DE102022104759A1 - Co-crystal screening method, in particular for the production of co-crystals - Google Patents
Co-crystal screening method, in particular for the production of co-crystals Download PDFInfo
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- DE102022104759A1 DE102022104759A1 DE102022104759.8A DE102022104759A DE102022104759A1 DE 102022104759 A1 DE102022104759 A1 DE 102022104759A1 DE 102022104759 A DE102022104759 A DE 102022104759A DE 102022104759 A1 DE102022104759 A1 DE 102022104759A1
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- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 239000004570 mortar (masonry) Substances 0.000 description 1
- RVTZCBVAJQQJTK-UHFFFAOYSA-N oxygen(2-);zirconium(4+) Chemical compound [O-2].[O-2].[Zr+4] RVTZCBVAJQQJTK-UHFFFAOYSA-N 0.000 description 1
- CHIFOSRWCNZCFN-UHFFFAOYSA-N pendimethalin Chemical compound CCC(CC)NC1=C([N+]([O-])=O)C=C(C)C(C)=C1[N+]([O-])=O CHIFOSRWCNZCFN-UHFFFAOYSA-N 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000011514 reflex Effects 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 229910052814 silicon oxide Inorganic materials 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- QGHREAKMXXNCOA-UHFFFAOYSA-N thiophanate-methyl Chemical compound COC(=O)NC(=S)NC1=CC=CC=C1NC(=S)NC(=O)OC QGHREAKMXXNCOA-UHFFFAOYSA-N 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 235000010215 titanium dioxide Nutrition 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
- 235000014692 zinc oxide Nutrition 0.000 description 1
Classifications
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D9/00—Crystallisation
- B01D9/0077—Screening for crystallisation conditions or for crystal forms
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D9/00—Crystallisation
- B01D9/005—Selection of auxiliary, e.g. for control of crystallisation nuclei, of crystal growth, of adherence to walls; Arrangements for introduction thereof
Abstract
Gegenstand der Erfindung ist ein Co-Kristall-Screening Verfahren für Co-Kristalle bzw. Molekülkomplexe.The invention relates to a co-crystal screening method for co-crystals or molecular complexes.
Description
Gegenstand der Erfindung ist ein Co-Kristall-Screening Verfahren für Co-Kristalle bzw. Molekülkomplexe.The invention relates to a co-crystal screening method for co-crystals or molecular complexes.
Bislang wurden Co-Kristalle durch Kristallisation aus einem Lösemittel hergestellt oder durch Aufschmelzen. Auch ein Vermahlen der Reinsubstanzen optional mit Zugabe eines Lösemittels ist bekannt. Bei der Kristallisation werden große Mengen an Lösemitteln benötigt, die wieder recycelt werden müssen. Das Aufschmelzen der Reinsubstanzen birgt die Gefahr von Zersetzungen und bedarf einer hohen Energiezufuhr. Bei einer direkten Vermahlung der Reinsubstanzen werden große Mengen der Edukte benötigt. Außerdem bleiben in der Regel große Mengen an Co-Kristall an den Mahlbechern und Mahlkörpern kleben. Das Verfahren hat sich aus diesem Grunde nicht durchgestezt.So far, co-crystals have been produced by crystallization from a solvent or by melting. It is also known to grind the pure substances, optionally with the addition of a solvent. Crystallization requires large amounts of solvents that have to be recycled. The melting of the pure substances harbors the risk of decomposition and requires a high supply of energy. If the pure substances are ground directly, large quantities of the educts are required. In addition, large amounts of co-crystals usually stick to the grinding bowls and grinding media. For this reason, the procedure did not prevail.
Aufgabe der Erfindung war es ein Verfahren zur Herstellung von Co-Kristallen bereitzustellen, bei dem auf Lösemittel verzichtet werden kann. Vorzugsweise soll das Verfahren es erlauben eine Vorabbewertung zu erlauben, ob Co-Kristalle erhalten werden können. Des Weiteren war es eine Aufgabe der Erfindung ein Verfahren bereitzustellen, mit dem eine sehr schnelle Aussage zur Bildung von Co-Kristallen möglich ist.The object of the invention was to provide a process for the production of co-crystals in which solvents can be dispensed with. Preferably, the method should allow a preliminary assessment to be made as to whether co-crystals can be obtained. Furthermore, it was an object of the invention to provide a method with which a very rapid statement on the formation of co-crystals is possible.
Überraschend wurde gefunden, dass ein Vermahlen oder Verreiben von mindestens zwei organischen Substanzen in Gegenwart einer mindestens einer anorganischen Substanz oder eines anorganischen Materials (synonym zu Substanz) zur Bildung von Co-Kristallen führt, wenn die mindestens zwei Substanzen einen Co-Kristall bilden.Surprisingly, it was found that grinding or triturating at least two organic substances in the presence of at least one inorganic substance or an inorganic material (synonymous with substance) leads to the formation of co-crystals if the at least two substances form a co-crystal.
Gegenstand der Erfindung ist daher ein Verfahren zum Co-Kristall-Screening, und/oder insbesondere zur Herstellung von Co-Kristallen (synonym zu Molekülkomplexen), umfassend mindestens zwei unterschiedliche organische Substanzen, umfassend die folgenden Schritte: i) Bereitstellen von mindestens zwei unterschiedlichen organischen Substanzen, insbesondere wobei die beiden Substanzen in einem definierten molaren Verhältnis vorliegen, ii) Bereitstellen mindestens einer anorganischen Substanz oder einer Mischung von anorganischen Substanzen, und Vermahlen und/oder Verreiben von i) und ii), und iii) Erhalten eines Co-Kristalls, wenn die Substanzen aus i) einen Co-Kristall bilden oder iv) Feststellen, dass die mindestens beiden unterschiedlichen organischen Substanzen keinen Co-Kristall ausbilden. Bevorzugt wird das Verfahren in einer Alternative als Screening-Verfahren eingesetzt. Ist bekannt, dass ich die Co-Kristalle aus den mindestens zwei organischen Substanzen bilden, dann kann das Verfahren bevorzugt zur Herstellung der Co-Kristalle verwendet werden. Somit ist Gegenstand der Erfindung auch ein Verfahren zur Herstellung von Co-Kristallen.The invention therefore relates to a method for co-crystal screening and/or in particular for the production of co-crystals (synonymous with molecular complexes) comprising at least two different organic substances, comprising the following steps: i) providing at least two different organic substances Substances, in particular where the two substances are present in a defined molar ratio, ii) providing at least one inorganic substance or a mixture of inorganic substances, and grinding and/or triturating i) and ii), and iii) obtaining a co-crystal, if the substances from i) form a co-crystal or iv) determining that the at least two different organic substances do not form a co-crystal. The method is preferably used in an alternative as a screening method. If it is known that I form the co-crystals from the at least two organic substances, then the method can be preferably used to produce the co-crystals. The subject matter of the invention is therefore also a method for producing co-crystals.
