EP1311861A2 - Unite d'analyse et procede de production de formulations stables - Google Patents

Unite d'analyse et procede de production de formulations stables

Info

Publication number
EP1311861A2
EP1311861A2 EP01958079A EP01958079A EP1311861A2 EP 1311861 A2 EP1311861 A2 EP 1311861A2 EP 01958079 A EP01958079 A EP 01958079A EP 01958079 A EP01958079 A EP 01958079A EP 1311861 A2 EP1311861 A2 EP 1311861A2
Authority
EP
European Patent Office
Prior art keywords
formulations
active ingredient
dispersing medium
solvent
mixing chamber
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP01958079A
Other languages
German (de)
English (en)
Inventor
Robert Heger
Wolfgang Schrof
Michael Seufert
Simon Nord
Harald Köhle
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
BASF SE
Original Assignee
BASF SE
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by BASF SE filed Critical BASF SE
Publication of EP1311861A2 publication Critical patent/EP1311861A2/fr
Withdrawn legal-status Critical Current

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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G01N35/10—Devices for transferring samples or any liquids to, in, or from, the analysis apparatus, e.g. suction devices, injection devices
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J19/0046—Sequential or parallel reactions, e.g. for the synthesis of polypeptides or polynucleotides; Apparatus and devices for combinatorial chemistry or for making molecular arrays
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00277—Apparatus
    • B01J2219/00279—Features relating to reactor vessels
    • B01J2219/00306—Reactor vessels in a multiple arrangement
    • B01J2219/00313—Reactor vessels in a multiple arrangement the reactor vessels being formed by arrays of wells in blocks
    • B01J2219/00315—Microtiter plates
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00277—Apparatus
    • B01J2219/00351—Means for dispensing and evacuation of reagents
    • B01J2219/00364—Pipettes
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00277—Apparatus
    • B01J2219/00351—Means for dispensing and evacuation of reagents
    • B01J2219/00373—Hollow needles
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00277—Apparatus
    • B01J2219/00479—Means for mixing reactants or products in the reaction vessels
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00583—Features relative to the processes being carried out
    • B01J2219/00585—Parallel processes
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00583—Features relative to the processes being carried out
    • B01J2219/00603—Making arrays on substantially continuous surfaces
    • B01J2219/00659—Two-dimensional arrays
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/0068—Means for controlling the apparatus of the process
    • B01J2219/00686—Automatic
    • B01J2219/00691—Automatic using robots
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/0068—Means for controlling the apparatus of the process
    • B01J2219/00702—Processes involving means for analysing and characterising the products
    • B01J2219/00704—Processes involving means for analysing and characterising the products integrated with the reactor apparatus
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/0068—Means for controlling the apparatus of the process
    • B01J2219/00702—Processes involving means for analysing and characterising the products
    • B01J2219/00707—Processes involving means for analysing and characterising the products separated from the reactor apparatus
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00718—Type of compounds synthesised
    • B01J2219/0072—Organic compounds
    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B40/00—Libraries per se, e.g. arrays, mixtures
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N13/00—Investigating surface or boundary effects, e.g. wetting power; Investigating diffusion effects; Analysing materials by determining surface, boundary, or diffusion effects
    • G01N2013/006—Dissolution of tablets or the like
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G01N2035/00178—Special arrangements of analysers
    • G01N2035/00188—Special arrangements of analysers the analyte being in the solid state
    • G01N2035/00198—Dissolution analysers
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G01N35/10—Devices for transferring samples or any liquids to, in, or from, the analysis apparatus, e.g. suction devices, injection devices
    • G01N2035/1027—General features of the devices
    • G01N2035/1032—Dilution or aliquotting

