Title of Invention	"PROCESS FOR THE PREPARATION OF NOVEL AMORPHOUS FORM OF OMEPRAZOLE SALTS"
Abstract	A process for the preparation of amorphous form of omeprazole salts of Formula II, as shown in the accompanied drawings, wherein n is 1,2 or 4; An+ is Li+, Na+, K+, Mg2+, Ca2"1", or Ti4+, which comprises reacting omeprazole with metal alkoxide of formula A(OR)n wherein n is 1, 2 or 4 and R is an alkyl group containing 1-4 carbon atoms, in a non aqueous solvent selected from alcohols, ethers or mixture(s) thereof to get a solution and recovering amorphous omeprazole salt by spray drying.

Title of Invention

"PROCESS FOR THE PREPARATION OF NOVEL AMORPHOUS FORM OF OMEPRAZOLE SALTS"

Abstract

A process for the preparation of amorphous form of omeprazole salts of Formula II, as shown in the accompanied drawings, wherein n is 1,2 or 4; An+ is Li+, Na+, K+, Mg2+, Ca2"1", or Ti4+, which comprises reacting omeprazole with metal alkoxide of formula A(OR)n wherein n is 1, 2 or 4 and R is an alkyl group containing 1-4 carbon atoms, in a non aqueous solvent selected from alcohols, ethers or mixture(s) thereof to get a solution and recovering amorphous omeprazole salt by spray drying.

