wo 94/27988
`
`Claims
`
`22
`
`PCT /SE94/00509
`
`1. Optically pure compounds c h a r a c t e r i z e d in that the compounds are
`Na+, Mg2+, Li+, K+, Ca2+ and N\R)4 salts of (+)-5-methoxy-2-[[(4-methoxy-
`3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-IH-benzirnidazole and (-)-5-methoxy-2-
`
`5
`
`[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzirnidazole, wherein
`
`R is an alkyl with 1-4 carbon atoms.
`
`2. Compounds according to claim 1 c h a r a c t e r i z e d in that the
`
`10
`
`compounds are ( + )-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-
`
`pyridinyl)methyl]sulfinyl]-1 H-benzirnidazole sodium salt, (-)-5-methoxy-2-[[ ( 4-
`
`methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzirnidazole sodium salt,
`
`(+)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H(cid:173)
`
`benzirnidazole magnesium salt, (-)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-
`
`15
`
`pyridinyl)methyl]sulfinyl]-1H-benzirnidazole magnesium salt, ( +)-5-methoxy-2-[[(4-
`
`methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-IH-benzimidazole calcium salt
`
`and (-)-5-methoxy-2-[[( 4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H(cid:173)
`
`benzirnidazole calcium salt.
`
`20
`
`3. Compounds according to claims 1 and 2 c h a r a c t e r i z e d in that the
`
`compounds are (+)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-
`
`pyridinyl)methyl]sulfinyl]-1H-benzimidazole sodium salt, (-)-5-methoxy-2-[[(4-
`
`methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole sodium salt,
`
`( + )-5-methoxy-2-[[ ( 4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1 H-
`
`25
`
`benzimidazole magnesium salt and (-)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-
`
`pyridinyl)methyl]sulfinyl]-1H-benzimidazole magnesium salt
`
`4. Compounds according to claims 1 and 2 c h a r a c t e r i z e d in that the
`
`compounds are (+)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]-
`
`30
`
`sulfinyl-1 H-benzirnidazole sodium salt and (-)-5-methoxy-2-[[ ( 4-methoxy-3,5-
`
`

`
`wo 94/27988
`
`23
`
`PCT /SE94/00509
`
`dimethyl-2-pyridinyl)methyl]sulfinyl-lH-benzimidazole sodium salt in their
`
`crystalline forms.
`
`5. Compounds according to claims 1 and 2 c h a r a c t e r i zed in that the
`compound is ( + )-5-methoxy-2-[[ ( 4-methoxy-3,5-dimethyl-2-pyridinyl)methyl](cid:173)
`
`5
`
`sulfinyl-lH-benzimidazole sodium salt in its crystalline form.
`
`6. Compounds according to claims 1 and 2 c h a r a c t e r i z e d in that the
`
`compound is (-)-5-methoxy-2-[[( 4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]-
`
`10
`
`sulfinyl-lH-benzimidazole sodium salt in its crystalline form,
`
`7.
`
`Process for the preparation of a compound according to claim 1
`
`c h a r a c t e r i z e d
`
`in that a diastereomeric ester of formula IV
`
`15
`
`20
`
`(IV)
`
`wherein Acyl designates a chiral acyl group such as mandeloyl, having either R or
`
`25
`
`S configuration, is separated, and each of the separated diastereomers is dissolved
`
`in an alkaline solution where the acyloxymethyl group is hydrolyzed to give the
`
`optically pure compound.
`
`8.
`
`Process according to claim 7 c h a r act e r i zed in that the
`
`30
`
`diastereomers are separated by chromatography or fractional crystallization.
`
`

