DE102022104759A1 - Co-crystal screening method, in particular for the production of co-crystals - Google Patents

Abstract

The invention relates to a co-crystal screening method for co-crystals or molecular complexes.

Description

The invention relates to a co-crystal screening method for co-crystals or molecular complexes.

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.

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.

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.

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.

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 .

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.

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.

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.

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.

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.

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.

An inorganic substance is a substance which preferably does not contain any carbon atoms. Preferred inorganic substances include only inorganic components.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Examples of active pharmaceutical ingredients are disclosed in the following patents and are incorporated herein by reference in their entirety for purposes of the screening method of the present invention: U.S.20030158188 , US20030158198 , US20030158198 , US20040157845 , US20040157849 , US20040209884 , US20050009841 , US20050080095 , US20050085512 , WO 02008221 , WO 02030956 , WO 02072536 , WO 02076946 , WO 02090326 , WO 03006019 , WO 03014064 , WO 03022809 , WO 03029199 , WO 03049702 , WO 03053945 , WO 03055484 , WO 03055484 , WO 03055848 , WO 03062209 , WO 03066595 , WO 03068749 , WO 03070247 , WO 03074520 , WO 03080578 , WO03093236 , WO 03095420 , WO 03097586 , WO 03097670 , WO03099284 , WO 04002983 , WO 04007459 , WO 04007495 , WO 0401 1441 , WO 04014871 , WO 04024710 , WO 04028440 , WO 04029031 , WO 04029044 , WO 04033435 , WO 04035533 , WO 04035549 , WO 04046133 , WO 04052845 , WO 04052846 , WO 04054582 , WO 04055003 , WO 04055004 , WO 04056774 , WO 04058754 , WO 04072020 , WO 04072069 , WO 04074290 , WO 04078101 , WO 04078744 , WO 04078749 , WO 04089877 , WO 04089881 , WO 04096784 , WO04099177 , WO04100865 , WO04103281 , WO04108133 , WO04110986 , WO 04111009 , WO 05003084 , WO 05004866 , WO 05007646 , WO 05007648 , WO 05007652 , WO 05009977 , WO 05009980 , WO 05009982 , WO 05009987 , WO 05009988 , WO 05012287 , WO 05014580 , WO 05016915 , WO 05016922 , WO 05030753 , WO 05030766 , WO 05032493 , WO 05033105 other WO 05035471 .

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.

Dispersing units include dissolvers, kneaders, three-rollers, ball mills, agitator ball mills and extruders (primarily co-rotating twin-screw extruders)

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.

According to the invention, ball mills are particularly preferably used in the process.

Examples:

• 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)

General example 1:

• 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)

• 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.

General example 2:

• 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 diffractograms: D-5000 diffractometer Siemens (Reflection geometry: from 2Θ = 4° - 35°, increments 0.02°, Cu-K _alpha, at 25°C.

Example 1a:

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.

Example 1b:

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.

Example 1c:

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.

Example 1c:

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.

Example 2:

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.

Example 3:

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 .

Example 4a:

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 .

Example 4b:

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 .

Example 4c:

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 .

Example 4d:

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 .

Example 4e:

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 .

Example 4f:

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.

Example 4g:

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.

Example 4h:

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.

Example 4i:

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.

Example 5a:

1.3 mg equimolar amounts of urea and carbamazepine were ground for 2 minutes according to general example 2 with 1 g KBr.

The IR spectrum of urea shows characteristic bands at 3448, 3346, 1683, 1626, 1600, 1466 and 1155 cm ^-1 .

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.

Example 5b:

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.

Example 5c:

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.

Example 5d:

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.

Example 6a:

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.

Example 6b:

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.

Example 6c:

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.

Example 7a:

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 equimolar amounts of rivaroxaban and malonic acid were ground according to general example 1 for 2 min with 1 g KCl. In the XRPD, a 2-theta angle of 15.08 can be observed alongside reflections of malonic acid. If 1.3 mg rivaroxaban and malonic acid are ground in a molar ratio of 2:1 with 1 g NaCl for 2 min, a 2-theta angle of 15.08 is observed in the XRPD. The full characterization can the EP2288606A1 be removed.

