Method for preparing complex of gadobenate dimeglumine in solid form

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a method for preparing a solid form of the compound gadobenate dimeglumine of formula (I) used as a contrast agent for diagnostic visualisation, particularly in magnetic resonant tomography. The presented method involves spray drying of a liquid composition of the above compound. Preferentially, the liquid composition represents an aqueous solution. The invention also refers to a solid powder form of gadobenate dimeglumine prepared by the method described above, a pharmaceutical kit containing this form, and a method for preparing a solid form of 4-carboxy-5,8,11-tris(carboxymethyl)-1-phenyl-2-oxa-5,8,11-triazatridecane-13 acid.

EFFECT: method enables preparing the high-yield and reproducible solid form of gadobenate dimeglumine, which possesses good flowability and dissolution rate.

15 cl, 3 ex

 

The present invention relates to a method for producing solid forms polyaminopolycarboxylate complex of gadolinium in the process of spray drying. This method allows to obtain a solid form of the complex gadobenate of dimeglumine that can be used, for example, as contrast agents in diagnostic imaging.

The level of technology

Contrast agents are substances used to enhance the contrast of structures or fluid in the body in medical imaging. Among the currently used methods of imaging magnetic resonance imaging (MRI) is one of the most important because of its efficacy and safety, and with this end in recent decades developed a number of contrast agents. These contrast agents for MRI include, mainly, the paramagnetic metal (usually gadolinium), which forms chelate complexes with polyaminocarboxylic ligands, including cyclic or acyclic. Examples of these paramagnetic complexes are Gd-DTPA, Gd(HP-DO3A) and Gd-BOPTA. In particular, the last physiologically compatible salt (i.e., dimeglumine salt, see the Merck index, XII edition, 2001, No. 4344), also called "complex gadobenate of dimeglumine", see below formula I is an active ingredient one of the most widely used contrast agents for MRI, known under the trade name MultiHance®.

MultiHance® receive, for example, as described in patent EP 0230893.

It should be noted that the degree of purity for contrast agents, and to pharmaceutical compounds in General is vital. In particular, for pharmaceutical compounds to be injected, the quality standards are indeed highly restrictive to fully comply with all requirements of the competent authorities.

In the field of visualization, respectively, the contrast agent must be received in clean, sustainable, and convenient physical form, and, in most cases, this represents a critical issue and a problem that must be solved for every manufacturer. Suitable physical form must be such that allows, above all, reliable and practical to obtain a connection in final form, ready for the reception, which guarantees safe and prolonged storage of the product.

In this respect, if only possible, it is often desirable solid form chemical compounds. Indeed, when the product is obtained in the form of liquid, or oil, or in a suitable solution or suspension, then use a number of methods of isolation and purification, in order to transform this product is t to the corresponding solid form (see, for example, article Huang and others, Advanced Drug Delivery Reviews, 2004, 56 so, S. 321-334).

Among the known methods of selective deposition of a suitable solution, solvent evaporation, lyophilization and crystallization from a suitable organic solvent or mixture of solvents are some examples of techniques that are widely used in this respect (see, for example, articles TUMJ; 2001, 59(3), 53-59; and Palermo and others, Chemical Reviews, 1968, I. 60, S. 65-93).

The above methods, used separately or even in any combination, used at the present time from laboratory to industrial scale, when the final solid form of a chemical compound is desirable or necessary, for example, for reasons of manufacturability or obtain solid dosage forms of the drug. Generally, stage filtration and final drying, usually under reduced pressure, carried out for the purpose of allocating the specified product in the form of dried solids (as General information, see Takashi and others, Journal of Society of Powdered Technology, 2006, T. 43, No. 12, S. 882-889).

An alternative to the above methods is a method of spray drying, in which a solid connection is allocated, on the basis of the corresponding solution (typically an aqueous solution or suspension using a spray is drying. However, this method suffers from several disadvantages, in particular when applied to molecules with specific chemical properties, such as, for example, organic complexes or similar connection. In fact, you can see some structural and/or chemical and physical changes, including, among others, polymorphic changes, the formation of the solvate or even undesirable glassy form of the product (as General information, see, for example, article Corrigan and others, Thermochimica Acta, 1995, I. 248, C. 245-258).

The authors of the present invention unexpectedly found that, when appropriate liquid composition of the complex gadobenate of dimeglumine subjected to the spray drying procedure, it may be convenient allocation thus obtained solid form with a high and reproducible outputs, and it should be noted that the solid form substantially retains the specifications of the original liquid composition, even when the latter is intended for administration to patients, and, thus, complies with the limitations and conditions required for security reasons.

The invention

The present invention describes a method of obtaining a solid form of compound gadobenate of dimeglumine, characterized in that the liquid composition of the compounds according to the will versaut the spray drying procedure.

The liquid composition is preferably a water composition, preferably an aqueous solution, whose concentration is at least 0.2 M and preferably is in the range from 0.25 M to 0.6 M

The liquid composition serves the spray dryer and sprayed using a nozzle high-pressure or two-fluid nozzle. The rate of flow of the liquid composition depends on the type and scale of the equipment; as an example, and according to a preferred variant implementation, it is set at a level from about 5 g/min to about 13 g/min for equipment laboratory scale, from about 2.5 to 8 kg/h for the installation of a pilot scale, and from about 30 to 80 kg/h for the installation of industrial scale.

