IE84049B1 - A factory scale process for producing crystalline atorvastatin trihydrate hemi calcium salt - Google Patents
A factory scale process for producing crystalline atorvastatin trihydrate hemi calcium salt Download PDFInfo
- Publication number
- IE84049B1 IE84049B1 IE2000/1034A IE20001034A IE84049B1 IE 84049 B1 IE84049 B1 IE 84049B1 IE 2000/1034 A IE2000/1034 A IE 2000/1034A IE 20001034 A IE20001034 A IE 20001034A IE 84049 B1 IE84049 B1 IE 84049B1
- Authority
- IE
- Ireland
- Prior art keywords
- vessel
- make
- delivery
- butyl ether
- delivery vessel
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 26
- 229960005370 atorvastatin Drugs 0.000 title claims description 23
- 159000000007 calcium salts Chemical class 0.000 title claims description 14
- -1 atorvastatin trihydrate Chemical class 0.000 title claims description 12
- BZLVMXJERCGZMT-UHFFFAOYSA-N MeOtBu Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 41
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 32
- 238000006243 chemical reaction Methods 0.000 claims description 27
- 239000002002 slurry Substances 0.000 claims description 18
- 238000007792 addition Methods 0.000 claims description 16
- 238000002425 crystallisation Methods 0.000 claims description 16
- 230000005712 crystallization Effects 0.000 claims description 16
- VSGNNIFQASZAOI-UHFFFAOYSA-L Calcium acetate Chemical compound [Ca+2].CC([O-])=O.CC([O-])=O VSGNNIFQASZAOI-UHFFFAOYSA-L 0.000 claims description 15
- 239000001639 calcium acetate Substances 0.000 claims description 14
- 229960005147 calcium acetate Drugs 0.000 claims description 14
- 235000011092 calcium acetate Nutrition 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- 239000011159 matrix material Substances 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- 239000010410 layer Substances 0.000 claims description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 9
- 239000011877 solvent mixture Substances 0.000 claims description 8
- 239000012535 impurity Substances 0.000 claims description 7
- 239000012044 organic layer Substances 0.000 claims description 6
- OUCSEDFVYPBLLF-KAYWLYCHSA-N 5-(4-fluorophenyl)-1-[2-[(2R,4R)-4-hydroxy-6-oxooxan-2-yl]ethyl]-N,4-diphenyl-2-propan-2-ylpyrrole-3-carboxamide Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@H]2OC(=O)C[C@H](O)C2)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 OUCSEDFVYPBLLF-KAYWLYCHSA-N 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 4
- 159000000000 sodium salts Chemical class 0.000 claims description 4
- 239000011268 mixed slurry Substances 0.000 claims description 2
- 238000007789 sealing Methods 0.000 claims description 2
- 229960001770 Atorvastatin calcium Drugs 0.000 description 15
- FQCKMBLVYCEXJB-MNSAWQCASA-L atorvastatin calcium Chemical compound [Ca+2].C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC([O-])=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1.C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC([O-])=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 FQCKMBLVYCEXJB-MNSAWQCASA-L 0.000 description 15
- XUKUURHRXDUEBC-KAYWLYCHSA-N atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 description 13
- HVYWMOMLDIMFJA-DPAQBDIFSA-N (3β)-Cholest-5-en-3-ol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 8
- 229940107161 Cholesterol Drugs 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 235000012000 cholesterol Nutrition 0.000 description 4
- 150000002596 lactones Chemical class 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 3
- 239000008367 deionised water Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- KJTLQQUUPVSXIM-ZCFIWIBFSA-M (R)-mevalonate Chemical compound OCC[C@](O)(C)CC([O-])=O KJTLQQUUPVSXIM-ZCFIWIBFSA-M 0.000 description 2
- CABVTRNMFUVUDM-SJBCKIPMSA-N 3-hydroxy-3-methylglutaryl-CoA Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)CC(O)(CC(O)=O)C)O[C@H]1N1C2=NC=NC(N)=C2N=C1 CABVTRNMFUVUDM-SJBCKIPMSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 2
