U.S. patent application number 12/002069 was filed with the patent office on 2008-04-24 for processes for preparation of crystalline mycophenolate sodium.
Invention is credited to Judith Aronhime, Janos Hajko, Adrienne Kovacsne-Mezei, Sandor Molnar, Csaba Szabo, Tivadar Tamas.
Application Number | 20080097096 12/002069 |
Document ID | / |
Family ID | 35385154 |
Filed Date | 2008-04-24 |
United States Patent
Application |
20080097096 |
Kind Code |
A1 |
Molnar; Sandor ; et
al. |
April 24, 2008 |
Processes for preparation of crystalline mycophenolate sodium
Abstract
Provided are crystalline mycophenolate sodium forms and
processes for their preparation.
Inventors: |
Molnar; Sandor; (Debrecen,
HU) ; Szabo; Csaba; (Debrecen, HU) ; Tamas;
Tivadar; (Debrecen, HU) ; Hajko; Janos;
(Debrecen, HU) ; Kovacsne-Mezei; Adrienne;
(Debrecen, HU) ; Aronhime; Judith; (Rehovot,
IL) |
Correspondence
Address: |
KENYON & KENYON LLP
ONE BROADWAY
NEW YORK
NY
10004
US
|
Family ID: |
35385154 |
Appl. No.: |
12/002069 |
Filed: |
December 14, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11186164 |
Jul 20, 2005 |
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12002069 |
Dec 14, 2007 |
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60589909 |
Jul 20, 2004 |
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60631849 |
Nov 29, 2004 |
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Current U.S.
Class: |
544/153 |
Current CPC
Class: |
C07D 307/83 20130101;
A61P 37/06 20180101; C07D 307/88 20130101; A61P 35/00 20180101;
A61K 31/365 20130101 |
Class at
Publication: |
544/153 |
International
Class: |
C07D 413/02 20060101
C07D413/02 |
Claims
1. A process for preparing anhydrous crystalline mycophenolate
sodium (Form M2) characterized by a powder XRD pattern with peaks
at 5.3, 8.0, 9.8, 10.7, and 21.9.+-.0.2 degrees 2-theta comprising
the steps of: (a) preparing a solution of mycophenolic acid in a
C.sub.3-C.sub.8 ketone; (b) combining a base and a source of sodium
with the solution to precipitate the crystalline form; and (c)
recovering the crystalline form.
2. The process of claim 1, wherein the C.sub.3-C.sub.7 ketone is
acetone.
3. The process of claim 1, wherein sodium methoxide, sodium
ethoxide, or sodium hydroxide is used in step (b).
4. The process of claim 3, wherein sodium hydroxide is used in step
(b).
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional of U.S. patent application
Ser. No. 11/186,164, filed Jul. 20, 2005, which claims the benefits
of U.S. Provisional Patent Application Nos. 60/589,909, filed Jul.
20, 2004, and 60/631,849 filed Nov. 29, 2004, the contents of all
of which are incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to the solid state chemistry
of mycophenolate sodium.
BACKGROUND OF THE INVENTION
[0003] At the end of 1960's, Eli Lilly disclosed the inhibiting
effect of mycophenolate sodium salt (MPS) on the growth of
malignant tumor cells in warm-blooded mammals. Nowadays Novartis
has introduced an enteric-coated formulation of mycophenolate
sodium, referred to as Myfortic.RTM.. Mycophenolic acid can be
formed either as mono- or disodium salt. South African patent No.
6804959 describes the preparation of mono- and disodium
mycophenolate. Monosodium mycophenolate can be isolated after
reaction of one molar equivalent of sodium methoxide with
mycophenolic acid in a mixture of methanol and chloroform by
precipitation with n-pentane. Preparation of the corresponding
disodium salt is also described. In this case two molar equivalents
of sodium methoxide were added to a solution of mycophenolic acid
in 2:1 benzene-chloroform mixture. The evaporated material was
crystallized from aqueous acetone.
[0004] The synthetic route of WO 97/38689 is identical to the one
described in South African patent No. 6804959. The compound may be
obtained in crystalline form by recrystallization from
acetone/ethanol if necessary with water (m.p. 189-191.degree.
C.).
[0005] The present invention relates to the solid state physical
properties of mycophenolate sodium. These properties may be
influenced by controlling the conditions under which mycophenolate
sodium is obtained in solid form. Solid state physical properties
include, for example, the flowability of the milled solid.
Flowability affects the ease with which the material is handled
during processing into a pharmaceutical product. When particles of
the powdered compound do not flow past each other easily, a
formulation specialist must take that fact into account in
developing a tablet or capsule formulation, which may necessitate
the use of glidants such as colloidal silicon dioxide, talc, starch
or tribasic calcium phosphate.
[0006] Another important solid state property of a pharmaceutical
compound is its rate of dissolution in aqueous fluid. The rate of
dissolution of an active ingredient in a patient's stomach fluid
may have therapeutic consequences since it imposes an upper limit
on the rate at which an orally-administered active ingredient may
reach the patient's bloodstream. The rate of dissolution is also a
consideration in formulating syrups, elixirs and other liquid
medicaments. The solid state form of a compound may also affect its
behavior on compaction and its storage stability.
[0007] These practical physical characteristics are influenced by
the conformation and orientation of molecules in the unit cell,
which defines a particular polymorphic Form of a substance. The
polymorphic form may give rise to thermal behavior different from
that of the amorphous material or another polymorphic form. Thermal
behavior is measured in the laboratory by such techniques as
capillary melting point, thermogravimetric analysis (TGA) and
differential scanning calorimetry (DSC) and may be used to
distinguish some polymorphic forms from others. A particular
polymorphic form may also give rise to distinct spectroscopic
properties that may be detectable by powder X-ray crystallography,
solid state C NMR spectrometry and infrared spectrometry.