The present method is preferably carried out when the inlet temperature (Tentrance) spray dryers ranges from 140°C to 280°C, while the outlet temperature (Toutlet) takes a value between 70°C to 120°C.

In another aspect, the present invention relates to gadobenate of dimeglumine in solid form obtained by the present method is spray drying. Preferably obtained in this way solid form is a powder whose average particle size ranges from approximately 1 μm to approximately the nutrient 200 microns, preferably from about 20 μm to 70 μm.

In the following aspect the present invention relates to a kit of parts comprising gadobenate of dimeglumine obtained in solid form according to the present method, together with a physiologically acceptable aqueous carrier.

Finally, according to an additional aspect, the present invention relates to a method for producing solid forms of the ligand BOPTA, different spray drying a liquid solution of the specified connection.

Detailed description of the invention

The present invention relates to a method for producing solid forms of compounds gadobenate of dimeglumine formula (I):

includes spray drying the liquid composition specified connection.

According to a preferred variant implementation, a spray drier, the liquid composition containing the active ingredient of the formula I, is subjected to:

i) stage of spray,

ii) drying inside the chamber for spray drying using a co-flow of the drying gas at the chosen temperature and, finally,

iii) collection phase thus obtained particles.

If not provided by another condition, the term "solid form" is intended to define the shape, not dissolved and is not suspended in any environment.

The term p is ocess spray is designed to determine the formation of microparticles, usually in the form of droplets, etc., the Term "microparticles" refers to particles whose average diameter is from about 10 μm to 600 μm.

The term "co-directed flow" refers to the way in which the sprayed composition and the drying gas passes through the dryer in the same direction, while the term "liquid composition" means a solution or suspension of the selected connection in any appropriate solvent system, including, for example, organic or inorganic solvent, and mixtures thereof.

Typical examples of these systems solvents are, in particular, water systems, such as purified water (e.g., demineralized, distilled or deionized water and so on), or a mixture of water and miscible with water solvents. Examples miscible with water solvents are, for example, polar solvents, including, but not limited to, lower alcohols (for example, C1-C4), acetone, etc., the Liquid composition is preferably a water composition, preferably water, most preferably purified water.

Gadobenate of dimeglumine formula I is present in the above-mentioned liquid composition in any appropriate amount, such as to prevent clogging of the nozzle. predpochtitelnye concentrations are, at least 0.2 M, preferably from about 0.25 M to about 0.6 M, most preferably from about 0.45 to about 0.55 M (where M means both molarity of a solution).

In more detail, in the present method, the liquid composition is fed into the device at a temperature of from 15°C to 40°C, preferably from approximately 20°to approximately 25°C, and is directed to the process of spraying into the chamber of the spray dryer according to the above stage i), using the known spraying device (located, for example, on the upper part of the specified camera). Examples of suitable spray devices include, among other things, the nozzle high-pressure, rotating or two-fluid nozzle. Especially preferred are two-fluid nozzle or nozzle high pressure.

As for the speed of flow of the liquid composition, the preferred values for the equipment of the laboratory scale approximately from 5 to 13 g/min, preferably from about 8 to 10 g/min, while in the case of the use of this method in a pilot plant feed rate may range from 2500 to 8000 g/h, preferably from about 2800 to 3200 g/h, whereas in the case of its application on an industrial scale feed rate may range from 30 to 80 is g/h, preferably from 35 to 45 kg/h

The term "laboratory scale" designed to determine the quantities of the compounds constituting approximately up to 1 kg, while the terms "experimental setup" and "industrial plant" means the number comprising, as a rule, from 1 kg to 10 kg for the first case and more than 10 kg for the latter.

Sprayed in this way, the liquid composition is then dried in the dryer, using co-directed the flow of drying gas, which is used in the technique in similar procedures, such as, for example, air or nitrogen. According to the present invention, the temperature at the gas inlet (herein denoted "Tentrance") is approximately 140°C to 280°C; preferably, the inlet temperature is from 160°C to 200°C.

Accordingly, the outlet temperature (herein denoted "Toutlet"natural gas is from about 70°C to about 120°C.

Gadobenate of dimeglumine finally get in solid form, preferably by passing it through a cyclone with high conversion (up to 98%) and residual water constituting from approximately 0.7% to approximately 5.5% (calculated by titration according to Karl Fischer (Karl Fisher) and is denoted in this document as "KF"), as described in detail is below in the experimental part of this document.

This method can be carried out using the equipment or installation for spray drying, which is selected from commercially available devices, such as, for example, a spray dryer LAB-PLANT SD-04, or, alternatively, in the case of production on an industrial scale, the experimental set-up MOBILE MINOR™.

As for source material, liquid composition gadobenate of dimeglumine can easily be obtained when reacting polyaminocarboxylic derived 4-carboxy-5,8,11-Tris(carboxymethyl)-1-phenyl-2-oxa-5,8,11-trustregion-13-OIC acid (BOPTA) as ligand and Gd2O3and N-methyl-glucamine (meglumine), as described, for example, in patent EP 0230893 (Bracco Ind. Chimica).