Full Text	The present invention relates to a process for the preparation of amorphous form of omeprazole salts including alkaline salts of the Formula II, as shown in the accompanied drawings, wherein n is 1,2 or 4; An+ is Li+, Na+, K+, Mg2+, Ca2+ etc. Chemically omeprazole is 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl-1H-benzimidazole. Omeprazole, covered in US patent no. 4,255,431 is effective inhibitor of gastric acid secretion in mammals, by being inhibitor of H+, K+-ATP (proton pump) activity. The enzyme H+, K+ - ATPase is responsible for gastric acid production and is located in the secretory membranes of the parietal cell. Omeprazole itself is not an active inhibitor of this enzyme, but it is transformed within the acid compartments of parietal cell into the active inhibitor, close to the enzyme. In a more general sense, omeprazole may be used for prevention and treatment of gastric acid related disorders and gastrointestinal inflammatory diseases in mammal and man, including e.g. gastritis, gastric ulcer and duodenal ulcer. Furthermore, omeprazole may be used for prevention and treatment of other gastrointestinal disorders where cy to protective and/or gastric antisecretory effect is desirable e.g. in patients with gastrinomas, in patients with acute upper gastrointestinal bleeding, and in patients with history of chronic and excessive alcohol consumption. The term "omeprazole" as used in this specification designates the neutral form of the compound of the Formula I, as shown in the accompanied drawings. Active pharmaceutical ingredients that are easily destroyed in an acid medium (acid labile) such as omeprazole create a special problem for formulations when it is required to provide a pharmaceutical form designated for oral administration. Omeprazole is susceptible to degradation / transformation in acid and neutral media. The half-life of degradation of omeprazole in water solutions at pH-values less than four is shorter than ten minutes. Also at neutral pH- values degradation proceeds rapidly, e.g. at pH = 7 the half-life of omeprazole is about 14 hours, while at higher pH-values the stability in solution is much better [Ref.: Scand. J. Gastroenterology. 20 (suppl. 108), 113-120 (1985)]. Omeprazole also in the solid state is susceptible to degradation and is stabilized in mixtures with alkaline reacting compounds. The stability of omeprazole is also affected by moisture, heat, organic solvents and to some degree by light. Upon storage without any special precautions being taken, it is degraded at a rate, which is higher than desired. At storage during accelerated conditions, that is at +37°C and at a relative humidity of 80% for a period of 6 months, about 6% of the substance is converted to degradation products. Certain salts of omeprazole including alkaline (K+, Li+, Na+, K+, Mg2++, Ca2+ etc) and their manufacturing processes are described in US Patent No. 4,738,974. It has been found that alkaline salts of omeprazole of the structural Formula II, as shown in the accompanied drawings, wherein n is 1,2 or 4; An+ is Li+, Na*, K+, Mg2+, Ca2++ etc are more stable during storage than the corresponding neutral form of omeprazole. The salts of Formula II are also easier to handle than the neutral form in the manufacture of pharmaceutical dosage units. US 5,900,424 claims an omeprazole magnesium salts having a degree of crystallinity higher than 70% and also describes a process of producing thereof. However, the processes of isolation and purification through crystallization in full manufacturing scale of omeprazole salts described in US 4,738,974 and US 5,900,424 present one major problem in that the magnesium omeprazole salt crystals are very fragile, making pharmaceutical manufacturing processes utilizing this product less attractive in full scale production. It is nevertheless desirable to obtain novel physical forms of omeprazole salts which exhibit improved stability and make full scale manufacturing feasible. The latest trend that has of late, crept into the pharmaceutical industry is the studies on polymorphism in drugs and the difference in the activity of different polymorphic forms of a given drug. The term polymorphism include different physical forms, crystal forms, crystalline / liquid crystalline /non-crystalline (amorphous) forms. This has especially become very interesting after observing that many antibiotics, antibacterials, tranquilizers etc, exhibit polymorphism and some / one of the polymorphic forms of a given drug exhibit superior bioavailability and consequently show much higher activity compared to other polymorphs. It has also been disclosed that the amorphous forms in a number of drugs exhibit different dissolution characteristics and in some cases different bioavailability patterns compared to the crystalline form [Konne T., Chem. Pharm. Bull. 38, 2003 (1990)]. For some therapeutic indications one bioavailability pattern may be favoured over another. Cefuroxime axetil is the classical example of amorphous form exhibiting higher bioavailability. We reasoned that an amorphous form of omeprazole salt would have an even better intrinsic dissolution, more stable, more feasible to manufacture at large scale and therefore, set out to prepare in this invention, hitherto unknown, solid amorphous form of omeprazole salt. It is an objective of the present invention to provide new amorphous form of omeprazole salts and an efficient method for the preparation of these