ES2391197B1 - PROCEDURE FOR OBTAINING RABEPRAZOL SODIUM AMORFO. - Google Patents

Abstract

The present invention relates to a new process for obtaining the amorphous form of rabeprazole sodium salt from the acetone solvate of said salt by treatment in a solvent system formed by a C {sub, 6} -C alkane {sub, 8} and water, and using said process to obtain rabeprazole sodium salt from the acetone solvate thereof.

Description

Procedure for obtaining amorphous rabeprazole sodium.

FIELD OF THE INVENTION

The present invention relates to a new process for obtaining the amorphous form of rabeprazole sodium salt from the acetone solvate of said salt.

BACKGROUND OF THE INVENTION

Rabeprazole, 2 - ({[4- (3-methoxypropoxy) -3-methylpyridin-2-yl] methyl} sulfinyl) -1H-benzimidazole, is an active substance belonging to the class of antisecretory compounds, substituted benzimidazoles, which suppress gastric acid secretion by specific inhibition of the enzyme H + / K + -ATPase (the proton or acid pump). It is marketed formulated as the corresponding sodium salt of formula (I) under the trademark Aciphex®, owned by the company Eisai.

    (I)

Rabeprazole was first described in the family of patents corresponding to European patent application EP 0 268 956 A2. Said document describes a procedure for obtaining the sodium salt of rabeprazole (I), as shown in Scheme 1, by reaction of 2-mercapto-1H-benzimidazole (III) and 2-chloromethyl-4- (3-methoxypropoxy) -3-methylpyridine (II) to yield an intermediate 2 - [(4- (3-methoxypropoxy) -3-methylpyridin-2-yl) methylthio] -1 H -benzimidazole (IV), whose oxidation to 2 - [{(4- ( 3-Methoxypropoxy) -3-methylpyridin-2-yl) methyl} sulfinyl] -1Hbenzimidazole (V) and subsequent treatment with sodium hydroxide leads to the product of interest. The sodium salt of rabeprazole of formula (I) obtained is characterized by a melting point of 141-142 ° C.

Scheme 1

OO

H OR NOT

N

S

SH

+ NNCl

N HN Sulfide

(II) (III) (IV)

OO

Na

H

OR ON O ON S

S N

N NN

Rabeprazole Rabeprazole Sodium Salt

(SAW)

Subsequently, in the European patent application EP 1 000 943 A1 the obtaining of acetone solvates of sulfoxide type compounds is discussed, among which rabeprazole is included. Many sulfoxide compounds and their pharmaceutically acceptable salts are unstable to air, moisture, heat, light, pH, etc. Therefore, during conventional purification steps such as column chromatography and storage, they decompose. This document describes that the use of acetone complexes allows an effective reduction of impurities, as well as the stabilization of the product during storage. Specifically, different examples of obtaining an acetone solvate from rabeprazole sodium salt are described.

It is known that the acetone complex of rabeprazole sodium salt is not suitable for the manufacture of a pharmaceutical composition, therefore it is necessary to transform said acetone complex into rabeprazole sodium salt, to obtain a suitable product for said purpose. It is desirable that the sodium salt of rabeprazole obtained has very small amounts of acetone and / or acetone solvate.

The previous European patent application, EP 1 000 943 A1, discloses a lyophilization process of an aqueous solution of acetone solvate of rabeprazole sodium salt to obtain the amorphous form of said salt. The amorphous form obtained corresponds to the sodium salt of rabeprazole as identified in Japanese patent application JP 2001/039975 A as the melting point compound 141-142 ° C, synthesized by the procedure described in patent application EP 0 268 956 A2. However, from an industrial point of view, the lyophilization process is not an easily applicable methodology, and in addition, high times are required to remove the solvent used to obtain the solution prior to lyophilization (48 hours are described in said European patent).

European patent application EP 1 607 395 A1 describes a process for preparing the amorphous form of rabeprazole sodium salt from the acetone solvate of said salt by removing the solvation acetone by drying preferably at high temperature ( 85-115 ° C) and under reduced pressure. Some examples of this patent eliminate solvation acetone from rabeprazole sodium salt at lower temperatures and under reduced pressure, however, long times are needed to obtain the product of interest. Apart from the fact that the drying processes are preferably carried out at temperatures close to 100 [deg.] C., which causes the degradation and coloring of the final product, the times used in drying hinder the possibility of an effective industrial preparation.