`
`wo 94/27988
`
`24
`
`PCT /SE94/00509
`
`9.
`
`Process according to claim 7 c h a r act e r i zed in that the solvolysis
`
`is perlormed in alkaline solution consisting of a base in a protic solvent, such as
`
`alcohols or water; or a base in an aprotic solvent, such as dimethylsulfoxide or
`
`5
`
`dimethylformamide.
`
`I 0. Process for the preparation of a compound according to claim I in crystalline
`
`form c h a r a c t e r i z e d in that a product from the process in claim 7 is
`
`neutralized with a neutralizing agent which can be an acid or an ester such as
`
`10
`
`methyl formate, followed by treatment with a base in non-aqueous solution.
`
`11. Process for preparation of (+)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-
`
`pyridinyl)methyl]-sulfinyl-1H-benzimidazole sodium salt and (-)-5-methoxy-2-[[( 4-
`
`methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl-1 H-benzimidazole sodium salt in
`
`15
`
`their crystalline forms c h a r act e r i zed in that (+)-5-methoxy-2-[[(4-
`
`methoxy-3,5-dimethyl-2-pyridinyl)methyl]-sulfinyl]-IH-benzimidazole sodium salt
`
`and (-)-5-methoxy-2-[[ ( 4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl-lH(cid:173)
`
`benzimidazole sodium salt crude product respectively is neutralized followed by
`
`treatment with N aOH in a non-aqueous medium.
`
`20
`
`25
`
`12. Process for the preparation of (+)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-
`
`pyridinyl)methyl]sulfinyl]-IH-benzimidazole and (-)-5-methoxy-2-[[(4-methoxy-3,5-
`
`dimethyl-2-pyridinyl)methyl]sulfinyl]-lH-benzimidazole characterized
`
`in that a diastereomeric ester of formula IV
`
`

`
`wo 94/27988
`
`25
`
`PCT /SE94/00509
`
`OX)-
`
`11
`
`N
`
`5
`
`10
`
`cH2-s--{ I
`N
`I
`CH2..._0Acyl
`
`~
`ocH3
`
`#
`
`(IV)
`
`wherein Acyl designates a chiral acyl group such as mandeloyl, having either R or
`
`S configuration, is separated, and each of the separated diastereomers is dissolved
`
`in an alkaline solution where the acyloxymethyl group is hydrolyzed off to give the
`
`optically pure compound after neutralization with a neutralizing agent which can be
`
`15
`
`an acid or an ester.
`
`13. Process according to claim 12 c h a r a c t e r i zed in that the
`
`diastereomers are separated by chromatography or fractional crystallization.
`
`20
`
`14. Process according to claim 12 c h a r a c t e r i z e d
`
`in that the solvolysis
`
`is performed in alkaline solution consisting of a base in a protic solvent, such as
`
`alcohols or water; or a base in an aprotic solvent, such as dimethylsulfoxide or
`
`dimethylformamide.
`
`25
`
`15. The compound (+)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-
`
`pyridinyl)methyl]-sulfinyl]-1H-benzimidazole obtained by the process defined in
`
`claim 12.
`
`16. The compound (-)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]-
`
`30
`
`sulfinyl]-1H-benzimidazole obtained by the process dermed in claim 12.
`
`

`
`wo 94/27988
`
`26
`
`PCT /SE94/00509
`
`17. Pharmaceutical preparation co~taining an optically pure compound according
`
`to any of claims 1-6 as active ingredient.
`
`18. Optically pure compounds according to any of claims 1-6 for use in therapy.
`
`5
`
`19. Use of an optically pure compound according to any of claims 1-6 in the
`
`preparation of a pharmaceutical formulation for inhibiting gastric acid secretion.
`
`20. Use of an optically pure compound according to any of claims 1-6 for the
`
`10
`
`preparation of a pharmaceutical formulation for the treatment of gastrointestinal
`
`inflammatory diseases.
`
`21. A method for inhibiting gastric acid secretion comprising administration to a
`
`mammal including man in need of such treatment an effective amount of an
`
`15
`
`optically pure compound according to any of claims 1-6.
`
`22. A method for the treatment of gastrointestinal inflammatory diseases
`
`comprising administration to a mammal including man in need of such treatment
`
`an effective amount of an optically pure compound according to any of claims 1-6.
`
`20
`
`23. The compound 6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl](cid:173)
`
`l-[mandeloyloxymethyl]-1H-benzimidazole.
`
`

