U.S. patent application number 12/218197 was filed with the patent office on 2009-01-22 for amorphous ibandronic acid.
Invention is credited to Thomas Bayer, Ben-Zion Dolitzky, Revital Lifshitz-Liron, Inna Perutski, Michael Pinchasov.
Application Number | 20090023949 12/218197 |
Document ID | / |
Family ID | 35285644 |
Filed Date | 2009-01-22 |
United States Patent
Application |
20090023949 |
Kind Code |
A1 |
Bayer; Thomas ; et
al. |
January 22, 2009 |
Amorphous ibandronic acid
Abstract
Amorphous ibandronic acid is provided with methods for its
preparation. The methods include dissolution of ibandronic acid in
a solvent such as acetonitrile, DMSO, methanol, or water, and spray
drying.
Inventors: |
Bayer; Thomas; (Tel Aviv,
IL) ; Dolitzky; Ben-Zion; (Petach Tiqva, IL) ;
Lifshitz-Liron; Revital; (Hertzlia, IL) ; Perutski;
Inna; (Hadera, IL) ; Pinchasov; Michael;
(Dover, NJ) |
Correspondence
Address: |
KENYON & KENYON LLP
ONE BROADWAY
NEW YORK
NY
10004
US
|
Family ID: |
35285644 |
Appl. No.: |
12/218197 |
Filed: |
July 10, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11525804 |
Sep 22, 2006 |
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12218197 |
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11331995 |
Jan 12, 2006 |
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11525804 |
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11165481 |
Jun 22, 2005 |
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11331995 |
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60582500 |
Jun 23, 2004 |
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60620016 |
Oct 18, 2004 |
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60690868 |
Jun 16, 2005 |
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Current U.S.
Class: |
562/13 |
Current CPC
Class: |
A61P 19/10 20180101;
C07F 9/3873 20130101; A61P 19/08 20180101 |
Class at
Publication: |
562/13 |
International
Class: |
C07F 9/38 20060101
C07F009/38 |
Claims
1. Amorphous ibandronic acid.
2. A method of making amorphous ibandronic acid comprising the
steps of subjecting a solution of ibandronic acid in a solvent
selected from the group consisting of: acetonitrile (ACN),
dimethylsulfoxide (DMSO), methanol, and water, to a solvent-removal
step selected from vacuum evaporation, lyophilization, and spray
drying.
3. The process of claim 2, wherein the solvent is water.
4. A method of making amorphous ibandronic acid comprising the step
of spray drying an aqueous solution of ibandronic acid.
Description
RELATED APPLICATIONS
[0001] This application is a divisional application of U.S. Ser.
No. 11/525,804, titled "Solid and Crystalline Ibandronic Acid" and
filed Sep. 22, 2006, which is a continuation of prior application
U.S. Ser. No. 11/331,995 filed Jan. 12, 2006, which is a
continuation of prior application U.S. Ser. No. 11/165,481 filed
Jun. 22, 2005, which claims the benefit of the Jun. 23, 2004,
filing date of U.S. Provisional Patent Application 60/582,500, of
the Oct. 18, 2004, filing date of U.S. Provisional Patent
Application 60/620,016, and the benefit of the Jun. 16, 2005,
filing date of the U.S. Provisional Patent Application 60/690,868,
the contents of all of which are incorporated herein by
reference.
BACKGROUND OF THE INVENTION
[0002] Ibandronate Sodium is a third-generation nitrogen-containing
bisphosphonate characterized by an aliphatic tertiary amine side
chain.
[0003] Ibandronate Sodium is a white crystalline powder. The free
acid has MW 319.23 (CAS No.: 114084-78-5). The monosodium salt
(anhydrous) of the acid has MW 341.23 (CAS No.: 138844-81-2). The
monosodium salt monohydrate has MW 359.23 (CAS No.:
138926-19-9).
##STR00001##
[0004] The preparation of ibandronic acid monosodium salt is
described in, for example, U.S. Pat. No. 4,927,814. The '814 patent
describes the following schemes:
##STR00002##
[0005] The preparation of ibandronic acid is taught in U.S. Pat.
No. 4,927,814, wherein an ion-exchange chromatography is used in
work-up. The present inventors repeated the procedure described in
the '814 patent. No solid material was obtained, but an oily
precipitate was the crude product. The skilled artisan knows that
solids are easier to manipulate than oils. Clearly there is a need
for a method of making a solid ibandronic acid.
[0006] The monosodium salt of ibandronic acid is marketed under the
trade name Boniva.RTM.. Boniva.RTM. was developed by Hoffmann-La
Roche for the treatment of bone disorders such as: hypercalcaemia
of malignancy, osteolysis, Paget's disease, osteoporosis and
metastatic bone disease. Boniva.RTM. is also marketed in Europe
under the name Bondronat for cancer-related bone complications.
Bondronat is available in ampoule with 1 ml concentrate for
solution for infusion contains 1.125 mg of Ibandronic acid
monosodium salt monohydrate, corresponding to 1 mg of ibandronic
acid.
[0007] Ibandronic acid can be used as an intermediate in the
process for the preparation of Ibandronate sodium.
[0008] The discovery of new polymorphic forms of a pharmaceutically
useful compound 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. There is a need in the art for polymorphic forms of
ibandronic acid.
SUMMARY OF THE INVENTION
[0009] In one aspect, the present invention provides amorphous
ibandronic acid.
[0010] In another aspect, the present invention provides a method
of preparing amorphous ibandronic acid that includes the step of
isolating amorphous ibandronic acid from an aqueous solution of
ibandronic acid which isolating step is selected from a vacuum
evaporation step or a lyophilization step.
[0011] In still a further aspect, the present invention relates to
a method of making amorphous ibandronic comprising the step of
spray drying an aqueous solution of ibandronic acid.
[0012] In yet another aspect, the present invention provides solid
ibandronic acid.
[0013] In one aspect, the present invention provides a process for
preparing solid Ibandronic acid comprising the steps of: [0014] a)
combining, at a temperature of about 72.degree. C. to about
78.degree. C., a halo-phosphorous compound and phosphorous acid
with N-methyl-N-pentyl propionic acid hydrochloride in a diluent to
obtain a reaction mixture; [0015] b) maintaining the reaction
mixture, while heating to a temperature of about 80.degree. C. to
about 100.degree. C.; [0016] c) further combining the reaction
mixture with water, whereby two phases, one aqueous and one
nonaqueous, are obtained; [0017] d) separating the two phases
obtained; [0018] e) maintaining the aqueous phase at a temperature
of about 95.degree. C. to about 100.degree. C.; [0019] f)
evaporating the aqueous phase to obtain a residue; [0020] g)
combining an alcohol with the residue to obtain whereby a
suspension is obtained; and [0021] h) recovering solid ibandronic
acid from the suspension, for example by filteration or
centrifugation; and optionally, drying the recovered solid
ibandronic acid
[0022] The residue of step f) may be dissolved in water prior to
the addition of the alcohol in step g). After the addition of the
alcohol, the reaction mixture may be heated in order to facilitate
the formation of the precipitate.
[0023] In another aspect, the present invention provides
crystalline ibandronic acid in several crystalline forms and
hydrates and solvates, especially alcoholates, thereof. The present
invention also provides ibandronic acid alcoholates.
[0024] In yet another aspect, the present invention provides a
solid crystalline form of ibandronic acid, denominated form S1,
characterized by a powder X-ray diffraction pattern having
reflections at about 8.2, 11.5, 11.9, 13.9, 18.6 and 22.2.+-.0.2
deg. 2-theta. The present invention further provides processes for
preparing ibandronic acid form S1.
[0025] In one aspect, the present invention provides a solid
crystalline form of ibandronic acid, denominated form S2,
characterized by a powder X-ray diffraction pattern having
reflections at about 8.1, 14.2, 16.1, 18.2 and 24.4.+-.0.2 deg.
2-theta. The present invention further provides a process for
preparing ibandronic acid form S2.
[0026] In another aspect, the present invention provides a solid
crystalline form of ibandronic acid, denominated form S3,
characterized by a powder X-ray diffraction pattern having
reflections at about 4.4, 8.8, 11.3, 17.6 and 26.4.+-.0.2 deg.
2-theta. The present invention further provides a process for
preparing ibandronic acid form S3.
[0027] In yet another aspect, the present invention provides a
solid crystalline form of ibandronic acid, denominated form S4,
characterized by a powder X-ray diffraction pattern having
reflections at about 4.4, 8.6, 11.2, 17.3, 20.8, 22.5 and
26.0.+-.0.2 deg. 2-theta. The present invention further provides a
process for preparing ibandronic acid form S4.
[0028] In one aspect, the present invention provides a solid
crystalline form of ibandronic acid, denominated form S5,
characterized by a powder X-ray diffraction pattern having
reflections at about 4.5, 8.9, 12.0, 16.0, 16.3, 21.4, 22.1 and
26.9.+-.0.2 deg. 2-theta. The present invention further provides
processes for preparing ibandronic acid form S5.
[0029] In another aspect, the present invention provides a solid
crystalline form of ibandronic acid, denominated form S6,
characterized by a powder X-ray diffraction pattern having
reflections at about 5.7, 11.7, 14.3, 18.5, 21.2 and 21.7.+-.0.2
deg. 2-theta. The present invention further provides processes for
preparing ibandronic acid form S6.
[0030] In yet another aspect, the present invention provides a
solid crystalline form of ibandronic acid, denominated form S7,
characterized by a powder X-ray diffraction pattern having
reflections at about 4.6, 11.5, 16.3, 16.8, 21.0 and 22.8.+-.0.2
deg. 2-theta. The present invention further provides processes for
preparing ibandronic acid form S7.
[0031] In one aspect, the present invention provides a solid
crystalline form of ibandronic acid, denominated form S8,
characterized by a powder X-ray diffraction pattern having
reflections at about 4.5, 6.0, 11.9, 12.3, 16.2, 17.8 and
21.7.+-.0.2 deg. 2-theta. The present invention further provides
processes for preparing ibandronic acid form S8.
[0032] In another aspect, the present invention provides a solid
crystalline form of ibandronic acid, denominated form S10,
characterized by a powder X-ray diffraction pattern having
reflections at about 4.8, 6.1, 12.0, 12.3, 16.4, 18.0 and
21.7.+-.0.2 deg. 2-theta. The present invention further provides
processes for preparing ibandronic acid form S10.
[0033] In yet another aspect, the present invention provides a
solid crystalline form of ibandronic acid, denominated form S12,
characterized by a powder X-ray diffraction pattern having
reflections at about 4.7, 9.0, 11.6, 20.9, 21.1, 21.7, 22.9 and
26.3.+-.0.2 deg. 2-theta. The present invention further provides a
process for preparing ibandronic acid form S5.
[0034] In one aspect, the present invention provides a solid
crystalline form of ibandronic acid, denominated form S13,
characterized by a powder X-ray diffraction pattern having
reflections at about 4.5, 8.9, 12.0, 16.0, 16.3, 21.3 and
22.1.+-.0.2 deg. 2-theta. The present invention further provides
processes for preparing ibandronic acid form S13.
[0035] In another aspect, the present invention provides a process
for purifying Ibandronic acid from inorganic impurities by
crystallization from an organic solvent selected from the group
consisting of C.sub.2-4 alcohols and acetonitrile.
[0036] In yet another aspect, the present invention provides a HPLC
method of assaying ibandronic acid comprising the steps of:
providing a sample solution of a sample of ibandronic acid in a
diluent, loading the sample solution (ca. 50 .mu.L) onto a
250.times.4.1 mm, Hamilton type PRP-X100 anion exchange column,
eluting the sample from the column at 2.0 ml/min. with an eluent
including nitric acid (HNO.sub.3: 35 vol-%), potassium nitrate
(KNO.sub.3: 45 vol-%) and ethanol (20 vol-%), and measuring the
ibandronic acid content of the eluent at 240 nm wavelength with a
UV detector to identify the relevant fractions.
