FORM 2
THE PATENTS ACT 1970 [39 OF 1970]
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
[See Section 10; rule 13]
"THE COMPOUND 4-AMINO-L-HYDROXYBUTYLIDENE-l,l-BISPHOSPHONIC ACID MONOSODIUM SALT"
TEVA PHARMACEUTICAL INDUSTRIES, LTD., of 5 Basel Street, P.O. Box 3190, Petah Tiqva 49131, ISRAEL,
The following specification particularly describes the invention and the manner in which it is to be performed:

The present invention relates to the compound 4-amino-l-hydroxybutylidene-l,l-bisphosphonic acid monosodium salt.
This invention relates to new hydrate and crystalline forms of alendronate sodium, processes for the manufacture thereof, and pharmaceutical compositions thereof.
BACKGROUND OF THE INVENTION
Alendronate sodium, the sodium salt of alendronic acid, also known as 4-amino- I -hydroxybutylidene-1, l-bisphosphonic acid monosodium, has the formula I:

It is an agent for combating bone resorption in bone diseases including osteoporosis and Paget's disease.
Various methods for preparing alendronic acid are known in the art and have been disclosed in M.I. Kabachnik et al., Synthesis and Acid - Base and Complexing Properties of Amino-Substituted a-Hydroxyalkylidene-diphosphonic Acids, Izv. Akad. Nauk USSR, Ser. Khim, 2,433 (1978) and in U.S. Patent Nos. 4,407,761, 4,621,077, 4,705,65 I, 5,039,819 and 5,159,108.
U.S. Patent No. 4,922,007 describes the preparation of a trihydrate of alendronate sodium by reaction of 4-aminobutyric acid with phosphorous acid and phosphorous trichloride in the presence of methanesulfonic acid followed by the addition of sodium hydroxide.
The present invention provides new hydrate forms of alendronate sodium, having water content of 1.3 to II .7 percent, and processes for their manufacture. Moreover, the present invention provides new crystalline forms of alendronate sodium,

WO 00/12517 PCT/US99/19838
designated forms B, D, E, F, G and H, and processes for the manufacture thereof.
OBJECTS AND SUMMARY OF THE INVENTION
The present invention provides novel hydrate forms of alendronate sodium
5 having water content of between 1. 3 and 11.7 percent water. Typically, but without
limitation, the present invention relates to the following novel hydrate forms of/;.-,
alendronate monosodium: 1/4 hydrate, 1/3 hydrate, hemihydrate, 2/3 hydrate, 3/4 hydrate,
monohydrate, 5/4 hydrate. 4/3 hydrate, 3/2 hydrate, 5/3 hydrate, 7/4 hydrate and dihydrate.
10 The present invention provides a new crystalline Form B of alendronate
sodium, having a powder x-ray diffractogram substantially as depicted in Fig. la, with characteristic peaks at 12.2 ±0.2, 13.3 ±0.2, 14.8 ±0.2, 15,8 ±0.2, 16.3 ±0.2, 16.6 ±0.2, 17.2 ±0.2, 19.4 ±0.2,
21.3±0.2, 22.6 ±0.2, 23.2 ±0.2, 24.0 ±0.2, 25.2 ±0.2, 25.8 ±0.2, 27.4 ±0.2, 29.4 ±0.2, and
15 36.0±0.2 degrees 2 theta. Alendronate sodium Form B has significant IR bands as
depicted in Fig. 1'c at 654 cm"1, 955 cm"1, 1074 cm-1, 1261 cm"', 1309 cm"1, and 1614 cm"1.
The TGA curve, Fig. 1 b, shows a clear two-step loss on drying of 7.2%, which implies
that the crystal form B contains a stoichiometric quantity of water close to that of the
monohydrate (expected loss on drying value: 6.2%).
20 Another embodiment of the invention is a new crystalline Form D of
alendronate sodium, having a powder X-ray diffractogram substantially as depicted in Fig.
4a, with characteristic peaks at 13.1 ±0.2, 15.2 ±0.2, 16.3 ±0.2, 18.4 ±0.2, 20.8 ±0.2, 22.3
±0.2, 22.5 ±0.2, 23.4 ±0.2, 23.7 ±0.2, 31.4 ±0.2, and 35.7 ±0.2 degrees 2 theta. Form D as
depicted in Fig. 4b has significant IR bands at 662 cm"', 919 cm"', 934 cm"1, 954 cm"',
25 1054 cm"', 1072 cm"1 1297 cm"' and 1318 cm"1. The TGA curve, as depicted in Fig. 4b,
shows a gradual loss on drying of 4.1 % up to 180°C.
An additional embodiment is a new crystalline Form E of alendronate
sodium, having a powder X-ray diffractogram substantially as depicted in FIG. 5a, with
characteristic peaks at 7.0 ±0.2, 9.3 ±0.2, 11.8 ±0.2, 13.3 ±0.2, 14.0 ±0.2,15.3 ±0.2, 16.2
30 ±0.2, 17.4 ±0.2, and 19.4 ±0.2 degrees 2 theta. Form E has significant IR bands as
depicted in Fig. 5c-at 660 cm*1, 897 cm"1, 924 cm"', 953 cm-1 ,970 cm"1, 1017 cm"1, 1040