As Gd2O3and meglumin comes on sale, for example, from the company Sigma-Aldrich (PN 278513 and M9179, respectively), while the ligand BOPTA can be obtained according to methods known to the specialist in General practice, for example as described in patent application WO 2007/031390 (Bracco Imaging SpA).

It should be noted that the present method of obtaining gadobenate of dimeglumine spray drying is particularly useful on an industrial scale, because the spray dried form can be obtained by using as solvent water, which is easy to operate, and for which, generally, does not require difficult measures to ensure the of health or safety. Finally, the total time of the process is also very convenient; for example, in the case of equipment of laboratory scale spray drying method allows you to get up to 6-7 g/min solid gadobenate, while in the case of installation on an industrial scale, you can get up to 40 kg/h As is evident from the following experimental part of this document (see, in particular, the section "Example 2: comparative examples), the method according to the present invention advantageously allows to obtain a suitable solid form gadobenate of dimeglumine, and this solid shape that differs from that obtained by other commonly used methods, resulting in solid forms with poor processability, workability (resinous, sticky or glassy solids) and extremely low yields of the products due to requiring large expenditures of time and labor procedures necessary for their retrieval.

Thus, according to further aspect, the present invention relates to spray dried form gadobenate of dimeglumine obtained by the present method is spray drying.

Solid form according to the present invention, in particular, has such distinctive features as good flowability, good stability (up to two years when stored in appropriate services which were i.e., in an inert atmosphere and good wettability and dissolution rate (solid form dissolves in water even at room temperature within a very short period of time, e.g. a few seconds), along with an adjustable average particle size (measured by laser light scattering and is denoted by D(v,0,5), representing the equivalent diameter of 50% of the particles, expressed as a distribution by volume).

In fact, using the preferred spacing of the working conditions of the above-described method, spray drying, get a solid form gadobenate of dimeglumine, characterized in that it is a stable water soluble powder in which the particle size ranges from 1 μm to 200 μm.

Preferably powdered gadobenate receive in the form of a powder in which the particle size is from 10 μm to 150 μm by spray drying of a solution gadobenate having a concentration from 0.2 M to 0.8 m, where the inlet temperature is from 100°C to 250°C.

Preferably, the dried spray gadobenate receive in the form of a powder in which the particle size is from about 20 microns to about 70 microns.

Particles in the specified interval conveniently be obtained preferably by spray drying of a solution gadobenate, the concentration of which ranges from 0.45 is to 0.55 M, when the inlet temperature from 160°C to 180°C, using the nozzle of a high pressure. In addition, the solid product obtained by this method shows high end quality (purity up to 99.9% according to HPLC), because not found any education impurities or thermal decomposition during the process, as well as excellent is the rate of dissolution in water. In this regard it should be noted that powdered gadobenate obtained according to the present invention has optimal characteristics of dissolution, requiring less than 1 ml of water per 1 g of the product at room temperature (i.e., at temperature of from 20°C to 30°C), and easily dissolves in less than one minute.

If required, the solid product can be stored in proper condition without known in the art precautions (for example, protective packaging, such as waterproof bags), in a satisfactory manner, avoiding the formation of by-products or changes in physico-chemical properties of a solid material. In this respect, according to the observations, powdery solid obtained in this way, you can properly store even within two years, maintaining the desired degree of purity and the original physical properties, such as color, solubility, etc., Present in solid form can be formed is about to use in the preparation of pharmaceutical compositions, such as compositions for injection, used as a contrast agent for MRI.

The following aspect of the present invention solid gadobenate of dimeglumine formula I obtained by this method, Packed in a two-part set, preferably for administration by injection. The set can include a first container containing spray dried gadobenate of dimeglumine, and a second container containing a physiologically acceptable aqueous carrier. Examples of suitable carriers are water, usually sterile, containing pyrogenic substances water (also commonly referred to as water for injection), an aqueous solution such as a solution of salt (which can mostly be balanced so that the final product for injection was not hypotonic), or aqueous solutions of one or more regulatory toychest substances, such as salts or sugars, polyalcohols, xylytol, glycols or other non-ionic materials such as polyols (e.g., glucose, sucrose, glycerol, glycols, etc.,). These two sets may include two separate container or double chamber container. In the first case, the container preferably is a traditional sealed membrane vessel, where the vessel containing the solid material, sealed by a membrane, through which one enters the carrier liquid, using a syringe, optional pre-filled. In this case, the syringe is used as the container for the second component, then also use for injection of contrast medium. In the second case, a two-chamber container preferably is a two-chamber syringe, and when the solid material is dissolved and then properly mix or gently shaking the container can be used directly for injection of contrast medium.

According to a further aspect, the present invention relates to the manufacture of the set in which the first container includes an aliquot of the dried spray gadobenate of dimeglumine according to the method described above, which combine a second container comprising an aliquot of a suitable solvent, to obtain a set of parts according to a variant implementation, ready for preparation of a contrast agent injection.

In addition, according to an additional aspect, the present invention relates to a method for producing solid forms of 4-carboxy-5,8,11-Tris(carboxymethyl)-1-phenyl-2-oxa-5,8,11-trustregion-13-OIC acid (ligand BOPTA, as shown in the following formula (II), characterized by spray drying the liquid composition specified connection.

