CA2166794C - Magnesium omeprazole - Google Patents

Magnesium omeprazole

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Publication number
CA2166794C
CA2166794C CA002166794A CA2166794A CA2166794C CA 2166794 C CA2166794 C CA 2166794C CA 002166794 A CA002166794 A CA 002166794A CA 2166794 A CA2166794 A CA 2166794A CA 2166794 C CA2166794 C CA 2166794C
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Prior art keywords
magnesium omeprazole
magnesium
omeprazole
crystals
process according
Prior art date
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Expired - Lifetime
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CA002166794A
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French (fr)
Inventor
Lars Ake Kallstrom
Monica Annelie Nygren
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AstraZeneca AB
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Astra AB
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Conductive Materials (AREA)
  • Contacts (AREA)
  • Electroplating Methods And Accessories (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Fats And Perfumes (AREA)
  • Medicinal Preparation (AREA)
  • Transition And Organic Metals Composition Catalysts For Addition Polymerization (AREA)
  • Powder Metallurgy (AREA)
  • Glass Compositions (AREA)

Abstract

A novel compound form of magnesium omeprazole useful in the manufacture of pharmaceutical formulations, the use of the product and the process for its production are described.

Description

I wo 951019M 2 ~ ~ 6 7 g 4 PCT/SE94/00680 MAGNESIUM OMEPRAZOLE
Field of the invention The present invention relates to a novel process for ' g the .0 salt of ~ r, the IIIA~ salt o~ r in a novel physical form, especially the ,, salt as a product of the novel process; the use of the novel form of the ~ ~ c~ salt of ~ lr in the, r ~ of ~o , ~ 1 r ~ and to the use of the novel form of the rna~n~ci~lrn salt of ~ '''`'If in medicine.
l~a.,~K., ' of the invention 15 The compound known under the generic name ",".I..",.,lr is described i.a. in European patent ~ . ;fi~ 0005129.
~m.-rr:l7rll~ is useful for inhibiting gastric acid secretion and has gastric mucosa protective activity in marnmals and man. In a more general sense, ~ml-rr:~7r~1r may 20 be used for prevention and treatment of gastlic acid related disorders and Oa~ n ' y diseases in mammal and man, including e.g. gastritis, gastric ulcer and duodenal ulcer.
The term ".. ~ lr.~ as used in this ~I~ ;ri~ designates the neutral form of 25 the compound, that is the form without a sait forming cation present.
Certain salts of ~""~ "lr are described in European patent ~ ;r~ 0124495.
In said patent ~ . ;ri~ .n the .~ I and importance regarding storage stability of 1)~ ua~l~ are . ."1.~ .l Sa~ts possessing superior 30 properties with regard i.a. to storage stability are described in the said European patent~ ;ri ~ ;f~'~

WO 95/019M ~,1 S ~ 7 g l~ PCT/SE94/00680 In EP 0124495; examples 5 and 6 disclose the synthesis of a mA~nFci-lm salt of ulll~ lLUle.
The isolation and y~lircaLivll in full - ' ~ scale of the described 11~ salts presents one major problem in that II~
r salt crystals are very fragile making processes utilising such crystals less attractive in full scale production. P~rfomling the process without crystallizavion of the I~Ag~ ;1..ll Ulll~lJIA OIe gives a product which is less suitable as a 1,~ ;I A1 substance.
In order to use the ... ~ - .. salt of ~... I..A".lF, in this ~ l;., denoted omeprazole, in full ."-- -,rA, l...; ~ scale in preparing yll~ ,c~lih,~l r -, .,.--lA~ primarily for oral a~ such as tablets, it is necessary that sa~d IIIA~ 11 omeprazole possesses a ..~,.1.;. -~;~. of properties which makes 15 such full scale, r ,, feasible. One object of the present invention is to provide a process for full scale production of ~, I-m~ rr~7~ 1F A further object of the present invention is to provide a novel form of the mo.~nF~illm salt of U,l,.l"~,Lule which can be used in full scale ,.,- rA~ l. ;,.~ o fu~lll.llaliulla, such as tablets.
The frlmhinorion of physical properties of the novel -".~ . ~:-,.,.. ,. I.l,.~.-lF.
product of the present invention with respect to the degree of crystallinity, particle diameter, density, hy~;lua~ulJh,i~y, water content and content of other solvents are favorable and permit the ' c of "''`L"' ` ""' Oll~ /lAL.UIe in a form which 25 possesses the desired properties.
The novel form of ~ r can also be formulated into other forms fo} oral ad."ll.;a~ ion and other types of Alll~ such as rectal Alllll; l;~l~Al;--l) Examples of rul"",l_~iu--s are tablets, pellets, granules, capsules, ~ c and ~ I-yO~ C