salts. The present process uses conditions which are convenient to perform on a commercial scale and operationally safe. A preferred group of omeprazole salts of Formula II are those wherein An+ is Li+, Na+, K+, Mg2+, Ca2+, Ti4+. Further preferred salts are those wherein An+ is Na+, Mg2+ and Ca2+. The Mg2+ salt is particularly more preferred. Accordingly the present invention provides a process for the preparation of omeprazole salt particularly Mg2+ salt in new amorphous form which comprises reacting omeprazole with metal alkoxide in a non aqueous solvent such as an alcohol, ROH (only for alcoholates) or in an ether to get a solution followed by recovering amorphous form of omeprazole salt by spray drying. A metal alkoxide may be a compound of Formula A (OR) n, wherein R is an alkyl group containing 1 -4 carbon atoms and n is 1 ,2 or 4. Illustrative examples of the radical R are CH3, C2H5, n-C3H7, n-C4H9 i-C4H9, sec-C4H9 and tert. -C4H9. Preferably, the solvent may be selected from the group consisting of methanol, ethanol, isopropanol, n-butanol, tetrahydrofuran, 1,4-dioxane or mixture(s) thereof. In accordance with the present invention, omeprazole salt is recovered from the solution in an amorphous form using spray-drying technique. The Mini-Spray Dryer (Model: Buchi 190, Switzerland), which has been used, operates on the principle of nozzle spraying product and the drying gas flows in the same direction. The drying gas can be air or inert gases such as nitrogen, argon, and carbon dioxide. Nitrogen gas is preferred in this case. More particularly, amorphous omeprazole magnesium prepared according to the process of the invention may be characterized by the infrared spectrum (Figure 1) and by its x-ray powder diffraction pattern (Figure 2) as shown in the accompanied drawings. The infrared spectrum (Figure 1) obtained for the sample, prepared by the process of the present invention is different from the infrared spectrum of crystalline form (Figure 3) of omeprazole magnesium, as shown in the accompanied drawings. X-ray powder diffraction patterns of the newly prepared form also gave a plain halo (Figure 2) and show no peaks which are characteristic of the crystalline form of omeprazole magnesium, as shown in Figure 4 of the accompanied drawings, thus demonstrating the amorphous nature of the product. Accordingly, the present invention relates to a process for the preparation of amorphous form of omeprazole salts of Formula II, as shown in the accompanied drawings, wherein n is 1,2 or 4; An+ is Li+, Na+, K+, Mg2+, Ca2+, or Ti4+, which comprises reacting omeprazole with metal alkoxide of formula A(OR)n wherein n is 1, 2 or 4 and R is an alkyl group containing 1-4 carbon atoms, in a non aqueous solvent selected from alcohols, ethers or mixture(s) thereof to get a solution and recovering amorphous omeprazole salt by spray drying. The present invention is illustrated by the following example, which is not intended to limit the effective scope of the claims. Example 1 PREPARATION OF AMORPHOUS OMEPRAZOLE MAGNESIUM: Step A: Preparation of omeprazole base slurry: Omeprazole (100gm) was added to methanol (900ml) and stirred at 25-30°C for about 30 minutes to get uniform slurry. Step B: Preparation of fresh magnesium methoxide solution Methanol (500ml) was heated to reflux at 65-67°C and to it was added iodine crystals (100mg). Magnesium turnings (3.86gm) were added portion wise to the above solution during a period of 30 minutes maintaining reflux temperature of 65-67°C. The resulting reaction mixture was further refluxed for 30 minutes and was cooled to 30-35°C. Step C: Preparation of amorphous omeprazole magnesium The freshly prepared magnesium methoxide solution (from Step A) was added into omeprazole slurry in methanol (from Step B) in one lot at 25-30°C. Stirred the resulting reaction mixture at 25-30°C for about 1 hour. The clear solution thus obtained was subjected to spray drying in a mini - spray dryer (Buchi Model 190) at an inlet temperature of 60°C with a feed rate of 15ml per minute. Omeprazole magnesium (69gm) in an amorphous form was thus isolated. X-ray powder diffraction pattern (Figure 2, as shown in the accompanied drawings) shows a plain halo thus demonstrating the amorphous nature of the product. Infra red spectrum in KBr (Figure 1, as shown in the accompanied drawings) is different from the Infra red spectrum for crystalline omeprazole magnesium, as shown in Figure 3 of the accompanied drawings. WE CLAIM: 1. A process for the preparation of amorphous form of omeprazole salts of Formula II, as shown in the accompanied drawings, wherein n is 1,2 or 4; An+ is Li+, Na+, K+, Mg2+, Ca2+, or Ti4+, which comprises reacting omeprazole with metal alkoxide of formula A(OR)n wherein n is 1, 2 or 4 and R is an alkyl group containing 1-4 carbon atoms, in a non aqueous solvent selected from alcohols, ethers or mixture(s) thereof to get a solution and recovering amorphous omeprazole salt by spray drying. 2. The process as claimed in claim 1, wherein metal alkoxide is magnesium methoxide or magnesium ethoxide. 3. The process of as claimed in claim 1, wherein the alcohol is selected from methanol, ethanol, isopropanol, n-butanol or mixture(s) thereof. 4. The process of as claimed in claim 1, wherein the ether is selected from tetrahydrofuran, 1,4-dioxane ormixture(s) thereof. 5. The process for the preparation of amorphous salts of omeprazole substantially as herein described and exemplified by the example.

