Attorney Docket No. 01662/01176
CRYSTALLINE FORMS OF IBANDROMC ACID AND PROCESSES FOR
PRJ3PARATION THEREOF
CROSS-REFERENCE TO RELATED APPLICATIONS
[OOl] This application claims the benefit of priority to US. provisional
Application Serial No. 601794,515, filed April 25,2006, hereby incorporated by
reference.
FlELD OF TKE INVENTION
Loo21 The invention relates to the solid state chemistry of lbandronic acid.
BACKGROUND OF THE INVENTION
PO31 Ibandronate Sodium is a third-generation nitrogen-containing
bisphosphonate characterized by an aliphatic tertiary amine side chain.
10041 lbandronate Sodium is a white crystalline powder. The fiee acid has a
molecular weight of 319.23 (CAS No.: 114084-78-5). The monosodium salt (anhydrous)
of the acid has a molecular weight of 341.23 (CAS No.: 138844-81-2). The monosodium
sdt monohydrate has a molecular weight of 359.23 (CAS No.: 138926-19-9).
r
0
11
I HO-P-OH
I
C-OH
WN-I
HO-P-OH
II
0
L 1
Ihandronic acid
r 0
I I
I HO-P-0-Na+
I
C-OH 'Hz0
-N-I
HO-P-OH
I I
0
\ 2
lbandronic acid Monosodium Salt - Monohydrate
~0051 The preparation of ibandronic acid monosodium salt is described in, for
example,U.S. patent No. 4,927,814 ('"814 patent"). The '814 patent describes the
following reaction schemes:
\N-COOH 1) H ~ mP H~~PO, , PCIa~ POCI~P, ~CII,O OOC \N-P-~~
p 2) 6N HCI *- PaHz
MPA
Ibanic acid
IBb-Ac
Ibandronic acid
IBO
Ibandronate Sodium monohydrate
0 0
COCI
'N- -
0
1'~0-Na*
c'I-OH - 0 ~ saponification
f
'N-1
- LN/\/P-OH - PO,H, - P03R2
[0061 The preparation of a class of bisphosphonic acids, which includes
ibandronic acid, is taught in U.S. patent No. 4,927,814 ("'814 patent"). In the process of
the '81 4 patent, ion-exchange chromatography is used dusing work-up to isolate the
bisphosphonic acid. See, e.g., '814 patent, col. 7, ll. 20-47 (example 1)- The present
inventors performed experiments based upon the procedures described in the '8 14 patent.
See Examples 5-7 below. 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 and
consequently there is a need for a method of making a solid ibandronic acid.
[OO~I Additional methods for the preparation of ibandronic acid are described in
PCT publication No- WO 03/097655, in which ibandronic acid is obtained by reaction of
a carboxylic acid, phosphorous acid and a halophosphorous compound in the presence of
aromatic hydrocarbon or a silicone fluid.
loo81 The monosodium salt of ibandronic acid is marketed under the trade name
BOMVA@. BONTVA* was developed by Hofbann-La Roche for the treatment of bone
disorders such as hypercalcaemia of malignancy, osteolysis, Paget's disease, osteoporosis
and metastatic bone disease. BOWA@ is also marketed in Europe under the name
BONDRONAT@ for cancer-related bone complications. BONDRONAT@ is available in
ampoule with Iml concentrate for solution for infbsion contains 1 -125mg of ibandronic
acid monosodium salt monohydrate, corresponding to 1mg of ibandronic acid.
~0091 Crystalline forms of ibandronic acid, as well as the amorphous form, are
described in PCT publication No. WO 2006/002348.
COO 1 O] Ibandronic acid can be used as an intermediate in the process for the
preparation of Ibandronate sodium.
[OOl 11 The invention relates to the solid state physical properties of ibandronic
acid. These properties can be influenced by controlling the conditions under which
ibandronic acid is obtained in solid form. Solid state physical properties include, for
example, the flowability of the milled solid. Flowability affects the ease with which the
material is handled during processing into a pharmaceutical product. When particles of
the powdered compound do not flow past each other easily, a formulation specialist must
use glidants such as colloidd silicon dioxide, talc, starch, or tribasic calcium phosphate.
[OOl 21 Another important solid state property of a pharmaceutical compound- is its
rate of dissolution in aqueous fluid. The rate of dissolution of an active ingredient in a
patient's stomach fluid can have therapeutic consequences since it imposes an upper limit
on the rate at which an orally-administered active ingredient can reach the patient's
- bloodstream. The rate of dissolution is also a consideration in formulation syrups, elixirs,
and other liquid medicaments. The solid state form of a compound can also affect its
behavior on compaction and its storage stability.
[OO 131 These practical physical characteristics are influenced by the conformation
and orientation of molecules in the unit cell, which define a particular polymorphic form
of a substance. The polymorphic form can give rise to .thermal behavior different itom
that of the amorphous material or anotfier polymorphic form. Thermal behavior is
measured in the laboratory by such techniques as capillary melting point,
thermogravimetric analysis (TGA), and diffaential scanning calorimetry (DSC) and can
be used to distinguish some polymorphic forms from others. A particular polymorphic
form can also give rise to distinct spectroscopic properties that can be detectable by
powder x-ray crystallography, solid state I3c NMR spectrometry, and infrared
spectrometry.