[0008] WO2004/020426 discloses preparation of sodium mycophenolate
by reacting mycophenolic acid or its ammonium or dibenzyl-amine
salt with a sodium salt of C.sub.2 to C.sub.10 carboxylic acid.
Mycophenolic acid is converted to its ammonium salt by reacting
with ammonia. This compound is reacted with sodium acetate to
obtain the sodium salt of mycophenolic acid.
[0009] WO 2004/064806 discloses additional polymorphic forms of
mycophenolate sodium and acid.
Monosodium Salt
[0010] South African patent No. 68/4,959 provides an example for
preparing monosodium mycophenolate salt (Example 3). Sodium
methylate in anhydrous methanol was added to mycophenolic acid in
chloroform, then the monosodium salt was precipitated by adding
n-pentane and collected by filtration and vacuum dried.
[0011] Acta Chrystallographica Sect. C, (2000), C56, 432-433
describes another process for producing monosodium mycophenolate. A
methanolic solution of the commercially available mycophenolic acid
was treated with one equivalent of sodium methanolate. After
stirring for 1 hour at room temperature, the solvent was evaporated
to dryness in vacuum. The melting point of the product was 463 K
(190.degree. C.). Single crystals were grown by evaporation and
cooling of a water/ethyl acetate solution from about 323K to room
temperature. The crystal structure of the produced sodium
mycophenolate measured by single crystal diffractometer is also
described.
[0012] Based on the given crystal parameters, the calculated powder
diffractogram done by the inventors of the present invention show
that the crystal form obtained is the crystal form denominated Form
M2. Form M2 is an anhydrous form. Form M2 is characterized by a
powder XRD pattern with peaks at 5.3, 8.0, 9.8, 10.7, and
21.9.+-.0.2 degrees 2 theta (FIG. 3) and FTIR peaks at 1719, 1571,
1317, 1266, 1134 and 927 cm-1 (FIG. 4). Form M2 may be further
characterized by XRD peaks at 13.6 and 19.0.+-.0.2 degrees 2 theta.
Form M2 may be further characterized by IR peaks at 1194, 1108,
1075, 1034, 971, 875, 826, 794 and 722 cm-1. Form M2 may be further
characterized by a DSC curve (FIG. 43).
[0013] PCT 97/38689 describes sodium mycophenolate salts as known
from South African Patent. It also describes the process for
obtaining monosodium salt in crystalline form by recrystallization
from acetone/ethanol if necessary with water. The melting point
provided is 189-191.degree. C.
[0014] J. Med. Chem. (1996), 39, 1236-1242 describes treating a
solution of mycophenolic acid in ethanol with equimolar sodium
ethylate at room temperature and stirring for 30 minutes. The
solvent was evaporated in vacuum.
[0015] J. Pharm. Sciences (1970), 59(8), 1157-1159 asserts that
monosodium mycophenolate may be formed by adjusting the slurry of
mycophenolic acid to pH 7-8 with sodium hydroxide. No physical data
is provided.
[0016] South African patent No. 68/4,959 provides an example for
producing disodium mycophenolate (Example 2). Mycophenolic acid was
dissolved in benzene:chloroform 2:1 solvent mixture and sodium
methoxide dissolved in anhydrous methanol was added to it. The
solution was stirred for 15-20 minutes, evaporated to dryness and
redissolved in water. Crystallization was effected by the addition
of acetone to the hot water solution and chilling overnight. No
physical data was given.
[0017] The discovery of new polymorphic forms of a pharmaceutically
useful compound and/or new processes for their preparation provides
a new opportunity to improve the performance characteristics of a
pharmaceutical product. It enlarges the repertoire of materials
that a formulation scientist has available for designing, for
example, a pharmaceutical dosage form of a drug with a targeted
release profile or other desired characteristic.
SUMMARY OF THE INVENTION
[0018] In one embodiment, the present invention provides a process
for preparing anhydrous crystalline mycophenolate sodium (Form M2)
characterized by a powder XRD pattern with peaks at 5.3, 8.0, 9.8,
10.7, and 21.9.+-.0.2 degrees 2-theta comprising the steps of:
(a) preparing a solution of mycophenolic acid in a C1-C4
alcohol;
(b) combining a base and a source of sodium with the solution to
obtain a reaction mixture;
(c) crystallizing the crystalline form the mixture; and
(d) recovering the crystalline form.
[0019] In another embodiment, the present invention provides a
process for preparing anhydrous crystalline mycophenolate sodium
(Form M2) characterized by a powder XRD pattern with peaks at 5.3,
8.0, 9.8, 10.7, and 21.9.+-.0.2 degrees 2-theta comprising the
steps of:
(a) preparing a solution of mycophenolic acid in a C3-C8 ester;
(b) combining a base and a source of sodium with the solution to
precipitate the crystalline form;
(c) recovering the crystalline form.
[0020] In another embodiment, the present invention provides a
process for preparing anhydrous crystalline mycophenolate sodium
(Form M2) characterized by a powder XRD pattern with peaks at 5.3,
8.0, 9.8, 10.7, and 21.9.+-.0.2 degrees 2-theta comprising the
steps of:
(a) preparing a solution of sodium mycophenolate in 1-butanol;
(b) crystallizing the crystalline form from the solution; and
(c) recovering the crystalline form.
[0021] In another embodiment, the present invention provides a
process for preparing anhydrous crystalline mycophenolate sodium
(Form M2) characterized by a powder XRD pattern with peaks at 5.3,
8.0, 9.8, 10.7, and 21.9.+-.0.2 degrees 2-theta comprising the
steps of:
(a) preparing a solution of mycophenolic acid in a C3-C8
ketone;
(b) combining a base and a source of sodium with the solution to
precipitate the crystalline form; and
(c) recovering the crystalline form.