In this respect, in the technique known what about getting solid form BOPTA by numerous kristallizatsii from a mixture of acetone and water in combination with elution on a chromatographic resin, as described, for example, in patent application WO 2007/031390 (Bracco Imaging SpA). In particular, this procedure involves first the selection of wet solid BOPTA and then the final stage of drying under controlled temperature to obtain a final solid product with satisfactory solvent content.

Alternatively, at the present time, the authors of the present invention have found that the selection BOPTA dried in a convenient solid form can be accomplished by dissolving the above-mentioned wet solid BOPTA in the aquatic environment thus, to obtain the aqueous liquid composition, and then directing it to the spray drying procedure. In this way dried solid BOPTA can be easily obtained within a short period of time, avoiding the stage of drying, as described above.

If not specified other conditions, this method can be conveniently implemented using the same device and conditions described above for spray drying gadobenate of dimeglumine.

By analogy, the term "liquid composition" in this additional aspect of the present invention has the same meaning as defined above, i.e., means a solution or suspension of the selected connection (in this case BOPTA) in any appropriate solvent system as above.

Accordingly, a suitable liquid comp is the position BOPTA process for spray drying can be obtained by dissolving the wet BOPTA, obtained according to patent application WO 2007/031390 (Bracco Imaging SpA), in an appropriate solvent system, as described above for the process of spray drying gadobenate of dimeglumine.

Thus, the selection of solid BOPTA is possible to carry out the spray drying of the appropriate liquid solution whose concentration is preferably from 7 wt.% up to 14 wt.% (where wt.% means of mass percentage of compounds in relation to the total weight of the composition), at a temperature at the input device, preferably selected from about 120°C to 160°C and the outlet temperature of approximately 60°C to 95°C.

The rate of flow of the liquid composition is preferably chosen from about 1200 g/h to 2400 g/h at a temperature of feed component from about 40°C to 50°C, using, for example, the experimental setup MOBILE MINOR™.

The obtained solid BOPTA can be conveniently used, for example, to obtain the paramagnetic complexes, for example, to obtain the above gadobenate of dimeglumine, by methods known in the art and previously reported.

As described below in the experimental part of this paper, all the obtained data clearly confirm the consistency and reliability of the method of the present invention, intended for production of solid forms gadobenate of dimeglumine f is rmula I spray drying an appropriate liquid, preferably an aqueous solution. In addition, the solid form obtained by this method, there are distinctive features (e.g., high stability, purity and dissolution rate), which can easily allow it to allocate and store it, and also be included in pharmaceutical kits. Hereinafter the present invention will be illustrated in more detail by way of examples, which are presented in the following experimental part and are not intended as limitations of the scope of the present invention.

Experimental part

Example 1: solid form gadobenate of dimeglumine (formula I), obtained by spray drying

The device used for spray drying:

Spray dryer LAB PLANT SD04 with co-flow, equipped with a two-fluid nozzle.

The experimental set-up MOBILE MINOR™ s co-flow, equipped with a two-fluid nozzle or nozzle high pressure.

Installing SD 12.5 with co-flow, equipped with a nozzle high pressure.

General procedure spray drying gadobenate of dimeglumine.

The solution was applied to the device for spray drying at room temperature through a two-fluid nozzle or the nozzle of a high pressure, which was located on top of the camera, and raspily is in the camera.

At the same time, the camera was breathed hot air to dry the sprayed particles.

Thus obtained powder was then separated from the exhaust air by passing through the cyclone.

The solid substance was collected in the device for sampling, located in the lower part of the chamber.

Tried different conditions (examples 1a-g), in order to optimize the process parameters and also to confirm the reliability of this method.

Example 1a

In a lab setup Lab Plant SD04 downloaded 842 0,485 M aqueous solution gadobenate of dimeglumine formula I, using the following parameters:

Tentrance: 160°C

Toutlet: 87°C

Feed rate: 8 g/min

Received 310 g gadobenate of dimeglumine in the form of a white powder (yield 85%; KF 2,23%).

Example 1b

In a lab setup Lab Plant SD04 downloaded 804 g 0,530 M aqueous solution gadobenate of dimeglumine, using the following parameters:

Tentrance: 160°C

Toutlet: 88°C

Feed rate: 8.8 g/min

Received 333 g gadobenate of dimeglumine in the form of a white powder (yield 91%; KF 1,74%).

Example 1c

In a lab setup Lab Plant SD04 downloaded 790 g 0,348 M aqueous solution gadobenate of dimeglumine formula I, using the following parameters:

Tentrance: 160°C

Toutlet: 88°C

Feed rate: 5.9 g/min

Received 208 is gadobenate of dimeglumine in the form of a white powder (yield of 81.5%; KF 1,36%).

Example 1d

In a lab setup Lab Plant SD04 downloaded 608 g 0,535 M aqueous solution gadobenate of dimeglumine formula, using the following parameters:

Tentrance: 195°C

Toutlet: 95°C

Feed rate: 6,1 g/min

Received 232 g gadobenate of dimeglumine in the form of a white powder (yield of 83.4%; KF 2,95%).

