Method for increasing solubility

Abstract

The invention relates to a method for providing a water-soluble adduct and an ibuprofen adduct, wherein the membrane permeability of the adduct is improved and the classification according to the Biopharmaceutics Classification System is influenced.

Description

Methods for increasing solubility TECHNICAL AREA

[0001] The invention relates to a method for providing a water-soluble formulation, in particular a water-soluble formulation containing ibuprofen. TECHNICAL BACKGROUND

[0002] Many highly effective pharmaceutical substances, such as curcumin, paracetamol, ibuprofen, tocopherol, artesunate, calcitriol, and taxol, have relatively low water solubility. However, sufficient water solubility is necessary, at least temporarily, to enable rapid and effective distribution throughout the patient's body via the bloodstream. Therefore, it is of interest to develop methods that increase the water solubility of substances, especially those relevant to pharmaceuticals. BRIEF DESCRIPTION OF THE FIGURES

[0003] Fig. 1: Solubility of celecoxib in octanol compared to the corresponding water-soluble formulation of celecoxib according to the invention, Celecluster liquid according to Example 1d or 1e in Table 3. The solubility in octanol serves as a model for membrane permeability.

[0004] Figures 2a and 2b: Octanol solubility of various CeleClusters compared to pure celecoxib and the matrices after 2 and 24 hours. Celecluster liquid corresponds to example 1d or 1e in Table 3, Celecluster solid to example 1c in Table 3. Octanol solubility serves as a model for membrane permeability.

[0005] Fig. 3: Water solubility of various CeleClusters compared to pure celecoxib and the matrices. Celecluster liquid according to example 1d or 1e in Table 3, Celecluster solid according to example 1c in Table 3.

[0006] Figure 4: Two cancer cell lines (A549 = lung cancer cell line; MCF7 = breast cancer cell line) were exposed to paclitaxel and the TaxoCluster solid according to the invention. Concentriome determined at which cell death or impairment of metabolic activity occurs. TaxoCluster solid corresponds to embodiment 1c in Table 3.

[0007] Figure 5: Two cancer cell lines (A549 = lung cancer cell line; MCF7 = breast cancer cell line) were exposed to paclitaxel and to the TaxoCluster liquid I according to the invention, and the concentration at which cell death or impairment of metabolic activity occurs was determined. TaxoCluster liquid I corresponds to embodiment 1e in Table 3.

[0008] Figure 6: Two cancer cell lines (A549 = lung cancer cell line; MCF7 = breast cancer cell line) were exposed to paclitaxel and to the TaxoCluster liquid II according to the invention, and the concentration at which cell death or impairment of metabolic activity occurs was determined. TaxoCluster liquid II corresponds to embodiment 1d in Table 3.

[0009] Figure 7: Solubility in octanol was tested as a model for the membrane permeability of the Taxol formulations. A: Test of TaxoCluster liquid I and paclitaxel after 0.2 and 24 h; B: Test of solubility in octanol after 2 h of TaxoCluster liquid II, TaxoCluster solid, and paclitaxel; C: Test of solubility in octanol after 24 h of TaxoCluster liquid II, TaxoCluster solid, and paclitaxel.

[0010] Figure 8: Solubility of TaxoCluster liquid II, TaxoCluster solid, and paclitaxel in water.

[0011] Figure 9: A: Solubility of TaxoCluster solid over time in octanol. B: Solubility of Taxol over time in octanol. C: Solubility of TaxoCluster liquid II over time in octanol.

[0012] Figure 10: IR spectrum for formulation 3.2.

[0013] Figure 11: IR spectrum for formulation 3.3.

[0014] Figure 12: IR spectrum for formulation 3.4.

[0015] Figure 13: IR spectrum for formulation 3.5.

[0016] Figure 14: IR spectrum of the precipitate from the reaction mixture according to comparative example 1 from W02009 / 006799 A1 .

[0017] Figure 15: IR spectrum paclitaxel (IR spectrum).

[0018] Figure 16: UV / VIS spectrum of the filtrate from comparison example 4.

[0019] Figure 17: UV / VIS spectrum of embodiment 1e.

[0020] Figure 18: Examples of methods according to the invention. SUMMARY OF THE INVENTION

[0021] The invention relates to a method for providing a water-soluble formulation comprising the steps I) a) Addition of at least one solubilizer (LV1) to the sparingly soluble substance (SS) to obtain composition (A); optionally b) Addition of at least one further solubilizer (LV2) to composition (A) to obtain composition (B). wherein the sparingly soluble substance (SS) is optionally dissolved in a water-miscible organic solvent (OL1); optionally the solubilizer (LV1) or (LV2) may be dissolved in water; or II) a) Addition of at least one solubilizer (LV1) to the sparingly soluble substance (SS) to obtain composition (A); optionally b) Addition of at least one further solubilizer (LV2) to composition (A) to obtain composition (B); wherein the solubilizer (LV1) and / or (LV2) may be dissolved in water; wherein step a) is carried out at a temperature of 40 to 90 °C.

[0022] The invention further relates to a method for providing a water-soluble ibuprofen-containing formulation, comprising the steps a) mixing solution F with solution G to obtain solution H; optionally b) mixing solution H with solution I to obtain solution J; wherein solution F comprises water, optionally carbonic acid and / or a base (BA1) and a substance selected from the group consisting of 4-aminobenzoic acid 2-( / V, / \ / -diethylamino)ethyl ester (procaine), 4-aminobenzoic acid ethyl ester (benzocaine), 2-(diethylamino)ethyl-4-amino-2-chlorobenzoate (chloroprocaine), 4-amino-3-butoxybenzoic acid 2-diethylaminoethyl ester (oxybu procaine), (2-(Dimethylamino)ethyl)-4-(butylamino)benzoate (tetracaine), preferably 4-aminobenzoic acid-2-( / V, / \ / -diethylamino- )ethyl ester (procaine) or a pharmaceutically acceptable salt of these substances or a carbonic acid adduct (CA) of these substances; Solution G comprises water, optionally carbon dioxide and a pharmaceutically acceptable salt of ibuprofen; Solution I comprises water as a solvent and at least one solubilizer (LV).

[0022] The method according to the invention enables the conversion of particularly medically relevant compounds that are poorly soluble in water into significantly more water-soluble formulations, as demonstrated in the examples. In addition, the formulations according to the invention also exhibit improved membrane permeability (see Example 2.2). DETAILED DESCRIPTION OF THE INVENTION

[0023] The invention relates to a method for providing a water-soluble formulation comprising the steps: I) a) Addition of at least one solubilizer (LV1) to the sparingly soluble substance (SS) to obtain composition (A); optionally b) Addition of at least one further solubilizer (LV2) to composition (A) to obtain composition (B). wherein the sparingly soluble substance (SS) is optionally dissolved in a water-miscible organic solvent (OL1); optionally the solubilizer (LV1) or (LV2) may be dissolved in water; or II) a) Addition of at least one solubilizer (LV1) to the sparingly soluble substance (SS) to obtain composition (A); optionally b) Addition of at least one further solubilizer (LV2) to composition (A) to obtain composition (B); wherein the solubilizer (LV1) and / or (LV2) may be dissolved in water; wherein step a) is carried out at a temperature of 40 to 90 °C.