~66~94 WO 95/01977 PCT~SE94~00680 'IAhe invention We now provide a novel form of ~he mApA.. Sillm salt of v.,.. 1",.,.~1~ exhibiting the desired ~O~ of physical properties. Al'his makes full scale production of 5 ~ ir as well as full scale production of ~ ullld~c~icd r....,..,lAI;.. -- thereof feasible.
The novel process for the r ~ of ",AL,.. " nm~rA7rl~ also l~ilUUII~
the above described r ' ~ problems and renders possible the recovery and 10 work-up of the ~ L -- ~ u~ lr, substdnce in traditional chemical process equipment.
It has been found that the following property is significant to obtdin such product:
15 a) Crystdlline form, with a degree of crystdllinity of not less than 70%, preferably higher than 75% as ~r-~rmiArd by X-rAly powder diffraction It is desirable that the product aiso exhibits the following properties;
20 b) Particle si_e measured as mean mass diameter (MMD) less than 30,um, preferably less than 20 ,um as ~' ' by laser diffrdction technique.
c) Density between 1.33 g/cm3 and 1.35 g/cm3 as detemlined by powder I'Y'~
d) Hy~u~ y not exceeding 2% increase of weight upon storage for one month up to 94% relative -- . ' ' humidity as determinec vi~ lly.
30 e) A content of water of between 5% and 10% by weight as determined by titration according to Karl Fischer.

WO 95/019~7 PCT/SE94/00680 ~1~6~ 4 f) A content of methanol less than 0.1% preferably less than 0.05% by weight as determined by gas ~h~ull~a~u~ y, in case methanol is used as solvent.
In a further aspect, the invention also relates to a process for m~ f:ir~llnn~ the 5 novel form of ~ "A~ r This process is described in more detail below.
The invention relates to all of the aspects given under Field of the invention.
0 The process for producing the novel form of ""'L"' ~ is t- ..7~,'1 by the following ~ulls~ulive steps a) treating ~ r or a salt thereof with ~IIA~I-- `;"'~1 alcoholate in a solution 15 b) separating inorganic salts from the reaction mixture c) crystdllizing m~n-~ci~m ~
d) isolating the obtdined crystalline .. ~.. ~:.. ~IIA~OIr~ and, optionally,0 e) purifying and drying the crystalline ~ lA~Olr using uu...~lLiulldl methods.
The process for ,.. l.rA, 1.--;.. ~, the new product can be described in the following 25way.
A lower alcohol, such as methanol, ethanol, n-propanol or iso-propanol, preferably methanol, is treated in a solution of polar solvents with a weighed amount of 111- at t~..,-p~ uc~ between 0C and reflux l~ l4~UIti. The t~ ul~
30 should preferably be between 10 and 30C. After addition of the magnesium to the solution the t~ "AL~ can, in a second step be raised further to between 0C and reflux t ll~ UU~;, preferably 20-50C. After termination of the reaction the ~--` 2~.~6~