[0014] Generally, the crystalline solid has improved chemical and physical
stability over the amorphous form and forms with low crystallinity. The crystalline solid
can also exhibit improved solubility, hygroscopicity, bulk properties, and/or flowability.
[OOl 51 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
additional polymorphic forms of ibandronic acid.
SUMMARY OF THE INVENTION
1001 63 In one embodiment, the invention encompasses a crystalline form of
ibandronic acid (denominated "Form S 15") characterized by a powder x-ray diffraction
pattern having peaks at about 8.2, 1 1.4,11.8,22.0 and 24.5 h 0.2 degrees two-theta.
1001 73 In another embodiment, the invention encompasses a method for preparing
the crystalline ibandronic acid Form S 15 comprising: a) combining a halo-phosphorous
compound and phosphorous acid with 3-N-methyl-N-pentylamino propionic acid or a salt
thereof in a silicon oil to obtain a reaction mixture; b) heating the reaction mixture; c)
combining the reaction mixture with water to obtain a biphasic mixture having an
aqueous and a non-aqueous phase; d) separating the aqueous and non-aqueous phases; e)
heating the aqueous phase; f) concentrating the aqueous phase to obtain a residue; g)
adding about 40 to about 60 milliliters of ethanol per g r b of the N-methyl-N-pentyl
propionic acid or salt thereof to the residue to obtain a precipitate; and h) recovering the
crystalline ibandronic acid Form Sl5 h m the precipitate.
[0018] In another embodiment, the invention encompasses a method for preparing
a pharmaceutically acceptable salt of ibandronic acid comprising: a) preparing crystalline
ibandronic acid Form Sf 5 by the above-described method; and b) converting the
crystalline ibandronic acid Form S15 into a pharmaceutically accep.table salt of
ibandronic acid.
[OOlg'J In another embodiment, the invention encompasses a crystalline form of
ibandronic acid (denominated "Form S16") characterized by a powder x-ray difiction
pattern having peaks at about 4.7,12.4, 16.4,20.8 and 22.7 f 0.2 degrees two-theta.
[OOZO] h another embodiment, the invention encompasses a method for preparing
crystalline ibandronic acid Form S16 comprising: a) combining a halo-phosphorous
compound and phosphorous acid with 3-N-methyl-N-pentylaminop ropionic acid or a
salt thereof in a silicon oil to obtain a reaction mixture; b) heating the reaction mixture; c)
combining the reaction mixture with water to form a biphasic mixture having an aqueous
and a non-aqueous phase; d) separating the aqueous and non-aqueous phases; e) heating
the aqueous phase; f ) concentrating the aqueous phase to obtain a residue; g) adding about
85 to about 100 milliliters of a C2-4 alcohol per gram of the N-methyl-N-pentyl propionic
acid or salt thereof to the residue to obtain a precipitate; and h) recovering the crystalline
ibandronic acid Form S16 from the precipitate.
1002 11 In another embodiment, the invention encompasses a method for preparing
a pharmaceutically acceptable salt of ibandronic acid comprising: a) preparing crystalline
.ibandronic acid Form S16 by the above-described method; and b) converting the
crystalline ibandronic acid Form S16 into a pharmaceutically acceptable salt of
ibandrdnic acid.
[0022] In another embodiment, the invention encompasses crystalline ibandronic
acid Form S15 or S16 having a maximum particle size of 500 pm. Preferably, the
crystalline ibandronic acid Fonn 515 or 51 6 has a particle size of less than about 300 pm,
more preferably less than about 200 pm, even more preferably less than about 100 pm,
and most preferably less than about 50 pm.
BRIEF DESCRIPTION OF THE FIGURES
to0231 Figure 1 is a PXRD dif%ractogramo f ibandronic acid Form S1 5 (obtained
in Example 1).
[OOZS] Figure 2 is a PXRD diffi-actogram of ibandronic acid Form S 15 (obtained
in Example 2).
10025) Figure 3 is a PXRD diffractogram of ibandronic acid Form S 16 (obtained
in Example 3).
[0026] Figure 4 is a PXRD dif3-actogra.m of ibandronic acid Form S 16 (obtained
in Example 4)-
DETAILED DESCRZPTION OF THE INVENTION
[0027] The invention provides crystalline forms of ibandronic acid, as well
methods of preparation of these crystalline forms. The invention further provides
pharmaceutical compositions and methods for treating bone disorders.
COO28 J As used herein, the term "room temperature" refers to a temperature of
about 15°C to about 30°C.
[0029] The invention encompasses a crystalline form of ibandronic acid,
characterized by a powder x-ray diffraction ("PXRD") pattern having peaks at about 8.2,
I 1.4,11.8,22.0 and 24.5 * 0.2 degrees two-theta (hereinafter referred to as "Form S 15").
Form S15 can be further characterized by a PXRD pattern having peaks at about 13.8,
18.4,18.7 and 2 1-5 =t 0.2 degrees two-theta Form S15 can be even M e r characterized
by a PXRD pattern substantially as depicted in Figures 1 and 2. Typically, Form S15
does not contain more than about 5% by weight of ibandronic acid Form S 16, based on
the PXRD detection of the strongest characteristic peak of ibandronic acid Form S16, as
defined below.
