U.S. patent application number 09/450462 was filed with the patent office on 2002-01-31 for indole derivatives.
Invention is credited to DALLMANN, CHRISTOPHER IAN, OGILVIE, RONALD JAMES.
Application Number | 20020013358 09/450462 |
Document ID | / |
Family ID | 10843140 |
Filed Date | 2002-01-31 |
United States Patent
Application |
20020013358 |
Kind Code |
A1 |
DALLMANN, CHRISTOPHER IAN ;
et al. |
January 31, 2002 |
INDOLE DERIVATIVES
Abstract
The present invention provides eletriptan hydrobromide
monohydrate of the formula (I): 1 together with processes for
preparing, uses of, and compositions containing, said
monohydrate.
Inventors: |
DALLMANN, CHRISTOPHER IAN;
(SANDWICH, GB) ; OGILVIE, RONALD JAMES; (SANDWICH,
GB) |
Correspondence
Address: |
PFIZER INC
150 EAST 42ND STREET
5TH FLOOR - STOP 49
NEW YORK
NY
10017-5612
US
|
Family ID: |
10843140 |
Appl. No.: |
09/450462 |
Filed: |
November 29, 1999 |
Current U.S.
Class: |
514/415 ;
548/468 |
Current CPC
Class: |
A61P 9/12 20180101; A61P
25/00 20180101; A61P 25/30 20180101; A61K 31/4045 20130101; A61P
25/22 20180101; A61P 1/08 20180101; A61P 25/04 20180101; A61P 25/06
20180101; A61P 25/36 20180101; A61P 25/24 20180101; C07D 403/06
20130101; A61P 1/14 20180101; A61P 3/04 20180101; A61P 43/00
20180101 |
Class at
Publication: |
514/415 ;
548/468 |
International
Class: |
A61K 031/404; C07D
43/02 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 27, 1998 |
GB |
9825988.0 |
Claims
1. Eletriptan hydrobromide monohydrate of the formula (I): 4
2. A pharmaceutical composition including eletriptan hydrobromide
monohydrate as claimed in claim 1 together with a pharmaceutically
acceptable excipient, diluent or carrier.
3. Eletriptan hydrobromide monohydrate as claimed in claim 1 for
use as a medicament.
4. The use of eletriptan hydrobromide monohydrate as claimed in
claim 1 for the manufacture of a medicament for the treatment of a
disease or condition for which a selective agonist of a
5-HT.sub.1B/1D receptor is indicated.
5. Use as claimed in claim 4 for the treatment of a disease or
condition for which a selective agonist of a 5-HT.sub.1B/1D
receptor is indicated.
6. The use of eletriptan hydrobromide monohydrate as claimed in
claim 1 for the manufacture of a medicament for the treatment of a
disease or condition selected from migraine, recurrent migraine,
hypertension, depression, emesis, anxiety, an eating disorder,
obesity, drug abuse, cluster headache, pain, chronic paroxysmal
hemicrania and headache associated with a vascular disorder.
7. Use as claimed in claim 6 for the treatment of migraine or
recurrent migraine.
8. A method of treatment of a mammal to treat a disease or
condition for which a selective agonist of a 5-HT.sub.1 receptor is
indicated which includes treating said mammal with an effective
amount of eletriptan hydrobromide monohydrate as claimed in claim
1.
9. A method as claimed in claim 8 to treat a disease or condition
for which a selective agonist of a 5-HT.sub.1B/1D receptor is
indicated.
10. A method of treatment of a mammal to treat a disease or
condition selected from migraine, recurrent migraine, hypertension,
depression, emesis, anxiety, an eating disorder, obesity, drug
abuse, cluster headache, pain, chronic paroxysmal hemicrania and
headache associated with a vascular disorder which includes
treating said mammal with an effective amount of eletriptan
hydrobromide monohydrate as claimed in claim 1.
11. A method as claimed in claim 10 to treat migraine or recurrent
migraine.
12. A process for the preparation of eletriptan hydrobromide
monohydrate as claimed in claim 1 which comprises treatment of a
solution of eletriptan in water, or in an organic solvent
containing a sufficient amount of water to facilitate formation of
the required monohydrate, with hydrogen bromide or a source
thereof.
13. A process as claimed in claim 12 wherein the organic solvent is
tetrahydrofuran or acetone.
14. A process as claimed in claim 12 or 13 wherein hydrogen bromide
is used in the form of an aqueous solution.
15. A process for the preparation of eletriptan hydrobromide
monohydrate as claimed in claim 1 which comprises crystallisation
of any other form of eletriptan hydrobromide, or a mixture thereof,
from water, or from an organic solvent containing a sufficient
amount of water to facilitate formation of the required
monohydrate.