Finally, international patent application WO 2007/023393 A2 describes procedures for obtaining rabeprazole sodium salt by suspending or dissolving acetone solvate from rabeprazole sodium salt in one or more organic solvent systems, total distillation or partial solvent and / or filtration, and drying at temperatures below 100 ° C of the solid obtained by the previous treatment. On the one hand, the procedures described in examples 1 and 2 of the international patent application provide rabeprazole sodium salt with lower purity (: 99.7%, determined by HPLC) than the process of the present application.

The present invention provides a simple and easily applicable method from an industrial point of view, which allows the amorphous form of rabeprazole sodium salt to be obtained effectively from the acetone solvate of said salt with significantly lower amounts of acetone, less than 1000 ppm. . Surprisingly, the inventors have found that the treatment of rabeprazole acetone solvate with a solvent system comprising small amounts of water leads to obtaining the amorphous form of rabeprazole sodium salt with high yield (> 89.5%) , excellent purity (� 99.9%, determined by HPLC) and without color problems. The inventors have proven that water is essential to desolvate the initial product up to the indicated levels and to efficiently remove acetone. In addition, although the instability of rabeprazole sodium salt in contact with water is described and recognized, the product is stable in the aqueous medium used in the present invention.

BRIEF DESCRIPTION OF THE INVENTION

In a first aspect, the present invention provides a method for obtaining the amorphous form of the sodium salt of rabeprazole comprising the following steps:

a) provide acetone solvate with rabeprazole sodium salt;

b) add a solvent mixture consisting of C6-C8 alkane and water;

c) partially distill the solvent mixture;

d) optionally repeat one or more times steps b) and c);

e) optionally add C6-C8 alkane;

f) isolate the amorphous form of rabeprazole sodium salt; Y

g) dry the amorphous form of rabeprazole sodium salt.

DESCRIPTION OF THE FIGURES

Figure 1 shows the differential scanning calorimetry (DSC) curve of the acetone solvate of the rabeprazole sodium salt obtained in example 1.

Figure 2 shows the X-ray diffractogram (XRPD) of an acetone solvate of rabeprazole sodium salt.

Figure 3 shows the differential scanning calorimetry (DSC) curve of the acetone solvate mixture of rabeprazole sodium salt and the amorphous form of rabeprazole sodium salt obtained in example 2.

Figure 4 shows the differential scanning calorimetry (DSC) curve of the amorphous form of rabeprazole sodium salt obtained in example 3.

Figure 5 shows the X-ray diffractogram (XRPD) of the amorphous form of the sodium salt of rabeprazole obtained in example 3.

Figure 6 shows the differential scanning calorimetry (DSC) curve of the amorphous form of rabeprazole sodium salt obtained in example 4.

Figure 7 shows the X-ray diffractogram (XRPD) of the amorphous form of the sodium salt of rabeprazole obtained in example 4.

Figure 8 shows the differential scanning calorimetry (DSC) curve of the amorphous form of rabeprazole sodium salt obtained in example 5.

Figure 9 shows the X-ray diffractogram (XRPD) of the amorphous form of the sodium salt of rabeprazole obtained in example 5.

DETAILED DESCRIPTION OF THE INVENTION

The invention relates to a new process for obtaining the amorphous form of rabeprazole sodium salt by treating rabeprazole acetone solvate with a single solvent system formed by a C6-C8 alkane and small amounts of water.

The first aspect of the present invention is directed to a process for obtaining the amorphous form of the sodium salt of rabeprazole comprising the following steps:

a) provide acetone solvate with rabeprazole sodium salt;

b) add a solvent mixture consisting of C6-C8 alkane and water;

c) partially distill the solvent mixture;

d) optionally repeat one or more times steps b) and c);

e) optionally add C6-C8 alkane;

f) isolate the amorphous form of rabeprazole sodium salt; Y

g) dry the amorphous form of rabeprazole sodium salt.

The first stage of the process, step a) comprises the provision of acetone solvate of rabeprazole sodium salt. Obtaining said solvate can be carried out by procedures described in the state of the art, such as those described in EP 1 000 943 A1.

In the second stage of the process, step b), a mixture of solvents consisting of a C6-C8 alkane and water is added to the acetone solvate of the rabeprazole sodium salt provided in the previous stage. C6-C8 alkanes suitable for this step are selected from linear, branched or cyclic alkanes, such as n-octane, n-heptane, isoheptane, n-hexane, isohexane, cyclohexane and mixture thereof. Preferably, the alkane is n-heptane.