[0024] Steps a) and / or b) can be carried out at an elevated temperature, preferably at a temperature of 40 to 90 °C.

[0025] In the context of this invention, an "adduct" is understood to be an isolable compound of at least two molecules, wherein the at least two molecules are preferably held together by non-covalent bonds, such as hydrogen bonds, ionic bonds, or van der Waals bonds. Within the scope of this invention, this relates in particular to adducts of CO2 or carbonic acid to the amines described in this application.

[0026] The formulation is preferably in the form of composition (A), (B), solution (A) or composition (C).

[0027] In the context of this invention, "water-soluble" means that at least 34 to 100 g / l of the solid substance dissolves in water, or preferably 1 ml of the liquid formulations dissolves in 1 ml of water. Preferably, the sparingly soluble substance (SS) has a solubility in water of at most < 0.1 to 33 g / l, more preferably of at most 1 to 10 g / l at 15 to 25 °C. Table 1: The European Pharmacopoeia defines the following solubility categories at 15 °C to 25 °C:

[0028] Preferably, the sparingly soluble substance (SS) is a pharmaceutically active agent or a diagnostic agent.

[0029] Preferably, the poorly soluble substance (SS) is selected from the group consisting of paracetamol, ibuprofen, calcitriol, prednisolone acetate, procaine, atenolol, carbamazepine, amoxicillin, artesunate, tocopherol; vitamin K, curcumin, celecoxib, itraconazole, ritonavir, taxol. Table 2: Drug classes

[0030] Preferably, the organic solvent (OL1) forms a common phase with the water after mixing;

[0031] Preferably the organic solvent (OL1) is selected from the group consisting of acetone, (Ci-Cs)alkyl-OH, DMSO, DMF.

[0032] (Ci-Cs)Alkyl-OH is preferably selected from methanol, ethanol, propanol, butanol, pentanol, more preferably ethanol.

[0033] Preferably, the finished formulation does not contain ethanol.

[0034] Preferably, at least one solubilizer (LV1), (LV2) and / or (LV) selected from the group consisting of polyvinylpyrrolidone (PVP), Tween, polyethylene glycol (PEG) is used.

[0035] Polyethylene glycol (PEG), selected from, is more preferred. where n is an even number between 300 and 600, particularly preferably between 200 and 600, most preferably 400.

[0036] Polyethylene glycol (PEG) selected from is preferred. , where n is an even number between 1000 and 35,000, preferably between 1000 and 3000.

[0037] “Tweens” are ethoxylated sorbitan fatty acid esters. Preferably, a tween comprises one or more compounds according to formula (I). Preferably, the sum of w+x+y+z is an even number between 15 and 30, more preferably 17 to 25, and particularly preferably 20. Preferably, the sum of w+x+y+z is an even number between 15 and 30, more preferably 17 to 25, most preferably 20. R is selected from -COCH2(CH2)nCH3, -COCH2(CH2) o CH2CH=CHCH2(CH2) p CH3. n is an even number between 5 and 20, preferably between 8 and 16, more preferably 9, 13, or 15. o is an even number between 0 and 8, preferably 4 and 7, more preferably 5. p is an even number between 0 and 9, preferably 5 to 8, more preferably 6.

[0038] Preferably, the polyvinylpyrrolidone (PVP) is defined according to the following formula: N HR n The polyvinylpyrrolidone (PVP) preferably has an average molecular weight of 10,000 to 40,000 g / mol, more preferably 15,000 to 35,000 g / mol, even more preferably 24,000 to 33,000 g / mol, and particularly preferably 17,000 to 32,000 g / mol. Where n is 90 to 360, preferably 135 to 315, more preferably 216 to 297, and particularly preferably 153 to 288.

[0039] The procedure may optionally include a further step c): c) Diluting composition (A) or (B) with water, preferably with isotonic NaCl solution, to obtain solution (A).

[0040] The process may optionally include a further step d), drying of composition (A), (B) or solution (A), to obtain composition C.

[0041] The drying in step d) is preferably carried out in i) a drying oven or by ii) lyophilization.

[0042] In one embodiment, the method for providing a water-soluble formulation comprises the steps: a) adding the at least one solubilizer (LV1) dissolved in water to the sparingly soluble substance (SS) dissolved in (OL1) to obtain composition A; optionally c) diluting composition (A) with water; d) drying composition (A) to obtain composition (C).

[0043] In one embodiment, the method for providing a water-soluble formulation comprises the steps: a) adding the at least one solubilizer (LV1) to the sparingly soluble substance (SS) dissolved in (OL1) to obtain composition (A); optionally c) diluting composition (A) with water; d) drying composition (A) to obtain composition (C).

[0044] In one embodiment, the method for providing a water-soluble formulation comprises the steps: a) adding the at least one solubilizer (LV1) to the sparingly soluble substance (SS) dissolved in (OL1) to obtain composition A; b) adding the at least one further solubilizer (LV2) dissolved in water to composition A to obtain composition B; c) diluting composition (A) or (B) with water to obtain solution (A); d) drying solution (A) to obtain composition (C).

[0045] In one embodiment, the method for providing a water-soluble formulation comprises the steps: a) adding the at least one solubilizer (LV1) to the sparingly soluble substance (SS) to obtain composition A; b) adding the at least one further solubilizer (LV2) to composition A to obtain composition B; wherein optionally step b) is carried out at a temperature of 40 to 90 °C.

[0046] In one embodiment, the method for providing a water-soluble formulation comprises the steps: a) adding the at least one solubilizer (LV1), preferably polyethylene glycol, more preferably PEG400, to the sparingly soluble substance (SS), preferably Taxol, to obtain composition A; wherein step a) is carried out at a temperature of 40 to 90 °C.

[0047] In one embodiment, the method for providing a water-soluble formulation comprises the steps: a) Adding three solubilizers (LV1) previously mixed at a temperature of 40 to 90 °C to the sparingly soluble substance (SS), wherein step a) is carried out at a temperature of 40 to 90 °C.

[0037] In one embodiment, the method for providing a water-soluble formulation comprises the steps: a) adding the at least one solubilizer (LV1) to the sparingly soluble substance (SS) dissolved in (OL1), while maintaining composition A; Optional c) Diluting composition A with water, preferably with isotonic NaCl solution, to obtain solution A.

[0038] In one embodiment, the method for providing a water-soluble formulation comprises the steps: a) adding the at least one solubilizer (LV1) dissolved in water to the sparingly soluble substance (SS) dissolved in (OL1), obtaining composition A; c) diluting composition A with water, preferably with isotonic NaCl solution, to obtain solution A.