16. A process as claimed in claim 15 wherein the organic solvent is
acetone.
17. A process for the preparation of anhydrous eletriptan
hydrobromide which comprises dehydration of any hydrated form of
eletriptan hydrobromide, preferably eletriptan hydrobromide
monohydrate as claimed in claim 1, or a mixture thereof.
Description
[0001] This invention relates to indole derivatives. More
specifically the present invention relates to eletriptan
hydrobromide monohydrate, to processes for the preparation thereof,
to processes for its conversion to anhydrous eletriptan
hydrobromide, and to the uses of, and to compositions containing,
said monohydrate.
[0002] Eletriptan,
3-([1-methylpyrrolidin-2(R)-yl]methyl)-5-(2-phenylsulph-
onylethyl)-1H-indole, has the formula: 2
[0003] and is disclosed in WO-A-92/06973. Eletriptan is classified
as a 5-HT.sub.1B/1D receptor agonist and is particularly useful for
the treatment of migraine and for the prevention of migraine
recurrence.
[0004] Anhydrous alpha- and beta-hydrobromide salt forms of
eletriptan are disclosed in WO-A-96106842.
[0005] WO-A-99/01135 (PCT/EP98/04176) discloses a pharmaceutical
formulation including eletriptan hemisulphate and caffeine.
[0006] As previously mentioned, WO-A-96/06842 describes the
anhydrous polymorphic alpha-and beta-hydrobromide salt forms of
eletriptan. The problem addressed by the invention disclosed
therein is to obtain a salt form of eletriptan that is, inter alia,
stable and essentially non-hygroscopic in nature. That problem is
solved by the provision of a stable, anhydrous, alpha-form of
eletriptan hydrobromide. The anhydrous beta-form of eletriptan
hydrobromide that is also described therein is stated not to be a
viable option for the development of a suitable solid dosage form
of the drug because it is unstable and has a tendency to undergo
polymorphic conversion to the alpha-form previously described on
attempted further processing.
[0007] The problem addressed by the present invention is to provide
a further stable, non-hygroscopic, crystalline form of eletriptan
hydrobromide which has acceptable solubility and dissolution
characteristics, and which can be economically prepared and
processed to provide suitable solid dosage forms of the drug.
[0008] This problem has surprisingly been solved by the present
invention that provides, in one aspect, eletriptan hydrobromide
monohydrate. Eletriptan hydrobromide monohydrate has the formula
(I): 3
[0009] Eletriptan hydrobromide monohydrate is, most advantageously,
stable under normal conditions and essentially non-hygroscopic.
Also included within the scope of the present invention are
radiolabelled derivatives and any other isotopic variations of
eletriptan hydrobromide monohydrate.
[0010] It should be noted that WO-A-96/06842 does not disclose the
preparation of eletriptan hydrobromide monohydrate. The anhydrous
alpha-form of eletriptan hydrobromide mentioned therein is
essentially non-hygroscopic under normal conditions as is
demonstrated by the described hygroscopicity test results. These
results show that it absorbs a maximum of 1.23% by weight of water
on standing for 4 weeks at 40.degree. C. and 90% relative humidity,
that is under extreme conditions (an absorption of 3.9% by weight
of water by anhydrous eletriptan hydrobromide would be required to
form eletriptan hydrobromide monohydrate in this experiment). In
contrast, the anhydrous beta-form of eletriptan hydrobromide
mentioned therein is stated to be unstable and to undergo
polymorphic conversion to the alpha-form on further processing.
WO-A-96/06842 therefore does not specifically disclose a stable
monohydrate form of eletriptan hydrobromide.
[0011] Eletriptan hydrobromide monohydrate has been made available
by the surprising finding that treatment of a solution of
eletriptan in water, or in a suitable organic solvent containing a
sufficient amount of water to facilitate formation of the required
monohydrate, with hydrogen bromide or a suitable source thereof,
e.g. ammonium bromide, produces said monohydrate. In a second
aspect the present invention therefore provides a process for the
preparation of eletriptan hydrobromide monohydrate from eletriptan.