WO 00712517 PCT/US99/19838
cm"1, 1093 cm-1 149 cm-1, 1177 cm'1, 1252 cm"1 1293 cm"1 1337 cm"', 1535 cm"1, 1606 cm" ', and 1639 cm"1.' The TGA curve, as depicted in Fig.'5b, shows a gradual loss on drying of 4.1 %upto 150° C.
A still further embodiment of the invention is a new. crystalline Form F of
5 alendronate sodium, having a powder X-ray diffractograrm substantially as depicted in
FIG. 6a, with characteristic peaks at 9.3 ±0.2, 11.7 ±0.2, 13.0 ±0.2,13.4 ±0.2, 14.2 ±0.2,
15.3 ±0.2, 16.2 ±0.2, 17.4 ±0.2, 19.1 ±0.2, 19.4 ±0.2 and 25.5 ±0.2 degrees 2 theta. Form
F has significant IR bands as depicted in Fig. 6 at 660 cm"1, 893 cm"1, 930 cm"1, 9953 cm"
', 970 cm"', 982 cm"1, 1010 cm"', 1033 cm"' 1052 cm"1, 1060 cm"1, 1069 cm"', 1109 cm"1
10 and 1169 cm"', 1251 cm"', 1338 cm"', 1498 cm"1, 1544 cm"', 1603 cm"', 1637 cm"1, 1664
cm"'. The TGA Fig. 5b curve shows a gradual loss on drying of 4.1 % up to 150°C.
A further embodiment is a new crystalline Form G of alendronate sodium,
having a powder X-ray diffractogram substantially as depicted in FIG. 7a, with
characteristic peaks at 9.5 ±0.2; 10.1 ±0.2, 12.7 ±0.2, 16.2 ±0.2, 17.3 ±0.2, 17.6 ±0.2, 19.1
15 ±0.2, 20.4 ±0.2, 20.9 ±0.2, 22..I ±0.2, 24.8 ±0.2, 25.5 ±0.2, 28.0 ±0.2, 29.0 ±0.2, 29.6±0.2,
30.4 ±0.2, 32.4 ±0.2, and 32.8 ±0.2 degrees 2 theta. Form G has significant IR bands as
depicted in Fig. 7b at 665 """', 751 cm"', 856 cm"', 895 cm"', 913 cm"', 939 cm"', 1011 cm"',
1021 cm"', 1050 cm"', 1091 cm"', 1155.cm-1, 1273 cm"', 1305 cm"1, 1337 cm"', 1510 cm"',
and 1639 cm"' . The TGA curve, Fig. 7b, shows a Joss on drying of 6.5% which indicates
20 that the crystal form G contains a stoichiometric quantity of water corresponding to that of
the monohydrate (expected loss on drying value: 6.2%). This TGA step is sharp and
occurs at 195°C. The relatively high temperature of dehydration implies that the water is
bound tightly to the alendronate molecule. The dehydration step is immediately followed
by another step due to decomposition. Due to the decomposition process that occurs
25 adjacent to the dehydration, the conventional loss of drying method is not feasible, and for
loss on drying determination the TGA is used.
Yet another embodiment is a new crystalline Form H of alendronate
sodium, having a powder X-ray diffractogram substantially as depicted in FIG. 8a, with .
characteristic peaks at 9.2 ±0.2, 13.0 ±0.2, 14.2 ±0.2, 15.0 ±0.2, 17.1 ±0.2, 20.7 ±0.2, 22.0
30 ±0.2, 22.4 ±0.2, degrees two theta. Form H has significant IR bands, as depicted in Fig.
8b, of 664 cm"1, 688 cm"', 722 cm"', 751 cm"', 863 cm"1, 893 cm"', 918 cm"', 936 cm"',

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984 cm-', 1010 cm"', 1036 cm'1, 1052 cm'1, 1092 cm'', 1157 cm-', 1273 cm"', 1303 cm-', and 1338 cm"1, 1499 cm"', 1598 cm'1, 1636 cm"', and 1664 cm"'. The TGA curve Fig. 8b shows a-sharp loss on drying of 3.7% at 170°C.
All of sodium alendronate crystalline forms B, D, E, F, G and H contain water in the amount of 2.2 to 9.0% by weight. ■
The invention further provides a new hydrate form of alendronate sodium 'having a water content of 1.3 % to 3-. 1 %.
A further embodiment is a new hydrate form of alendronate sodium having
a water content of 2.5% to 3.5%.
10 A further embodiment is a new hydrate form of alendronate sodium having
a water content of 2.8% to 3.9%,
An additional embodiment is a new hydrate form of alendronate sodium having a water content of 3.2% to 5.8%.
Another embodiment is a new hydrate form of alendronate sodium having a
15 water content of 5.1 % to 7. 0%.
A still further embodiment is a new hydrate form of alendronate sodium having a water content of 6.4% to 9.0%. '
The invention also provides a new crystalline Form B of alendronate
sodium, having a water content of 6.4% to 9.0%o.
20 The invention further provides a new crystalline Form D of alendronate
sodium, having a water content of 3.2% to 5.8%.
The invention further provides a new crystalline Form F of alendronate sodium, having a water content of 1.3 % to 3.1 %.
The invention further provides a new crystalline Form G of alendronate
25 sodium having a water content of 5.1 % to 1.0%.
The invention further provides a new crystalline Form E of alendronate sodium, having a water content of 2.8%> to 3.9%.
The invention further provides a new crystalline Form H of alendronate
sodium, having a water content of 2.5% to 3.5%.
30 The invention provides a new monohydrate and anew df hydrate of
alendronate sodium, having an X-ray diffractogram substantially as depicted in FIG. 2a
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and 3a, accordingly, with characteristic peaks at 9.3 ±0.2, 12.4 ±0.2, 13.5 ±0.2,17.1 ±0.2,
18.5±0.2, 19.7 ±0.2, 20.3 ±0.2, 21.0 ±0.2, 21.8 ±0.2, 23.4 ±0.2, 24.3 ±0.2, 24.9. ±0.2,
•26.3±0.2, 30.0 ±0.2, and 34.4 ±0.2 degrees 2 theta. Form C as depicted in Figs. 2'c and 3b
has significant 1R bands at 660 cm"1, 745 cm"1, 865 cm-1, 913 cm-1 , 952 cm"', 966 cm"',
5 1017 cm'1, 1046 cm'1, 1128 cm"1, 1174 cm"1, 1235 cm"1, 1340 cm"1, 1402 cm'1, 1544 cm'1,
1606 cm"1, and 1644 cm"1. The TGA curve of the monohydrate Form C (Fig. 2b) shows a
loss on drying of 5.6% which implies that the crystal Form C contains a stoichiometric
quantity of water close to that of the monohydrate (expected loss on drying value: 6.2%).
The TGA curve of the dehydrate Form C (Fig. 3b) shows a sharp loss on drying of 12.0%
10 which implies that the crystal Form C contains a stoichiometric quantity of water
corresponding to dthydrate (expected loss on drying value: 11.7%).
The present invention also relates to the method of preparing the compound
4-amino-l-hydroxybutylidene-l, 1-bisphosphonic acid monosodium salt having water
content of 1.3% to 11.7% by reacting alendronic acid with one equivalent of sodium base
15 in an aqueous organic solvent selected from the group consisting of. acetone, DMSO,
DMF, acetonitrile, alcohols, polyalcohols and/or their ethers, pyridine, sulfolane, N-methyl pyrrolidinone and dioxane.
The invention further provides a method for making Form D of alendronate
sodium, comprising treating alendronic acid anhydrous in a lower alkanol with 1
20 equivalent of sodium base and 0 to 4 equivalents of water, followed by isolating the
crystalline alendronate sodium Form D.
The invention further provides a method for making Form E of alendronate
sodium, comprising treating alendronic acid, which is in anhydrous or monohydrate form,
in a lower alkanol with I equivalent of sodium base and 9 to 15 equivalents of water,
25 followed by isolating the crystalline alendronate sodium Form E.
The invention further provides a method for making Form F of alendronate
sodium, comprising treating alendronic acid, in a lower alkanol with 1 equivalent of
sodium base and 5 to 8 equivalents of water for anhydrous form and 3 to 20 equivalents of
water for monohydrate form, followed by isolating the crystalline alendronate sodium
30 Form F.
The invention further provides a method for making alendronate sodium