[0039] Furthermore, the invention comprises a method for providing a water-soluble ibuprofen-containing formulation, comprising the steps a) Mixing solution F with solution G to obtain solution H; optionally b) Mixing solution H with solution I to obtain solution J; wherein solution F comprises water, optionally carbonic acid and / or a base (BA1) and a substance selected from the group consisting of 4-aminobenzoic acid-2-( / V, / \ / -diethylamino-)ethyl ester (procaine), 4-aminobenzoic acid-ethyl ester (benzocaine), 2-(diethylamino)ethyl-4-amino-2-chlorobenzoate (chloroprocaine), 4-amino-3-butoxybenzoic acid-2-diethylaminoethyl ester (oxybu procaine), (2-(dimethylamino)ethyl)-4- (butylamino)benzoate (tetracaine), preferably 4-aminobenzoic acid 2-( / V, / \ / -diethylamino-)ethyl ester (procaine) or a pharmaceutically acceptable salt of these substances or a carbonic acid adduct (KA) of these substances; Solution G comprises water, optionally carbon dioxide and a pharmaceutically acceptable salt of ibuprofen, preferably the sodium salt of ibuprofen; Solution I comprises water as a solvent and at least one solubilizer (LV). (LV) corresponds to the same solubilizers as defined for (LV1) and (LV2), preferably (LV) is PVP.

[0040] Ibuprofen is isobutylphenyl)propionic acid, CAS: 15687-27-1 , 51146-56-6, 51146-57-7.

[0041] Preferably, the mass ratio of the pharmaceutically acceptable ibuprofen salt to the sum of the masses of the carbonic acid adduct or the substance selected from the group consisting of 4-aminobenzoic acid 2-( / V, / / -diethylamino-)ethyl ester (procaine), 4-aminobenzoic acid ethyl ester (benzocaine), 2-(diethylamino)ethyl-4-amino-2-chlorobenzoate (chloroprocaine), 4-amino-3-butoxybenzoic acid 2-diethylaminoethyl ester (oxybuprocaine), (2-(dimethylamino)ethyl)-4-(butylamino)benzoate (tetracaine), preferably 4-aminobenzoic acid 2-( / V, / V-diethylamino-)ethyl ester (procaine) or a pharmaceutically acceptable salt of these substances and optionally the base (BA1) is 2:1 to 1:1, preferably 1:1.

[0042] "Pharmaceutically acceptable salt" includes salts with a pharmaceutically acceptable acid or base. Pharmaceutically acceptable acids include both inorganic acids, for example hydrochloric acid, sulfuric acid, phosphoric acid, diphosphoric acid, hydrobromic acid, iodic acid, and nitric acid, as well as organic acids, for example citric acid, fumaric acid, maleic acid, malic acid, mandelic acid, ascorbic acid, oxalic acid, succinic acid, tartaric acid, benzoic acid, acetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, or p-toluenesulfonic acid. Pharmaceutically acceptable bases include alkali metals (e.g., sodium or potassium) and alkaline earth metals (e.g., calcium or magnesium), hydroxides, and organic bases, e.g., alkylamines, arylalkylamines, and heterocyclic amines.

[0043] The process optionally includes a further step c), drying the solution H or J while retaining the composition D.

[0044] The drying in step c) is preferably carried out in i) a drying oven or by ii) lyophilization.

[0045] The carbonic acid adduct (KA) and its production are also described in application W02019 / 048590A1, to which reference is expressly made here.

[0046] The carbonic acid adduct (KA) comprises carbonic acid, at least one amine (AM) selected from the group consisting of 4-aminobenzoic acid 2-( / V, / -diethylamino)ethyl ester (procaine), 4-aminobenzoic acid ethyl ester (benzocaine), 2-(diethylamino)ethyl-4-amino-2-chlorobenzoate (chloroprocaine), 4-amino-3-butoxybenzoic acid 2-diethylaminoethyl ester (oxybuprocaine), (2-(dimethylamino)ethyl)-4-butylamino)benzoate (tetracaine), preferably 4-aminobenzoic acid 2-( / V, / -diethylamino)ethyl ester (procaine) or a pharmaceutically acceptable salt of these substances, and at least one salt (S), prepareable by a process comprising the steps of: a) providing a solution (J) comprising at least one solvent and dissolved in the at least one solvent CO2 includes, optionally b) dissolving a base (BA) that is not the amine (AM) in solution (J) to obtain solution (J 1 ), c) dissolving the at least one amine (AM) in solution (J) or (J 1 ),d) obtaining the solution (K), e) freezing the solution obtained after completion of step c), e) storing the solution frozen in step d) at -100 to 0 °C for no longer than 4 days.

[0047] The salt (S) is preferably a salt composed of at least one cation selected from Na + , K + , Li + , Mg 2+ , Zn 2+ , Fe 2+ , Fe 3+ and Mn 2+ , more preferred Na + and at least one anion selected from CI Br, JF SO4 2 ; SO3 2 ; HSOT HSO3; 'HCCh', COs 2 ' , PO4 3 HPO4 2 ; H2PO4; SiC>4 4 ', AIO2; SiCh' and / or [AIO2)i2(SiO2)2] 2 ', preferably CI' and Br, especially preferably CI'.

[0048] Preferably, step a) comprises at least one of the following sub-steps: a1) Cooling the solvent, preferably water, to 3 to 8 °C, preferably 5 °C and / or a2) Introducing CO2 into the solvent, preferably to a saturation concentration of 3 to 10 g / l, more preferably to a saturation concentration of 4.5 to 7.5 g / l, preferably the pH of the solution after saturation with CO2 is 3.0 to 6.0, even more preferably < 4.3 to 4.8 and / or a3) Storing the solution (A) at 1 to 10 °C, preferably for at least 30 min, more preferably for at least 50 min, even more preferably for at least 60 min; for a maximum of 5 days (120 h); preferably storage at 3 to 8 °C is preferably for at least 30 min, more preferably for at least 50 min, even more preferably for at least 60 min; for a maximum of 5 days (120 h); preferably step a) includes all sub-steps a1), a2) and a3), preferably the sub-steps a1), a2) and a3) are carried out in the order a2) follows a1) and a3) follows a2).

[0049] The base (BA) in step b) is preferably a hydrogen carbonate or a carbonate, more preferably a hydrogen carbonate, and even more preferably sodium hydrogen carbonate.

[0050] The CO2 content in the solution undergoing step d) is at least 6 g / l, preferably at least 10 g / l, more preferably at least 12 g / l, even more preferably at least 14 g / l and most preferably at least 15 g / l.

[0051] The amine (AM) can also be used in the form of a salt.

