WO2024008326A1 - Technique de fabrication d'un dispositif de support d'échantillon réfléchissant pour spectrophotométrie nir et raman - Google Patents

Technique de fabrication d'un dispositif de support d'échantillon réfléchissant pour spectrophotométrie nir et raman Download PDF

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Publication number
WO2024008326A1
WO2024008326A1 PCT/EP2022/088091 EP2022088091W WO2024008326A1 WO 2024008326 A1 WO2024008326 A1 WO 2024008326A1 EP 2022088091 W EP2022088091 W EP 2022088091W WO 2024008326 A1 WO2024008326 A1 WO 2024008326A1
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WIPO (PCT)
Prior art keywords
sample
manufacturing technique
sample holder
curvature
container
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PCT/EP2022/088091
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English (en)
Inventor
Laura RODRÍGUEZ GARCÍA
David Mainka
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Ayna Analytics Gmbh
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Publication date
Priority claimed from PCT/EP2022/069161 external-priority patent/WO2023281090A1/fr
Application filed by Ayna Analytics Gmbh filed Critical Ayna Analytics Gmbh
Publication of WO2024008326A1 publication Critical patent/WO2024008326A1/fr

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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/01—Arrangements or apparatus for facilitating the optical investigation
    • G01N21/03—Cuvette constructions
    • G01N21/0303—Optical path conditioning in cuvettes, e.g. windows; adapted optical elements or systems; path modifying or adjustment
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/01—Arrangements or apparatus for facilitating the optical investigation
    • G01N21/03—Cuvette constructions
    • G01N2021/0339—Holders for solids, powders
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/01—Arrangements or apparatus for facilitating the optical investigation
    • G01N21/03—Cuvette constructions
    • G01N2021/0378—Shapes
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
    • G01N21/25—Colour; Spectral properties, i.e. comparison of effect of material on the light at two or more different wavelengths or wavelength bands
    • G01N21/31—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry
    • G01N21/35—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry using infrared light
    • G01N21/359—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry using infrared light using near infrared light
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/65—Raman scattering
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2201/00—Features of devices classified in G01N21/00
    • G01N2201/06—Illumination; Optics
    • G01N2201/063—Illuminating optical parts
    • G01N2201/0634—Diffuse illumination
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2201/00—Features of devices classified in G01N21/00
    • G01N2201/06—Illumination; Optics
    • G01N2201/063—Illuminating optical parts
    • G01N2201/0636—Reflectors

Definitions

  • the present invention relates to any set-up directed towards spectroscopic measurements based on transflection of a light, particularly to a sample receiving chamber comprising a reflective or mirror surface configured for such a set-up.
  • Transflection is an extension of the transmission technique.
  • a mirror When a mirror is placed behind a sample, the light transmitted through the sample is reflected back through the sample and into a diffuse reflectance probe used as detector.
  • transflection measures a combination of transmission and reflection.
  • This technique is applicable, for example, to emulsions, suspensions, gels, turbid liquids, and thus to various pharmaceutical intermediates, formulations, and products, as well as to crop products, food, feed, and hence, useful in related technologies.
  • transflective near-infrared spectroscopy allows the identification and/or quantification of an active pharmaceutical ingredient (API), an excipient and/or the detection of falsification and/or substandard quality of a product or impurity of an API, as well as the quantification/detection/verification of the physical properties (agglomeration, particle size, etc.) of these components, whether they are in a liquid state in a sterile package or even in a bulk pile of dry particles, e.g. dried medicinal plants.
  • fruits, e.g. berries, cherries, or other plants or foods can also be analyzed without compromising their integrity.
  • the proposed sample holder can also be used to determine an ingredient or a harvest date. All in all, the proposed sample holder as well as the proposed method using it can thus also be assigned to non-destructive testing.
  • sample beam a measuring light beam
  • Raman- spectrophotometer a Raman- spectrophotometer which is directed through the sample
  • gathered information can be used to identify or even quantify chemical components in the sample and/or to analyze physical properties of the sample.
  • Such measurements can be made simultaneously with respect to different analytes, their parameters and/or properties.
  • sample holders are provided that are specially configured by a shape of their sample receiving chamber, the surface structure of a diffusive mirror surface of the sample receiving chamber, and a reflectivity of the diffusive mirror surface for characterizing a sample, e.g. pharmaceutical products by NIR spectroscopy or Raman spectroscopy via transflectance or even via transmission.
  • the sample holders enable an overall higher quality and an overall higher reproducibility of the measurement results.
  • the NIR or Raman instrument, the sample, and the suggested sample receiving chamber comprising the diffusive mirror are positioned with respect to each other to ensure that high quality measurement results are achieved.
  • additive manufacturing techniques could be adapted for manufacturing of different sample holders comprising a sample receiving chamber for pharmaceutical products, formulations or other samples, each sample holder comprising at least a reflective surface that is either partly or fully covered with a diffusive mirror surface which is used for a transflection measurement of the sample.
  • subtractive manufacturing processes may be used to manufacture the sample holder described herein, which comprises the sample holding chamber having a diffusive mirror and/or a reflective coating, wherein a curvature of the diffusive mirror and/or reflective coating thereof is adapted for transflection measurements with pharmaceutical products, formulations, or other samples, e.g., for a capsule, a coated tablet, for dried herbs, flower buds, or a crop.
  • Such various samples are quite different in terms of their size(s) and shape(s).
  • the chosen manufacturing technique for producing a corresponding diffusive mirror whose curvature is adapted to the size and curvature, i.e., dimensions, of the sample to be measured must be quite flexible.
  • Modem CNC machines i.e., machines that are generally understood to be based on computer numerical control, use a computer-controlled machine tool to produce a part from solid material in a defined shape. They can easily be adapted for manufacturing varying shapes of sample holders and diffusive mirrors, each with a curvature adapted to the sample.
  • Subtractive manufacturing techniques suitable for producing the diffusive mirror with a curvature adapted to a curvature of a surface of the sample and/or to a curvature of a surface of a container containing the sample include techniques such as, e.g., turning, milling, boring, planing, drilling, reaming, electrical discharge machining (electro erosion), etching, photolithography, and laser ablation to name a few.
  • the sample receiving chamber of the sample holder may be manufactured so that the diffusive mirror of the sample receiving chamber has curvature which is adapted to a curvature of a surface of the sample and/or a curvature of a surface of a container including the sample, and that the diffusive mirror can encase and/or enclose, in a cross-section, at least 30% of the surface of the sample and/or of the surface of the container, at least 50% of the surface of the sample and/or of the surface of the container or even at least 75% of the surface of the sample and/or of the surface of the container.
  • the suggested sample holder comprising the sample receiving chamber encompassing a diffusive mirror and/or a reflective coating
  • a new method for characterization e.g. identification, verification of conformity, semi-quantification and quantification of medicinal caffeine containing solutions, with respect to their content of caffeine or other APIs.
  • the caffeine solutions can be sterile or non- sterile.
  • a syringe is used as primary packaging of the caffeine solution.
  • These medicinal caffeine solutions are, for example, used in the treatment of apnea for premature infants.
  • Using the suggested sample holder allows for a simpler, faster, and cheaper characterization of various APIs which is as reliable as previously used methods.
  • the use of the sample receiving chamber guarantees that the diffusive mirror will not have direct contact to a sample and therefore will not require cleansing.
  • Figure 1 shows a vertical cross-section of an embodiment of a one piece cylindric-shaped sample holder which is configured for measuring, e.g., samples comprising dried herbs or flower buds held in a transparent container, e.g. a quartz glass baker.
  • Figure 2 shows a vertical cross-section of an embodiment of a two-piece sample holder which is configured for measuring, e.g., a liquid sample held in a cuvette, e.g. a quartz glass baker.
  • a liquid sample held in a cuvette e.g. a quartz glass baker.
  • Figure 3 shows a cross-section of another embodiment of a two-piece sample holder adapted for measuring, e.g., a liquid sample held in a cuvette.
  • Figure 4 shows a cross-section of an embodiment of a sample holder configured for transflection measurements with a capsule or a dragee.
  • Figure 5 shows sections which are used for the generation of a surface structure of a diffusive mirror.
  • Figure 6 shows several planar surface structures of a diffusive mirror that can be generated from the sections shown in Figure 5.
  • Figure 7 shows the curved surface structure of a diffusive mirror as well as a reflective surface without such a surface structure.
  • Figure 8 shows the cross section of a reflective sample holder for measuring syringes with the transflection technique.
  • Figure 9 shows the cross section of a reflective sample holder for measuring syringes with the transmission technique.
  • Figure 10 shows an NIR-spectrum, obtained with the transflection technique, that contains measurements of syringes that hold medicinal caffeine solutions.
  • Figure 11 shows the first derivation of a section of the NIR-spectrum, obtained with the transflection technique, shown in Figure 10, that contains measurements of syringes that hold medicinal caffeine solutions.