Definitions

  • the invention relates to a test unit for finding and / or identifying stable formulations, a method for producing an array of n formulations and an array containing n formulations, and the use of the test unit for producing an array of n formulations.
  • No. 4,973,352 relates to herbicides based on aqueous microemulsions which contain a combination of phenoxyphenoxy- or heteroaryloxyphenoxycarboxylic acid esters and a salt of betazone as the active ingredient. These systems are made up of the active ingredient, one or more emulsifiers and one or more organic solvents, and water as the dispersing medium. According to US 4,973,352, the difficulty lies in producing stable formulations which are stable in storage and have no inhomogeneities. For this it is necessary to find the suitable ones from the large number of possible components and mixing ratios of the components. WO 97/07787 relates to the production of cyclosporin formulations which are suitable for oral administration.
  • These formulations contain the active ingredient, at least one alcohol with two to three carbon atoms as solvent and at least one nonionic surfactant. If these formulations are diluted with an aqueous medium, amorphous, bioavailable cyclosporin nanoparticles are obtained, 50% by weight of the nanoparticles having a particle size of ⁇ 1 ⁇ m. Here, too, the problem is finding suitable formulations that are sufficiently stable and have good bioavailability.
  • No. 4,522,743 relates to the production of finely divided carotenoid or retinoid compositions with particle sizes of ⁇ 0.5 ⁇ m.
  • the preparation is carried out by dissolving the active substance at elevated temperature in a water-miscible organic solvent. This solution is then rapidly mixed in a mixing chamber with water or with an aqueous solution of a formulation aid, the active substance being precipitated in finely divided form.
  • suitable formulation auxiliaries in order to obtain stable formulations.
  • the desired active ingredient is often expensive or difficult to obtain, especially at an early stage in the development of the active ingredient.
  • Another job of It is therefore the present invention to start from the lowest possible amounts of the desired active ingredient when searching for suitable formulations.
  • test unit for finding and / or identifying stable formulations which contain the following components at least one active ingredient which is sparingly soluble or insoluble in a dispersing medium, at least one formulation aid, one dispersing medium and, if appropriate, at least one solvent, the test unit has a robot for controlling a matrix of positions on a substrate, which has at least one robot arm.
  • test unit according to the invention is then characterized in that a mixing chamber is integrated in the robot arm.
  • a method for producing an array containing n formulations each of the n formulations being in a known position of m positions on a substrate, n and m each being a natural number greater than or equal to 2 and m is greater than or equal to m and the formulations contain the following components at least one active ingredient which is sparingly soluble or insoluble in a dispersion medium, at least one formulation aid, a dispersion medium, and optionally at least one solvent, wherein
  • Formulations are obtained, wherein at least one of the parameters selected from the components used, the concentration of the components used, the temperature or the mixing time, if appropriate the at least one solvent or dispersing medium used and optionally further components used is different in the preparation of each of the formulations.
  • active ingredient “ formulation aid ”and“ solvent ”used in the description in the singular each mean“ at least one active ingredient, “at least one formulation aid” and “at least one solvent”.
  • the test unit according to the invention With the help of the test unit according to the invention and the method according to the invention, it is possible to produce more than 1000 formulations in one day, whereas with conventional methods of the prior art approximately two formulations can be produced per laboratory worker.
  • the probability of finding stable formulations for various active substances using the method of the present invention is significantly greater than using conventional methods.
  • the time in which these stable formulations can be found is considerably shorter than when using classic methods.
  • the amounts of components used, in particular the active ingredient are very small.
  • the amount of active ingredient per formulation produced is ⁇ 10 mg, preferably ⁇ 1 mg, particularly preferably ⁇ 0.1 mg. This is an important factor since the active ingredient used is often expensive or is difficult to obtain.
  • test unit according to the invention and the method and the array according to the invention make it possible to find stable active substance formulations in a quick and cost-effective way.
  • Formulations in the sense of the present invention are systems which have at least one continuous phase, which is generally liquid, and at least one dispersed phase (dispersions).