- 230000001808 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000005755 formation reaction Methods 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- ZYVYEJXMYBUCMN-UHFFFAOYSA-N 1-methoxy-2-methylpropane Chemical compound COCC(C)C ZYVYEJXMYBUCMN-UHFFFAOYSA-N 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- 208000008787 Cardiovascular Disease Diseases 0.000 description 1
- 210000004185 Liver Anatomy 0.000 description 1
- 230000036823 Plasma Levels Effects 0.000 description 1
- 235000004443 Ricinus communis Nutrition 0.000 description 1
- 240000000528 Ricinus communis Species 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000003529 anticholesteremic agent Substances 0.000 description 1
- 239000003524 antilipemic agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 201000001320 atherosclerosis Diseases 0.000 description 1
- 229960004829 atorvastatin calcium trihydrate Drugs 0.000 description 1
- 230000037348 biosynthesis Effects 0.000 description 1
- 235000012970 cakes Nutrition 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000003518 caustics Substances 0.000 description 1
- 230000002860 competitive Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- MDKXBBPLEGPIRI-UHFFFAOYSA-N ethoxyethane;methanol Chemical compound OC.CCOCC MDKXBBPLEGPIRI-UHFFFAOYSA-N 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 238000005649 metathesis reaction Methods 0.000 description 1
- 150000002894 organic compounds Chemical group 0.000 description 1
- 230000001575 pathological Effects 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- OZAIFHULBGXAKX-UHFFFAOYSA-N precursor Substances N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000009790 rate-determining step (RDS) Methods 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- BBCAQPYJVYMQFB-UHFFFAOYSA-N sodium;2-methylpropane Chemical compound [Na+].C[C-](C)C BBCAQPYJVYMQFB-UHFFFAOYSA-N 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 150000003432 sterols Chemical class 0.000 description 1
- 235000003702 sterols Nutrition 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 150000004684 trihydrates Chemical class 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Description
A factory scale process for producing crystalline atorvastatin trihydrate hemi
calcium salt
Introduction
The invention relates to an improved process for producing crystalline atorvastatin
calcium which is known by the chemical name [R—(R*,R*)]—2~(4—fluoropheny1)—[3,6-
dihydroxy~5-(1—methylethyl)—3—pheny1—4—[(phenylamino)carbonyl]—lH—pyrrole— l-
heptanoic acid hemi calcium salt.
Atorvastatin is useful as a selective and competitive inhibitor of the enzyme 3—
hydroxy—3—methylglutaryl—coenzyme A (HMG—CoA) reductase, the rate—limiting
enzyme that converts 3-hydroxy-3—methylglutaryl-coenzyme A to mevalonate, a
precursor of sterols such as cholesterol. The conversion of HMG-CoA to mevalonate
is an early and rate—limiting step in cholesterol biosynthesis.
Atorvastatin as well as some of its metabolites are pharmacologically active in
humans and are thus useful as a hypolipidemic and hypocholesterolemic agent. The
liver is the primary site of action and the principal site of cholesterol synthesis.
Clinical and pathological studies show that elevated plasma levels of total cholesterol
and associated triglycerides promote human atherosclerosis and are risk factors for
developing cardiovascular disease.
United States Patent Number 4,681,893, which is herein incorporated by reference,
discloses certain t_r@s-6—[2—(3-— or 4—carboxamido—substituted—pyrrol—1—y1) a1kyl]—4
—hydroxy—pyran—2—ones including trans (i)—5—(4—fluorophenyl)—2—(1—methylethyl)—
N,4—diphenyl—l—[(2—tetrahydro-4—hydroxy—6——oxo—2H—pyran—2—yl)ethyl]— l H-
pyrrole—3—carboxamide.