[0052] Step c) may comprise at least one of the following sub-steps: c1) dissolving the at least one amine (AM) in solution (J) or (J1) to obtain solution (K) and / or c2) adding solution (J) to solution (K) to obtain solution (K1) and / or c3) enriching solution (K) or (K1) with CO2 and / or c4) storing solution (K) or (K1) at 1 to 10°C, preferably 3 to 8°C, for at least 1 h, preferably 24 h to 120 h, more preferably 24 to 72 h, and / or c5) enriching solution (K) or (K1) with CO2 to a concentration of at least 6 g / l, preferably at least 10 g / l, more preferably at least 12 g / l, even more preferably at least 14 g / l and most preferably at least 15 g / l; where optionally i) the concentration of the amine (AM) in solution (K) or, when carrying out substep c2), in solution (B1) is 0.01 to 0.25 g / ml, preferably 0.03 to 0.20 g / ml, more preferably 0.08 to 0.15 g / ml and / or ii) the pH of solution (K) or (K1) after carrying out step c5) is < 7.0 and / or iii) the ratio of the amine (AM) to the base (BA), when carrying out step b), in solution (K) is 2 to 5, more preferably 3 to 4, more preferably 3.23 to 3.26 [g / g] and / or iv) in step c1) the at least one amine (AM) comprises as an acid addition salt, preferably as a hydrohalide, hydrogen sulfate, hydrogen sulfite, hydrogen phosphate, hydromesylate, hydrotosylate, hydroacetate, hydroformate, hydropropanoate, hydromalonate, hydrosuccinate, hydrofumarate, hydroxalate, hydrotartrate, hydrocitrate, hydromaleate, more preferably as a hydrochloride or hydrobromide. Preferably, step c) comprises all sub-steps c1), c2), c3), c4) and c5). Preferably, the sub-steps c1), c2), c3), c4) and c5) are carried out in the order c2) follows c1), c3) follows c2), c4) follows c3), c5) follows c4).

[0053] In step d): i) the solution (K) or (K1) is preferably frozen at -100 °C to -20 °C, more preferably at -90 °C to -30 °C, even more preferably at -80 °C to -40 °C and most preferably at -70 °C to -50 °C and / or ii) the solution (K) or (K1) is preferably frozen within 0.3 to 60 min, more preferably within 1 to 30 min, even more preferably within 1.1 to 10 min, and most preferably within 1.5 to 5 min and / or iii) the vessel in which the solution (K) or (K1) is rotated during the freezing process, preferably in the cooling medium, at 10 to 1000 rpm, preferably at 50 to 600 rpm, more preferably at 100 to 400 rpm and even more preferably at 100 to 250 rpm and / or iv) the solution (K) or (K1) is preferably frozen at a cooling rate of 10 to 100 K / min, more preferably at 20 to 80 K / min, even more preferably at 30 to 70 K / min and particularly preferably at 40 to 60 K / min.

[0054] In step e): i) the frozen solution (K) or (K1) is preferably stored for 1.5 to 4 days, more preferably for 2.5 to 4 days and / or ii) the frozen solution (K) or (K1) is preferably stored at -50 to 0 °C, more preferably at -30 to -5 °C, even more preferably at -25 to -10 °C, particularly preferably at -20 to -15 °C.

[0055] The process may optionally include a further step f), which is carried out after step e), f) drying the solution stored in step e) to obtain dried carbonic acid adduct (KA), wherein in step f) optionally i) the water is removed from the solution (K) or (K1) to a residual content of < 0.8 wt.%, preferably < 0.1 wt.% based on the total weight of the dried product (C) and / or ii) CO2 not bound in the carbonic acid adduct (KA) is removed from the solution (K) or (K1) to a residual content of < 0.8 wt.%, preferably < 0.1 wt.%.-% based on the total weight of the dried product (C) is removed and / or iii) the drying is carried out by means of lyophilization and / or iv) during drying the pressure is 0.01 to 30 mbar, preferably 0.02 to 20 mbar, more preferably 0.03 to 10 mbar, even more preferably 0.03 to 0.5 mbar and most preferably 0.05 to 0.1 mbar and is preferably maintained throughout the entire drying process and / or v) the pressure during drying according to iv) is reached within 10 h, preferably within 7 h, more preferably within 5 h and most preferably within 4 h from the start of evacuation and / or vi) the temperature during the entire drying in step f) is 0 to 20 °C, preferably 4 to 18 °C, more preferably 8 to 16 °C and / or vii) the total drying time is 10 to 60, preferably 30 up to 55 hours, preferably 41 to 52 hours.

[0056] Furthermore, the invention relates to solution C, which can be produced by the method described above.

[0057] The invention also includes composition D, which can be produced by the method described above.

[0058] A water-soluble formulation comprising: i) 0.25 to 40 wt% of a sparingly soluble substance (SS), based on the total mass of the formulation; and / or ii) 10 to 25 wt% polyethylene glycol based on the total mass of the formulation; and / or iii) 40 to 80 wt% Tween based on the total mass of the formulation. EXAMPLES

[0059] 1. Preparation of the water-soluble formulations Figure 18 shows an overview of exemplary examples of possible embodiments. Tables 3, 4, and 5 show the implementation of individual embodiments of the method according to the invention. Table 3: Examples of different embodiments of the method according to the invention Specific examples of embodiments of the invention, according to the general provisions listed in Table 3: Formulation 1.1: 30 mg ibuprofen are mixed with 2 mL PEG400 and 400 pL TweenßO and dissolved in a water bath at 80 °C. The resulting concentrate is diluted with 6 mL of water to obtain an aqueous ibuprofen solution. Formulation 1.2: 10 mg of curcumin are dissolved in 2 mL of PEG400 in a water bath at 80 °C. An aqueous solution can be obtained from the resulting concentrate by adding 1 mL of water. Formulation 1.3: 100 mg of atenolol are dissolved in 2.5 mL of ethanol, mixed with 2 mL of Ween80 and 10 mL of 50% PEG3000 solution, resulting in a clear solution after the addition of 10 mL of water. This solution is frozen and lyophilized. A white, water-soluble solid will be obtained. Formulation 1.4: 10 mg of oseltamivir are dissolved in 100 pL of ethanol, mixed with 1 mL of 50% PEG3000 solution, and a clear solution is obtained after the addition of 1 mL of water. This is dried in an oven at 90 °C. A white, solid substance, which is water-soluble, will be present. Formulation 1.5: 100 mg of paracetamol are dissolved in 2 mL of ethanol and added to 10 mL of an aqueous PVP solution containing 3.33 g of PVP25. A clear solution is obtained, which is dried in an oven at 90 °C. A water-soluble solid is formed. Formulation 1.6: 100 mg ibuprofen is dissolved in 25 mL of ethanol and added to 50 mL of an aqueous PVP solution containing 5 g of PVP25. This solution is dried in an oven at 90 °C, yielding a water-soluble solid. Formulation 1.7: 15 mg ibuprofen is mixed with 200 pL Tween80 and 1 mL of 50% PEG3000 solution, resulting in a clear solution after the addition of 1 mL of water. This solution is then dried in an oven at 90 °C. A white, water-soluble solid substance will be present. Formulation 1.8: 10 mg of tocopherol are dissolved in 200 pL of ethanol. 400 pL of Tween80 are added and mixed. After adding 2 mL of water, a clear aqueous solution is obtained. Formulation 1.9: Formulation 1.10: 3 mg itraconazole are mixed with 2 mL PEG400, 200 pL Tween80 and 400 pL 30% PVP25 solution. After adding 1.5 mL of water, a clear aqueous solution is obtained. Table 4: Solubility depending on the order of component addition Table 5 shows the improvements achieved in the water solubility of various sparingly soluble substances through the inventive process. Table 5: Improved solubility after application of the inventive method at 15 to 25 °C Drugbank (htps: / / qo.druqbank.com) 3 SDB Carl Roth Table 6: Examples of the solubility of various substances without ethanol or DMSO **) Combination of oseltamivir and voriconazole ***) Combination of procaine and ibuprofen

[0060] 2. Pharmacodynamic and pharmacokinetic testing 2.1 In vitro / intratrometry testing of Taxol vs. various TaxoClusters (water-soluble Taxol adducts) for their activity against two cancer cell lines Two cancer cell lines (A549 = lung cancer cell line; MCF7 = breast cancer cell line) were exposed to Taxol, as well as various Taxol formulations according to the invention, and the concentration at which cell death or impairment of metabolic activity occurs was determined (Figs. 4 to 6). Taxol was tested dissolved in DMSO. TaxoCluster solid corresponds to embodiment 1c in Table 2 TaxoCluster liquid I corresponds to embodiment 1e in Table 3. TaxoCluster liquid II corresponds to embodiment 1d in Table 3. The following could be shown. Table 7: Test results: It was shown that the Taxol formulations according to the invention are at least as effective as Taxol and, in the case of embodiments 1e and 1d, significantly more effective.