  • This dispersed phase can be a solid, liquid or gaseous phase.
  • the formulations are preferably suspensions or nanosuspensions, emulsions or microemulsions, solubilisates or foams.
  • Preferred microdisperse and nanodisperse systems have an average particle size of the dispersed phase of generally from 1 nm to 50 ⁇ m, preferably from 5 nm to 5 ⁇ m, particularly preferably from 10 nm to 500 nm (hydrodynamic radius (r ⁇ )).
  • the average particle size can e.g. determined by means of light scattering or analytical ultracentrifuge.
  • Stable formulations in the sense of the present invention are characterized in that the dispersed phase is present in the dispersing medium in a substantially fine and uniformly distributed manner. This means that over a period of time which generally depends on the field of application in which the stable formulation is used, there is no particle size growth (for example by agglomeration) of the dispersed phase, or that nothing settles or creames in the stable formulation.
  • the formulations are made depending on what type of dispersions it is.
  • Suspensions or nanosuspensions can be obtained in various ways: a) by dispersing: the active substance in turbulent form is mixed with a solution of the formulation aid. One spontaneously forms
  • Suspension or nanosuspension if suitable components and mixing ratios are selected.
  • the medium in which the active ingredient is suspended and the solvent of the formulation aid (dispersing medium) must be miscible with one another in the ratio in which they are used, so that the formation of several liquid phases is prevented.
  • the solvent in which the active ingredient is dissolved and the solvent of the formulation aid (dispersing medium) must be miscible with one another in the ratio in which they are used, so that the formation of more than one liquid Phases is avoided.
  • the active substance can be precipitated in the dipping medium in different ways, of which two preferred ways are listed below:
  • a solution of the active ingredient in a suitable solvent is mixed with the formulation aid dissolved in the dispersing medium in the mixing chamber in such a way that the resulting mixture of the solvent and the dispersing medium exceeds the saturation concentration of the active ingredient in the solvent / dispersing medium mixture and the active ingredient fails.
  • the spontaneous formation of stable formulations can be achieved.
  • the state of aggregation of the active substance is changed, but not its chemical identity. This can be achieved by using chemically different solution / dispersion media or by
  • Reactive precipitation by using a suitable precursor of the active ingredient A solution of one or more suitable reactive precursors of the
  • Active ingredient in a suitable solvent is mixed with the formulation aid dissolved in the dispersing medium in the mixing chamber.
  • the actual active ingredient is formed by a reaction of the precursor (s) and precipitates out of the reaction mixture to form a stable formulation.
  • the reaction of the precursor (s) can be, for example, a chemical reaction, salt formation or complexation.
  • Suitable formulation auxiliaries (dispersants) are generally high and low molecular surfactants.
  • Emulsions or microemulsions are Emulsions or microemulsions.
  • Emulsions or microemulsions are obtained by emulsification.
  • the active ingredient is mixed turbulently in liquid form or in solution with a solution of the formulation aid in the mixing cell.
  • An emulsion or microemulsion forms spontaneously if suitable components and mixing ratios are selected.
  • Solubilisates are obtained by solubilization, that is to say by solubilizing a substance which is insoluble in a certain liquid by adding a formulation aid.
  • the active ingredient is dissolved in the smallest possible amounts of a solvent that is able to dissolve the active ingredient and mixed turbulently with a solution of the emulsifier in the mixing cell.
  • solvent and the amounts of solvent used depend on the active ingredient used and / or the desired application.
  • Formulation auxiliaries used with preference are, depending on the active ingredient and the dispersant used, for example hydrotropic substances, e.g. monohydric and polyhydric alcohols, esters, ethers, nonionic and ionic surfactants, alkali or alkaline earth metal salts of certain organic acids, amides and other nitrogen-containing compounds.
  • hydrotropic substances e.g. monohydric and polyhydric alcohols, esters, ethers, nonionic and ionic surfactants, alkali or alkaline earth metal salts of certain organic acids, amides and other nitrogen-containing compounds.
  • the dispersing medium is the medium in which the active ingredient is formulated and applied.
  • the Dispersing medium forms the continuous phase of the formulations.
  • the active ingredient is poorly soluble or insoluble in the dispersing medium.
  • the dispersing medium can be composed of various chemical compounds.