United States Patent Number 5,273,995, which is herein incorporated by reference,
discloses the enantiomer having the R form of the ring—opened acid of trans —5—(4—
fluorophenyl)—2—(l—methylethyl)—N, 4—diphenyl—l—[(2—tetrahydro—4—hydroxy~6—
oxo—2H—pyran—2—yl)ethyl]-1H—pyrrole—3—carboxamide, i.e., [R—(R*,R*)]—2—(4—
fluorophenyl)-[3, 6-dihydroxy—5—(l—methylethyl)-3—phenyl—4—[(phenylamino)
carbony1]—lH—pyrrole—l—heptanoic acid.
The above described atorvastatin compounds have been prepared by a superior
convergent route disclosed in the following United States Patent Numbers 5,003,080;
,097,045; 5,103,024; 5,124,482 and 5,149,837 which are herein incorporated by
reference and Baumann K.L., Butler D.E., Deering C.F., et al, Tetrahedron Letters
;33:2283-2284.
One of the critical intermediates disclosed in United States Patent Number 5,097,045
has also been produced using novel chemistry, as disclosed in United States Patent
Number 5,155,251, which is herein incorporated by reference and Brower P.L.,
Butler D.E., Deering C .F., et al, Tetrahedron Letters l992;33:2279-2282.
United States Patent Numbers 5,216,174; 5,245,047; 5,248,793; 5,280,126;
,397,792; 5,342,952; 5,298,627; 5,446,054; 5,470,981; 5,489,690; 5,489,691;
,109,488; 5,969,156; US6,087,5l1; US5,998,663 and W099/32434 which are
herein incorporated by reference, disclose various processes and key intermediates for
preparing atorvastatin.
Atorvastatin is prepared as its calcium salt, i.e., [R—(R*, R*)]—2—(4—fluorophenyl)-[3,
6—dihydroxy—5—(l—methylethyl)—3—phenyl—4—[(phenylamino) carbony1]-lH—pyrrole-
1-heptanoic acid calcium salt (2:1). The calcium salt is desirable since it enables
atorvastatin to be conveniently formulated in, for example, tablets, capsules,
lozenges, powders, and the like for oral administration.
It was unexpectedly found that on scale up to a commercial factory scale, the average
crystal size of atorvastatin calcium was in some instances smaller than expected.
The object of the present invention is therefore to provide a process for producing
crystalline atorvastatin calcium on a factory scale which routinely and consistently
produces material in a consistent size range.
Statements of Invention
According to the invention there is provided a factory scale process for producing
crystalline atorvastatin trihydrate hemi calcium salt comprising the steps of:-
reacting a mixture of atorvastatin lactone, methanol and methyl tert-butyl
ether with sodium hydroxide to form the ring—opened sodium salt;
forming a product rich aqueous layer and an organic layer comprising methyl
tert-butyl ether containing impurities;
removing the organic layer comprising methyl tert-butyl ether containing
impurities;
extracting the product rich aqueous layer with methyl tert-butyl ether;
adding an extra charge of methyl rert-butyl ether to a vessel containing the
product rich aqueous layer in an amount of at least 1% w/v of the contents of
the vessel;
sealing the reaction vessel;
heating the contents of the sealed reaction vessel to 47 to 57°C in the presence
of the extra charge of methyl tert-butyl ether which saturates the the
crystallisation matrix on heating; and
WARNOI/C/IE
_ 4 _
adding calcium acetate hemihydrate to the sealed reaction vessel to
form atorvastatin trihydrate hemi calcium salt.
It was found that the addition of an extra charge of methyl tert-butyl ether after
extractions with methyl tert-butyl ether ensures a saturated crystallisation matrix at
the elevated temperature which has suflicient organic solvent content compensating
for any increased solubility with heat and any loss to the headspace and was
surprisingly found to result in the formation of crystals of atorvastatin calcium within
a consistent size range on a factory scale.
In a preferred embodiment of the invention the process includes the steps of:
preparing a mixed slurry in a pressurised slurry make-up/ delivery vessel by:
introducing water into the make-up/ delivery vessel;
introducing methanol into the make-up/ delivery vessel;
subsequently adding seed crystals of atorvastatin trihydrate hemi calcium salt
to the make-up/ delivery vessel; and
after addition of calcium acetate hemihydrate to the vessel, adding the seed
mixture thus formed from the pressurised make-up/ delivery vessel to the
sealed reaction vessel under pressure to maintain saturation of the
crystallisation matrix by methyl tert-butyl ether at the elevated temperature in
the reaction vessel.