In a preferred embodiment of the invention, the ratio of C6-C8 alkane and water of the solvent mixture of step b) is 5 to 15 mL of C6-C8 alkane and 0.01 to 0.1 mL of water with respect to each gram of acetone solvate provided in step a). Preferably the alkane is n-heptane.

In a more preferred embodiment of the invention, the solvent mixture of step b) contains 7 to 13 mL of C6-C8 alkane and 0.01 to 0.1 mL of water relative to each gram of acetone solvate provided. in stage a). Preferably the alkane is n-heptane.

In another preferred embodiment of the invention, the volume of water of the solvent mixture of step b) is 0.03 to 0.07 mL relative to each gram of acetone solvate provided in step a).

Therefore, in one embodiment of the invention the solvent mixture of step b) contains 5 to 15 mL of C6-C8 alkane and 0.03 to 0.07 mL of water with respect to each gram of solvate of acetone provided in step a). Preferably the alkane is n-heptane.

In another embodiment of the invention the solvent mixture of step b) contains 7 to 13 mL of C6-C8 alkane and 0.03 to 0.07 mL of water with respect to each gram of acetone solvate provided in step a ). Preferably the alkane is n-heptane.

The third stage of the process, step c), is the partial distillation of the solvent mixture. In a particular embodiment, said distillation is carried out at a temperature below 50 ° C, preferably at a temperature in the range of 30 to 35 ° C. It is part of the usual practice of the person skilled in the art to determine the appropriate pressure to perform the partial distillation, according to the selected temperature and the solvent mixture added in step b) (mainly depending on the C6-C8 alkane used). In a particular embodiment, the distillation will be carried out at a pressure below 200 mbar, preferably at a pressure below 150 mbar when the C6-C8 alkane is n-heptane.

By partial distillation, in the context of the present invention, it is understood that a volume of solvent less than 100% of the volume of the solvent mixture added in step b) is distilled. In a preferred embodiment of the invention, between 25% and 85% of the volume of the solvent mixture added in step b) is distilled.

The next stage, step d), is optional and consists of the repetition one or more times of the steps b) and c), that is, first of all a mixture of the mixture obtained in the previous stage, stage c) is added. solvents consisting of C6-C8 alkane and water, followed by a partial distillation of the solvent mixture. This process of addition-distillation of a solvent mixture can be repeated one or more times, for example once, twice, three or four times. In a particular embodiment of the invention, step d) is performed once.

The solvent mixture added at this stage is formed by a C6-C8 alkane, preferably the same as that used in step b), and water.

C6-C8 alkanes suitable for this step are selected from linear, branched or cyclic alkanes, such as n-octane, n-heptane, isoheptane, n-hexane, isohexane, cyclohexane and mixture thereof. Preferably, the alkane is n-heptane.

In one embodiment of the invention, the ratio of C6-C8 alkane and water of the solvent mixture of step d) is 3 to 15 mL of C6-C8 alkane and 0.01 to 0.1 mL of water relative to to each gram of acetone solvate provided in step a). Preferably the alkane is n-heptane.

In another embodiment, the solvent mixture of step d) contains 3 to 8 mL of C6-C8 alkane and 0.01 to 0.1 mL of water relative to each gram of acetone solvate provided in step a) . Preferably the alkane is n-heptane.

In another embodiment, the volume of water in the solvent mixture of step d) is 0.03 to 0.07 mL per gram of acetone provided in step a). Therefore, the proportion of C6-C8 alkane and water of the solvent mixture of step d) may be 3 to 15 mL of C6-C8 alkane and 0.03 to 0.07 mL of water relative to each gram of acetone solvate provided in step a). Also, the ratio of C6-C8 alkane and water of the solvent mixture of step d) can also be 3 to 8 mL of C6-C8 alkane and 0.03 to 0.07 mL of water with respect to each gram of acetone solvate provided in step a).

The next step in step d) is the partial distillation of the solvent mixture. In a particular embodiment of the present invention the distillation is carried out at a temperature below 50 ° C, preferably at a temperature in the range of 30 to 35 ° C. The selection of the appropriate pressure is part of the usual practice of the person skilled in the art. In a particular embodiment of the present invention, distillation will be carried out at a pressure below 200 mbar, preferably at a pressure below 150 mbar when the C6-C8 alkane is n-heptane.