  • Figure 12 shows an NIR-spectrum, obtained with the transmission technique, that contains measurements of syringes that hold medicinal caffeine solutions.
  • Figure 13 shows the first derivation of a section of the NIR-spectrum, obtained with the transmission technique, shown in Figure 12, that contains measurements of syringes that hold medicinal caffeine solutions.
  • Figure 14 shows schematically typical shapes of soft gel capsules, suppositories etc. which can individually be measured with the suggested sample holder.
  • additive manufacturing describes a technology which different to subtractive techniques encompasses techniques also known as fused deposition modeling (FDM), powder bed fusion (LPBF) technique or a variation thereof, like Selective Laser Melting (SLM), Selective Laser Sintering (SLS), Electron Beam Melting (EBM) and Direct Metal Laser Sintering (DMLS), which are typically applied to a layer or a bed comprising distinct particles or a powder comprising a metal, a ceramic and/or a polymer; a binder jetting or a material jetting technique used with particles comprising a polymer, a ceramic, or a metal or an alloy; a material extrusion technique in which a material is drawn through an optionally heated nozzle, comprising a continuous deposition of the extruded material; and a wire arc melting technique, comprising a metal melting in an electric arc.
  • FDM fused deposition modeling
  • LPBF powder bed fusion
  • SLM Selective Laser Melting
  • SLS Selective Laser Sintering
  • a technique of producing the proposed reflective sample holder comprising the sample receiving chamber comprises at least one of the mentioned additive manufacturing techniques or a combination of mentioned ones.
  • additive manufacturing is usually very flexible and allows easy adaptation of, e.g., size, shape, and surface structure of components of the suggested sample holder, particularly of the sample receiving chamber it comprises of, and/or the mirror surface thereof or therein.
  • subtractive manufacturing methods can also be used to manufacture the sample holder described herein with its diffusive mirror, wherein a curvature of the diffusive mirror is designed to correspond to a curvature of a surface of the sample to be measured.
  • subtractive manufacturing in addition to the possibility of generating a model that serves for manufacturing a mold, subtractive manufacturing also allows direct manufacturing of the sample holder with the diffusive mirror having the adapted curvature.
  • a curvature of the diffusive mirror is adapted to a curvature of a surface of the sample and/or to a surface of the container for the sample
  • a curvature of the diffusive mirror is intended to describe, for example, a typically uniform distance to be obtained between corresponding surfaces of the diffusive mirror and the sample when the sample is held by the sample holder.
  • this allows an exact and reproducible measurement of a transflected light of a sample, such as, e.g., a dragee or a suppository, whose shape may vary depending on the manufacturer.
  • At least the surface of the sample receiving chamber is either partly of fully covered by a reflective surface and comprises the mentioned diffusive mirror and/or the reflective coating.
  • Reflective materials and corresponding deposition techniques may be selected from chemical vapor deposition techniques (CVD), physical vapor deposition techniques (PVD), vacuum deposition techniques, plating (electroless and galvanic), and atomic layer deposition (ALD), to name a few.
  • the reflective material is gold, steel, aluminum or any other NIR-reflective material, e.g. Teflon, or an alloy that contains at least one of these materials.
  • the favorable wavenumber ranges of the measurement light beam, i.e. sample beam, are 4,000 - 12,500 cm' 1 corresponding to a wavelength range from 800 nm through 2.5 pm.
  • a surface of the sample holder which is directed towards the sample is reflective for NIR.
  • the sample holder, particularly its sample receiving chamber encases the sample as a whole or at least along a circumferential direction of a tubular part of the sample or of the container which protects the sample against contamination.
  • the reflective surface described may result in an integrating sphere - even though the shape of the sample-receiving chamber may differ from an ideal sphere, it may be referred to as an integrating sphere (Ulbricht sphere).
  • the proposed reflective sample holder especially its sample receiving chamber is configured by its shape, its size, its reflective surface, the material used for the reflective surface, the diffusive mirror which can partly or fully cover the reflective surface and the geometry and/or shape of the surface of the diffusive mirror for spectrophotometric measurements of the mentioned above samples, e.g. pharmaceutical formulations, their components, and products using transflective NIR spectrophotometry and/or transflective Raman spectrophotometry, regardless of their shape, size, or consistency, e.g., viscosity.
  • the geometry and/or shape of the surface of the diffusive mirror is configured by a planar, a curved or any other surface which comprises geometrical bodies such as pyramids, or inclined distinct surfaces, such as triangles (e.g. in the case of these pyramids).
  • geometrical bodies such as pyramids, or inclined distinct surfaces, such as triangles (e.g. in the case of these pyramids).
  • These geometrical bodies can be arranged adjacent to each other, i.e. side by side or with distances to each other and can form several adjacent rows which are either arranged side by side or with equal or gradually varying distances to each other.
  • the result can be, for example, parametric geometries.
  • Those surfaces can be polished, partly polished or nonpolished.
  • the described configurations determine the reflectivity of the diffusive mirror and therefore the overall reflectivity of the reflective sample holder, especially of its sample receiving chamber (SRC).
  • the resulting corrugated surface is coated with a reflective layer, e.g. with a gold layer.
  • the herein described reflective sample holders are compared by measure experiments to commonly commercially available reflective gold mirrors with a similar high reflectivity.
  • the commonly available reflective gold mirrors are limited to flat, i.e. planar surfaces.
  • the herein suggested reflective sample holders enable an overall higher quality and an overall higher reproducibility of measurement results.
  • the achieved technical effects in regard to the achieved measurement results are a higher signal to noise ratio, a higher spectral resolution and therefore, an improved detection limit (limit of detection / LOD) and sensitivity and, furthermore, an improved reproducibility compared to commonly available reflective gold mirrors of similar reflectivity.
  • sample as used herein comprises any natural product (plant extracts, dried plant matter and so on), any pharmaceutical formulation, any liquid, any solution, any dispersion, any solid (such as a powder, a lyophilizate and so on), any two-phased-system that is or is not partly or fully enclosed by a container.
  • a container examples for such a container are syringes, infusion bags, vials, bottles, cuvettes, blisters or any other container.
  • the primary container can be partially or fully enclosed by a second container.
  • a semi-solid as used herein, comprises a gel, hydrogel, a paste or a lotion (of higher viscosity in comparison to usual physiological (aqueous) solutions and therefore mostly a two-phased-system, solid/liquid or liquid/liquid).
  • the term is used in correspondence to its common understanding by the skilled person in pharmaceutical technology and/or food technology.
  • liquid compositions which can be measured using the suggested reflective sample holder may comprise solutions and dispersions, for example, consist of a multicomponent/multiphase system (foam, emulsion, aerosol). Solutions can be sterile or non-sterile.
  • the pharmaceutical formulations comprising the soft or hard gelatin capsule, the dragee, the suppository, the tablet, or the film-coated tablet which is characterized using the reflective sample holder, they may comprise a liquid medium and a dissolved or dispersed therein pharmaceutically active ingredient (API).
  • API pharmaceutically active ingredient
  • they may comprise the API and a liquid excipient.
  • the excipient may also be a solid or comprise solid particles.
  • pharmaceutical dosage forms intends to describe any pharmaceutical dosage form known to those skilled in the art for transporting a pharmaceutically active compound into the human or animal body in order to achieve its desired therapeutic and/or diagnostic effects.
  • pharmaceutical dosage forms comprise a mixture of (a) drug component(s), i.e. pharmaceutically active ingredient(s), and nondrug components (i.e. excipients).
  • these pharmaceutical dosage forms can be categorized by different aspects, e.g. their route of administration, (e.g. oral, inhalational, parenteral, topical administration and more specifically ophthalmic drug administration) or their physical appearance (e.g. solid, semi-solid, liquid, gaseous).
  • dosage forms are used, which can be administered topically, via parenteral injection or orally.
  • dosage forms comprise ointments, creams, gels, lotions, dispersions, granulates, solutions or sterile solutions or injection solutions or infusion solutions, soft or hard gelatin capsules, a dragee, a suppository, a tablet, or a film-coated tablet which is meant to be a non- exhaustive list of possible dosage forms.
  • the pharmaceutical formulation comprises an intermediate composition.
  • the concentration of the intermediate composition may be from 0.1% w/w to 99.9% w/w, particularly from 1% w/w to 99% w/w, particularly from 2,5% w/w to 90% w/w, particularly from 5% w/w to 80% w/w, more particularly from 10% w/w to 60% w/w, more particularly from 15% w/w to 40% w/w, based on the total weight of the pharmaceutical formulation.
  • the concentration of the intermediate composition can be from 10% w/w to 45% w/w, particularly from 20% w/w to 40% w/w, more particularly from 30% w/w to 38% w/w, based on the total weight of the pharmaceutical formulation. Also, the concentration of the intermediate composition can be from 1% w/w to 30% w/w, particularly from 5% w/w to 25% w/w, more particularly from 10 % w/w to 20% w/w, based on the total weight of the pharmaceutical formulation.