10030 3 The invention further encompasses a method for preparing Form S 15,
comprising: a) combining a halo-phosphorous compound and phosphorous acid with 3-
N-methyl-N-pentylarnino propionic acid or a salt thereof in a silicon oil to obtain a
reaction mixture; b) heating the reaction mixture; c) combining the reaction mixture with
water to obtain a biphasic mixture having an aqueous and a non-aqueous phase; d)
separating the aqueous and non-aqueous phases; e) heating the aqueous phase; f)
concentrating the aqueous phase to obtain a residue; g) adding about 40 to about 60
milliliters (volumes) of ethanol per gram of the 3-N-methyl-N-pentylamino propionic
acid or salt thereof to the residue to obtain a precipitate; and h) recovering Fonn S15 from
the precipitate.
[003 11 Preferably, the halo-phosphorous compound is selected from the group
consisting of PC13, POC13, PBr3, POBr3, PCls or PBr5. More preferably, the halophosphorous
compound is PC13.
[0032] Preferably, the salt of 3-N-methyl-N-pentylamino propionic acid is a
hydrochloride or hydrobromide salt-
[0033] Suitable silicon oils (also known as silicone fluids) are miscible with
organic solvents such as benzene, toluene, and carbon tetrachIoride, but are insoluble in
water. Preferred silicon oils include, but are not limited to, polydimethylsiloxane
("PDMS"), poly[oxy(dimethylsilene)], dimethicone, methylsilicone oil, Dow corningm
200 fluid (a poly(dimethy~siloxane))W, acker SWS 101.f luid (a poly(dirnethylsiloxane)),
~a~silonMe@PH 350 fluid, poly[oxy(methylphenylsilylene)], methylphenyl silicone oil,
and Dow comingB 71 0 fluid (phenyl methylsiloxane).
100343 The halo-phosphorous compound may be added to the phosphorous acid
and 3-N-methyl-N-pentylamino propionic acid or salt thereof slowly, in small aliquots,
preferably dropwise. Alternatively, the halo-phosphorous compound may be added in
one portion. The components of step a) are combined at about room temperature to about
78"C, preferably, about 73°C.
[0035] Typically, the reaction mixture in step b) is heated while stirring.
Preferably, the reaction mixture in step b) is heated for about 3 to about 11 hours, more
preferably for about 3 hours to about 9.5 hours, and most preferably for about 4 hours to
about 8 hours. Preferably, the reaction mixture in step b) is heated at a temperature of
about 60°C to about 1 OO°C, more preferably about 80°C to about 90°C, and most
preferably about 80°C. The water may be added to the reaction mixture slowly, in small
aliquots, preferably dropwise. Preferably, the aqueous phase is heated at reflux
temperature. The residue of step f) may be dissolved in water prior to the addition of the
ethanol in step g). The ethanol of step g) may be added slowly, in small aliquots,
preferably dropwise.
[003q The invention further encompasses a crystalline form of ibandronic acid,
characterized by a PXRD pattern having peaks at about 4.7, 12.4, 16.4,20.8 and 22.7 =t
0.2 degrees two-theta (hereinafter referred to as ccFormS 16"). Form S16 can be further
characterized by a PXRD pattern havingpeaks at about 9.1,10.6, 18.3, 19.6 and 21.6 *
0.2 degrees two-theta. Form S 16 can be even fUrther characterized by a PXRD pattern
substantially as depicted in Figures 3 and 4. Typically, Form S16 does not contain more
than about 5% by weight of ibandronic acid Fom S10, based on the XRD detection of the
strongest characteristic peak of ibandronic Form S 10 (6.1 & 0.2 degrees two-theta).
Ibandronic acid Form S 10 is described in PCT publication No. WO 20061002348, and is
characterized by a PXRD pattern having peaks at about 4.8,6.1, 12.0, 12.3, 16.4, 18.0 and
21 -7 * 0.2 degrees two-theta.
[0037] The invention further encompasses a method for preparing ibandronic acid
Form 51 6, comprising: a) combining a halo-phosphorous compound and phosphorous
acid with 3-N-methyl-N-pentylamino propionic acid or a salt thereof in a silicon oil to
obtain a reaction mixture; b) heating the reaction mixture; c) combining the reaction
mixture with water to form a biphasic mixture having an aqueous and a non-aqueous
phase; d) separating the aqueous and non-aqueous phases; e) heating the aqueous phase;
f ) concentrating the aqueous phase to obtain a residue; g) adding about 85 fo about 100
milliliters (volumes) of a (22-4 alcohol per gram of the N-methyl-N-pentyl propionic acid
or salt thereof to the residue to obtain a precipitate; and h) recovering Form S16 fiom the
precipitate.
[0038] Preferably, the halo-phosphorous compound is selected from the group
consisting of PC13, POCL, PBr3, POBr3, PC15, or PBr5. More preferably, the halophosphorous
compound is PC13.
[0039] Preferably, the salt of 3-N-methyl-N-pentylamino propionic acid is the
hydrochloride or hydrobromide salt.
[0040] The halo-phosphorous compound may be added to the phosphorous'acid
and 3-N-methyl-M-pentylaminop ropionic acid or salt thereof slowly, in Small aliquots,
preferably dropwise. Alternatively, the halo-phosphorous compound may be added as a
single portion. The components of step a) may be combined at about room temperature,
preferably about 25OC.