By partial distillation, it is understood that a volume of solvent less than 100% of the volume of the solvent mixture added in step d) is distilled. In a particular embodiment of the present invention, more than 80% of the volume of the solvent mixture added in step d) is distilled.

The next stage, step e), is optional and consists of the addition of C6-C8 alkane to the residue obtained in the previous stage, steps c) or d). In a particular embodiment of the present invention, the volume of C6-C8 alkane added at this stage is less than 10 mL relative to each gram of acetone solvate of the rabeprazole sodium salt provided in step a). Even more preferably it is comprised between 5 and 8 mL with respect to each gram of acetone solvate of the rabeprazole sodium salt provided in step a).

C6-C8 alkanes suitable for this step are selected from linear, branched or cyclic alkanes, such as n-octane, n-heptane, isoheptane, n-hexane, isohexane, cyclohexane and mixture thereof. Preferably, the alkane is n-heptane.

In one embodiment of the invention, after the addition of the C5-C8 alkane to the residue obtained in steps c) or d), the resulting suspension is cooled, preferably at a temperature below 20 ° C. Even more preferably at a temperature in the range of 5 to 15 ° C.

The next stage of the procedure, step f), is to isolate the amorphous form of rabeprazole sodium salt. This step can be carried out by any conventional method known to a person skilled in the art to isolate a solid from a solvent or a mixture of solvents. Suitable methods for isolating the amorphous form of rabeprazole sodium salt are, for example, filtration, decantation and centrifugation.

In a particular embodiment, the amorphous form of rabeprazole sodium salt is isolated by filtration.

The last stage of the procedure, stage g), is the drying of the amorphous form of the sodium salt of rabeprazole. The amorphous form of the sodium salt of rabeprazole isolated in step f) is subjected to a drying process. This step can be carried out by any conventional method known to a person skilled in the art. Drying can be carried out, for example, at atmospheric pressure or at reduced pressure, that is, at a pressure below atmospheric, preferably at a pressure below 100 mbar. Preferably, the temperature at which drying is performed is below 80 ° C, preferably between 50 and 75 ° C.

In the present invention the term "alkane" refers to a linear, branched and / or cyclic hydrocarbon consisting of carbon and hydrogen atoms, which does not contain unsaturation.

The terms "rabeprazole sodium salt", "amorphous form of rabeprazole sodium salt", "rabeprazole sodium" or "amorphous rabeprazole sodium" or "amorphous form of rabeprazole sodium" are used interchangeably in the present invention and are referred to in all cases to the amorphous form of rabeprazole sodium salt.

In order to facilitate the understanding of the preceding ideas, some examples of the experimental procedures and embodiments of the present invention are described below. These examples are merely illustrative.

EXAMPLES

In the experimental part the following abbreviations are used:

HPLC high performance liquid chromatography (from English High-Performance Liquid Chromatography)

DSC differential scanning calorimetry (Differential Scanning Calorimetry)

XRPD X-ray powder diffraction (X-Ray Powder Diffraction)

Analysis methods

HPLC

The analysis is performed on a Waters 2690 Mod. Alliance chromatograph with a 2487 dual UV wavelength detector, equipped with a 5 µm 25 x 0.46 cm Octadecylsilyl column. Parameters: flow rate 1 mL / min, temperature 30 ºC, detection at 285 nm, volume injected 20! L And analysis time of 50 min.

Gas chromatography by Head Space

The analysis is performed on a Thermo Mod chromatograph. Finnigan Focus GC equipped with a Static HeadSpace automatic system and Rtx-1301 30 m x 0.53 mm ID column. Parameters: oven temperature 40-150 ° C, ramp 10 ° C / min, injector temperature 140 ° C, detector temperature 250 ° C, sample incubation temperature 50 ° C, incubation time 30 min and injected volume 1 mL.

DSC

A Mettler Toledo 822e device with STARe SW8.01 software is used. Parameters: heating range is 50 to 350 ° C with a ramp of 10 ° C / min and N2 flow of 50 mL / min. The measurement is made with closed perforated capsule.

XRPD

X-ray powder diffraction patterns were measured on a Bruker D-8 Advance 28/8 Series X-ray powder diffractometer, equipped with a Copper anode. Parameters: scanning performed in 1 hour in a range of 4-40 degrees 28. Approximately 20 mg of sample is used.

