 7100, 5250 cm⁻¹) can be seen. -1 (See the value in) is significantly reduced, and other wave frequencies, such as the typical CH band range of 6000 to approximately 5400 cm², are reduced. -1 In this case, it becomes possible to obtain content-specific signals. Other frequency bands, typical of organic materials with hydrogen bonds, e.g., CH and / or NH, are important for identifying typical APIs and can therefore be used. Figure 10B shows the corresponding second derivative of the NIR spectrum from Figure 10A (NaCl - red and gray lines; Glucosis - blue line). Clearly, around 5800 cm⁻¹ -1 A highly differential band (blue spectrum, 5% glucose solution) can be easily identified. This allows for the confirmation of a very strong API signal, enabling the quantification of glucosis.
[0100] Figure 11 shows the spectrum of a ready-to-use syringe containing Lucentis 2.3 mg (concentration 10.0 mg / ml).
[0101] The described embodiments have diverse application areas in the fields of pharmaceutical, medical, veterinary, or biochemical applications of biologically effective substances, for the detection of pharmaceutical substances, their possible contaminants, and / or admixtures, or their degradation products as a result of, for example, incorrect storage conditions, but also in the fields of food, such as food additives, concentrates, etc., and convenience products. Several examples illustrating the apparatus and methods used are given below for the purpose of demonstrating the feasibility of the proposed embodiments.
[0102] The present invention has been described with reference to various exemplary embodiments and examples. These embodiments and examples are not intended to limit the scope of the invention, which is defined by the claims and their equivalents. As will be apparent to those skilled in the art, the embodiments described herein can be implemented in various ways without departing from the scope of the invention. Various features, aspects, and functions described in the embodiments can be combined with other embodiments. [Explanation of symbols] 1. Spectrophotometer (NIR or Raman spectrophotometer) 2. Liquids, such as biologically effective substances, drugs, vaccines, and food additives. 3. Polymer containers (infusion bags, pumps, or disposable plastic syringes, packaged as optional) 3a Tubular section of polymer container 3b. Corners of polymer containers, especially IV bags 4. Aseptic packaging (typically made from polymer foil) 5. Optical elements, such as mirrors or optical guides. 55 Multiple mirrors 6 channels, for example, light guide channels 66 Contact portion, tongue-shaped portion of holder 13 7. Container holder 8 Lid 87 Lip, channel flange 88 Opening of light-shielding box 9 Light-blocking box 10 Measurement chamber expansion section 11 adapters, adapters 11' Adapter opening 13 Receptacle, retaining member for tubular portion 15 Mirror fixing member 20 Measurement Chamber 40 Bag orientation member 41 Outer contour of bag orientation member
Claims
1. A measurement chamber extension (10) for spectrophotometric characterization of a liquid (2) in a polymer container (3) including a tubular section (3a) using an NIR spectrophotometer (1) or a Raman spectrophotometer (1), wherein the measurement chamber extension (10) Adapter (11) having an adapter opening (11'); A container holder (7) having a receptacle (13); and A mirror is selected from an optical element (5); The adapter (11) is light-shieldingly connectable to the measurement chamber (20) of the NIR spectrophotometer (1) or the Raman spectrophotometer (1) by its outer contour which conforms to the outer contour of the measurement chamber (20) of the NIR spectrophotometer (1) or the Raman spectrophotometer (1), and the adapter opening (11') is positioned to surround the measurement window of the NIR spectrophotometer (1) or the Raman spectrophotometer (1) and to provide exposure of the liquid (2) to the measurement light beam emitted from the measurement chamber (20) of the NIR spectrophotometer (1) or the Raman spectrophotometer (1) through the measurement window; The receptacle (13) of the container holder (7) is configured to position the optical element (5) adjacent to the surface of the polymer container (3) containing the liquid (2), thereby providing lossless transmission and reflection of the measurement light beam from the optical element (5) to the detector of the NIR spectrophotometer (1) or the Raman spectrophotometer (1). The receptacle (13) is configured to hold the tubular section (3a) of the polymer container (3) so as to enable a reproducible layer thickness in the transmission and reflection measurement. The container holder (7) has an optical element support structure including a light guide channel (6), and the width of the light guide channel (6) is adapted to match the width of the measurement window of the NIR spectrophotometer (1) or the Raman spectrophotometer (1). The optical element (5) has the mirror containing a gold layer, The polymer container (3) is selected from a syringe (3), an infusion pump (3), or a cartridge for the infusion pump (3), and an infusion bag (3). Measurement chamber extension.
2. The measurement chamber extension (10) according to claim 1, wherein the receptacle (13) is formed together with the mirror (5) by the light guide channel (6).
3. The surface (66) of the light guide channel (6) is covered with a gold layer, the measurement chamber extension (10) according to claim 2.