`
`1
`INTERNATIONAL SEARCH REPORT
`
`International application No.
`PCT/SE 94/00509
`
`A. CLASSIFICATION OF SUBJECT MATTER
`
`IPC5: C07D 401/12, A61K 31/44
`According to International Patent Classification (IPC) or to both national classification and IPC
`
`B. FIELDS SEARCHED
`Minimum documentation searched (classification system followed by classification symbols)
`
`IPC5: C07D
`Documentation searched other than minimum documentation to the extent that such documents are included in the frelds searched
`SE,DK,FI,NO classes as above
`
`Electronic data base consulted during the international search (name of data base and, where practicable, search terms used)
`
`CAS-ONLINE
`c. DOCUMENTS CONSIDERED TO BE RELEVANT
`
`Category* Citation of document, with indication, where appropriate, of the relevant passages
`
`Relevant to claim No.
`
`EP, A2, 0124495 (AKTIEBOLAGET HASSLE),
`7 November 1984 (07.11.84)
`--
`DE, A1, 4035455 (BYK GULDEN LOMBERG CHEMISCHE
`FABRIK GMBH), 14 May 1992 (14. 05. 92)
`
`y
`
`y
`
`X
`
`--
`--------
`
`1-6,11,15-20
`
`1-6,11,15-20
`
`7-10,12-14,
`23
`
`[X] See patent family annex.
`
`D Further documents are listed in the continuation of Box C.
`•
`Special categories of cited documents:
`*A* document defming the general state of the art wbich is not considered
`to be of particular relevance
`*E" erlier document but published on or after the international flling date
`•L• document which may throw doubts on priority claim(s) or which is
`cited to establish the publication date of another citation or other
`special reason (as specified)
`*0* document referring to an oral disclosure, use, exhibition or other
`means
`"P* document published prior to the international filing date but later than
`the priority date claimed
`
`'"T*
`
`later documem published after the international filing date or priority
`date and not in conflict with the application but cited to understand
`the principle or theory underlying the invention
`·x· document of particular relevance: the claimed invention cannot be
`considered novel or cannot be considered to involve an inventive
`step when the document is taken alone
`*Y* document of particular relevance: the claimed invention cannot be
`considered to involve an inventive step wben the document is
`combined with one or more other such documents, such combination
`being obvious to a person skilled in the art
`*&H document member of the same patent family
`
`Date of the actual completion of the international search
`
`Date of mailing of the international search report
`
`29 Julv 1994
`Name and mailing address of the ISA/
`Swedish Patent Office
`Box 5055, S-102 42 STOCKHOLM
`Facsimile No. +46 8 666 02 86
`Form PCf/ISA/210 (second sheet) (July 1992)
`
`17 -08- 1994
`
`Authorized officer
`
`Goran Karlsson
`Telephone No. +46 8 782 25 00
`
`

`
`INTERNATIONAL SEARCH REPORT
`
`International application No.
`
`PCT/SE 94/00509
`
`Box I
`
`Observations where certain claims were round unsearchable (Continuation or Item 1 or first sheet)
`
`This international search report has not been established in respect of certain claims under Article 17(2)(a) for the following reasons:
`1. [i]
`
`Claims Nos.: 21-22
`because they relate to subject matter not required to be searched by this Authority, namely:
`A method for treatment of the human or animal body by therapy, see
`rule 39.1(iv).
`
`Claims Nos.:
`because they relate to parts of the international application that do not comply with the prescribed requirements to such
`an extent that no meaningful international search can be carried out, specifically:
`
`Claims Nos.:
`because they are dependent claims and are not drafted in accordance with the second and third sentences of Rule 6.4(a).
`
`Box II
`
`Observations where unfty of Invention ls JackJng (Continuation of Item 2 of first sheet)
`
`This International Searching Authority found multiple inventions in this international application, as follows:
`
`As all required additional search fees were timely paid by the applicant, this international search report covers all
`searchable claims.
`
`As all searcha bJe c1aims could be searched without effort justifying an additional fee, this Authority did not invite payment
`of any additional fee.
`
`As only some of the required additional search fees were timely paid by the applicant, this international search report
`covers only those claims for which fees were paid, specifically claims Nos.:
`
`No required additional search fees were timely paid by the applicant. Consequently, this international search report is
`restricted to the invention first mentioned in the claims; it is covered by claims Nos.:
`
`Remark on Protest
`
`0 The additional search fees were accompanied by the applicant's protest.
`0 No protest accompanied the pa)'tDent of additional search fees.
`
`Form PCTnSA/210 (continuation of first sheet (1)) (July 1992)
`
`