COO4 11 Typically, the reaction mixture in step b) is heated while stimng.
Preferably, the reaction mixture in step b) is heated for about 3 to about 11 hours, more
preferably for about 3 hours to about 9.5 hours, and most prefkiably f oa~bo ut 4 hours to
about 8 hours.. Preferably, the reaction mixture in step b) is heated at a temperature of
about 60°C to about 1 OO°C, more preferably about 80°C to about 90°C, and most
preferably about 80°C. The water may be added to the reaction mixture slowly, in small
aliquots, preferably dropwise. Preferably, the aqueous phase is heated at reflux
temperature. The residue of step f) may be dissolved in water prior to the addition of the
CZ-'a$lc ohol in step g). Preferably, the C2-4 alcohol in step g) is selected from the group
consisting of ethanol, 1 -propano1 and 2-propanol, where ethanol is most preferred. The
reaction may include an additional step between steps c) and d) where 30% H202is added
to the two phases. The gradual addition of the 30% Hz02 results in improved phase
separation.
[0042] The crystalline ibandronic acid forms S 15 and S16 may be recovered by
any means known in the art. For example, the crystalline form can be isolated by vacuum
filtration. The processes can also include washing and/or drying the precipitated
crystalline fonn. For example, the crystalline form can be washed with the same solvent
used for dissolution. It can be dried in a vacuum oven at about 50°C for about 24 hours
or until constant weight, or it can be dried by evaporation. -
100433 The invention further encompasses crystalline ibandronic acid Form S 15
or Form S16 having a maximum particle size of about 5 0 0 ~T.y pically, Form S 15 or
Fonn S16 has a particle size of less than about 300pm, preferably less than about 200p,
more preferably less than about l o o p , and most preferably less than about 50p-n.
Particle size is measured by at least one of the following methods: sieves, sedimentation,
electrozone sensing (coulter counter), microscopy, and Low Angle Laser Light Scattering
(LALLS).
100441 The crystalline ibandronic acid Form S 15 or S 16 may subsequently be
converted into a pharmaceutically acceptable salt of ibandronic acid by any method
known to one of ordinary skill in the art, Preferably, the method comprises: preparing
crystalIine ibandronic acid Form S 15 or Form S 16 according to the above-described
processes; and converting the crystalline ibandronic acid Form S 15 or S 16 into a
pharmaceutically acceptable salt of ibandronic acid. Preferably, the pharmaceutically
acceptable salt is a sodium salt.
[0045] The crystalline ibandroGc acid Form S 15 or S16, or pharmaceutically
acceptable salts of ibandronic acid prepared the crystalline forms, may be formulated into
pharmaceutical formulations with at Ieast one pharmaceutically acceptable excipient.
[0046] Suitable pharmaceutically acceptable excipients include those known to
one of ordinary skill in the art. Excipients are added to the formulation for a variety of
purposes.
[0047] Diluents increase the bulk of a solid pharmaceutical composition, and can
make a pharmaceutical dosage form containing the composition easier for the patient and
caregiver to handle. Diluents for solid compositions include, for example,
microcrystalline cellulose (e-g. AVICEL?, 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@), potassium chloride, powdered cellulose, sodium chloride, sofbitol, and
talc.
[0048 3 Solid pharmaceutical compositions that are compacted into a dosage form,
such as a tablet, can 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@'),
hydroxypropyl methyl cellulose (e-g. METHOCEL~, liquid glucose, magnesium
aluminum silicate, maltodextxin, methylcellulose, polymethacrylates, povidone (e.g.
KOLLIDON@, PLASDONE~, pregelatinized starch, sodium alginate, and starch.
[0049] The dissolution rate of a compacted solid pharmaceutical composition in
the patient's stomach can be increased by the addition of a disintegrant to the
composition, Disintegrants include alginic acid, carboxymethylcellulose calcium,
carboxymethylcellulose sodium (e-g. AC-DI-SOL@, PRIM EL LOSE^, colloidal silicon
dioxide, croscarmellose sodium, crospovidone {e-g. KOLLIDON@, POLYPLASDONE~,
guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose,
polacrilin potassium, powdered cellulose, pregelatinlzed starch, sodium alginate, sodium
starch glycolate (e.g. EXPLOTAB~, and starch.
[OOSO] Glidants can be added to improve the flowability of a non-compacted solid
composition and to improve the accuracy of dosing. Excipients that can function as
glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose,
starch, talc, and tribasic calcium phosphate.
[OOS 11 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 fiom 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 fizmarate, stearic acid, talc, and zinc stearate.
[0052] Flavoring agents and flavor enhancers make the dosage fonn more
palatable to the patient. Common flavoring agents and flavor enhancers for
pharmaceutical products that can be included in the composition of the invention include
maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric
acid.
[0053] Solid and liquid compositions can also be dyed using any pharmaceutically
acceptable colorant to improve their appearance and/or facilitate patient identification of
the product and unit dosage level.
[0054] In liquid pharmaceutical compositions of the invention, the crystalline
ibandronic acid or pharmaceutically acceptable salt thereof and any other solid excipients
are suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene
glycol, propylene glycol, or glycerin, wherein the crystalline form of the ibandronic acid
is maintained.