temperature 18 reduced to 0-40C, preferably 10-25C.
Omeprazole or a salt of omeprazole 18 then added to the solutlon and after terminatlon of the reaction the mlxture 18 cooled to -10C to +20C, preferably -5C to +5C. The solvent 18 then evaporated to 40-60% of the lnltlal volume, whlch makes the lnorganlc salts preclpitate. The preclpltate 18 separated from the reactlon solutlon for example by centrlfugatlon or flltratlon and the solutlon 18 heated to 5C to 30C whereafter the solutlon 18 seeded wlth magneslum omeprazole crystals. An amount of water, whlch 18 approxlmately egual to the volume of the solut lon, 18 added to start the crystalllzatlon. The solutlon 18 cooled to -10 to +20C, preferably 0-10C to complete the crystalllzatlon.
The crystals are then separated from the mother llquld for example by centrlfugatlon or flltratlon and washed wlth polar solvents preferably an agueous lower alcohol such as agueous methanol. Flnally, the produced crystals are drled uslng reduced pressure or heatlng or preferably a comblnatlon thereof .
The process for manufacturlng the new form of magneslum omeprazole dlffers from the earller known processes ln that the product is recovered after a controlled crystalllzation step ln agueous alcohol, preferably methanol by, first, separatlng the lnorganlc salts from the mother llguor. The crystalllnlty resultlng from thls step 18, unexpectedly, hlgher and the product possesses a hlgher degree of purlty and 18 more stable to ~ ltlon from uptake of molsture. The drylng step can be performed wlthout = .
23940-871 ( S) 21 667Q~
- 5a -caklng. The new process 18 posslble to perform ln convent lonal chemical proce3s equlpment and glves a product wlth a hlgher yleld than the proces~es hltherto known.
The followlng detalled Exa~ple 1 wlll serve to more fully lllustrate the process for manufacturlng magneslum omeprazole ln full scale accordlng to the present lnventlon.
In Flgures 1 and 2 sample A 18 manufactured accordlng to thls example .

r --2394Q-871 ( S ) WO 95/01977 216 ~ 7 9 ~ PCTISE94/00680 Example 1 A reactor was filled with 2026 litres of methanol. The stirrer was started and the t~ Lul~ was adjusted to 20C. 3,90 kg of magnesium was added to the vessel and ' 'y thereafter 1,0 litre of CH2C12. The reactor was heated to 40C
and kept aî this t~."~ u-~ for 60 min. It was then cooled to 15C before the addition of 99,9 kg of ~ r The reactor was kept at this L,~ for 60 min and then cooled to 0C. The h.~ ulc was kept at this level for 30 minutes before 10001 of methanol were evaporated under vacuum and the inorganic solid salt was separated from the liquid first by ~ I ;r. c~ l.. and then by filtration. The liquid was heated to 10C and the liquid was seeded with magnesium omepra_ole crystals whereafter the ,, u..~. l....,..lr salt was ~ . ' by addition of 9001 of water. The mixture was then cooled to 5C. After the crystalli_ation hadbeen completed the ~;c~ - r-...- ~ lr crystals were centrifuged off and then washed with a mixture of 501 of methanol and 1501 of water. Tbe produced "",~". ,: ", ,J,~.r~ r was dried under reduced pressure fLnally producing 92,5 kg of crystalline product u-lui"~u--Ji~g to a yield of 81,4%.
The novel form of the ~ salt of nmr~rr~7nl~ according to Example I
20 possesses the following properties:
a) Crystalline form, with a degree of crystallinity of 76%, as determined by X-ray powder diffraction.
25 b) Particle si_e measured as mean mass diameter (MMD) of 19pm as determined by laser diffraction technique.
c) Density of 1.342 g/cm3 as determined by powder ~ ,L..
30 d) ~ .u~u~il,i~y of 1.62% increase of weight upon storage for one month at 94% relative, ~ l ;c humidity as determined gravimetrically.