Full Text

The present invention relates to a process for the preparation of amorphous form of omeprazole salts including alkaline salts of the Formula II, as shown in the accompanied drawings, wherein n is 1,2 or 4; An+ is Li+, Na+, K+, Mg2+, Ca2+ etc.
Chemically omeprazole is 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl-1H-benzimidazole. Omeprazole, covered in US patent no. 4,255,431 is effective inhibitor of gastric acid secretion in mammals, by being inhibitor of H+, K+-ATP (proton pump) activity. The enzyme H+, K+ - ATPase is responsible for gastric acid production and is located in the secretory membranes of the parietal cell. Omeprazole itself is not an active inhibitor of this enzyme, but it is transformed within the acid compartments of parietal cell into the active inhibitor, close to the enzyme. In a more general sense, omeprazole may be used for prevention and treatment of gastric acid related disorders and gastrointestinal inflammatory diseases in mammal and man, including e.g. gastritis, gastric ulcer and duodenal ulcer. Furthermore, omeprazole may be used for prevention and treatment of other gastrointestinal disorders where cy to protective and/or gastric antisecretory effect is desirable e.g. in patients with gastrinomas, in patients with acute upper gastrointestinal bleeding, and in patients with history of chronic and excessive alcohol consumption. The term "omeprazole" as used in this specification designates the neutral form of the compound of the Formula I, as shown in the accompanied drawings.
Active pharmaceutical ingredients that are easily destroyed in an acid medium (acid labile) such as omeprazole create a special problem for formulations when it is required to provide a pharmaceutical form designated for oral administration. Omeprazole is susceptible to degradation / transformation in acid and neutral media. The half-life of degradation of omeprazole in water solutions at pH-values less than four is shorter than ten minutes. Also at neutral pH- values degradation proceeds rapidly, e.g. at pH = 7 the half-life of omeprazole is about 14 hours, while at higher pH-values the stability in solution is much better [Ref.: Scand. J. Gastroenterology. 20 (suppl. 108), 113-120 (1985)]. Omeprazole also in the solid state is susceptible to degradation and is stabilized in mixtures with alkaline reacting compounds. The stability of omeprazole is also affected by moisture, heat, organic solvents and to some degree by light. Upon storage without any special precautions being taken, it is degraded at a rate, which is higher than desired. At storage during accelerated conditions, that is at +37°C and at a relative humidity of 80% for a period of 6 months, about 6% of the substance is converted to degradation products.

Certain salts of omeprazole including alkaline (K+, Li+, Na+, K+, Mg2++, Ca2+ etc) and their manufacturing processes are described in US Patent No. 4,738,974. It has been found that alkaline salts of omeprazole of the structural Formula II, as shown in the accompanied drawings, wherein n is 1,2 or 4; An+ is Li+, Na*, K+, Mg2+, Ca2++ etc are more stable during storage than the corresponding neutral form of omeprazole. The salts of Formula II are also easier to handle than the neutral form in the manufacture of pharmaceutical dosage units. US 5,900,424 claims an omeprazole magnesium salts having a degree of crystallinity higher than 70% and also describes a process of producing thereof.
However, the processes of isolation and purification through crystallization in full manufacturing scale of omeprazole salts described in US 4,738,974 and US 5,900,424 present one major problem in that the magnesium omeprazole salt crystals are very fragile, making pharmaceutical manufacturing processes utilizing this product less attractive in full scale production.
It is nevertheless desirable to obtain novel physical forms of omeprazole salts which exhibit improved stability and make full scale manufacturing feasible.
The latest trend that has of late, crept into the pharmaceutical industry is the studies on polymorphism in drugs and the difference in the activity of different polymorphic forms of a given drug. The term polymorphism include different physical forms, crystal forms, crystalline / liquid crystalline /non-crystalline (amorphous) forms. This has especially become very interesting after observing that many antibiotics, antibacterials, tranquilizers etc, exhibit polymorphism and some / one of the polymorphic forms of a given drug exhibit superior bioavailability and consequently show much higher activity compared to other polymorphs. It has also been disclosed that the amorphous forms in a number of drugs exhibit different dissolution characteristics and in some cases different bioavailability patterns compared to the crystalline form [Konne T., Chem. Pharm. Bull. 38, 2003 (1990)]. For some therapeutic indications one bioavailability pattern may be favoured over another. Cefuroxime axetil is the classical example of amorphous form exhibiting higher bioavailability. We reasoned that an amorphous form of omeprazole salt would have an even better intrinsic dissolution, more stable, more feasible to manufacture at large scale and therefore, set out to prepare in this invention, hitherto unknown, solid amorphous form of omeprazole salt.