[0055 J Liquid pharmaceutical compositions can contain emulsifying agents to
disperse uniformly throughout the composition an active ingredient or other excipient that
is not soluble in the liquid carrier. Emulsifj4ng agents that can be useful in liquid
compositions of the invention include, for exaniple, gelatin, egg yolk, casein, cholesterol,
acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer, cetostearyl.alcohol, and
cetyl alcohol.
I00561 Liquid pharmaceutical compositions of the invention can 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, polyviny1 alcohol, povidone, propylene
carbonate, propylene glycol dginate, sodiurn alginate, sodium starch glycolate, starch
tragacanth, and xanthan gum.
[0057] Sweetening agents such as sorbitol, saccharin, sodium saccharin, sucrose,
aspartame, fructose, mannitol, and invert sugar can be added to improve the taste.
[OOSS] Preservatives and &elating agents such as alcohol, sodium benzoate,
butylated hydroxyl toluene, butylated hydroxyanisole, and ethylenediamine tetraacetic
acid can be added at levels safe for ingestion to improve storage stability.
[0059 ] According to the invention, a liquid composition can also contain a buffer
such as gluconic acid, lactic acid, citric acid, or acetic acid, sodium gluconate, sodium
lactate, sodium citrate, or sodium acetate. Selection of excipients and the amounts used
can be readily determined by the formulation scientist based upon experience and
consideration of standard procedures and reference works in the field.
[0060] The solid compositions of the 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 invention is oral. The dosages can be conveniently presented
in unit dosage form and prepared by any of the methods well-known in the
pharmaceutical arts.
[0061] Dosage forms include solid dosage forms like tablets, powders, capsules,
suppositories, sachets, troches, and lozenges, as well as liquid syrups, suspensions, and
elixirs.
100621 The dosage form of the invention can 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 can be made Erom gelatin and optionally
contain a plasticizer such as glycerin and sorbitol, and an opacifying agent or colorant.
[0063] The active ingredient and excipients can be formulated into compositions
and dosage forms according to methods known in the art.
100641 A composition for tableting or capsule filling can 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 andlor milled to the desired particle size. The granulate
can then be tableted, or other excipients can be added prior to tableting, such as a glidant
andlor a lubricant.
[0065] A tableting composition can be prepared conventionally by dry blending.
For example, the blended composition of the actives and excipients can be compacted
into a slug or a sheet and then comminuted into compacted granules. The compacted
granules can subsequently be compressed into a tablet.
[0066] As an alternative to dry granulation, a blended composition can be
compressed directly into a compacted dosage fonn 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, dicaIcium 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.
' to0671 A capsule filling of the invention cm comprise any of the aforementioned
blends and granulates that were described with reference to tableting, but they are not
subjected to a final tableting step.
[0068] The invention also provides methods of treating bone disorders comprising
administering a pharmaceutical formulation of ibandronic acid or a pharamceutically
acceptable salt thereof to a patient in need thereof. Bone disorders include, but are not
limited to hypercalcaernia of malignancy, osteolysis, Paget's disease, osteoporosis and
metastatic bone disease. Ibandronic acid or a pharmaceutically acceptable salt thereof is
preferably fonnulated for administration by injection, preferably to a mammal, more
preferably to a human. Ibandronic acid can be fonnulated, for example, as a viscous
liquid suspension for injection. The formulation can contain one or more solvents. A
suitable solvent can be selected by considering the solvent's physical and chemical
stability at various pH levels, viscosity (which would allow for syringeability), fluidity,
boiling point, miscibility, and purity. Suitable solvents include alcohol USP, benzyl
alcohol NF, benzyl benzoate USP, and Castor oil USP. Additional substances can be
added to the formulation such as buffers, solubilizers, and antioxidants, among others.
Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th ed.
[0069] BoNIVA@ and/or BONDRONAT@ can be used as guidance for
formulation. BONIVA@ is available as an intravenous injection administered every 2-3
months and as an oral formulation. BONDRONAT~ is available in ampoule with 1 ml
concentrate for solution for inhsion contains 1.125 mg of ibandronic monosodium salt
monohydrate, corresponding to I mg of ibandronic acid.
[0070] Having thus described the invention with reference to particular preferred
embodiments, other embodiments will become apparent to one skilled in the art from
consideration of the specification. The invention is fb-ther defined by reference to the
following examples describing in detail the synthesis of ibandr~naic~id Forms 5 15 and
S 16. The Examples are set forth to aid in understanding the invention but are not
intended to, and should not be construed to, limit its scope in any way. The examples do
not include detailed descriptions of conventional methods. ~ u imhe thods are well known
to those of ordinary skill in the art and are described in numerous publications.
Polymorphism in Pharmaceutical Solids, Drugs and the Pharmaceutical Sciences, Volume
95 can be used for guidance. It will be apparent to those skilled in the art that many
modifications, both to materials and methods may be practiced without departing f?om
the scope of the invention.
[0071] All references mentioned herein are incorporated in their entirety.
EXAMPLES
Powder X-rav Diffiaction
[0072] Powder X-ray difiaction analysis was performed using a SCINTAG
powder X-ray diffiactometer model X'TRA equipped with a solid-state detector. Copper
radiation of X=1.5418 A was used. The sample was introduced using a round standard
aluminum sample holder with a round zero background quartz plate in the bottom. The
scanning parameters were: range: 2-40 degrees two-theta; scan mode: continuous scan;
step size: 0.05 deg.; and a rate of 5 deg./rnin.