WARNOl/C/IE
Preferably the process includes the step of agitating the methanol and water in the
make-up/ delivery vessel to produce a solvent mixture before addition of the seed
crystals to the make-up/ delivery vessel.
In one embodiment of the invention the process includes the step of mixing the
mixture of water, methanol and seed crystals of atorvastatin trihydrate hemi calcium
salt in the make-up/ delivery vessel to form a seed crystal slurry for delivery from the
pressurised slurry make-up/ delivery vessel into the sealed pressurised reaction vessel
containing the heated crystallisation matrix saturated with methyl tert—butyl ether.
In a preferred embodiment the make—up delivery vessel is pivotally mounted on a
support frame and the methanol and water mixture are agitated by rocking the make-
up/ delivery vessel to produce the solvent mixture.
In a particularly preferred embodiment the make-up/ delivery vessel is pivotally
mounted on a support frame and the solvent mixture and seed crystals are mixed by
rocking the make-up/ delivery vessel to form the seed crystal slurry.
The invention also provides a process which allows a seed slurry of atorvastatin to be
prepared quickly and efficiently and which can be introduced to the reaction vessel
under pressure thereby maintaining a sealed system. A sealed system is maintained
throughout the atorvastatin calcium crystallisation process to prevent the loss of
solvents to evaporation.
In one embodiment of the invention delivery of the seed slurry from the pressurised
make-up/ delivery vessel into the sealed pressurised reaction vessel is commenced not
more than 5 minutes after commencement of the addition of calcium acetate.
WARNOI/C/IE
Brief Description of the Drawings
The invention will be more clearly understood from the following description given
by way of example only with reference to the accompanying drawings in which:-
Fig. l is a perspective view of a make-up/ delivery vessel used in the process of
the invention;
Fig. 2 is a front elevational view of the make-up/ delivery vessel; and
Fig. 3 is a side view of the make-up/ delivery vessel illustrating the direction of
movement when the vessel is rocked.
Detailed Description
The invention will be more clearly understood from the following description given
by way of example only.
Crystalline atorvastatin calcium is a white to off white solid that is insoluble in
aqueous solutions of pH4 and above. Atorvastatin calcium is very slightly soluble in
distilled water, pH7.4 phosphate buffer and acetonitrile, slightly soluble in ethanol
and freely soluble in methanol. Crystalline atorvastatin calcium trihydrate has the
following chemical structure:
WARNO1/C/IE
_ F _
OH OH 0
@/ o' Ca++ .3H20
H\N_< Y
O
— "2
Scheme 1
The process for the preparation of atorvastatin calcium from atorvastatin lactone
involves saponification in a water/ methyl alcohol/ methyl ten‘-butyl ether (2-
methoxymethyl-propane; ten‘-butyl methyl ether) mixture with sodium hydroxide.
The aqueous layer containing the sodium salt of atorvastatin is washed with methyl
tert-butyl ether to remove small quantities of process impurities. A small aliquot of
methyl ten‘-butyl ether is added to the crystallisation matrix. Sodium-to—calcium salt
metathesis with concurrent crystallisation is accomplished by the slow addition of an
aqueous calcium acetate solution to the sodium salt solution. To ensure
crystallisation simultaneous with addition, the reaction mixture is seeded with
crystalline atorvastatin shortly after the start of the calcium acetate addition. The
product is isolated by filtration and, after washing with water/ methyl alcohol and
water, is centrifuged, vacuum dried and milled to give crystalline atorvastatin as the
trihydrate. This reaction scheme is shown in Scheme 2 below.
<3’ _N/\/ on 2. Ca(OAc)2
WARNOI/C/IE
. 2NaOH(aq)/ OH on 0
O MTBE/Me0H
Scheme 2
Primarily the crystallisation matrix consists of water, some methanol, methyl tert-
butyl ether and sodium atorvastatin.