79~
~WO 95/OI977 PCT/SE94/00680 e) Content of moisture water of 7.6 by weight as determined by titration according to Karl Fischer.
i ) Content of methanol of 0.006% by weight as determined by gas A ~u~ u~ between two different samples of the novel form of m:l~n.
o,l~ ".lLule of the present invention obtained from two laboratory scale by prior art methods and .. ~ -.. u~ ulc goes forth from 10 diagrams I and 2. In these diagrams sample A represents the novel form of the present invention as ' ~i.l in full scale process equipment. Sample B
represents the product of preparation via synthesis by treatment of .. ".. ~ with Mg(OCH3)2. Sample C represens the product of preparation via treatment of sodium ~.".. I,,~,.-lr with MgC12.
Figure I shows in diagram I that the particle size measured as mean mass diameter of the product of method A is 19 pm which is smaller than the ~u..e~u,.di..~, particle size for the products of method B which is 25 ,um and of method C which is greater than 600 ,um.
hgure 2 shows in diagram 2 that the degree of crystallinity of the particles of the product of method A is 76% which is higher than the ~ r~ g figure for the product of sample B, which is 0% and also higher than the cu.-t~l,u...l;..g figure of sample C, which 67%.
.

Claims (31)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. Magnesium omeprazole characterized in having a degree of crystallinity which is higher than 70% as determined by X-ray powder diffraction.
2. Magnesium omeprazole according to claim 1 wherein the degree of crystallinity is higher than 75%.
3. Magnesium omeprazole according to claim 1 wherein the mean particle diameter as determined by laser diffraction technique is less than 30µm.
4. Magnesium omeprazole according to claim 3 wherein the mean particle diameter is less than 20µm.
5. Magnesium omeprazole according to claim 1 wherein the density is between 1.33 g/cm3 and 1.35 g/cm3 as determined by powder pycnometer.
6. Magnesium omeprazole according to claim 1 wherein the hygroscopicity is less than 2% increase of weight upon storage for one month at up to 94% relative atmospheric humidity as determined by gravimetry.
7. Magnesium omeprazole according to claim 1 wherein the water content is between 5% and 10% by weight.
8. Magnesium omeprazole according to claim 1 containing less than 0.1% by weight of solvent as determined by gas chromatography.
9. Magnesium omeprazole according to claim 1 containing less than 0.05% by weight of solvent as determined by gas chromatography.
10. A process for the manufacture of magnesium omeprazole according to any one of claims 1 to 8 characterized by in consecutive steps a) treating omeprazole or a salt thereof with magnesium alcoholate in a solution, b) separating inorganic salts from the reaction mixture, c) crystallizing magnesium omeprazole, d) isolating the obtained crystalline magnesium omeprazole and, optionally, e) purifying and drying the crystalline magnesium omeprazole.
11. A process according to claim 9 wherein the magnesium alcoholate is magnesium methyl alcoholate.
12. A process according to claim 9 wherein the solvent is methanol.
13. A process according to claim 9 wherein the crystallization is accomplished by addition of water.
14. A process according to claim 9 wherein the isolation of the magnesium omeprazole is performed by centrifugal separation of the crystals.
15. A process according to claim 9 wherein the isolation of the magnesium omeprazole is performed by filtration of the crystals.
16. A process according to claim 9 wherein the purification of the magnesium omeprazole crystals is performed by washing the crystals with a solution of polar solvents.
17. A process according to claim 9 wherein the magnesium omeprazole crystals are dried.
18. A process according to claim 17 wherein the magnesium omeprazole crystals are dried under reduced pressure.
19. A process according to claim 9 wherein the drying of the magnesium omeprazole crystals is performed by evaporating the remaining solvent by heating.
20. A pharmaceutical composition containing magnesium omeprazole according to any one of claims 1 to 8 as active ingredient, together with a pharmaceutically acceptable diluent or carrier.
21. A pharmaceutical formulation for oral administration containing magnesium omeprazole according to any one of claims 1 to 8 as active ingredient, together with a pharmaceutically acceptable diluent or carrier.
22. A tablet formulation containing magnesium omeprazole according to any one of claims 1 to 8 as active ingredient, together with a pharmaceutically acceptable diluent or carrier.
23. Magnesium omeprazole according to any one of claims 1 to 8 for use in therapy.
24. Magnesium omeprazole according to any one of claims 1 to 8 for use in inhibiting gastric acid secretion in mammals and man.
25. Magnesium omeprazole according to any one of claims 1 to 8 for use as an agent with gastric mucosa protective activity in mammals and man.
26. Magnesium omeprazole according to any one of claims 1 to 8 for use in the treatment of gastric acid related diseases in mammals and man.
27. The use of magnesium omeprazole according to any one of claims 1 to 8 in the manufacture of a medicament for inhibiting gastric acid secretion.
28. The use of magnesium omeprazole according to any one of claims 1 to 8 in the manufacture of a medicament for obtaining gastric mucosa protective activity.
29. The use of magnesium omeprazole according to any one of claims 1 to 8 in the manufacture of a medicament for the treatment of gastric acid related diseases.
30. Use of magnesium omeprazole according to any one of claims 1 to 8 for inhibiting gastric acid secretion in mammals and man.
31. Use of magnesium omeprazole according to any one of claims 1 to 8 for the treatment of gastric acid related diseases in mammals and man.
CA002166794A 1993-07-09 1994-07-08 Magnesium omeprazole Expired - Lifetime CA2166794C (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE19939302396A SE9302396D0 (en) 1993-07-09 1993-07-09 A NOVEL COMPOUND FORM
SE9302396-8 1993-07-09