[0061] 2.2 Membrane permeability The solubility of the Taxol formulations in octanol was tested as a model for their membrane penetration. The results are shown in Figures 7 to 9. As shown in Figures 7 to 9, the solubility of the Taxol formulations according to the invention in octanol and water is significantly increased. Table 8: Comparison with commercially available Taxol formulations Paclitaxel contains polyoxyl castor oil (Cremophor), which can cause serious allergic reactions. Paclitaxel contains 393 mg of alcohol (ethanol) per ml, corresponding to 39.3% w / v. The amount in 52.5 ml of this medicine is equivalent to 515.8 ml of beer or 206.3 ml of wine. Therefore, the use of paclitaxel should be avoided in cases of liver problems, epilepsy, and alcohol dependence. In addition, co-medication with dexamethasone, diphenhydramine and cimetidine is required. The taxane formulations according to the invention do not have these disadvantages and, based on the in vitro results to date, it is expected that the dosage can be significantly lower than with paclitaxel.

[0062] 3. Formulations containing ibuprofen

[0063] 3.1 Production of the carbonic acid adduct (KA) as also disclosed in W02019 / 048590A1 1.1 Materials: • Amine (AM): 68.8 to 110.1 g of procaine hydrochloride (e.g., pure, for use as a pharmaceutical active ingredient; Ph. Eur. or of a quality suitable for this purpose) • Base (BA): 22.2 to 33.9 g sodium bicarbonate (e.g. pure or of a quality suitable for this purpose), • Solvent: 630 to 900 mL water (Aqua ad iniectiabilia) • CO2: min. 12.0 g / L carbon dioxide from pressurized steel cylinders (CO2 of suitable quality) • Dry ice for preparing freezing mixtures and for cooling • Methanol, used for technical purposes in the preparation of refrigeration mixtures Step a) Water (e.g. Aqua ad iniectiabilia) is filled into a cleaned plastic pressure bottle up to the mark (approx. 800 to 900 mL) and pre-cooled for at least 1 hour in the refrigerator (3 to 8 °C) or by means of external cooling to 5 °C. A carbon dioxide-saturated solution is prepared. For this, CO₂ is introduced into pre-chilled water at intervals under pressure (1.6 to 8 bar). The hissing sound (escaping gas via the pressure relief valve) indicates that the solution is saturated with CO₂. Saturation is checked by weight until 4.0 to 6.0 g of CO₂ (corresponding to 4.5 to 7.5 g / L) are dissolved. The saturated solution has a pH value of < 4.3 to 4.8. This carbonated water is immediately sealed and stored in the refrigerator for at least one hour. Step b) In a second plastic pressure bottle, 21.2 g of sodium bicarbonate is placed, mixed with 320 mL of cooled CO2-containing water and dissolved by swirling. Step c) To this solution, the equivalent amount of solid procaine hydrochloride is added at a constant temperature, forming a nearly neutral solution. After the addition of a further 320 mL of cold, carbonated water, a clear, weakly acidic solution is obtained. The solution is then enriched with CO2. The solution prepared in this way is stored in a refrigerator for at least one hour. The solution is then conditioned again with CO2 until a CO2 concentration of 12 g / L is reached. The pH value is checked using pH indicator strips. The pH value is < 6.6. Step d) Round-bottom flasks are pre-cooled. For freezing, the reaction solution is measured in a pre-cooled graduated cylinder, transferred in portions into round-bottom flasks, and frozen by immersion in a dry ice / methanol freezing mixture (<-60°C) using the shell-freezing method within 1.5–3.5 minutes per flask (-200 rpm). The immersion angle of the flask on the rotary evaporator is set to approximately 40°. Step e) The flasks containing the frozen goods are sealed with a ground glass stopper and stored in a freezer at -15 to -20 °C for 2 to 4 days. Step f) The cooled pistons are encased in pre-cooled polystyrene containers and immediately connected individually to an evacuated (0.060 ± 0.01 mbar, approx. -46 °C, leak test) freeze-drying system via a flexible rubber cone. The valve taps They are carefully opened and the individual flasks are placed under vacuum. Finally, all flasks must be evacuated. To monitor the process, temperature sensors are placed at the bottom of the polystyrene casing, recording the entire temperature profile throughout the drying process. Before the start of lyophilization, the temperature sensors indicate temperatures below -5 °C. During lyophilization, the pressure is 0.07 ± 0.02 mbar. This sublimation pressure is reached within 4 hours and maintained throughout the entire lyophilization period. The cooling chamber is kept at a temperature of 9 to 15 °C throughout the drying process. The endpoint of lyophilization is determined graphically from the temperature profile recordings. The total drying time was a maximum of 52 hours. The dry lyophilisate is transferred to an amber glass jar with a twist-off lid, fitted with a desiccant bag, and stored in a refrigerator at 0 to 15 °C.

[0064] Formulation 3.2 • Materials: o Procainium hydrogen carbonate*NaCl = Lyophilisate of the carbonic acid adduct, as described above (e.g., pure, for use as a pharmaceutical active ingredient; Ph. Eur. or of a quality suitable for this purpose) o Ibuprofen sodium salt (e.g., pure, for use as a pharmaceutical active ingredient; Ph. Eur. or of a quality suitable for this purpose) o Solvent: 850 mL water (e.g., Aqua ad iniectiabilia) o CO2: min. 7.5 g / L carbon dioxide from pressurized steel cylinders (CO2 of suitable quality) o CO2-water: Water (e.g., Aqua ad iniectiabilia) is filled into a cleaned plastic pressurized cylinder up to the mark (approx. 800 to 900 mL) and pre-cooled for at least 1 hour in a refrigerator (3 to 8 °C) or by external cooling to 5 °C. A carbon dioxide-saturated solution is prepared. For this, CO2 is introduced into the pre-cooled water at intervals under pressure (1.6 to 8 bar).The hissing sound (escaping gas through the pressure relief valve) indicates that the solution is saturated with CO2. Saturation is checked by weight until 4.0 to 6.0 g of CO2 (corresponding to 4.5 to 7.5 g / L) are dissolved. The saturated solution has a pH value of < 4.3 to 4.8. This carbonated water is immediately sealed and stored in the refrigerator for at least 1 hour. • 10.43 g of carbonic acid adduct are dissolved in 55 mL of CO2-containing water (pH 6.5 to 7). 6.77 g of ibuprofen sodium salt are dissolved in 55 mL of CO2-containing water (pH 7.5 to 8). The carbonic acid adduct solution (pH 7.5 to 8) is added portionwise to this solution while swirling or stirring and cooling in an ice bath. This solution is frozen, stored at < -15 °C, and then lyophilized. A white, water-soluble solid is obtained.