Preferred organic solvents for use in this process include
water-miscible or -immiscible organic solvents such as
tetrahydrofuran (THF), acetone, methyl ethyl ketone,
1,2-dimethoxyethane, methyl isobutyl ketone, ethyl acetate and a
C.sub.1-C.sub.4 alkanol (e.g. isopropanol). Most preferred organic
solvents are THF and acetone. The solution of eletriptan may be
treated with hydrogen bromide either in gaseous form or in the form
of a suitable solution, e.g. dissolved in water, acetic acid,
acetone or THF. Preferably, a concentrated (e.g. 48% or 62% by
weight) solution of hydrogen bromide in water is used. Where
non-aqueous sources of hydrogen bromide are used, water must be
present in the reaction mixture. Alternatively, ammonium bromide
may be used as a source of hydrogen bromide which forms a solution
in the presence of water.
[0012] In a third aspect of the present invention it has been
surprisingly found that any form of eletriptan hydrobromide other
than the monohydrate, including mixtures thereof, may be converted
to eletriptan hydrobromide monohydrate by crystallisation from
water, or from a suitable organic solvent containing a sufficient
amount of water to facilitate formation of the required
monohydrate. Suitable organic solvents include acetone, THF,
1,2-dimethoxyethane and a C.sub.1-C.sub.4 alkanol, e.g.
methanol.
[0013] In a fourth aspect of the present invention it has been
found that any hydrated form of eletriptan hydrobromide, including
eletriptan hydrobromide monohydrate, or mixtures thereof, may be
converted to anhydrous eletriptan hydrobromide under suitable
dehydration conditions. Suitable conditions include reslurry in, or
crystallisation from, a suitable organic solvent, optionally with
heating. Small amounts of water are tolerated in the organic
solvent used in this process. Such dehydration conditions may
optionally involve distillation or azeotropic distillation of the
organic solvent used to remove the water associated with the
hydrate. Preferred organic solvents for use in this process include
toluene, acetone, THF and acetonitrile. Other suitable organic
solvents include ethanol, n-propanol, isopropanol, t-butanol,
industrial methylated spirit, methyl ethyl ketone, methyl isobutyl
ketone, ethyl acetate, n-butyl acetate, cyclohexane, t-amyl
alcohol, xylene and dichloromethane. Alternatively, this conversion
may be effected by drying the hydrate, e.g. eletriptan hydrobromide
monohydrate, either under reduced pressure and/or at elevated
temperatures, or in a low-humidity environment.
[0014] Eletriptan hydrobromide monohydrate may be used for the
treatment of a disease or condition for which a selective agonist
of 5-HT.sub.1 receptors, and particularly of 5-HT.sub.1B/1D
receptors, is indicated. Such conditions include migraine,
recurrent migraine, hypertension, depression, emesis, anxiety, an
eating disorder, obesity, drug abuse, cluster headache, pain,
chronic paroxysmal hemicrania and headache associated with a
vascular disorder.
[0015] Eletriptan hydrobromide monohydrate can be administered
alone but it will generally be administered in admixture with a
suitable pharmaceutical excipient, diluent or carrier selected with
regard to the intended route of administration and standard
pharmaceutical practice.
[0016] For example, eletriptan hydrobromide monohydrate can be
administered orally or sublingually in the form of tablets,
capsules, ovules, elixirs, solutions or suspensions, which may
contain flavouring or colouring agents, which may be formulated as
immediate- or controlled-release, or fast-dissolving,
compositions.
[0017] Such tablets may contain excipients such as microcrystalline
cellulose, lactose, sodium citrate, calcium carbonate, dicalcium
phosphate and glycine, disintegrants such as starch, croscarmellose
sodium and certain complex silicates, and granulation binders such
as polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally,
lubricating agents such as magnesium stearate, glyceryl benhenate
and talc may be included.
[0018] Solid compositions of a similar type may also be employed as
fillers in gelatin capsules. Preferred excipients in this regard
include lactose or milk sugar as well as high molecular weight
polyethylene glycols. For aqueous suspensions and/or elixirs,
eletriptan hydrobromide monohydrate may be combined with various
sweetening or flavouring agents, colouring matter or dyes, with
emulsifying and/or suspending agents and with diluents such as
water, ethanol, propylene glycol and glycerin, and combinations
thereof.
[0019] Eletriptan hydrobromide monohydrate can also be injected
parenterally, for example, intravenously, intraperitoneally,
intrathecally, intraventricularly, intrasternally, intracranially,
intramuscularly or subcutaneously, or it may be administered by
infusion techniques. It is best used in the form of a sterile
aqueous solution which may contain other substances, for example,
enough salts or glucose to make the solution isotonic with blood.
The aqueous solutions should be suitably buffered (preferably to a
pH of from 3 to 9), if necessary. The preparation of suitable
parenteral formulations under sterile conditions is readily
accomplished by standard pharmaceutical techniques well-known to
those skilled in the art.