  • the dispersing medium is an aqueous system.
  • the active ingredient is a substance which is sparingly soluble or insoluble in the dispersing medium.
  • An active ingredient selected from vitamins, retinoids, dyes, in particular carotenoids, pharmaceuticals, crop protection agents, fine chemicals, catalysts, enzymes, flame retardants, inhibitors against the deposition of lime, cosmetics and UV stabilizers is preferably used.
  • Suitable solvents, in particular for suspensions and nanosuspensions, which can be used according to the present invention are those which are at least partially miscible with the dispersing medium.
  • Solvents are preferably used which are up to at least 10% by weight, particularly preferably up to at least 25% by weight, miscible with the dispersing medium.
  • Solvents which have a boiling point below 200 ° C. are preferably used, since such solvents can be removed from the reaction mixture without overheating the active ingredient.
  • Solvents which have less than 10 carbon atoms are particularly preferably used.
  • solvents selected from alcohols, ethers, esters, ketones and acetals are preferred. Ethanol, n-propanol, isopropanol, butane-1,2-diol, 1-methyl ether, propane-1,2-diol, 1-n-propyl ether or acetone are particularly preferred.
  • Solvents particularly suitable for emulsions are those which are essentially immiscible or only slightly miscible with the dispersing medium.
  • halogenated solvents such as chloroform or Methylene chloride
  • non-halogenated solvents such as ethers, for example t-butyl methyl ether or dimethyl ether
  • esters for example ethyl acetate or butyl acetate
  • hydrocarbons for example cyclohexane or n-hexane and oils
  • vegetable oils such as sunflower, peanut and wheat germ oil, animal oils or synthetic oils.
  • the substrate is a material with a rigid surface or a parallel reactor. This surface has physically separate regions (positions).
  • the substrate is a microtiter plate or a parallel reactor and the positions are wells in the microtiter plate or reaction tubes in the parallel reactor.
  • An essential factor in the production of formulations of an active ingredient which is sparingly soluble or insoluble in a dispersing medium is thorough, thorough mixing of the individual components.
  • a mixing chamber is used for this. This enables turbulent mixing of the components and thus the formation of stable formulations.
  • this mixing chamber is integrated in the arm of a robot. This makes it possible, in a micronized automated and / or parallelized process, to mix the active ingredient, optionally dissolved in a solvent and the formulation aid, dissolved in the dispersing medium, in the mixing chamber and then add it to specific positions on a substrate and then add it to screen certain properties.
  • Parallel or serial screening can be carried out.
  • a first screening parallel screening
  • Formulations examined visually Furthermore, an investigation of the formulations obtained by parallel measurement of the optical transmission at selected wavelengths possible.
  • the formulations obtained can be screened by means of dynamic light scattering to measure the average particle size. Suitable methods for characterizing the formulations obtained are, for example, FOQELS (Fiber Optic Quasi Elastic Light Scattering) and FODLS (Fiber Optic Dynamic Light Scattering).
  • the formulations are characterized in such a way that an optical measuring cell is integrated in the robot arm, which carries, for example, a micropipetting apparatus for applying the formulations to the substrate, or in a further robot arm.
  • an optical measuring cell is integrated in the robot arm, which carries, for example, a micropipetting apparatus for applying the formulations to the substrate, or in a further robot arm.
  • This is particularly preferably an optical fiber for measuring particle sizes by means of dynamic light scattering.
  • a fiber-optic sensor for measuring particle sizes by means of quasi-elastic light scattering (FOQELS) is described, for example, in EP-A-0 295 564.
  • test unit it is possible, for example, to find suitable formulation auxiliaries for a specific active ingredient which stabilize the nanodisperse to microdisperse in a dispersing medium.
  • a solution or suspension of the poorly soluble or insoluble active ingredient in the dispersion medium in a certain solvent or suspending agent or the pure active ingredient for example if it is in liquid form, in different mixing processes with different solutions of a formulation aid in different concentrations or different formulation aids in the desired dispersion medium in the Mixing chamber according to the invention mixed turbulently and then applied to certain positions on the substrate.
  • the mixing chamber is designed such that it has two supply lines and one outlet, the supply lines being arranged at an angle of> 0 ° to 180 ° to one another.
  • the angle is particularly preferably 80 to 100 ° or 160 to 180 °.