[0065] Formulation 3.3 A carbonic acid adduct solution is prepared as described above, comprising (Amine (AM): 64.99 g procaine hydrochloride (e.g., pure, for use as a pharmaceutical active ingredient; Ph. Eur. or of a quality suitable for this purpose) Base (BA): 20.01 g sodium bicarbonate (e.g., pure or of a quality suitable for this purpose) Solvent: 530 to 850 mL water (Aqua ad iniectiabilia). CO2: min. 7.5 g / L carbon dioxide from pressurized steel cylinders (CO2 of suitable quality) Carbonated Water: Fill a clean plastic pressure bottle with water (e.g., Aqua ad iniectiabilia) up to the fill line (approx. 800 to 900 mL) and pre-chill it for at least 1 hour in a refrigerator (3 to 8 °C) or using external cooling to 5 °C. Prepare a carbon dioxide saturated solution. To do this, intermittently introduce CO₂ under pressure (1.6 to 8 bar) into the pre-chilled water. The hissing sound (escaping gas via the pressure relief valve) indicates that the solution is saturated with CO₂. Check the saturation by weight until 4.0 to 6.0 g of CO₂ (corresponding to 4.5 to 7.5 g / L) are dissolved. The saturated solution has a pH value of < 4.3 to 4.8. Immediately seal this carbonated water and store it in the refrigerator for at least 1 hour. In a second plastic pressurized bottle, 20.01 g of sodium bicarbonate is placed, mixed with 265 mL of chilled carbonated water, and dissolved by swirling. The equivalent amount of solid procaine hydrochloride is added to this solution at a constant temperature, forming a nearly neutral solution. After adding another 265 mL of cold carbonated water, a clear, weakly acidic solution is obtained. The solution is enriched with CO2. The solution prepared in this way is stored in the refrigerator for at least one hour. 65.5 mL of this solution are added in portions, while cooling in an ice bath, to a solution of 6.7 g ibuprofen sodium salt dissolved in 55 mL of CO2 water (as described above) (pH value: 7 to 7.5). This solution is frozen, stored at < -15 °C, and then lyophilized. A white, water-soluble solid is obtained.

[0065] Formulation 3.4 o = Procainium hydrogen carbonate*NaCl = Lyophilisate of the carbonic acid adduct (e.g., pure, for use as a pharmaceutical active ingredient; Ph. Eur. or of a quality suitable for this purpose) o Ibuprofen sodium salt (e.g., pure, for use as a pharmaceutical active ingredient; Ph. Eur. or of a quality suitable for this purpose) o PVP: 17.16 g PVP (PVP = polyvinylpyrrolidone, also called povidone or povidone) in 20 ml / L water o Solvent: 850 mL water (e.g., Aqua ad iniectiabilia) o CO2: min. 7.5 g / L carbon dioxide from pressurized steel cylinders (CO2 of suitable quality) o CO2-water: Water (e.g., Aqua ad iniectiabilia) is filled into a cleaned plastic pressurized cylinder up to the mark (approx. 800 (up to 900 mL) and pre-cooled for at least 1 hour in a refrigerator (3 to 8 °C) or by external cooling to 5 °C. A carbon dioxide saturated solution is prepared.For this process, CO2 is introduced into the pre-cooled water at intervals under pressure (1.6 to 8 bar). The hissing sound (escaping gas via the pressure relief valve) indicates that the solution is saturated with CO2. Saturation is checked by weight until 4.0 to 6.0 g of CO2 (corresponding to 4.5 to 7.5 g / L) are dissolved. The saturated solution has a pH value of < 4.3 to 4.8. This carbonated water is then immediately sealed and stored in the refrigerator for at least 1 hour. • 10.43g of carbonic acid adduct are dissolved in 55mL of CO2-containing water (pH value: 6.5 to 7) 6.77 g of ibuprofen sodium salt are dissolved in 55 mL of CO2-containing water (pH 7.5 to 8). The carbonic acid adduct solution is added portionwise to this solution while swirling or stirring and cooling in an ice bath. 20 mL of the PVP solution are then added to this solution while continuing to cool and stirring for 10 minutes. This solution is frozen, stored at < -15 °C, and subsequently lyophilized. A white, water-soluble solid is obtained.

[0066] Formulation 3.5 A carbonic acid adduct solution is prepared as described above. (Amin (AM): 64.99 g procaine hydrochloride (e.g., pure, for use as a pharmaceutical active ingredient; Ph. Eur. or of a quality suitable for this purpose) Base (BA): 20.01 g sodium bicarbonate (e.g., pure or of a quality suitable for this purpose). PVP: 17.16g PVP (PVP = polyvinylpyrrolidone, also called polyvidone or povidone) in 20mlL water Solvent: 530 to 850 mL water (Aqua ad iniectiabilia) CO2: min. 7.5 g / L carbon dioxide from pressurized steel cylinders (CÜ2 of suitable quality) CO2 Water: Fill a clean plastic pressurized bottle with water (e.g., Aqua ad iniectiabilia) up to the fill line (approx. 800 to 900 mL) and pre-chill it for at least 1 hour in the refrigerator (3 to 8 °C) or using external cooling to 5 °C. Prepare a carbon dioxide saturated solution. To do this, intermittently introduce CO2 into the pre-chilled water under pressure (1.6 to 8 bar). The hissing sound (escaping gas via the pressure relief valve) indicates that the solution is saturated with CO2. Check the saturation by weight until 4.0 to 6.0 g of CO2 (corresponding to 4.5 to 7.5 g / L) are dissolved. The saturated solution has a pH value of < 4.3 to 4.8. Immediately seal this carbonated water and store it in the refrigerator for at least 1 hour. In a second plastic pressurized bottle, 20.01 g of sodium bicarbonate is placed, mixed with 265 mL of chilled water containing carbon dioxide, and dissolved by swirling. The equivalent amount of solid procaine hydrochloride is added to this solution at a constant temperature, forming a nearly neutral solution. After the addition of another 265 mL of cold, carbonated water, a clear, weakly acidic solution is obtained. The solution is enriched with CO₂. The solution prepared in this way is stored in the refrigerator for at least one hour. 65.5 mL of this solution are added portionwise, while cooling in an ice bath, to a solution of 6.7 g ibuprofen sodium salt dissolved in 55 mL of CCh water (pH: 7 to 7.5). 20 mL of the PVP solution are added to this solution while continuing to cool and stirring for 10 minutes. This solution is frozen, stored at < -15 °C, and then lyophilized. A white, water-soluble solid is obtained.