High Performance Liauid Chromatography ("'HPLC")
100731 Elution fiom the Amberlite column in Examples 5 to 7 was monitored by
HPLC using a Hamilton type PRP-X100, Anion exchange, 250*4.lmm column at a
temperature of 35°C. The eluent was a mixture containing 35% HN03, 45% KNO% and
20% ethanol. The flow rate was 2.0 mZ./min and the detector was set at a wavelength of
240 nrn. The injection volume of each sample was 50 pL and the diluent was water.
Example 1 : Preparation of Ibandronic acid Form S15
[0074] A 500ml reactor was loaded with silicon oil (2lOml), 3-N-methyl-Npentylamino
propionic acid hydrochloride ("ibanic acid hydrochloride" or '=A HCl")
(30g) and H$O3 (44g) at room temperature. The mixture was heated to 73OC and PC13
(47mI) was added drop-wise to form a reaction mixture over a period of 10 minutes. The
reaction mixture was heated to 80°C and stirred at 80°C for 9.5 hours. Distilled water
(2101111) was then added drop-wise to fm a biphasic mixture. The two phases were
stirred for 0.5 hour. The lower aqueous phase was separated and hydrolyzed at reflux in a
250ml reactor for 22 hours. Vacuum filtration through hyflo was done, The obtained
solution was evaporated until dryness to obtain 64.3g of colorless oil. The oily residue
was dissolved in distilled water (10ml) and absolute ethanol (1 607m1, ) was added dropwise
over a period of 25 minutes at room temperature. The sluny was stirred for 16 hours
at room temperature and then it was cooled to 4 O C . The product was isolated by vacuum
filtration, washed with ethanol 96% (2x50ml) and dried in a vacuum oven at 50°C for 24
hours to obtain 22.53g of ibandronic acid crystalline Form 5 15.
Example 2: Preparation of Ibandronic acid Form S15
[0075] A 500ml reactor was loaded with silicon oil (210ml), Banic acid
hydrochloride (MPPA HCl) (30g), H3PO3 (44g) and PC13 (47ml) at room temperature.
The mixture was heated to 80°C over a period of 2 hours. The reaction mixture was
stirred for 3 hours. Distilled water (210ml) was then added drop-wise to the reaction
mixture to form a biphasic mixture. The two phases were stirred for 10 minutes. The
lower aqueous phase was separated and hydrolyzed at reflux in a 250mI reactor for 15
hours. The obtained solution was evaporated until dryness to obtain 75g of colorless oil.
Absolute ethanol (1440ml) was added drop-wise over a period of 40 minutes at room
temperature. The sluny was stirred for about 72 hours at room temperature. The product
was isolated by vacuum filtration, washed with absolute ethanol (2x40m.l) and dried in a
vacuum oven at 50°C for 22 hours to obtain 23.5g of ibandronic acid crystalline Form
s15.
Example 3: Pre~arationo f Ibandronic acid Form S 16
[00763 A 500ml reactor was loaded with silicon oil (105ml), Ibanic acid
hydrochloride (MPPA HCI) (1 5g) and H3P03 (22g) at room temperature. The mixture
was heated to 80°C in order to melt W3PO3. The mixture was then cooled to 25OC and
Pel3 (23.4mI) was added in one portion. The reaction mixture was heated to 80°C over a
period of 2 hours and stirred at 80°C for 7.5 hours. Distilled water (105rnl) was then
added drop-wise to the reaction mixture to form a biphasic mixture- The two phases were
stirred for 10 minutes. The lower aqueous phase was separated and hydrolyzed at reflux
in a 250ml reactor during 15.5 hours. The obtained solution was evaporated until dryness
to obtain 53.3g of colorless oil. The oily residue was dissolved in distilled water (8ml)
and absolute ethanol (1333m1) was added drop-wise over a period of 55 minutes at room
temperature. The slurry was stirred for 16 hours at room temperature. The product was
isolated by vacuum filtration, washed with absolute ethanol (2x25~111) and dried in a
vacuum oven at 50°C during 20 hours to obtain 22g of ibandronic acid crystalline Form
S16.
Examvle 4: Prmaration of Ibandronic acid Form S 16
COO771 A 500rnl reactor was loaded with silicon oil (105ml), Ibanic acid
hydrochloride (MPPA HC1) (1 5g), H3P03 (22g) and PC13 (1 9ml) at room temperature.
The reaction mixture was heated to 80°C during 15 minutes and stirred at this temperature
for 3 hours. Distilled water (105ml) was added drop-wise to the reaction mixture to form
a biphasic mixture. Then 30% Hz02 solution (3ml) was added gradually to improve phase
separation. The two phases were stirred for 30 minutes. The lower aqueous phase was
separated and hydrolyzed at reflux in a 250ml reactor during 18 hours. The obtained
solution was evaporated until dryness to obtain 44.8g of colorless oil. The oily residue
was dissolved in distilled water (9ml) and absolute ethanol (1 500ml) was added dropwise
during about 5 minutes at room temperature. The slurry was stirred for about 72 .
hours at room temperature. The product was isolated by vacuum filtration, washed with
absolute ethanol (2x25ml) and dried in a vacuum oven at 50°C during 24 hours to obtain
20.2g of ibandronic acid crystalline Fonn S 16.