[0020] For oral and parenteral administration to human patients,
the daily dosage level of eletriptan hydrobromide monohydrate will
usually be from 0.1 to 4 mg/kg (in single or divided doses).
[0021] Thus tablets or capsules of eletriptan hydrobromide
monohydrate may contain from 5 to 240 mg, preferably from 5 to 100
mg, of active compound for administration singly or two or more at
a time, as appropriate. The physician in any event will determine
the actual dosage which will be most suitable for any individual
patient and it will vary with the age, weight and response of the
particular patient. The above dosages are exemplary of the average
case. There can, of course, be individual instances where higher or
lower dosage ranges are merited and such are within the scope of
this invention.
[0022] Eletriptan hydrobromide monohydrate can also be administered
intranasally or by inhalation and is conveniently delivered in the
form of a dry powder inhaler or an aerosol spray presentation from
a pressurised container or a nebuliser with the use of a suitable
propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane,
dichlorotetrafluoroethane, a hydrofluoroalkane such as
1,1,1,2-tetrafluoroethane (HFA 134A [trade mark] or
1,1,1,2,3,3,3-heptafluoropropane (HFA 227EA [trade mark]), carbon
dioxide or other suitable gas. In the case of a pressurised
aerosol, the dosage unit may be determined by providing a valve to
deliver a metered amount. The pressurised container or nebuliser
may contain a solution or suspension of the active compound, e.g.
using a mixture of ethanol and the propellant as the solvent, which
may additionally contain a lubricant, e.g. sorbitan trioleate.
Capsules and cartridges (made, for example, from gelatin) for use
in an inhaler or insufflator may be formulated to contain a powder
mix of eletriptan hydrobromide monohydrate and a suitable powder
base such as lactose or starch. Alternatively, eletriptan
hydrobromide monohydrate may be administered intranasally by
delivery from a non-pressurised unit or multi-dose, pump-type
device.
[0023] Alternatively, eletriptan hydrobromide monohydrate can be
administered in the form of a suppository or pessary, or it may be
applied topically in the form of a lotion, solution, cream,
ointment or dusting powder. Eletriptan hydrobromide monohydrate may
also be transdermally administered by the use of a skin patch.
[0024] For application topically to the skin, eletriptan
hydrobromide monohydrate can be formulated as a suitable ointment
containing the active compound suspended or dissolved in, for
example, a mixture with one or more of the following: mineral oil,
liquid petrolatum, white petrolatum, propylene glycol,
polyoxyethylene polyoxypropylene compound, emulsifying wax and
water. Alternatively, it can be formulated as a suitable lotion or
cream, suspended or dissolved in, for example, a mixture of one or
more of the following: mineral oil, sorbitan monostearate, a
polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters
wax, cetearyl alcohol, 2-octyidodecanol, benzyl alcohol and
water.
[0025] Suitable formulations of eletriptan hydrobromide monohydrate
are similar to those disclosed in WO-A-92/06973, WO-A-96/06842 and
WO-A-99/01135. Preferred formulations of eletriptan hydrobromide
monohydrate, particularly for use in the prevention of migraine
recurrence, include dual-, sustained-, controlled-, delayed- or
pulsed-release formulations.
[0026] Sustained-release dosage forms are designed to release
eletriptan hydrobromide monohydrate to the gastro-intestinal tract
of a patient over a sustained period of time following
administration of the dosage form to the patient. Suitable dosage
forms include:
[0027] (a) those in which eletriptan hydrobromide monohydrate is
embedded in a matrix from which it is released by diffusion or
erosion,
[0028] (b) those in which eletriptan hydrobromide monohydrate is
present in or on a multiparticulate core which is coated with a
rate controlling membrane,
[0029] (c) those in which eletriptan hydrobromide monohydrate is
present in a dosage form containing a coating impermeable to the
drug where release is via a drilled aperture, and
[0030] (d) those in which eletriptan hydrobromide monohydrate is
released through a semi-permeable membrane, allowing the drug to
diffuse across the membrane or through liquid filled pores within
the membrane.
[0031] The skilled person would appreciate that some of the above
means of achieving sustained-release may be combined, for example,
a matrix containing the active compound may be formed into a
multiparticulate and/or coated with an impermeable coating provided
with an aperture.
[0032] Pulsed-release formulations are designed to release the
active compound in pulses over a sustained period of time following
administration of the dosage form to the patient. The release may
then be in the form of immediate- or sustained-release. Delay in
release may be achieved by releasing the drug at particular points
in the gastro-intestinal tract or by releasing drug after a
pre-determined time. Pulsed-release formulations may be in the form
of tablets or multiparticulates or a combination of both. Suitable
dosage forms include:
[0033] (a) osmotic potential triggered release forms (e.g. see U.S.