[0053] 4. Comparative example In W02009 / 006799 A1 a comparative example was revealed: Paclitaxel 30mg Polyethylene glycol 400 300mg Tween - 80 1400 Mannitol 400mg Water for injection 4ml

[0049] Paclitaxel, polyethylene glycol 400, and Tween 80 were mixed and stirred. An aqueous mannitol solution was then added and mixed again. The solution was treated with 0.1% activated carbon and stirred for 20 minutes. After filtration through a 0.8 pm coarse filter and subsequent sterilization through a 0.22 pm membrane, the solution was filled into vials. Part of the solution was stored at room temperature, and the other part was freeze-dried. After one hour at room temperature, the solution became cloudy. The freeze-dried samples were reconstituted with water for injection and were cloudy again after one hour.

[0050] The example was reproduced. Neither before nor after the addition of the activated carbon was a clear solution obtained. Thus, the filtration step removes not only the activated carbon but also undissolved taxol. IR spectroscopy confirmed that the precipitate was undissolved paxlitaxel. Compare Figures 14 and 15. The filtrate was examined by UV / VIS spectroscopy. This revealed that it did not contain the full 30 mg used, but only a fraction of this amount (approximately 11%), see Figure 16. In embodiment 1e according to Table 2, the amount of paxlitaxel used in the corresponding aqueous solutions was detected by UV / VIS spectroscopy, see Figure 17. Furthermore, clear solutions were obtained in the concentrates prepared according to the inventive process with PEG400, which remained clear for at least 4 hours.

Claims

REQUIREMENTS 1. A method for providing a water-soluble adduct comprising the steps I) a) Addition of at least one solubilizer (LV1) to the sparingly soluble substance (SS) to obtain composition (A); optionally b) Addition of at least one further solubilizer (LV2) to composition (A) to obtain composition (B), wherein the sparingly soluble substance (SS) is dissolved in a water-miscible organic solvent (OL1); optionally, the solubilizer (LV1) and / or (LV2) may be dissolved in water; II) a) Addition of at least one solubilizer (LV1) to the sparingly soluble substance (SS) to obtain composition (A); optionally b) Addition of at least one further solubilizer (LV2) to composition (A) to obtain composition (B); wherein the solubilizer (LV1) and / or (LV2) may be dissolved in water; wherein step a) is carried out at a temperature of 40 to 90 °C.

2. A method for providing a water-soluble ibuprofen-containing formulation, comprising the steps a) mixing solution (F) with solution (G) to obtain solution (H); optionally b) mixing solution (H) with solution (I) to obtain solution (J); wherein solution (F) comprises water, optionally carbonic acid and / or a base (BA1) and a carbonic acid adduct (KA); Solution (G) comprises water, optionally carbon dioxide and a pharmaceutically acceptable salt of ibuprofen; Solution (I) comprises water as solvent and at least one solubilizer (LV); wherein the carbonic acid adduct (KA), carbonic acid, and at least one amine (AM) selected from the group consisting of 4-aminobenzoic acid 2-( / V, / \ / -diethylamino-)ethyl ester (procaine), 4-aminobenzoic acid ethyl ester (benzocaine), and 2-(diethylamino)ethyl-4-amino-2-chlorobenzoate (Chloroprocaine), 4-Amino-3-butoxybenzoic acid 2-diethylaminoethyl ester (oxybuprocaine), (2-(dimethylamino)ethyl)-4-(butylamino)benzoate (tetracaine), preferably 4-Aminobenzoic acid 2-( / V, / V-diethylamino)ethyl ester (procaine) or a pharmaceutically acceptable salt of these substances and at least one salt (S), prepareable by a process comprising the steps of: a) providing a solution (J) comprising at least one solvent and CO2 dissolved in the at least one solvent, optionally b) dissolving a base (BA) not corresponding to the amine (AM) in the solution (J) to obtain solution (J1), c) dissolving the at least one amine (AM) in the solution (J) or (J1) to obtain solution (K), d) freezing the solution obtained after completion of step c), e) storing the solution obtained in step d) frozen solution at -100 to 0 °C for no longer than 4 days.

3. The method according to claim 2, wherein i) the salt (S) is a salt composed of at least one cation selected from Na + , K + , Li + , Mg 2+ , Zn 2+ , Fe 2+ , Fe 3+ and Mn 2+ , preferably Na + and at least one anion selected from CI Br, JF SO4 2 ; SO3 2 ; HSCL' HSO3; 'HCCh', CO3 2 ; PO4 3 HPO4 2 ; H2PO4; SiC>4 4 ', AIO2; SiCh" and / or [AIO2)i2(SiO2)2] 2', preferably CI' and Br, particularly preferably CI'; and / or ii) wherein step a) comprises at least one of the following sub-steps: a1) cooling the solvent, preferably water, to 3 to 8 °C, preferably 5 °C and / or a2) introducing CO2 into the solvent, preferably to a saturation concentration of 3 to 10 g / l, more preferably to a saturation concentration of 4.5 to 7.5 g / l, preferably the pH of the solution after saturation with CO2 being 3.0 to 6.0, more preferably < 4.3 to 4.8 and / or a3) storing the solution (A) at 1 to 10 °C, preferably for at least 30 min, more preferably for at least 50 min, more preferably for at least 60 min; for a maximum of 5 days (120 h); preferably the storage is carried out at 3 to 8 °C, preferably for at least 30 min, more preferably for at least 50 min, even more preferably for at least 60 min; up to a maximum of 5 days (120 h); preferably step a) comprises all substeps a1), a2) and a3), preferably substeps a1), a2) and a3) are carried out in the order a2) follows a1) and a3) follows a2); and / or iii) the base (BA) in step b) is a hydrogen carbonate or a carbonate, more preferably a hydrogen carbonate, even more preferably sodium hydrogen carbonate; and / or iv) the CO2 content in the solution undergoing step d) is at least 6 g / l, preferably at least 10 g / l, more preferably at least 12 g / l, even more preferably at least 14 g / l and most preferably at least 15 g / l and the amine (AM) can also be used in the form of a salt; and / or 4. The method according to claim 2 or 3, wherein step c) comprises at least one of the following sub-steps: c1) dissolving the at least one amine (AM) in solution (J) or (J1) to obtain solution (K) and / or c2) adding solution (J) to solution (K) to obtain solution (K1) and / or c3) enriching solution (K) or (K1) with CO2 and / or c4) storing solution (K) or (K1) at 1 to 10°C, preferably 3 to 8°C, for at least 1 h, preferably 24 h to 120 h, more preferably 24 to 72 h, and / or c5) enriching solution (K) or (K1) with CO2 to a concentration of at least 6 g / l, preferably at least 10 g / l, more preferably at least 12 g / l, even more preferably at least 14 g / l and most preferably at least 15 g / l;wherein optionally i) the concentration of the amine (AM) in solution (K) or, when performing step c2), in solution (B1), is 0.01 to 0.25 g / ml, preferably 0.03 to 0.20 g / ml, more preferably 0.08 to 0.15 g / ml and / or ii) the pH of solution (K) or (K1) after performing step c5) is < 7.0 and / or iii) the ratio of the amine (AM) to the base (BA), when performing step b), in solution (K), is 2 to 5, more preferably 3 to 4, even more preferably 3.23 to 3.26 [g / g] and / or iv) in step c1) the at least one amine (AM) is as an acid addition salt, preferably as a hydrohalide, hydrogen sulfate, hydrogen sulfite, hydrogen phosphate, hydromesylate, or hydrotosylate. Hydroacetate, hydroformate, hydropropanoate, hydromalonate, hydrosuccinate, hydrofumarate, hydroxyalate, hydrotartrate, hydrocitrate, hydromaleate, more preferably comprising hydrochloride or hydrobromide; preferably step c) includes all sub-steps c1), c2), c3), c4) and c5); preferably the sub-steps c1), c2), c3), c4) and c5) are carried out in the order c2) follows c1), c3) follows c2), c4) follows c3), c5) follows c4).