Example 5: Example based uuon Examvle 9 of U.S. patent No. 4,927.814
COO781 15 g N-Methyl-N-pentylaminopropionic acid were kept for 23 hours at
100°C with 8.8 g phosphorous acid and 18.7 ml phosphorous trichloride in 75ml
chlorobenzene. The solvent was then decanted off and the residue was stirred under reflux
with 222m16N HCI for 12.5 hours. Insoluble material was filtered off and the filtrate was
concentrated and applied to column of Amberlite IR 120 @+). The elution with water
was monitored by HPLC, using the HPLC method described above. The desired fractions
were combined, evaporated and stirred up with acetone to obtain a sticky oily precipitate
as a crude product.
Examvle 6: Exam~leba sed uuon Example 9 of U.S. patent No. 4.927.814 (substituting
methvl ethvl ketone for acetone)
[0079] 15 g N-Methyl-N-pentylaminopropionic acid were kept for 23 hours at
1 OO°C with 8.8 g phosphorous acid and 1 8.7 ml phosphorous trichloride in 75 ml
chlorobenzene. The solvent was then decanted off and the residue was stirred under
reflux with 222 ml6N HC1 for 12.5 hours. Insoluble material was filtered off and the
filtrate was concentrated and applied to column of Amberlite IR 120 (W). The elution
with water was monitored by HPLC, using the HPLC method described above. The
desired fiactions were combined, evaporated and stirred up with methyl ethyl ketone
('NEK") to obtain a sticky oily precipitate as a crude product.
Example 7: Example based upon Exarnvle 9 of U.S. patent No. 4,927.814 (substituting
acetoni trile for acetone)
[OOSO] 15 g N-Methyl-N-pentylarninopropionic acid were kept for 23 hours at
100°C with 8.8 g phosphorous acidand 18.7 ml phosphorous trichloride in 75 ml
chlorobenzene. The solvent was then decanted off and the residue was stirred under reflux
with 222ml6N HCl for 12.5 hours. Insoluble material was filtered off and the filtrate was
concentrated and applied to column of Amberlite TR 120 (H+). The elution with water
was monitored by HPLC, using the HPLC method described above. The desired fractions
were combined, evaporated and stirred up with acetonitrile to obtain a sticky oily
precipitate as a crude product.

We claim:
1. A crystalline form of ibandronic acid characterized by a powder x-ray
diBaction pattern having peaks at about 8.2, 11.4, 1 1.8,22.0 &d 24.5 0.2 degrees twotheta.
2. The crystalline form of ibandronic acid of claim 1, further characterized by
a powder x-ray diffraction pattern having peaks at about 13.8, 18.4, 18.7 and 21.5 rt 0-2
degrees two-theta.
3. The crystalline form of ibandronic acid of claim 1 or 2, fhther
characterized by a powder x-ray diffraction pattern substantially as depicted in Figure 1
or Figure 2.
4. A method for preparing the crystalline form of ibandronic acid of any one
of claims 1 to 3 comprising:
a) combining a halo-phosphorous compound and phosphorous acid with 3-Nmethyl-
N-pentylarnino propionic acid or salt thereof in a silicon oil to obtain a reaction
mixture;
b) heating the reaction mixture for about 3 hours to about 11 hours;
c) combining the reaction mixture with water to obtain a biphasic mixture
having an aqueous and a non-aqueous phase;
d) separating the aqueous and non-aqueous phases;
e) heating the aqueous phase;
f) concentrating the aqueous phase to obtain a residue;
g) adding about 40 to about 60 milliliters of ethanol per gram of the Nmethyl-
N-pentyl propionic acid or salt thereof to the residue to obtain a precipitate; and
h) recovering the crystalline form of ibandronic acid of claim Z &om the
precipitate.
5. The method of claim 4, wherein the salt of 3-N-methyl-N-pentylamino
propionic acid is the hydrochloride salt or the hydrobromide salt.
6. The method oT clam 4 or 5, wherein the halo-~hosphorousc ompound is
selected from the group consisting of POC13, PBr3, POBr3, PC15, or PBrs.
7. The method of any one of claims 4 to 6, wherein the halo-phosphorous
compound is PC13.
8. The method of Any one of claims 4 to 7, wherein the halo-phosphorous
compound is added dropwise to the phosphorous acid and 3-N-methyl-N-pentylamino
propionic acid or salt thereof.
9. The method of any one of claims 4 to 8, wherein the components of step a)
are combined at a temperature of about room temperature to about 78°C.
10. The method of any one of claims 4 to 9, wherein the reaction mixture in
step b) is heated while stirring.
11. The method of any one of claims 4 to 10, wherein the reaction mixture in
step b) is heated for about 3 hours to about 9.5 hours.
12. The method of any one of claims 4 to 11, wherein the reaction mixture in
step b) is heated for about 4 hours to about 8 hours.
13. The method of any one of claims 4 to 12, wherein the reaction mixture in
step b) is heated at a temperature of about 60°C to about 100°C.
14. The method of any one of claims 4 to 13, wherein the reaction mixture in
step b) is heated at a temperature of about 80°C to about 90°C.