[0037] In still a further aspect, the present invention provides A
process for purifying ibandronic acid from inorganic impurities
comprising the steps of: providing a solution of ibandronic acid
containing inorganic impurities in water or methanol; and b)
combining the solution with a C.sub.2-C.sub.4 alcohol, especially
wherein the C.sub.2-4 alcohol is selected from the group consisting
of ethanol, 1-propanol, isopropanol (IPA) and tert-butanol whereby
ibandronic acid precipitates.
BRIEF DESCRIPTION OF THE FIGURES
[0038] FIG. 1 illustrates an x-ray diffraction diagram of amorphous
ibandronic acid.
[0039] FIG. 2 illustrates a DSC thermogram of amorphous ibandronic
acid.
[0040] FIG. 3 illustrates a TGA thermogram of ibandronic acid.
[0041] FIG. 4 illustrates an x-ray diffraction diagram of
ibandronic acid form S1.
[0042] FIG. 5 illustrates an x-ray diffraction diagram of
ibandronic acid form S2.
[0043] FIG. 6 illustrates an x-ray diffraction diagram of
ibandronic acid form S3.
[0044] FIG. 7 illustrates an x-ray diffraction diagram of
ibandronic acid form S4.
[0045] FIG. 8 illustrates an x-ray diffraction diagram of
ibandronic acid form S5.
[0046] FIG. 9 illustrates an x-ray diffraction diagram of
ibandronic acid form S6.
[0047] FIG. 10 illustrates an x-ray diffraction diagram of
ibandronic acid form S7.
[0048] FIG. 11 illustrates an x-ray diffraction diagram of
ibandronic acid form S8.
[0049] FIG. 12 illustrates an x-ray diffraction diagram of
ibandronic acid form S10.
[0050] FIG. 13 illustrates an x-ray diffraction diagram of
ibandronic acid form S12.
[0051] FIG. 14 illustrates an x-ray diffraction diagram of
ibandronic acid form S13.
DETAILED DESCRIPTION OF THE INVENTION
[0052] The present invention provides processes which utilize
halo-phosphorous compounds. Such compounds include, but are not
limited to, phosphorous trichloride, phosphorous oxychloride,
phosphorous pentachloride, phosphorous tribromide, phosphorous
oxybromide, phosphorous pentabromide.
[0053] In particular embodiments of the present invention,
C.sub.2-C.sub.4 alcohols are used. The C.sub.2-C.sub.4 alcohols
have the general structure ROH wherein R is a linear or branched
alkyl group having 2 to 4 carbon atoms. Ethanol, n-propanol
(1-propanol), iso-propanol (2-propanol, IPA), and t-butanol
(2-methylpropan-2-ol) are preferred C2-C4 alcohols.
[0054] The present invention also provides processes that, in
particular embodiments, utilize strong acids which do not act as
oxidants for amino-phosphonic acids. Such non-oxidizing acids
include, but are not limited to, para-toluene sulfonic acid, HCl,
HBr, and trichloroacetic acid.
[0055] The present invention provides amorphous ibandronic acid.
Amorphous ibandronic acid has an x-ray diffraction diagram not
unexpected for an essentially amorphous solid. FIG. 1 shows a
representative x-ray diffraction diagram of amorphous ibandronic
acid.
[0056] FIG. 2 shows a representative thermogram from differential
scanning calorimetry (DSC) for amorphous ibandronic acid. The DSC
thermogram does not exhibit any feature that can be clearly
associated with a first-order transition like crystal melting.
[0057] FIG. 3 shows a representative thermogram from
thermogravimetric analysis (TGA).
[0058] Amorphous ibandronic acid can be prepared by a method that
includes an isolation step. An isolation step is a step (procedure)
in which a solvent, for example water is removed from a solution of
ibandronic acid and can be called a "water-removal" step. This step
comprises isolation of amorphous ibandronic acid from a solution of
ibandronic acid in a solvent selected from the group consisting of
acetonitrile (ACN), dimethylsulfoxide (DMSO), methanol, and water.
Preferably, the solvent is water. The isolation step can be a
vacuum evaporation (i.e. concentration) step, a lyophilization
step, or a spray drying step.
[0059] The term "spray drying" broadly refers to processes
involving breaking up liquid mixtures into small droplets
(atomization) and rapidly removing solvent from the mixture.
[0060] In a typical spray drying apparatus, there is a strong
driving force for evaporation of solvent from the droplets, which
may be provided by providing a drying gas. Spray drying processes
and equipment are described in Perry's Chemical Engineer's
Handbook, pgs. 20-54 to 20-57 (Sixth Edition 1984).
[0061] By way of non-limiting example only, the typical spray
drying apparatus comprises a drying chamber, atomizing means for
atomizing a solvent-containing feed into the drying chamber, a
source of drying gas that flows into the drying chamber to remove
solvent from the atomized-solvent-containing feed, an outlet for
the products of drying, and product collection means located
downstream of the drying chamber. Examples of such apparatuses
include Niro Models PSD-1, PSD-2 and PSD-4 (Niro A/S, Soeborg,
Denmark). Typically, the product collection means includes a
cyclone connected to the drying apparatus. In the cyclone, the
particles produced during spray drying are separated from the
drying gas and evaporated solvent, allowing the particles to be
collected. A filter may also be used to separate and collect the
particles produced by spray drying. The process of the invention is
not limited to the use of such drying apparatuses as described
above.
[0062] Spray drying may be performed in a conventional manner in
the processes of the present invention (see, e.g., Remington: The
Science and Practice of Pharmacy, 19th Ed., vol. II, pg. 1627,
herein incorporated by reference). The drying gas used in the
invention may be any suitable gas, although inert gases such as
nitrogen, nitrogen-enriched air, and argon are preferred. Nitrogen
gas is a particularly preferred drying gas for use in the process
of the invention. The amorphous ibandronic acid product produced by
spray drying may be recovered by techniques commonly used in the
art, such as using a cyclone or a filter. Spray drying of
ibandronic acid from a solution of ibandronic acid in water results
in amorphous ibandronic acid.
[0063] The present invention also provides solid ibandronic acid.
When intermediate compounds are Solid substances rather than
liquid, it enables the possibility of isolating and purifying the
intermediate by crystallization thereby improving the quality of
the final product.
[0064] The present invention also provides solid ibandronic
acid.
[0065] Solid ibandronic acid can be prepared by a process that
includes the steps of: [0066] a) combining, at a temperature of
about 70.degree. C. to about 78.degree. C., a halo-phosphorous
compound and phosphorous acid with N-methyl-N-pentyl propionic acid
hydrochloride in a diluent; [0067] b) maintaining the reaction
mixture, while heating to a temperature of about 80.degree. C. to
about 100.degree. C.; [0068] c) combining the reaction mixture with
water, whereby two phases are obtained; [0069] d) separating the
two phases obtained; [0070] e) maintaining the aqueous phase at a
temperature of about 95.degree. C. to about 110.degree. C.; [0071]
f) evaporating the aqueous phase to obtain a residue; [0072] g)
combining a C.sub.2-4 alcohol or acetone with the reaction mixture
to obtain a precipitate; and [0073] h) recovering the precipitate
of solid ibandronic acid.
[0074] Preferably, the halo-phosphorous compound of step a) is
added in small aliquots, especially dropwise. Preferably, the
diluent in step a) is selected from the group consisting of
silicone oil, toluene and a mixture of toluene and phosphoric acid.
Preferably, the temperature in step a) is about 75.degree. C.
[0075] Preferably, the mixture in step b) is heated to a
temperature of about 80.degree. C.
[0076] Preferably, the C.sub.2-4 alcohol in step g) is selected
from the group consisting of ethanol, 1-propanol, isopropyl alcohol
(IPA) and tert-butanol. Most preferably, the alcohol in step g) is
ethanol or IPA. The residue of step f) can be combined with water
prior to the addition of the alcohol in step g). After the addition
of the C.sub.2-4 alcohol, the reaction mixture is optionally heated
in order to facilitate the formation of the precipitate.
[0077] The present invention further provides crystalline
ibandronic acid, hydrates and solvates thereof. The present
invention also provides ibandronic acid alcoholates. As a general
rule, crystalline forms possess the advantage of being readily
filterable, easily dried, and stable for extended periods of time
without the need for specialized storage conditions.
[0078] In another embodiment, the present invention provides a
solid crystalline form of ibandronic acid, denominated form S1,
characterized by a powder X-ray diffraction pattern having
reflections at about 8.2, 11.5, 11.9, 13.9, 18.6 and 22.2.+-.0.2
deg. 2-theta. Solid crystalline ibandronic acid form S1 is further
characterized by X-ray powder diffraction pattern having
reflections at about 21.6, 23.8, 24.7 and 28.1.+-.0.2 deg. 2-theta.
A typical x-ray diffraction diagram for ibandronic acid form S1 is
given in FIG. 4. Form S1 can be a hemihydrate.
[0079] Ibandronic acid form S1 can be prepared by combining an
organic solvent selected from the group consisting of tert-butanol,
ethanol, and acetone, with an aqueous solution of ibandronic acid,
and maintaining the resulting combination for up to about 24 hours
to obtain a precipitate of ibandronic acid form S1. Preferably, the
organic solvent is selected from the group consisting of
tert-butanol, ethanol and acetone.
[0080] Form S1 can be also prepared by combining amorphous
ibandronic acid and an organic solvent at a temperature that ranges
from room temperature to reflux, and maintaining the reaction
mixture for a sufficient time to obtain form S1 in a slurry.
Preferably, the organic solvent is selected from the group
consisting of tert-butanol, ethanol and acetone.
[0081] Ibandronic acid form S1 can also be prepared in a process
that includes the steps of dissolving amorphous ibandronic acid in
water, adding acetone to obtain in a slurry, and stirring the
slurry for a sufficient time to obtain form S1.
[0082] Form S1 can be also prepared by a process that includes the
steps of: [0083] a) combining, at a temperature of about 70.degree.
C. to about 78.degree. C., a halo-phosphorous compound and
phosphorous acid with N-methyl-N-pentyl propionic acid
hydrochloride in toluene; [0084] b) maintaining the reaction
mixture, while heating to a temperature of about 80.degree. C. to
about 100.degree. C.; [0085] c) removing the toluene and adding
water to the reaction mixture; [0086] d) maintaining the reaction
mixture at a reflux temperature; [0087] e) evaporating to obtain a
residue; [0088] f) combining ethanol with the residue to obtain a
precipitate; and [0089] g) recovering crystalline ibandronic acid
form S1.
[0090] Preferably, the halo-phosphorous compound of step a) is
added in small aliquots, most preferably dropwise. Preferably, the
temperature in step a) is about 75.degree. C. Preferably, the
reaction mixture in step b) is heated to a temperature of about
80.degree. C.
[0091] In a further embodiment, the present invention further
provides a solid crystalline form of ibandronic acid, denominated
form S2, characterized by a powder X-ray diffraction pattern having
reflections at about 8.1, 14.2, 16.1, 18.2 and 24.4.+-.0.2 deg.
2-theta. Solid crystalline ibandronic acid form S2 can be further
characterized by X-ray reflections at about 10.9, 19.2, 22.3, 23.3,
and 28.2.+-.0.2 deg. 2-theta. A typical x-ray diffraction diagram
for ibandronic acid form S2 is given in FIG. 5.