  • the concentration of the intermediate composition may be from 0.1% w/w to 15% w/w, particularly from 1% w/w to 10% w/w, more particularly from 2% w/w to 5% w/w, based on the total weight of the pharmaceutical formulation.
  • the pharmaceutical composition further comprises a liquid medium.
  • the liquid medium in the sample is selected from an aqueous solution, such as phosphate buffer saline (PBS), water, such as aqua ad injectabilia, a glycerol, or oils such as hemp oil, castor oil, clove oil, cassia oil, almond oil, corn oil, Arachis oil, peanut oil, cottonseed oil, safflower oil, maize oil, linseed oil, rapeseed oil, soybean oil, caraway oil, rosemary oil, peanut oil, peppermint oil, sunflower oil, eucalyptus oil, olive oil, Mentha oil, peppermint oil, eucalyptus oil, bergamot oil, anise oil, fennel oil, or rose oil.
  • PBS phosphate buffer saline
  • oils such as hemp oil, castor oil, clove oil, cassia oil, almond oil, corn oil, Arachis oil, peanut oil, cottonseed oil, safflower oil, maize oil, lins
  • the concentration of the liquid medium may be from 1% w/w to 99.9% w/w, particularly from 5% w/w to 95% w/w, particularly from 10% w/w to 90% w/w, particularly from 20% w/w to 80% w/w, more particularly from 30% w/w to 70% w/w, based on the total weight of the pharmaceutical formulation.
  • the pharmaceutical component characterized for its pharmaceutically important constituents using the proposed sample receiving chamber is medicinal caffeine solution.
  • Medicinal caffeine solution is used in the treatment of apnea in premature infants.
  • All commonly available analytical methods either destroy the sample or risk contamination of the sample and therefore risk the loss of sterility of the sample.
  • the main difficulty is to analyze the medicinal caffeine solution while it is still contained in the primary packaging, for example in a syringe.
  • the syringe makes analysis using currently available methods of the held solution impossible, because of its shape, the material it consists of and the thickness of the materials.
  • the concentration of the medicinal caffeine solution can be from 0.05% w/w to 30% w/w, particularly from 0.25% w/w to 15% w/w, more particularly from 0.5% w/w to 1.5% w/w of liquid medium, based on the total weight of the pharmaceutical formulation.
  • the pharmaceutical component characterized for its pharmaceutically important constituents using the proposed sample receiving chamber is cannabis extract.
  • the extract from cannabis can be contained in any container, more specifically in vials or syringes. So far, it has not been possible to identify or quantify the content of e.g. cannabidiol (CBD) and tetrahydrocannabinol (THC) in extracts from cannabis in medicinal cannabis preparations in a simple and fast way.
  • CBD cannabidiol
  • THC tetrahydrocannabinol
  • CBD and THC are: cannabidiol Acid (CBDA), tetrahydrocannabinolic Acid (THCA), cannabinol (CBN), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabidivar (CBCV), cannabichromen (CBC), cannabicyclol (CBL), cannabielsoin (CBE), cannabinodiol (CBND), cannabitriol (CBTL), cannabidivarin (CBDV) and tetrahydrocannabivarin (THCV).
  • CBDDA cannabidiol Acid
  • THCA cannabidiol Acid
  • CBD cannabinol
  • CBG cannabigerol
  • CBDG cannabigerolic acid
  • CBDV cannabidivar
  • CBCV cannabichromen
  • CBL cannabicyclol
  • CBE cannabielsoin
  • CBND cann
  • the concentration of the liquid medium can be from 0,05% w/w to 99,9% w/w, particularly from 0,5% w/w to 50% w/w, more particularly from 0,75% w/w to 20% w/w of liquid medium, more particularly from 1% w/w to 10% w/w of liquid medium, based on the total weight of the pharmaceutical formulation.
  • the pharmaceutical formulation mentioned above is a dispersion comprising the pharmaceutical formulation as dispersed phase, and the liquid medium as dispersant.
  • the dispersed phase may be a colloidal dispersed phase.
  • colloidal dispersed phase in relation to the pharmaceutical formulation means that the dispersed phase has a particle size of from 1 pm to 500 pm, particularly of from 10 pm to 300 pm, more particularly of from 50 pm to 200 pm.
  • the dispersion is a gel, a suspension, a foam or an emulsion.
  • a reflective sample holder for spectrophotometric measurements of a sample by transflection and/or by transmission is suggested. It comprises a sample receiving chamber which is configured by its shape, its size, its reflective surface, and/or a surface structure of at least a portion of the reflective surface, and the material used for the reflective surface, in particular of its diffusive mirror surface which partly or fully covers the reflective surface and the geometry and/or shape of the surface of the diffusive mirror to different samples and sample geometries.
  • the herein described reflective sample holders are compared by measure experiments to commonly available reflective gold mirrors with a similar high reflectivity. Importantly, the commonly available reflective gold mirrors are limited to planar surfaces.
  • a sample holder for spectrophotometric measurements of a sample using a transflection technique comprises a sample receiving chamber comprising a diffusive mirror.
  • a curvature of the diffusive mirror is adapted to a curvature of a surface of the sample and/or adapted to a curvature of a surface of a container comprising the sample.
  • the herein described reflective sample holders enable an overall higher quality and an overall higher reproducibility of the measurement results. More specifically, with use of the reflective sample holder a higher signal to noise ratio, a higher spectral resolution and therefore an improved detection limit and sensitivity are achieved. Furthermore, the reproducibility of measurements is greatly improved.
  • the suggested sample holder comprises a hollow light guiding channel.
  • a fluid inside the channel is typically ambient air or a gas but not a liquid or a solid as used typically in a light guiding fiber or in a waveguide.
  • a shape of a crosssection and/or a diameter thereof varies over the length of the light-guiding channel and is adapted to the shape of the sample.
  • the light-guiding channel partly or fully encloses the sample and/or the container.
  • the light guiding channel may be adapted as well to be optically connected to the measurement window of the spectrophotometer or a detector of the spectrophotometer, e.g. an integrating sphere inside the spectrophotometer.
  • signal losses can greatly be minimized and sensitivity of Raman and/or NIR measurements of the sample can be enhanced.
  • the sample holder is configured for spectrophotometric measurements of a sample using a transmission technique and/or transflection technique by a hollow light guiding channel which is optically connected with the sample receiving chamber, wherein an inner wall of the hollow light guiding channel is covered by a smooth reflective coating.
  • the light guiding channel is configured to encase at least partially a part of the sample or a part of the container containing the sample. Typically, a portion of the light guiding channel covers or is adjacently positioned along a surface of the part of the sample or of the container, more preferably along a circumferential direction of a curved surface of the sample or of the container.
  • the light guiding channel may be adapted as well to be optically connected to the measurement window of the spectrophotometer or a detector of the spectrophotometer, e.g. an integrating sphere inside or even outside the spectrophotometer.
  • the part of the sample and/or of the container may be tubular (e.g. with a circular cross-section).
  • the sample holder is adapted by a size and shape of its sample receiving chamber to any size or shape of a flexible or non-flexible container which contains an analyte.
  • a shape of the sample receiving chamber is configured to receive the container comprising the sample, wherein the container either represents a primary container and single containment of the sample, i.e. is a primary container, or the container represents a secondary container which encases the primary container, wherein the sample is disposed in said primary container.
  • the container is a closed and germ-proof container and provides a barrier against any contamination of the sample, e.g. a contamination by a liquid, a dust, a virus, and a microorganism or a spore thereof.
  • the container comprises at least one of a plastic, a paper, a glass, a metal, and a textile, e.g. a nonwoven; wherein the paper and the textile may optionally be coated with a polymer in order to ensure a sterility of a volume encased by the container.
  • the plastic is selected from a thermoformed polymer film, a polymer shrink film, and a plastic film bag.
  • said container and measurement signals generated by its material do not interfere with the signals obtained from the analyte.
  • These containers ensure the sterility of the sample, e.g. the sterility of a pharmaceutical formulation.
  • the sample receiving chamber encases the sample completely as a whole or at least along a circumferential direction of a curved or even circular surface of the sample or container, or tubular part of the sample or container comprising same.
  • signal loss can be minimized and signal intensity be enhanced to ameliorate a sensitivity of a detection method for an analyte, e.g. a pharmaceutically active substance.
  • an inner side of a channel wall of the light guiding channel is at least partially covered with a reflective coating, wherein the reflective coating is reflective for a light used in a measurement light beam used in the spectrophotometric measurements.
  • a material used as the reflective coating is selected from a metal, a glass, a ceramic, and a polymer, e.g. Teflon.
  • the reflective coating material is reflective for NIR within the used wavelength range.
  • the sample the sample holder is adapted to or used for is selected from a crop, a fruit, a flower bud, an inflorescence, a plant extract, a plant oil, a powder or powder mixture that may be formed into a solid - such as a tablet, a pharmaceutical dosage form selected from: a tablet, a coated tablet, a suppository, a coated suppository, a hard gelatin capsule, a soft gelatin capsule, a candy, a drop, an ointment, a cream, a gel, a lotion, a dispersion, a granulate, a solution, an injection solution, an infusion solution, a liquid food - especially a liquid food intended for enteral administration.