  • the material of the mixing chamber and the leads leading into the mixing chamber or leads leading out of the mixing chamber is any material that is inert to the components used. Suitable materials are, in particular for the mixing chamber, for example steel or glass. Teflon hoses or steel capillaries are particularly suitable for the supply and discharge lines.
  • the mixing chamber generally has a volume of 10 to 5000 ⁇ l, preferably 50 to 1000 ⁇ l. In this way, small amounts of the individual components can be mixed without significant losses.
  • the diameter of the feed lines and the discharge line is generally 0.1 to 5 mm, preferably 0.1 to 1 mm, particularly preferably 0.2 to 0.9 mm, the diameter of the individual feed lines and the discharge line being different.
  • the compression speed of the syringes for the active ingredient feed is 0.01 to 0.1 ml / s and for the formulation aid feed 0.1 to 5 ml / s , This results in turbulent mixing when the inlets meet.
  • the feed rates of the two feeds are set so that, regardless of the total volume of the two feed solutions, the total feed quantities of the respective components to be mixed reach the mixing chamber in the same period.
  • the feed rate of the formulation aid feed is twice as high as that of the active ingredient feed.
  • the mixing process can be set precisely for each mixture, so that a very good reproducibility of the mixtures obtained is guaranteed.
  • the two volume flows from active ingredient feed and formulation aid feed can be kept constant or can be supplied via gradients.
  • the mixing chamber is designed in the form of a T-piece, as shown in FIG. 1.
  • the angle 6 between the active ingredient feed and the formulation aid feed is generally between> 0 ° and 180 °.
  • the angle is preferably 80 ° to 100 °, particularly preferably approximately 90 ° or 160 ° to 180 °, particularly preferably approximately 180 °.
  • the active ingredient feed and the formulation aid feed flow in opposite directions.
  • the outlet is at an angle of approximately 90 ° to the inlets.
  • the storage vessels, syringes, inlets and the mixing chamber can be heated to below the boiling point of the solvent used, depending on the solvent.
  • FIG. 2 A further embodiment of the mixing chamber is shown in FIG. 2 in the attached drawing.
  • the mixing chamber is designed such that it has two supply lines and one outlet, a first supply line being arranged within a second.
  • the angle between the feed lines is 0 °, ie the active ingredient feed and formulation aid feed are brought together in the form of a sheath flow geometry.
  • solutions of the poorly soluble or insoluble active ingredient in a solvent, or the pure active ingredient or a suspension of the active ingredient in a suspending agent, and the formulation aid in the dispersing medium are generally removed from storage vessels.
  • a known position on a substrate is carried out by means of dispensers.
  • a further possibility of applying the reaction components into the mixing chamber or onto the substrate are feed lines, which via pumps, in particular HPLC pumps, can feed the corresponding components precisely into the mixing chamber or onto the substrate.
  • the solution of the active ingredient which is sparingly soluble or insoluble in the dispersing medium is added to the solvent or the pure active ingredient, and the solution of the formulation aid in the dispersing medium is added to the mixing chamber by means of feed lines which carry the corresponding components can be pumped into the mixing chamber via a control system or by means of Syringes, e.g. Hamilton ⁇ l syringes.
  • Syringes e.g. Hamilton ⁇ l syringes.
  • the corresponding solutions are taken from storage vessels.
  • the test device according to the invention is preferably a precisely movable micropipetting apparatus into which the mixing chamber is installed and which is moved with the aid of a robot.
  • the formulations obtained can be applied directly from the mixing chamber to the substrate by means of the micropipetting apparatus.
  • the present invention further relates to a method for producing an array comprising n formulations, each of the n formulations being in a known position of m positions on a substrate, where n and m are each a natural number greater than or equal to 2 and m is greater than or equal to m and the formulations contain the following components at least one active ingredient which is sparingly soluble or insoluble in a dispersing medium, at least one formulation aid, one dispersing medium, and - optionally at least one solvent, in each case at least one active ingredient, optionally in the at least one solvent, and in each case a solution of the at least one formulation aid in the dispersing medium is mixed turbulently in a mixing chamber, n formulations being obtained in n mixing processes, at least one of the parameters selected from the components used, the concentrate ion of the components used, the temperature or the mixing time, optionally the at least one used Solvent or dispersing medium and optionally other components used in the preparation of each of the formulations is different.