[0022] In another embodiment, the present invention provides a
process for preparing anhydrous crystalline mycophenolate sodium
(Form M2) characterized by a powder XRD pattern with peaks at 5.3,
8.0, 9.8, 10.7, and 21.9.+-.0.2 degrees 2-theta comprising the
steps of:
(a) preparing a solution of sodium mycophenolate in ethanol;
(b) crystallizing the crystalline form from the solution;
(c) recovering the crystalline form; and
(d) drying the recovered crystalline form.
[0023] In another embodiment, the present invention provides a
process for preparing anhydrous crystalline mycophenolate sodium
(Form M2) characterized by a powder XRD pattern with peaks at 5.3,
8.0, 9.8, 10.7, and 21.9.+-.0.2 degrees 2-theta comprising the
steps of:
(a) preparing a solution of sodium mycophenolate in ethyl
lactate;
(b) combining acetone with the solution to precipitate the
crystalline form; and
(c) recovering the crystalline form.
[0024] In another embodiment, the present invention provides a
process for preparing anhydrous crystalline mycophenolate sodium
(Form M2) characterized by a powder XRD pattern with peaks at 5.3,
8.0, 9.8, 10.7, and 21.9.+-.0.2 degrees 2-theta comprising the
steps of:
(a) preparing a solution of sodium mycophenolate in
dimethylformide;
(b) combining 1-propanol with the solution to precipitate the
crystalline form;
(c) recovering the crystalline form; and
(d) drying the recovered crystalline form.
[0025] In another embodiment, the present invention provides a
process for preparing anhydrous crystalline mycophenolate sodium
(Form M2) characterized by a powder XRD pattern with peaks at 5.3,
8.0, 9.8, 10.7, and 21.9.+-.0.2 degrees 2-theta comprising the
steps of:
(a) preparing a solution of sodium mycophenolate in methanol;
(b) combining an antisolvent with the solution to precipitate the
crystalline form;
(c) recovering the crystalline form; and
(d) drying the recovered crystalline form,
wherein the antisolvent is selected from the group consisting of
ethyl acetate, methyl-tert-butyl ether, and mixtures thereof.
[0026] In another embodiment, the present invention provides a
process for preparing anhydrous crystalline mycophenolate sodium
(Form M2) characterized by a powder XRD pattern with peaks at 5.3,
8.0, 9.8, 10.7, and 21.9.+-.0.2 degrees 2-theta comprising the
steps of:
(a) preparing a solution of sodium mycophenolate in methanol;
(b) combining the solution with an antisolvent to precipitate the
crystalline form; and
(c) recovering the crystalline form,
wherein the antisolvent solvent is selected from the group
consisting of acetone, isopropanol, tetrahydrofuran, diisopropyl
ether, nitromethane, isobutanol, and mixtures thereof.
[0027] In another embodiment, the present invention provides a
process for preparing anhydrous crystalline mycophenolate sodium
(Form M2) characterized by a powder XRD pattern with peaks at 5.3,
8.0, 9.8, 10.7, and 21.9.+-.0.2 degrees 2-theta comprising the
steps of:
(a) preparing a solution of mycophenolic acid in a mixture of
dichloromethane and methanol; and
(b) combining a base and a source of sodium with the solution to
precipitate the crystalline form; and
(c) recovering the crystalline form.
[0028] In another embodiment, the present invention provides a
process for preparing anhydrous crystalline mycophenolate sodium
(Form M2) characterized by a powder XRD pattern with peaks at 5.3,
8.0, 9.8, 10.7, and 21.9.+-.0.2 degrees 2-theta comprising the
steps of heating a solid mixture of a crystalline mycophenolate
sodium (Form M1) characterized by a powder XRD pattern with peaks
at 4.7, 6.6, 11.2 and 15.6.+-.0.2 degrees 2-theta and a crystalline
mycophenolate sodium (Form M3) characterized by at least one of a
powder XRD pattern with peaks at 6.0, 9.3, 15.5, and 18.4.+-.0.2
degrees 2-theta.
BRIEF DESCRIPTION OF THE FIGURES
[0029] FIG. 1 is a characteristic X-ray powder diffraction pattern
for monosodium mycophenolate form M2.
[0030] FIG. 2 is a characteristic FT-IR spectrum of monosodium
mycophenolate form M2.
[0031] FIG. 3 is a characteristic DSC curve for monosodium
mycophenolate form M2.
[0032] FIG. 4 is a calculated XRD pattern of a single crystal data
of article Acta Crystallographica Sect. C, (2000), C56,
432-434.
[0033] FIG. 5 is a characteristic X-ray powder diffraction pattern
for monosodium mycophenolate form M1.
[0034] FIG. 6 is a characteristic FT-IR spectrum of monosodium
mycophenolate form M1.
[0035] FIG. 7 is a characteristic DSC curve for monosodium
mycophenolate form M1.
[0036] FIG. 8 is a characteristic X-ray powder diffraction pattern
for monosodium mycophenolate form M3.
[0037] FIG. 9 is a characteristic FT-IR spectrum of monosodium
mycophenolate form M3.
[0038] FIG. 10 is a characteristic DSC curve for monosodium
mycophenolate form M3.
DETAILED DESCRIPTION OF THE INVENTION
[0039] The present invention provides various processes for
preparation of Form M2 of mycophenolate sodium on an industrial
scale. Most of the processes developed in the present invention are
crystallization or slurry processes, which are suitable for use on
an industrial scale (batches of at least 0.5 Kg). Further,
crystallization often allows for obtaining a product with higher
purity.