Methyl ten‘-butyl ether is an organic compound which is liquid at room temperature.
It is used in the process for preparing atorvastatin to remove process-generated
impurities and/ or impurities present in the lactone.
Methyl tert-butyl ether is very volatile and in the crystallisation matrix could be lost to
the headspace of the reaction vessel thereby disturbing the equilibrium of the
crystallisation matrix.
It was found that the addition of an extra charge of methyl tert-butyl ether after
extractions with methyl ten‘-butyl ether ensures a saturated crystallisation matrix at
the elevated temperature which has sufficient organic solvent content compensating
for any loss to the headspace or increase in solubility with heat and was surprisingly
found to result in the formation of crystals of atorvastatin calcium within a
consistent size range on a factory scale.
Ca++ .3H2O
/
@_ ° +2NaOAc
WARNOI/C/IE
The invention also provides a process which allows a seed slurry of atorvastatin to be
prepared quickly and efficiently and which can be introduced to the reaction vessel
under pressure thereby maintaining a sealed system. A sealed system is maintained
throughout the atorvastatin calcium crystallisation process to prevent the loss of
solvents to evaporation.
Figs. 1 to 3 illustrate a make-up/ delivery vessel 1 to charge, under pressure,
atorvastatin calcium seed crystals to a reaction vessel. The make—up delivery vessel 1
comprises a funneled base 2, a top lid 3 and a generally cylindrical side wall 4
extending between the base 2 and the lid 3. The base 2 has an outlet pipe 5 fitted
with a manually operated valve 6. An outlet hose may be connected via a quick
release coupling to the outlet pipe 5.
The lid 3 has an inlet pipe 10 with a flanged end 11 and a side branch 12 fitted with a
manual valve 13 for connection via a quick-release coupling to a feed hose. The lid 3
has a connecting line 15 with a pressure gauge 16 and a pressure relief valve 17.
A pair of diametrically opposed pins 19 are mounted to and extend outwardly of the
side wall 4 to engage in mountings 20 carried on a support frame 21 having ground
engaging castors 22. A handle 25 in the form of a length of pipe is attached to the
vessel sidewall 4 to facilitate rocking motion of the vessel 1 to mix the contents. In
use, solvents are added through the inlet pipe 10 and atorvastatin calcium seed, is
added after removal of lid, 3. Thorough mixing is facilitated by rocking the vessel 1.
This process is carried out under pressure and, on completion of mixing, the contents
of the vessel 1 are rapidly delivered under pressure through the outlet line 5 to a
reaction vessel.
The invention will be more clearly understood from the following example.
WARNOI/C/IE
_ 10 _
Example 1
kg atorvastatin lactone, l028kg methyl terr—buty1 ether and 496kg of methanol are
charged to a 6000 litre glass lined reaction vessel. The lactone is prepared as
described in US 5,273,995, the entire contents of which are incorporated by
reference. The reaction mixture is agitated and heated to about 30°C to dissolve the
lactone. When the lactone is dissolved, approximately 3200 litres of caustic solution
is added (l9kg of sodium hydroxide 97.5% dissolved in 3165 litres of deionised
water). The contents of the vessel are heated to 47 to 57°C and agitated for at least 45
minutes.
After cooling to 25 to 35°C under an inert atmosphere the contents are allowed to
settle and the organic layer is discarded. 765kg methyl tert-butyl ether is charged to
the aqueous layer, the contents mixed and allowed to settle. The organic layer is
discarded.
kg of extra methyl tert-butyl ether is charged to the product rich aqueous layer in
the reaction vessel which is then sealed. The contents of the sealed reaction vessel
are heated to 47 to 57°C maintainin a ressurised s stem.
8 P Y
A solution of calcium acetate (40kg calcium acetate hemihydrate in 1365 litres
deionised water) is transferred to the pressurised vessel. Shortly after commencement
of the calcium acetate addition the transfer is stopped and atorvastatin trihydrate
hemi calcium salt seed, prepared as described in US5,969,l56 which is herein
incorporated by reference, is introduced.