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WO 00/12517 PCT/US99/19838
monohydrate. comprising treating alendronic acid, in a lower alkanol with 1 equivalent of sodium base and water under the conditions described hereinafter, followed by isolating the alendronate sodium monohydrate
The invention further provides a method for making Form G of alendronate
5 sodium, comprising treating alendronic acid, in a lower alkanol with 1 equivalent of
sodium base and water under the conditions described hereinafter, followed by isolating the crystalline alendronate sodium Form G.
Typical but not limiting conditions for preparing alendronate sodium Form G are as described in the following table:
10 Starting Alendronic Solvent Preferred Range Range of
Acid Hydrate Form of Water Water
Equivalent Equivalent
Monohydrate Methanol 20-200 40-175
Monohydrate Ethanol 15-100 20-80
Monohydrate Isopropanol 5-40 10-20
15 Anhydrous Methanol 50-125 80-100
Anhydrous Ethanol 15-40 25-35
The invention further provides a method for making Form G of alendronate
20 sodium comprising treating any one or more of the crystal forms of alendronate sodium
selected from the group which consists of Form B, Form C, Form D, Form E, Form F and
Form H, in a lower alkanol, preferably ethanol, with 20-40 equivalents of water under the
conditions described hereinafter followed by isolating the crystalline alendronate sodium
Form G.
25 The invention further provides a method for making Form G of alendronate
sodium comprising treating alendronate monosodium trihydrate in a lower alkanol, preferably ethanol, with 25-35 equivalents of water under the condition described hereinafter, followed by isolating the crystalline alendronate sodium Form G.
The invention further provides a method for making Form G of alendronate
30 sodium comprising treating any one or more forms of alendronate sodium salts preferably
selected from the group consisting of monosodium, disodium, trisodium and tetrasodium
SUBSTITUTE SHEET (RULE 26)

WOOO/12517 PCT/US99/19838
salts, in a lower alkanol preferably ethanol with 20-40 equivalents of water under the
conditions described hereinafter, followed by isolating the crystalline alendronate sodium
Form G. In the event that the starting sodium salt is higher than monosodium (e.g.
disodium, trisodium or tetrasodium) it is necessary to add an acid, preferably alendronic
5 acid, in order to maintain the pH at about 4.4.
The invention further provides a method for making Form H of alendronate
sodium, comprising treating alendronic acid, which is the anhydrous or monohydrate
form, in a lower alkanol with one equivalent of sodium base and 25 to 35 equivalents of
water, under the conditions described hereinafter, followed by isolating the crystalline
10 alendronate sodium Form H.
The invention further provides a method for making Form B of alendronate
sodium, comprising treating alendronic acid monohydrate in a lower alkanol with one
equivalent of sodium base and 0 to 4 equivalents of water, followed by obtaining the
crystalline alendronate sodium Form B.
15 The invention further provides a method for making alendronate sodium
dehydrate comprising treating crystalline alendronate sodium trihydrate with an effective amount of drying agent followed by isolating the crystalline alendronate sodium dehydrate.
The invention further provides a method for making alendronate sodium
20 monohydrate comprising treating crystalline alendronate sodium trihydrate with a
sufficient amount of drying agent followed by isolating the crystalline alendronate sodium monohydrate.
The invention further provides a method for making alendronate sodium
monohydrate comprising treating crystalline alendronate sodium dthydrate with a
25 sufficient amount of drying agent followed by isolating the crystalline alendronate sodium
monohydrate.
The invention further relates to a pharmaceutical composition which
comprises alendronate sodium, having water content of 1.3 to 11.7 percent in a
therapeutically effective amount, and a pharmaceutically acceptable carrier.
30 The invention further relates to a pharmaceutical composition which
• comprises alendronate sodium in Form B, D, E, F, G and/or H in a therapeutically