`
`,..--. ------------,
`International application No.
`PCT/SE 94/00509
`
`02/07/94
`
`Patent family
`member(s)
`
`SE-T3-
`AU-B(cid:173)
`AU-A(cid:173)
`CA-A(cid:173)
`GB-A,B(cid:173)
`JP-C(cid:173)
`JP-8-
`JP-A(cid:173)
`SU-A(cid:173)
`US-A-
`
`AU-A(cid:173)
`WO-A-
`
`0124495
`563842
`2525784
`1264751
`2137616
`1651336
`3013233
`59167587
`1314953
`4738974
`
`8840691
`9208716
`
`Publication
`date
`
`I
`
`23/07/87
`06/09/84
`23/01/90
`10/10/84
`30/03/92
`22/02/91
`21/09/84
`30/05/87
`19/04/88
`
`11/06/92
`29/05/92
`
`INTERNATIONAL SEARCH REPORT
`Information on patent family members
`
`Patent document
`cited in search report
`
`EP-A2-
`
`0124495
`
`I
`
`Publication
`date
`
`07/11/84
`
`I
`
`DE-Al-
`
`4035455
`
`14/05/92
`
`Form PCT/ISA/210 (patent family annex) (July 1992)
`
`

`
`PCT
`WORLD INTElLECTUAL PROPERTY ORGANIZATION
`International Bureau
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PA1ENT COOPERATION TREATY (PCT)
`wo 95/01977
`
`(11) International Publication Number:
`
`(51) International Patent Classification 6:
`C07D 401112, A61K 31/44
`
`A1
`
`(43) International Publication Date:
`
`19 January 1995 (19.01.95)
`
`(21) International Application Number:
`
`PCT/SE94/00680
`
`(22) International Filing Date:
`
`8 July 1994 (08.07.94)
`
`(30) Priority Data:
`9302396-8
`
`9 July 1993 (09.07.93)
`
`SE
`
`(71) Applicant (for all designated States except US): AS1RA
`AKTIEBOLAG [SFJSE]; S-151 85 Sooertiilje (SE).
`
`(72) Inventors; and
`(75) Inventors/Applicants (for US only): KALLsTROM, Lars,
`Alee [SFJSEJ; Ronnbiirsvagen 3, S-152 52 SOdertiilje (SE).
`NYGREN, Monica, Annelie [SE/SE]; Myrstigen 21, S-151
`60 Sooertiilje (SE).
`
`(74) Agent: LARSSON, Birgitta; Astra Aktiebolag, Patent Dept.,
`S-151 85 Soo~je (SE).
`
`(81) Designated States: AM, AT, AU, BB, BG, BR. BY, CA, CH,
`CN, CZ, DE, OK, ES, Fl. GB, GE, HU, JP, KE, KG, KP,
`KR. KZ, LK, LT, LU, LV, :MD, MG, MN, MW, NL, NO,
`NZ, PL, PT, RO, RU, SO, SE, Sl, SK, TJ, TT, UA, US,
`UZ, VN, European patent (AT, BE, CH, DE, OK, ES, FR,
`GB, GR. IE, IT, LU, MC, NL, PT, SE), OAPI patent (BF,
`BJ, CF, CG, CI, CM, GA, m:. ML, MR. NE, SN, TO, TG),
`ARIPO patent (KE, MW, SD;.
`
`Published
`With international search report.
`
`(54) Title: MAGNESIUM OMEPRAZOLE
`
`IJ!Tt
`100 ..
`90
`80-
`70
`60
`50-
`40·
`30.
`20
`10
`0
`
`-~,
`
`,I r
`
`<#
`
`Magnesium omeprazole-Hean Hass Diameter
`
`>600
`
`A
`
`I
`
`8
`
`I
`
`[
`
`I
`
`(57) 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.
`
`