Example 1e

In the experimental setup MOBILE MINOR™ downloaded 1300 g of 0.5 M aqueous solution gadobenate of dimeglumine formula I, using the following parameters:

Tentrance: 190°C

Toutlet: 100°C

Feed speed: 3,9 kg/h

Received 406,1 g gadobenate of dimeglumine in the form of a white powder (yield 97%; KF 2,6%).

Example 1f

In the experimental setup MOBILE MINOR™ has been downloaded 1500 g, 0.5 M aqueous solution gadobenate of dimeglumine formula I, using the following parameters:

Tentrance150°C

Toutlet: 80°C

Feed rate: 3.0 kg/h

Received 608,3 g gadobenate of dimeglumine in the form of a white powder (yield 94%; KF 2,2%).

Example 1g

In the installation for spray drying SD 12.5 downloaded 198 kg 0,48 M aqueous solution gadobenate of dimeglumine formula I, using the following parameters:

Tentrance: 170°C

Toutlet: 100°C

Feed rate: 40,0 kg/h

Got to 75.6 kg gadobenate of dimeglumine in the form of a white powder (yield 91%; KF 1,7%).

Powder of Gadabay is, obtained according to examples 1a-g, can be easily dissolved in aqueous solution within a very short period of time, as indicated in the above description.

Example 2: comparative examples

Solid form gadobenate of dimeglumine formula I, obtained in an alternative way

Comparative example 2a: allocation by water evaporation

In the reactor of 1 liter at 50°C until complete dissolution was stirred BOPTA (73,5 g, 143 mmol), N-methyl-glucamine (53,0 g, 271 mmol) and water (700 ml). Added Gd2O3(26,15 g; 72,1 mmol) and was stirred suspension at 80°C for 75 minutes. Then the mixture was filtered, brought the pH up to 7 and evaporated the solvent in vacuo, getting sticky residue, similar to glue.

The residue was dried at 25°C in vacuum at 1 mm RT. Art. (133 PA) with P2O5getting glassy solid, which was difficult to collect and, if necessary, to re-dissolve due to its toughness.

Comparative example 2b: selection by lyophilization

Liofilizirovanny 100 ml of 0.5 M aqueous solution gadobenate of dimeglumine (obtained according to the procedure described in comparative example 2a), using lyophilizator Christ Alpha 1-4, within 24 hours and getting glassy solid, the extraction of which was difficult and unprofitable, especially if use is for industrial scale quantities.

Comparative example 2c: allocation by deposition

Added drops 5 ml of 0.5 M solution gadobenate of dimeglumine (obtained according to the procedure described in comparative example 2a) to 100 ml of 2-propanol, which was stirred at room temperature.

Deposition in the reactor got sticky resinous solid, the extraction of which was problematic and time-consuming due to adverse consistency solid form.

Comparative example 2d: allocation by deposition

Added drops of 4 ml of 0.5 M solution gadobenate of dimeglumine (obtained according to the procedure described in comparative example 2a) to 100 ml of ethanol was stirred at room temperature.

Deposition was obtained a white resinous solid, but in this case its extraction was problematic and time-consuming due to adverse consistency solid form.

Example 3: the solid form of the ligand BOPTA (formula II), obtained by spray drying

Device for spray drying:

The experimental set-up MOBILE MINOR™ s co-flow, equipped with a two-fluid nozzle or nozzle of high pressure

General procedure spray drying BOPTA

Used the same General procedure as described above, the spray drying procedure gadobenate is meglumine.

The aqueous suspension or solution of the ligand BOPTA was applied at a temperature comprised approximately 45-50°C, the spray dryer with allied air flow, equipped with a two-fluid nozzle.

The aqueous suspension or solution of the ligand BOPTA was obtained by dissolving the appropriate amount of wet solid BOPTA in the aquatic environment. The wet solid BOPTA was obtained in a manner analogous to that described in the aforementioned patent application WO2007/031390.

For General information, 452 g of an aqueous solution of carboxylate sodium salt of N-[2-[(2-amino-ethyl)amino]ethyl]-O-(phenylmethyl)serine (0.43 mol) were loaded into a three-liter vessel containing 92 ml of water. The solution was heated to 55°C and introduced into reaction with 356 g of 80% aqueous solution bromoxynil acid. Maintained pH at 11-12, adding 30 wt.% the sodium hydroxide solution. The reaction was completed after about 5 hours at 55°C and pH 11-12. The solution was cooled to 25°C and brought the pH to 5.5 by adding 34% HCl, resulting in the obtained aqueous solution of the target compound, which was suirable on chromatographic resin, concentrated, acidified and then was led. Obtained after filtration of the wet solid was dissolved in appropriate amount of water and then was subjected to spray drying procedure, to obtain a final dried solid BOPTA.

Example 3a

In the experimental setup MOBILE MINOR™ at 50°C was downloaded 920 g of 14.0 wt.% solution BOPTA, using the following parameters:

Tentrance: 160°C

Toutlet: 73°C

Feed rate: 2400 g/h

Got to 121.5 g BOPTA in the form of a white powder (yield 94%; KF 1,5%).