SUBSTITUTE SHEET (RULE 26)
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PCT/US99/19838

effective amount, and a pharmaceutically acceptable carrier.
BRIEF DESCRIPTION OF THE DRAWINGS
FIGS. la, lb, and lc show, respectively, the powder X-ray diffraction
5 spectrum, the thermograviometric (TGA) curve and the infrared spectrum of alendronate
sodium Form B.
FIGS. 2a, 2b, and 2c show, respectively, the powder X-ray diffraction
spectrum, the thermograviometric (TGA). curve and the infrared spectrum of alendronate
sodium monohydrate Form C.
10 FIGS. 3a, 3b, and 3c show, respectively, the powder X-ray diffraction
spectrum, the thermograviometric (TGA) curve and the infrared spectrum of alendronate sodium dthydrate Form C.
FIGS. 4a, 4b, and 4c show, respectively, the powder X-ray diffraction
spectrum, the thermograviometric (TGA) curve and the infrared spectrum of alendronate
15 sodium Form D.
FIGS. 5a, 5b, and 5c show, respectively, the powder X-ray diffraction spectrum, the (thermograviometric (TGA) curve) and the infrared spectrum of alendronate sodium Form E.
FIGS. 6a, 6b, and 6c show, respectively, the powder X-ray diffraction
20 spectrum, the thermograviometric (TGA) curve and the infrared spectrum of alendronate
sodium Form F.
FIGS. 7a, 7b, and 7c show, respectively, the powder X-ray diffraction
spectrum, the then-nograviometric (TGA) curve and the infrared spectrum of alendronate
sodium Form G.
25 Figures 8a, 8b and 8c show respectively the powder X-ray diffraction
spectrum, the thermograviometric (TGA) curve and the infrared spectrum of alendronate sodium of Form H.
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WO 00/12517 PCT/US99/19838
DETAILED DESCRIPTION OF THE INVENTION
The invention discloses new hydrate forms of alendronate sodium having water contents of 1. 3 percent to 11.7 percent.
The present invention also discloses.new crystalline forms of alendronate
5 sodium which have been designated Forms B, D, E, F, G and H.
The term "water content" refers to the content of water based upon the Loss
on Drying method as described in Pharmacopeial Forum, Vol. 24, No. 1, page 5438 (Jan -
Feb 1998). The calculation of water content is based upon the percent of weight that is
lost by drying. For Forms G and H the term "water content" refers to the content of water
10 based upon a TGA measurement and a step analysis in the temperature range of about
25°C - 215°C for Form G, and 25°C - 200°C for Form H.
The term "lower alkanol" refers to alkanols having 1 to 4 carbon atoms. Preferred lower alkanols include ethanol, methanol and isopropanol.
The term "equivalents of water" means molar equivalents of water.
15 The term "equivalents of sodium base" means molar equivalents of sodium
base.,
Those skilled in the art will appreciate that the term monohydrate" when
used in reference to alendronic acid describes a crystalline material having a water content
of 6.7%. Those skilled in the art will also understand that the term "anhydrous" when used
20 in reference to alendronic acid describes alendronic acid that is substantially free of water.
One of skill in the art will appreciate that the term "monohydrate" when used in reference to the monosodium salt of alendronic acid describes a crystalline material having a water content of approximately 6.2%.
One skilled in the art will also appreciate that the term "dthydrate" when
25 used in reference to the monosodium salt of alendronic acid describes a crystalline
material having a water content of approximately 11.7%.
One skilled in the art will also appreciate that the term "1/4 hydrate" when
used in reference to the monosodium salt of alendronic acid describes a crystalline
material having a water content of approximately 1.6%.
30 ' One skilled in the art will also appreciate that the term "1/3 hydrate" when
used in reference to the monosodium salt of alendronic acid describes a crystalline