It is an objective of the present invention to provide new amorphous form of omeprazole salts and an efficient method for the preparation of these salts. The present process uses conditions which are convenient to perform on a commercial scale and operationally safe.
A preferred group of omeprazole salts of Formula II are those wherein An+ is Li+, Na+, K+, Mg2+, Ca2+, Ti4+. Further preferred salts are those wherein An+ is Na+, Mg2+ and Ca2+. The Mg2+ salt is particularly more preferred.
Accordingly the present invention provides a process for the preparation of omeprazole salt particularly Mg2+ salt in new amorphous form which comprises reacting omeprazole with metal alkoxide in a non aqueous solvent such as an alcohol, ROH (only for alcoholates) or in an ether to get a solution followed by recovering amorphous form of omeprazole salt by spray drying. A metal alkoxide may be a compound of Formula A (OR) n, wherein R is an alkyl group containing 1 -4 carbon atoms and n is 1 ,2 or 4.
Illustrative examples of the radical R are CH3, C2H5, n-C3H7, n-C4H9 i-C4H9, sec-C4H9 and tert. -C4H9. Preferably, the solvent may be selected from the group consisting of methanol, ethanol, isopropanol, n-butanol, tetrahydrofuran, 1,4-dioxane or mixture(s) thereof.
In accordance with the present invention, omeprazole salt is recovered from the solution in an amorphous form using spray-drying technique. The Mini-Spray Dryer (Model: Buchi 190, Switzerland), which has been used, operates on the principle of nozzle spraying product and the drying gas flows in the same direction. The drying gas can be air or inert gases such as nitrogen, argon, and carbon dioxide. Nitrogen gas is preferred in this case.
More particularly, amorphous omeprazole magnesium prepared according to the process of the invention may be characterized by the infrared spectrum (Figure 1) and by its x-ray powder diffraction pattern (Figure 2) as shown in the accompanied drawings. The infrared spectrum (Figure 1) obtained for the sample, prepared by the process of the present invention is different from the infrared spectrum of crystalline form (Figure 3) of omeprazole magnesium, as shown in the accompanied drawings. X-ray powder diffraction patterns of the newly prepared form also gave a plain halo (Figure 2) and show no peaks which are characteristic of the crystalline form of omeprazole magnesium, as shown in Figure 4 of the accompanied drawings, thus demonstrating the amorphous nature of the product.