Example 3b

In the experimental setup MOBILE MINOR™ at 45°C was downloaded 930 g of 14.0 wt.% suspension BOPTA, using the following parameters:

Tentrance: 140°C

Toutlet: 72°C

Feed speed: 1750 g/h

Received 93,8 g BOPTA in the form of a white powder (yield 72%; KF 1,9%).

1. Method of producing solid forms of compounds gadobenate of dimeglumine formula (I)
,
includes spray drying the liquid composition specified connection.

2. The method according to p. 1, in which the specified liquid composition, the concentration is at least 0.2 M

3. The method according to p. 2, in which the specified concentration ranges from 0.45 M to 0.55 M

4. The method according to any of paragraphs.1-3, in which the liquid composition is an aqueous solution.

5. The method according to p. 4, wherein said aqueous solution is a purified water solution.

6. The method according to p. 1, in which the inlet temperature (Tentrance) spray dryers ranges from 140°C to 280°C and outlet temperature (Toutlet) is from 70°C to 120°C.

7. The method according to p. 1, comprising spraying the Jew is the second song on p. 1 using high pressure jets or two-fluid nozzle.

8. Solid powdered form gadobenate of dimeglumine obtained by the method according to any of paragraphs.1-7.

9. Solid form gadobenate of dimeglumine under item 8, characterized in that it is a water-soluble powder comprising gadobenate of dimeglumine, whose particle size ranges from 1 μm to 200 μm.

10. Solid form gadobenate of dimeglumine under item 8, characterized in that the particle size is from 20 μm to 70 μm.

11. Pharmaceutical kit comprising a first container containing spray dried gadobenate of dimeglumine according to any one of paragraphs.8-10, and a second container containing a physiologically acceptable aqueous carrier.

12. The pharmaceutical kit according to p. 11, wherein said physiologically acceptable aqueous carrier is a water for injection.

13. A method of obtaining a solid form of 4-carboxy-5,8,11-Tris(carboxymethyl)-1-phenyl-2-oxa-5,8,11-trustregion-13-OIC acid, characterized by spray drying the liquid composition specified connection.

14. The method according to p. 13, in which the specified liquid composition is an aqueous solution.

15. The method according to PP.13 and 14, in which the concentration of the specified solution is from 7 wt.% up to 14 wt.%.



 

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13 cl, 5 ex

FIELD: nuclear technique.

SUBSTANCE: method involves treatment of an aqueous medium containing isotopes of alkali-earth metal, transient element or heavy metal of atomic mass less 209 with an organic ligand binding one or some isotopes of element to be separated. Ligand is comprised in resin or as a component of ion-exchange resin carrier or forms complex with isotope and it is retained by nano-filtration membrane. Residue comprising complex of isotopes with ligand is separated from filtrate comprising isotopes not formed the complex. For example, ligand represents N-acetamidostyrene ethylenediamine triacetate of the formula: . Invention provides enhancing effectiveness of separation and easy regulating the separation degree. Method is simple, economy and doesn't require volume equipments. Invention can be used in preparing inhibitors or absorbers of neutrons in nuclear reactors.

EFFECT: improved separating method.

35 cl, 10 ex

FIELD: metalloorganic compounds, chemical technology.

SUBSTANCE: invention relates to a method for preparing hexamethylenediamine tetraacetate dicopper (II) by synthesis of intrachelate compounds of metals with organic substances. The end product synthesized by this method can be used as a fungicide and copper trace-element fertilizer in agriculture, trace-element supplement to polyvitamin preparations and fodders for animals, for antibacterial treatment of water, as a catalyst in synthesis of organic substances, for preparing high-temperature semiconductors, for synthesis of other compounds comprising copper (II) with hexamethylenediamine tetraacetic acid. Hexamethylenediamine tetraacetate dicopper (II) is prepared by crystallization from an aqueous solution obtained by mixing hexamethylenediamine tetraacetate and depleted etching solution of printed boards wherein the reaction solution has pH value 1.0-6.5 and hexamethylenediamine tetraacetate and depleted etching solution of printed boards are mixed in the amount providing the mole ratio hexamethylenediamine tetraacetate : copper (II) = 1.0:(1.0-10.0), respectively. Invention provides reducing cost of product, retention of its purity and simultaneous utilization of toxic waste in manufacturing.

EFFECT: improved preparing method.

8 cl, 6 ex

The invention relates to the chemistry of chelate (chelate) metal compounds with organic substances, in particular to a method for monohydrate ethylenediaminetetraacetate copper(II), which can be used for protection against corrosion of equipment in the oil and petrochemical industry, for the preparation of electrolytes chemical and galvanic copper plating, to fight sulfatoxymelatonin bacteria in the circulating water supply systems, as a trace element Supplement multivitamin preparations and animal feed, as a fungicide and copper micronutrients in agriculture, for other complexes of copper(II) with ethylenediaminetetraacetic acid
The invention relates to the chemistry of chelate (chelate) metal compounds with organic substances, in particular to a method for ethylenediaminetetraacetate dimed(II), which can be used for protection against corrosion of equipment in the oil and petrochemical industry, to combat sulfatoxymelatonin bacteria in the circulating water supply systems, as a fungicide and copper micronutrients in agriculture, for the preparation of electrolytes chemical and galvanic copper plating, for other complexes of copper(II) with ethylenediaminetetraacetic acid

The invention relates to agriculture, and is intended for destruction of shellfish

FIELD: chemistry.

SUBSTANCE: invention relates to methods of obtaining formula (I) compound from compounds of formula (III) or (X) . Claimed regioselective method makes it possible to regulate formation of vapour-substituted product, makes it possible to realise reactions in continuous mode without necessity to include stages of purification for separation of isomers.

EFFECT: invention also relates to methods of obtaining intermediate compounds and to compounds applied in claimed methods.

16 cl, 8 ex

FIELD: medicine.

SUBSTANCE: invention refers to new compounds of formula (I) where X is carboxylic acid, carboxylates, carboxylic anhydride, diglyceride, triglyceride, phospholipid, or carboxamides, or to any their pharmaceutically acceptable salt. The invention particularly refers to (4Z, 7Z, 10Z, 13Z, 16Z, 19Z)-ethyl 2-ethyldocosa-4,7,10,13,16,19-hexanoate. The invention also refers to a food lipid composition and to a composition for diabetes, for reducing insulin, blood glucose, plasma triglyceride, for dislipidemia, for reducing blood cholesterol, body weight and for peripheral insulin resistance, including such compounds. Besides, the invention refers to methods for treating and/or preventing diabetes, dislipidemia, peripheral insulin resistance, body weight reduction and/or weight gain prevention, insulin, blood cholesterol, blood glucose and/or plasma triglyceride reduction.

EFFECT: higher clinical effectiveness.

61 cl, 4 tbl, 16 dwg, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing enantiomeric excess of asymmetrically alkynylated α-aminoesters of formula (III) in which R1 and R2 independently denote C1-7-alkyl, optionally substituted with phenyl or trimethylsilyl, or C3-5-cycloalkyl; Y denotes H or a nitrogen atom protecting group. The method involves reaction of α-iminoester of formula (I), in which R1 and Y assume values given for formula III, with an alkyl containing a terminal triple bond, of formula (II), in which R2 assumes values given for formula III, in the presence of a catalyst. The catalyst used contains a transition metal complex CuPF6·4MeCN or CuOTf·0.5C6H6 and a chiral ligand selected from , enantiomers thereof and mixture of enantiomers thereof.

EFFECT: method provides high output of asymmetrically alkynylated α-aminoesters of formula (III), which can be used in synthesis as optically active derivatives of amino acids which do not occur naturally.

3 cl, 3 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to (2R)-2-phenylcarbonyloxypropyl (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate mesylate which is a levodopa prodrug and can be used to treat Parkinson's disease, schizophrenia, cognitive disorders, restless legs syndrome, periodic limp movement disorder, tardive dyskinesia, Huntington's disease, arterial hypertension and excessive diurnal drowsiness. The invention also relates to the crystalline form of the said compound, methods of producing said compound and its crystalline form, pharmaceutical compositions and treatment methods.

EFFECT: highly effective treatment.

46 cl, 6 dwg, 1 tbl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (I) capable of bonding with S1P receptor (specifically EDG-6, preferably EDG-1 and EDG-6), its non-toxic water-insoluble salts or its methyl or ethyl ester.

EFFECT: obtaining compounds which can be used in preventing and/or treating graft rejection, graft-versus-host diseases, autoimmune diseases and allergic diseases.

11 cl, 66 ex

FIELD: chemistry.

SUBSTANCE: described is a compound of formula I , where R1 is C1-C6alkyl; R2 is a radical of formula a, where R6 is C1-C12alkyl, R7 is H, X is O, R3 is -A-B-COOH, where A and B each independently represents a chemical bond, or CDE, where D and E each independently represents H, and each R4 and R5 independently represents H, under the condition that, if R4 is H, R5 is H, R3 is COOH, R2 is a radical of formula a, and R7 is H, R1 is CH3, and XR6 is an unsubstituted OC1-C12alkyl radical, then XR6 is not in the meta-position to (CH2)2-CR1R3(NR4R5), in free form or in form of a pharmaceutically acceptable salt, as well a production method and use thereof primarily during transplantation, as well as pharmaceutical composition containing said compounds.

EFFECT: new compounds have useful biological properties.

7 cl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to levodop prodrugs, their stereoisomers, enantiomers or pharmaceutically acceptable salts and based on them pharmaceutical composition for ensuring slowed levodop release, as well as to versions of their application and methods of obtaining them, compounds can be applied for treatment or prevention of diseases in which levodop application is indicated. In general formula (I): , Q is selected from X-CO-; X is selected from -O- and -NH-; n equals integer number from 2 to 4; each R1 and R2 is independently selected from hydrogen, -OH, C1-4alkyl and substituted C1-4alkyl, where substituting group is -OH; R3 and R4 represent hydrogen; R5 is selected from hydrogen, C1-4alkyl, phenyl, substituted phenyl, where each substituting group is independently selected from C1-6alcoxy, C1-6alkyl, halogen and -OH; C3-8cycloalkyl, pyridyl, substituted pyridyl, where each substituting group is independently selected from C1-6alkyl and C1-6alcoxy; on condition that formula (I) compound is not a derivative of 1,3-dihexadecanoylpropane-1,2,3-triol.