SUBSTITUTE SHEET (RULE 26)
WO 00/12517 PCT/US99/19838
material having a water content of approximately 2.1 %.
One skilled in the art will also appreciate that the term "hemihydrate" when
used in reference to the monosodium salt of alendronic acid describes a crystalline
materia] having a water content of approximately 3.2%.
5 One skilled in the art will also appreciate that the term "2/3 hydrate" when
used in reference to the monosodium salt of alendronic acid describes a crystalline material having a water content of approximately 4.2%.
One skilled in the art will also appreciate that the term "3/4 hydrate" when
used in reference to the monosodium salt of alendronic acid describes a crystalline
10 material having a water content of approximately 4.7%.
One skilled in the art will also appreciate that the term "5/4 hydrate" when used in reference to the monosodium salt of alendronic acid describes a crystalline material having a water content of approximately 7.6%.
One skilled in the art will also appreciate that the term "4/3 hydrate" when
15 used in reference to the monosodium salt of alendronic acid describes a crystalline
material having a water content of approximately 8.1 %.
One skilled in the art will also appreciate that the term "3/2 hydrate" when
used in reference to the monosodium salt of alendronic acid describes a crystalline
material having a water content of approximately 9.1 %.
20 Finally, those skilled in the art will appreciate that the term "trihydrate"
when used in reference to the monosodium salt of alendronic acid refers to a crystalline material having a water content of approximately 16.6%.
The term "sodium base" refers to sodium hydroxide and the sodium
alkoxide of a lower alkanol. .
25 Alendronic acid can be prepared by methods that are well known in the art.
MI Kabachnik et al., Izv. Akad. Nauk USSR, Ser. Khim, 2, 433 (1978) discloses a reaction for making alendronic acid;
Alendronic acid can also be prepared by the process disclosed in U.S.
Patent No. 4,621,077. It will be appreciated that when alendronic acid is recrystallized
30 from water, as in the above process, the monohydrate is formed.
Alendronate sodium trihydrate can be prepared by the process disclosed in
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WO 00/12517 PCT/US99/19838
U.S. Patent No. 4,922,007.
The contents of all references cited are incorporated by reference.
Alendronic acid mono-hydrate can be converted to alendronic acid
anhydrous by heating in a vacuum oven at 110-220°C at a vacuum of less than 5 mm Hg
5 for 24 hours.
In accordance with the process aspect of the present invention, alendronic
acid anhydrous as prepared by any of the known methods is added to a lower alkanol,
preferably ethanol, together with a sodium base, preferably sodium hydroxide, and an
amount of water that depends upon the desired crystal form of alendronate sodium. The
10 molar ratio of sodium base to alendronic acid is 1:1. Those skilled in the art will
appreciate that a higher ratio of NaOH would yield the undesirable disodium and
trisodium salts. The reaction mixture is boiled under reflux while being stirred vigorously
for approximately 15 hours, until the pH of the liquid phase remains constant (approx. pH
7). Crystalline alendronate sodium is then isolated, preferably by filtration after cooling to
15 ambient temperature, washing with absolute ethanol, optionally washing with absolute
ethyl ether and drying overnight in a vacuum oven at ambient temperature and at a pressure of 10 mm to 15 mm of mercury. For the purposes of this specification, ambient temperature is from about 20°G to about 25°C.
In accordance with the aspects of this invention wherein alendronic acid
20 . . monohydrate is converted to alendronate sodium, alendronic acid monohydrate as
prepared by any of the known methods is added to an alkanol, preferably ethanol, together
with a sodium base, preferably sodium hydroxide, and a desired amount of water. The
amount of water depends upon the crystal form that is desired. The molar ratio of sodium
base to alendronic acid is 1:1. The reaction mixture is boiled under reflux while stirring •
25 vigorously for approximately 15 hours, until the pH of the liquid phase remains constant
' (approx. pH 7). Crystalline alendronate sodium is then isolated, preferably by filtration
after cooling to ambient temperature followed by washing with absolute ethanol, washing
with absolute ether and drying overnight in a vacuum oven at ambient temperature and at
a pressure of 10 mm to 15 mm of mercury.
30 . In accordance with the aspects of this invention wherein alendronate
sodium trihydrate (Form C) is converted to alendronate sodium dehydrate (Form C),
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WO 00/12517 PCT/US99/19838
alendronate sodium trihydrate as prepared by methods known in the art is added to an
alkanol which is substantially free of water, preferably absolute ethanol. This mixture is
treated with a drying agent, preferably by refluxing the mixture in a reflux condenser
■ wherein the condensate formed passes through 3A molecular sieves. The weight weight
5 ratio of molecular sieves to alendronate sodium trihydrate is preferably about 2:1 and most
preferably 12:5. Refluxing of the mixture is preferably done for 24 hours with stirring.
Alendronate sodium dehydrate is then isolated, preferably by filtration after cooling to
ambient temperature, washing with absolute ether and drying overnight in a vacuum oven
at ambient temperature and at a pressure of 10 mm to 15 mm of mercury.
10 In accordance with the aspects of this invention wherein alendronate
sodium trihydrate (Form C) is converted to alendronate sodium monohydrate (Form C),
alendronate sodium trihydrate as prepared by any of the methods known in the art is added
to an alkanol which is substantially free of water, preferably absolute ethanol. This
mixture is treated with a drying agent, preferably by refluxing the mixture in a reflux
15 condenser wherein the condensate formed passed through 3 A molecular sieves. If and
when a first portion of molecular sieves is exhausted, a second portion of fresh molecular
sieves is used. The weight: weight ratio of molecular sieves to alendronate sodium
trihydrate is preferably about 2:1 and most preferably 12:5. Refluxing of the mixture is
preferably done for 24 hours with stirring. The mixture is allowed to cool to ambient
20 temperature before recharging with an equivalent amount of molecular sieves.
Alendronate sodium monohydrate is then isolated, preferably by cooling to ambient temperature, filtration, washing with absolute ether and drying overnight in a vacuum oven at ambient temperature and a pressure of 10 mm and 15 mm of mercury.
In accordance with the present invention, the new crystalline forms of
25 alendronate sodium and the new hydrate forms of alendronate sodium may be prepared as
pharmaceutical compositions which are particularly useful for the treatment of bone
resorption in bone diseases including osteoporosis and Paget's disease. Such compositions
may comprise one of the new crystalline and hydrate forms of alendronate sodium with
pharmaceutically acceptable carriers and/or excipients.
30 For example, these compositions may be prepared as medicaments to be
administered orally, parenterally, rectally, transdermally, bucally, or nasally. Suitable
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WO 00/12517 PCT/US99/19838
forms for oral administration include tablets, compressed or coated pills, dragees, sachets,
hard or gelatin capsules, sub-lingual tablets, syrups and suspensions; for parenteral
administration the invention provides ampoules or vials that include an aqueous or non-
• aqueous solution or emulsion; for rectal administration there are provided suppositories
5 with hydrophilic or hydrophobic vehicles; and for topical application as ointments or
aerosol formulations known in the art; transdermal delivery there are provided suitable delivery systems as known in the art; and for nasal delivery there are provided suitable aerosol delivery systems known in the art.
The powder X-ray diffraction patterns were obtained by methods known in
10 the art using a Philips X-Ray powder diffractorneter, Goniometer model 1050/70 at a
scanning speed of 2° per minute.
The thfermogravimetric curves were obtained by methods known in the art
using a Mettler TGA TG50. The weight of the samples was about 10 mg. The
temperature range was from 25 °C to at least 200 °C, at the rate of 10°C/min. Samples
15 were purged with rnitrogen gas at a flow rate of 40 ml/min. Standard 150 ml aluminum
crucibles were used.
The infrared spectra were obtained by methods known in the art using a
Perkin Elmer FT-IR Paragon 1000 spectrometer. Samples were analyzed in Nujol mulls.
Spectra were obtained at 4 cm'1 resolution and 16 scans each.
20 The atomic absorption analysis was obtained by methods known in the art
using a Perkin Elmer 5000 Flame Atomic Absorption instrument. Sodium content was determined against standard solutions obtained from Merck and Aldrich.
EXAMPLES
25 This invention will be better understood from the experimental details
which follow. However, one skilled in the art will readily appreciate that the specific methods and results discussed are merely illustrative of the invention as described more fully in the claims that follow thereafter.
Example 1
30 Preparation of Alendronic Acid Monohydrate
Alendronic acid was crystallized from-water to make alendronic acid
SUBSTITUTE SHEET (RULE 26)