Dabei ist es bevorzugt, wenn in Schritt iii) das Erhalten eines Co-Kristalls mittels mindestens eines Analyseverfahren ermittelt wird, insbesondere umfasst das mindestens eine Analyseverfahren Infrarot-Spektroskopie, UV-Festkörper-Spektroskopie, Vis-Festkörper-Spektroskopie, Festkörper-NMR-Spektroskopie.It is preferred if in step iii) the obtaining of a co-crystal is determined by means of at least one analysis method, in particular the at least one analysis method comprises infrared spectroscopy, UV solid-state spectroscopy, Vis solid-state spectroscopy, solid-state NMR spectroscopy .
Die anorganische Substanz kann auch als Matrix, insbesondere als Verdünnungsmatix dienen. Ferner kann die mindestens eine anorganische Substanz oder die anorganischen Substanzen zugleich als Formulierungshilfstoffe bei der Weiterverarbeitung zu einer pharmazeutischen Formulierung dienen.The inorganic substance can also serve as a matrix, in particular as a dilution matrix. Furthermore, the at least one inorganic substance or the inorganic substances can also serve as formulation auxiliaries during further processing to form a pharmaceutical formulation.
Ferner ist Gegenstand der Erfindung ein Verfahren das in einem elektrischen Dispergieraggregat durchgeführt wird, insbesondere in einer elektrischen Mühle, insbesondere umfassend Kugelmühle, Planetenmühle, Hammermühle, Stiftmühle, Walzenstuhl, Dissolver, Kneter, Dreiwalze, Rührwerkskugelmühle und/oder Extruder, insbesondere Gleichdrall-Doppelschneckenextruder. Bevorzugt sind elektrische Mühlen, wie Kugelmühlen und Kugelmühlen mit Planetengetriebe. Alternativ können kontinuierlich betreibbare Kugelmühlen in dem Verfahren eingesetzt werden.The invention also relates to a process that is carried out in an electric dispersing unit, in particular in an electric mill, in particular comprising a ball mill, planetary mill, hammer mill, pin mill, roller mill, dissolver, kneader, three-roller, agitator ball mill and/or extruder, in particular co-rotating twin-screw extruder. Electric mills such as ball mills and ball mills with planetary gears are preferred. Alternatively, continuously operable ball mills can be used in the process.
Nach einer weiteren Alternative ist Gegenstand der Erfindung ein Verfahren in dem die mindestens zwei unterschiedlichen Substanzen in einem definierten molaren Verhältnis in Schritt i) bereitgestellt werden, insbesondere werden die beiden unterschiedlichen Substanzen in einem molaren Verhältnis von 1 : 2 bis 2 : 1, bevorzugt von 1 : 1, insbesondere von jeweils +/- bis 15 % bereitgestellt.According to a further alternative, the invention provides a method in which the at least two different substances are provided in a defined molar ratio in step i), in particular the two different substances are in a molar ratio of 1: 2 to 2: 1, preferably from 1 : 1, in particular provided by +/- to 15% in each case.
Nach einer weiteren Alternative ist Gegenstand der Erfindung ein Verfahren in dem die Substanzen aus i) in einem molaren Verhältnis zu den Substanzen aus ii) von größer gleich 1 : 2, insbesondere 1 : 10, bevorzugt 1 : 100, besonders bevorzugt 1: 1000 eingesetzt werden, insbesondere von 1 : 1,1 bis 1 : 10.000. Gleichfalls ist kann das molare Verhältnis der Substanzen aus i) zu ii) von 100 : 1 bis 1 : 1.000.000 oder 1 : 1.000.000.000 betragen.According to a further alternative, the invention relates to a method in which the substances from i) are used in a molar ratio to the substances from ii) of greater than or equal to 1:2, in particular 1:10, preferably 1:100, particularly preferably 1:1000 in particular from 1:1.1 to 1:10,000. Likewise, the molar ratio of the substances from i) to ii) can be from 100:1 to 1:1,000,000 or 1:1,000,000,000.
Ebenfalls Gegenstand der Erfindung ist ein Screening-Verfahren zur Feststellung der Bildung von Co-Kristallen aus mindestens zwei unterschiedlichen chemischen und organischen Substanzen. Insbesondere kann das dazu angewendet werden, die Bildung von Mehrkomponenten-Kristallen, wie drei Komponenten oder vier Komponenten Kristalle, zu überprüfen oder diese herzustellen.The invention also relates to a screening method for determining the formation of co-crystals from at least two different chemical and organic substances. In particular, this can be used to monitor the formation of or produce multi-component crystals such as three-component or four-component crystals.