4. The container holder (7) is optionally placed in a light-shielding box (9) including a lid (8), and the lid (8) is fitted to close the light-shielding box (9) in a light-shielding manner. The measurement chamber expansion unit (10) according to claim 2 or 3, wherein the optical element (5) is optionally fixed to the lid (8).
5. The measurement chamber extension (10) according to claim 3, wherein the gold layer on the surface (66) of the light guide channel (6) is fused with the gold layer of the mirror (5), and the mirror (5) is integrated with the light guide channel (6).
6. The measurement chamber extension (10) according to any one of claims 3 to 5, wherein the mirror (5) is a diffusion mirror (5).
7. The measurement chamber extension (10) according to claim 6, wherein the gold layer surrounds a plurality of mirrors (55), each of which includes a flat polygonal surface, and the plurality of mirrors (55) are arranged as the corrugated surface of the mirror (5).
8. The measurement chamber extension (10) according to claim 7, wherein the waveform surface of the mirror (5) has a roughness in the range of 20 μm to 1000 μm.
9. The end of the light guide channel (6) is shaped to form a tongue-shaped portion (66), the tongue-shaped portion (66) forming a receptacle (13) for fitting and holding the tubular section (3a) of the syringe (3) in an orientation perpendicular to the central axis of the light guide channel (6), the surface of the tongue-shaped portion (66) substantially oriented toward the light guide channel (6) includes a corrugated surface (55) including the mirror (5), and the tubular section (3a) of the syringe (3) is positionable in the receptacle within the optical path of the sample beam, the measurement chamber extension (10) according to claim 8.
10. The adapter opening (11') is fitted to accommodate the corner (3b) of the infusion bag (3), The present invention further comprises a bag orientation member (40), wherein when the bag orientation member (40) is at least partially inserted into the adapter opening (11'), the outer contour (41) of the bag orientation member (40) is configured to conform to the inner contour of the adapter opening (11') over most of the length of the outer contour. The corresponding pair of permanent magnets is positioned at or near the fitting edge of the adapter opening (11') and the bag orientation member (40), The measurement chamber expansion unit (10) according to claim 1 or 2.
11. The thickness of the liquid (2) layer in the infusion bag (3) can be adjusted between 0.2 mm and 5.1 mm by the layer fixing member (15), preferably between 0.5 mm and 2.1 mm, according to the measurement chamber expansion unit (10) of claim 10.
12. The mirror (5) can be fixed by the mirror fixing member (15), The mirror fixing member (15) and the bag orientation member (40) include at least one magnet from the pair of permanent magnets for stabilizing the mirror within the light guide channel (6), and the light guide channel (6) is sized to surround the mirror (5). The measurement chamber extension (10) according to claim 10 or 11.
13. A use of the measurement chamber extension (10) according to any one of claims 1 to 12 for analyzing a liquid (2) in a polymer container (3) selected from an infusion bag (3), a syringe (3), a pump (3), a cartridge for the pump (3), or a syringe (3) enclosed in a sterile package (4), in combination with an NIR spectrophotometer (1) or a Raman spectrophotometer (1), wherein the use is: The step of holding the tubular section (3a) of the polymer container (3) with the receptacle (13); The step of positioning the optical element (5) of the measurement chamber extension (10) adjacent to the surface of the polymer container (3); The step involves directing the measurement light beam toward the optical element (5), and analyzing the transmitted and reflected light with a spectrophotometer (1) selected from an NIR spectrophotometer (1) and a Raman spectrophotometer (1); A step of comparing the signal generated by the transmitted and reflected light with a dataset stored in a database containing NIR spectra or Raman spectra of similar or identical samples; A step of determining the identity of the solute dissolved in the liquid (2), or determining the particles dispersed in the liquid (2), and / or detecting admixtures in the liquid (2), or detecting contaminants in the liquid (2); or A step of determining the amount of solute dissolved in the liquid (2) or determining the amount of particles dispersed per unit volume in the liquid (2), and / or detecting admixtures or contaminants in the liquid (2); and / or A step to determine the physical properties (e.g., particle size, aggregation) of the solute dissolved in the liquid (2), or to determine the number of particles dispersed per unit volume of the liquid (2), and / or to detect admixtures or contaminants in the liquid (2). Equipped with, The measurement light beam has light in the wavenumber range of 4,000 cm⁻¹ to 12,500 cm⁻¹. In continuous measurement, sample beams of different wavelengths are directed toward the optical element (5), and / or the measurement light beam is directed toward the optical element (5) at different angles. use.
14. The use according to claim 13, wherein the database includes datasets belonging to different sample types, which include a product range of typical materials in sterile packaging (4) of polymer containers and / or syringes (3).
15. The use according to claim 14, wherein the software of the NIR spectrophotometer (1) or the Raman spectrophotometer (1), or the software of their control units, is adapted to extract from the measured NIR or Raman spectrum the corresponding spectrum belonging to the material including the polymer container (3) or the sterile package (4) of the syringe (3).