`
`FOR THE PURPOSES OF INFORMATION ONLY
`
`Codes used to identify States party to the PCr on the front pages of pamphlets publishing international
`applications under the Per.
`
`AT
`AU
`BB
`BE
`BF
`BG
`BJ
`BR
`BY
`CA
`CF
`CG
`CB
`Cl
`CM
`CN
`cs
`cz
`DE
`DK
`ES
`FI
`FR
`GA
`
`Austria
`Australia
`Barbados
`Belgium
`Burkina Faso
`Bulgaria
`Benin
`Brazil
`Belarus
`Canada
`Cenlral African Republic
`Congo
`Switzerland
`COte d'Ivoire
`Cameroon
`anna
`Czechoslovakia
`C:r.ecb Republic
`Germany
`Denmark
`Spain
`Finland
`France
`Gabon
`
`GB
`GE
`GN
`GR
`HU
`m
`IT
`JP
`KE
`KG
`KP
`
`KR
`KZ
`LI
`LK
`LU
`LV
`MC
`MD
`MG
`ML
`:MN
`
`United Kingdom
`Georgia
`Guinea
`Greece
`Hungacy
`Ireland
`Italy
`Japan
`Kenya
`Kyrgyst.an
`Democratic People's Republic
`of Korea
`Republic of Korea
`Kazakhstan
`Liechtenstein
`Sri Lanka
`Luxembourg
`Latvia
`Monaco
`Republic of Moldova
`Madagascar
`Mali
`Mongolia
`
`MR
`Mauritania
`MW Malawi
`NE
`Niga
`NL
`Netherlands
`Norway
`NO
`NZ
`New Zealand
`PL
`Poland
`Portugal
`PT
`RO
`Romania
`Russian Federation
`RU
`Sudan
`SD
`Sweden
`SE
`Slovenia
`Sl
`Slovakia
`SK
`Senegal
`SN
`Owl
`TD
`Togo
`TG
`Tajikistan
`TJ
`TT
`Trinidad and Tobago
`Ukraine
`UA
`us
`United States of America
`uz
`Uzbek:ist.m
`VN
`VietNam
`
`.,
`
`

`
`wo 95/01977
`
`PCT /SE94/00680
`
`l
`MAGNESIUM OMEPRAZOLE
`
`Field of the invention
`
`5
`
`The present invention relates to a novel process for manufacturing the magnesium
`
`salt of omeprazole; the magnesium salt of omeprazole in a novel physical form,
`
`especially the magnesium salt as a produ(-t: of the novel process; the use of the
`
`novel form of the magnesium salt of omeprazole in the manufacture of
`
`10
`
`pharmaceutical formulations; and to the use of the novel form of the magnesium
`
`salt of omeprazole in medicine.
`
`Background of the invention
`
`15
`
`The compound known under the generic name omeprazole is described i.a. in
`European patent specification 0005129.
`
`Omeprazole is useful for inhibiting gastric acid secretion and has gastric mucosa
`
`protective activity in mammals and man. In a more general sense, omeprazole may
`
`20
`
`be used for prevention and treatment of gastric a~ "d related disorders and
`
`gastrointestinal inflammatory diseases in mammal and man, including e.g. gastritis,
`
`gastric ulcer and duodenal ulcer.
`
`The term "omeprazole" as used in this specification designates the neutral form of
`
`25
`
`the compound, that is the form without a salt forming cation present.
`
`Certain salts of omeprazole are described in European patent specification 0124495.
`
`In said patent specification th requirements and importance regarding storage
`
`stability of pharmaceutical preparations are emphasized. Salts· possessing superior
`
`30
`
`properties with regard i.a. to storage stability are described in the said European
`
`patent specification.
`
`

`
`wo 95/01977
`
`PCT /SE94/00680
`
`In EP 0 124495; examples 5 and 6 disclose the synthesis of a magnesium salt of
`
`omeprazole.
`
`2
`
`The isolation and purification in full manufacturing scale of the 'described
`
`5
`
`magnesium omeprazole salts presents one major problem in that magnesium
`
`omeprazole salt crystals are very fragile making processes utilising such crystals
`
`less attractive in full scale production. Perfonning the process without
`
`crystallization of the magnesium omeprazole gives a product which is less suitable
`
`as a pharmaceutical substance.
`
`10
`
`In order to use the magnesium salt of omeprazole, in this specification denoted
`
`magnesium omeprazole, in full manufacturing scale in preparing pharmaceutical
`
`formulations primarily for oral administration, such as tablets, it is necessary that
`
`said magnesium omeprazole possesses a combination of properties which makes
`
`15
`
`such full scale manufacturing feasible. One object of the present invention is to
`
`provide a process for full scale production of magnesium omeprazole. A further
`
`object of the present invention is to provide a novel form of the magnesium salt of
`
`omeprazole which can be used in full scale manufacturing of pharmaceutical
`
`formulations, such as tablets.
`
`20
`
`The combination of physical properties of the novel magnesium omeprazole
`
`product of the present invention with respect to the degree of crystallinity, particle
`
`diameter, density, hygroscopicity, water content and content of other solvents are
`
`favorable and permit the manufacture of magnesium omeprazole in a form which
`
`25
`
`possesses the desired properties.
`
`The novel form of magnesium omeprazole can also be formulated into other forms
`
`for oral administration and other types of administration such as rectal
`
`administration. Examples of formulations are tablets, pellets, granules, capsules,
`
`30
`
`suspensions and suppositories.
`
`