EFFECT: elaboration of pharmaceutical composition for ensuring slowed levodop release.

48 cl, 4 dwg, 32 ex

FIELD: chemistry.

SUBSTANCE: invention describes method of obtaining novel intermediates, which are suitable for synthesis of amino acids, used for obtaining peptide receptor modulators, for instance agonists or partial agonists of said peptide receptors. Such modulators of peptide receptors include, for instance modulators of glucagon-like peptide receptors.

EFFECT: efficiency of application for relief of diabetic condition.

3 cl, 3 ex, 2 dwg

FIELD: chemistry.

SUBSTANCE: described is method of synthesis of glutei acid derivative, usually monatin, in which 4-protected derivative of hydroxypyroglutei acid is subjected to alkylation with use of alkylating agent, obtaining protected in 4-position derivative of hydroxyl-4-alkylglutei acid, then, obtained derivative is subjected to stages of hydrolysis and protective group removal. Protected in 4-position derivative of hydroxypyroglutei acid can be easily obtained from hydroxyprolin. Said 4-protected derivative of hydroxypyroglutei acid is especially suitable for efficient synthesis of monatin with high optic purity, because reaction of alkylation for this derivative can be carried out selectively in 4-position and stereoselectively, and after alkylation said derivative can be easily converted into derivative of glutei acid.

EFFECT: creation of efficient method of obtaining hydroxypyroglutei acid derivative.

47 cl, 3 ex

FIELD: organic synthesis.

SUBSTANCE: invention claims a method for preparing glutamic acid derivatives having general formula (7): in particular such as monatin: (radicals in the formulas are specified in description), for use as sweeteners or intermediates for production of drugs and the like. A method for preparing intermediates used in above method, including preparation of novel intermediates, is also claimed. Method of preparing optically active monatin and relevant intermediates also includes preparation of novel intermediates. More specifically, a method for preparing glutamic acid derivatives or salts thereof comprises preparation of a ketoglutaric acid derivative as precursor of desired glutamic acid derivative via aldol cross-condensation of a pyruvic acid derivative with oxaloacetic acid or pyruvic acid and, if necessary, decarboxylation of condensation product and replacement of carbonyl group of ketoglutaric acid derivative by amino group.

EFFECT: expanded synthetic possibilities in amino acid derivatives class.

24 cl, 26 ex

FIELD: chemistry.

SUBSTANCE: anhydride is a physiologically active substance and can be used, for example, in chemotherapy as a low-toxic agent for inhibiting growth of carcinoma 755 (breast cancer). The object of the present invention is synthesis of a novel mixed anhydride based on dichloroacetic and aminoacetic acid which, for instance, enables to inhibit growth of carcinoma 755 (breast cancer) in monotherapy. The given task is solved through synthesis of a novel mixed anhydride based on dichloroacetic acid and aminoacetic acid of formula 1, which can be used in medical practice as an anti-tumour agent which enables, for example, to inhibit growth of carcinoma 755. The other objective of the invention is designing a method of producing the mixed anhydride based on dichloroacetic acid and aminoacetic acid. This task is solved using a method which involves successive reaction of aminoacetic acid with an alkali metal hydroxide in an aqueous medium followed by treatment of the reaction mass with dichloroacetyl chloride in a chloroalkane solution, acidation of the reaction medium with aqueous hydrochloric acid solution and extraction of the end product using existing techniques. The disclosed compound can be used in medical practice as an anti-tumour compound.

EFFECT: use of said compound in oncological practice inhibits growth of carcinoma.

2 cl, 1 ex

FIELD: organic chemistry, biochemistry, chemical technology.

SUBSTANCE: invention relates to a method for purification of synthetic 5-aminolevulinic (5-amino-4-oxopentaenic) acid hydrochloride (5-ALA) representing endogenous substance and biological precursor of porphyrines in living organism and plants. Preliminary purification of 5-ALA hydrochloride is carried out by electrodialysis of 5-ALA solutions with the concentration 140-300 g/l in current density 0.5-2.0 A/dm2 and at temperature 20-30°C. Proposed method of purification of 5-ALA hydrochloride provides isolating expensive preparation from filtrates and to enhance the content of basic substance in technical 5-ALA hydrolyzate prepared by catalytic and electrochemical methods with the parent content of basic substance 87.0%, not above, that results to enhancing yield of final 5-ALA hydrochloride. Purified substance can be used in research and industrial practice.

EFFECT: improved purifying method.

8 ex

FIELD: analytical methods.

SUBSTANCE: method of determining glycine when developing continuous protein fermentation processes consisting in preparing aqueous solution of glycine followed by extraction and further analysis of organic phase is characterized by that 20-35% by weight of lithium sulfate as salting-out agent is added to aqueous solution of glycine (pH˜5) and then solution is extracted with ternary mixture of hydrophilic solvents: 65-65.5% isopropyl alcohol, 20-20.5% acetone, and 14-15% ethyl acetate at volume ratio of extractant mixture to aqueous salt solution 1:10. Nonaqueous concentrate is further analyzed using potentiometric titration technique.

EFFECT: increased degree of glycine recovery to 98-99% and avoided use of dangerous reagents in organic phase analysis.

1 tbl, 11 ex

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