Example 7b:

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 equimolar amounts of rivaroxaban and malonic acid were ground according to general example 1 for 2 min with 1 g NaCl. In the XRPD, a 2-theta angle of 15.08 can be Reflexes of malonic acid can be observed. If 1.3 mg rivaroxaban and malonic acid are ground in a molar ratio of 2:1 with 1 g NaCl for 2 min, a 2-theta angle of 15.08 is observed in the XRPD. The full characterization can the EP2288606A1 be removed.

example 8

1.3 mg equimolar amounts of imidacloprid and oxalic acid were ground according to general example 1 for 2 min with 1 g of KCl. The P-XRD corresponds to that in EP2418954A1 revealed.

example 9

1.3 mg in a 2:1 molar ratio of 4-{[(6-chloroyrid-3-yl)methyl](2,2-difluoroethyl)amino}furan-2(5H)-one and oxalic acid were prepared according to the general example 1 grind for 2 min with 1g KCI. It became a co-crystal according to EP2493883A1 receive.

Example 10

1.3 mg of equimolar amounts of metconazole and thiophanate-methyl were ground with 1 g of KCl for 2 min according to general example 1. It became a co-crystal EP2117297A1 receive.

Example 11

1.3 mg equimolar amounts of metazachlor and pendimethalin were ground according to general example 1 for 2 min with 1 g MgSO ⁴ . It became a co-crystal EP2346326A2 receive.

Example 12:

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.

QUOTES INCLUDED IN DESCRIPTION

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.

Patent Literature Cited

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• EP 2346326 A2 [0062]

Claims (15)

Co-crystal screening method for the production of co-crystals (molecular complexes) comprising at least two different organic substances, comprising the following steps: i) providing at least two different organic substances, in particular the two substances being 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. procedure after claim 1 , characterized in that the grinding takes place in an electrical dispersing unit, in particular 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 a co-rotating twin-screw extruder a ball mill. procedure after claim 1 or 2 , characterized in that a method for the production of co-crystals (molecular complexes). Procedure according to one of Claims 1 until 3 , characterized in that 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 1: 1, in particular of each +/- up to 15% provided. Procedure according to one of Claims 1 until 4 , characterized in that 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. Procedure according to one of Claims 1 until 5 , characterized in that the method is a screening method for determining the formation of co-crystals from at least two different chemical and organic substances. Procedure according to one of Claims 1 until 6 , characterized in that the at least one inorganic substance comprises an 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 metal salts and/or alkaline earth metal salts of carboxylic acids, fruit acids, hydroxy acids, in particular each independently having 1 to 30 carbon atoms. Procedure according to one of Claims 1 until 7 , characterized in that the at least one inorganic substance comprises 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. Procedure according to one of Claims 1 until 8th , characterized in that 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. Procedure according to one of Claims 1 until 9 , characterized in that in step ii) the grinding and/or grinding takes place continuously or discontinuously for a total of less than 5 hours. Procedure according to one of Claims 1 until 10 , characterized in that in step ii) at least one inorganic substance or a mixture of inorganic substances each with at least one organic pharmaceutical excipient is provided. Composition comprising a co-crystal obtainable by a method according to claim 1 comprising steps i), ii) and iii) and optionally after any of claims 2 until 11 . composition after claim 12 , characterized in that it comprises at least one inorganic substance or a mixture of inorganic substances each with at least one organic pharmaceutical excipient. A pharmaceutical formulation comprising a co-crystal obtainable by a process according to claim 1 comprising steps i), ii) and iii) and optionally after any of claims 2 until 11 and comprising at least one inorganic substance or a mixture of inorganics Substances, each with at least one organic pharmaceutical excipient. Using a co-crystal obtainable by a method according to claim 1 comprising steps i), ii) and iii) and optionally after any of claims 2 until 11 for use as a medicine.