  • a pharmaceutical dosage form selected from: a tablet, a coated tablet, a suppository, a coated suppository, a hard gelatin capsule, a soft gelatin capsule, a candy, a drop, an ointment, a cream, a gel,
  • the container is selected from: a syringe, an infusion bag, a vial, a bottle, a cuvette, a blister, a hard or soft gelatin capsule, a film of a film-coated tablet, a dragee, a suppository, and a film coated suppository.
  • At least a portion of the sample receiving chamber comprises one of: a cylinder, a tube, a sphere, a half sphere, a prolate spheroid, an oblate spheroid, an ellipsoid, an elliptic a paraboloid, a cube, a cuboid, a prism, a pyramid, a cone, a truncated cone, a hyperboloid, a parabolic, a helix, a torus, a parametric geometry, and a differential geometry.
  • a corresponding shape of the sample receiving chamber or at least of a portion thereof is adapted for an optimal fitting of the sample into the sample receiving chamber and thus an overall higher quality and an overall higher reproducibility of the measurement is achieved.
  • a surface structure of the diffusive mirror comprises multiple geometric bodies or parts thereof, wherein the geometrical bodies are selected from: a cylinder; a tube; a sphere; a half sphere; a prolate spheroid; an oblate spheroid; an ellipsoid; an elliptic; a paraboloid; a cube; a cuboid; a prism - particularly from oblique prisms, more particularly from triangular or quadrangular or pentagonal or hexagonal oblique prisms, in particular from oblique triangular prisms.
  • the geometrical bodies can also be selected from: pyramids - more particularly from oblique and/or straight pyramids, even more particularly from triangular, quadrangular, pentagonal or hexagonal oblique and/or straight pyramids. They can as well be selected from cones, truncated cones, hyperboloids, parabolics, a helix (or helices), and a torus (or tori). According to typical embodiments these geometrical bodies are arranged side by side, i.e. immediately adjacent to each other, or with a certain distance with respect to each other. Therein said distance can gradually vary along a row of such geometric bodies and/or their parts, wherein said rows are either arranged side by side or with a distance to each other.
  • the sample holder further comprises an identifying element, wherein the identifying element is optically or electronically readable and configured to provide information selected from: the contained sample type (e.g. syringe or infusion bag), the sample holder ID, a length of an optical path, a type of a surface structure of the diffusive mirror (M), a diameter of a measurable sample; and/or a shape of the measurable sample.
  • the contained sample type e.g. syringe or infusion bag
  • M diffusive mirror
  • M a diameter of a measurable sample
  • shape of the measurable sample e.g. a shape of the measurable sample.
  • the identifying element comprises a 2D-code such as, e.g., a barcode or a QR-code; a RFID and/or a hologram.
  • a manufacturing technique for producing the suggested sample holder comprises at least an additive manufacturing technique selected from: a 3D printing of a wax model of at least a part of the sample holder; and applying a lost wax casting; wherein the lost wax casting comprises casting a molten metal, a molten metal alloy and/or a molten IR-reflective polymer, e.g. Teflon.
  • a manufacturing method for manufacturing the proposed sample holder comprising an additive manufacturing method and/or a subtractive manufacturing method, wherein the subtractive manufacturing method comprises preferably a CNC method comprising at least one of the following: Turning, milling, boring, planing, drilling, reaming, grinding, electrical discharge machining, photolithography, etching, and laser ablation, e.g. femtosecond laser ablation.
  • Subtractive processes can be used, for example, to create a wax model for the lost wax process or to directly fabricate the sample holder and/or its diffusive mirror with a surface whose curvature is matched to the curvature of the surface of a sample.
  • Processed materials can be selected from a wax - e.g. a wax comprising bees wax, a polymer - e.g. Teflon (PTFE), a metal, an alloy, and a ceramic.
  • This surface can additionally be coated with a reflective material, e.g. gold, if the reflectivity of the base material, e.g. a metal, is not sufficient.
  • a reflective material e.g. gold
  • a material of the sample holder or its blank is typically selected from: a polymer, a copolymer, a polymer mixture, a metal, an alloy, a mineral, and a ceramic.
  • a coating e.g. comprising a gold layer can be applied.
  • Applicable coating techniques comprise PVD, CVD, and plating.
  • the manufacturing method can comprise forming or transforming techniques such as rubber pad forming and deep drawing.
  • the diffusive mirror encases and/or encloses at least 30 % or even up to 50% of the cross-sectioned surface of the sample and/or of the cross-sectioned surface of the container, comprising the sample.
  • the achieved correspondence of the mirror’s surface with the surface of the sample and/or of the container comprising the sample results in collecting a representative transflection signal. Such allows for precise measurement using NIR- or Raman-spectrophotometry.
  • a manufacturing technique of producing a sample holder which is configured for spectrophotometric measurements of a sample using a transflection technique is suggested.
  • said sample holder comprises a sample receiving chamber which encompasses a diffusive mirror.
  • a curvature of said diffusive mirror is adapted to a curvature of a surface of the sample and/or adapted to a curvature of a surface of a container which comprises the sample.
  • the suggested manufacturing technique comprises a subtractive manufacturing technique.
  • subtractive manufacturing processes are well established. Corresponding machines and tools are well accessible to the person of skill in the art, typically an engineer in a workshop. These techniques are applicable to the scale of typical samples to be measured. Typically, the samples to be measured reach maximum dimensions of up to several centimeters. Subtractive manufacturing processes can typically achieve accuracies of one to several pm (micrometers) or mm (millimeters). It goes without saying that subtractive manufacturing techniques can achieve accuracies (precision) of pm or mm even at a size scale of several dm (decimeters) or m (meters). It also goes without saying that precision machining photolithography or laser ablation, for example, can achieve an accuracy of less than 1 pm - sub-micrometer precision, which is advantageously for fabricating a diffusive mirror for transflection measurement.
  • a manufacturing technique of producing a sample holder which is configured for spectrophotometric measurements of a sample using a transflection technique comprises: manufacturing a sample receiving chamber of the sample holder so that the sample receiving chamber comprises a diffusive mirror, wherein a curvature of the diffusive mirror is adapted to a curvature of a surface of the sample and/or adapted to a curvature of a surface of a container comprising the sample, and wherein the diffusive mirror is adapted to encase and/or enclose, in a cross-section, at least about 30% of the surface of the sample and/or of the surface of the container.
  • a curvature of the diffusive mirror corresponds at least over a length of 30% of an outer contour length of a cross-section of the sample or of the container comprising the sample to the corresponding curvature of sample and/or container.
  • the diffusive mirror is adapted to encase and/or enclose, in the cross-section, at least about 50% of the surface of the sample and/or of the surface of the container or even at least about 75% of the surface of the sample and/or of the surface of the container.
  • the expression “about” is meant to encompass ⁇ 5%.
  • the indicated range of at least 45-55% corresponding to the indicated value of at least about 50% enhances the achievable precision of transflection measurements.
  • the indicated range of at least about 75 % corresponds to the range from at least 70% - 80% of a contour length of a cross-section. Such high values enhance the achievable precision of transflection measurements even further.
  • the manufacturing technique of the sample receiving chamber comprises at least one of a subtractive manufacturing technique and an additive manufacturing technique.
  • the subtractive manufacturing technique is used for manufacturing the diffusive mirror.
  • the subtractive manufacturing technique is selected from: turning, milling, boring, planing, drilling, reaming, grinding, electrical discharge machining, electro erosion, etching, photolithography, and laser ablation.
  • the manufacturing technique comprises a CNC machining.
  • the CNC machining comprises at least one of turning, milling, boring, planing, drilling and grinding.
  • the subtractive manufacturing technique is applied to a material selected from: a wax, a polymer, a metal, an alloy, and a ceramic.
  • a material selected from: a wax, a polymer, a metal, an alloy, and a ceramic are well suited for subtractive manufacturing and allow obtaining appropriately fine- structured surfaces comprising a defined curvature.
  • the suggested manufacturing technique further comprises an additive manufacturing technique.
  • a combination of additive and subtractive manufacturing techniques allows to obtain any shape and structure of the diffusive mirror, which thus can be adapted to the curvature of the sample and/or the curvature of the container comprising the sample.
  • the suggested manufacturing technique comprises the process steps: - providing a blank; - providing a first digital data set, the first digital data set describing a shape and/or a curvature of a surface of the sample;
  • the second digital data set describing a shape and/or a curvature at least of the diffusive mirror of the sample holder comprising the diffusive mirror; - applying the second data set for numerically controlling a movement and/or an action of a tool of a machine, wherein the tool forms at least a part of the sample holder from the blank.
  • the corresponding part of the sample holder is fabricated using the machine starting from the blank and is thus homogeneous.