  • active ingredient “ formulation aid ”and“ solvent ”used in the description in the singular each mean“ at least one active ingredient, “at least one formulation aid” and “at least one solvent”.
  • n and m in the method according to the invention are each a natural number greater than or equal to 2, preferably greater than or equal to 10, particularly preferably greater than or equal to 70, very particularly preferably greater than or equal to 100.
  • n and m are independent of one another, where m however, is at least equal to n or greater.
  • M is preferably equal to n.
  • the active substances, formulation auxiliaries, dispersing media and solvents which are suitable according to the invention, and the formulations, such as suspensions, nanosuspensions, emulsions, microemulsions and solubilisates, which can be obtained using the process according to the invention, have already been listed above.
  • Substrates suitable according to the present invention and positions on the substrates as well as suitable embodiments of the mixing chamber have likewise already been disclosed above.
  • a solution of the sparingly soluble or insoluble active ingredient in the solvent, or the pure active ingredient, and a solution of the formulation aid in the dispersion medium are mixed turbulently in a mixing chamber, n mixtures containing the active ingredient in n mixing processes precipitated form, the formulation aid, optionally the solvent and the dispersing medium are obtained.
  • each of the n formulations obtained differs in at least one of the parameters selected from the components used, the concentration of the components used, the temperature or the mixing time, the solvent or dispersing medium used and, if appropriate, further components used.
  • the mixing processes take place in an automated and / or parallelized process.
  • the corresponding solutions of the sparingly soluble or insoluble active ingredient in a solvent or the pure active ingredient, for example if it is in liquid form, and the formulation aid in the dispersing medium are particularly preferably added in an automated and / or parallel process.
  • the n formulations obtained are present in wells on a microtiter plate or in reaction tubes of a parallel reactor.
  • formulations are obtained in which the dispersed phase is present in a particle size of generally 1 nm to 50 ⁇ m, preferably 5 nm to 5 ⁇ m, particularly preferably 10 nm to 500 nm (hydrodynamic radius). These small particle sizes enable stable formulations to be produced.
  • an array can be obtained containing n formulations, each of the n formulations being in a known position of m positions on a substrate, where n and m are each a natural number greater than or equal to 2 and m greater than or equal to n and the formulations contain the following components at least one active ingredient which is sparingly soluble or insoluble in a dispersing medium, at least one formulation aid, one dispersing medium and optionally at least one solvent.
  • n and m in the array according to the invention are each a natural number greater than or equal to 2, preferably greater than or equal to 10, particularly preferably greater than or equal to 70, very particularly preferably greater than or equal to 100.
  • n and m are independent of one another, where m however, is at least equal to n or greater.
  • M is preferably equal to n.
  • the active substances, formulation auxiliaries, dispersing media and solvents which are suitable according to the invention, and the formulations, such as suspensions, nanosuspensions, emulsions, microemulsions and solubilisates, which can be obtained using the process according to the invention, have already been listed above.
  • This array can be classified according to certain properties, e.g. the physicochemical stability of the formulations and / or the particle size.
  • Parallel or rapid serial screening can be carried out.
  • a first screening parallel screening
  • the formulations obtained are e.g. visually, e.g. with the help of the eyes or with a camera, with regard to their physicochemical stability (e.g. with regard to sedimentation, creaming, formation of macroscopic phase boundaries).
  • an examination of the formulations obtained is possible by parallel measurement of the optical transmission at selected wavelengths.
  • the formulations obtained can be screened by means of dynamic light scattering to measure the average particle size.
  • Suitable methods for characterizing the formulations obtained are, for example, FOQELS (Fiber Optic Quasi Elastic Light Scattering) and FODLS (Fiber Optic Dynamic Light Scattering).
  • FOQELS Fiber Optic Quasi Elastic Light Scattering
  • FODLS Fiber Optic Dynamic Light Scattering
  • a test unit according to the invention is preferably used to produce the array.
  • the array is preferably produced using the method according to the invention.
  • the present invention further provides a process for the preparation of n solid compositions which are obtained by Dispersing medium and, if appropriate, the solvent of the formulations obtained according to the process according to the invention are removed after the preparation of the formulations by spray drying, drying in vacuo, freeze drying or by distilling off the solvent and, if appropriate, at least part of the dispersing medium and subsequent drying using one of the aforementioned drying processes becomes.
  • the solvent and the dispersing medium are removed after the n formulations have been introduced into certain positions on the substrate.
  • an array comprising n solid compositions, each of the n solid compositions being in a known position of m positions on a substrate, where n and m are each a natural number greater than or equal to 2, preferably greater than or equal to 10, particularly preferably greater than or equal to 70, very particularly preferably greater than or equal to 100 and the solid compositions contain the following components: at least one active ingredient which is sparingly soluble or insoluble in a dispersing medium, and - at least one formulation auxiliary.
  • the preferred substrate as well as the positions on the substrate, preferably used active ingredients and formulation solvents have already been mentioned.
  • the particle size of the dispersed phase in the solid compositions is preferably 1 nm to 50 ⁇ m, particularly preferably 5 nm to 5 ⁇ m, very particularly preferably 10 nm to 500 nm.
  • These solid compositions are for the preparation of stable formulations with the addition of a dispersing medium, preferably below Addition of an aqueous system, suitable. However, it is also possible to use a hydrophobic system as the dispersing medium.
  • Another object of the present invention is the use of an array containing n formulations, each of the n formulations being in a known position of m positions on a substrate, n and m each being a natural number greater than or equal to 2, preferably greater than or equal to 10, particularly preferably greater than or equal to 70, very particularly preferably greater than or equal to 100, and the compositions contain the following components: a dispersing medium, optionally at least one solvent, at least one active ingredient which is sparingly soluble or insoluble in the dispersing medium, and at least one formulation aid for detection and / or identification of stable formulations.
  • Suitable active substances, formulation auxiliaries, dispersion media and solvents as well as suitable substrates and positions on the substrates have already been listed above.
  • the formulations are identified with the help of a screening which can be carried out in parallel and / or in series.
  • Various screening methods have already been mentioned above. This use makes it possible to quickly find stable formulations, which would require a considerably higher amount of time and therefore also more expense using classic methods.
  • Example 1 Preparation of suspensions by case, several formulation auxiliaries for one active ingredient (UVINUL T 150) being tested
  • formulation aid solution Uvinul T 150 solution fed to the mixing chamber and mixed there; - The mixture obtained is passed into a 15 ml glass reaction tube; the syringe containing the formulation aid is 3 times with 10 ml
  • Reaction tubes can be given; after about 1 hour with the help of fiber optic quasi-elastic
  • Formulation determined - 5 min. Before the measurement, the samples are gently whirled up with a magnetic stirrer to make a representative To obtain particle size distribution of formulations of optionally removed active ingredient; the FOQELS sensor is rinsed with water after each measurement, then with acetone and then again with water.
  • Example 2 Preparation of suspensions by precipitation, in which a formulation aid (gelatin B100) is tested for several active ingredients.
  • a formulation aid gelatin B100
  • Microtiter plate can be given; after about 1 hour, the particle sizes of the active ingredient in the formulation are determined using fiber optic quasi-elastic light scattering (FOQELS) - 5 min. Before the measurement, the samples are gently whirled up with a magnetic stirrer to make a representative
  • the FOQELS sensor is rinsed with water after each measurement, then with acetone and then again with water.
  • the parallelized and automated measurement of the particle sizes of the 18 formulations obtained and the parallelized and automated preparation of the formulations take place in parallel, i.e. the next precipitation takes place before the first measurement of the particle sizes takes place.
  • Example 3 Preparation of emulsions, several formulation auxiliaries for one active ingredient (vitamin A palmitate) being tested
  • the digital images are evaluated automatically using a program for digital image processing.
  • the parallelized and automated determination of the phase behavior of the 15 formulations obtained and the parallelized and automated preparation of the formulations take place in parallel, ie the next emulsification takes place before the first determination of the phase behavior takes place.