[0092] Ibandronic acid form S2 can be prepared by providing a
solution of amorphous ibandronic acid in methanol; adding
acetonitrile solvent to the solution to obtain a slurry and
recovering ibandronic acid form S2.
[0093] In a further embodiment, the present invention provides a
solid crystalline form of ibandronic acid, denominated form S3,
characterized by a powder X-ray diffraction pattern having
reflections at about 4.4, 8.8, 11.3, 17.6 and 26.4.+-.0.2 deg.
2-theta. Solid crystalline ibandronic acid form S3 can be further
characterized by X-ray reflections at about 21.6, 23.8, 24.7 and
28.1.+-.0.2 deg. 2-theta. A typical x-ray diffraction diagram for
ibandronic acid form S3 is given in FIG. 6. Form S3 can exist as a
tert-butanolate.
[0094] Ibandronic acid form S3 can be prepared by adding
tert-butanol, to an aqueous solution of ibandronic acid, and
maintaining the resulting mixture for at least about 24 hours or
more to obtain form S3.
[0095] In another embodiment, the present invention provides a
solid crystalline form of ibandronic acid, denominated Form S4,
characterized by a powder X-ray diffraction pattern having
reflections at about 4.4, 8.6, 11.2, 17.3, 20.8, 22.5 and
26.0.+-.0.2 deg. 2-theta. Solid crystalline ibandronic acid Form S4
can be further characterized by X-ray reflections at about 16.2,
20.5 and 21.3.+-.0.2 deg. 2-theta. A typical x-ray diffraction
diagram for ibandronic acid Form S4 is given in FIG. 7. Form S4 can
be a propanolate.
[0096] Ibandronic acid Form S4 can be prepared by combining at room
temperature an aqueous solution of ibandronic acid and 1-propanol
until precipitation occurs, and isolating Form S4. Preferably the
combination is stirred for at least about 3 hours. Optionally, the
combination is heated to a reflux temperature, in order to obtain a
stirrable mixture, which is then cooled to room temperature.
[0097] In yet another embodiment, the present invention provides a
solid crystalline form of ibandronic acid, denominated Form S5,
characterized by a powder X-ray diffraction pattern having
reflections at about 4.5, 8.9, 12.0, 16.0, 16.3, 21.4, 22.1 and
26.9.+-.0.2 deg. 2-theta. Solid crystalline ibandronic acid Form S1
can be further characterized by X-ray reflections at about 5.9,
10.5 and 17.8.+-.0.2 deg. 2-theta. A typical x-ray diffraction
diagram for ibandronic acid Form S5 is given in FIG. 8. Form S5
exists as a hemihydrate or an iso-propanolate (isopropyl alcohol
solvate).
[0098] Ibandronic acid Form S5 can be prepared by a process that
includes the steps of: [0099] a) combining, at a temperature of
about 70.degree. C. to about 78.degree. C., a halo-phosphorous
compound and phosphorous acid with N-methyl-N-pentyl propionic acid
hydrochloride in a silicone oil to obtain a reaction mixture;
[0100] b) heating the reaction mixture to a temperature of about
80.degree. C. to about 100.degree. C., and maintaining while
stirring; [0101] c) combining water with the reaction mixture,
whereby two phases, one aqueous, one nonaqueous, are obtained;
[0102] d) separating the two phases obtained; [0103] e) maintaining
the aqueous phase at a reflux temperature; [0104] f) evaporating
the aqueous phase to obtain a residue; [0105] g) adding IPA to the
residue, [0106] h) maintaining the reaction mixture for 24 hours or
more to obtain a precipitate; and [0107] i) recovering crystalline
ibandronic acid Form S5.
[0108] Preferably, the halo-phosphorous compound of step a) is
added in small aliquots, most preferably dropwise. Preferably, the
temperature in step a) is about 75.degree. C. Preferably, the
reaction mixture in step b) is heated to a temperature of about
80.degree. C. The residue of step f) can be dissolved in water
prior to the addition of the IPA in step g). Optionally, the
mixture of the IPA and the residue is cooled to facilitate
precipitation.
[0109] Form S5 can be also prepared by a process including the
steps of: [0110] a) combining, at a temperature of about 70.degree.
C. to about 78.degree. C., a halo-phosphorous compound and
phosphorous acid with N-methyl-N-pentyl propionic acid
hydrochloride in toluene to form a multi-phase reaction mixture
[0111] b) maintaining the reaction mixture, while heating to a
temperature of about 80.degree. C. to about 100.degree. C.; [0112]
c) removing the toluene, especially by decanting or any other
liquid-liquid separation technique, and combining water with the
reaction mixture; [0113] d) maintaining the reaction mixture at a
reflux temperature, and evaporating to obtain a residue; [0114] e)
adding IPA to the residue to obtain a slurry; and [0115] f)
recovering crystalline ibandronic acid Form S5 from the slurry.
[0116] Preferably, the temperature in step a) is about 75.degree.
C. Preferably, the reaction mixture in step b) is heated to a
temperature of about 80.degree. C. Preferably, the halo-phosphorous
compound of step a) is added slowly, in small aliquots, most
preferably dropwise. In addition to water, a strong acid which does
not act as oxidant for amino-phosphonic acids may be added to the
reaction mixture of step c). The acid is thought to hydrolize the
phosphorous intermediates that form during the previous steps.
Preferably, the acid is concentrated HCl.
[0117] Ibandronic acid Form S5 can be prepared by stirring a
combination of amorphous ibandronic acid with an organic solvent
selected from the group consisting of tetrahydrofuran (THF) and
ethanol; and recovering Form S5. The combination is optionally
heated to reflux temperature.
[0118] In another embodiment, the present invention provides a
solid crystalline form of ibandronic acid, denominated Form S6,
characterized by a powder X-ray diffraction pattern having
reflections at about 5.7, 11.7, 14.3, 18.5, 21.2 and 21.7.+-.0.2
deg. 2-theta. Solid crystalline ibandronic acid Form S6 can be
further characterized by X-ray reflections at about 14.8, 22.7,
22.8 and 30.6.+-.0.2 deg. 2-theta. A typical x-ray diffraction
diagram for ibandronic acid form S6 is given in FIG. 9. Form S6 can
exist as a hemihydrate, tert-butanolate, or a mixture of both.
[0119] Ibandronic acid Form S6 can be prepared by a process
including the steps of: [0120] a) combining, at a temperature of
about 70.degree. C. to about 78.degree. C., a halo-phosphorous
compound and phosphorous acid with N-methyl-N-pentyl propionic acid
hydrochloride in a silicone oil to obtain a reaction mixture;
[0121] b) heating the reaction mixture to a temperature of about
80.degree. C. to about 100.degree. C., and maintaining while
stirring; [0122] c) combining water with the reaction mixture,
whereby two phases, one aqueous, one nonaqueous, are obtained;
[0123] d) separating the two phases obtained; [0124] e) maintaining
the aqueous phase at a reflux temperature; [0125] f) evaporating
the aqueous phase to obtain a residue; [0126] g) dissolving the
residue in water, followed by the addition of tert-butanol to
obtain a precipitate; and [0127] h) recovering crystalline
ibandronic acid Form S6.
[0128] Preferably, the halo-phosphorous compound of step a) is
added slowly, in small aliquots, especially dropwise. Preferably,
the temperature in step a) is about 75.degree. C. Preferably, the
reaction mixture in step b) is heated to a temperature of about
80.degree. C.
[0129] Form S6 can be also prepared by a process that includes the
steps of: [0130] a) combining, at a temperature of about 70.degree.
C. to about 78.degree. C., a halo-phosphorous compound and
phosphorous acid with N-methyl-N-pentyl propionic acid
hydrochloride in toluene to obtain a multiphase reaction mixture;
[0131] b) maintaining the reaction mixture, while heating to a
temperature of at least about 95.degree. C.; [0132] c) separating
the toluene by decantation or any technique for liquid-liquid
separation, and adding an acid to the reaction mixture; [0133] d)
maintaining the reaction mixture at a reflux temperature, and
evaporating to obtain a residue; [0134] e) dissolving the residue
in water, followed by the addition of tert-butanol to obtain a
precipitate; [0135] f) recovering crystalline ibandronic acid Form
S6.
[0136] Preferably, the halo-phosphorous compound of step a) is
added dropwise. Preferably, the acid in step c) is a strong acid
which does not act as oxidant for amino-phosphonic acids. Most
preferably, the acid in step c) is concentrated HCl. Preferably,
the temperature in step a) is about 75.degree. C.
[0137] In another embodiment, the present invention provides a
solid crystalline form of ibandronic acid, denominated Form S7,
characterized by a powder X-ray diffraction pattern having
reflections at about 4.6, 11.5, 16.3, 16.8, 21.0 and 22.8.+-.0.2
deg. 2-theta. Solid crystalline ibandronic acid Form S7 can be
further characterized by X-ray reflections at about 9.0, 17.7, 19.8
and 21.8.+-.0.2 deg. 2-theta. A typical x-ray diffraction diagram
for ibandronic acid Form S7 is given in FIG. 10. Form S7 can exist
as a hemihydrate, a 1-propanolate, or an iso-propanolate.
[0138] Ibandronic acid Form S7 can be prepared by a process
including the steps of: [0139] a) combining, at a temperature of
about 70.degree. C. to about 78.degree. C., a halo-phosphorous
compound and phosphorous acid with N-methyl-N-pentyl propionic acid
hydrochloride in a silicone oil to obtain a reaction mixture;
[0140] b) heating the reaction mixture to a temperature of about
80.degree. C. to about 100.degree. C., and maintaining while
stirring; [0141] c) combining the reaction mixture with water,
whereby two phases, one aqueous, one nonaqueous, are obtained;
[0142] d) separating the two phases obtained; [0143] e) maintaining
the aqueous phase at a reflux temperature; [0144] f) concentrating
the aqueous phase to obtain a residue; [0145] g) adding IPA or
n-propanol? to the residue, [0146] h) maintaining the reaction
mixture for less than 24 hours to obtain a precipitate; and [0147]
i) recovering crystalline ibandronic acid Form S7.
[0148] Preferably, the halo-phosphorous compound of step a) is
added slowly, in small aliquots, most preferably dropwise.
Preferably, the temperature in step a) is about 70.degree. C.
Preferably, the reaction mixture in step b) is heated to a
temperature of about 80.degree. C.
[0149] Form S7 can be also prepared by a process including the
steps of: [0150] a) combining, at a temperature of about 70.degree.
C. to about 78.degree. C., a halo-phosphorous compound and
phosphorous acid with N-methyl-N-pentyl propionic acid
hydrochloride in toluene to obtain a multiphase reaction mixture;
[0151] b) maintaining the reaction mixture, while heating to a
temperature of about 80.degree. C. to about 100.degree. C.; [0152]
c) separating the toluene, for example by decanting or any
technique for liquid-liquid separation, and combining water with
the reaction mixture; [0153] d) maintaining the reaction mixture at
a reflux temperature, and concentrating to obtain a residue; [0154]
e) combining 1-propanol with the residue obtain a precipitate;
[0155] f) recovering crystalline ibandronic acid Form S7.
[0156] Preferably, the halo-phosphorous compound of step a) is
added slowly, in small aliquots, most preferably dropwise.
Preferably, the temperature in step a) is about 75.degree. C.
Preferably, the reaction mixture in step b) is heated to a
temperature of about 80.degree. C.