Pat. No. 3,952,741),
[0034] (b) compression coated two layer tablets (e.g. see U.S. Pat.
No. 5,464,633),
[0035] (c) capsules containing an erodible plug (e.g. see U.S. Pat.
No. 5,474,784),
[0036] (d) sigmoidal releasing pellets (e.g. as referred to in U.S.
Pat. No 5,112,621) and
[0037] (e) formulations coated with or containing pH dependent
polymers including shellac, phthalate derivatives, polyacrylic acid
derivatives and crotonic acid copolymers.
[0038] Dual-release formulations can combine the active compound in
immediate-release form with additional active compound in
sustained-release form. For example, a bilayer tablet can be formed
with one layer containing eletriptan hydrobromide monohydrate in an
immediate-release form and the other layer containing eletriptan
hydrobromide monohydrate embedded in a matrix from which it is
released by diffusion or erosion. Dual-release formulations can
also combine the active compound in immediate-release form with
additional active compound in pulsed-release form. For example, a
capsule containing an erodible plug could liberate active compound
initially and after a predetermined period of time further active
compound may be delivered in immediate- or sustained-release
form.
[0039] Preferred drug dual release profiles include
[0040] (a) immediate release followed by controlled release;
[0041] (b) immediate release followed by zero order release;
[0042] (c) immediate release followed by sigmoidal release; and
[0043] (d) double pulse release.
[0044] Delayed-release formulations are designed to release the
active compound a predetermined time after administration. The
release from delayed-release formulations may be in the form of
immediate-release or sustained-release.
[0045] Controlled-release formulations impart control with respect
to the rate of release or the time of release, or both, of the
active compound and include sustained-, pulsed-, dual- and
delayed-release formulations.
[0046] It is to be appreciated that all references herein to
treatment include curative, palliative and prophylactic
treatment.
[0047] The invention is illustrated by the following Examples.
EXAMPLE 1
[0048] Preparation of Eletriptan Hydrobromide Monohydrate from
Eletriptan
[0049] Eletriptan (2 kg) was dissolved in acetone (24.2 L) and
filtered. The mixture was diluted with further acetone (7.4 L) and
water (2.36 L) added. A chilled (<5.degree. C.) mixture of a
solution of 48% by weight hydrogen bromide in water (0.863 kg) and
acetone (12.4 L) was added in portions over about a 6 hour period
whilst maintaining the temperature below 25.degree. C. throughout
the addition. Full transfer of the hydrogen bromide solution was
ensured by washing the residues into the reaction mixture using
further acetone (2.4 L). The resulting slurry was granulated and
chilled prior to collection of the product obtained by filtration.
The product was washed carefully with acetone and then dried under
reduced pressure and at ambient temperature in the presence of a
water reservoir to provide eletriptan hydrobromide monohydrate
(1.75 kg, 70%). This material was then milled before further
use.
[0050] .sup.1H-NMR (400 MHz, d.sub.6-DMSO): delta=10.90 (1H, d,
J=2.2 Hz), 9.35 (1H, br s), 7.95 (2H, d, J=7.5 Hz), 7.76 (1H, t,
J=7.5 Hz), 7.66 (2H, t, J=7.5 Hz), 7.38 (1H, s), 7.24 (1H, d, J=8.3
Hz), 7.23 (1H, d, J=2.2 Hz), 6.92 (1H, dd, J=8.3, 1.4 Hz), 3.63
(2H, m), 3.58 (2H, br m), 3.24 (1H, m), 3.06 (1H, m), 2.95 (2H, m),
2.86 (1H, m), 2.83 (3H, s), 2.00 (1H, m), 1.90 (2H, m), 1.70 (1H,
m).
[0051] Found: C, 54.85; H, 6.03; N, 5.76.
C.sub.22H.sub.29N.sub.2O.sub.3SB- r requires C, 54.87; H, 6.08; N,
5.82%.
[0052] PXRD, DSC, moisture sorption and IR data are provided in the
Analytical Section that follows.
EXAMPLE 2
[0053] Preparation of Eletriptan Hydrobromide Monohydrate from
Eletriptan
[0054] Eletriptan (1.9 kg) was dissolved in a solution of 97.5:2.5,
by volume, THF:water (30 L) and filtered. A solution of hydrogen
bromide (ca. 48% by weight) in water (0.87 kg) was added to the
solution at 15-25.degree. C. A dense crystalline slurry was formed.