`
`wo 95/01977
`
`PCT /SE94/00680
`
`The invention
`
`3
`
`We now provide a novel form of the magnesium salt of omeprazole exhibiting the
`
`desired combination of physical properties. This makes full scale production of
`
`5
`
`magnesium omeprazole as well as full scale production of pharmaceutical
`
`formulations thereof feasible.
`
`The novel process for the manufacture of magnesium omeprazole also circumvents
`
`the above described manufacturing problems and renders possible the recovery and
`
`10
`
`work-up of the magnesium omeprazole substance in traditional chemical process
`
`equipment.
`
`It has been found that the following property is significant to obtain such product:
`
`15
`
`a)
`
`Crystalline form, with a degree of crystallinity of not less than 70%,
`
`preferably higher than 75% as determined by X-ray powder diffraction
`
`It is desirable that the product also exhibits the following properties;
`
`20
`
`b)
`
`Particle size measured as mean mass diameter (MMD) less than 30pm,
`
`preferably less than 20 pm as determined by laser diffraction technique.
`
`c) Density between 1.33 g/cm3 and 1.35 g/cm3 as detennined by powder
`pycnometer.
`
`25
`
`d) Hygroscopicity not exceeding 2% increase of weight upon storage for one
`
`month up to 94% relative atmospheric humidity as determined
`
`gravimetrically.
`
`30
`
`e)
`
`A content of water of between 5% and 10% by weight as determined by
`
`titration according to Karl Fischer.
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`f)
`
`A content of methanol less than 0.1% preferably less than 0.05% by weight
`
`as detennined by gas chromatography, in case methanol is used as solvent.
`
`4
`
`In a further aspect, the invention also relates to a process for manufacturing the
`
`5
`
`novel form of magnesium omeprazole. This process is described in more detail
`
`below.
`
`The invention relates to all of the aspects given under Field of the invention.
`
`10
`
`The process for producing the novel form of magnesium omeprazole is
`
`characterized by the following consecutive steps
`
`a)
`
`treating omeprazole or a salt thereof with magnesium alcoholate in a solution
`
`15
`
`b)
`
`separating inorganic salts from the reaction mixture
`
`c)
`
`crystallizing magnesium omeprazole
`
`d)
`
`isolating the obtained crystalline magnesium omeprazole and, optionally,
`
`20
`
`e)
`
`purifying and drying the crystalline magnesium omeprazole using
`
`conventional methods.
`
`The process for manufacturing the new product can be described in the following
`
`25
`
`way.
`
`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
`magnesium at temperatures between 0°C and reflux temperat~e. The temperature
`should preferably be between 10 and 30°C. After addition of the magnesium to the
`
`30
`
`solution the temperature can, in a second step be raised further to between 0°C and
`
`reflux temperature, preferably 20-50°C. After termination of the reaction the
`
`

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`wo 95/01977
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`PCT /SE94/00680
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`s
`
`temperature is reduced to 0-40°C, preferably 10-2S°C. Omeprazole or a salt of
`
`omeprazole is then added to the solution and after termination of the reaction the
`mixture is cooled to -10°C to +20°C, preferably -S°C to +S0 C. The solvent is then
`evaporated to 40-60% of the initial volume, which makes the inorganic salts
`
`S
`
`precipitate. The precipitate is separated from the reaction solution for example by
`
`centrifugation or filtration and the solution is heated to S°C to 30°C whereafter the
`
`solution is seeded with magnesium omeprazole crystals. An amount of water,
`
`which is approximately equal to the volume of the solution, is added to start the
`
`crystallization. The solution is cooled to -10 to +20°C, preferably 0-10°C to
`
`10
`
`complete the crystallization. The crystals are then separated from the mother liquid
`
`for example by centrifugation or filtration and washed with polar solvents
`
`preferably an aqueous lower alcohol such as aqueous methanol. Finally, the
`
`produced crystals are dried preferably under reduced pressure and heating.
`
`1S
`
`The process for manufacturing the new form of magnesium omeprazole differs
`
`from the earlier known processes in that the product is recovered after a controlled
`
`crystallization step in aqueous alcohol, preferably methanol by, first, separating the
`
`inorganic salts from the mother liqueur. The crystallinity resulting from this step is,
`
`unexpectedly, higher and the product possesses a higher degree of purity and is
`
`20
`
`more stable to decomposition from uptake of moisture. The drying step can be
`
`performed without caking. The new process is possible to perform in conventional
`
`chemical process equipment and gives a product with a higher yield than the
`
`processes hitherto known.
`
`25
`
`The following detailed Example 1 will serve to more fully illustrate the process for
`
`manufacturing magnesium omeprazole in full scale according to the present
`
`invention. In Figures 1 and 2 sample A is manufactured according to this example.
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`