A seed slurry is prepared by charging 37 litres deionised water and 13kg methanol to
a stainless steel make-up/ delivery vessel 1 as described above with reference to Figs.
1 to 3. The solvent mixture is agitated by rocking the vessel 1 back and forth. 3.6kg
atorvastatin calcium seed crystals are then charged to the solvent mixture. The
contents of the delivery vessel 1 are then mixed by rocking until a seed slurry is
WARNOI/C/IE
_ 11 _
formed. Pressure is applied to the make-up/ delivery vessel 1 so that the pressure in
the vessel 1 is greater than that of the reaction vessel to which its contents are to be
delivered. The make—up/ delivery vessel 1 is then attached to the reaction vessel via a
flexible hose attached to the outlet pipe 5 and the seed slurry is charged rapidly over 2
to 3 minutes, under pressure, into the reaction vessel. We have found that for
optimum results the seed slurry delivery should be commenced not more than 5 and
not less than 3 minutes after the addition of calcium acetate.
After the addition of the seed slurry the calcium acetate addition is immediately
resumed to complete the calcium transfer.
The product cake is washed first with a methanol/water solution followed by a water
wash. The product is dried at 60° to 70°C under vacuum for 1 to 4 days to yield
atorvastatin calcium. The dried product is then loaded into drums.
We have found that the process facilitates routine production of atorvastatin calcium
on a factory scale with a consistent size range.
The invention is not limited to the embodiments hereinbefore described which may
be varied in detail.
Claims (8)
1. A factory scale process for producing crystalline atorvastatin trihydrate hemi calcium salt comprising the steps of:- reacting a mixture of atorvastatin lactone, methanol and methyl terr- butyl ether with sodium hydroxide to form the ring-opened sodium salt; forming a product rich aqueous layer and an organic layer comprising methyl tert-butyl ether containing impurities; removing the organic layer comprising methyl tefl-butyl ether containing impurities; extracting the product rich aqueous layer with methyl rert-butyl ether; adding an extra charge of methyl tert-butyl ether to a vessel containing the product rich aqueous layer in an amount of at least 1% w/v of the contents of the vessel; sealing the reaction vessel; heating the contents of the sealed reaction Vessel to 47 to 57°C in the presence of the extra charge of methyl tert-butyl ether which saturates the crystallisation matrix on heating; and adding calcium acetate hemihydrate to the sealed reaction vessel to form atorvastatin trihydrate hemi calcium salt.
2. A process as claimed in claim 1 including the steps of:- preparing a mixed slurry in a pressurised slurry make-up/delivery vessel by: introducing water into the make-up/ delivery vessel; introducing methanol into the make-up/ delivery vessel; subsequently adding seed crystals of atorvastatin trihydrate hemi calcium salt to the make-up/ delivery vessel; and after addition of calcium acetate hemihydrate to the vessel, adding the seed mixture thus formed from the pressurised make-up/ delivery vessel to the sealed reaction vessel under pressure to maintain saturation of the crystallisation matrix by methyl tert-butyl ether at the elevated temperature in the reaction vessel.
A process as claimed in claim 2 including the step of agitating the methanol and water in the make-up/ delivery vessel to produce a solvent mixture before addition of the seed crystals to the make-up/ delivery vessel.
A process as claimed in claim 2 or 3 including the step of mixing the mixture of water, methanol and seed crystals of atorvastatin trihydrate hemi calcium salt in the make-up/ delivery vessel to form a seed crystal slurry for delivery from the pressurised slurry make-up/ delivery vessel into the sealed pressurised reaction vessel containing the heated crystallisation matrix saturated with methyl tert-butyl ether.
A process as claimed in claim 3 wherein the make-up/ delivery vessel is pivotally mounted on a support frame and the methanol and water mixture are agitated by rocking the make-up/ delivery vessel to produce the solvent mixture.