  • the curvature and surface structure of the diffusive mirror can easily be adapted to dimension and shape of the sample by modifying the digital data sets.
  • the part of the sample holder which is fabricated by the above mentioned manufacturing technique comprising said tool with said machine is the diffusive mirror.
  • the diffusive mirror is configured to reproducibly collecting a representative transflection signal from a sample held within/by the sample holder/sample receiving chamber.
  • the machine used is a CNC machine.
  • providing the first digital data set comprises digitally scanning the sample to be measured, preferably by a 3D laser scanning technique, and obtaining a digital representation of the sample.
  • the second digital data set is based on or corresponds to a data set obtainable using a slicing software.
  • said second digital data set is obtained from the first digital data set by scaling a curvature radius of the curvature of the surface of the sample.
  • said scaling allows to easily adapt a mirror’s shape, curvature, and size to another sample, which differs in size and/or shape and has therefore a sample surface of another curvature.
  • the sample holder comprising the diffusive mirror can easily be configured to, e.g., match any selected type of samples to be measured, e.g. suppositories of different shapes, tablets of different size and shape, tabs, prefilled syringes etc.
  • the suggested manufacturing technique comprises a coating step to produce a reflective layer, wherein the coating step is selected from: a galvanic plating, an electroless plating, a chemical vapor deposition, and a physical vapor deposition, particularly of a gold layer.
  • a sample holder which is configured for spectrophotometric measurements of a sample using a transflection technique
  • the sample holder comprises a sample receiving chamber comprising a diffusive mirror, wherein a curvature of the diffusive mirror is adapted to a curvature and/or a shape of a surface of the sample and/or adapted to a curvature of a surface of a container comprising the sample, wherein at least a part of the sample holder comprising the diffusive mirror is produced using a manufacturing technique according to any of the preceding embodiments, and/or wherein the diffusive mirror is adapted to encase and/or enclose, in a cross-section, at least 30% of the surface of the sample (S) and/or of the surface of the container.
  • the part of the sample holder comprising the diffusive mirror is the diffusive mirror.
  • the lost wax casting comprises: generating a casting mold for the part of the sample holder by embedding the 3D printed wax model, wherein the embedding may comprise providing paths for the molten wax to flow and for air to escape the casting mold.
  • the lost wax casting further comprises covering the wax model with a mold forming material to generate a mold, wherein the mold forming material is typically selected from a silica slurry, a ceramic slip, and a stucco.
  • the application of these techniques and a drying of the obtained green body results in obtaining a green shell.
  • the green body / green shell is heated, burnt out and typically sintered to a solid, i.e. hard and stable mold, while the wax melts and leaves the shell and/or the mold.
  • the mold is used for casting by pouring a molten metal or a molten metal alloy into the mold.
  • the mold can also be used for injection molding, e.g. with a molten polymer.
  • the cast is freed from the mold - or released. Releasing may comprise destruction of the shell / the mold.
  • the released (raw) cast is further finished, wherein the finishing comprises at least one of grinding, polishing, plating, electroplating and/or depositing a reflective layer, particularly a gold layer.
  • molten wax techniques are well established and can be adapted to any shape or surface structure of the elements of the suggested sample holder. Further, as stated before, gold reflects more than 95 per cent of incident radiation at wavelengths above 700 nm. Therefore, less intensity of the original light beam is lost during the transflection.
  • the additive manufacturing comprises fused deposition modelling for a plastic part of the sample holder, wherein the plastic part comprises a thermoplastic, e.g. a polylactic acid (PLA) or, e.g., an Acrylonitrile Butadiene Styrene (ABS).
  • a thermoplastic e.g. a polylactic acid (PLA) or, e.g., an Acrylonitrile Butadiene Styrene (ABS).
  • PLA polylactic acid
  • ABS Acrylonitrile Butadiene Styrene
  • these polymers are commercially available and easily to process.
  • a method for analyzing a sample comprising an analyte comprises: providing a sample holder for the sample according to any of the embodiments described above and further below; arranging the sample in the sample receiving chamber of the sample holder; directing a measurement light beam into the sample receiving chamber; and collecting a transmitted and/or transflected light from the sample receiving chamber.
  • the method may be performed such that an integrity parameter of the sample such as a sterility, a volume, a composition, a color; a viscosity and/or a shelf life remains unchanged.
  • the analyte is selected from a biologically active substance, more typically a pharmaceutically active substance and/or a contaminant thereof.
  • the analyte is typically dispersed or dissolved in a liquid or solid sample and/or the sample typically comprises a sterile medicinal/pharmaceutical preparation, e.g. for injection.
  • a NIR light beam e.g. C-H-, O-H-, N-H-bonds
  • the analyte is typically dissolved in a liquid and/or the sample typically comprises a sterile medicinal/pharmaceutical solution, e.g. for injection.
  • the suggested method further comprises: generating and analyzing a spectrum of the collected transmitted and/or transflected light; and determining a parameter of the sample, e.g. identifying a presence of the analyte and/or a content of the analyte in the sample, a particle size, a water content.
  • the suggested above method further comprises: quantifying a transmitted or a transflected light, wherein the transflected light comprises a transmitted light emitted from a NIR spectrophotometer or a Raman spectrophotometer which is reflected at a diffusive mirror of the sample receiving chamber.
  • a method for characterizing a sample for identification, detection or verification of conformity, semi-quantification or quantification of an analyte is suggested, wherein said method encompasses a measurement of a transflected and/or of a transmitted light by NIR spectrophotometry and/or by Raman spectrophotometry using the sample holder according to any of the embodiments described above and further below.
  • the analyte comprises a cannabinoid selected from: cannabidiol (CBD), tetrahydrocannabinol (THC), cannabidiol Acid (CBDA), tetrahydrocannabinolic Acid (THC A), cannabinol (CBN), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabidivar (CBCV), cannabichromen (CBC), cannabicyclol (CBL), cannabielsoin (CBE), cannabinodiol (CBND), cannabitriol (CBTL), cannabidivarin (CBDV) and tetrahydrocannabivarin (THCV).
  • CBD cannabidiol
  • THC cannabidiol
  • CBDA cannabidiol Acid
  • CBDA cannabidiol Acid
  • THC A cannabinol
  • CBG cannabigerol
  • these analytes can usually be detected in medicinal Cannabis preparations after their extraction, by HPLC and/or mass spectrometry.
  • HPLC and MS require special (and expansive) laboratory equipment, and highly qualified specialists, whereas the suggested method is cheaper and at least not less sensitive/reliable.
  • the cannabinoid is provided as a cannabis extract in a syringe, in an infusion bag, in a vial, in a bottle or in a cuvette, in a soft or hard gelatin capsule, in a suppository or in a Cannabis inflorescence, wherein the syringe, the infusion bag, the vial, the bottle, the cuvette, the soft or hard gelatin capsule, the suppository and the Cannabis inflorescence comprises an oil, a solution or a resin containing the cannabinoid.
  • the analyte detected with the method previously described comprises caffeine.
  • the proposed method is simple, rugged, reliable and cheap in comparison to established methods.
  • the analyte is dissolved in a solution, and/or the analyte is contained in a syringe, an infusion bag, a vial, a bottle, a cuvette, a dragee, a soft or hard gelatin capsule, a tablet or a film-coated tablet, or in a suppository.
  • the syringe, the infusion bag, the vial, the bottle, the cuvette, the dragee, the soft or hard gelatin capsule, the tablet or the film-coated tablet, and the suppository is enclosed by a secondary container.
  • the shape of the sample receiving chamber is adapted to a shape of the secondary container.
  • the secondary container is made of a flexible material which will smoothly cover the primary container which holds the sample.
  • the drawing in Fig. 1 represents an embodiment 100 of a one piece cylindric sample holder 10 which is configured for measuring, e.g., a sample S comprising, e.g., dried herbs or flower buds and/or inflorescences held in a transparent container C.
  • the sample holder 10 comprises a diffusive mirror M.
  • the container C is placed on the measurement window W of the spectrophotometer.
  • the container C with the sample S is covered by the bell-shaped sample holder 10.
  • a seam (not shown) is shaped such as to center the sample holder 10 covering the container C directly over the measuring beam emitted by the light source LS of the spectrophotometer.
  • Transmitted through the sample S light TL is reflected as reflected light RL by the diffusive mirror M and by the reflective surface of the cylindric sample holder 10 and finally arrives as transfected light in the measuring chamber of the spectrophotometer at the corresponding detector, e.g. a photoelement or an avalanche photodiode.
  • the corresponding detector e.g. a photoelement or an avalanche photodiode.
  • Fig. 2 shows another embodiment suitable for smaller volumes of a sample S, e.g. a liquid, a solution, a suspension, a dispersion or a gel.
  • This type of sample holder can also be used for compressing a medicinal plant material, e.g. dried herbs or flower buds in a container C.
  • the container C is disposed inside a tubular element 11 having an inner diffusive mirror surface.