WO 00/12517 PCT/US99/19838
monohydrate. The resulting alendronic acid monohydrate was dried at 50°C at 10 mm Hg pressure for 15 hours to give dry alendronic acid monohydrate containing 6.9% water.
Example 2
5 Preparation of Anhydrous Alendronic Acid
The alendronic acid monohydrate from Example 1 was further dried at 110-120°C in 1 mm Hg for 4 hours to give anhydrous alendronic acid. The water content was 0.3% by weight.
Example 3
10 Preparation of Alendronate Sodium from Anhydrous Alendronic Acid
A 250 ml flask was fitted with a mechanical stirrer, a thermometer, and a
reflux condenser. The flask was charged with 41.1 ml of a solution of sodium hydroxide
in ethanol (0.49N, 20.1 mmol), 8.9 ml of ethanol, water (0 to 40 mol. eq., according to the
crystal form desired), and 5g (20.1 mmol) of anhydrous alendronic acid. The reaction
15 mixture was boiled with vigorous stirring for about 15 hours until the of pH of the liquid
phase remained constant (approx. pH 7). After cooling of the reaction mixture to ambient
temperature, the solid material was filtered, washed with absolute ethanol, and dried
overnight in a vacuum oven (I0-15mmHg, ambient temperature) to give 96-99% sodium
alendronate having the following crystal forms: crystal Form D, when 0-4 (preferably 0-2)
20 mol. eq. water were used; crystal Form F, when 5-8 (preferably 6-7) mol. eq. water were
used; crystal Form E, when 9-15 (preferably 12) mol. eq. water were used; and crystal Form G, when 15-40 (preferably 25-35) mol. eq. water were used. The monosodium salt was confirmed by atomic absorption and by measuring the pH of a 0.5% aqueous solution of the salt (approx. pH 4.4). 25
Example 4
Preparation of Alendronate Sodium from Alendronic Acid Monohydrate
A 250 ml flask was fitted with a mechanical stirrer, a thermometer, and a
reflux condenser. The flask was charged with 38.2 ml of a solution of sodium hydroxide
30 in ethanol (0.49 N, 18.7 mmol), 4.8 ml of ethanol, water (0 to 100 mol. eq., according to
the crystal form desired), and 5 g (18.7 mmol) of alendronic acid monohydrate. The
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WO 00/12517 PCT/US99/19838
. reaction mixture was boiled with vigorous stirring for about 15 hours until stability of pH
of the liquid phase was reached (approx. pH 7). After cooling of the reaction mixture to
•ambient temperature the precipitate was filtered, washed with absolute ethanol, and dried
overnight in a vacuum oven (10-15mm Hg, ambient temperature) to give 96-99% sodium
5 alendronate having the following crystalline forms: crystalline Form B, when 0-4
(preferably 0-2) mol. eq. water were used; crystalline Form F> when 3-5 mol. eq. water were used; crystalline Form E, when 11-13 (preferably 12) mol. eq. water were used; and crystalline Form G, when 15-100 (preferably 20-80) mol. eq. water were used.
The monosodium salt was confirmed by atomic absorption and by
10 measuring the pH of a 0.5% aqueous solution of the salt (approx. pH 4.4).
The water content is determined using the TGA technique, heating the sample to 230°C and calculating the sharp LOD (loss on drying) step, which occurs above 150 °C.
15 Example 5
Preparation of Sodium Alendronate Dihydrate
A one liter flask Was fitted with a magnetic bar stirrer, Soxhlet extraction
funnel (operating volume 150 ml) charged with 3A molecular sieves (60 g), and reflux
condenser connected to a drying tube with 3A molecular sieves. The flask was charged
20 with sodium alendronate trihydrate (25 g) and absolute ethanol (450 ml, vol.% of water <
0.1%). The mixture was boiled with stirring for 24 hours. After cooling to ambient temperature the solid material was filtered, washed with absolute ethyl ether, and dried overnight in a vacuum oven (10-15 mm Hg, ambient temperature) to give sodium alendronate dihydrate.
25
Example 6
Preparation of Sodium Alendronate Monohydrate
A one liter flask was fitted with a magnetic bar stirrer, Soxhlet'extraction
■ funnel (operating volume 150 ml) charged with 3 A molecular sieves (60 g), and reflux
30 ■ condenser connected to a drying tube with 3 A molecular sieves. The flask was charged
with sodium alendronate trihydrate (25 g) and absolute ethanol (450 ml, vol.% of water <
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WO 00/12517 PCT/US99/19838
0.1%). The mixture was boiled with stirring for 24 hours. After cooling to ambient
temperature, the used molecular sieves were replaced by a new portion of 3A molecular
sieves (60 g) and the reflux was continued for additional 24 hours. After cooling to
ambient temperature the solid material was filtered, washed with absolute ethyl ether, and
5 dried overnight in a vacuum oven (10-15 mm Hg, ambient temperature) to give sodium
alendronate monohydrate.
Example 7
Preparation of Alendronate Sodium Form G from Alendronic Acid
10 Monohydrate
Preparation of aqueous ethanolic sodium hydroxide:
Absolute ethanol (250 ml) and water (59 ml, 35x0.094mol) were mixed.
Sodium hydroxide (3.8 g, assay 99%, 0.094 mol) was dissolved in 45 ml of this aqueous
ethanol. The remaining aqueous ethanol was used to prepare a suspension of alendronic
15 acid monohydrate.
A one liter flask was fitted with a mechanical stirrer, a thermometer, and a
reflux condenser. The flask was charged with alendronic acid monohydrate (25 g, 0.094
mol) and aqueous ethanol. The mixture was heated to boiling with stirring. The aqueous
ethanolic sodium hydroxide was added dropwise to the suspension of alendronic acid
20 monohydrate in aqueous ethanol for 3 hours at reflux with vigorously stirring. Then the
mixture was stirred at reflux for additional 15 hours. The mixture was cooled to room
temperature with stirring. The solid was filtered, washed with absolute ethanol, then with
absolute ethyl ether, and dried overnight in a vacuum oven (10-15 mm Hg, ambient
temperature) to give 26.2 g of alendronate sodium, having crystalline Form G.
25
Example 8
Preparation of Alendronate Sodium Form G from Alendronic Acid
Monohydrate
30 Preparation of aqueous ethanolic sodium hydroxide:
Absolute ethanol (250 ml) and water (59 ml, 35x0.094 mol) were mixed. Sodium hydroxide (3.8 g, assay 99%, 0.094 mol) was dissolved in 45 ml of this aqueous ethanol. The remaining aqueous ethanol was used to prepare a suspension of alendronic
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WO 00/12517 PCT/US99/19838
acid monohydrate.
A one liter flask was fitted with a mechanical stirrer, a thermometer, and a
reflux condenser. The flask was charged with alendronic acid monohydrate (25 g, 0.094
• mol) andaqueous-ethanol. The mixture was heated to boiling with stirring. The aqueous.
5 ethanblic sodium hydroxide was added dropwise to the suspension of alendronic acid
monohydrate in aqueous ethanol for 3 hours at reflux with vigorously stirring. Then the
mixture was stirred at reflux for additional 15 hours. The mixture was cooled to room
temperature with stirring. The solid was. filtered, washed with absolute ethanol, and dried
overnight in a vacuum oven (10-15 mm Hg, ambient temperature) to give 26.2 g of
10 alendronate sodium, having crystalline Form G.
Example 9
Preparation of Alendronate Sodium Form G from Alendronic Acid
15 Monohydrate
Preparation of aqueous ethanolic sodium hydroxide:
Absolute ethanol (250 ml) and water (59 ml, 35x0.094 mol) were mixed.
Sodium hydroxide (3.8 g, assay 99%, 0.094 mol) was dissolved in 45 ml of this aqueous
20 ethanol. The remaining aqueous ethanol was used to prepare a suspension of alendronic
acid monohydrate.
. A one liter flask was fitted with a mechanical stirrer, a thermometer, and a
reflux, condenser. The flask was charged with alendronic acid monohydrate (25 g, 0.094
mol) and aqueous ethanol. The mixture was heated to boiling with stirring. The aqueous
25 ethanolic sodium hydroxide was added dropwise to the suspension of alendronic acid
monohydrate in aqueous ethanol for 3 hours at reflux with vigorously stirring. Then the
mixture was stirred at reflux for additional 15 hours. The mixture was cooled to room
temperature with stirring. The solid was filtered, washed with absolute ethanol, and dried
; overnight in a vacuum oven (10-15 mm Hg, 40-50°C) to give 26.2g of alendronate
30 sodium, having crystalline Form G.