6. A process as claimed in claim 4 wherein the make-up/ delivery vessel is pivotally mounted on a support frame and the solvent mixture and seed crystals are mixed by rocking the make-up/ delivery vessel to form the seed crystal slurry.
7. A process as claimed in any of claims 2 to 6 wherein delivery of the seed slurry from the pressurised make—up/ delivery Vessel into the sealed pressurised reaction vessel is not more than 5 minutes after the commencement of the addition of calcium acetate.
8. A process as claimed in claim 7 wherein delivery of the seed slurry is commenced not less than 3 minutes after the addition of calcium acetate.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IE2000/1034A IE84049B1 (en) | 2000-12-18 | A factory scale process for producing crystalline atorvastatin trihydrate hemi calcium salt |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IEIRELAND17/12/19991999/1073 | |||
IE991073 | 1999-12-17 | ||
IE2000/1034A IE84049B1 (en) | 2000-12-18 | A factory scale process for producing crystalline atorvastatin trihydrate hemi calcium salt |
Publications (2)
Publication Number | Publication Date |
---|---|
IE20001034A1 IE20001034A1 (en) | 2002-02-06 |
IE84049B1 true IE84049B1 (en) | 2005-11-02 |
Family
ID=
Similar Documents
Publication | Publication Date | Title |
---|---|---|
AU776613B2 (en) | A factory scale process for producing crystalline atorvastatin trihydrate hemi calcium salt | |
BE1012420A6 (en) | Salt paroxetine new method for its preparation and pharmaceutical composition containing same. | |
AU780247B2 (en) | A process for producing crystalline atorvastatin calcium | |
EP1948598B1 (en) | Process for preparation of (3r, 5r)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-hydroxy methyl phenyl amino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid hemi calcium salt | |
CN100528850C (en) | Indane acetic acid derivatives and their use as pharmaceutical agents, intermediates, and method of preparation | |
NO309899B1 (en) | Form III crystalline (R- (R *, R *) - 2- (4-fluorophenyl) - <beta> - <delta> -dihydroxy-5- (1-methylethyl) -3-phenyl-4- (phenylamino) carbonyl ) - 1H-pyrrole-1-heptanoic acid hemicalcium salt, use thereof and pharmaceutical composition containing the compound | |
CZ294108B6 (en) | Crystalline form I of atorvastatin hydrate, i.e. [R-(R*,R*)]-2-(4-fluorophenyl)- beta, delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid hemi calcium salt | |
MXPA03004276A (en) | Hydrolysis of [r(r*,r*)]-2 -(4-fluorophenyl) -beta, delta -dihydroxy- 5-(1-methylethyl) -3-phenyl-4 -[(phenylamino) carbonyl]- 1h-pyrrole-1 -heptanoic acid esters with calcium hydroxide. | |
WO2006048893A2 (en) | A process for synthesis of large particle size statin compounds | |
US7652152B2 (en) | Synthetic method of optically pure (S)-3-hydroxypyrrolidine | |
IE84049B1 (en) | A factory scale process for producing crystalline atorvastatin trihydrate hemi calcium salt | |
IES20001035A2 (en) | A factory scale process for producing crystalline atorvastatin trihydrate hemi calcium salt | |
IE20001034A1 (en) | A factory scale process for producing crystalline atorvastatin trihydrate hemi calcium salt | |
WO2006048894A1 (en) | Novel crystalline forms of atorvastatin calcium and processes for preparing them. | |
CN1040747C (en) | N-substituting group-4-substituted benzyl-5-alkyl-5-substituted benzyl-pyrrolidone-2, and its intermediate, its synthetic method and its appliance | |
IES20001033A2 (en) | An improved process for producing crystalline atorvastation calcium | |
IE20001032A1 (en) | An improved process for producing crystalline atorvastatin calcium | |
EA030553B1 (en) | Tapentadol maleate and crystalline forms thereof | |
US20050143431A1 (en) | Novel crystalline forms of parecoxib sodium | |
MXPA01000307A (en) | Paroxetine methanesulfonate |