The slurry was heated under reflux for approximately one hour. The
slurry was cooled to from 15 to 20.degree. C. and granulated for a
minimum of 1 hour. The product was filtered and washed with THF (10
L) to provide eletriptan hydrobromide monohydrate (2.3 kg).
[0055] Analytical data obtained were identical to those obtained
for the product of Example 1.
EXAMPLE 3
[0056] Preparation of Eletriptan Hydrobromide Monohydrate from
Eletriptan
[0057] Eletriptan (25 g) was dissolved in a solution of 95:5, by
volume, THF:water and filtered. A solution of hydrogen bromide (ca.
48% by weight) in water (10.7 g) was added to the solution at
15-25.degree. C. A dense crystalline slurry was formed. The slurry
was heated under reflux for approximately one hour. The slurry was
cooled to from 15 to 25.degree. C. The product was filtered and
washed with THF (50 ml) to produce eletriptan hydrobromide
monohydrate (28.4 g, 96%).
[0058] Analytical data obtained were identical to those obtained
for the product of Example 1.
EXAMPLE 4
[0059] Preparation of Eletriptan Hydrobromide Monohydrate by
Reprocessing Eletriptan Hydrobromide
[0060] Eletriptan hydrobromide (4.91 g) was dissolved in a mixture
of acetone (10 ml) and water (1.85 ml) by heating under reflux. The
mixture was treated with acetone (63.6 ml), dropwise over about 20
minutes, and then cooled to ambient temperature. The mixture was
granulated overnight (16 hours), cooled to 0-5.degree. C. and
granulated at this temperature for a further hour. The resulting
solid was filtered, washed with acetone (3 ml) and then dried under
reduced pressure and at ambient temperature to give eletriptan
hydrobromide monohydrate (4.8 g).
[0061] Analytical data obtained were identical to those obtained
for the product of Example 1.
EXAMPLE 5
[0062] Preparation of Anhydrous Eletriptan Hydrobromide from
Eletriptan Hydrobromide Monohydrate
[0063] A slurry of eletriptan hydrobromide monohydrate (6.5 g) in
acetone (97.5 ml) was heated under reflux for three hours and then
cooled and filtered. The filtered solid was washed with acetone
(6.5 ml) and dried under reduced pressure to give anhydrous
eletriptan hydrobromide (5.78 g).
[0064] FIG. 6 shows the DSC thermogram obtained for this product by
the method of paragraph (b) of the Analytical section below. This
was consistent with that previously obtained for the alpha-form of
anhydrous eletriptan hydrobromide described in WO-A-96/06842.
EXAMPLE 6
[0065] Preparation of Anhydrous Eletriptan Hydrobromide from
Eletriptan Hydrobromide Monohydrate
[0066] A slurry of eletriptan hydrobromide monohydrate (1.0 g) in
toluene (30 ml) was heated under reflux. An aliquot of the toluene
(5 ml) was removed by distillation and the mixture was held at
below the reflux temperature for 2-3 hours. A further aliquot of
toluene (5 ml) was removed by distillation. The residual slurry was
cooled to ambient temperature over about one hour and the solid
obtained collected by filtration and dried under reduced pressure
at 60.degree. C. to provide anhydrous eletriptan hydrobromide (0.81
g).
[0067] FIG. 7 shows the DSC thermogram obtained for this product by
a similar method to that of paragraph (b) of the Analytical section
below except that a 10 mg weight of sample and a heating rate of
40.degree. C./minute were used. This showed the product to be a
mixture of the alpha- and beta-forms of anhydrous eletriptan
hydrobromide, both as disclosed in WO-A-96/06842, the former with
an endotherm maximum at 176.degree. C. and the latter with an
endotherm maximum at 161.degree. C. No evidence for the presence of
eletriptan hydrobromide monohydrate was detected in this DSC
analysis.
EXAMPLE 7
[0068] Preparation of a Tablet Formulation of Eletriptan
Hydrobromide Monohydrate
1 Each tablet to contain: Eletriptan hydrobromide monohydrate
100.629 mg Microcrystalline cellulose (Avicel PH102, trade mark)
182.371 mg Lactose (fast-flo) 92.000 mg Croscarmellose sodium
(Ac-di-sol) 20.000 mg Magnesium stearate 3.000 mg Magnesium
stearate 2.000 mg Total 400.000 mg
[0069] Eletriptan hydrobromide monohydrate was blended with lactose
for 10 minutes and then microcrystalline cellulose and
croscarmellose sodium added. The mixture was blended for 20 minutes
and screened through a 500 micron screen. The screened material was
blended for a further 20 minutes and a first portion of magnesium
stearate (0.75% w/w) added. The mixture was roller compacted and
blended for 20 minutes then a second portion of magnesium stearate
(0.50% w/w) added. The mixture was compressed into tablets each
containing a 80 mg dose of eletriptan. The tablets were then
film-coated using Opadry Orange (trade mark) film coat
(OY-LS-23016) as a 12% solids system at 3.0% w/w followed by Opadry
Clear (trade mark) overcoat (YS-2-19114-A) as a 5% solution at 0.5%
w/w.