Example 10
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WO 00/12517 PCT/US99/19838
Preparation of Alendronate Sodium Form G from Alendronic Acid
Monohydrate
Preparation of aqueous ethanolic sodium hydroxide:
Absolute ethanol (250 ml) and water (59 ml, 35x0.094 mol) were mixed.
5 Sodium hydroxide (3.8 g, assay 99%, 0.094 mol) was dissolved in 45 ml of this aqueous
ethanol. The remaining aqueous ethanol was used to prepare a suspension of alendronic
acid monohydrate.
A one liter flask was fitted with a mechanical stirrer, a thermometer, and a
reflux condenser. The flask was charged with alendronic acid monohydrate (25 g, 0.094
10 mol) and aqueous ethanol. The mixture was heated to boiling with stirring. The aqueous
ethanolic sodium hydroxide was added dropwise to the suspension of alendronic acid
monohydrate in aqueous ethanol for 3 hours at reflux with vigorously stirring. Then the
mixture was stirred at reflux for additional 15 hours. The mixture was cooled to room
temperature with stirring. The solid was filtered, washed with absolute ethanol, then with
15 absolute ethyl ether, and dried overnight in a vacuum oven (10-15 mm Hg, 40-50°C) to
give 26.2g of alendronate sodium, having crystalline Form G.
Example 11
Preparation of alendronate sodium Form (G) from Alendronate Sodium Trihydrate
20 A suspension of alendronate sodium trihydrate l.0g (3.08 mmol) in
aqueous ethanol (10 ml of ethanol + 1.9 ml of water) was boiled at reflux with stirring for 15 hrs. After cooling to ambient temperature the solid was filtered, washed with absolute ethanol and ether, and dried overnight in a vacuum oven (10-15 mm Hg, ambient temperature) to give 0.9 g of alendronate sodium, containing crystal form G.
25
Example 12
Preparation of Alendronate Sodium Form H from Alendronic Acid Monohydrate Preparation of aqueous ethanolic sodium hydroxide:
Absolute ethanol (50 ml) and water (6.7 ml, 20x0.019 mol) were mixed.
30 Sodium hydroxide (0.76 g, assay 99%, 0.019 mol) was dissolved in 8.5 ml of this aqueous
ethanol. The remaining aqueous ethanol was used to prepare a suspension of alendronic acid monohydrate.
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WO 00/12517 PCT/US99/19838
A 250 ml flask was fitted with a mechanical stirrer, a thermometer, a
dropping funnel, and a reflux condenser. The flask was charged with alendronic acid
monohydrate (5 g, 0.019 mol) and aqueous ethanol. The aqueous ethanolic sodium
hydroxide was added dropwise to the suspension of alendronic acid monohydrate in
5 aqueous ethanol for 15 minutes at reflux with vigorously stirring. The mixture was then
refluxed for additional 15 hours. The mixture was then cooled to room temperature with stirring. The solid was filtered, washed with absolute ethanol, then with absolute ethyl ether, and dried overnight in a vacuum oven (10-15 mm Hg, ambient temperature) to give 5.2 g of alendronate sodium, having crystalline Form H.
10
Although certain presently preferred embodiments of the invention have
been described herein, it will be apparent to those skilled in the art to which the invention
pertains that variations and modifications of the described embodiments may be made
without departing from the spirit and scope of the invention. Accordingly, it is intended
15 that the invention be limited only to the extent required by the appended claims and the
applicable rules of law.
SUBSTITUTE SHEET (RULE 26)