  • the reflectivity of the inner surface may be different from the reflectivity of the diffusive mirror M at the frontal face of the plug shaped element 12.
  • the sample material S in the container C can be compressed.
  • the plug-shaped element 12 is inserted into the container C containing the sample S.
  • a diffusion mirror M on its front surface.
  • the plug-shaped element fits into the container C, which is tightly enclosed by the outer tube of the sample holder 110 having an inner reflective surface.
  • a defined distance D between the wall of the container C sitting on the measuring window W and the diffusive mirror M can thus be set in a self-adjusting manner.
  • Fig. 3 shows an embodiment 120 which is a variation of the previous embodiment 110.
  • the combination of an outer tube 11 with a piston-like inner element 12, which is hollow, enables a material saving.
  • the sample holder 140 provides a sample receiving chamber SRC which is adapted to hold a sample S, e.g. an individual soft or hard gelatin capsule, a dragee, a suppository, a tablet or a film coated tablet.
  • the sample receiving chamber SRC is formed by a first element providing an outer barrier 11 and a second element 12 comprising a diffusive mirror M.
  • An outer contour of the second element 12 fits optimally with an inner contour of the first element 11 / or vice-versa.
  • an outer rim of the second element may be shaped to close in a light-tight manner the sample receiving chamber at a side which is far from the spectrophotometer.
  • the first element 11 and the second element 12 together form a bell-like structure resembling the sample holder according to the embodiment 100 described above.
  • mirror M encloses about 50% of the surface of the sample S.
  • Mirror M may encloses about 50% of the surface of the sample S in a plurality of parallel (virtual) crosssections.
  • mirror M may enclose about 50% of the (total) surface of the sample S.
  • Fig. 5 shows sections which are used for the generation of a surface structure of a diffusive mirror.
  • a section is made by the iteration of a polygon unit/module along an axis, e.g. an x-axis.
  • the polygon is a triangle with the height B, the length of the Base C as well as the angles a, P and y.
  • a copy of the first section (Section 1) is offset for dimension A on the Axis Y and is furthermore offset on the Axis X, in order to let the top vertex of the triangles of the first section (Section 1) share the same coordinate on the Axis X as the bottom vertex of the triangles of the second section (Section 2).
  • the described process of adding another section is repeated until the required area for the diffusive mirror is covered.
  • the required area of the diffusive mirror is defined by the specific requirements, for example the sample’s geometry.
  • Fig. 5 shows merely an example of two periodically arranged repetitions, therefore the four shown sections.
  • Other combinations of more sections comprising different values for A, B, and/or C and a, P and y can be used for adapting the resulting corrugated diffusive mirror to either a curvature of the container and/or of the sample and or to a distance from a center of the sample receiving chamber and/or a central axis of the sample beam.
  • the reflective surface comprises a planar, a curved or a more complex surface whose curvature and shape is adapted to an outer contour or shape of the sample. It is a primary objective of said adaptation to ensure reproducible and optimal measurement conditions and ensure that a loss of intensity of the measurement light beam does primary happen due to absorption by the sample.
  • the reflective surface comprises a 3D-pattern or 3D-micropattern, providing the surface with a pitted texture acting as diffusive mirror.
  • the 3D-pattern is generated by lofting sections.
  • a section is made by the iteration of a polygon unit/module, more particularly a triangle unit/module, more particularly an isosceles triangle unit/module along an axis.
  • This axis can be a straight line, a curved line or a polyline or a spline or an irregular line (in 2D or 3D).
  • This triangle is repeated along in a row (Axis X) for a longitude defined by the position and size of the reflecting area needed, and its total length is typically adapted to the specific sample or a section thereof.
  • a copy of this described section is offset by dimension A in the direction of, for example, Axis Y and then this copy is moved in Axis X in order to let the top vertex of the triangle of Section 1 share the same coordinate on Axis X as the bottom vertex of the triangle of Section 2.
  • the volume of such oblique triangular prisms can vary between 0,0005 mm 3 and 8 mm 3 more particularly between 0,005 mm 3 and 1 mm 3 .
  • the resulting surfaces of the oblique triangular prism are arranged in an angle between 89 and 1 degrees, more particularly between 60 and 20 degrees towards measurement light beam .
  • the triangular section is adapted to for example a semicircular row, the triangle unit/module as well as the resulting oblique triangular prism and their angles are distorted.
  • Fig 6 shows several planar surface structures of a diffusive mirror that can be generated from the sections shown in Figure 5.
  • the different planar surface structures of the diffusive mirrors are generated by lofting and parametrically adapting the surface with different procedures - two points can be unified in infinite ways, which affects the result in the surface and/or pattern.
  • Fig. 6A shows an embodiment comprising a smooth fit
  • Fig. 6B shows an embodiment with a ruled fit
  • Fig. C shows an embodiment comprising a normal to all sections
  • Fig. 6D shows an example of a normal to start section
  • Fig. 6E shows an example of a normal to end section
  • Fig. 6F shows an example of a normal to start and normal to end sections
  • FIG. 6G shows an example of an embodiment of the corrugated mirror surface comprising a draft angle.
  • the repetition and mirroring of this volume as unit along the reflecting surface generates the 3D-pattern with diffusive properties. This results in a density between 500.000 and 10 per 1 cm 2 , more particularly between 50.000 and 25 per 1 cm 2 on the surface of the diffusive mirror.
  • Fig. 7 shows the curved surface structure of a diffusive mirror M as well as a reflective surface obtained by a reflective coating R on a smooth portion of the mirror without such a surface structure.
  • the shown curved surface structure of a diffusive mirror can be used for reflective sample holders which hold samples that have non-planar shapes, e.g. cylindric shapes.
  • the curved corrugated mirror encompasses at least a portion of the sample receiving chamber SRC.
  • Fig. 8 shows a sectional view of reflective sample holder 150 according to an embodiment for measuring a sample within a typical one-way syringe using the transflection technique.
  • the shown reflective sample holder 150 consists of two elements: a main body and the corrugated mirror M which is connected to a light guiding channel G comprising a reflective coating R on its curved walls.
  • Said light guiding channel has a circular crosssection at its base which is directed towards the light source of the spectrophotometer and centered with respect to the sample beam.
  • the reflective sample holder according to embodiment 150 provides a sample receiving chamber SRC which is configured by a size and a shape of its main body to hold a sample S of cylindric shape, e.g.
  • the sample receiving chamber SRC is formed by a first functional element providing the reflectively coated surface R and a second functional element, i.e. the diffusive corrugated mirror M.
  • An outer contour of the first functional element comprising the reflective coating fits optimally with an inner contour of the second functional element and vice-versa.
  • the curved surface (its curvature) of the reflective coating R and the diffusive mirror M are adapted to the cylindric shape of the sample S in order to enable minimum loss of light intensity and maximum gain of information from the sample.
  • mirror M encloses, in the region of the light guiding channel G and/or in (at least one, typically a plurality of or even all of the) cross-sections which are parallel to the optical axis OA and cut the light guiding channel G, about 50% of an outer surface of the inserted syringe and the sample (not shown), respectively. In other embodiments, more or less than 50% of the outer surface of the inserted syringe and the sample, respectively, are enclosed by mirror M. As further illustrated in Fig.
  • the cross-section(s) may be (at least substantially) parallel to the optical axis OA and (at least substantially) perpendicular to a symmetry axis SA of the sample receiving chamber SRC (and the sample when inserted into the sample receiving chamber SRC, respectively).
  • Fig. 9 shows the cross section of reflective sample holder according to another embodiment 160 for measuring a liquid contained in a syringe via transmission mode.
  • the shown reflective sample holder 160 consists of two elements and provides a sample receiving chamber SRC which is adapted to hold a sample S of cylindric shape, e.g. a syringe that holds medicinal caffeine solution.
  • the sample receiving chamber SRC is formed by a first functional element for guiding the incoming sample beam providing a reflectively coated surface R which is curved.
  • the sample receiving chamber of this embodiment encompasses a second functional element for guiding the outgoing measurement beam comprising a reflectively coated surface as well, wherein the reflective coating R covers planar and flat channel walls of the light guiding channel G.
  • the outgoing sample beam (atop the main body) “carries” or comprises the signal which is characterized, e.g., by an intensity which is modulated mainly by a specific absorption and a specific scattering of the (incoming) measurement beam caused by the sample constituents.
  • both reflective surfaces represent the light guiding channel G that directs and guides the measurement light beam (sample beam) from one side of the reflective sample holder, through the sample, through the other side of the reflective sample holder.
  • An outer contour of the second element fits optimally with an inner contour of the first element or vice-versa.
  • the reflective light guiding channel G is adapted to the cylindric shape of the sample S to enable minimum loss of light intensity and maximum gain of information from the sample S.
  • Fig. 10 shows an NIR-spectrum that contains measurements of syringes that hold medicinal caffeine solutions. These measurements were generated with the transflection technique.
