U.S. patent application number 13/271445 was filed with the patent office on 2012-02-09 for process for preparation of high-purity meloxicam and meloxicam potassium salt.
Invention is credited to Gyorgyi Vereczkeyne Donath, Valeria Hofmanne Fekete, Gyulane Kortvelyessy, Gyorgy Krasznai, Gyula Lukacs, Norbert Mesterhazy, Tibor MEZEI, Eniko Molnar, Kalman Nagy, Eva Pecsi, Marta Porcs-Makkay, Gyula Simig, Balazs Volk.
Application Number | 20120035162 13/271445 |
Document ID | / |
Family ID | 34224969 |
Filed Date | 2012-02-09 |
United States Patent
Application |
20120035162 |
Kind Code |
A1 |
MEZEI; Tibor ; et
al. |
February 9, 2012 |
PROCESS FOR PREPARATION OF HIGH-PURITY MELOXICAM AND MELOXICAM
POTASSIUM SALT
Abstract
The invention provides a process for the preparation of high
purity meloxicam of the Formula (II). The meloxicam raw product is
reacted with the solution of potassium hydroxide or potassium
carbonate, whereby high purity meloxicam potassium salt monohydrate
is produced. Said salt is subsequently treated with mineral or
organic acid to yield high-purity meloxicam.
Inventors: |
MEZEI; Tibor; (Budapest,
HU) ; Simig; Gyula; (Budapest, HU) ; Molnar;
Eniko; (Erd, HU) ; Lukacs; Gyula; (Budapest,
HU) ; Porcs-Makkay; Marta; (Pomaz, HU) ; Volk;
Balazs; (Budapest, HU) ; Hofmanne Fekete;
Valeria; (Budapest, HU) ; Nagy; Kalman;
(Budapest, HU) ; Mesterhazy; Norbert;
(Szombathely, HU) ; Krasznai; Gyorgy; (Budapest,
HU) ; Donath; Gyorgyi Vereczkeyne; (Budapest, HU)
; Kortvelyessy; Gyulane; (Budapest, HU) ; Pecsi;
Eva; (Budapest, HU) |
Family ID: |
34224969 |
Appl. No.: |
13/271445 |
Filed: |
October 12, 2011 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
11793548 |
Jan 7, 2009 |
|
|
|
13271445 |
|
|
|
|
Current U.S.
Class: |
514/226.5 ;
544/49 |
Current CPC
Class: |
A61P 29/00 20180101;
A61P 27/00 20180101; A61P 43/00 20180101; C07D 417/12 20130101 |
Class at
Publication: |
514/226.5 ;
544/49 |
International
Class: |
A61K 31/5415 20060101
A61K031/5415; A61P 29/00 20060101 A61P029/00; C07D 279/16 20060101
C07D279/16 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 18, 2004 |
HU |
P0402634 |
Dec 16, 2005 |
HU |
PCT/HU2005/000136 |
Claims
1-13. (canceled)
14. Meloxicam potassium salt monohydrate of the Formula (I)
##STR00006##
15. Meloxicam potassium salt monohydrate of the Formula (I)
##STR00007## essentially free of
4-hydroxy-2-methyl-N-alkyl-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3--
carboxamide-1,1-dioxide of the Formula (V) ##STR00008## wherein R
is methyl, ethyl or isopropyl.
16. A pharmaceutical composition comprising a therapeutically
effective amount of meloxicam potassium salt monohydrate of the
Formula (I) ##STR00009## according to claim 14 and one or more
pharmaceutically acceptable vehicles or auxiliary agents.
17. A process for the preparation of 99.8% pure meloxicam potassium
salt monohydrate of the Formula (I) ##STR00010## as defined in
claim 14, which comprises the steps of: (a) reacting crude
meloxicam of the Formula (II) ##STR00011## which also contains
water-insoluble impurities including the compound of the Formula
(V) ##STR00012## wherein R is methyl, ethyl or isopropyl with
potassium hydroxide or potassium carbonate dissolved in water or in
the mixture of water and an organic solvent, (b) separating pure
meloxicam potassium salt monohydrate from the water-insoluble
impurities of the Formula (V) and if desired, (c) crystallizing the
pure meloxicam potassium salt monohydrate of the Formula (I) thus
formed.