ES 2 391 197 1 Obtaining acetone solvate from rabeprazole sodium salt

Example 1

In a reactor, 24 kg of a 30% aqueous solution of NaOH, 320 L of isopropyl alcohol and about 66 kg of rabeprazole were loaded. The reaction mixture was maintained at a temperature between 15 and 20 ° C and subsequently the resulting solution was filtered. A vacuum of less than 100 mbar was applied and distilled at a temperature below 40 ° C until a thick mass was obtained. Subsequently, 50 L of isopropyl alcohol were charged and distilled again maintaining the same vacuum conditions and temperature. 50 L of acetone were charged and the distillation process was repeated.

Then 150 L of acetone were charged and the resulting reaction mass was cooled to a temperature between 0 and 5 ° C. The solid was filtered to finally obtain 56 kg corresponding to the acetone solvate of the rabeprazole sodium salt.

The product thus obtained has a DSC corresponding to Figure 1. The XRPD pattern of an acetone solvate of rabeprazole sodium salt is shown in Figure 2.

Reference Example

Example 2

19.3 g moist (approximately 15.4 g dry) of acetone solvate of rabeprazole sodium salt and 150 mL of n-heptane were loaded into a reaction flask. A vacuum of less than 150 mbar was connected and the reaction mass was carefully heated under vigorous stirring at a temperature between 30 and 35 ° C. An approximate volume of 50 mL of solvent was distilled.

Subsequently, 50 mL of n-heptane were recharged and, maintaining the indicated conditions of vacuum and temperature, approximately 30 mL of solvent was distilled off.

After distillation, 60 mL of n-heptane was charged and the resulting reaction mass was cooled to a temperature of 20 ° C. It was filtered to obtain wet 14.3 g of a solid having a DSC corresponding to that presented in Figure 3 (mixture of acetone solvate and amorphous form of rabeprazole sodium salt).

Examples of obtaining the amorphous form of rabeprazole sodium salt

Example 3

In a reaction flask 32.3 g wet (approximately 25.1 g dry) of acetone solvate of rabeprazole sodium salt, 250 mL of n-heptane and 1.5 mL of water were charged. A vacuum of less than 150 mbar was applied and the reaction mass was carefully heated under vigorous stirring at a temperature between 30 and 35 ° C. A volume of 100 mL of solvent was distilled off.

Subsequently, 100 mL of n-heptane and 1 mL of water were recharged and, maintaining the above conditions of vacuum and temperature, 100 mL of solvent was distilled. A control of the reaction mass by DSC indicates the presence of amorphous form, without observing a signal corresponding to the initial acetone solvate, as shown in Figure 4.

After the distillation, 200 mL of n-heptane was recharged, the reaction mass was cooled to a temperature between 5 and 10 ° C and the solid present therein was filtered. Wet 22.5 g of the rabeprazole sodium salt were obtained, which were dried under vacuum at a temperature between 60 and 70 ° C for 8 hours to finally obtain 19.9 g of the rabeprazole sodium salt (yield 92%). The product thus obtained has an XRPD pattern corresponding to the amorphous form as shown in Figure 5.

Example 4

128.6 g moist (approximately 100 g dry) of the acetone solvate of rabeprazole sodium salt, 1250 mL of n-heptane and 10 mL of water were charged into a reaction flask. A vacuum of less than 150 mbar was applied and the reaction mass was carefully heated under vigorous stirring at a temperature between 30 and 35 ° C. An approximate volume of 400 mL of solvent was distilled.

Subsequently, 400 mL of n-heptane and 10 mL of water were recharged and, maintaining the above conditions of vacuum and temperature, 400 mL of solvent was distilled. A control of the reaction mass by DSC indicates the presence of amorphous form, without observing a signal corresponding to the initial acetone solvate, as shown in Figure 6.

After the distillation, 600 mL of n-heptane was recharged, the reaction mass was cooled to a temperature between 10 and 15 ° C and the solid present therein was filtered. 99 g wet of rabeprazole sodium salt were obtained, which were dried under vacuum at a temperature between 55 and 60 ° C for 8 hours to finally obtain 77.7 g of rabeprazole sodium salt (yield 89.5%). The product thus obtained has an XRPD pattern corresponding to the amorphous form as shown in Figure 7.

Example 5

73 kg of wet (approximately 62 kg dry) of acetone solvate from the

5 rabeprazole sodium salt, 600 L of n-heptane and 2 L of water. A vacuum of less than 150 mbar was applied and the reaction mass was carefully heated under vigorous stirring at a temperature between 30 and 35 ° C. An approximate volume of 400 L of solvent was distilled.