WE CLAIM:
1. The compound 4-amino-l-hydroxybutylidene-l,l-bisphosphonic acid monosodium salt having water content of 1.3 % to 11.7% .
2. The compound as claimed in claim 1 wherein said compound is any of the hydrate forms selected from the group that consists of 1/4 hydrate, 1/3 hydrate, hemihydrate, 2/3 hydrate, 3/4 hydrate, monohydrate, 5/4 hydrate, 4/3 hydrate, 3/2 hydrate, and dihydrate.
3. The compound as claimed in claim 1 wherein said compound is a crystalline monosodium alendronate monohydrate.
4. The compound as claimed in claim 3 wherein said crystalline monosodium alendronate monohydrate having a water content of about 6.2% weight. "
5. The compound as claimed in claim 1 wherein said compound is crystalline monosodium alendronate monohydrate wherein said compound having its stability against dehydration at temperatures up to about 150°C.
6. The crystalline monosodium alendronate monohydrate as claimed in claim 5 wherein peaks in the powder xray diffraction pattern at values of two theta of 12.7 ±0.2, 16.2 ±0.2, 17.3 ±0.2, 17.6 ±0.2, 24.8 ±0.2, and 25.5 ±0.2.
7. A compound as claimed in claim 3, wherein said compound having peaks in the powder x-ray diffraction at values of two theta of 9.3 ±0.2, 12.4 ±0.2, 13.5 ±0.2, 26.3 ±0.2 and 30.0 ±0.2.

8. The compound as claimed in claim 1 wherein said compound is alendronate monosodium hemihydrate.
9. The compound as claimed in claim 1 wherein said compound is the compound 4-amino-l-hydroxybutylidene-I, 1-bisphosphonic acid monosodium salt having water content of 2.8% to 3.9%.
10. The compound as claimed in claim 9, wherein said compound having water content of about 3.2%.
11. The compound as claimed in claim 9, wherein said compound having peaks in the powder x-ray diffraction at values of two theta of 7.0 ±0.2, 9.3 +0.2, and 14.0 ±0.2.
12. The compound as claimed in claim 1 wherein said compound is the compound 4-amino-l-hydroxybutylidene- 1, 1 -bisphosphonic acid monosodium salt having water content of 2.5% to 3.5%.
13. The compound as claimed in claim 12, wherein said compound having peaks in the powder x-ray diffraction at values of two theta of 9.2 ±0.2, 14.2 ±0.2, 15.0 ±0.2, 17.1 ±0.2, 20.7 ±0.2, 22.0 ±0.2, 22.4 ±0.2.
14. The compound as claimed in claim 1 wherein said compound is the compound 4-amino-l -hydroxybutylidene- 1, 1 -bisphosphonic acid monosodium salt having water content of 6.4% to 9.0%.
15. The compound as claimed in claim 14, wherein said compound having peaks in the powder x-ray diffraction at values of two theta of 12.2 ±0.2, 13.3 ±0.2, 14.8 ±0.2, 15.8 ±0.2, 16.3 ±0.2. and 17.2 ±0.2.

16. The compound as claimed in claim 1 wherein said compound is the compound 4-amino-l-hydroxybutylidene-l, 1-bisphosphonic acid monosodium salt having water content of 3.2% to 5.8%.
17. The compound as claimed in claim 16, wherein said compound having peaks in the powder x-ray diffraction at values of two theta of 13.1 ±0.2. 15.2 ±0.2, 16.3 ±0.2, 22.3 ±0.2, 22.5 ±0.2, 23.4 ±0.2, and 23.7 ±0.2.
18. The compound as claimed in claim 1 wherein said compound is the compound 4-amino-l-hydroxybutylidene-l, 1-bisphosphonic acid monosodium salt having water content of 1 .3 % to 3.1 %.
19. The compound as claimed in claim 18, wherein said compound having peaks in the powder x-ray diffraction at values of two theta of 13.0 ±0.2, 13.4 ±0.2, 14.2 ±0.2, 19.1±0.2, and 19.4 ±0.2.
20. The compound as claimed in claim 1 wherein said compound is alendronate monosodium dihydrate.
21. The compound as claimed in claim 1 wherein said compound is the compound 4-amino-l -hydroxybutylidene- 1, 1 -bisphosphonic acid monosodium salt having water content of about 11.7%.
22. The compound as claimed in claim 1 wherein said compound is the compound 4-amino-l-hydroxybutylidene-l, 1-bisphosphonic acid monosodium salt having water content of 5.1% to 7.0%
23. The compound as claimed in claim 21, wherein said compound having peaks in the powder x-ray diffraction at values of two theta of 9.3 ±0.2, 12.4 ±0.2, 13.5 ±0.2. 26.3 ±0.2 and 30.0 ±0.2.

24. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound as claimed in any of claims 1, 3, 9, 12, 14, 16 and 18 and other pharmaceutically acceptable carriers.