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  • Chemical & Material Sciences (AREA)
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  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicinal Preparation (AREA)
  • Automatic Analysis And Handling Materials Therefor (AREA)
  • Feeding, Discharge, Calcimining, Fusing, And Gas-Generation Devices (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)

Abstract

L'invention concerne une unité d'analyse pour la détection et/ou l'identification de formulations stables contenant les composants suivants : au moins un agent peu soluble ou insoluble dans un milieu dispersif, au moins un agent auxiliaire de formulation, un milieu dispersif et éventuellement au moins un solvant. Cette unité d'analyse est équipée d'un robot pour la commande d'une matrice de positions sur un substrat. Ce robot présente au moins un bras caractérisé en ce qu'il intègre une chambre de mélange. Ladite invention concerne également un procédé de production d'un réseau contenant n formulations, selon lequel chacune des n formulations figure sur un substrat dans une position connue parmi m positions, les lettres n et m représentant chacune un entier naturel supérieur ou égal à 2 et m étant supérieur ou égal à n. Cette invention concerne en outre un réseau contenant n formulations et l'utilisation de ce réseau pour l'identification et/ou la détection de formulations stables ainsi que l'unité d'analyse pour la production dudit réseau.
EP01958079A 2000-08-17 2001-08-16 Unite d'analyse et procede de production de formulations stables Withdrawn EP1311861A2 (fr)

Applications Claiming Priority (3)

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US64009100A 2000-08-17 2000-08-17
US640091 2000-08-17
PCT/EP2001/009470 WO2002014876A2 (fr) 2000-08-17 2001-08-16 Unite d'analyse et procede de production de formulations stables

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JP (1) JP2004506902A (fr)
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WO (1) WO2002014876A2 (fr)

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FR2832630B1 (fr) * 2001-11-28 2005-01-14 Oreal Composition cosmetique et/ou dermatologique contenant au moins un actif hydrophile sensible a l'oxydation stabilise par au moins un copolymere de n-vinylimidazole
EP1374849B1 (fr) 2002-06-20 2005-11-23 L'oreal Utilisation cosmétique et/ou dermatologique d'une composition contenant au moins un actif hydrophile sensible à l'oxydation stabilisé par au moins un copolymère d'anhydride maléique

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US4199013A (en) * 1977-04-01 1980-04-22 Packard Instrument Company, Inc. Liquid sample aspirating and/or dispensing system
DE3916465A1 (de) * 1989-05-20 1990-11-22 Bayer Ag Herstellung kugelfoermiger dispersionen durch kristallisation von emulsionen
US5499745A (en) * 1994-02-18 1996-03-19 Nordson Corporation Apparatus for mixing and dispensing two chemically reactive materials
WO1998032002A1 (fr) * 1997-01-22 1998-07-23 Biacore Ab Pipette et ensemble support pour capteurs
US5979794A (en) * 1997-05-13 1999-11-09 Ingersoll-Rand Company Two-part stream dispensing for high viscosity materials
US6151123A (en) * 1997-07-14 2000-11-21 Symyx Technologies, Inc. Systems and methods for employing optical probes to characterize material properties
DE19805719A1 (de) * 1998-02-12 1999-08-19 Basf Ag Verfahren zur kombinatorischen Herstellung und Testung von Heterogenkatalysatoren
US6271209B1 (en) * 1998-04-03 2001-08-07 Valentis, Inc. Cationic lipid formulation delivering nucleic acid to peritoneal tumors
BR0009588A (pt) * 1999-04-05 2001-12-26 Millennium Pharm Inc Arranjo de múltiplas formulações localizadas emlocais separados ou em poços separados, sistemade múltiplo processamento automático parapreparar o mesmo, e, método para determinar umaformulação
DE10034893A1 (de) * 2000-07-18 2002-01-31 Basf Ag Arrays von n wässrigen Polymerdispersionen und m Formulierungen wässriger Polymerdispersionen

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WO2002014876A2 (fr) 2002-02-21
WO2002014876A3 (fr) 2003-01-30
JP2004506902A (ja) 2004-03-04

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