18. Meloxicam of the Formula (II) ##STR00013## free of
water-insoluble impurities of the compound of the Formula (V)
##STR00014## wherein R is methyl, ethyl or isopropyl, prepared
according to a process which comprises the following steps: (a)
dissolving meloxicam potassium salt monohydrate of the Formula (I)
##STR00015## with the water-insoluble impurities of the Formula
(V), in water or in a mixture of water and an organic solvent, (b)
removing from the meloxicam potassium salt monohydrate, the
water-insoluble impurities of the compound of the Formula (V); and
(c) treating the resulting solution with an organic or inorganic
acid, and crystallizing 99.8% pure meloxicam
19. Meloxicam of the Formula (II) ##STR00016## free of
water-insoluble impurities of the compound of the Formula (V)
##STR00017## wherein R is methyl, ethyl or isopropyl, prepared
according to a process which comprises the following steps: (a)
transforming meloxicam raw product into crystalline meloxicam
potassium salt monohydrate of the Formula (I) ##STR00018## with the
water-insoluble impurities of the compound of the Formula (v), (b)
dissolving said meloxicam potassium salt monohydrate of the Formula
(I) with the water-insoluble impurities of the Formula (V) in water
or in a mixture of water and an organic solvent, (c) removing from
the meloxicam potassium salt monohydrate, the water-insoluble
impurities of the compound of the Formula (V), and (d) treating the
dissolved potassium salt of meloxicam with an organic or inorganic
acid, followed by crystallization of 99.8% pure meloxicam of the
Formula (II).
20. Meloxicam of the Formula (II) ##STR00019## free of
water-insoluble impurities of the compound of the Formula (V)
##STR00020## wherein R is methyl, ethyl or isopropyl, prepared
according to a process which comprises the following steps: (a)
reacting a compound of the Formula (III) ##STR00021## wherein R is
methyl, ethyl or isopropyl with 2-amino-5-methyl-thiazole of the
Formula (IV) ##STR00022## to form a meloxicam raw product of the
Formula (II); (b) transforming the resulting meloxicam of the
Formula (II) into its potassium monohydrate salt along with the
water-insoluble impurities of the compound of the Formula (V), (c)
separating the water-insoluble impurities of the compound of the
Formula (V) from an aqueous or aqueous-organic solution of said
meloxicam potassium salt to form a solution of 99.8% pure
meloxicam; and (d) treating said solution with an organic or
inorganic acid and crystallizing 99.8% pure meloxicam.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to a process for the
preparation of
4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carbox-
amide-1,1-dioxide of the Formula (II),
##STR00001##
also known by the International Nonproprietary Name (INN) meloxicam
and its potassium salt monohydrate of the Formula (I)
##STR00002##
in high purity.
TECHNICAL BACKGROUND OF THE INVENTION
[0002] Meloxicam belongs to the group of non-steroidal
antiinflammatory drugs. It exerts its pharmacological effect by the
inhibition of the cyclooxygenase (COX) enzyme system, which has
significant role in the development of inflammatory processes. The
medicinal importance of meloxicam resides in the fact that
meloxicam selectively inhibits the COX-2 enzyme. This phenomenon
results in less adverse effects during the medication period. It
was found that the probability of the development of kidney-related
or gastrointestinal adverse effects is significantly lower during
the treatment using meloxicam than in those cases, when different,
non-selective COX-inhibitors were administered.
[0003] Processes for the preparation of meloxicam have been
disclosed in European Patent No. 2482. According to the first
process, an activated form of
4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylic acid of the
Formula (III),
##STR00003##
such as its methyl-, ethyl- or isopropyl ester (wherein the meaning
of the R group in the Formula (III) is methyl, ethyl or isopropyl,
respectively) is reacted with 2-amino-5-methyl-thiazole of the
Formula (IV)
##STR00004##
at high temperature. During this reaction, by-products with similar
chemical structure to meloxicam and some tar are also formed,
therefore further purification of the raw product is required.
Solvents most often used for the recrystallization of raw meloxicam
are dichloroethane and dichloromethane. The above mentioned process
has the disadvantage that toxic and costly solvents are used, which
are harmful to the environment as well. During the subsequent
drying, it must be assured that the residual solvent concentration
in the finished active ingredient should not exceed a threshold
concentration set by health authorities and pharmacopoeias. At the
drying temperature, thermal decomposition of the active ingredient
also takes place. Use of halogenated organic solvents requires
extensive analytical testing, because the residual solvent
concentration must be determined in costly analytical
measurements.
[0004] In the second known process, the nitrogen atom of the
2H-1,2-benzothiazine ring is methylated using either the very
expensive methyl jodide or the extremely toxic dimethyl sulfate.
Due to its low yield and high production costs, this process is not
used on an industrial scale.
[0005] It was found that when using the above mentioned processes,
the by-product
4-hydroxy-2-methyl-N-alkyl-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3--
carboxamide-1,1-dioxide of the Formula (V),
##STR00005##
wherein the alkyl group corresponds identical to the R group in the
starting compound of the Formula (III), i.e. methyl, ethyl or
isopropyl, is formed in an amount of 1-20% by weight. Compounds of
the Formula (V) are crystalline compounds poorly soluble in organic
solvents and having their melting point above 250.degree. C.
Impurities of the Formula (V) can be removed partly by filtering
the hot solution of meloxicam crude product. However, a dissolved
portion of the compounds of Formula (V) amounting to a few tenth
percent crystallizes together with meloxicam upon cooling,
therefore compounds of the Formula (V) appear in the final
pharmaceutical active ingredient as impurity. It was observed that
the compounds of the Formula (V) are produced in the largest
quantity (10-20% by weight), if the compound of the Formula (III)
is used as starting material wherein R is methyl. The smallest
amount of the compound of Formula (V) is produced in the case when
R is isopropyl in the starting compound of the Formula (III).
According to the specifications of the pharmacopoeias, threshold
concentration of the compounds of the Formula (V) is 0.1% by
weight, which could be achieved only after recrystallizing the
crude product several times from dichloromethane.
[0006] United States Patent Application No. 20030109701 discloses
processes for the preparation of several meloxicam polymorph forms
by dissolving meloxicam in sodium-hydroxide solution prepared in
water or in the mixture of water and an organic solvent,
subsequently acidifying the solution of meloxicam sodium salt, thus
setting meloxicam free from its sodium salt. In this way, different
crystalline modifications of meloxicam are obtained, depending upon
the conditions used during dissolution and precipitation.
Subsequently, the polymorph form obtained in the above described
process is converted into the pharmaceutically acceptable polymorph
I form.
SUMMARY OF THE INVENTION
[0007] The objective of our research has been to develop a process
for the preparation of high purity meloxicam suitable as
pharmaceutical active ingredient and said high purity meloxicam
being essentially free of
4-hydroxy-2-methyl-N-alkyl-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3--
carboxamide-1,1-dioxide impurity of the Formula (V), wherein the
meaning of alkyl is methyl, ethyl or isopropyl.
[0008] The above objective is solved according to the present
invention.
[0009] Surprisingly, it has been found that meloxicam potassium
salt monohydrate of the Formula (I) can be crystallized from
aqueous solution in exceptionally high purity, thus allowing the
purification of raw meloxicam.
[0010] According to an aspect of the present invention, there is
provided a process for the preparation of
4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carbox-
amide-1,1-dioxide (meloxicam) of the Formula (II) of high purity,
which comprises [0011] (a) dissolving meloxicam potassium salt
monohydrate of the Formula (I) in water or in the mixture of water
and an organic solvent, removing insoluble impurities and treating
the resulting solution with an organic or inorganic acid, and
crystallizing meloxicam; or [0012] (b) transforming meloxicam raw
product into crystalline meloxicam potassium salt monohydrate of
the Formula (I), dissolving said meloxicam potassium salt
monohydrate of the Formula (I) in water or in a mixture of water
and an organic solvent, removing insoluble impurities and treating
the dissolved potassium salt of meloxicam with an organic or
inorganic acid, followed by crystallization meloxicam of the
Formula (II); or [0013] (c) reacting a compound of the general
Formula (III), wherein R is methyl, ethyl or isopropyl with
2-amino-5-methyl-thiazole of the Formula (IV), transforming the
resulting meloxicam of the Formula (II) into its potassium salt,
separating insoluble impurities from aqueous or aqueous-organic
solution of said meloxicam potassium salt, treating said solution
with an organic or inorganic acid and crystallizing meloxicam.
[0014] According to a further aspect of our invention, there is
provided a process for the preparation of meloxicam potassium salt
of the Formula (I), by reacting meloxicam of the Formula (II) with
potassium hydroxide or potassium carbonate dissolved in water or in
the mixture of water and an organic solvent and if desired,
crystallizing the meloxicam potassium salt monohydrate of the
compound of the Formula (I) thus formed.
[0015] In the above mentioned process directed to the preparation
of meloxicam potassium salt of the Formula (I) or monohydrate
thereof, the molar amount of potassium hydroxide or potassium
carbonate is 1-10 molar equivalent, preferably 4-5 molar equivalent
of the molar amount of meloxicam.
[0016] If desired, any of the processes can be performed in water
or in the mixture of water and an organic solvent. As organic
solvent, an alcohol containing 1-4 carbon atoms, for example,
methanol, ethanol or isopropanol, preferably ethanol can be
used.
[0017] In the above mentioned process variants a) to c), meloxicam
of the Formula (II) is set free from its potassium salt dissolved
in water or in the mixture of the water and an organic solvent by
treatment with an inorganic or an organic acid. Said acidic
treatment is carried out by mixing the solution of meloxicam
potassium salt of the Formula (I) with concentrated acid or an
aqueous solution thereof. Suitable acids include any mineral or
organic acids, for example, sulphuric acid, hydrochloric acid,
phosphoric acid, tartaric acid, acetic acid.
[0018] Acidic treatment can be preferably carried out under the
control of the acidity (pH value) of the solution of meloxicam
potassium salt of the Formula (I). The acidic treatment is
continued until pH 3 to 6, preferably until pH 6 is reached.
[0019] According to a further aspect of the present invention,
there is provided
4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-
-3-carboxamide-1,1-dioxide (meloxicam) of the Formula (II)
essentially free from
4-hydroxy-2-methyl-N-alkyl-(5-methyl-2-thiazolyl)-2H-1,2-benzot-
hiazine-3-carboxamide-1,1-dioxide of the Formula (V), wherein the R
alkyl group of the Formula (V) is methyl, ethyl or isopropyl.
[0020] The invention further relates to meloxicam potassium salt
monohydrate of the Formula (I), preferably in a purified state
wherein said salt is essentially free from
4-hydroxy-2-methyl-N-alkyl-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3--
carboxamide-1,1-dioxide of the Formula (V), wherein alkyl (Group R
in the Formula (V)) is methyl, ethyl or isopropyl.
[0021] According to a still further aspect of the invention, there
are provided pharmaceutical preparations comprising meloxicam
potassium salt monohydrate of the Formula (I) as active ingredient
and one or more pharmaceutically acceptable vehicle or auxiliary
agent, preferably in a purified state wherein said salt is
essentially free from
4-hydroxy-2-methyl-N-alkyl-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3--
carboxamide-1,1-dioxide of the Formula (V), wherein alkyl (Group R
in the Formula (V)) is methyl, ethyl or isopropyl.
[0022] The invention further relates to pharmaceutical preparations
comprising high purity meloxicam of the Formula (II) as active
ingredient and one or more pharmaceutically acceptable vehicle or
auxiliary agent, wherein the active ingredient meloxicam is
essentially free from
4-hydroxy-2-methyl-N-alkyl-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3--
carboxamide-1,1-dioxide of the Formula (V), wherein alkyl (Group R
in the Formula (V)) is methyl, ethyl or isopropyl.
DETAILED DESCRIPTION OF THE INVENTION
[0023] Organic acids and phenols form salt with metals, which are
usually well soluble in water. This phenomenon is often exploited
for the purification of said compounds by dissolving the product in
alkaline-aqueous medium and removing the alkaline- and
water-insoluble organic impurities by filtration or extraction with
a suitable non-miscible solvent.
[0024] It is known according to the state of the art that potassium
salts crystallize less easily and have greater solubility in water
and in organic solvents, than sodium salts. Potassium salts can be
hygroscopic, therefore said salts are preferably isolated from
their solution in organic solvents.
[0025] The preparation of sodium salt of meloxicam was disclosed in
Example 2 of European Patent No. 2482. The methanolic solution of
meloxicam is mixed with approximately equimolar amount of sodium
methylate, the reaction mixture is evaporated to dryness, the
sodium salt is suspended in the mixture of acetone-ether and
filtered.
[0026] United States Patent Application No. 20030109701 discloses
the preparation of meloxicam sodium salt by dissolving meloxicam in
aqueous-organic solution of sodium hydroxide.
[0027] Although according to the state of the art, among alkaline
metal salts of meloxicam, the potassium salt is also mentioned, no
disclosure is available for the preparation of the potassium salt
of meloxicam in solid form and no data can be found with regard to
its stability, solubility and purity. According to the state of the
art, salts prepared from meloxicam and inorganic or organic bases
are prepared exclusively with the purpose to increase the
solubility of meloxicam.
[0028] According to the state of the art, there is no disclosure
for the preparation of meloxicam in high purity form or its
purification via its salt formed an with inorganic or organic
base.
[0029] It has been found very surprisingly, that the meloxicam
potassium salt of the Formula (I) can be isolated easily in
especially pure monohydrate form from the solution of the raw
product prepared with water or, if desired, with aqueous-organic
solvents, even in the case when the impurity of the Formula (V) is
present in the amount of approximately 20% by weight.
[0030] The advantage of the preparation of the potassium salt of
the Formula (I) resides in the fact that in this way impurities of
the Formula (V) as well as other alkaline-insoluble contaminants
can be completely and very easily removed from the raw product.
[0031] Despite of the fact that the compounds of Formula (V)
contain an aromatic hydroxy group, they do not form salt with
alkali metals, therefore they are insoluble in alkaline aqueous
solution and can be removed from the solution of meloxicam
potassium salt by filtration. The small amount of impurity present
on the surface of the solid crystalline meloxicam potassium salt
monohydrate of the Formula (II), including the traces of the
compounds of Formula (V) can be removed by simple washing with an
appropriate solvent, since meloxicam potassium salt monohydrate of
the Formula (I) is practically insoluble in organic solvents, for
example, in ethyl-acetate.
[0032] According to a further aspect of the present invention,
there is provided a process for the preparation of high purity,
crystalline meloxicam potassium salt monohydrate of the Formula
(I). In the first step, meloxicam is produced starting from the
compound of the Formula (III), wherein the meaning of R is methyl,
which is reacted with the compound of Formula (IV). In this
process, a by-product of the Formula (V), wherein the meaning of R
is methyl, is produced in an amount of 10-15% by weight. The raw
product is dissolved in aqueous potassium hydroxide or potassium
carbonate solution at the temperature of 50 to 60.degree. C., the
impurities insoluble in the alkaline-aqueous solvent are removed by
filtration or centrifugation, the clear solution is cooled and the
crystalline, high purity meloxicam potassium salt monohydrate of
the Formula (I) is isolated by filtration or centrifugation.
[0033] According to a further aspect of the present invention,
there is provided a process to transform meloxicam potassium salt
monohydrate of the Formula (I) into high purity meloxicam. The
meloxicam potassium salt monohydrate of the Formula (I) is
dissolved in water or in a mixture of water and an organic solvent,
the solution is filtered, the filtrate is acidified by aqueous acid
solution and cooled. Subsequently the crystalline meloxicam is
collected, washed and dried.
[0034] According to another aspect of the present invention, there
is provided a process for the production of high purity meloxicam
polymorf I form. The potassium salt of the Formula (I) is dissolved
in water at a temperature between 50 and 60.degree. C., the aqueous
solution is filtered, and the yellow solution is acidified until pH
6 using concentrated acid solution, the solution is cooled and the
precipitated crystalline meloxicam polymorph I form is isolated by
centrifugation or filtration.
[0035] The advantage of the process according to the present
invention resides in the fact that the only solvent used during the
purification process is water, therefore it is not necessary to
remove organic solvent residues from the product. At the acidity
(pH value) given above, the product is almost insoluble in water,
therefore the yield is almost quantitative. During the above
described process, heat stress of the product and thermal
decomposition thereof is minimal, which allows the production of
high purity product. The above described process does not involve
hazardous chemicals, therefore it is advantageous from the
environmental viewpoint. The use of the above described process
results in significant cost reduction as well.
[0036] The above inventive concept according to our invention can
be applied more generally. Among esters of the Formula (III), the
methyl ester is the cheapest and is produced on the greatest scale.
However, said methyl ester of the Formula (III), wherein R is
methyl, has received but limited attention during the production of
meloxicam, because of the fact that the by-product of the Formula
(V), wherein R is methyl, is produced during the amidation reaction
in a significant amount, about 10-15% by weight, which could not be
removed by crystallization. Using the process according to the
present invention, contaminated raw products containing the above
mentioned high amounts of the compound of the Formula (V), wherein
R is methyl, can be purified. In this manner, it has become
possible to use the cheaper methyl ester of the Formula (III),
wherein R is methyl, instead of the isopropyl ester of Formula
(III), wherein R is isopropyl.
[0037] The preparation of the raw meloxicam of the Formula (II) is
carried out according to state of the art by reacting an ester of
the Formula (III), wherein R is methyl, ethyl or isopropyl and
2-amino-5-methyl-thiazole of the Formula (IV) in solvents having
high boiling point, for example, in chloro-benzene, decaline or
xylene, preferably, in xylene. The reaction takes place at the
boiling point of the reaction mixture, at the temperature between
about 130 and about 170.degree. C. The reaction time is usually
12-24 hours. Besides the product meloxicam, the reaction mixture
contains a significant amount of the compound of the Formula (V)
corresponding to the starting compound of the Formula (III) with
respect to the R group and tar-like substance as well. If desired,
the reaction can be carried out in presence of activated carbon to
decrease the amount of tar. During the reaction, meloxicam and the
by-product of the Formula (V) crystallizes and precipitates from
the reaction mixture, and can be removed by filtration together
with activated carbon, if present.
[0038] The raw meloxicam, which may contain activated carbon as
well, is dissolved in a 20-50-fold weight amount of aqueous
potassium hydroxide solution at a temperature between 50 and
80.degree. C. under stirring. If desired, the dissolution rate of
meloxicam can be increased by adding about 3-5 volume % of low
molecular weight alcohol, for example, methanol, ethanol or
isopropanol. The volume of the potassium hydroxide solution is
determined taking into account the quality and quantity of the low
molecular weight alcohol.
[0039] The aqueous-alkaline solvent dissolves meloxicam only. The
compound of the Formula (V), which is insoluble in alkaline medium
is filtered together with activated carbon, if present. The clear
yellow filtrate is cooled while the precipitation of crystalline
meloxicam potassium salt monohydrate of the Formula (I) takes
place.
[0040] Crystallization of meloxicam potassium salt monohydrate can
be enhanced by salting-out. To achieve salting-out effect, an
amount of potassium hydroxide or potassium carbonate is added to
the solution of meloxicam potassium salt as solid or as
concentrated aqueous solution in excess to the equimolar amount
required for salt formation. Total amount of potassium ions present
in the solution according to the present invention can be between
1-10 molar equivalents, preferably 4-5 molar equivalents relative
to the molar amount of meloxicam.
[0041] The solid crystalline meloxicam potassium salt monohydrate
of the Formula (I) is isolated, the impurities present on the
surface of the crystals are washed away using cold water or an
organic solvent or a mixture of thereof, for example, using
ethylacetate, ethanol, methanol, isopropanol as organic
solvent.
[0042] According to our observations, using the process of the
present invention, meloxicam potassium salt monohydrate can be
obtained in high purity even in the unfavourable case when the
reaction mixture contained 15-20% of the compound of the Formula
(V) by weight.
[0043] According to the present invention, there is provided a
process for the preparation of meloxicam polymorph I form of the
Formula (II) in high purity, which comprises dissolving meloxicam
potassium salt monohydrate of the Formula (I) in water or in the
mixture of water and 1-20 volume % of a low molecular weight
alcohol at a temperature between 50 and 100.degree. C., preferably
at a temperature between 60 and 70.degree. C. The solvent
preferably comprises 2-5 volume % ethanol in water.
[0044] The solution is filtered, and the clear yellow filtrate is
acidified to pH 6 using a mineral or organic acid. For
acidification, any mineral or organic acid, for example,
hydrochloric acid, sulphuric acid or phosphoric acid, acetic acid,
tartaric acid can be used. The crystalline meloxicam is filtered
off and washed with water and ethanol.
[0045] According to a further aspect of the present invention,
there are provided pharmaceutical preparations comprising meloxicam
potassium salt monohydrate of the Formula (I) in admixture with one
or more conventional carrier(s) or auxiliary agent(s), essentially
free of the impurity of the Formula (V).
[0046] Another further aspect of the present invention relates to
pharmaceutical preparations comprising meloxicam of the Formula
(II) in admixture with one or more conventional carrier(s) or
auxiliary agent(s), essentially free from the impurity of the
Formula (v).
[0047] The pharmaceutical compositions according to the present
invention contain generally 0.1-95% by weight, preferably 1-50% by
weight, particularly 5-30% by weight active ingredient.
[0048] The pharmaceutical compositions of the present invention may
be suitable for oral (e.g. powders, tablets, coated tablets,
capsules, microcapsules, pills, solutions, suspensions or
emulsions), parenteral (e.g. injection solutions for intravenous,
intramuscular, subcutaneous or intraperitoneal use), rectal (e.g.
suppositories) transdermal (e.g. plasters) or local (e.g. ointments
or plasters) administration or for the application in form of
implants. The solid, soft or liquid pharmaceutical compositions
according to the invention may be produced by methods
conventionally applied in the pharmaceutical industry.
[0049] The solid pharmaceutical compositions for oral
administration containing the compound of the Formula (I) may
comprise vehicles, fillers or carriers (such as lactose, glucose,
starch, potassium phosphate, micro-crystalline cellulose), binding
agents (such as gelatine, sorbite, polyvinyl pyrrolidone),
disintegrants (such as croscarmelose, Na-carboxy-methyl cellulose,
crospovidone), tabletting auxiliary agents (such as magnesium
stearate, talc, polyethylene glycol, silicic acid, silicon dioxide)
and surface-active agents (e.g. sodium lauryl sulfate).
[0050] The liquid compositions containing meloxicam potassium salt
of the Formula (I) in dissolved form are known according to the
state of the art. Liquid pharmaceutical preparations suitable for
oral administration according to the present invention can be
suspensions or emulsions. Such compositions may contain suspending
agents (e.g. gelatine, carboxymethyl cellulose), emulsifiers (e.g.
sorbitan monooleate, solvents (e.g. water, oils, glycerol,
propylene glycol, ethanol), buffering agents (e.g. acetate,
phosphate, citrate buffers) or preservatives (e.g.
methyl-4-hydroxybenzoate).
[0051] Soft pharmaceutical compositions containing as active
ingredient a compound of the general Formula (I) or a
pharmaceutically acceptable acid addition salt thereof, such as
suppositories, contain the active ingredient evenly dispersed in
the basic material of the suppository (e.g. in polyethylene glycol
or cocoa butter).
[0052] The pharmaceutical compositions according to the present
invention can be prepared by known methods of the pharmaceutical
industry. The active ingredient is admixed with pharmaceutically
acceptable solid or liquid carriers and/or auxiliary agents and the
mixture is brought to galenic form. The carriers and auxiliary
agents together with the methods which can be used in the
pharmaceutical industry are disclosed in the literature
(Remington's Pharmaceutical Sciences, Edition 18, Mack Publishing
Co., Easton, USA, 1990).
[0053] The pharmaceutical compositions according to the present
invention contain generally a dosage unit.
[0054] Further details of the present invention are provided in the
following examples without limiting the scope of protection to said
examples.
Example 1
4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxa-
mide-1,1-dioxide potassium salt monohydrate (compound of the
Formula I)
[0055] 350 ml of xylene are transferred into an apparatus equipped
with Marcusson head and provided with means for inert gas purging.
Purging with argon is started and 35.0 g (130 mmol)
4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylic acid
methylester of the Formula (III) [wherein the meaning of R is
methyl], 15.0 g (132 mmol) of 2-amino-5-methyl-thiazole of the
Formula (IV) and 6.0 g of activated carbon are added during
continous stirring and argon purge.
[0056] The reaction mixture is heated for 24 hours using an oil
bath at a temperature between 170 and 180.degree. C. The heating is
adjusted in a way that only a minimal amount of distillate (2-5
ml/hour) is produced in the head. Distillation of methanol is
ceased by the end of the reaction.
[0057] The reaction mixture is cooled to 25.degree. C., crude
meloxicam containing carbon and approximately 12% of the impurity
of Formula (V) are filtered off and washed on the filter with
xylene and ethanol. The crude product containing carbon is stirred
in 1200 ml of 0.5% aqueous potassium hydroxide solution at the
temperature of 50.degree. C. for one hour, carbon and the impurity
of Formula (V) insoluble in the alkaline solution are filtered off
and the clear yellow solution at 25.degree. C. are added dropwise
the solution of 30 g potassium hydroxide in 100 ml water. The
potassium salt of meloxicam is precipitated in the form of yellow
crystals which are easily separable by filtration. The crystal
suspension is stirred for two hours at 10.degree. C., filtered and
washed with water.
[0058] Yield, 42.9 g [81.0%, calculated on the amount of the
compound of Formula (III)]
[0059] Content (on the basis of potassium content): 99.5%
[0060] Water (Karl Fischer method): 4.6%
[0061] Melting point, 170-171.degree. C.
[0062] Elemental analysis
[C.sub.14H.sub.12KN.sub.3O.sub.4S.sub.2.H.sub.2O (407,5)]:
TABLE-US-00001 Calculated C: 41.26 H: 3.46 N: 10.31 S: 15.74
Measured C: 41.20 H: 3.52 N: 10.21 S: 15.61
[0063] Purity (HPLC): 99.8%.
[0064] Thermogravimetry: the product loses 4.75% water at
175-245.degree. C.
Example 2
4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxa-
mide-1,1-dioxide (compound of Formula (II), polymorph I form of
meloxicam
[0065] 34.1 g (83.7 mmol) meloxicam potassium salt monohydrate are
dissolved in the mixture of 1500 ml of 0.5% aqueous potassium
hydroxide solution and 25 ml of ethanol at the temperature of
40-45.degree. C. by stirring for 30 minutes. The yellow solution
are added 2.0 g of activated carbon and after stirring for ten
minutes, the carbon is filtered off. The filtrate are added 100 ml
aqueous hydrochloric acid solution prepared by diluting 20 ml (23.6
g) concentrated hydrochloric acid to 100 ml final volume, at
30.degree. C. in 30 minutes (pH 3-5). The suspension is stirred for
two hours at 10.degree. C. temperature, filtered and the product is
washed on the filter with water.
[0066] Yield: 28.5 g (97.1% calculated on the basis of the weight
of meloxicam potassium salt monohydrate as starting compound)
[0067] Melting point: 246-248.degree. C.
[0068] Elemental analysis (C.sub.14H.sub.13N.sub.3O.sub.4S.sub.2
(351,4)
TABLE-US-00002 Calculated C: 47.85 H: 3.73 N: 11.96 S: 18.25
Measured C: 47.80 H: 3.82 N: 11.87 S: 18.20
[0069] Purity (HPLC): 99.8%.
Example 3
4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxa-
mide-1,1-dioxide potassium salt monohydrate (compound of the
Formula (I))
[0070] One proceeds according to Example 1 with the difference that
instead of 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylic
acid methylester [compound of the Formula (III), wherein R is
methyl)], 36.83 g (130 mmol)
4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylic acid
ethylester [compound of the Formula (III), wherein R is ethyl] are
used.
[0071] Yield: 46.9 g (88.5% calculated on the basis of the weight
of the starting compound
-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylic acid
methylester of the Formula (III)).
[0072] Content (on the basis of potassium content): 99.6%
[0073] Water (Karl Fischer method): 4.7%
[0074] Elemental analysis
[C.sub.14H.sub.12KN.sub.3O.sub.4S.sub.2.H.sub.2O (407,5)]
TABLE-US-00003 Calculated C: 41.26 H: 3.46 N: 10.31 S: 15.74
Measured C: 41.22 H: 3.38 N: 10.25 S: 15.69
[0075] Purity (HPLC): 99.8%.
Example 4
Meloxicam Polimorf I Form
[0076] One proceeds according to Example 2 with the only difference
that the solution of the potassium salt is treated with 6.0 ml 96%
acetic acid instead of hydrochloric acid.
[0077] Yield: 29.0 g (98.5% calculated on the basis of the amount
of meloxicam potassium salt monohydrate of the Formula (I) used as
starting compound).
[0078] Melting point: 246-248.degree. C.
[0079] Elemental analysis (C.sub.14H.sub.L3N.sub.3O.sub.4S.sub.2
(351,4):
TABLE-US-00004 Calculated C: 47.85 H: 3.73 N: 11.96 S: 18.25
Measured C: 47.89 H: 3.68 N: 11.91 S: 18.29
[0080] Purity (HPLC) 99.8%.
* * * * *