  • the blue lines show ten measurements conducted with use of the herein described reflective sample holder 150, while the red lines show ten measurements conducted without a reflective sample holder but with a commonly available reflective gold mirror.
  • the results prove that the suggested reflective sample holder enables an overall higher quality and an overall higher reproducibility of the measurement results.
  • the abscissa shows the wavelength expressed in wavenumber and the y-axis (ordinate) shows the corresponding signal intensity (absorbance).
  • Fig. 11 shows the first derivation of a section of the NIR-spectrum shown in Figure 10, that contains measurements of syringes that hold medicinal caffeine solutions. These measurements were generated with the transflection technique.
  • the blue lines show ten measurements conducted with use of the herein described reflective sample holder 150, while the red lines show ten measurements conducted without a reflective sample holder but with a commonly available reflective gold mirror. The results prove that the reflective sample holder enables an overall higher quality and an overall higher reproducibility of the measurements.
  • Fig. 12 shows an NIR-spectrum that contains measurements of syringes that hold medicinal caffeine solutions. These measurements were generated with the transmission technique.
  • the blue lines show ten measurements conducted with use of reflective sample holder 160 that allow the use of the transmission technique, while the red lines show ten measurements conducted without any additional tool. The results prove that such a reflective sample holder enables an overall higher quality and an overall higher reproducibility of the measurement results.
  • Fig. 13 shows the first derivation of a section of the NIR-spectrum shown in Figure 12, that contains measurements of syringes that hold medicinal caffeine solutions. These measurements were generated with the transmission technique.
  • the blue lines show ten measurements conducted with use of reflective sample holder 160 that allow the use of the transmission technique, while the red lines show ten measurements conducted without any additional tool. The results prove that such a reflective sample holder enables an overall higher quality and an overall higher reproducibility of the measurement results.
  • Figure 14 shows schematically typical shapes of soft gel capsules, suppositories etc. which can individually be measured with the suggested sample holder
  • Fig. 14 schematically shows some typical shapes of soft gel capsules, suppositories, pills, etc., which can be individually measured with the proposed sample holder, since the shape and curvature of the diffusive mirror are adapted to the shape and curvature of the respective sample.
  • a) shows an oval shape
  • d) and g) suppositories e) a tetraeder
  • f) tubs h) a star-like cushion, i.e. a “special shape”, and i) a twist-off soft gel capsule, containing, e.g., a skin-care product.
  • the manufacturing methods proposed herein for the sample holder comprising the diffusive mirror are flexible and adjustable to advantageously obtain digital data from a digital data set describing the sample.
  • the digital data set can be used to control a machine for either additive and/or subtractive processing of a selected base material (a blank).
  • a sample holder (100, 110, 120, 140, 150) for spectrophotometric measurements of a sample (S) using a transflection technique
  • the sample holder comprising a sample receiving chamber (SRC) comprising a diffusive mirror (M), wherein a curvature of the diffusive mirror (M) is adapted to a curvature of a surface of the sample (S) and/or adapted to a curvature of a surface of a container (C) comprising the sample (S).
  • a sample holder (160) for spectrophotometric measurements of a sample (S) using a transmission technique comprising a hollow light guiding channel (G), wherein an inner wall of the hollow light guiding channel (G) is covered by a smooth reflective coating (R) and is configured to encase at least partially a tubular part of the sample (S) or of a container (C) containing the sample (S) along a circumferential direction of the tubular part of the sample (S) or of the container (C).
  • a combination of manufacturing techniques for producing the sample holder is disclosed, wherein the combination comprises at least one of an additive and a subtractive manufacturing.
  • the additive manufacturing comprising 3D printing of a wax model of at least a part of the sample holder; and applying a lost wax casting; wherein the lost wax casting comprises casting a molten metal, a molten metal alloy and/or a molten IR- reflective polymer.
  • a method for analyzing a sample comprising an analyte comprises: providing the sample holder for the sample; arranging the sample in the sample receiving chamber (SRC) of the sample holder; directing a measurement light beam into the sample receiving chamber (SRC); and collecting a transmitted and/or transflected light from the sample receiving chamber (SRC).
  • a method for characterizing a sample for identification, conformity, semi-quantification and quantification of an analyte comprising measurement of a transflected and/or transmitted light by a NIR spectrophotometry and/or by a Raman spectrophotometry using the sample holder.
  • the described embodiments have versatile application areas for the detection of pharmaceutical substances, possible contaminants thereof and/or adulterants or their degradation products, e.g. as a result of incorrect storage conditions in the area of pharmaceutical, medical, veterinarian or biochemical application of biologically active substances but also in food, e.g. food additives, concentrates etc., and convenience products.
  • food e.g. food additives, concentrates etc.
  • convenience products e.g. food additives, concentrates etc.
  • a manufacturing technique for a sample holder wherein the sample holder is configured for spectrophotometric measurements of a sample using a transflection technique, the sample holder comprising a sample receiving chamber comprising a diffusive mirror, wherein a curvature of the diffusive mirror is adapted to a curvature of a surface of the sample and/or adapted to a curvature of a surface of a container comprising the sample.
  • a sample holder for spectrophotometric measurements of a sample using a transmission technique comprising a hollow light guiding channel, wherein an inner wall of the hollow light guiding channel is covered by a reflective coating and the diffusive mirror is configured to encase and/or enclose at least partially a part of the sample, e.g. a soft gel capsule or of a container containing the sample along a convex part of the sample or of the container.
  • F film or coating e.g. of a capsule
  • spectrophotometer NIR- or Raman-spectrophotometer
  • liquid e.g. a biologically active substance, a drug, a vaccine, a food additive polymer container (infusion bag, pump or disposable plastic syringe, optionally packaged) a tubular section of polymer container b corner of polymer container, esp. of infusion bag sterile package (typically made from a polymer foil) optical element, e.g. mirror or light guide channel, e.g.
  • a measurement chamber extension (10) for a spectrophotometric characterization with a NIR-spectrophotometer (1) or a Raman-spectrophotometer (1) of a liquid (2) in a polymer container (3) wherein the measurement chamber extension (10) comprises: an adapter plate (11) having an adapter opening (11’); a container holder (7); and an optical element (5), selected from a mirror and a waveguide; wherein the adapter (11) is configured to cover in a light-tight manner the measurement chamber (20) of the NIR-spectrophotometer (1) or of the Raman- spectrophotometer (1) and the adapter opening (11’) is arranged to encompass a measurement window of the NIR-spectrophotometer (1) or Raman-spectrophotometer (1) to provide exposition of the liquid (2) to a measurement light beam emitted from the measurement chamber (20) of the NIR-spectrophotometer (1) or Raman- spectrophotometer (1) through the measurement window; wherein the container holder (7) is configured to allow a close placement of the optical element
  • the measurement chamber extension (10) according to any of preceding clauses, wherein the mirror (5) is a diffusive mirror (5).
  • the measurement chamber extension (10) according to clause 10 or 11, wherein the corrugated surface of the mirror (5) has a roughness in a range of 20 pm - 1000 pm.
  • the measurement chamber extension (10) according to clause 13, where on the measurement window of the spectrophotometer (1) a first waveguide is positioned guiding a measuring light from a light source of the spectrophotometer (1) to the liquid (2) within the polymer container (3) and to the optical element (5), i.e. a second waveguide (5) which is configured to guide the measuring light after its passage of a layer of the liquid (2) within the polymer container (3) from the polymer container (3) to a photodetector of the spectrophotometer (1).
  • the measurement chamber extension (10) according to any of preceding clauses, wherein the polymer container is a disposable syringe (3).
  • the light guide (6) comprises a channel (6), wherein an end of the channel (6) is shaped into a tongue (66) which forms a receptacle (13) for fitting and holding a tubular section (3a) of the syringe (3) in an orthogonal orientation relative to a central axis of the channel (6), wherein a surface of the tongue (66) which is oriented substantially towards the channel (6) comprises a corrugated surface (55) comprising the mirror (5), and the circular section (3a) of the syringe (3) is arrangeable in the receptacle within a light path of the sample beam.
  • the measurement chamber extension (10) according to any of clauses 15 or 16, wherein the syringe (3) is enclosed by a sterile package (4).
  • the measurement chamber extension (10) according to clause 19, wherein corresponding pairs of permanent magnets are arranged at or near to fitting edges of the adapter opening (11’) and the bag orienting member (40).
  • the measurement chamber extension (10) according to any of clauses 18 - 20, wherein a thickness of a layer of the liquid (2) in the bag (3) is adjustable between 0.2 mm - 5.1 mm, preferably adjustable at 0.5 - 2.1 mm.
  • the measurement chamber extension (10) according to clause 22, wherein the mirror fixing member (15) and the bag orienting member (40) comprise at least one magnet of a pair of permanent magnets for stabilization of the mirror within the channel (6), wherein the channel (6) is dimensioned to encompass the mirror (5).
  • the measurement light beam comprises light within a wavenumber range of 4,000 cm' 1 - 12,500 cm' 1 .