[0040] Form M2 may be prepared by slurry or crystallization from a
solution of the sodium salt in a C.sub.3 to C.sub.8 organic ester
as solvent, such as ethyl acetate or isobutyl acetate. The solution
or slurry may contain charcoal for removal of colored impurities,
which charcoal is then removed by filtration. To prepare a solution
of the sodium salt, a source of sodium is added to the solution of
MPA in the ester. In one embodiment, a base in methanol, such as
about a 30% solution of sodium methoxide in methanol is added
portion-wise, preferably at a temperature of about 10 to about
60.degree. C., most preferably at about room temperature. The
reaction mixture is preferably stirred for an additional
approximately of 1 or 2 hours. A solid precipitates from the
solution, which is then recovered by conventional techniques. The
solid material is then preferably dried, preferably at about 40 to
about 85.degree. C. in a vacuum oven. A slurry process with such
ester is illustrated in example 3.
[0041] Form M2 may be prepared by crystallization from a
C.sub.1-C.sub.4 alcohol, preferably methanol. In this embodiment, a
solution of the mycophenolic acid in the alcohol is combined with a
base or source of sodium, preferably sodium methoxide. The
combining may be carried out portion-wise, or in one step. The
resulting reaction mixture may be heated to a temperature of at
least about 35.degree. C. to obtain complete dissolution, though
the reaction may be carried out without heating. A crystalline form
is then crystallized from the solution, preferably by cooling, more
preferably by cooling to a temperature of less than about 0.degree.
C., most preferably about -10.degree. C. to about -20.degree. C.
The crystals are then recovered and may be dried. Analysis of the
dried product showed that it was Form M2. During this process, the
reaction mixture is kept for at least about 5 hours during
crystallization. In other embodiments, an antisolvent is added to
the methanol to precipitate Form M2. In this embodiment, sodium
mycophenolate is dissolved in methanol, preferably at room
temperature, then a halogen-free solvent such as a C.sub.3 to
C.sub.8 ketone (preferably acetone) or ester (preferably ethyl
acetate iso-butyl acetate) or a C.sub.2 to C.sub.8 ether
(preferably tetrahydrofuran or t-butyl methyl ether or diisopropyl
ether) or a C.sub.2 to C.sub.4 alcohol (preferably isopropanol or
isobutanol) is added to the solution. Nitromethane may also be
used. A solid then crystallizes from the solution, preferably at
room temperature overnight. The solid is then recovered, and
preferably dried at room temperature. With ethyl acetate and
methyl-t-butyl-ether as anti-solvents, the product may have to be
dried to obtain Form M2. Drying may be carried out at room
temperature and/or under atmospheric pressure.
[0042] Form M2 of sodium mycophenolate may also be obtained when
sodium mycophenolate (MPS) is crystallized from ethanol or
1-butanol. The ethanol is preferably absolute ethanol. In one
embodiment, sodium mycophenolate is dissolved in ethanol or
1-butanol at ambient or elevated temperature, cooled to room
temperature and crystallized at this temperature for overnight. The
solution may be heated to a temperature of at least about
60.degree. C., such as the reflux temperature of the solvent. The
crystals obtained from ethanol may have to be dried to obtain Form
M2. Drying may be carried out at room temperature under atmospheric
pressure (ambient conditions).
[0043] In another embodiment, mycophenolate sodium Form M2 is
prepared by precipitating Form M2 by adding acetone as an
antisolvent to a solution of mycophenolate sodium in ethyl lactate.
In one embodiment, sodium mycophenolate is dissolved in ethyl
lactate at elevated temperature, such as about 60.degree. C. The
solution is then cooled, preferably to about room temperature, and
acetone is added to the solution. After addition of the acetone,
the solution is further cooled, preferably to about 0.degree. C. to
about 10.degree. C. and allowed to crystallize. The product is then
recovered by conventional techniques and may be dried.
[0044] In another embodiment, mycophenolate sodium Form M2 is
prepared by precipitating Form M2 by adding 2-propanol as an
antisolvent to a solution of mycophenolate sodium in
dimethylformide. As exemplified, in this embodiment, 2-propanol is
combined with a solution of sodium mycophenolate in dimethylformide
and allowed to crystallize. The product is then recovered by
conventional techniques. The product may have to be dried to obtain
Form M2. The crystalline form may be dried at room temperature
and/or under atmospheric pressure.
[0045] Form M2 may also be obtained by crystallization from a
C.sub.3 to C.sub.8 ketone, such as acetone. In this embodiment, a
base and a source of sodium, preferably an aqueous solution of
sodium hydroxide, is added to a solution of MPA in acetone.
Examples of other bases include sodium methoxide and sodium
ethoxide. The reaction is preferably carried out with stirring. The
solid product is then recovered by conventional techniques and may
be dried.
[0046] Another process for preparing crystalline mycophenolate
sodium M2 comprises heating a solid mixture of crystalline
mycophenolate sodium Form M1 and Form M3. In a preferred
embodiment, mycophenolate sodium Form M2 is prepared by heating a
solid mixture of mycophenolate sodium Forms M1 and M3 in an oven at
about 170.degree. C. to obtain Form M2, preferably about 30
minutes, and placing the mixture in a desicator to allow it to cool
to room temperature.
[0047] In another embodiment, mycophenolate sodium Form M2 by
adding a base and a source of sodium to a solution of mycophenolic
acid in a mixture of dichloromethane and methanol. Preferably
sodium methoxide in methanol is added to the solution. To further
induce precipitation, a C.sub.5 to C.sub.7 cyclic or acyclic
saturated hydrocarbon, such as n-hexane, may be added.
[0048] The hygroscopicity of monosodium mycophenolate crystal Form
M2 was investigated. Form M2 was exposed to different level of
humidity for one week and after equilibrium it was analysed by TGA
and XRD for water content and crystal structure. Table 5 summarizes
the results: TABLE-US-00001 TABLE 5 Results Crystal forms % RH
LOD(%) Form M2 (example 3) 40 0.1 M2 60 0.2 M2 80 0.4 M2
[0049] Crystalline Form M2 obtained with the processes of the
present invention preferably contains less than 30%, more
preferably less than 20%, more preferably less than 10%, and most
preferably less than about 5% of other polymorphic forms by
weight.
[0050] The single particle size for Form M2 is less than about 100
micrometers, as measured by polarizing light microscope of crystal
described in the invention.
[0051] The starting material used for the processes of the present
invention, unless otherwise specified, may be any crystalline or
amorphous form of mycophenolate sodium or acid, including various
solvates and hydrates.
[0052] The processes of the present invention may also be practiced
as the last step of prior art processes that synthesize
mycophenolate sodium.
[0053] The base and the source of sodium as used throughout this
invention can be different, or they can be the same. For example,
sodium methoxide, sodium ethoxide, or sodium hydroxide can be used
as both the base and the source of sodium. The preferred base and
source of sodium is sodium methoxide.
[0054] Many processes of the present invention involve
crystallization out of a particular solvent. One skilled in the art
would appreciate that the conditions concerning crystallization may
be modified without affecting the form of the polymorph obtained.
For example, when mixing mycophenolate sodium in a solvent to form
a solution, warming of the mixture may be necessary to completely
dissolve the starting material. If warming does not clarify the
mixture, the mixture may be diluted or filtered. To filter, the hot
mixture may be passed through paper, glass fiber or other membrane
material, or a clarifying agent such as celite. Depending upon the
equipment used and the concentration and temperature of the
solution, the filtration apparatus may need to be preheated to
avoid premature crystallization.
[0055] The conditions may also be changed to induce precipitation.
A preferred way of inducing precipitation is to reduce the
solubility of the solvent. The solubility of the solvent may be
reduced, for example, by cooling the solvent or adding an
anti-solvent.
[0056] In one embodiment, an anti-solvent is added to a solution to
decrease its solubility for a particular compound, thus resulting
in precipitation. Another way of accelerating crystallization is by
seeding with a crystal of the product or scratching the inner
surface of the crystallization vessel with a glass rod.
[0057] Pharmaceutical compositions of the present invention contain
mycophenolate sodium Form M2. In addition to the active
ingredient(s), the pharmaceutical compositions of the present
invention may contain one or more excipients. Excipients are added
to the composition for a variety of purposes.
[0058] Diluents increase the bulk of a solid pharmaceutical
composition and may make a pharmaceutical dosage form containing
the composition easier for the patient and care giver to handle.
Diluents for solid compositions include, for example,
microcrystalline cellulose (e.g. Avicel.RTM.), microfine cellulose,
lactose, starch, pregelatinized starch, calcium carbonate, calcium
sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium
phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium
carbonate, magnesium oxide, maltodextrin, mannitol,
polymethacrylates (e.g. Eudragit.RTM.), potassium chloride,
powdered cellulose, sodium chloride, sorbitol and talc.
[0059] Solid pharmaceutical compositions that are compacted into a
dosage Form like a tablet may include excipients whose functions
include helping to bind the active ingredient and other excipients
together after compression. Binders for solid pharmaceutical
compositions include acacia, alginic acid, carbomer (e.g.
carbopol), carboxymethylcellulose sodium, dextrin, ethyl cellulose,
gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl
cellulose, hydroxypropyl cellulose (e.g. Klucel.RTM.),
hydroxypropyl methyl cellulose (e.g. Methocel.RTM.), liquid
glucose, magnesium aluminum silicate, maltodextrin,
methylcellulose, polymethacrylates, povidone (e.g. Kollidon.RTM.,
Plasdone.RTM.), pregelatinized starch, sodium alginate and
starch.
[0060] The dissolution rate of a compacted solid pharmaceutical
composition in the patient's stomach may be increased by the
addition of a disintegrant to the composition. Disintegrants
include alginic acid, carboxymethylcellulose calcium,
carboxymethylcellulose sodium (e.g. Ac-Di-Sol.RTM.,
Primellose.RTM.), colloidal silicon dioxide, croscarmellose sodium,
crospovidone (e.g. Kollidon.RTM., Polyplasdone.RTM.), guar gum,
magnesium aluminum silicate, methyl cellulose, microcrystalline
cellulose, polacrilin potassium, powdered cellulose, pregelatinized
starch, sodium alginate, sodium starch glycolate (e.g.
Explotab.RTM.) and starch.
[0061] Glidants can be added to improve the flowability of
non-compacted solid composition and improve the accuracy of dosing.
Excipients that may function as glidants include colloidal silicon
dioxide, magnesium trisilicate, powdered cellulose, starch, talc
and tribasic calcium phosphate.
[0062] When a dosage Form such as a tablet is made by compaction of
a powdered composition, the composition is subjected to pressure
from a punch and dye. Some excipients and active ingredients have a
tendency to adhere to the surfaces of the punch and dye, which can
cause the product to have pitting and other surface irregularities.
A lubricant can be added to the composition to reduce adhesion and
ease release of the product Form the dye. Lubricants include
magnesium stearate, calcium stearate, glyceryl monostearate,
glyceryl palmitostearate, hydrogenated castor oil, hydrogenated
vegetable oil, mineral oil, polyethylene glycol, sodium benzoate,
sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc
and zinc stearate.
[0063] Flavoring agents and flavor enhancers make the dosage Form
more palatable to the patient. Common flavoring agents and flavor
enhancers for pharmaceutical products that may be included in the
composition of the present invention include maltol, vanillin,
ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol,
and tartaric acid.
[0064] Solid and liquid compositions may also be dyed using any
pharmaceutically acceptable colorant to improve their appearance
and/or facilitate patient identification of the product and unit
dosage level.
[0065] In liquid pharmaceutical compositions of the present
invention hydrochloride Forms and any other solid excipients are
dissolved or suspended in a liquid carrier such as water, vegetable
oil, alcohol, polyethylene glycol, propylene glycol or
glycerin.
[0066] Liquid pharmaceutical compositions may contain emulsifying
agents to disperse uniformly throughout the composition an active
ingredient or other excipient that is not soluble in the liquid
carrier. Emulsifying agents that may be useful in liquid
compositions of the present invention include, for example,
gelatin, egg yolk, casein, cholesterol, acacia, tragacanth,
chondrus, pectin, methyl cellulose, carbomer, cetostearyl alcohol
and cetyl alcohol.
[0067] Liquid pharmaceutical compositions of the present invention
may also contain a viscosity enhancing agent to improve the
mouth-feel of the product and/or coat the lining of the
gastrointestinal tract. Such agents include acacia, alginic acid
bentonite, carbomer, carboxymethylcellulose calcium or sodium,
cetostearyl alcohol, methyl cellulose, ethylcellulose, gelatin guar
gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl
methyl cellulose, maltodextrin, polyvinyl alcohol, povidone,
propylene carbonate, propylene glycol alginate, sodium alginate,
sodium starch glycolate, starch tragacanth and xanthan gum.
[0068] Sweetening agents such as sorbitol, saccharin, sodium
saccharin, sucrose, aspartame, fructose, mannitol and invert sugar
may be added to improve the taste. Preservatives and chelating
agents such as alcohol, sodium benzoate, butylated hydroxy toluene,
butylated hydroxyanisole and ethylenediamine tetraacetic acid may
be added at levels safe for ingestion to improve storage
stability.
[0069] A liquid composition according to the present invention may
also contain a buffer such as gluconic acid, lactic acid, citric
acid or acetic acid, sodium guconate, sodium lactate, sodium
citrate or sodium acetate.
[0070] Selection of excipients and the amounts to use may be
readily determined by the Formulation scientist based upon
experience and consideration of standard procedures and reference
works in the field.
[0071] The solid compositions of the present invention include
powders, granulates, aggregates and compacted compositions. The
dosages include dosages suitable for oral, buccal, rectal,
parenteral (including subcutaneous, intramuscular, and
intravenous), inhalant and ophthalmic administration. Although the
most suitable route in any given case will depend on the nature and
severity of the condition being treated, the most preferred route
of the present invention is oral. The dosages may be conveniently
presented in unit dosage Form and prepared by any of the methods
well-known in the pharmaceutical arts.
[0072] Dosage Forms include solid dosage Forms like tablets,
powders, capsules, suppositories, sachets, troches and losenges as
well as liquid syrups, suspensions and elixirs.
[0073] A dosage Form of the present invention is a capsule
containing the composition, preferably a powdered or granulated
solid composition of the invention, within either a hard or soft
shell. The shell may be made from gelatin and optionally contain a
plasticizer such as glycerin and sorbitol, and an opacifying agent
or colorant. The active ingredient and excipients may be Formulated
into compositions and dosage Forms according to methods known in
the art.
[0074] A composition for tableting or capsule filing may be
prepared by wet granulation. In wet granulation some or all of the
active ingredients and excipients in powder Form are blended and
then further mixed in the presence of a liquid, typically water,
that causes the powders to clump up into granules. The granulate is
screened and/or milled, dried and then screened and/or milled to
the desired particle size. The granulate may then be tableted or
other excipients may be added prior to tableting such as a glidant
and or lubricant.
[0075] A tableting composition may be prepared conventionally by
dry blending. For instance, the blended composition of the actives
and excipients may be compacted into a slug or a sheet and then
comminuted into compacted granules. The compacted granules may be
compressed subsequently into a tablet.
[0076] As an alternative to dry granulation, a blended composition
may be compressed directly into a compacted dosage Form using
direct compression techniques. Direct compression produces a more
uniform tablet without granules. Excipients that are particularly
well suited to direct compression tableting include
microcrystalline cellulose, spray dried lactose, dicalcium
phosphate dihydrate and colloidal silica. The proper use of these
and other excipients in direct compression tableting is known to
those in the art with experience and skill in particular
Formulation challenges of direct compression tableting.
[0077] A capsule filling of the present invention may comprise any
of the aforementioned blends and granulates that were described
with reference to tableting, only they are not subjected to a final
tableting step.
Abbreviations
MPA=Mycophenolic acid
NaOMe=Sodium methoxide
DMF=Dimethyl formamide
Experimental Methodology (Physical)
XRD
[0078] ARL X-ray powder diffractometer model X'TRA-030, Peltier
detector, round standard aluminum sample holder with round zero
background quartz plate was used. Scanning parameters: Range: 2-40
deg. 2.theta., continuous Scan, Rate: 3 deg./min. The accuracy of
peak positions is defined as +/-0.2 degrees due to experimental
differences like instrumentations, sample preparations etc.
FT-IR Spectroscopy
Perkin-Elmer Spectrum 1000 Spectrometer, at 4 cm.sup.-1 resolution
with 16 scans, in the range of 4000-400 cm.sup.-1 was used. The
samples were analyzed in Nujol mull. The spectra were recorded
using an empty cell as a background.
Differential Scanning Calorimetry (DSC)
DSC 822.sup.e/700, Mettler Toledo, Sample weight: 3-5 mg.
Heating rate: 10.degree. C./min., Number of holes of the crucible:
3
In N.sub.2 stream: flow rate=40 ml/min
Scan range: 30-250.degree. C., 10.degree. C./minutes heating
rate.
The DSC curves of the novel forms of mycophenolate monosodium
indicates only endothermic peaks due to dehydration, desolvation
and melting.
Thermal Gravimetric Analysis (TGA)
TGA/SDTA 851.sup.e, Mettler Toledo, Sample weight 7-15 mg.
Heating rate: 10.degree. C./min., In N.sub.2 stream: flow rate=50
m/min
Scan range: 30-250.degree. C.
Microscope
The particle size of single crystals was observed by a polarizing
light Microscope, Type: Zeiss TOPIC-B. Sample preparation was done
by dispersing a sample in one drop of mineral oil. The
magnification was 200.
EXAMPLES
[0079] The following examples are offered for illustrative purposes
only, and are not intended to limit the scope of the present
invention in any way.
Example 1
Preparation of Mycophenolate Monosodium Crystal Form M2
[0080] To a stirred solution of MPA (6.4 g) in methanol (32 ml),
30% sodium methoxide in methanol (3.8 ml) was added dropwise at
room temperature. The reaction mixture was warmed to reflux
temperature, then cooled to -15.degree. C. with constant stirring.
The reaction mixture was stirred at -15.degree. C. for 24 hours.
The precipitated product was then filtered off and washed with cold
methanol. The solid material was dried at 40-45.degree. C. in a
vacuum oven. Form M2 of mycophenolate sodium was obtained in 38%
yield.
Example 2
[0081] To a stirred solution of MPA (6.4 g) in acetone (130 ml),
sodium hydroxide (0.8 g) in water (2 ml) was added dropwise at room
temperature. The stirring was continued at this temperature for 0.5
hours. The precipitated product was filtered off and washed with
cold acetone. The solid material was dried at 40-45.degree. C. in a
vacuum oven. Form M2 of mycophenolate sodium was obtained in 85%
yield.
Example 3
[0082] A mixture of MPA (128 g) and charcoal (2.56 g) in ethyl
acetate (4750 ml) was stirred for 0.5 h, then the charcoal was
filtered off and washed with ethyl acetate (250 ml). 30% sodium
methoxide in methanol (75.9 ml) was then added dropwise to the
stirred filtrate at room temperature. The mixture was stirred for
an additional 30 minutes, then the precipitated product was
filtered off and washed with ethyl acetate (250 ml). The solid
material was dried at 40-45.degree. C. in a vacuum oven. Form M2 of
mycophenolate sodium was obtained in 97% yield.
Example 4
[0083] To a stirred solution of MPA (6.4 g) in ethyl acetate (250
ml), 30% sodium methoxide in methanol (3.8 ml) was added dropwise
at room temperature. The reaction mixture was stirred for an
additional 30 minutes, then the precipitated product was filtered
off and washed with ethyl acetate. The solid material was dried at
40-45.degree. C. in a vacuum oven. Form M2 of mycophenolate sodium
was obtained in 94% yield.
Example 5
[0084] To a stirred solution of MPA (128 g) in ethyl acetate (5 L),
30% sodium methoxide in methanol (74 ml) was added dropwise at room
temperature. The reaction mixture was stirred for an additional 30
minutes, then the precipitated product was filtered off and washed
with ethyl acetate. The solid material was dried at 60-65.degree.
C. in a vacuum oven. Form M2 of mycophenolate sodium was obtained
in 96% yield.
Example 6
[0085] To a stirred solution of MPA (24 g) in ethyl acetate (0.93
L), 30% sodium methoxide in methanol (14 ml) was added dropwise at
room temperature. The reaction mixture was stirred for an
additional 30 minutes, then the precipitated product was filtered
off and washed with ethyl acetate. A part of the solid material was
divided into three parts and dried at 40-45.degree. C.,
60-65.degree. C. and 80-85.degree. C. in vacuum oven, respectively.
Form M2 of mycophenolate sodium was obtained.
Example 7
[0086] Sodium mycophenolate (1 g) was dissolved at reflux
temperature in absolute ethanol (165 ml). The solution was allowed
to cool to room temperature, and crystallized at this temperature
overnight. The solid was filtered off, and a part of the wet
material was dried at normal pressure at room temperature. Form M1
of mycophenolate sodium was obtained from the wet sample. Form M2
of mycophenolate sodium was obtained from the dry sample.
Example 8
[0087] Sodium mycophenolate (1 g) was dissolved at reflux
temperature in 1-butanol (175 ml). The solution was allowed to cool
to room temperature, and crystallized at this temperature
overnight. The solid was filtered off, and a part of the wet
material was dried at normal pressure at room temperature. Form M2
of mycophenolate sodium was obtained from both the dry and the wet
sample.
Example 9
[0088] Sodium mycophenolate (0.5 g) was dissolved at about
60.degree. C. in ethyl lactate (5 ml). The solution was allowed to
cool to room temperature, then acetone (200 ml) was added to the
solution. The solution was stored at +4.degree. C. overnight. The
solid was filtered off, and a part of the wet material was dried at
normal pressure at room temperature. Form M2 of mycophenolate
sodium was obtained from both the dry and the wet sample.
Example 10
[0089] Sodium mycophenolate (1 g) was dissolved at room temperature
in methanol (15 ml), then acetone (180 ml) was added to the
solution. The solution was allowed to stand at room temperature
overnight to promote crystallization of the product. The solid was
then filtered off, and a part of the wet material was dried at
normal pressure at room temperature. Form M2 of mycophenolate
sodium was obtained from both the wet and the dry sample.
Example 11
[0090] Sodium mycophenolate (1 g) was dissolved at room temperature
in methanol (15 ml), then isopropanol (285 ml) was added to the
solution. The solution was allowed to stand at room temperature
overnight to promote crystallization of the product. The solid was
then filtered off, and a part of the wet material was dried at
normal pressure at room temperature. Form M2 of mycophenolate
sodium was obtained from both the wet and the dry sample.
Example 12
[0091] Sodium mycophenolate (1 g) was dissolved at room temperature
in methanol (15 ml), then tetrahydrofuran (200 ml) was added to the
solution. The solution was allowed to stand at room temperature
overnight to promote crystallization of the product. The solid was
then filtered off, and a part of the wet material was dried at
normal pressure at room temperature. Form M2 of mycophenolate
sodium was obtained from both the wet and the dry sample.
Example 13
[0092] Sodium mycophenolate (1 g) was dissolved at room temperature
in methanol (15 ml), then diisopropyl ether (55 ml) was added to
the solution. The solution was allowed to stand at room temperature
overnight to promote crystallization of the product. The solid was
then filtered off, and a part of the wet material was dried at
normal pressure at room temperature. Form M2 of mycophenolate
sodium was obtained from both the wet and the dry sample.
Example 14
[0093] Sodium mycophenolate (1 g) was dissolved at room temperature
in methanol (15 ml), then nitromethane (220 ml) was added to the
solution. The solution was allowed to stand at room temperature
overnight to promote crystallization of the product. The solid was
then filtered off, and a part of the wet material was dried at
normal pressure at room temperature. Form M2 of mycophenolate
sodium was obtained from the both the wet and the dry sample.
Example 15
[0094] Sodium mycophenolate (1 g) was dissolved at room temperature
in methanol (15 ml), then isobutanol (200 ml) was added to the
solution. The solution was allowed to stand at room temperature
overnight to promote crystallization of the product. The solid was
then filtered off, and a part of the wet material was dried at
normal pressure at room temperature. Form M2 of mycophenolate
sodium was obtained from both the wet and the dry sample.
Example 16
[0095] To a stirred solution of MPA (6.4 g) in dichloromethane (320
ml) and methanol (60 ml) 30% of sodium methoxide in methanol (3.8
ml) was added dropwise at room temperature. The product was
precipitated by addition of n-hexane (960 ml) and filtered off. The
solid material was dried at 40.degree. C. in vacuum oven. The yield
was 86%. Polymorphism was determined by X-ray diffraction. The
obtained material was form M2.
Example 17
[0096] To a stirred solution of MPA (6.4 g) in isobutyl acetate
(500 ml) 30% of sodium methoxide in methanol (3.8 ml) was added
dropwise at room temperature. The reaction mixture was stirred for
additional 30 minutes, then the precipitated product was filtered
off and washed with isobutyl acetate. The solid material was dried
at 40.degree. C. in vacuum oven. The yield was 66%. Polymorphism
was determined by X-ray diffraction. The obtained material was form
M2.
Example 18
[0097] Sodium mycophenolate was dissolved at about 60.degree. C. in
DMF (5 ml). The solution was allowed to cool to room temperature,
then 2-propanol (300 ml) was added to the solution. The solution
was stored at +4.degree. C. overnight. The solid was filtered off,
and a part of the wet material was dried at normal pressure at room
temperature. Forms M1+M2 of mycophenolate sodium were obtained from
the wet sample. Form M2 of mycophenolate sodium was obtained from
the dry sample.
Example 19
Transformation of M1+M3 to M2 by heating
[0098] 200 mg of a mixture of Forms M1+M3 as identified by XRD, was
put into an oven in a glass weighing bottle at 170.degree. C. for
0.5 h. Then it was put into a desiccator and allowed to cool to
room temperature. Upon XRD analysis, its crystal form was found to
be Form M2.
Example 20
J. Med. Chem., 39 (1996) 1236-1242
Reproduction of Literature Methods
[0099] To a stirred solution of MPA (9.6 g) in absolute ethanol
(360 ml), 21% sodium ethoxide in ethanol (8.6 ml) was added
dropwise at room temperature. The reaction mixture was stirred for
an additional 60 minutes, then the solvent was evaporated on a
rotary evaporator at 40-45.degree. C. under vacuum. The wet
material was dried at 40-45.degree. C. in a vacuum oven and proved
to be Form M2.
Example 21
ZA 68/4,959
[0100] To a stirred solution of MPA (13 g) in chloroform (650 ml),
sodium methoxide solution (2.3 g NaOMe dissolved in 130 ml of
methanol) was added dropwise at room temperature. The reaction
mixture was stirred for an additional 30 minutes, then n-pentane
(2.34 L) was added to the solution. After 30 minutes, the reaction
mixture was filtered and a part of the wet material was dried at
40-45.degree. C. in a vacuum oven. Both the wet sample and the
dried material proved to be Form M2.
Example 22
Acta Cryst. Sect. C, C56 (2000) 432-433
[0101] To a stirred solution of MPA (9.6 g) in methanol (300 ml),
30% sodium methoxide in methanol (5.6 ml) was added dropwise at
room temperature. The reaction mixture was stirred for an
additional 60 minutes, then the solvent was evaporated on a rotary
evaporator at 40-45.degree. C. under vacuum. The wet material was
dried at 40-45.degree. C. in a vacuum oven and proved to be a
mixture of Forms M2 and M3.
[0102] Having thus described the invention with reference to
particular preferred embodiments and illustrative examples, those
in the art can appreciate modifications to the invention as
described and illustrated that do not depart from the spirit and
scope of the invention as disclosed in the specification. The
Examples are set forth to aid in understanding the invention but
are not intended to, and should not be construed to, limit its
scope in any way. The examples do not include detailed descriptions
of conventional methods. Such methods are well known to those of
ordinary skill in the art and are described in numerous
publications. Polymorphism in Pharmaceutical Solids, Drugs and the
Pharmaceutical Sciences, Volume 95 may be used for guidance. All
references mentioned herein are incorporated in their entirety.
* * * * *