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`wo 95/01977
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`Example 1
`
`PCT /SE94/00680
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`6
`
`A reactor was filled with 2026 litres of methanol. The stirrer was started and the
`
`5
`
`temperature was adjusted to 20°C. 3,90 kg of magnesium was added to the vessel
`and immediately thereafter 1,0 litre of CH2CI2. The reactor was heated to 40°C
`and kept at this temperature for 60 min. It was then cooled to 15°C before the
`
`addition of 99,9 kg of omeprazole. The reactor was kept at this temperature for 60
`
`min and then cooled to 0°C. The temperature was kept at this level for 30 minutes
`
`before 1000 I of methanol were evaporated under vacuum and the inorganic solid
`
`10
`
`salt was separated from the liquid frrst by centrifugation and then by filtration. The
`
`liquid was heated to 10°C and the liquid was seeded with magnesium omeprazole
`
`crystals whereafter the magnesium omeprazole salt was precipitated by addition of
`
`900 1 of water. The mixture was then cooled to 5°C. After the crystallization had
`
`been completed the magnesium omeprazole crystals were centrifuged off and then
`
`15
`
`washed with a mixture of 50 1 of methanol and 150 I of water. The produced
`
`magnesium omeprazole was dried under reduced pressure frnally producing 92,5 kg
`
`of crystalline product corresponding to a yield of 81,4%.
`
`The novel form of the magnesium salt of omeprazole according to Example 1
`
`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 size 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 pycnometer.
`
`30
`
`d) Hygroscopicity of 1.62% increase of weight upon storage for one month at
`
`94% relative atmospheric humidity as determined gravimetrically.
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`7
`
`e)
`
`Content of moisture water of 7.6 by weight as determined by titration
`
`according to Karl Fischer.
`
`f)
`
`Content of methanol of 0.006% by weight as determined by gas
`
`5
`
`chromatography.
`
`A comparison between two different samples of the novel form of magnesium
`
`omeprazole of the present invention obtained from two laboratory scale
`
`experiments by prior art methods and magnesium omeprazole goes forth from
`
`10
`
`diagrams 1 and 2. In these diagrams sample A represents the novel form of the
`
`present invention as manufactured in full scale process equipment Sample B
`
`represents the product of preparation via synthesis by treatment of omeprazole with
`Mg(OCH3)2. Sample C represents the product of preparation via treatment of
`sodium omeprazole with MgCI2.
`
`15
`
`20
`
`Figure 1 shows in diagram 1 that the particle size measured as mean mass
`
`diameter of the product of method A is 19 pm which is smaller than the
`
`corresponding particle size for the products of method B which is 25 pm and of
`
`method C which is greater than 600 pm.
`
`Figure 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 corresponding figure for the
`
`product of sample B, which is 0% and also higher than the corresponding figure of
`
`sample C, which 67%.
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`

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`wo 95/01977
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`CLAIMS
`
`PCT /SE94/00680
`
`8
`
`1. Magnesium omeprazole characterized in having a degree of crystallinity
`
`which is higher than 70% as determined by X-ray powder diffraction.
`
`5
`
`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
`
`10
`
`diameter as determined by laser diffraction technique is less than 30pm, and
`
`preferably less than 20pm.
`
`4. Magnesium omeprazole according to claim I wherein the density is between
`1.33 g/cm3 and 1.35 g/cm3 as determined by powder pycnometer.
`
`15
`
`5. 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.
`
`20
`
`6. Magnesium omeprazole according to claim 1 wherein the water content is
`
`between 5% and 10% by weight as determined by titration according to Karl
`
`Fischer.
`
`7. Magnesium omeprazole according to claim 1 containing less than 0.1% by
`
`25
`
`weight of solvent as determined by gas chromatography.
`
`8. Magnesium omeprazole according to claim 1 containing less than 0.05% by
`
`weight of solvent as determined by gas chromatography.
`
`30
`
`A process for the manufacture of magnesium omeprazole according to any of
`
`9.
`claims 1 to 8 characterized by in consecutive steps
`
`