5. The method according to claims 2 to 4, wherein in step d): i) the solution (K) or (K1) is frozen at -100 °C to -20 °C, preferably at -90 °C to -30 °C, more preferably at -80 °C to -40 °C and most preferably at -70 °C to -50 °C and / or v) the solution (K) or (K1) is frozen within 0.3 to 60 min, preferably within 1 to 30 min, more preferably within 1.1 to 10 min, more preferably within 1.5 to 5 min and / or vi) the vessel in which the solution (K) or (K1) is located during the freezing process, preferably in the cooling medium, is rotated at 10 to 1000 rpm, preferably at 50 to 600 rpm, more preferably at 100 to 400 rpm and more preferably at 100 to 250 rpm is rotated and / or vii) the solution (K) or (K1) is frozen at a cooling rate of 10 to 100 K / min, preferably at 20 to 80 K / min, more preferably at 30 to 70 K / min and particularly preferably at 40 to 60 K / min.

6. The method according to claims 2 to 5, wherein in step e): i) the frozen solution (K) or (K1) is stored for 1.5 to 4 days, preferably for 2.5 to 4 days and / or ii) the frozen solution (K) or (K1) is preferably stored at -50 to 0 °C, more preferably at -30 to -5 °C, even more preferably at -25 to -10 °C, particularly preferably at -20 to -15 °C.

7. The method according to claims 2 to 6, wherein the method comprises a further step f) carried out after step e), f) drying the solution stored in step e) to obtain dried carbonic acid adduct (KA), wherein in step f) optionally i) the water is removed from the solution (K) or (K1) to a residual content of < 0.8 wt.%, preferably < 0.1 wt.% based on the total weight of the dried product (C) and / or ii) CO2 not bound in the carbonic acid adduct (KA) from solution (K) or (K1) to a residual content of < 0.8 wt.%, preferably < 0.1 wt.%.-% based on the total weight of the dried product (C) is removed and / or iii) the drying is carried out by means of lyophilization and / or iv) during drying the pressure is 0.01 to 30 mbar, preferably 0.02 to 20 mbar, more preferably 0.03 to 10 mbar, even more preferably 0.03 to 0.5 mbar and most preferably 0.05 to 0.1 mbar and is preferably maintained throughout the entire drying process and / or v) the pressure during drying according to iv) is reached within 10 h, preferably within 7 h, more preferably within 5 h and most preferably within 4 h from the start of evacuation and / or vi) the temperature during the entire drying in step f) is 0 to 20 °C, preferably 4 to 18 °C, more preferably 8 to 16 °C and / or vii) the total drying time is 10 to 60, preferably 30 up to 55 hours, preferably 41 to 52 hours.

8. The method according to claim 1, wherein the method comprises a further step c): c) diluting the composition (A) or (B) with water, preferably with isotonic NaCl solution, to obtain solution A.

9. The method according to claims 1 to 8, wherein the method in claim 1 comprises a further step d), drying the composition (A), (B) or the solution (A); or the method in claim 2 comprises a further step c), drying the solution H or J; while retaining the composition (C).

10. The method according to claim 9, wherein the drying is carried out in i) a drying oven or by ii) lyophilization.

11. The method according to claims 1 and 8 to 10, wherein the organic solvent, i) (OL1) is water-soluble and / or forms a common phase with the water after mixing; and / or ii) (OL1) is selected from the group consisting of acetone, (Ci-Cs)alkyl-OH, DMSO, DMF.

12. The method according to claims 1 and 8 to 11, wherein i) one or more than one solubilizer (LV1) and / or (LV2) is selected from the group consisting of polyvinylpyrrolidone (PVP), Tween, polyethylene glycol (PEG) and / or ii) the polyethylene glycol (PEG) is selected from , where n is an even number Number between 1000 and 35,000, preferably between 1000 and 3000 and / or Polyethylene glycol (PEG) is selected from , where n is an even number between 300 and 600, particularly preferably between 200 and 600, most preferably 400; and / or iv) defines the polyvinylpyrrolidone (PVP) according to the following formula: is. Polyvinylpyrrolidone (PVP) preferably has an average molecular weight of 10,000 to 40,000 g / mol, more preferably of 15,000 to 35,000 g / mol, even more preferably of 24,000 to 33,000 g / mol, and particularly preferably of 17,000 to 32,000 g / mol. Where n is 90 to 360, preferably 135 to 315, more preferably 216 to 297, and particularly preferably 153 to 288; and / or v) Tween comprises one or more compounds according to formula (I); preferably the The sum of w+x+y+z must be an even number between 15 and 30, preferably 17 to 25, and especially preferably 20. Preferably, the sum of w+x+y+z is an even number between 15 and 30, more preferably 17 to 25, most preferably 20; R is selected from -COCH2(CH2)nCH3, -COCH2(CH2) o CH2CH=CHCH2(CH2)pCH 3; n is an even number between 5 and 20, preferably between 8 and 16, more preferably 9, 13, or 15. o is an even number between 0 and 8, preferably 4 and 7, more preferably 5. p is an even number between 0 and 9, preferably 5 to 8, more preferably 6.

13. The method according to claims 1 and 8 to 12, wherein the sparingly soluble substance (SS) i) is a pharmaceutically active agent and / or ii) has a solubility in water of at most 10 to 33 g / l at 15 to 25 °C and / or iii) is selected from the group consisting of paracetamol, ibuprofen, calcitriol, prednisolone acetate, procaine, atenolol, carbamazepine, amoxicillin, oxytetracycline, artesunate, tocopherol; vitamin K, curcumin, celecoxib, itraconazole, voriconazole, ritonavir, oseltamivir, Taxol, TEtOHB-DAZA; DOI: 10.1039 / c8dt01038b.

14. The method according to claims 2 to 7 and 9, 10 wherein the base (BA1) is a hydrogen carbonate or a carbonate, more preferably a hydrogen carbonate, even more preferably sodium hydrogen carbonate.

15. The solution (A), producible by the method according to claims 8 and 11 to 14.

16. Composition (C), producible by the process according to claims 9 or 10.

17. A water-soluble formulation comprising i) 0.25 to 40 wt% of a sparingly soluble substance (SS), based on the total mass of the formulation; and / or ii) 10 to 25 wt% polyethylene glycol, based on the total mass of the formulation; and / or iii) 40 to 80 wt% Tween, based on the total mass of the formulation.

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