ANALYTICAL DATA
[0070] Analytical data obtained for eletriptan hydrobromide
monohydrate prepared by the method of Example 1 are presented
below.
[0071] a) PXRD
[0072] The powder X-ray diffraction (PXRD) pattern was determined
using a Siemens D5000 powder X-ray diffractometer fitted with an
automatic sample changer, a theta-theta goniometer, automatic beam
divergence slits, a secondary monochromator and a scintillation
counter.
[0073] The sample was prepared for analysis by packing the powder
sample into a 12 mm diameter, 0.25 mm deep cavity that had been cut
into a silicon wafer specimen mount. The specimen was rotated
whilst being irradiated with copper K-alpha, X-rays
(wavelength=1.5046 Angstroms) with the X-ray tube operated at 40
kV/40 mA. The analysis was performed with the goniometer running in
step-scan mode set for a 5 second count per 0.02.degree. step over
a two-theta range of 2.degree. to 55.degree..
[0074] FIG. 1 shows the PXRD pattern obtained.
[0075] Table 1 shows the peak listings for FIG. 1 in which
dA.degree. is a measurement of the interplanar spacing and
I/I.sub.i is a measurement of the relative intensity.
2TABLE I d.ANG. l/I.sub.i d.ANG. l/I.sub.i d.ANG. l/I.sub.i d.ANG.
l/I.sub.i d.ANG. l/I.sub.i 10.76 3.6 4.337 11.8 3.165 17.0 2.407
8.5 2.010 11.1 9.015 4.6 4.305 24.1 3.143 37.7 2.401 10.5 2.005
11.5 7.697 4.4 4.164 4.7 3.110 10.2 2.370 23.9 1.988 15.4 7.496 1.8
4.060 28.8 3.048 16.6 2.328 16.7 1.968 15.9 7.084 12.0 4.048 27.0
3.040 11.5 2.324 13.1 1.958 13.1 6.700 94.4 3.979 6.7 3.006 38.4
2.310 11.9 1.951 11.9 6.507 7.8 3.941 21.6 2.959 8.5 2.305 10.7
1.929 11.4 6.288 10.1 3.890 15.0 2.925 29.8 2.290 7.7 1.913 25.6
5.849 45.4 3.847 91.8 2.889 8.9 2.271 15.2 1.908 21.2 5.475 14.3
3.764 84.0 2.857 8.1 2.265 12.0 1.877 17.2 5.377 7.3 3.738 25.4
2.797 11.9 2.229 11.8 1.872 14.9 5.227 19.2 3.684 100.0 2.739 9.2
2.201 16.2 1.832 14.8 5.093 4.4 3.569 19.1 2.719 14.3 2.190 19.7
1.827 14.9 5.060 10.7 3.474 10.3 2.699 9.3 2.171 17.5 1.823 13.3
4.735 12.0 3.351 10.2 2.629 20.5 2.152 14.4 1.792 11.1 4.716 9.3
3.295 22.6 2.612 10.8 2.138 12.6 1.776 9.3 4.697 15.3 3.264 40.3
2.564 17.3 2.096 10.5 1.762 10.4 4.680 17.0 3.253 43.5 2.554 27.0
2.081 13.4 1.740 9.8 4.502 36.9 3.241 40.3 2.532 8.9 2.066 7.3
1.734 10.9 4.475 14.8 3.189 15.7 2.480 17.3 2.041 12.1 1.721 9.3
4.435 35.1 3.178 15.0 2.468 15.2 2.024 13.8 1.701 9.6
[0076] b) DSC
[0077] Differential scanning calorimetry (DSC) was performed using
a Perkin-Elmer DSC-7 instrument fitted with an automatic sample
changer. Approximately 3 mg of sample was accurately weighed into a
50 microliter aluminium pan and crimp-sealed with a perforated lid.
The sample was heated at 20.degree. C./minute over the range 40 to
220.degree. C. with a nitrogen gas purge.
[0078] FIG. 2 shows the DSC thermogram obtained.
[0079] The DSC thermogram of FIG. 2 shows a broad endotherm at
103.degree. C. due to the dehydration of the monohydrate followed
by a melting endotherm at 135.degree. C.