Subsequently, 400 L of n-heptane and 2 L of water were recharged and, while maintaining the above conditions of vacuum and temperature, 400 L of solvent was distilled. A control of the reaction mass by DSC indicates the presence of amorphous form, without signal corresponding to the solvate of

Initial acetone, as shown in Figure 8.

After the distillation, the reaction mass was cooled to a temperature between 15 and 20 ° C and the solid present therein was filtered. 61 kg wet of rabeprazole sodium salt were obtained. Analysis by Head Space gas chromatography of a representative sample indicates a value of 1030 ppm of acetone

15 residual in the wet product.

The wet product was dried in a vacuum oven at a temperature between 50 and 55 ° C for 20 hours to finally obtain 50 kg of the rabeprazole sodium salt (93% yield). Analysis by Head Space gas chromatography of a representative sample indicates a value of 222 ppm of residual acetone in the wet product. The product thus obtained has an XRPD pattern corresponding to the amorphous form, such

20 as shown in figure 9.

The purity of rabeprazole sodium salt obtained by the method described in the examples is 99.9% or higher according to HPLC analyzes.

Claims (14)

one.

A process for obtaining the amorphous form of the sodium salt of rabeprazole comprising the following steps: a) providing the acetone solvate of the sodium salt of rabeprazole; b) add a solvent mixture consisting of C6-C8 alkane and water; c) partially distill the solvent mixture; d) optionally repeat one or more times steps b) and c); e) optionally add C6-C8 alkane;

f) isolate the amorphous form of rabeprazole sodium salt; Y g) dry the amorphous form of rabeprazole sodium salt.

2.

The process according to claim 1 wherein the solvent mixture added in step b) contains 5 to 15 mL of C6-C8 alkane and 0.01 to 0.1 mL of water with respect to 1 g of acetone solvate of the sodium salt of rabeprazole provided in step a); and the solvent mixture added in step d) contains 3 to 15 mL of C6-C8 alkane and 0.01 to 0.1 mL of water relative to 1 g of acetone solvate of the rabeprazole sodium salt provided in stage a).

3.

The process according to claim 2 wherein the volume of C6-C8 alkane added in step b) is 7 to 13 mL with respect to 1 g of acetone solvate of the rabeprazole sodium salt provided in step a).

Four.

The process according to any of the preceding claims wherein the volume of C6-C8 alkane added in step d) is 3 to 8 mL with respect to 1 g of acetone solvate of the rabeprazole sodium salt provided in step a).

5.

The process according to any of the preceding claims wherein the volume of water added in step b) is 0.03 to 0.07 mL with respect to 1 g of acetone solvate of the rabeprazole sodium salt provided in step a) .

6.

The process according to any of the preceding claims wherein the volume of water added in step d) is 0.03 to 0.07 mL with respect to 1 g of acetone solvate of the rabeprazole sodium salt provided in step a) .

7.

The process according to any of the preceding claims wherein the C6-C8 alkane is selected from the group consisting of n-octane, n-heptane, isoheptane, n-hexane, isohexane, cyclohexane or mixture thereof.

8.

The process according to claim 7 wherein the C6-C8 alkane is n-heptane.

9.

The process according to any of the preceding claims wherein the partial distillation of steps c) and d) is carried out at a temperature below 50 ° C.

10.

The method according to claim 9 wherein the partial distillation is carried out in the temperature range between 30 and 35 ° C.

eleven.

The process according to any of the preceding claims wherein the volume of solvent distilled in step c) corresponds to 25% to 85% of the volume of the solvent mixture added in step b).

12.

The process according to any of the preceding claims wherein the volume of solvent distilled in step d) is greater than 80% of the volume of the solvent mixture added in step d).

13.

The method according to any of the preceding claims in which step f) is carried out by filtration.