Publications (1)

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CA2166794C true CA2166794C (en) 1997-03-04

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EP (2) EP0707580B1 (en)
JP (2) JP3635432B2 (en)
KR (1) KR100353783B1 (en)
CN (1) CN1064680C (en)
AT (1) ATE212628T1 (en)
AU (1) AU679766B2 (en)
BR (1) BR9406940A (en)
CA (1) CA2166794C (en)
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DE (2) DE707580T1 (en)
DK (1) DK0707580T3 (en)
DZ (1) DZ1792A1 (en)
EE (1) EE03127B1 (en)
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FI (1) FI114154B (en)
GR (1) GR970300015T1 (en)
HR (1) HRP940385B1 (en)
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SA (1) SA94150058B1 (en)
SE (1) SE9302396D0 (en)
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TW (1) TW504509B (en)
UA (1) UA43343C2 (en)
WO (1) WO1995001977A1 (en)
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Cited By (6)

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US6048981A (en) * 1998-04-22 2000-04-11 Torcan Chemical Ltd. Magnesium omeprazole and process for its preparation
US6077541A (en) * 1997-11-14 2000-06-20 Andrx Pharmaceuticals, Inc. Omeprazole formulation
US6174548B1 (en) 1998-08-28 2001-01-16 Andrx Pharmaceuticals, Inc. Omeprazole formulation
US6713495B1 (en) 1999-11-16 2004-03-30 Bernard Charles Sherman Magnesium omeprazole
US6733778B1 (en) 1999-08-27 2004-05-11 Andrx Pharmaceuticals, Inc. Omeprazole formulation
EP2147918A1 (en) 2008-07-21 2010-01-27 LEK Pharmaceuticals D.D. Process for the preparation of S-omeprazole magnesium in a stable form

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US6699885B2 (en) * 1996-01-04 2004-03-02 The Curators Of The University Of Missouri Substituted benzimidazole dosage forms and methods of using same
US6489346B1 (en) * 1996-01-04 2002-12-03 The Curators Of The University Of Missouri Substituted benzimidazole dosage forms and method of using same
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TW385306B (en) * 1996-11-14 2000-03-21 Takeda Chemical Industries Ltd Method for producing crystals of benzimidazole derivatives
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PT1131316E (en) * 1998-11-18 2004-10-29 Astrazeneca Ab IMPROVED CHEMICAL PROCESS AND PHARMACEUTICAL FORMULA
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DE19959419A1 (en) * 1999-12-09 2001-06-21 Ratiopharm Gmbh Stable pharmaceutical preparations comprising a benzimidazole and process for their preparation
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US20030212274A1 (en) * 2000-05-15 2003-11-13 Bakthavathsalan Vijayaraghavan Novel amorphous form of omeprazole salts
CA2386716C (en) * 2002-05-17 2012-07-24 Bernard Charles Sherman Magnesium salt of s-omeprazole
JP5412023B2 (en) 2000-08-04 2014-02-12 武田薬品工業株式会社 Salts of benzimidazole compounds and uses thereof
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