Die mindestens eine anorganische Substanz umfasst vorzugsweise mindestens ein anorganisches Salz, anorganisches Doppelsalz, anorganisches Oxid, anorganische Sulfide, anorganisches Sulfat, anorganisches Phosphat, anorganisches Carbonat, anorganische Hydrogencarbonat, anorganische Halogenide, Halogenide von organischen Kationen, anorganisches Kation mit organischem Anion, wie Alkalisalz und/oder Erdalkalisalz von Carbonsäuren, Fruchtsäuren, Hydroxysäuren, insbesondere jeweils unabhängig mit 1 bis 30 C-Atomen. Bevorzugte anorganische Substanzen umfassen: mindestens ein Alkalihalogenid, wie NaCl, KCI, KBr und/oder KJ, mindestens ein Erdalkalihalogenid, wie Calciumchlorid und/oder Magnesiumclorid, Erdalkalisulfat, wie Calciumsulfat und/oder Magnesiumsulfat, Alkalisulfat, wie Na2SO4 und/oder K2SO4, Erdalkalicarbonat, wie CaCO3 und/oder MgCO3, Alkalicarbonat, wie Na2CO3, K2CO3, und/oder NaHCO3, Metalloxid, insbesondere Siliziumoxid, Siliziumdioxid, Zirkondioxid, Magnesiumoxid, Mischoxide, Calciumsulfat, Magnesiumsulfat, Calciumcarbonat, Calciumhydrogencarbonat, Natriumcarbonat, Natriumhydogencarbonat, Kaliumcarbonat und/oder Kaliumhydrogencarbonat sowie Mischungen von mindestens zwei der vorgenannten Substanzen. Besonders bevorzugt sind Kaliumchlorid, Natriumchlorid, Magensiumsulfat und/oder Magnesiumoxid. Alternativ geeignet sind Zinkoxid, Natriumdihydrogenphosphat, Natriumhydrogencarbonat, Calciumhydrogenphosphat, Titandioxide, Eisenoxide, Natriumlaurylsulfat, Aerosil, Natriumstärkeglykolat, Salz der Alginsäure, Metallstearate, Magnesiumstearat, Talkum, physiologisch verträgliche Mineralien, anorganische Füllstoffe, Glimmer, Silikate, Calciumsilikat und/oder Calciumcarbonat. Auch ein Good-Puffer (20 Puffer gemäß Norman Good Kriterium) kann als mindestens Hilfsstoff im Gemisch mit einer anorganischen Substanz verwendet werden. Good-Puffer umfassen Morpholinoethansulfonsäure (MES), 3-(N-Morpholino)propansulfonsäure (MOPS), ADA, BES und Bicin. Besonders bevorzugt sind anorganische Salze der Good Puffer, ausgewählt aus MES, ADA, PIPES, ACES, MOPSO, Cholaminchlorid, MOPS, BES,TES, HEPES,DIPSO, Acetamidoglycin, TAPSO, POPSO, HEPPSO,HEPPS, Tricin, Glycinamid, Bicin, TAPS, AMPSO, CABS, CHES, CAPS und CAPSO. Gleichfalls können als Hilfsstoffe eingesetzt werden Hydrochlorid von Tris(hydroxymethyl)aminomethan. Ebenso bevorzugte anorganische Substanzen umfassen anorganische Phosphate.The at least one inorganic substance preferably includes at least one inorganic salt, inorganic double salt, inorganic oxide, inorganic sulfide, inorganic sulfate, inorganic phosphate, inorganic carbonate, inorganic bicarbonate, inorganic halide, halide of organic cation, inorganic cation with organic anion such as alkali salt and /or alkaline earth metal salts of carboxylic acids, fruit acids, hydroxy acids, in particular each independently with 1 to 30 carbon atoms. Preferred inorganic substances include: at least one alkali metal halide such as NaCl, KCl, KBr and/or KI, at least one alkaline earth metal halide such as calcium chloride and/or magnesium chloride, alkaline earth metal sulfate such as calcium sulfate and/or magnesium sulfate, alkali metal sulfate such as Na 2 SO 4 and/or K 2 SO 4 , alkaline earth metal carbonate such as CaCO 3 and/or MgCO 3 , alkali metal carbonate such as Na 2 CO 3 , K 2 CO 3 , and/or NaHCO 3 , metal oxide, in particular silicon oxide, silicon dioxide, zirconium dioxide, magnesium oxide, mixed oxides, calcium sulfate, Magnesium sulphate, calcium carbonate, calcium bicarbonate, sodium carbonate, sodium bicarbonate, potassium carbonate and/or potassium bicarbonate and mixtures of at least two of the aforementioned substances. Potassium chloride, sodium chloride, magnesium sulfate and/or magnesium oxide are particularly preferred. Alternatively suitable are zinc oxide, sodium dihydrogen phosphate, sodium hydrogen carbonate, calcium hydrogen phosphate, titanium dioxide, iron oxide, sodium lauryl sulfate, aerosil, sodium starch glycolate, salt of alginic acid, metal stearates, magnesium stearate, talc, physiologically tolerable minerals, inorganic fillers, mica, silicates, calcium silicate and/or calcium carbonate. A Good's buffer (20 buffer according to Norman Good's criterion) can also be used as at least an auxiliary substance in a mixture with an inorganic substance. Good's buffers include morpholinoethanesulfonic acid (MES), 3-(N-morpholino)propanesulfonic acid (MOPS), ADA, BES, and bicine. Inorganic salts of Good buffers are particularly preferred, selected from MES, ADA, PIPES, ACES, MOPSO, cholamine chloride, MOPS, BES,TES, HEPES,DIPSO, acetamidoglycine, TAPSO, POPSO, HEPPSO,HEPPS, tricine, glycineamide, bicine, TAPS , AMPSO, CABS, CHES, CAPS and CAPSO. The hydrochloride of tris(hydroxymethyl)aminomethane can also be used as auxiliaries. Also preferred inorganic substances include inorganic phosphates.
Als anorganische Substanz gilt eine Substanz die vorzugsweise keine Kohlenstoffatome umfasst. Bevorzugte anorganische Substanzen umfassen nur anorganische Komponenten. An inorganic substance is a substance which preferably does not contain any carbon atoms. Preferred inorganic substances include only inorganic components.
Als mindestens eine anorganische Substanz besonders geeignet sind: Alkalichlorid, Erdalkalichlorid, insbesondere Kaliumchlorid, Natriumchlorid, Speisesalz, Meersalz und/oder Mischungen umfassend zwei der vorgenannten Substanzen.Particularly suitable as at least one inorganic substance are: alkali metal chloride, alkaline earth metal chloride, in particular potassium chloride, sodium chloride, table salt, sea salt and/or mixtures comprising two of the aforementioned substances.
Nach einer weiteren Alternative kann das Verfahren in Schritt ii) umfassen, dass das Vermahlen und/oder Verreiben kontinuierlich oder diskontinuierlich erfolgt, insbesondere insgesamt für kleiner 5 Stunden, bevorzugt kleiner 4 Stunden, besonders bevorzugt kleiner 60 Minuten, ganz besonders bevorzugt kleiner 5 Minuten.According to a further alternative, the method in step ii) can include grinding and/or triturating continuously or discontinuously, in particular for a total of less than 5 hours, preferably less than 4 hours, particularly preferably less than 60 minutes, very particularly preferably less than 5 minutes.
Nach einer weiteren Alternative ist es bevorzugt, wenn in dem Verfahren in Schritt ii) ein Bereitstellen mindestens einer anorganischen Substanz oder eine Mischung von anorganischen Substanzen mit jeweils mindestens einem organischen pharmazeutischen Hilfsstoff erfolgt. Als organische pharmazeutische Hilfsstoffe gelten Bindemittel, Sprengmittel, Gleitmittel. Ein üblicher Hilfsstoff kann Cellulose, Lactose, Stärke, Mikrokristalline Cellulose, Hydroxypropylcellulose, Stärke, Povidon, Stärke, Alginate, Magnesiumstearat, und/oder Cellulosederivate wie Hydroxypropylcellulose sowie Mischungen umfassen mindestens zwei der genannten Hilfsstoffe umfassen.According to a further alternative, it is preferred if at least one inorganic substance or a mixture of inorganic substances each with at least one organic pharmaceutical excipient is provided in the method in step ii). Binding agents, disintegrants, lubricants are considered to be organic pharmaceutical excipients. A typical excipient can include cellulose, lactose, starch, microcrystalline cellulose, hydroxypropyl cellulose, starch, povidone, starch, alginates, magnesium stearate, and/or cellulose derivatives such as hydroxypropyl cellulose, and mixtures comprising at least two of the excipients mentioned.
Ebenfalls Gegenstand der Erfindung ist eine Zusammensetzung umfassend einen Co-Kristall erhältlich nach einem erfindungsgemäßen Verfahren umfassend die Schritte i), ii) und iii) und optional nach einem der Ansprüche 2 bis 11.The invention also relates to a composition comprising a co-crystal obtainable by a method according to the invention comprising steps i), ii) and iii) and optionally according to one of claims 2 to 11.
Ferner ist Gegenstand der Erfindung eine Zusammensetzung umfassend mindestens eine anorganische Substanz oder eine Mischung von anorganischen Substanzen mit jeweils mindestens einem organischen pharmazeutischen Hilfsstoff.Furthermore, the subject matter of the invention is a composition comprising at least one inorganic substance or a mixture of inorganic substances each with at least one organic pharmaceutical excipient.
Nach einer weiteren Ausführungsform ist Gegenstand der Erfindung eine pharmazeutische Formulierung umfassend einen Co-Kristall erhältlich nach dem erfindungsgemäßen Verfahren umfassend die Schritte i), ii) und iii) und optional nach einem der Ansprüche 2 bis 11 sowie umfassend mindestens eine anorganische Substanz oder eine Mischung von anorganischen Substanzen mit jeweils mindestens einem organischen pharmazeutischen Hilfsstoff.According to a further embodiment, the subject of the invention is a pharmaceutical formulation comprising a co-crystal obtainable by the method according to the invention comprising steps i), ii) and iii) and optionally according to one of claims 2 to 11 and comprising at least one inorganic substance or a mixture of inorganic substances, each with at least one organic pharmaceutical excipient.
Gegenstand der Erfindung ist auch die Verwendung eines Co-Kristalls erhältlich nach einem Verfahren umfassend die Schritte i), ii) und iii) und optional nach einem der Ansprüche 2 bis 11 zur Verwendung als Arzneimittel.The invention also relates to the use of a co-crystal obtainable by a process comprising steps i), ii) and iii) and optionally according to any one of claims 2 to 11 for use as a medicament.
Die mindestens eine anorganische Substanz oder Mischung von anorganischen Substanzen kann optional zusätzlich jeweils mindestens einem organischen pharmazeutischen Hilfsstoff umfassen. Die Hilfsstoffe können ferner umfassen Ectoin, Hydroxyectoin, Galaktolipide, Crucumin, Dimethylsulfon unud/oder Ascorbinsäure.The at least one inorganic substance or mixture of inorganic substances can optionally additionally comprise at least one organic pharmaceutical excipient. The adjuvants may further include Ectoin, Hydro xyectoin, galactolipids, crucumin, dimethylsulfone and/or ascorbic acid.
Des Weiteren ist Gegenstand der Erfindung ein Verfahren in dem die mindestens eine anorganische Substanz mindestens eine physiologisch verträgliche anorganische Substanz, ein Solvat, ein Hydrat und/oder eine Mischung dieser ist.Furthermore, the subject matter of the invention is a method in which the at least one inorganic substance is at least one physiologically tolerable inorganic substance, a solvate, a hydrate and/or a mixture of these.
Beispiele pharmazeutischer Wirkstoffe sind in den folgenden Patenten offenbart und zum Zwecke des erfindungsgemäßen Screening-Verfahren vollständig in dieser Offenbarung in Bezug genommen:
Definition Vermahlen ist ein technologischer Prozess zur Gewinnung von pulverförmigen Produkten aus groben, festen Stoffen. Trituratio ist eine Verreibung unlöslicher Arzneistoffe in einer Reibeschale mit Milchzucker, um feine zu Pulver erhalten.Definition Grinding is a technological process for obtaining powdered products from coarse, solid materials. Trituratio is a trituration of insoluble medicinal substances in a mortar with lactose to obtain a fine powder.
Dispergieraggregate umfassen Dissolver, Kneter, Dreiwalze, Kugelmühle, Rührwerkskugelmühle und Extruder (vornehmlich Gleichdrall-Doppelschneckenextruder)Dispersing units include dissolvers, kneaders, three-rollers, ball mills, agitator ball mills and extruders (primarily co-rotating twin-screw extruders)
Dissolver kommen bei der Dispergierung von leicht benetzbaren Materialien oder dort, wo keine hohen Feinheitsansprüche bestehen, zum Einsatz. Es ist üblich die meist gezahnte Rührscheibe mit einer Umfangsgeschwindigkeit von 20 - 25m / s laufen zu lassen. Je höher die Umfangsgeschwindigkeit, desto größer sind die Scherkräfte, allerdings steigt die Temperatur dementsprechend an.Dissolvers are used to disperse easily wettable materials or where there are no high demands for fineness. It is customary to let the usually toothed agitator disk run at a peripheral speed of 20 - 25m / s. The higher the peripheral speed, the greater the shear forces, but the temperature rises accordingly.
Erfindungsgemäß besonders bevorzugt werden Kugelmühlen im Verfahren eingesetzt.According to the invention, ball mills are particularly preferably used in the process.
Ausführungsbeispiele:Examples:
Allgemeines Beispiel 1:
- Mühle Retsch MM2 Schwingmühle
- Mahlbecher V=22mL, rostfreier Stahl
- 4 Kugeln, d=10 mm, gehärteter Stahl
- Bedingungen 2 min, (50 % Maximalauslastung) ca. 22-23 Hz
- Ball zu Pulver Verhältnis: 80:1 (16 g zu 0.2 g)
- Stoffmengenverhältnis: 1 eq KBr (200 mg / 1,6806 mmol) zu 0.01 eq (0,0168 mmol) für jedes Molekül (gesamt 0.02 eq)
- Mill Retsch MM2 vibratory mill
- Grinding jar V=22mL, stainless steel
- 4 balls, d=10 mm, hardened steel
- Conditions 2 min, (50% maximum load) approx. 22-23 Hz
- Ball to Powder Ratio: 80:1 (16g to 0.2g)
- Molar ratio: 1 eq KBr (200 mg / 1.6806 mmol) to 0.01 eq (0.0168 mmol) for each molecule (total 0.02 eq)
Allgemeines Beispiel 2:
- Alternativ Pulverisette 7, Achatbecher 22 mL, 4 Achatkugeln (d=10 mm), Mahldauer 2 min, höchste Stufe. Massenverhältnis 1 g anorganische Substanz sowie ca 1,3 mg organische Substanzen, wobei die organischen Substanzen im äquimolaren Verhältnis vorliegen.
- Alternatively Pulverisette 7, agate beaker 22 mL, 4 agate balls (d=10 mm), grinding time 2 min, highest level. Mass ratio 1 g inorganic substance and approx. 1.3 mg organic substances, the organic substances being present in an equimolar ratio.
XRPD Diffractogramme: D-5000 Diffraktometer Siemens (Reflection geometry: von 2Θ = 4° - 35°, Inkrementen 0.02°, Cu-Kalpha, bei 25°C.XRPD diffractograms: D-5000 diffractometer Siemens (Reflection geometry: from 2Θ = 4° - 35°, increments 0.02°, Cu-K alpha, at 25°C.
Beispiel 1 a:Example 1a:
0,0168 mmol Phenazin und 0,0168 Oxalsäure werden mit 200 mg KBr gemäß dem allgemeinen Beispiel für 2 Minuten gemahlen. Das erhaltene Produkt ist lichtempfindlich und wird bei Belichtung violett. Im IR-Spektrum ist ausschließlich das IR-Spektrums des 1: 1 Co-Kristalls aus Phenazin und Oxalsäure zu erkennen.0.0168 mmol of phenazine and 0.0168 of oxalic acid are ground with 200 mg of KBr according to the general example for 2 minutes. The product obtained is light sensitive and turns violet on exposure. Only the IR spectrum of the 1:1 co-crystal of phenazine and oxalic acid can be seen in the IR spectrum.
Beispiel 1b:Example 1b:
0,0168 mmol Phenazin und 0,0168 Oxalsäure werden mit 200 mg NaCl gemäß dem allgemeinen Beispiel für 2 Minuten gemahlen. Das erhaltene Produkt ist lichtempfindlich und wird bei Belichtung violett. Im IR-Spektrum ist ausschließlich das IR-Spektrums des 1: 1 Co-Kristalls aus Phenazin und Oxalsäure zu erkennen.0.0168 mmol of phenazine and 0.0168 of oxalic acid are ground with 200 mg of NaCl according to the general example for 2 minutes. The product obtained is light sensitive and turns violet on exposure. Only the IR spectrum of the 1:1 co-crystal of phenazine and oxalic acid can be seen in the IR spectrum.
Beispiel 1c:Example 1c:
0,0168 mmol Phenazin und 0,0168 Oxalsäure werden mit 200 mg MgO gemäß dem allgemeinen Beispiel für 2 Minuten gemahlen. Das erhaltene Produkt ist lichtempfindlich und wird bei Belichtung violett. Im IR-Spektrum ist ausschließlich das IR-Spektrums des 1: 1 Co-Kristalls aus Phenazin und Oxalsäure zu erkennen.0.0168 mmol phenazine and 0.0168 oxalic acid with 200 mg MgO according to the general milled for 2 minutes. The product obtained is light sensitive and turns violet on exposure. Only the IR spectrum of the 1:1 co-crystal of phenazine and oxalic acid can be seen in the IR spectrum.
Beispiel 1c:Example 1c:
0,0168 mmol Phenazin und 0,0168 Oxalsäure werden mit 200 mg MgSO4 gemäß dem allgemeinen Beispiel für 2 Minuten gemahlen. Das erhaltene Produkt ist lichtempfindlich und wird bei Belichtung violett. Im IR-Spektrum ist ausschließlich das IR-Spektrums des 1: 1 Co-Kristalls aus Phenazin und Oxalsäure zu erkennen.0.0168 mmol of phenazine and 0.0168 of oxalic acid are ground with 200 mg of MgSO 4 according to the general example for 2 minutes. The product obtained is light sensitive and turns violet on exposure. Only the IR spectrum of the 1:1 co-crystal of phenazine and oxalic acid can be seen in the IR spectrum.
Beispiel 2:Example 2:
1,3 mg Phenazin und Oxalsäure werden im Stoffmengenverhältnis von 1 : 1 mit 1 g KBr gemäß dem allgemeinen Beispiel 2 für 2 Minuten gemahlen. Das erhaltene Produkt ist lichtempfindlich und wird bei Belichtung violett. Im IR-Spektrum ist ausschließlich das IR-Spektrums des 1: 1 Co-Kristalls aus Phenazin und Oxalsäure zu erkennen.1.3 mg of phenazine and oxalic acid are ground in a molar ratio of 1:1 with 1 g of KBr according to general example 2 for 2 minutes. The product obtained is light sensitive and turns violet on exposure. Only the IR spectrum of the 1:1 co-crystal of phenazine and oxalic acid can be seen in the IR spectrum.
Beispiel 3:Example 3:
0,0168 mmol Phenazin und 0,0168 meso-1,2-Diphenyl-1,2-ethandiol werden mit 200 mg KBr gemäß dem allgemeinen Beispiel für 2 Minuten gemahlen. Das erhaltene Produkt ist lichtempfindlich und wird bei Belichtung violett. Im IR-Spektrum ist ausschließlich das IR-Spektrums des 1: 1 Co-Kristalls aus Phenazin und meso-1,2-Diphenyl-1,2-ethandiol zu erkennen. IR-Spektrum: 3378, 3256 cm-1.0.0168 mmol of phenazine and 0.0168 mmol of meso-1,2-diphenyl-1,2-ethanediol are ground with 200 mg of KBr according to the general example for 2 minutes. The product obtained is light sensitive and turns violet on exposure. Only the IR spectrum of the 1:1 co-crystal of phenazine and meso-1,2-diphenyl-1,2-ethanediol can be seen in the IR spectrum. IR spectrum: 3378, 3256 cm -1 .
Beispiel 4a:Example 4a:
1,3 mg Phenazin und meso-1,2-Diphenyl-1,2-ethandiol werden im Stoffmengenverhältnis von 1 : 1 mit 1 g KBr gemäß dem allgemeinen Beispiel 2 für 2 Minuten gemahlen. Das erhaltene Produkt ist lichtempfindlich und wird bei Belichtung violett. Im IR-Spektrum ist ausschließlich das IR-Spektrums des 1: 1 Co-Kristalls aus Phenazin und meso-1,2-Diphenyl-1,2-ethandiol zu erkennen. IR-Spektrum: 3378, 3256 cm-1.1.3 mg of phenazine and meso-1,2-diphenyl-1,2-ethanediol are ground in a molar ratio of 1:1 with 1 g of KBr according to general example 2 for 2 minutes. The product obtained is light sensitive and turns violet on exposure. Only the IR spectrum of the 1:1 co-crystal of phenazine and meso-1,2-diphenyl-1,2-ethanediol can be seen in the IR spectrum. IR spectrum: 3378, 3256 cm -1 .
Beispiel 4b:Example 4b:
1,3 mg Phenazin und meso-1,2-Diphenyl-1,2-ethandiol werden im Stoffmengenverhältnis von 1 : 1 mit 1 g MgO gemäß dem allgemeinen Beispiel 2 für 2 Minuten gemahlen. Das erhaltene Produkt ist lichtempfindlich und wird bei Belichtung violett. Im IR-Spektrum ist ausschließlich das IR-Spektrums des 1: 1 Co-Kristalls aus Phenazin und meso-1,2-Diphenyl-1,2-ethandiol zu erkennen. IR-Spektrum: 3378, 3256 cm-1.1.3 mg of phenazine and meso-1,2-diphenyl-1,2-ethanediol are ground in a molar ratio of 1:1 with 1 g of MgO according to general example 2 for 2 minutes. The product obtained is light sensitive and turns violet on exposure. Only the IR spectrum of the 1:1 co-crystal of phenazine and meso-1,2-diphenyl-1,2-ethanediol can be seen in the IR spectrum. IR spectrum: 3378, 3256 cm -1 .
Beispiel 4c:Example 4c:
1,3 mg Phenazin und meso-1,2-Diphenyl-1,2-ethandiol werden im Stoffmengenverhältnis von 1 : 1 mit 1 g MgSO4 gemäß dem allgemeinen Beispiel 2 für 2 Minuten gemahlen. Das erhaltene Produkt ist lichtempfindlich und wird bei Belichtung violett. Im IR-Spektrum ist ausschließlich das IR-Spektrums des 1: 1 Co-Kristalls aus Phenazin und meso-1,2-Diphenyl-1,2-ethandiol zu erkennen. IR-Spektrum: 3378, 3256 cm-1.1.3 mg of phenazine and meso-1,2-diphenyl-1,2-ethanediol in a molar ratio of 1:1 are ground with 1 g of MgSO 4 according to general example 2 for 2 minutes. The product obtained is light sensitive and turns violet on exposure. Only the IR spectrum of the 1:1 co-crystal of phenazine and meso-1,2-diphenyl-1,2-ethanediol can be seen in the IR spectrum. IR spectrum: 3378, 3256 cm -1 .
Beispiel 4d:Example 4d:
1,3 mg Phenazin und meso-1,2-Diphenyl-1,2-ethandiol werden im Stoffmengenverhältnis von 1 : 1 mit 1 g MgCO3 gemäß dem allgemeinen Beispiel 2 für 2 Minuten gemahlen. Das erhaltene Produkt ist lichtempfindlich und wird bei Belichtung violett. Im IR-Spektrum ist ausschließlich das IR-Spektrums des 1: 1 Co-Kristalls aus Phenazin und meso-1,2-Diphenyl-1,2-ethandiol zu erkennen. IR-Spektrum: 3378, 3256 cm-1.1.3 mg of phenazine and meso-1,2-diphenyl-1,2-ethanediol are ground in a molar ratio of 1:1 with 1 g of MgCO 3 according to general example 2 for 2 minutes. The product obtained is light sensitive and turns violet on exposure. Only the IR spectrum of the 1:1 co-crystal of phenazine and meso-1,2-diphenyl-1,2-ethanediol can be seen in the IR spectrum. IR spectrum: 3378, 3256 cm -1 .
Beispiel 4e:Example 4e:
1,3 mg Phenazin und meso-1,2-Diphenyl-1,2-ethandiol werden im Stoffmengenverhältnis von 1 : 1 mit 1 g CaCO3 gemäß dem allgemeinen Beispiel 2 für 2 Minuten gemahlen. Das erhaltene Produkt ist lichtempfindlich und wird bei Belichtung violett. Im IR-Spektrum ist ausschließlich das IR-Spektrums des 1: 1 Co-Kristalls aus Phenazin und meso-1,2-Diphenyl-1,2-ethandiol zu erkennen. IR-Spektrum: 3378, 3256 cm-1.1.3 mg of phenazine and meso-1,2-diphenyl-1,2-ethanediol are ground in a molar ratio of 1:1 with 1 g of CaCO 3 according to general example 2 for 2 minutes. The product obtained is light sensitive and turns violet on exposure. Only the IR spectrum of the 1:1 co-crystal of phenazine and meso-1,2-diphenyl-1,2-ethanediol can be seen in the IR spectrum. IR spectrum: 3378, 3256 cm -1 .
Beispiel 4f:Example 4f:
1,3 mg Phenazin und meso-1,2-Diphenyl-1,2-ethandiol werden im Stoffmengenverhältnis von 1 : 1 mit 1 g (Ca3PO4)4 gemäß dem allgemeinen Beispiel 2 für 2 Minuten gemahlen. Das erhaltene Produkt ist lichtempfindlich und wird bei Belichtung violett. Im IR-Spektrum ist ausschließlich das IR-Spektrums des 1: 1 Co-Kristalls aus Phenazin und meso-1,2-Diphenyl-1,2-ethandiol zu erkennen.1.3 mg of phenazine and meso-1,2-diphenyl-1,2-ethanediol in a molar ratio of 1:1 are ground with 1 g of (Ca 3 PO 4 ) 4 according to general example 2 for 2 minutes. The product obtained is light sensitive and turns violet on exposure. Only the IR spectrum of the 1:1 co-crystal of phenazine and meso-1,2-diphenyl-1,2-ethanediol can be seen in the IR spectrum.
Beispiel 4g:Example 4g:
1,3 mg Phenazin und meso-1,2-Diphenyl-1,2-ethandiol werden im Stoffmengenverhältnis von 1 : 1 mit 1 g CaCl2 gemäß dem allgemeinen Beispiel 2 für 2 Minuten gemahlen. Das erhaltene Produkt ist lichtempfindlich und wird bei Belichtung violett. Im IR-Spektrum ist ausschließlich das IR-Spektrums des 1: 1 Co-Kristalls aus Phenazin und meso-1,2-Diphenyl-1,2-ethandiol zu erkennen.1.3 mg of phenazine and meso-1,2-diphenyl-1,2-ethanediol are ground in a molar ratio of 1:1 with 1 g of CaCl 2 according to general example 2 for 2 minutes. The product obtained is light sensitive and turns violet on exposure. Only the IR spectrum of the 1:1 co-crystal of phenazine and meso-1,2-diphenyl-1,2-ethanediol can be seen in the IR spectrum.
Beispiel 4h:Example 4h:
1,3 mg Phenazin und meso-1,2-Diphenyl-1,2-ethandiol werden im Stoffmengenverhältnis von 1 : 1 mit 1 g Meersalz gemäß dem allgemeinen Beispiel 2 für 2 Minuten gemahlen. Das erhaltene Produkt ist lichtempfindlich und wird bei Belichtung violett. Im IR-Spektrum ist ausschließlich das IR-Spektrums des 1: 1 Co-Kristalls aus Phenazin und meso-1,2-Diphenyl-1,2-ethandiol zu erkennen.1.3 mg of phenazine and meso-1,2-diphenyl-1,2-ethanediol in a molar ratio of 1:1 are ground with 1 g of sea salt according to general example 2 for 2 minutes. The product obtained is light sensitive and turns violet on exposure. Only the IR spectrum of the 1:1 co-crystal of phenazine and meso-1,2-diphenyl-1,2-ethanediol can be seen in the IR spectrum.
Beispiel 4i:Example 4i:
1,3 mg Phenazin und meso-1,2-Diphenyl-1,2-ethandiol werden im Stoffmengenverhältnis von 1 : 1 mit 1 g Speisesalz gemäß dem allgemeinen Beispiel 2 für 2 Minuten gemahlen. Das erhaltene Produkt ist lichtempfindlich und wird bei Belichtung violett. Im IR-Spektrum ist ausschließlich das IR-Spektrums des 1: 1 Co-Kristalls aus Phenazin und meso-1,2-Diphenyl-1,2-ethandiol zu erkennen.1.3 mg of phenazine and meso-1,2-diphenyl-1,2-ethanediol in a molar ratio of 1:1 are ground for 2 minutes with 1 g of table salt according to general example 2. The product obtained is light sensitive and turns violet on exposure. Only the IR spectrum of the 1:1 co-crystal of phenazine and meso-1,2-diphenyl-1,2-ethanediol can be seen in the IR spectrum.
Beispiel 5a:Example 5a:
1,3 mg äquimolare Mengen an Harnstoff und Carbamazepin wurden 2 Min gemäß dem allgemeinen Beispiel 2 mit 1 g KBr vermahlen.1.3 mg equimolar amounts of urea and carbamazepine were ground for 2 minutes according to general example 2 with 1 g KBr.
Das IR-Spektrum des Harnstoffs weist charakteristische Banden bei 3448, 3346, 1683, 1626, 1600 1466 und 1155 cm-1 auf.The IR spectrum of urea shows characteristic bands at 3448, 3346, 1683, 1626, 1600, 1466 and 1155 cm -1 .
Das IR-Spektrum von Carbamazepin weist charakteristische Banden bei 3466, 3161, 1677, 1489 cm-1 auf. Im IR-Spektrum des Co-Kristalls aus Harnstoff und Carbamazepin werden, neben weiteren weniger charakteristischen Banden bei 1684, 1595, 1492 und 1407, die folgenden charakteristische Banden bei 3465, 3191 beobachtet. Zudem sind die intensiven Banden bei 1466 und 1155 cm-1 des Harnstoffs weitgehend verschwunden.The IR spectrum of carbamazepine shows characteristic bands at 3466, 3161, 1677, 1489 cm-1. In the IR spectrum of the co-crystal of urea and carbamazepine, the following characteristic bands at 3465, 3191 are observed in addition to other less characteristic bands at 1684, 1595, 1492 and 1407. In addition, the intense bands at 1466 and 1155 cm -1 of the urea have largely disappeared.
Beispiel 5b:Example 5b:
1,3 mg äquimolare Mengen an Harnstoff und Carbamazepin wurden 2 Min gemäß dem allgemeinen Beispiel 2 mit 1 g NaCl vermahlen. Das IR-Spektrum entspricht dem des Co-Kristalls gemäß Beispiel 5a.1.3 mg of equimolar amounts of urea and carbamazepine were ground for 2 minutes according to general example 2 with 1 g of NaCl. The IR spectrum corresponds to that of the co-crystal according to example 5a.
Beispiel 5c:Example 5c:
1,3 mg äquimolare Mengen an Harnstoff und Carbamazepin wurden 2 Min gemäß dem allgemeinen Beispiel 2 mit 1 g MgO vermahlen. Das IR-Spektrum entspricht dem gemäß Beispiel 5a.1.3 mg equimolar amounts of urea and carbamazepine were ground for 2 minutes according to general example 2 with 1 g MgO. The IR spectrum corresponds to that according to Example 5a.
Beispiel 5d:Example 5d:
1,3 mg äquimolare Mengen an Harnstoff und Carbamazepin wurden 2 Min gemäß dem allgemeinen Beispiel 2 mit 1 g MgSO4 vermahlen. Das IR-Spektrum entspricht dem gemäß Beispiel 5a.1.3 mg equimolar amounts of urea and carbamazepine were ground for 2 minutes according to general example 2 with 1 g MgSO 4 . The IR spectrum corresponds to that according to Example 5a.
Beispiel 6a:Example 6a:
1,3 mg äquimolare Mengen an Harnstoff und Carbamazepin wurden gemäß dem allgemeinen Beispiel 1 für 2 min mit 1 g KBr vermahlen. Es wird ein dem Beispiel 5a entsprechendes IR-Spektrum des Co-Kristalls erhalten.1.3 mg equimolar amounts of urea and carbamazepine were ground according to general example 1 for 2 min with 1 g KBr. An IR spectrum of the co-crystal corresponding to example 5a is obtained.
Beispiel 6b:Example 6b:
1,3 mg äquimolare Mengen an Harnstoff und Carbamazepin wurden gemäß dem allgemeinen Beispiel 1 für 2 min mit 1g KCI vermahlen. Es wird ein dem Beispiel 5a entsprechendes IR-Spektrum des Co-Kristalls erhalten.1.3 mg equimolar amounts of urea and carbamazepine were ground according to general example 1 for 2 min with 1 g KCI. An IR spectrum of the co-crystal corresponding to example 5a is obtained.
Beispiel 6c:Example 6c:
1,3 mg äquimolare Mengen an Harnstoff und Carbamazepin wurden gemäß dem allgemeinen Beispiel 1 für 2 min mit 1g KCI vermahlen. Es wird ein dem Beispiel 5a entsprechendes IR-Spektrum des Co-Kristalls erhalten.1.3 mg equimolar amounts of urea and carbamazepine were ground according to general example 1 for 2 min with 1 g KCI. An IR spectrum of the co-crystal corresponding to example 5a is obtained.
Beispiel 7a:Example 7a:
Rivaroxaban und Malonsäure (5-Chlor-N-({(55)-2-oxo-3- [4-(3-oxo-4-moφholinyl)-phenyl]-1,3-oxazolidin-5-yl}-methyl)-2-thiophencarboxamid (Rivaroxaban) und Malonsäure).Rivaroxaban and malonic acid (5-chloro-N-({(55)-2-oxo-3-[4-(3-oxo-4-moφholinyl)-phenyl]-1,3-oxazolidin-5-yl}-methyl )-2-thiophenecarboxamide (rivaroxaban) and malonic acid).
1,3 mg äquimolare Mengen an Rivaroxaban und Malonsäure wurden gemäß dem allgemeinen Beispiel 1 für 2 min mit 1 g KCI vermahlen. Im XRPD kann ein 2-ThetaWinkel von 15,08 neben Reflexen der Malonsäure beobachtet werden. Werden 1,3 mg im molaren Verhältnis von 2 : 1 mit 1 g NaCl für 2 min vermahlen Rivaroxaban und Malonsäure wird im XRPD ein 2-ThetaWinkel von 15,08 beobachtet. Die vollständige Charackterisierung kann der
Beispiel 7b:Example 7b:
Rivaroxaban und Malonsäure (5-Chlor-N-({(55)-2-oxo-3- [4-(3-oxo-4-moφholinyl)-phenyl]-1,3-oxazolidin-5-yl}-methyl)-2-thiophencarboxamid (Rivaroxaban) und Malonsäure).Rivaroxaban and malonic acid (5-chloro-N-({(55)-2-oxo-3-[4-(3-oxo-4-moφholinyl)-phenyl]-1,3-oxazolidin-5-yl}-methyl )-2-thiophenecarboxamide (rivaroxaban) and malonic acid).
1,3 mg äquimolare Mengen an Rivaroxaban und Malonsäure wurden gemäß dem allgemeinen Beispiel 1 für 2 min mit 1 g NaCl vermahlen. Im XRPD kann ein 2-ThetaWinkel von 15,08 neben Reflexen der Malonsäure beobachtet werden. Werden 1,3 mg im molaren Verhältnis von 2 : 1 mit 1 g NaCl für 2 min vermahlen Rivaroxaban und Malonsäure wird im XRPD ein 2-ThetaWinkel von 15,08 beobachtet. Die vollständige Charackterisierung kann der
Beispiel 8example 8
1,3 mg äquimolare Mengen an Imidacloprid und Oxalsäure wurden gemäß dem allgemeinen Beispiel 1 für 2 min mit 1g KCI vermahlen. Das P-XRD entspricht dem in
Beispiel 9example 9
1,3 mg im molaren Verhältnis von 2 1 von 4-{[(6-Chloyrid-3-yl)methyl](2,2-difluorethyl)armno}furan-2(5H)-on und Oxalsäure wurden gemäß dem allgemeinen Beispiel 1 für 2 min mit 1g KCI vermahlen. Es wurde ein Co-Kristall gemäß
Beispiel 10Example 10
1,3 mg äquimolare Mengen von Metconazol und Thiophanatemethyl wurden gemäß dem allgemeinen Beispiel 1 für 2 min mit 1g KCI vermahlen. Es wurde ein Co-Kristall
Beispiel 11Example 11
1,3 mg äquimolare Mengen von Metazachlor und Pendimethalin wurden gemäß dem allgemeinen Beispiel 1 für 2 min mit 1g MgSO4 vermahlen. Es wurde ein Co-Kristall
Beispiel 12:Example 12:
1,3 mg Phenazin und meso-1,2-Dicyclohexyl-1,2-ethandiol werden im Stoffmengenverhältnis von 1 : 1 mit 1 g KBr gemäß dem allgemeinen Beispiel 2 für 2 Minuten gemahlen. Das erhaltene Produkt ist lichtempfindlich und wird bei Belichtung violett. Im IR-Spektrum ist eine Überlagerung der Edukte.1.3 mg of phenazine and meso-1,2-dicyclohexyl-1,2-ethanediol are ground in a molar ratio of 1:1 with 1 g of KBr according to general example 2 for 2 minutes. The product obtained is light sensitive and turns violet on exposure. In the IR spectrum there is a superimposition of the starting materials.
ZITATE ENTHALTEN IN DER BESCHREIBUNGQUOTES INCLUDED IN DESCRIPTION
Diese Liste der vom Anmelder aufgeführten Dokumente wurde automatisiert erzeugt und ist ausschließlich zur besseren Information des Lesers aufgenommen. Die Liste ist nicht Bestandteil der deutschen Patent- bzw. Gebrauchsmusteranmeldung. Das DPMA übernimmt keinerlei Haftung für etwaige Fehler oder Auslassungen.This list of documents cited by the applicant was generated automatically and is included solely for the better information of the reader. The list is not part of the German patent or utility model application. The DPMA assumes no liability for any errors or omissions.
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Claims (15)
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