15. The method of any one of claims 4 to 14, wherein the reaction mixture is
step b) is heated at a temperature of about 80°C.
16. The method of any one of claims 4 to 15, wherein the aqueous phase is
heated at reflux temperature.
17. The method of any one of claims 4 to 16, wherein the residue of step f) is
dissolved in water prior to the addition of ethanol.
18. A method for preparing a pharmaceutically acceptable salt of ibandronic
acid comprising:
a) preparing a crystalline form of ibandronic acid by the method of any one
of claims 4 to 17; and
b) converting the crystalline form of ibandronic acid into a pharmaceutically
acceptable salt of ibandronic acid.
19. The method of claim 18, wherein the pharmaceutically acceptable salt is a
sodium salt.
20- A crystalline form of ibandronic acid characterized by a powder x-ray
difiaction pattern having peaks at about 4.7,12.4, 16.4,20.8 and 22.7 f 0.2 degrees twotheta.
2 1. The crystalline form of ibandronic acid of claim 20, fitrther characterized
by a powder x-ray diffraction pattern having peaks at about 9.1, 10.6,18.3, 19-6 and 21 -6
st 0.2 degrees two-theta.
22. The crystalline form of ibandronic acid of claim 20 or 2 1, fkther
characterized by a powder x-ray difiaction pattern substantially as depicted in Figure 3
or Figure 4.
23. A method for preparing the crystalline form of ibandronic acid of any one
of claims 20 to 22 comprising:
a) combining a halo-phosphorous compound and phosphorous acid with 3-
N-methyl-N-pentylamino propionic acid or a salt thereof in a silicon oil to obtain a
reaction mixture;
b) heating the reaction mixture for about 3 to about 11 hours;
c) combining the reaction mixture with water to form a biphasic mixture
having an aqueous and a non-aqueous phase;
d) separating the aqueous and non-aqueous phases;
e) heating the aqueous phase;
f) concentrating the aqueous phase to o.b ta- in a residue;
g) adding about 85 to about 100 milliliters of a C2-4 alcohol per gram of the
N-methyl-N-pentyl propionic acid or salt thereof to the residue to obtain a precipitate; and
h) recovering the crystalline form of ibandronic acid of claim 21 fiom the
precipitate.
24. The method of claim.23, wherein the salt of 3-N-methyl-N-pentylamino
propionic acid is the hydrochloride salt or the hydrobromide salt.
25. The method of claim 23 or 24, wherein the halo-phosphorous compound is
selected fiom the group consisting of PC13, POC13, PBr3, POBr3, PCI5, or PBr5.
26. The method of any one of claims 23 to 25, wherein the halo-phosphorous
compound is PC13.
27. The method of any one of clairns 23 to 26, wherein the halo-phosphorous
compound is added dropwise to the phosphorous acid and 3-N-methyl-N-pentylamino
propionic acid hydrochloride.
28. The method of any one of claims 23 to 27, wherein the components of step
a) are combined at a temperature of about room temperature.
29. The method of any one of claims 23 to 28, wherein the reaction mixture in
step b) is heated while stimng.
30. The method of any one of claims 23 to 29, wherein the reaction mixture in
step b) is heated for about 3 hours to about 9.5 hours.
31. The method of any one of claims 23 to 30, wherein the reaction mixture in
step b) is heated for about 4 hours to about 8 hours.
32. The method of any one of claims 23 to 3 1, wherein the reaction mixture in
step b) is heated at a temperature of about 60°C to about 1OVC.
33. The method of any one of claims 23 to 32, wherein the reaction mixture in
step b) is heated at a temperature of about 80°C to about 90°C.
34. The method of any one of claims 23 to 33, wherein the reaction mixture of
step b) is heated at a temperature of about 80°C.
35. The method of any one of claims 23 to 34, wherein the aqueous phase is
heated at refluc temperature.
36. The method of any one of claims 23 to 35, wherein the C24 alcohol is
selected fkom the group consisting of ethanol, 1-propanol, and 2-propanol.
37. The method of any one of claims 23 to 36, wherein the C24 alcohol is
ethanol.
38. The method of any one of claims 23 to 37, M e r comprising adding 30%
Hz02to the two phases prior to the separation of step d).
39. The method of any one of claims 23 to 38, wherein the residue of step f) is
dissolved in water prior to the addition of the C2-4al cohol.
40. A method for preparing a pharmaceutically acceptable salt of ibandronic
acid comprising:
a) preparing a crystalline form of ibandronic acid by the method of any one
of claims 23 to 39; and
b) converting the crystalline form of ibandronic acid into a pharmaceutically
acceptable salt of ibandronic acid.
41. The method of claim 40, wherein the pharmaceutically acceptable saIt is a
sodium salt.
42. The crystalline form of ibandronic acid of any one of claims 1 to 3 or 20 to
22, having a maximum particle size of about 500 pm.
43. The crystalline form of ibandronic acid of claim 42, having a particle size
of less than about 300 pm-
44. The crystalline form of ibandronic acid of claim 42 or 43, having a particle
size of less than about 200 pm.
45. The crystalline form of ibandronic acid of any one of claims 42 to 44,
having a particle size of less than about 100 pm.
46- The crystalline form of ibandronic acid of any one of claims 42 to 45,
having a particle size of Iess than about 50 pm.