[0157] In yet another embodiment, the present invention provides a
solid crystalline form of ibandronic acid, denominated Form S8,
characterized by a powder X-ray diffraction pattern having
reflections at about 4.5, 6.0, 11.9, 12.3, 16.2, 17.8 and
21.7.+-.0.2 deg. 2-theta. Solid crystalline ibandronic acid Form S8
can be further characterized by X-ray reflections at about 9.0,
16.5 and 18.9, .+-.0.2 deg. 2-theta. A typical x-ray diffraction
diagram for ibandronic acid Form S8 is given in FIG. 11. Form S8
can be exist as an ethanolate or an iso-propanolate.
[0158] Ibandronic acid Form S8 can be prepared by a process
including the steps of: [0159] a) combining, at a temperature of
about 70.degree. C. to about 78.degree. C., a halo-phosphorous
compound and phosphorous acid with N-methyl-N-pentyl propionic acid
hydrochloride in a silicone oil to obtain a reaction mixture;
[0160] b) heating the reaction mixture to a temperature of about
80.degree. C. to about 100.degree. C., and maintaining while
stirring; [0161] c) combining the reaction mixture with water,
whereby two phases, one aqueous, one nonaqueous, are obtained;
[0162] d) separating the two phases obtained; [0163] e) maintaining
the aqueous phase at a reflux temperature; [0164] f) concentrating
the aqueous phase to obtain a residue; [0165] g) adding a C.sub.2-4
alcohol to the residue to obtain a precipitate; and [0166] h)
recovering crystalline ibandronic acid Form S8.
[0167] Preferably, the halo-phosphorous compound of step a) is
added slowly, in small aliquots, most preferably dropwise.
Preferably, the temperature in step a) is about 75.degree. C.
Preferably, the reaction mixture in step b) is heated to a
temperature of about 80.degree. C. The residue of step f) may be
dissolved in water prior to the addition of the C.sub.2-4 alcohol
in step g). Preferably, the C.sub.2-4 alcohol in step g) is
selected from the group consisting of ethanol, 1-propanol and IPA.
Most preferably, the C.sub.2-4 alcohol in step g) is ethanol.
[0168] In another embodiment, the present invention provides a
solid crystalline form of ibandronic acid, denominated Form S10,
characterized by a powder X-ray diffraction pattern having
reflections at about 4.8, 6.1, 12.0, 12.3, 16.4, 18.0 and
21.7.+-.0.2 deg. 2-theta. Solid crystalline ibandronic acid Form
S10 can be further characterized by X-ray reflections at about
18.9, 20.9 and 22.8.+-.0.2 deg. 2-theta. A typical x-ray
diffraction diagram for ibandronic acid Form S10 is given in FIG.
12. Form S10 can exist as an ethanolate.
[0169] Ibandronic acid Form S10 can be prepared by a process
comprising the steps of: [0170] a) combining, at a temperature of
about 70.degree. C. to about 78.degree. C., a halo-phosphorous
compound and phosphorous acid with N-methyl-N-pentyl propionic acid
hydrochloride in a silicone oil to obtain a reaction mixture;
[0171] b) heating the reaction mixture to a temperature of about
80.degree. C. to about 100.degree. C., and maintaining while
stirring; [0172] c) combining the reaction mixture with water,
whereby two phases, one aqueous, one nonaqueous, are obtained;
[0173] d) separating the two phases obtained; [0174] e) maintaining
the aqueous phase at a reflux temperature; [0175] f) concentrating
the aqueous phase to obtain a residue; [0176] g) adding ethanol to
the residue to obtain a slurry; and [0177] h) recovering from the
slurry crystalline ibandronic acid Form S10.
[0178] Preferably, the halo-phosphorous compound of step a) is
added slowly, in small aliquots, most preferably dropwise.
Preferably, the reaction mixture in step b) is heated to a
temperature of about 80.degree. C. The residue of step f) may be
dissolved in water prior to the addition of the ethanol in step g).
The reaction mixture in step g) may be seeded with amorphous
ibandronic acid following the addition of the ethanol in step
g).
[0179] In another embodiment, the present invention provides a
solid crystalline form of ibandronic acid, denominated Form S12,
characterized by a powder X-ray diffraction pattern having
reflections at about 4.7, 9.0, 11.6, 20.9, 21.1, 21.7, 22.9 and
26.3.+-.0.2 deg. 2-theta. Solid crystalline ibandronic acid form
S12 may be further characterized by X-ray reflections at about
13.8, 17.1 and 18.4.+-.0.2 deg. 2-theta. A typical x-ray
diffraction diagram for ibandronic acid Form S12 is given in FIG.
13. Form S12 can be a hemihydrate and/or an isopropanolate.
[0180] Ibandronic acid Form S12 can be prepared by a process
including the steps of: [0181] a) combining, at a temperature of
about 70.degree. C. to about 78.degree. C., a halo-phosphorous
compound and phosphorous acid with N-methyl-N-pentyl propionic acid
hydrochloride in a silicone oil to obtain a reaction mixture;
[0182] b) heating the reaction mixture to a temperature of about
80.degree. C. to about 100.degree. C., and maintaining while
stirring; [0183] c) combining water with the reaction mixture,
whereby two phases, one aqueous, one nonaqueous, are obtained;
[0184] d) separating the two phases obtained; [0185] e) maintaining
the aqueous phase at a reflux temperature; [0186] f) concentrating
the aqueous phase to obtain a residue; [0187] g) combining the
residue with 1-propanol to obtain a precipitate; and [0188] h)
recovering crystalline ibandronic acid Form S12.
[0189] Preferably, the halo-phosphorous compound of step a) is
added slowly, in small aliquots, especially dropwise. Preferably,
the temperature in step a) is about 70.degree. C. Preferably, the
reaction mixture in step b) is heated to a temperature of about
80.degree. C.
[0190] In yet another embodiment, the present invention provides a
solid crystalline form of ibandronic acid, denominated Form S13,
characterized by a powder X-ray diffraction pattern having
reflections at about 4.5, 8.9, 12.0, 16.0, 16.3, 21.3 and
22.1.+-.0.2 deg. 2-theta. Solid crystalline ibandronic acid Form
S13 can be further characterized by X-ray reflections at about
10.5, 17.8 and 26.9.+-.0.2 deg. 2-theta. A typical x-ray
diffraction diagram for ibandronic acid Form S13 is given in FIG.
14. Form S13 can exist as an isopropanolate.
[0191] Ibandronic acid Form S13 can be prepared by a process
including the steps of: [0192] a) combining, at a temperature of
about 70.degree. C. to about 78.degree. C., a halo-phosphorous
compound and phosphorous acid with N-methyl-N-pentyl propionic acid
hydrochloride in a silicone oil to obtain a reaction mixture;
[0193] b) heating the reaction mixture to a temperature of about
80.degree. C. to about 100.degree. C., and maintaining while
stirring; [0194] c) combining the reaction mixture with water,
whereby two phases, one aqueous, one nonaqueous, are obtained;
[0195] d) maintaining the reaction mixture at a temperature of
about 100.degree. C.; [0196] e) separating the two phases obtained;
[0197] f) maintaining the aqueous phase at a temperature of about
75.degree. C. to about 100.degree. C.; [0198] g) concentrating the
aqueous phase to obtain a residue; [0199] h) adding IPA to the
residue to obtain a precipitate; and [0200] i) recovering
crystalline ibandronic acid Form S13.
[0201] Preferably, the halo-phosphorous compound of step a) is
added slowly, in small aliquots, especially dropwise. Preferably,
the temperature in step a) is about 75.degree. C. Preferably, the
reaction mixture in step b) is heated to a temperature of about
80.degree. C.
[0202] Ibandronic acid Form S13 can be also prepared by a process
including the steps of: [0203] a) combining, at a temperature of at
least about 95.degree. C., a halo-phosphorous compound and
phosphorous acid with N-methyl-N-pentyl propionic acid
hydrochloride to obtain a reaction mixture; [0204] b) maintaining
while stirring the reaction mixture at a temperature of about
95.degree. C. to about 100.degree. C.; [0205] c) combining the
reaction mixture with water; [0206] d) cooling the reaction mixture
to room temperature and concentrating to obtain a residue; [0207]
e) dissolving the residue in water, followed by the addition of IPA
to obtain a precipitate; and [0208] f) recovering crystalline
ibandronic acid Form S13. Preferably, the halo-phosphorous compound
of step a) is added slowly, in small aliquots, especially
dropwise.
[0209] Form S13 can be also prepared by providing a solution of
ibandronic acid in water at a temperature of about 38.degree. C. to
about 50.degree., cooling the solution to room temperature,
followed by the addition of IPA, and maintaining the mixture at
temperature for a sufficient time to obtain Form S13. Preferably,
ibandronic acid is dissolved in water at a temperature of about
40.degree. C. to provide the solution.
[0210] The following table summarizes the weight loss by TGA and
water content of the novel crystalline forms of ibandronic acid
described hereinabove.
TABLE-US-00001 Weight loss by Water content by Form TGA [%] Karl
Fisher [%] amorphous 5.1 4.2 S1 3.0 7.7 1.9 2.0 2.2 2.0 5.2 2.2 2.0
1.1 1.1 S2 1.9 S3 17.8 0.5 S4 14.8 0.1 15.2 0.1 55 13.0 0.7 14.1
1.1 2.7 2.3 1.2 1.1 S6 10.1 2.9 10.9 1.8 S7 13.4 1.2 11.4 1.9 S8
5.5 0.3 5.6 0.1 5.3 S10 5.5 0.6 S12 14.0 2.4 S13 15.0 1.0 15.4
[0211] In a further embodiment, the present invention also provides
a process for purifying Ibandronic acid from inorganic impurities
(i.e. reducing the amount of inorganic impurities in) that includes
the step of dissolving ibandronic acid in water or methanol, and
crystallizing by addition of a C.sub.2-4 alcohol. Preferably, the
C.sub.2-4 alcohol is selected from the group consisting of ethanol,
1-propanol, IPA and tert-butanol.
[0212] In yet another embodiment, the present invention further
provides a HPLC method of assaying ibandronic acid comprising the
steps of: dissolving an ibandronic acid sample in a diluent to
obtain a sample solution, loading the sample solution (ca. 50
.mu.L) onto a 250.times.4.1 mm, Hamilton type PRP-X100 anion
exchange column, eluting the sample from the column at 2.0 ml/min
using a mixture of nitric acid (HNO.sub.3: 35 vol-%), potassium
nitrate (KNO.sub.3: 45 vol-%) and ethanol (20 vol-%) as eluent, and
measuring the ibandronic acid content of the relevant sample at 240
nm wavelength with a UV detector. Preferably, the diluent is
water.
[0213] Some processes of the present invention involve
crystallization out of a particular solvent. One skilled in the art
knows that the conditions concerning crystallization can be
modified without affecting the form of the polymorph obtained. For
example, when mixing ibandronic acid 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. The conditions may also be changed
to induce precipitation. A preferred way of inducing precipitation
is to reduce the solubility of the solvent (reduce it "solubilizing
power"). The solubility of the solvent--that is its ability to
dissolve ibandronic acid--can be reduced, for example, by reducing
the temperature of the solvent.
[0214] In yet another embodiment, the present invention provides a
process for preparing ibandronate sodium (the sodium salt of
ibandronic acid) comprising converting any of the solid or
crystalline forms of ibandronic acid hereinabove described to
ibandronate sodium by combining the ibandronic acid with an aqueous
solution of sodium hydroxide at ambient temperature (about
20.degree. to about 28.degree. C.), concentrating the solution,
especially at reduced pressure, to obtain a residue; combining the
residue with acetone whereby a precipitate is formed, and
recovering ibandronate monosodium.
[0215] In yet another embodiment, the present invention provides
ibandronic acid having an assay of .gtoreq.99%.
[0216] In a further embodiment, the present invention provides
pharmaceutical formulations that include at least on
pharmaceutically acceptable excipient and one or more of the novel
crystalline forms of the present invention
[0217] Pharmaceutical formulations of the present invention contain
solid ibandronic acid or crystalline forms thereof, such as one of
those disclosed herein, optionally in a mixture with amorphous
ibandronic acid. In addition to the active ingredient(s), the
pharmaceutical formulations of the present invention can and
typically do contain one or more pharmaceutically acceptable
excipients. Such excipients are included in the formulations for a
variety of purposes.
[0218] 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.
[0219] Solid pharmaceutical compositions that are compacted into a
dosage form, such as 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.
[0220] 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.
[0221] Glidants can be added to improve the flowability of a
non-compacted solid composition and to 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.
[0222] When a dosage form such as a tablet is made by the
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 the release of the product from 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.
[0223] 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.
[0224] Solid and liquid compositions (suspensions or emulsions) 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.
[0225] In liquid pharmaceutical compositions of the present
invention, ibandronic acid and any other solid excipients are
suspended in a liquid carrier such as water, vegetable oil,
alcohol, polyethylene glycol, propylene glycol or glycerin.
[0226] 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.
[0227] 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.
[0228] Sweetening agents such as sorbitol, saccharin, sodium
saccharin, sucrose, aspartame, fructose, mannitol and invert sugar
may be added to improve the taste.
[0229] Preservatives and chelating agents such as alcohol, sodium
benzoate, butylated hydroxyl toluene, butylated hydroxyanisole and
ethylenediamine tetraacetic acid may be added at levels safe for
ingestion to improve storage stability.
[0230] According to the present invention, a liquid composition may
also contain a buffer such as guconic acid, lactic acid, citric
acid or acetic acid, sodium guconate, sodium lactate, sodium
citrate or sodium acetate. Selection of excipients and the amounts
used may be readily determined by the formulation scientist based
upon experience and consideration of standard procedures and
reference works in the field.
[0231] 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 administration 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.
[0232] Dosage forms include solid dosage forms like tablets,
powders, capsules, suppositories, sachets, troches and losenges, as
well as liquid syrups, suspensions and elixirs.
[0233] The dosage form of the present invention may be 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.
[0234] The active ingredient and excipients may be formulated into
compositions and dosage forms according to methods known in the
art.
[0235] A composition for tableting or capsule filling 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 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 a lubricant.
[0236] A tableting composition may be prepared conventionally by
dry blending. For example, 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
subsequently be compressed into a tablet.
[0237] 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 for 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.
[0238] A capsule filling of the present invention may comprise any
of the aforementioned blends and granulates that were described
with reference to tableting, however, they are not subjected to a
final tableting step.
[0239] Having described the invention with reference to certain
preferred embodiments, other embodiments will become apparent to
one skilled in the art from consideration of the specification. The
invention is further defined by reference to the following examples
describing in detail the preparation of the composition and methods
of use of the invention. It will be apparent to those skilled in
the art that many modifications, both to materials and methods, may
be practiced without departing from the scope of the invention.
EXAMPLES
Instrumentation
[0240] X-ray diffraction data were obtained with a scintag X-Ray
powder diffractometer model X'TRA, Cu-tube, solid state detector, a
round standard aluminum sample holder with round zero background
quartz plate was used. Scanning parameters: Range: 2-40 deg.28:
continues scan, Rate: 5 deg./min.
[0241] DSC data were obtained with a DSC821e, Mettler Toledo
instrument. The sample weight was 3-5 mg. The heating (scan) rate
was 10.degree. C./min. Number of holes in the crucible: 3.
[0242] TGA data were obtained using a Mettler TG50, sample weight:
7-15 mg, heating 30 rate: 10.degree. C./min.
[0243] Karl Fischer data were obtained using a Mettler Toledo DL38,
sample weight: 100-200 mg.
[0244] Spray drying technique were obtained using "Buchi Mini Spray
dryer B-290". The spray parameters are: evaporating capacity--1
lit/hr water (higher for organic solvents); the maximum temperature
input--220.degree. C.; Air flow--max of 35 m2/hr; spray
gas-compressed air or nitrogen 200-800 lit/hr, 5-8 bar; Nozzel
diameter--0.7 mm (standard); Nozzel cap--1.4 mm and 1.5 mm.
EXAMPLE 1
Amorphous Ibandronic Acid
[0245] An aqueous solution (40% w/w) of Ibandronic acid (150 mL)
was evaporated under vacuum (20-30 mmHg) until dryness while
heating the flask in a water bath (up to 70.degree. C.) to obtain
Amorphous Ibandronic acid (67 gr).
EXAMPLE 2
Amorphous Ibandronic Acid
[0246] An aqueous solution (40% w/w) of Ibandronic acid (303 gr)
was freeze-dried (-50.degree. C., 0.5 mmHg) for 3 days to obtain
Amorphous Ibandronic acid (120 gr).
EXAMPLE 3
Amorphous Ibandronic Acid
[0247] Phosphorous trichloride (3.3 mL) was added to a stirred
suspension of MPPA.HCl (8 g) in silicon oil (40 mL) at 75.degree.
C. Two additional portions of phosphorous trichloride (2.times.3.3
mL) were added during 2 hours after heating the reaction mixture to
81.degree. C. Two portions of phosphorus acid (2.times.3.1 g) were
thereafter added during 2 hours. The reaction mixture was stirred
at 81.degree. C. for 22 hours. Water (40 mL) was added drop-wise at
81.degree. C. The resulting phases were separated and the aqueous
phase was heated to 90.degree. C. for 16 hours. The obtained
solution was cooled to room temperature and then was evaporated to
obtain an oily residue. The oily residue was dissolved in water (7
mL) at room temperature. To the obtained solution, IPA (280 mL) was
added. The obtained sticky precipitate was heated to reflux and
then was cooled to room temperature, after complete dissolution.
Then the IPA was decanted-off and the residue was dried in vacuum
oven at 50.degree. C. for 20 hours to obtain 4.4 g of amorphous
ibandronic acid.
EXAMPLE 4
Amorphous Ibandronic Acid
[0248] Phosphorous trichloride (3.3 mL) was added to a stirred
suspension of MPA.HCl (8 g) in silicon oil (40 mL) at 75.degree. C.
Two additional portions of phosphorous trichloride (2.times.3.3 mL)
were added during 2 hours after heating the reaction mixture to
81.degree. C. Then two portions of phosphorus acid (2.times.3.1 g)
were added during 2 hours. The reaction mixture was stirred at
81.degree. C. for 22 hours. Water (40 mL) was added drop-wise at
81.degree. C. Then the phases were separated and the aqueous phase
was heated to 90.degree. C. for 16 hours. The obtained solution was
cooled to room temperature and then was evaporated to obtain an
oily residue. The oily residue was dissolved in water (7 mL) at
room temperature. The obtained solution was heated to 70.degree. C.
Then hot IPA (280 mL) (73.degree. C.) was added drop-wise. The
solution was cooled to room temperature. The solution was stirred
at room temperature for 21 hours. Then the IPA was decanted-off and
the residue was dried in vacuum oven at 50.degree. C. for 21 hours
to obtain 4.6 g of amorphous ibandronic acid.
EXAMPLE 5
Ibandronic Acid Crystal Form S1
[0249] Amorphous ibandronic acid (3.0 g) was dissolved in water (4
mL) at room temperature. Acetone (70 mL) was added to the stirred
solution. White slurry was obtained while stirring at room
temperature for 68 hours. The precipitate was isolated by vacuum
filtration, washed with acetone (2.times.25 mL) and dried in a
vacuum oven at 50.degree. C. for 24 hours to obtain 2.5 g of
ibandronic acid crystal form S1.
EXAMPLE 6
Ibandronic Acid Crystal Form S1
[0250] 40% w/w aqueous solution of ibandronic acid (22.2 g) was
concentrated under vacuum. To the concentrated solution (15.71 g),
tert-butanol was added drop-wise at room temperature in two
portions (2.times.50 mL) and the mixture was stirred at this
temperature for 4 hours. The obtained precipitate was isolated by
vacuum filtration, washed with tert-butanol (1.times.1.5 mL) and
dried in a vacuum oven at 5.degree. C. for 24 hours to obtain 5.5 g
of ibandronic acid crystal form S1.
EXAMPLE 7
Ibandronic Acid Crystal Form S1
[0251] 40% w/w aqueous solution of ibandronic acid (16.8 g) was
concentrated under vacuum. To the concentrated solution (12.1 g),
absolute Ethanol (100 mL) was added drop-wise at room temperature
and the mixture was stirred at this temperature for 4.5 hours. The
obtained precipitate was isolated by vacuum filtration, washed with
absolute Ethanol (2.times.25 mL) and dried in a vacuum oven at
50.degree. C. for 23 hours to obtain 5.2 g of ibandronic acid
crystal form S1.
EXAMPLE 8
Ibandronic Acid Crystal Form S1
[0252] Amorphous ibandronic acid (3.0 g) was dissolved in methanol
(12 mL) at room temperature. Acetone (40 mL) was added in one
portion to the stirred solution. The obtained slurry was stirred at
room temperature for 72 hours. The resulting precipitate was
isolated by vacuum filtration, washed with acetone (2.times.12.5
mL) and dried in a vacuum oven at 50.degree. C. for 22 hours to
obtain 2.5 g of ibandronic acid crystal form S1.
EXAMPLE 9
Ibandronic Acid Crystal Form S1
[0253] Amorphous ibandronic acid (3.0 g) was stirred in acetone (15
mL) at reflux temperature for 5 hours. The slurry was cooled to
room temperature and then it was stirred at this temperature for 16
hours. The product was dried in a vacuum oven at 50.degree. C. for
24 hours to obtain 2.8 g of ibandronic acid crystal form S1.
EXAMPLE 10
Ibandronic Acid Crystal Form S1
[0254] Amorphous ibandronic acid (3.0 g) was stirred in absolute
ethanol (20 mL) at reflux temperature for 2.5 hours. The slurry was
cooled to room temperature and then it was stirred at this
temperature for 40.5 hours. The product was isolated by vacuum
filtration, washed with absolute ethanol (2.times.20 mL) and dried
in a vacuum oven at 40.degree. C. for 25 hours to obtain 2.8 g of
ibandronic acid crystal form S1.
EXAMPLE 11
Ibandronic Acid Crystal Form S1
[0255] 40% w/w aqueous solution of ibandronic acid (10.95 g) was
concentrated under vacuum. To the concentrated solution (7.5 g),
acetone was added at room temperature in two portions (2.times.45
mL) and the mixture was stirred at this temperature for 22 hours.
The obtained precipitate was isolated by vacuum filtration, washed
with Acetone (2.times.20 mL) and dried in a vacuum oven at
50.degree. C. for 70 hours to obtain 2.9 g of ibandronic acid
crystal form S1.
EXAMPLE 12
Ibandronic Acid Crystal Form S1
[0256] Phosphorous oxychloride (17 mL) was added drop-wise to a
stirred suspension of MPA.HCl (10 g) and phosphorous acid (14.8 g)
in toluene (70 mL) at 75.degree. C. The reaction mixture was heated
to 80.degree. C. and was stirred at this temperature for 26 hours.
The reaction mixture was cooled to room temperature. The toluene
was decanted-off and the residue was stirred under reflux with
water (70 mL) for 15.5 hours. The obtained solution was cooled to
room temperature and then was evaporated to obtain an oily residue
(34.3 g). Absolute ethanol (853 mL) was added gradually to the oily
reside while stirring at room temperature during 45 hours. The
obtained precipitate was isolated by vacuum filtration, washed with
absolute ethanol (2.times.97 mL) and dried in a vacuum oven at
50.degree. C. for 24 hours to obtain 6.7 g of ibandronic acid
crystal form S1.
EXAMPLE 13
Ibandronic Acid Crystal Form S2
[0257] Amorphous ibandronic acid (3.0 g) was dissolved in methanol
(12 mL) at room temperature. Acetonitrile (ACN) (40 mL) was added
in one portion to the stirred solution. The obtained slurry was
stirred at room temperature for 72 hours. The precipitate was
isolated by vacuum filtration, washed with ACN (2.times.20 mL) and
dried in a vacuum oven at 50.degree. C. for 21.5 hours to obtain
2.4 g of ibandronic acid crystal form S2.
EXAMPLE 14
Ibandronic Acid Crystal Form S3
[0258] 40% w/w aqueous solution of ibandronic acid (11 g) was
concentrated under vacuum. To the concentrated solution (7.6 g),
tert-butanol (50 mL) was added at room temperature. The obtained
slurry was stirred at this temperature for 72 hours. Then the
precipitate was isolated by vacuum filtration, washed with
tert-butanol (2.times.40 mL) and dried in a vacuum oven at
50.degree. C. for 22.5 hours to obtain 4.2 g of ibandronic acid
crystal form S3.
EXAMPLE 15
Ibandronic Acid Crystal Form S4
[0259] 40% w/w aqueous solution of ibandronic acid (19.7 g) was
concentrated under vacuum. To the concentrated solution (12.5 g),
1-propanol (150 mL) was added gradually at room temperature. The
un-stirrable product was heated to reflux to obtain viscous
stirrable mixture. The mixture was cooled to room temperature and
stirred at this temperature for 16 hours. The obtained precipitate
was isolated by vacuum filtration, washed with 1-propanol
(2.times.17 mL) and dried in a vacuum oven at 50.degree. C. for 24
hours to obtain 6.6 g of ibandronic acid crystal form S4.
EXAMPLE 16
Ibandronic Acid Crystal Form S4
[0260] 40% w/w aqueous solution of ibandronic acid (23.7 g) was
concentrated under vacuum. To the concentrated solution (14 g),
1-propanol (100 mL) was added drop-wise at room temperature and the
mixture was stirred at this temperature for 3 hours. The obtained
precipitate was isolated by vacuum filtration, washed with
1-propanol (2.times.35 mL) and dried in a vacuum oven at 50.degree.
C. for 24 hours to obtain 10.2 g of ibandronic acid crystal form
S4.
EXAMPLE 17
Ibandronic Acid Crystal Form S5
[0261] Phosphorous trichloride (10.9 mL) was added drop-wise to a
stirred suspension of MPA.HCl (7 g) and phosphorous acid (10.3 g)
in silicon oil (49 mL) at 75.degree. C. The reaction mixture was
heated to 80.degree. C. Two additional portions of phosphorous
trichloride (1.times.1.5 ml and 1.times.1 mL) were added gradually
to the stirred reaction mixture at .about.80.degree. C. The
reaction mixture was stirred at this temperature for 50 hours.
Water (49 mL) was added drop-wise at 79.degree. C. The phases were
separated and the aqueous phase was heated to reflux for 15.5
hours. The obtained solution was cooled to room temperature and
then was evaporated until dryness to obtain an oily residue (27.2
g). The oily residue was dissolved in water (4 mL). To the obtained
solution, IPA (209 mL) was added drop-wise at room temperature and
the mixture was stirred at this temperature for 24 hours. The
obtained precipitate was isolated by vacuum filtration, washed with
IPA (2.times.52 mL) and dried in a vacuum oven at 50.degree. C. for
24 hours to obtain 9.9 g of ibandronic acid crystal form S5.
EXAMPLE 18
Ibandronic Acid Crystal Form S5
[0262] Phosphorous trichloride (8.2 mL) was added drop-wise to a
stirred suspension of MPA.HCl (7 g) and phosphorous acid (3.9 g) in
toluene (35 mL) at 75.degree. C. The reaction mixture was heated to
95.degree. C. and was stirred at this temperature for 23 hours. The
toluene was decanted-off and the residue was stirred under reflux
(96.degree. C.) with 6N HCl (104 mL) for 43 hours. The obtained
solution was cooled to room temperature and was then concentrated
to obtain an oily residue (8.1 g). The oily residue was dissolved
in water (4 mL). To the obtained solution, IPA (196 mL) was added
drop-wise at room temperature and the mixture was stirred at this
temperature for 72 hours. The obtained precipitate was isolated by
vacuum filtration, washed with IPA (2.times.40 mL) and dried in a
vacuum oven at 50.degree. C. for 24 hours to obtain 4.5 g of
ibandronic acid crystal form S5.
EXAMPLE 19
Ibandronic Acid Crystal Form S5
[0263] Phosphorous oxychloride (50 mL) was added drop-wise to a
stirred suspension of MPA.HCl (30 g) and phosphorous acid (44 g) in
silicone oil (210 mL) at 75.degree. C. The reaction mixture was
heated to 81.degree. C. Two additional portions of phosphorous
oxychloride (1.times.6.7 ml and 1.times.4 mL) were added gradually
to the stirred reaction mixture at 81.degree. C. The reaction
mixture was stirred at this temperature for 50 hours. Water (210
mL) was added drop-wise to the solution and the mixture was stirred
for 1 hr. Then the phases were separated and the aqueous phase was
heated to reflux for 16.5 hours. The obtained solution was cooled
to room temperature and then was evaporated until dryness to obtain
an oily residue (125.6 g). The oily residue was dissolved in water
(19 mL). To the obtained solution, IPA (1760 mL) was added at room
temperature and the mixture was stirred at this temperature for 24
hours and then was cooled to 7.degree. C. and stirred this
temperature for 72 hrs. The obtained precipitate was isolated by
vacuum filtration, washed with IPA (2.times.100 mL) and dried in a
vacuum oven at 50.degree. C. for 25 hours to obtain 22 g of
ibandronic acid crystal form S5.
EXAMPLE 20
Ibandronic Acid Crystal Form S5
[0264] Amorphous ibandronic acid (3.0 g) was stirred in THF (20 mL)
at reflux temperature for 2.5 hours to obtain almost complete
dissolution. The mixture was cooled to room temperature and then it
was stirred at this temperature for 21 hours. The obtained
precipitate was isolated by vacuum filtration under nitrogen flow,
washed with THF (2.times.15 mL) and dried in a vacuum oven at
40.degree. C. for 23.5 hours to obtain 2.7 g of ibandronic acid
crystal form S5.
EXAMPLE 21
Ibandronic Acid Crystal Form S5
[0265] Amorphous ibandronic acid (3.0 g) was stirred in Absolute
Ethanol (30 mL) at room temperature. The slurry was stirred at room
temperature for 72 hours. The product was isolated by vacuum
filtration, washed with Absolute Ethanol (2.times.20 mL) and dried
in a vacuum oven at 50.degree. C. for 22 hours to obtain 2.9 g of
ibandronic acid crystal form S5.
EXAMPLE 22
Ibandronic Acid Crystal Form S1
[0266] Phosphorous oxychloride (17 mL) was added drop-wise to a
stirred suspension of MPA.HCl (10 g) and phosphorous acid (14.8 g)
in toluene (70 mL) at 75.degree. C. The reaction mixture was heated
to 80.degree. C. and was stirred at this temperature for 26 hours.
The reaction mixture was cooled to room temperature. The toluene
was decanted-off and the residue was stirred under reflux with
water (70 mL) for 15.5 hours. The obtained solution was cooled to
room temperature and then was evaporated until dryness to obtain an
oily residue (34.3 g). IPA (834 mL) was added gradually to the oily
reside while stirring at room temperature during 72 hours. The
obtained precipitate was isolated by vacuum filtration, washed with
IPA (2.times.84 mL) and dried in a vacuum oven at 50.degree. C. for
23 hours to obtain 12.8 g of ibandronic acid crystal form S5.
EXAMPLE 23
Ibandronic Acid Crystal Form S5
[0267] Phosphorous trichloride (15.6 mL) was added drop-wise to a
stirred suspension of MPA.HCl (10 g) and phosphorous acid (14.7 g)
in silicon oil (70 mL) at 75.degree. C. The reaction mixture was
heated to 80.degree. C. Two additional portions of phosphorous
trichloride (1.times.2 ml and 1.times.1.3 mL) were added gradually
to the stirred reaction mixture at 80.degree. C. The reaction
mixture was stirred at this temperature for 48hours. Water (70 mL)
was added drop-wise at 80.degree. C. The phases were separated and
the aqueous phase was heated to reflux for 16 hours. The obtained
solution was cooled to room temperature and then was evaporated
until dryness to obtain an oily residue (38.2 g). IPA (746 mL) was
added to the oily residue at room temperature and the mixture was
stirred at this temperature for 53.5 hours. The obtained
precipitate was isolated by vacuum filtration, washed with IPA
(2.times.83 mL) and dried in a vacuum oven at 50.degree. C. for
24.5 hours to obtain 11.1 g of ibandronic acid crystal form S5.
EXAMPLE 24
Ibandronic Acid Crystal Form S6
[0268] Phosphorous trichloride (10.9 mL) was added drop-wise to a
stirred suspension of MPPA.HCl (7 g) and phosphorous acid (10.3 g)
in silicon oil (49 mL) at 75.degree. C. The reaction mixture was
heated to 80.degree. C. Two additional portions of phosphorous
trichloride (1.times.1.5 ml and 1.times.1 mL) were added gradually
to the stirred reaction mixture at .about.80.degree. C. The
reaction mixture was stirred at this temperature for 50 hours.
Water (49 mL) was added drop-wise at 79.degree. C. The phases were
separated and the aqueous phase was heated to reflux for 15.5
hours. The obtained solution was cooled to room temperature and
then was evaporated until dryness to obtain an oily residue (27.2
g). The oily residue was dissolved in water (3.8 mL). To the
obtained solution, tert-butanol (191 mL) was added at room
temperature and the mixture was stirred at this temperature for 42
hours. The obtained precipitate was isolated by vacuum filtration,
washed with tert-butanol (2.times.38 mL) and dried in a vacuum oven
at 50.degree. C. for 25.5 hours to obtain 6.2 g of ibandronic acid
crystal form S6.
EXAMPLE 25
Ibandronic Acid Crystal Form S6
[0269] Phosphorous trichloride (8.2 mL) was added drop-wise to a
stirred suspension of MPA.HCl (7 g) and phosphorous acid (3.9 g) in
toluene (35 mL) at 75.degree. C. The reaction mixture was heated to
95.degree. C. and was stirred at this temperature for 23 hours. The
Toluene was decanted-off and the residue was stirred under reflux
(96.degree. C.) with 6H HCl (104 mL) for 43 hours. The obtained
solution was cooled to room temperature and then was evaporated
until dryness to obtain an oily residue (8.1 g). The oily residue
was dissolved in water (4 mL). To the obtained solution,
tert-butanol (204 mL) was added drop-wise at room temperature and
the mixture was stirred at this temperature for 72 hours. The
obtained precipitate was isolated by vacuum filtration, washed with
tert-butanol (2.times.40 mL) and dried in a vacuum oven at
50.degree. C. for 23 hours to obtain 2.8 g of ibandronic acid
crystal form S6.
EXAMPLE 26
Ibandronic Acid Crystal Form S7
[0270] Phosphorous trichloride (15.6 mL) was added drop-wise to a
stirred suspension of MPA.HCl (10 g) and phosphorous acid (14.7 g)
in silicon oil (70 mL) at 70.degree. C. The reaction mixture was
heated to 80.degree. C. and was stirred at this temperature for
23.5 hours. Water (70 mL) was added drop-wise at 80.degree. C. Then
the phases were separated and the aqueous phase was heated to
reflux for 18 hours. The obtained solution was cooled to room
temperature and then was evaporated until dryness to obtain an oily
residue (24.5 g). IPA (443 mL) was added gradually to the oily
residue and the mixture was stirred at room temperature for 18
hours. The obtained precipitate was isolated by vacuum filtration,
washed with IPA (1.times.80 mL) and dried in a vacuum oven at
50.degree. C. for 24 hours to obtain 9.8 g of ibandronic acid
crystal form S7.
EXAMPLE 27
Ibandronic Acid Crystal Form S7
[0271] Phosphorous oxychloride (17 mL) was added drop-wise to a
stirred suspension of MPA.HCl (10 g) and phosphorous acid (14.8 g)
in toluene (70 mL) at 75.degree. C. The reaction mixture was heated
to 80.degree. C. and was stirred at this temperature for 26 hours.
Then the reaction mixture was cooled to room temperature. The
toluene was decanted-off and the residue was stirred under reflux
with water (70 mL) for 15.5 hours. The obtained solution was cooled
to room temperature and then was evaporated until dryness to obtain
an oily residue (34.3 g). 1-Propanol (695 mL) was added gradually
to the oily reside while stirring at room temperature during 18
hours. The obtained precipitate was isolated by vacuum filtration,
washed with 1-propanol (2.times.39 mL) and dried in a vacuum oven
at 50.degree. C. for 24 hours to obtain 10.8 g of ibandronic acid
crystal form S7.
EXAMPLE 28
Ibandronic Acid Crystal Form S8
[0272] Phosphorous trichloride (18.7 mL) was added drop-wise to a
stirred suspension of MPA.HCl (12 g) and phosphorous acid (17.6 g)
in silicone oil (84 mL) at 75.degree. C. The reaction mixture was
heated to 80.degree. C. Two additional portions of phosphorous
trichloride (1.times.2.5 ml and 1.times.1.5 mL) were added
gradually to the stirred reaction mixture at 80.degree. C. The
reaction mixture was stirred at this temperature for 51.5 hours.
Water (84 mL) was added drop-wise to the solution, stirred for 15
minutes. The phases were separated and the aqueous phase was heated
to reflux for 16 hours. The obtained solution was cooled to room
temperature and stirred at this temperature for 12 hours. A portion
(23 mL) of this solution (24.8 g) was concentrated to obtain an
oily residue (11.26 g). The oily residue was dissolved in water
(1.7 mL). To the obtained solution, IPA (87 mL) was added drop-wise
at room temperature and the mixture was stirred at this temperature
for 70 hours. The obtained precipitate was isolated by vacuum
filtration, washed with IPA (2.times.25 mL) and dried in a vacuum
oven at 50.degree. C. for 25 hours to obtain 3.27 g of ibandronic
acid crystal form S8.
EXAMPLE 29
Ibandronic Acid Crystal Form S8
[0273] Phosphorous trichloride (18.7 mL) was added drop-wise to a
stirred suspension of MPA.HCl (12 g) and phosphorous acid (17.6 g)
in silicone oil (84 mL) at 75.degree. C. The reaction mixture was
heated to 80.degree. C. Two additional portions of phosphorous
trichloride (1.times.2.5 ml and 1.times.1.5 mL) were added
gradually to the stirred reaction mixture at 80.degree. C. The
reaction mixture was stirred at this temperature for 51.5 hours.
Water (84 mL) was added drop-wise to the solution and the mixture
stirred for 15 minutes. The phases were separated and the aqueous
phase was heated to reflux for 16 hours. The obtained solution was
cooled to room temperature and stirred at this temperature for 12
hours. A portion (23 mL) from this solution (27 g) was evaporated
until dryness to obtain an oily residue (11 g). The oily residue
was dissolved in water (1.6 mL). To the obtained solution,
1-propanol (160 mL) was added drop-wise at room temperature and the
mixture was stirred at this temperature for 20 hours. The obtained
precipitate was isolated by vacuum filtration, washed with IPA
(2.times.10 mL) and dried in a vacuum oven at 50.degree. C. for 25
hours to obtain 3.16 g of ibandronic acid crystal form S8.
EXAMPLE 30
Ibandronic Acid Crystal Form S8
[0274] Phosphorous oxychloride (20 mL) was added drop-wise to a
stirred suspension of MPA.HCl (12 g) and phosphorous acid (17.6 g)
in Silicone oil (84 mL) at 75.degree. C. The reaction mixture was
heated to 80.degree. C. Two additional portions of phosphorous
oxychloride (1.times.2.7 ml and 1.times.1.6 mL) were added
gradually to the stirred reaction mixture at 80.degree. C. The
reaction mixture was stirred at this temperature for 50 hours.
Water (84 mL) was added drop-wise to the solution, stirred for 20
minutes. The phases were separated and the aqueous phase was heated
to reflux for 17 hours. The obtained solution was cooled to room
temperature and stirred at this temperature for 12 hours. A portion
(24 mL) from this solution (24 g) was concentrated to obtain an
oily residue (21.65 g). The oily residue was dissolved in water
(1.9 mL). To the obtained solution, IPA (177 mL) was added
drop-wise at room temperature and the mixture was stirred at this
temperature for 23 hours. The obtained precipitate was isolated by
vacuum filtration, washed with IPA (2.times.20 mL) and dried in a
vacuum oven at 50.degree. C. for 26.5 hours to obtain 2.37 g of
ibandronic acid crystal form S8.
EXAMPLE 31
Ibandronic Acid Crystal Form S8
[0275] Phosphorous trichloride (15.6 mL) was added drop-wise to a
stirred suspension of MPA.HCl (10 g) and phosphorous acid (14.7 g)
in silicon oil (70 mL) at 75.degree. C. The reaction mixture was
heated to 80.degree. C. Two additional portions of phosphorous
trichloride (1.times.2 ml and 1.times.1.3 mL) were added gradually
to the stirred reaction mixture at 80.degree. C. The reaction
mixture was stirred at this temperature for 48 hours. Water (70 mL)
was added drop-wise at 80.degree. C. Then the phases were separated
and the aqueous phase was heated to reflux for 16 hours. The
obtained solution was cooled to room temperature and then was
evaporated until dryness to obtain an oily residue (38.2 g).
Absolute ethanol (766 mL) was added to the oily residue at room
temperature and the mixture was stirred at this temperature for 53
hours. The obtained precipitate was isolated by vacuum filtration,
washed with absolute ethanol (2.times.61 mL) and dried in a vacuum
oven at 50.degree. C. for 25.5 hours to obtain 7.7 g of ibandronic
acid crystal form S8.
EXAMPLE 32
Ibandronic Acid Crystal Form S8
[0276] Phosphorous trichloride (57 mL) was added drop-wise to a
stirred suspension of MPA.HCl (30 g) and phosphorous acid (44 g) in
silicon oil (210 mL) at 75.degree. C. The reaction mixture was
heated to 80.degree. C. Two additional portions of phosphorous
trichloride (1.times.6.25 ml and 1.times.3.75 mL) were added
gradually to the stirred reaction mixture at 80.degree. C. The
reaction mixture was stirred at this temperature for 48 hours.
Water (210 mL) was added drop-wise at 80.degree. C. and stirred at
this temperature for 30 minutes. Then the phases were separated and
the aqueous phase was heated to reflux for 17 hours. The solution
was cooled to room temperature and then concentrated to obtain an
oily residue (121.1 g). The oily residue was dissolved in water (18
mL). Absolute ethanol (3027 mL) was added to the solution at room
temperature and the mixture was stirred at this temperature for 72
hours. Cooling to 5.degree. C. and stirring at this temperature for
7 hours. The obtained precipitate was isolated by vacuum
filtration, washed with absolute ethanol (2.times.48 mL) and dried
in a vacuum oven at 50.degree. C. for 23.5 hours to obtain 35.64 g
of ibandronic acid crystal form S8.
EXAMPLE 33
Ibandronic Acid Crystal Form S10
[0277] Phosphorous oxychloride (50 mL) was added drop-wise to a
stirred suspension of MPA.HCl (30 g) and phosphorous acid (44 g) in
silicon oil (210 mL) at 75.degree. C. The reaction mixture was
heated to 80.degree. C. Two additional portions of phosphorous
oxychloride (1.times.6.7 ml and 1.times.4 mL) were added gradually
to the stirred reaction mixture at 80.degree. C. The reaction
mixture was stirred at this temperature for 51 hours. Water (210
mL) was added drop-wise at 80.degree. C. and stirred at this
temperature for 30 minutes. Then the phases were separated and the
aqueous phase was heated to reflux for 16.5 hours. The solution was
cooled to room temperature and then was evaporated until dryness to
obtain an oily residue (128.5 g). The oily residue was dissolved in
water (19 mL). Absolute ethanol (3210 mL) was added to the solution
at room temperature and the mixture was stirred at this temperature
for 39 hours. The mixture was seeded with ibandronic acid and
stirred for 4.5 hours. The mixture was cooled to 0.degree. C. and
stirred at this temperature for 72 hours. The obtained precipitate
was isolated by vacuum filtration, washed with absolute ethanol and
dried in a vacuum oven at 50.degree. C. for 23 hours to obtain
13.82 g of ibandronic acid crystal form S10.
EXAMPLE 34
Ibandronic Acid Crystal Form S10
[0278] Phosphorous trichloride (15.6 mL) was added drop-wise to a
stirred suspension of MPA.HCl (10 g) and phosphorous acid (14.7 g)
in silicon oil (70 mL) at 70.degree. C. The reaction mixture was
heated to 80.degree. C. and was stirred at this temperature for
23.5 hours. Water (70 mL) was added drop-wise at 80.degree. C. The
phases were separated and the aqueous phase was heated to reflux
for 18 hours. The obtained solution was cooled to room temperature
and then concentrated to obtain an oily residue (24.5 g). Absolute
ethanol (597 mL) was added to the oily residue and the mixture was
stirred at room temperature for 20.5 hours. The obtained
precipitate was isolated by vacuum filtration, washed with absolute
ethanol (2.times.20 mL) and dried in a vacuum oven at 50.degree. C.
for 31 hours to obtain 7.3 g of ibandronic acid crystal form
S10.
EXAMPLE 35
Ibandronic Acid Crystal Form S10
[0279] Phosphorous trichloride (18.7 mL) was added drop-wise to a
stirred suspension of MPA.HC1 (12 g) and phosphorous acid (17.6 g)
in silicone oil (84 mL) at 75.degree. C. The reaction mixture was
heated to 80.degree. C. Two additional portions of phosphorous
trichloride (1.times.2.5 ml and 1.times.1.5 mL) were added
gradually to the stirred reaction mixture at 80.degree. C. The
reaction mixture was stirred at this temperature for 52 hours.
Water (84 mL) was added drop-wise to the solution, stirred for 15
minutes. Then the phases were separated and the aqueous phase was
heated to reflux for 16 hours. The obtained solution was cooled to
room temperature and stirred at this temperature for 13 hours. A
portion (23 mL) from this solution (27.31 g) was evaporated until
dryness to obtain an oily residue (11.25 g). The oily residue was
dissolved in water (1.7 mL). To the obtained solution, abs. ethanol
(270 mL) was added drop-wise at room temperature and the mixture
was stirred at this temperature for 20 hours. The obtained
precipitate was isolated by vacuum filtration, washed with abs
ethanol (2.times.12.5 mL) and dried in a vacuum oven at 50.degree.
C. for 24 hours to obtain 8.56 g of ibandronic acid crystal form
S10.
EXAMPLE 36
Ibandronic Acid Crystal Form S10
[0280] Phosphorous oxychloride (20 mL) was added drop-wise to a
stirred suspension of MPA.HCl (12 g) and phosphorous acid (17.6 g)
in silicone oil (84 mL) at 75.degree. C. The reaction mixture was
heated to 80.degree. C. Two additional portions of phosphorous
oxychloride (1.times.2.7 ml and 1.times.1.6 mL) were added
gradually to the stirred reaction mixture at 80.degree. C. The
reaction mixture was stirred at this temperature for 50 hours.
Water (84 mL) was added drop-wise to the solution, stirred for 20
minutes. The phases were separated and the aqueous phase was heated
to reflux for 13 hours. The obtained solution was cooled to room
temperature and stirred at this temperature for 12 hours. A portion
(24 mL) from this solution (29 g) was concentrated to obtain an
oily residue (12.8 g). The oily residue was dissolved in water (1.9
mL). To the obtained solution, abs. ethanol (300 mL) was added
drop-wise at room temperature and the mixture was stirred at this
temperature for 25 hours. The obtained precipitate was isolated by
vacuum filtration, washed with abs. ethanol (2.times.20 mL) and
dried in a vacuum oven at 50.degree. C. for 24 hours to obtain 1.81
g of ibandronic acid crystal form S10.
EXAMPLE 37
Ibandronic Acid Crystal Form S12
[0281] Phosphorous trichloride (15.6 mL) was added drop-wise to a
stirred suspension of MPA.HCl (10 g) and phosphorous acid (14.7 g)
in silicon oil (70 mL) at 70.degree. C. The reaction mixture was
heated to 80.degree. C. and was stirred at this temperature for
23.5 hours. Water (70 mL) was added drop-wise at 80.degree. C. The
phases were separated and the aqueous phase was heated to reflux
for 18 hours. The obtained solution was cooled to room temperature
and then was evaporated until dryness to obtain an oily residue
(24.5 g). 1-Propanol was added to the oily residue at room
temperature in two portions (2.times.25 mL) and the mixture was
stirred at this temperature for 17.5 hours. The obtained
precipitate was isolated by vacuum filtration, washed with
1-propanol (2.times.20 mL) and dried in a vacuum oven at 50.degree.
C. for 22.5 hours to obtain 10.1 g of ibandronic acid crystal form
S12.
EXAMPLE 38
Ibandronic Acid Crystal Form S13
[0282] Phosphorous oxychloride (11.7 mL) was added drop-wise to a
stirred suspension of MPA.HCl (7 g) and phosphorous acid (10.3 g)
in silicon oil (49 mL) at 75.degree. C. The reaction mixture was
heated to 80.degree. C. An additional portion of phosphorous
oxychloride (1.times.1.6 mL) was added to the reaction mixture at
80.degree. C. after 45.5 hours. The reaction mixture was stirred at
80.degree. C. for additional 2.5 hours. Water (49 mL) was added
drop-wise at 80.degree. C. The phases were separated and the
aqueous phase was heated to 100.degree. C. for 18 hours. The
obtained solution was cooled to room temperature and then was
concentrated to obtain an oily residue (26.7 g). The oily residue
was dissolved in water (4 mL). To the obtained solution, IPA (360
mL) was added drop-wise while stirring at room temperature during
48 hours. The obtained precipitate was isolated by vacuum
filtration, washed with IPA (1.times.20 mL) and dried in a vacuum
oven at 50.degree. C. for 24.5 hours to obtain 1.84 g of ibandronic
acid crystal form S13.
EXAMPLE 39
Ibandronic Acid Crystal Form S13
[0283] MPA.HCl (7 g) was added to melted phosphorous acid (3.4 g)
while stirring in an oil-bath at 95.degree. C. Phosphorous
trichloride (5.8 mL) was added drop-wise. The mixture was stirred
at 95-100.degree. C. (in an oil-bath) for 25.5 hours. Without
cooling, but removing the oil-bath, water (21 mL) was added
drop-wise. The reaction mixture was stirred at 97.degree. C. for 16
hours. The obtained solution was cooled to room temperature.
Insoluble particles were filtered off and the filtrate was
concentrated to obtain an oily residue (12.9 g). The oily residue
was dissolved in water (1.9 mL). To the obtained solution, IPA (290
mL) was added gradually while stirring at room temperature during
100 hours. The obtained precipitate was isolated by vacuum
filtration, washed with IPA (2.times.30 mL) and dried in a vacuum
oven at 50.degree. C. for 24 hours to obtain 8.11 g of ibandronic
acid crystal form S13.
EXAMPLE 40
Ibandronic Acid Crystal Form S13
[0284] Phosphorous trichloride (50 mL) was added drop-wise to a
stirred suspension of MPA.HCl (30 g) and phosphorous acid (44 g) in
silicone oil (210 mL) at 75.degree. C. The reaction mixture was
heated to 80.degree. C. Two additional portions of phosphorous
trichloride (1.times.6.25 ml and 1.times.3.75 mL) were added
gradually to the stirred reaction mixture at 80.degree. C. The
reaction mixture was stirred at this temperature for 48.5 hours.
Water (210 mL) was added drop-wise to the solution and the mixture
stirred for 15 minutes. The phases were separated and the aqueous
phase was heated to reflux for 16.5 hours. The obtained solution
was cooled to room temperature and then was concentrated to obtain
an oily residue (121.3 g). The oily residue was dissolved in water
(18 mL). To the obtained solution, IPA (1698 mL) was added at room
temperature and the mixture was stirred at this temperature for 22
hours and then was cooled to 4.degree. C. and stirred this
temperature for 4 hrs. The obtained precipitate was isolated by
vacuum filtration, washed with IPA (2.times.43 mL) and dried in a
vacuum oven at 50.degree. C. for 47 hours to obtain 39 g of
ibandronic acid crystal form S13.
EXAMPLE 41
Ibandronic Acid Crystal Form S13
[0285] Ibandronic acid (97 g) was dissolved in water (90 mL) at
40.degree. C. The solution was cooled to room temperature and IPA
(1100 mL) was added, stirred at this temperature for 22 hrs. The
obtained precipitate was isolated by vacuum filtration, washed with
IPA (2.times.50 mL) and dried in a vacuum oven at 50.degree. C. for
25 hours to obtain 97.6 g of ibandronic acid crystal form S13.
EXAMPLE 42
Comparative Example
[0286] Repetition of Example 9 of U.S. Pat. No. 4,927,814 15 g
N-Methyl-N-pentylaminopropionic acid (MPA.HCl) were kept for 23
hours at 100.degree. C. with 8.8 g phosphorous acid and 18.7 ml
phosphorous trichloride in 75 ml chlorobenzene. The solvent was
then decanted off and the residue was stirred under reflux with 222
ml 6N HCl for 12.5 hours. Insoluble material was filtered off and
the filtrate was concentrated and applied to column of Amberlite IR
120 (H+). The elution with water was monitored by HPLC. The desired
fractions were combined, evaporated and stirred up with acetone to
obtain a sticky oily precipitate as a crude product. (The HPLC
method for monitoring the ion-exchange chromatography is the one
described in this application).
EXAMPLE 43
Comparative Example
[0287] Repetition of Example 9 of U.S. Pat. No. 4,927,814--with
Methyl Ethyl Ketone Used Instead of Acetone
[0288] 15 g N-Methyl-N-pentylaminopropionic acid (MPA.HCl) were
kept for 23 hours at 100.degree. C. with 8.8 g phosphorous acid and
18.7 ml phosphorous trichloride in 75 ml chlorobenzene. The solvent
was then decanted off and the residue was stirred under reflux with
222 ml 6N HCl for 12.5 hours. Insoluble material was filtered off
and the filtrate was concentrated and applied to column of
Amberlite IR 120 (H+). The elution with water was monitored by
HPLC. The desired fractions were combined, evaporated and stirred
up with methyl ethyl ketone (MEK) to obtain a sticky oily
precipitate as a crude product.
(The HPLC method for monitoring the ion-exchange chromatography is
the one described in this application).
EXAMPLE 44
Comparative Example
[0289] Repetition of Example 9 of U.S. Pat. No. 4,927,814--with
Acetonitrile Used Instead of Acetone
[0290] 15 g N-Methyl-N-pentylaminopropionic acid (MPA.HCl) were
kept for 23 hours at 100.degree. C. with 8.8 g phosphorous acid and
18.7 ml phosphorous trichloride in 75 ml chlorobenzene. The solvent
was then decanted off and the residue was stirred under reflux with
222 ml 6N HCl for 12.5 hours. Insoluble material was filtered off
and the filtrate was concentrated and applied to column of
Amberlite IR 120 (H+). The elution with water was monitored by
HPLC. The desired fractions were combined, evaporated and stirred
up with acetonitrile to obtain a sticky oily precipitate as a crude
product. (The HPLC method for monitoring the ion-exchange
chromatography is the one described in this application).
HPLC Assay
[0291] Column: Hamilton type PRP-X100, Anion exchange, 250*4.1 mm
[0292] Temp.: 35.degree. C. [0293] Eluent: 35% HNO.sub.3, 45%
KNO.sub.3, 20% EtOH [0294] Flow: 2.0 mL/min [0295] Diluent:
H.sub.2O [0296] Injection volume: 50 .mu.L [0297] Detector: 240 nm
The following samples were analyzed according to the above
method:
TABLE-US-00002 [0297] Ex- am- ple Crystallization % area of % area
of % area of No. medium Polymorph PO.sub.4.sup.-3 PO.sub.3.sup.-3
Cl.sup.- 32 EtOH S8 0.4 ND* 33 EtOH S10 0.2 0.2 ND* *ND = not
detected
EXAMPLE 45
Amorphous Ibandronic Acid
[0298] Ibandronic acid (9 g) was dissolved in water (18 ml) at room
temperature. The solution was divided into three portions, and each
portion was spray dried using a Buchi mini spray dryer B-290 using
a standard nozzle 0.7 mm in diameter with a nozzle cap of 1.4 or
1.5 mm. The solution feed rate was about 1 L/h. The spray gas was
set at 200-800 L/h at a pressure of 5-8 bar. In each instance,
amorphous ibandronic acid was obtained.
[0299] For portion 1, nitrogen gas was at an inlet temperature of
50.degree. C. The evaporated solvent and nitrogen left the spray
dryer at a temperature of 41-36.degree. C.
[0300] For portion 2, nitrogen gas was at an inlet temperature of
100.degree. C. The evaporated solvent and nitrogen left the spray
dryer at a temperature of 71-72.degree. C.
[0301] For portion 3, nitrogen gas was at an inlet temperature of
150.degree. C. The evaporated solvent and nitrogen left the spray
dryer at a temperature of 100.degree. C.
[0302] Each of the three product was analyzed by powder x-ray
diffraction and found to be amorphous.
EXAMPLE 46
Conversion of Ibandronic Acid to Monosodium Ibandronate
[0303] Ibandronic acid (4.5 g) was dissolved in water (45 ml) at
room temperature. A solution of 1N aq. NaOH (14 ml) was added in
one portion. The reaction mixture was stirred at room temperature
for 2.5 hours. Then the solution was concentrated under reduced
pressure and was poured into Acetone (45 ml) at room temperature. A
white precipitate was obtained immediately. The obtained slurry was
stirred at room temperature for 72 hours. The product was isolated
by vacuum filtration, washed with Acetone (2.times.20 ml) and dried
in a vacuum oven at 50.degree. C. for 22 hours to obtain 4.45 g of
ibandronate monosodium salt (pH=4.26).
* * * * *