 Lin (accounts)  Lin (accounts) ºC 12 14 18 20 22 24 26 28 min  Lin (accounts) 900008000070000600005000040000300002000010000 30 2-Theta - scale  Lin (accounts) SPANISH OFFICE OF PATENTS AND BRANDS SPAIN REPORT ON THE STATE OF THE TECHNIQUE 51 Int. Cl.: See Additional Sheet twenty-one NAO application: 201130657 22 Date of submission of the application: 27A04A2011 32 Date of priority: RELEVANT DOCUMENTS

Category

56 Documents cited Claims Affected

X

WO 2007023393 A2 (MEDICHEM, SAAA) 01A03A2007, 1-13

page 1, paragraph 2; page 7, paragraphs 3.4; page 11, example 1A

TO

WO 2008155780 A2 (MATRIX LABORATORIES LTDA) 24A12A2008, 1-13

page 1, lines 5-7; pa9ina 6, line 20 - pa9ina 7, line 10A

TO

EP 1000943 A1 (EISAI COA, LTDA) 17A05A2000, 1-13

paragraphs [0021] - [0022], examples

TO

WO 2010004571 A2 (HETERO RESEARCHS FOUNDATION) 14A01A2010, 1-13

page 1, lines 3-6; page 2, lines 16-27A

Category of the documents cited X: of particular relevance Y: of particular relevance combined with other / s of the same category A: reflects the state of the art O: refers to unwritten disclosure P: published between the priority date and the date of priority submission of the application E: previous document, but published after the date of submission of the application

This report has been produced • for all claims • for claims No:

Date of realization of the report 26A09A2012

Examiner GA Esteban Garcia Page 1/4

TECHNICAL STATUS REPORT Application NO: 201130657 CLASSIFICATION OBJECT OF THE APPLICATION C07D401 / 12 (2006A01) A61K31 / 4439 (2006A01) A61P1 / 04 (2006A01) Minimum documentation sought (classification system based on classification symbols) C07D, A61K, A61P Electronic databases consulted during the search (name of the database and, if possible, terms of search used) INVENES, EPODOC, WPI, TXTE, REGISTRY, CAPLUS, MEDLINE, BIOSIS, XPESP, NPL, EMBASE, PUBMED State of the Art Report Pa9ina 2/4  WRITTEN OPINION Application NO: 201130657 Date of Written Opinion: 26A09A2012 Statement

Novelty (Art. 6.1 LP 11/1986)

Claims 1-13 Claims IF NOT

Inventive activity (Art. 8.1 LP11 / 1986)

Claims Claims 1-13 IF NOT

The application is considered to comply with the industrial application requirement A This requirement was evaluated during the formal and technical examination phase of the application (Article 31A2 Law 11/1986) A  Opinion Base.- This opinion has been made on the basis of the patent application as published. State of the Art Report Pa9ina 3/4  WRITTEN OPINION Application NO: 201130657  1. Documents considered.- Below are the documents pertaining to the state of the art taken into consideration for the realization of this opinion.

Document

Publication or Identification Number publication date

D01

WO 2007023393 A2 (MEDICHEM, SAAA) 01A03A2007

 2. Statement motivated according to articles 29.6 and 29.7 of the Regulations for the execution of Law 11/1986, of March 20, on Patents on novelty and inventive activity; quotes and explanations in support of this statement The object of the invention is a process for obtaining the amorphous form of the sodium salt of rabeprazole comprising a first stage of preparing the acetone solvate of said sodium salt. Document D01 disclosed a process for the preparation of rabeprazole sodium salt in amorphous form (see page 1, paragraph 2) from the acetone complex of rabeprazole sodium salt, by suspending it in a solvent, which may be , among others, n-pentane, n-hexane, n-heptane, cyclohexane and mixtures thereof; total or partial filtration or distillation of the solvent; optional repetition of the previous stages; and drying of the product obtained (see page 7, paragraphs 3 and 4) A This procedure allows yields of 87% to be obtained, the purity of the product obtained being 99A4% (see page 11, example 1) A The difference between the procedure disclosed in document D01 and the process of the invention is that in the latter the solvent system used includes a small proportion of water. However, there does not appear to be a significant technical effect associated with the use of water in systems. solvents, since the yield and purity values of the product obtained in the process of the invention are the same or as described in the procedure set forth in document D01A Therefore, in the absence of an advantage associated technique, it is not possible to recognize inventive activity for the process object of claim 1A In the same way, the dependent claims, which refer to specific reaction conditions of the procedure, do not contain technical characteristics that, in combination with the characteristics of claim 1, upon which they depend, comply with the existence of the Patent Law regarding inventive activity Therefore, it is considered that the object of claims 1-13 does not present inventive activity with respect to what is disclosed in document D01 (Article 8A1 of the Patent Law) A In conclusion, it is considered that the set of claims 1-13 does not meet, regarding the state of the art, the patentability requirements set forth in the Patent Law State of the Art Report Pa9ina 4/4