Accordingly, the present invention relates to a process for the preparation of amorphous form of omeprazole salts of Formula II, as shown in the accompanied drawings, wherein n is 1,2 or 4; An+ is Li+, Na+, K+, Mg2+, Ca2+, or Ti4+, which comprises reacting omeprazole with metal alkoxide of formula A(OR)n wherein n is 1, 2 or 4 and R is an alkyl group containing 1-4 carbon atoms, in a non aqueous solvent selected from alcohols, ethers or mixture(s) thereof to get a solution and recovering amorphous omeprazole salt by spray drying.
The present invention is illustrated by the following example, which is not intended to limit the effective scope of the claims.
Example 1
PREPARATION OF AMORPHOUS OMEPRAZOLE MAGNESIUM:
Step A: Preparation of omeprazole base slurry:
Omeprazole (100gm) was added to methanol (900ml) and stirred at 25-30°C for about 30
minutes to get uniform slurry.
Step B: Preparation of fresh magnesium methoxide solution
Methanol (500ml) was heated to reflux at 65-67°C and to it was added iodine crystals (100mg). Magnesium turnings (3.86gm) were added portion wise to the above solution during a period of 30 minutes maintaining reflux temperature of 65-67°C. The resulting reaction mixture was further refluxed for 30 minutes and was cooled to 30-35°C.
Step C: Preparation of amorphous omeprazole magnesium
The freshly prepared magnesium methoxide solution (from Step A) was added into omeprazole slurry in methanol (from Step B) in one lot at 25-30°C. Stirred the resulting reaction mixture at 25-30°C for about 1 hour. The clear solution thus obtained was subjected to spray drying in a mini - spray dryer (Buchi Model 190) at an inlet temperature of 60°C with a feed rate of 15ml per minute. Omeprazole magnesium (69gm) in an amorphous form was thus isolated.
X-ray powder diffraction pattern (Figure 2, as shown in the accompanied drawings) shows a plain halo thus demonstrating the amorphous nature of the product. Infra red spectrum in KBr (Figure 1, as shown in the accompanied drawings) is different from the Infra red spectrum for crystalline omeprazole magnesium, as shown in Figure 3 of the accompanied drawings.

WE CLAIM:
1. A process for the preparation of amorphous form of omeprazole salts of Formula II, as
shown in the accompanied drawings, wherein n is 1,2 or 4; An+ is Li+, Na+, K+, Mg2+,
Ca2+, or Ti4+, which comprises reacting omeprazole with metal alkoxide of formula
A(OR)n wherein n is 1, 2 or 4 and R is an alkyl group containing 1-4 carbon atoms, in
a non aqueous solvent selected from alcohols, ethers or mixture(s) thereof to get a
solution and recovering amorphous omeprazole salt by spray drying.
2. The process as claimed in claim 1, wherein metal alkoxide is magnesium methoxide
or magnesium ethoxide.
3. The process of as claimed in claim 1, wherein the alcohol is selected from methanol,
ethanol, isopropanol, n-butanol or mixture(s) thereof.
4. The process of as claimed in claim 1, wherein the ether is selected from
tetrahydrofuran, 1,4-dioxane ormixture(s) thereof.
5. The process for the preparation of amorphous salts of omeprazole substantially as
herein described and exemplified by the example.

Documents:

516-del-2000-abstract.pdf

516-del-2000-claims.pdf

516-del-2000-correspondence-others.pdf

516-del-2000-correspondence-po.pdf

516-del-2000-description (complete).pdf

516-del-2000-drawings.pdf

516-del-2000-form-1.pdf

516-del-2000-form-19.pdf

516-del-2000-form-2.pdf

516-del-2000-form-3.pdf

516-del-2000-petition-138.pdf

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Patent Number

231542

Indian Patent Application Number

516/DEL/2000

PG Journal Number

13/2009

Publication Date

27-Mar-2009

Grant Date

05-Mar-2009

Date of Filing

15-May-2000

Name of Patentee

RANBAXY LABORATORIES LIMITED

Applicant Address

19, NEHRU PLACE, NEW DELHI-110 019, INDIA.

Inventors:

#	Inventor's Name	Inventor's Address
1	BAKTHAVATHSALAN VIJAYA RAGHAVAN	RANBAXY LABORATORIES LIMITED, PLOT NO. 20, SECTOR - 18, UDYOG VIHAR INDUSTRIAL AREA, GURGAON- 122001 (HARYANA), INDIA.
2	TARUN SHARMA	RANBAXY LABORATORIES LIMITED, PLOT NO. 20, SECTOR - 18, UDYOG VIHAR INDUSTRIAL AREA, GURGAON- 122001 (HARYANA), INDIA.
3	NARESH KUMAR	RANBAXY LABORATORIES LIMITED, PLOT NO. 20, SECTOR - 18, UDYOG VIHAR INDUSTRIAL AREA, GURGAON- 122001 (HARYANA), INDIA.

PCT International Classification Number

C07D

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA