Note: Descriptions are shown in the official language in which they were submitted.
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PROCESS FOR THE PREPARATION OF FORM A OF TEGASEROD
Field of the invention
The present invention relates to a process for preparing polymorphic form A of
2-[(5-
methoxy-lH-indol-3-yl)methylene]-N-pentylhydrazinecarboximidamide maleate
(tegaserod
maleate) of formula (I).
NH
~ CH3
HN N
I H
N
H3CO (COOH
I \ ~)
H COOH
/0 The invention further relates to tegaserod maleate form A substantially
free of other
polymorphic forms and chemical impurities, to compositions comprising
tegaserod maleate
form A and to the use of said compositions in the treatment of
gastrointestinal disorders
such as irritable bowel syndrome and heartburn.
95 Background of the invention
Tegaserod is a 5-HT4 receptor partial agonist that is used to treat
gastrointestinal disorders
such as irritable bowel syndrome, heartburn, bloating, postoperative ileus,
abdominal pain
and discomfort, epigastric pain, nausea, vomiting, regurgitation, intestinal
pseudo-
20 obstruction, constipation and gastroesophageal reflux.
Tegaserod and a process for its preparation were first described in US
5510353. However,
this patent does not disclose any process for the preparation of tegaserod
salts. Tegaserod
maleate per se is disclosed and its melting point is reported in this patent
as 190 C, but the
25 method by which the melting point is determined is not given. Further,
there is no
disclosure of or claim to any crystalline form.
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The Journal of Medicinal Chemistry, 1995, vol. 38, no. 13, pages 2331-2338,
also describes
a process for preparing tegaserod. According to this publication, 5-methoxy-
indole-3-
carboxaldehyde was coupled with N-amino-N'-pentyl guanidine hydroiodide in
methanol
in the presence of concentrated hydrochloric acid to obtain tegaserod. Also
described is a
process for the preparation of the hydrochloride salt of tegaserod and
crystallisation of
tegaserod hydrochloride from methanol and diethyl ether. However, information
on the
crystalline form obtained is not disclosed.
/0 From the above it is clear that a process for the preparation of the
maleate salt of tegaserod
is not reported in US 5510353 or in the Journal of Medicinal Chemistry, 1995,
vol. 38, no.
13, pages 2331-2338. The only information available is the melting point of
tegaserod
maleate, which is reported in US 5510353 as 190 C. Further, there is no
disclosure of any
crystalline form.
Later patents and patent applications show that tegaserod maleate does indeed
exist in
different polymorphic forms.
US 2005/0119328 discloses four polymorphic forms, form I to form IV of
tegaserod
20 maleate. None of these forms is the same as form A of tegaserod maleate.
WO 2005/014544 describes crystalline form A of tegaserod maleate. There is
also
disclosed a process for preparing form A, comprising the step of crystallising
tegaserod
maleate from a solution consisting of an acetate ester and water. Preferred
embodiments
25 comprise using ethyl acetate and water, but other solvents that are
mentioned include n-
butyl acetate or isopropyl acetate and water. The application further
discloses crystalline
form B crystallised from THF and methanol, then recrystallised from ethanol
and ether at
90 C. Also disclosed are three crystalline solvate forms namely acetone,
isopropanol and
ethanol solvates. Form A is identified as being more stable than the other
disclosed forms
30 in the presence of heat and water. Form B readily converts to form A when
heated.
WO 2005/058819 discloses forms B, BI, B2, B3, C, D and E of tegaserod maleate.
Also
claimed is a process for preparing form A of tegaserod maleate, comprising the
steps of
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dissolving tegaserod maleate in a solvent and recovering the crystalline solid
as a
precipitate, where the solvent as shown in examples is acetonitrile, butyl
lactate, methyl
ethyl ketone, sec-butanol, dioxane, methanol/water (20:80), ethanol/water
(20:80),
isopropanol/water (1:1), isopropanol/water (20:80), acetonitrile/water (1:1),
acetonitrile/
water (20:80), chloroform/2-ethoxyethanol (1:1), chloroform/2-ethoxyethanol
(25:75),
water/2-ethoxyethanol (1:1), n-butanol, water/1-methyl-2-pyrrolidone (75:25),
dimethyl
sulfoxide, N,N-dimethylformamide, 1-methyl-2-pyrrolidone, or N,N-
dimethylacetamide.
There is always a need for alternative methods of preparing compounds for
pharmaceutical
>0 use in order to provide the skilled person with the optimum tools to
prepare
pharmaceutical products that are both safe and efficacious.
Object of the invention
>5 It is an object of the present invention to provide a novel process for
preparing
polymorphic form A of tegaserod maleate that is substantially free of other
polymorphic
forms and chemical impurities.
Summary of the invention
According to a first aspect of the present invention, there is provided a
process for
preparing polymorphic form A of tegaserod maleate, comprising the steps of:
(a) dissolving tegaserod maleate or tegaserod and maleic acid in an alcohol;
(b) adding ether to precipitate tegaserod maleate; and
(c) isolating the precipitated tegaserod maleate.
In step (a) either tegaserod maleate or tegaserod and maleic acid can be used.
Preferably
tegaserod maleate is used.
The alcohol used in step (a) is preferably a C1_4 alcohol, which may be
selected from the
non-exhaustive group comprising methanol, ethanol, n-propanol, isopropanol, n-
butanol,
sec-butanol, isobutanol, and mixtures thereof. Preferably the alcohol used in
step (a) is
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methanol. Preferably, the alcohol is used in step (a) at reflux temperature.
Preferably, the
alcohol is heated in step (a) until a clear solution is obtained.
In a preferred embodiment, the ether used in step (b) is tert-butyl methyl
ether (TBME).
In alternative embodiments, the ether can be selected from the non-exhaustive
group
comprising diisopropyl ether (DIPE), diethyl ether (DEE), tetrahydrofuran
(THF),
dioxane, dimethoxyethane, cyclopentyl methyl ether (CPME), dimethyl ether,
diethoxyethane, anisole, and tert-butyl ethyl ether.
>0 In another embodiment, in step (c) the precipitate is isolated by
filtration. Preferably, the
precipitate is isolated by vacuum filtration, more preferably at a temperature
of 25-30 C.
In a preferred embodiment, the tegaserod maleate polymorphic form A obtained
is
substantially free of other polymorphic forms. In another preferred
embodiment, the
>5 tegaserod maleate polymorphic form A obtained is substantially free of
chemical impurities.
In another embodiment, the tegaserod maleate polymorphic form A is prepared on
an
industrial scale, preferably in batches of 0.5kg, Ikg, 5kg, 10kg, 50kg, 100kg,
500kg, or more.
20 According to another aspect of the present invention, there is provided
polymorphic form
A of tegaserod maleate, prepared by a process according to the first aspect of
the present
invention. Preferably the polymorphic form A of tegaserod maleate is
characterized by an
X-ray diffraction pattern having peaks at 5.4, 6.0, 6.6 and 10.8 0.2 degree
two theta.
Preferably the polymorphic form A of tegaserod maleate is characterized by a
DSC curve
25 having one endothermic peak at about 185-188 C.
Preferably the polymorphic form A of tegaserod maleate is substantially free
of other
polymorphic forms. For the purposes of the present invention, polymorphic form
A of
tegaserod maleate, which is "substantially free" of other polymorphic forms,
comprises less
30 than about 10% by weight of other polymorphic forms of tegaserod maleate,
preferably
less than about 5%, preferably less than about 4%, preferably less than about
3%,
preferably less than about 2%, preferably less than about 1% (as measured by
XRPD).
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Preferably the polymorphic form A of tegaserod maleate is substantially free
of chemical
impurities. For the purposes of the present invention, polymorphic form A of
tegaserod
maleate, which is "substantially free" of chemical impurities, is about 90%,
preferably about
95%, preferably about 96%, preferably about 97%, preferably about 98%,
preferably about
99% or more chemically pure (as measured by HPLC).
According to another aspect of the present invention, there is provided
polymorphic form
A of tegaserod maleate, characterized by an X-ray diffraction pattern having
peaks at 5.4,
6.0, 6.6 and 10.8 0.2 degree two theta, substantially free of other
polymorphic forms,
>0 preferably comprising less than about 10% by weight of other polymorphic
forms of
tegaserod maleate, preferably less than about 5%, preferably less than about
4%, preferably
less than about 3%, preferably less than about 2%, preferably less than about
1% (as
measured by XRPD). Preferably the polymorphic form A of tegaserod maleate is
substantially free of chemical impurities, i.e. preferably the polymorphic
form A of
/5 tegaserod maleate is about 90%, preferably about 95%, preferably about 96%,
preferably
about 97%, preferably about 98%, preferably about 99% or more chemically pure
(as
measured by HPLC).
According to another aspect of the present invention, there is provided
polymorphic form
20 A of tegaserod maleate, characterized by an X-ray diffraction pattern
having peaks at 5.4,
6.0, 6.6 and 10.8 0.2 degree two theta, substantially free of chemical
impurities,
preferably wherein the polymorphic form A of tegaserod maleate is about 90%,
preferably
about 95%, preferably about 96%, preferably about 97%, preferably about 98%,
preferably
about 99% or more chemically pure (as measured by HPLC). Preferably the
polymorphic
25 form A of tegaserod maleate is substantially free of other polymorphic
forms, i.e.
preferably the polymorphic form A of tegaserod maleate comprises less than
about 10% by
weight of other polymorphic forms of tegaserod maleate, preferably less than
about 5%,
preferably less than about 4%, preferably less than about 3%, preferably less
than about
2%, preferably less than about 1% (as measured by XRPD).
The polymorphic form A of tegaserod maleate according to the present invention
may be
suitable for use in medicine, preferably for treating a gastrointestinal tract
disorder such as
irritable bowel syndrome, heartburn, bloating, postoperative ileus, abdominal
pain or
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discomfort, epigastric pain, nausea, vomiting, regurgitation, intestinal
pseudo-obstruction,
constipation or gastroesophageal reflux.
According to another aspect of the present invention, there is provided a
composition
comprising polymorphic form A of tegaserod maleate according to the present
invention
and one or more pharmaceutically acceptable excipients. Preferably the
composition is
suitable for treating a gastrointestinal tract disorder such as irritable
bowel syndrome,
heartburn, bloating, postoperative ileus, abdominal pain or discomfort,
epigastric pain,
nausea, vomiting, regurgitation, intestinal pseudo-obstruction, constipation
or
/0 gastroesophageal reflux.
According to another aspect of the present invention, there is provided a
method of
treating or preventing a gastrointestinal tract disorder, comprising
administering a
therapeutically of prophylactically effective amount of polymorphic form A of
tegaserod
>5 maleate according to the present invention to a patient in need thereof.
The
gastrointestinal tract disorder may be irritable bowel syndrome, heartburn,
bloating,
postoperative ileus, abdominal pain or discomfort, epigastric pain, nausea,
vomiting,
regurgitation, intestinal pseudo-obstruction, constipation or gastroesophageal
reflux. The
patient may be a mammal such as a human.
Detailed description of the invention
In the pharmaceutical industry, polymorphism control of an active
pharmaceutical
ingredient (API) is critical, since different polymorphs can have different
chemical and
physical stability, solubility, morphology, and hygroscopicity. During the
manufacturing
process, it is often necessary to convert a less stable form to a more stable
form.
A first aspect of the present invention describes a process for the
preparation of
polymorphic form A of tegaserod maleate, which is the most stable form. The
process of
preparing this polymorph is simple and reproducible and results in polymorphic
form A of
tegaserod maleate substantially free of other polymorphic forms and chemical
impurities.
Further, the process of the present invention is amenable to scale up and the
polymorph
has a uniform crystallinity.
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For the purposes of this invention, the term "substantially free" means that
the
polymorphic form A of tegaserod maleate is present at greater than or equal to
about 90%.
In particular, polymorphic form A of tegaserod maleate, which is
"substantially free" of
other polymorphic forms, comprises less than about 10% by weight of other
polymorphic
forms of tegaserod maleate, preferably less than about 5%, preferably less
than about 4%,
preferably less than about 3%, preferably less than about 2%, preferably less
than about 1%
(as measured by XRPD). Polymorphic form A of tegaserod maleate, which is
"substantially free" of chemical impurities, is about 90%, preferably about
95%, preferably
/0 about 96%, preferably about 97%, preferably about 98%, preferably about 99%
or more
chemically pure (as measured by HPLC).
Preferably the process of the present invention comprises the steps of:
(a) dissolving tegaserod maleate or tegaserod and maleic acid in an alcohol;
>5 (b) adding ether to precipitate tegaserod maleate; and
(c) isolating the precipitated tegaserod maleate.
It has been found that, when tegaserod maleate is used in step (a), any form
of tegaserod
maleate may be used as the starting material. The alcohol used in step (a) is
preferably a
20 C1_4 alcohol, which may be selected from the non-exhaustive group
comprising methanol,
ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, isobutanol, and
mixtures thereof.
Preferably the alcohol used in step (a) is methanol. It is further preferred
that the tegaserod
maleate or the tegaserod and maleic acid are dissolved completely in the
alcohol resulting in
a clear solution. In this respect, preferably the tegaserod maleate or the
tegaserod and
25 maleic acid are dissolved in the alcohol at high temperatures, preferably
reflux
temperatures.
Addition of the ether causes polymorphic form A of tegaserod maleate to
precipitate out of
solution. The precipitate is pure form A of tegaserod maleate substantially
free from other
30 polymorphic forms, typically comprising less than 5% by weight of other
polymorphic
forms of tegaserod maleate, preferably less than 4%, more preferably less than
3%, more
preferably less than 2%, most preferably less than 1%. In a further
embodiment, the ether
may be selected from the non-exhaustive list comprising tert-butyl methyl
ether (TBME),
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tert-butyl ethyl ether, diisopropyl ether (DIPE), diethyl ether (DEE),
tetrahydrofuran
(THF), dioxane, dimethoxyethane, cyclopentyl methyl ether (CPME), dimethyl
ether,
diethoxyethane, and anisole. A number of less commonly used ethers may also be
employed in the working of this invention and it is within the skillset of the
skilled person
to determine the suitability of other ethers without undue experimentation
over and above
the teaching of this invention. Preferably the ether used in step (b) is not
dioxane, 2-
methoxyethanol or 2-ethoxyethanol.
It will be apparent to the skilled person that isolating the precipitate may
be achieved by
>0 any of a number of means known in the art. The inventors have found that
filtering the
precipitate is advantageous. Particularly preferred is filtering the
precipitate from the
solution at about 25-30 C. Preferably, the precipitate is vacuum filtered at
about 25-30 C.
Another aspect of the invention is a pharmaceutical composition made by mixing
tegaserod
/5 maleate prepared according to the first aspect of the invention and one or
more
pharmaceutically acceptable excipients. It will of course be understood that
the number
and type of excipients can be varied within the scope of the invention and
depend on the
type of formulation required. It is well within the skillset of the skilled
person to determine
the excipients required for a particular composition.
Another aspect of the invention is a process for making a pharmaceutical
composition,
comprising mixing tegaserod maleate according to the invention and one or more
excipient(s). Solid pharmaceutical compositions of the present invention
comprise the
active ingredient tegaserod maleate as prepared by a process according to the
invention and
one or more excipient(s). Optionally, a further active ingredient can also be
present in the
composition, preferably an agent that complements or enhances the therapeutic
effect of
tegaserod; such agents may include 5-HT3 receptor antagonists, omeprazole,
rabeprazole,
dipeptidyl peptidase IV (DPP-IV) inhibitors etc. The compositions can be in
the form of
tablets, pills, powders, lozenges, sachets, soft and hard gelatine capsules,
suppositories etc.
The dosage form is preferably suitable for oral application. The compositions
are
preferably formulated in a unit dosage form, each dosage containing about I to
about 100
mg, more usually about I to about 6 mg of tegaserod maleate. The term "unit
dosage
form" refers to physically discrete units suitable as unitary dosages for
human subjects and
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other mammals, each unit containing a predetermined quantity of tegaserod
maleate
calculated to produce the desired therapeutic effect, in association with one
or more
suitable pharmaceutical excipient(s).
Pharmaceutical excipients for the solid dosage forms comprise in particular
binders,
disintegrants, diluents and lubricants. Other and further excipients can also
be used,
depending on the dosage form required. The skilled person is well equipped to
determine
the quality and quantity of excipient(s) needed without undue experimentation.
>0 A further aspect of the invention is a method for the treatment of
gastrointestinal tract
disorders such as irritable bowel syndrome, heartburn, bloating, postoperative
ileus,
abdominal pain and discomfort, epigastric pain, nausea, vomiting,
regurgitation, intestinal
pseudo-obstruction, constipation and gastroesophageal reflux in a subject in
need thereof,
comprising administering to the subject a therapeutically effective amount of
tegaserod
/5 maleate or a pharmaceutical composition according to the present invention
as described
above.
A yet further aspect provides the use of a composition comprising a
pharmaceutically
effective amount of tegaserod maleate form A according to the present
invention and one
20 or more pharmaceutically acceptable excipients to treat gastrointestinal
tract disorders such
as irritable bowel syndrome, heartburn, bloating, postoperative ileus,
abdominal pain and
discomfort, epigastric pain, nausea, vomiting, regurgitation, intestinal
pseudo-obstruction,
constipation and gastroesophageal reflux.
25 Examples
Preparation of polymorphic form A of tegaserod maleate
Tegaserod maleate (2 g) was dissolved in methanol (50 vol) and heated to 66 C
until a clear
30 solution was obtained. To the clear solution was added tert-butyl methyl
ether (50 vol) at
66 C. Solid tegaserod maleate precipitated out at this temperature. Then the
solution was
cooled to 25 C within 50-60 minutes. The solid obtained was filtered and dried
under
vacuum at 35 C for 2 hours.
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The product was identified as polymorphic form A of tegaserod maleate by XRPD
(peaks
at 5.4, 6.0, 6.6 and 10.8 0.2 degree two theta) and by DSC (one endothermic
peak at
about 185-188 C).
Yield = 75%.
Polymorphic purity > 99% (as measured by XRPD).
Chemical purity > 99% (as measured by HPLC).