[0080] c) Moisture Sorption
[0081] The moisture sorption of eletriptan hydrobromide monohydrate
was determined using a Dynamic Vapour Sorption (DVS) Automated
Sorption Analyser Model DVS-1 instrument manufactured by Surface
Measurements Systems Ltd., UK.
[0082] Approximately 25 mg of eletriptan hydrobromide monohydrate
was accurately weighed into a sample pan. This was exposed to
humidities in the range of from 0 to 90%RH. The analysis was
carried out in detail in the range of from 0 to 15%RH, using 15%RH
steps in the range of from 15 to 90%RH. The analysis temperature
was 30.degree. C. with a nitrogen flow rate of 200 cm.sup.3
min.sup.-1.
[0083] FIG. 3 shows the moisture sorption isotherm obtained for
eletriptan hydrobromide monohydrate. This isotherm shows that above
6%RH the sample remains as a monohydrate but at 0%RH the material
has lost all of the 3.8% w/w of water associated with its
monohydrate molecular structure. Once the monohydrate has formed
there is very little additional moisture sorbed and within the
range 10 to 90% RH less than 0.3% w/w of water is sorbed. These
data illustrate that eletriptan hydrobromide monohydrate is
essentially non-hygroscopic.
[0084] d) IR
[0085] Infrared (IR) spectroscopy was performed with a Nicolet 800
FT-IR spectrometer fitted with a d-TGS detector. The spectrum was
acquired at 2 cm.sup.-1 resolution from a KBr disc preparation of
the sample.
[0086] FIGS. 4 and 5 show the IR spectra obtained.
[0087] Table 2 gives the peak listing for FIGS. 4 and 5 in which
the wavenumber (cm.sup.-1) of each peak is recorded.
3TABLE 2 Peak position and intensity data from FIGS. 4 and 5
cm.sup.-1 % T 406.9 76.26 429.6 58.71 456.6 70.18 473.9 74.14 497.1
61.84 529.2 47.58 553.9 61.60 566.4 55.54 592.2 64.48 601.1 62.96
606.2 64.21 642.2 50.81 665.0 62.00 667.3 61.99 689.1 44.63 729.5
41.77 747.8 42.52 767.2 55.12 793.0 61.03 807.2 52.47 822.0 61.96
841.2 77.97 852.8 82.78 870.1 72.30 876.3 75.82 890.9 81.30 926.3
75.29 937.9 82.07 948.9 83.39 970.5 80.26 985.0 74.49 997.3 68.84
1010.2 63.67 1017.4 67.60 1071.0 59.34 1085.7 36.28 1102.4 59.40
1141.0 22.80 1150.4 29.87 1178.5 74.00 1189.1 74.80 1241.0 50.56
1267.1 36.51 1287.8 37.31 1305.4 32.74 1328.5 62.22 1346.7 62.04
1353.4 63.40 1387.3 70.61 1408.8 65.76 1444.9 33.08 1458.1 56.13
1482.5 52.58 1549.0 85.24 1581.3 76.69 1611.6 76.36 1622.0 76.12
1646.6 70.94 1703.4 85.34 1827.7 84.61 1893.3 82.46 1913.9 83.22
1937.2 83.53 1978.6 82.08 2001.7 81.75 2676.9 48.34 2852.6 58.00
2864.6 58.53 2893.3 55.24 2921.4 50.36 2952.9 51.31 2971.5 54.94
2994.2 52.24 3013.8 54.84 3038.5 56.17 3054.5 58.05 3071.0 60.25
3079.6 60.08 3117.0 56.27 3131.2 55.95 3246.0 31.56 3473.4
49.70
STABILITY DATA
[0088] 1) Eletriptan hydrobromide monohydrate was stored in double
polyethylene bags inside a fibreboard drum under the following
conditions:
4 25.degree. C./60% RH for 9 months 30.degree. C./60% RH for 9
months 40.degree. C./75% RH for 6 months (RH = relative
humidity)
[0089] HPLC analysis of the products at the end of the storage
periods showed no degradation had occurred.
[0090] 2) A batch of the tablets prepared according to Example 7
was stored in HDPE (high density polyethylene) bottles under the
following conditions:
5 25.degree. C./60% RH for 9 months 30.degree. C./60% RH for 9
months 40.degree. C./75% RH for 6 months (RH = relative
humidity)
[0091] HPLC analysis of the tablets at the end of the storage
periods showed no degradation had occurred.
[0092] The results of both stability tests show that eletriptan
hydrobromide monohydrate exhibits good stability.
* * * * *