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`wo 95/01977
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`PCT /SE94/00680
`
`a)
`
`treating omeprazole or a salt thereof with magnesium alcoholate in a solution,
`
`9
`
`b)
`
`separating inorganic salts from the reaction mixture,
`
`..
`
`5
`
`c)
`
`crystallizing magnesium omeprazole,
`
`d)
`
`isolating the obtained crystalline magnesium omeprazole and, optionally,
`
`e)
`
`purifying and drying the crystalline magnesium omeprazole using
`
`10
`
`conventional methods.
`
`10. A process according to Claim 9 wherein the magnesium alcoholate is
`
`magnesium methyl alcoholate.
`
`15
`
`11. A process according to claim 9 wherein the solvent is methanol.
`
`12. A process according to claim 9 wherein the crystallization is accomplished by
`
`addition of water.
`
`20
`
`13. A process according to claim 9 wherein the isolation of the magnesium
`
`omeprazole is performed by centrifugal separation of the crystals.
`
`14. A process according to claim 9 wherein the isolation of the magnesium
`
`omeprazole is performed by crystallization followed by filtration of the crystals.
`
`25
`
`15. 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.
`
`30
`
`16. A process according to claim 9 wherein the magnesium omeprazole crystals
`
`are dried preferably under reduced pressure.
`
`

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`wo 95/01977
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`PCT /SE94/00680
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`17. A process according to claim 9 wherein the drying of the magnesium
`omeprazole crystals is performed by evaporating the remaining solvent by heating.
`
`10
`
`18. Magnesium omeprazole obtained by a process according to any of
`
`5
`
`claims 9 to 17.
`
`19. A pharmaceutical composition containing magnesium omeprazole according
`
`to any of claims 1 to 8 as an active ingredient.
`
`10
`
`20. A pharmaceutical formulation for oral administration containing magnesium
`
`omeprazole according to any of claims 1 to 8 as an active ingredient.
`
`15
`
`20
`
`21. A tablet formulation containing magnesium omeprazole according to any of
`
`claims 1 to 8 as an active ingredient.
`
`22. Magnesium omeprazole according to any of claims 1 to 8 for use in therapy.
`
`23. Magnesium omeprazole according to any of claims 1 to 8 for use in
`inhibiting gastric acid secretion in mammals and man.
`
`24. Magnesium omeprazole according to any of claims 1 to 8 for use as an agent
`
`with gastric mucosa protective activity in mammals and man.
`
`25. Magnesium omeprazole according to any of claims I to 8 for use in the
`
`25
`
`treatment of gastric acid related diseases in mammals and man.
`
`26. The use of magnesium omeprazole according to any of claims 1 to 8 in the
`
`manufacture of a medicament for inhibiting gastric acid secretion.
`
`30
`
`27. The use of magnesium omeprazole according to any of claims 1 to 8 in the
`
`manufacture of a medicament for obtaining gastric mucosa protective activity.
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`

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`
`11
`
`28. The use of magnesium omeprazole according to any of claims 1 to 8 in the
`
`manufacture of a medicament for the treatment of gastric acid related diseases.
`
`29. A method for inhibiting gastric acid secretion in mammals and man by
`
`5
`
`administering to a host in need thereof a therapeutically effective dose of
`
`magnesium omeprazole according to any of claims 1 to 8.
`
`30. A method for the treatment of gastric acid related diseases in mammals and
`
`man by administering to a host in need thereof a therapeutically effective dose of
`
`10
`
`magnesium omeprazole according to any of claims 1 to 8.
`
`

`
`1
`INTERNATIONAL SEARCH REPORT
`
`r---
`International application No.
`PCT/SE 94/00680
`
`A. CLASSIFICATION OF SUBJECT MATIER
`
`IPCS: C07D 401/12, A61K 31/44
`According to International Patent Classification (IPC) or to both national classification and IPC
`B. FIELDS SEARCHED
`
`Minimum documentation searched (classification system followed by classific