  • a software of the NIR-spectrophotometer (1) or of the Raman- spectrophotometer (1) or in a control unit thereof is adapted to extract from a measured NIR- or Raman-spectrum the corresponding spectrum belonging to the material comprising the polymer container (3) or the sterile package (4) of the syringe (3).
  • a sample holder (100, 110, 120, 140, 150) for spectrophotometric measurements of a sample (S) using a transflection technique, the sample holder comprising a sample receiving chamber (SRC) comprising a diffusive mirror (M), wherein a curvature of the diffusive mirror (M) is adapted to a curvature of a surface of the sample (S) and/or adapted to a curvature of a surface of a container (C) comprising the sample (S).
  • SRC sample receiving chamber
  • M diffusive mirror
  • sample holder (100, 110, 120, 140, 150) comprises a hollow light guiding channel (G), wherein an inner wall of the hollow light guiding channel (G) is covered by a smooth reflective coating (R) and is configured to encase at least partially a part of the sample (S) or of a container (C) containing the sample (S) along a circumferential direction of the tubular part of the sample (S) or of the container (C).
  • a sample holder (160) for spectrophotometric measurements of a sample (S) using a transmission technique comprising a hollow light guiding channel (G), wherein an inner wall of the hollow light guiding channel (G) is covered by a smooth reflective coating (R) and is configured to encase at least partially a part of the sample (S) or of a container (C) containing the sample (S) along a circumferential direction of the tubular part of the sample (S) or of the container (C).
  • a shape of the sample receiving chamber is configured to receive the container (C) comprising the sample (S), wherein the container (C) either represents a primary container and single containment of the sample, i.e. is a primary container, or the container (C) represents a secondary container which encases a primary container, wherein the sample (S) is disposed in said primary container.
  • the container (C) comprises at least one of a plastic, a paper, a glass, a metal and a textile, wherein the paper and the textile may optionally be coated with a polymer, and wherein the plastic is selected from a thermoformed polymer film, a polymer shrink film, and a plastic film bag.
  • the sample receiving chamber (SRC) encases the sample completely or at least along a circumferential direction of a tubular part of the sample (S).
  • the container (C) is selected from: a syringe, an infusion bag, a vial, a bottle, a cuvette, a blister, a hard or soft gelatin capsule, a film of a film-coated tablet, a dragee, a suppository, and a film coated suppository.
  • sample receiving chamber comprises one of: a cylinder, a tube, a sphere, a half sphere, a prolate spheroid, an oblate spheroid, an ellipsoid, an elliptic a paraboloid, a cube, a cuboid, a prism, a pyramid, a cone, a truncated cone, a hyperboloid, a parabolic, a helix, a torus, a parametric geometry, and a differential geometry.
  • SRC sample receiving chamber
  • a surface structure of the diffusive mirror (M) comprises multiple geometric bodies or parts thereof, wherein the geometrical bodies are selected from: a cylinder, a tube, a sphere, a half sphere, a prolate spheroid, an oblate spheroid, an ellipsoid, an elliptic, a paraboloid, a cube, a cuboid, a prism, a pyramid, a cone, a truncated cone, a hyperboloid, a parabolic, a helix, and a torus.
  • the lost wax casting comprises generating a casting mold for the part of the sample holder by embedding the 3D printed wax model; covering the wax model with a mold forming material to generate a mold, wherein the mold forming material is selected from a silica slurry, a ceramic slip, and a stucco; and drying of the resulting green shell; burnout and sintering of the green shell to the mold, while the wax melts and leaves the shell and or the mold; casting by pouring a molten metal or metal alloy into the mold; releasing the cast; finishing the cast, wherein finishing comprises at least one of grinding, polishing, plating, electroplating and/or depositing a reflective layer, particularly a gold layer.
  • the additive manufacturing comprises fused deposition modelling for a plastic part of the sample holder, wherein the plastic part comprises a thermoplastic, e.g. a polylactic acid, an Acrylonitrile Butadiene Styrene.
  • a thermoplastic e.g. a polylactic acid, an Acrylonitrile Butadiene Styrene.
  • a method for analyzing a sample comprising an analyte comprising: providing a sample holder (100, 110, 120, 140, 150) for the sample according to any of clauses 29-39; arranging the sample in the sample receiving chamber (SRC) of the sample holder (100, 110, 120, 140, 150); directing a measurement light beam into the sample receiving chamber (SRC); and collecting a transmitted and/or transflected light from the sample receiving chamber (SRC).
  • the method according to clause 44 further comprising generating and analyzing a spectrum of the collected transmitted and/or transflected light; and determining a parameter of the sample, e.g.
  • TL transmitted light
  • M diffusive mirror
  • a method for characterizing a sample for identification, conformity, semi-quantification and quantification of an analyte comprising a measurement of a transflected and/or transmitted light by a NIR spectrophotometry and/or by a Raman spectrophotometry using a sample holder according to any of clauses 29-39.
  • the analyte comprises a cannabinoid selected from: cannabidiol (CBD), tetrahydrocannabinol (THC), cannabidiol Acid (CBDA), tetrahydrocannabinolic Acid (THCA), cannabinol (CBN), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabidivar (CBCV), cannabichromen (CBC), cannabicyclol (CBL), cannabielsoin (CBE), cannabinodiol (CBND), cannabitriol (CBTL), cannabidivarin (CBDV) and tetrahydrocannabivarin (THCV).
  • CBD cannabidiol
  • THC cannabidiol
  • CBDA cannabidiol Acid
  • THCA tetrahydrocannabinolic Acid
  • CBD cannabinol
  • CBG canna
  • the cannabinoid is contained in a cannabis extract in a syringe, in an infusion bag, in a vial, in a bottle or in a cuvette, in a soft or hard gelatin capsule, in a suppository or in a Cannabis inflorescence, wherein the syringe, the infusion bag, the vial, the bottle, the cuvette, the soft or hard gelatin capsule, the suppository and the Cannabis inflorescence comprises an oil, a solution or a resin containing the cannabinoid.
  • the analyte comprises caffeine.

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Abstract

L'invention concerne une technique de fabrication d'un dispositif de support d'échantillon (100, 110, 120, 140, 150), le dispositif de support d'échantillon étant conçu pour des mesures spectrophotométriques d'un échantillon (S) au moyen d'une technique de transfert, le dispositif de support d'échantillon comprenant une chambre de réception d'échantillon (SRC) comprenant un miroir (M) de diffusion, une courbure du miroir (M) de diffusion étant adaptée à une courbure d'une surface de l'échantillon (S) et/ou adaptée à une courbure d'une surface d'un récipient (C) comprenant l'échantillon (S). L'invention concerne, en outre, un dispositif de support d'échantillon (160) pour des mesures spectrophotométriques d'un échantillon (S) au moyen d'une technique de transmission, le dispositif de support d'échantillon comprenant un canal de guidage de lumière creux (G), une paroi intérieure du canal de guidage de lumière creux (G) étant recouverte par un revêtement réfléchissant (R) et conçue pour envelopper et/ou entourer au moins partiellement une partie de l'échantillon (S), par exemple une capsule de gel mou ou d'un récipient (C) contenant l'échantillon (S) le long d'une partie convexe de l'échantillon (S) ou du récipient (C).
PCT/EP2022/088091 2022-07-08 2022-12-30 Technique de fabrication d'un dispositif de support d'échantillon réfléchissant pour spectrophotométrie nir et raman WO2024008326A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
PCT/EP2022/069161 WO2023281090A1 (fr) 2021-07-09 2022-07-08 Dispositif de support d'échantillon réfléchissant fabriqué de manière additive pour spectrophotométrie nir et raman
EPPCT/EP2022/069161 2022-07-08

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WO2024008326A1 true WO2024008326A1 (fr) 2024-01-11

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6585939B1 (en) * 1999-02-26 2003-07-01 Orchid Biosciences, Inc. Microstructures for use in biological assays and reactions
US20100128255A1 (en) * 2007-07-06 2010-05-27 Bp Oil International Limited Optical cell
US20190285471A1 (en) * 2016-07-20 2019-09-19 Verifood, Ltd. Accessories for handheld spectrometer
US20210197188A1 (en) * 2018-04-23 2021-07-01 Meon Medical Solutions Gmbh & Co Kg Automatic analyzer and optical measurement method for obtaining measurement signals from liquid media

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6585939B1 (en) * 1999-02-26 2003-07-01 Orchid Biosciences, Inc. Microstructures for use in biological assays and reactions
US20100128255A1 (en) * 2007-07-06 2010-05-27 Bp Oil International Limited Optical cell
US20190285471A1 (en) * 2016-07-20 2019-09-19 Verifood, Ltd. Accessories for handheld spectrometer
US20210197188A1 (en) * 2018-04-23 2021-07-01 Meon Medical Solutions Gmbh & Co Kg Automatic analyzer and optical measurement method for obtaining measurement signals from liquid media

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