Hydrate forms of alendronate sodium, processes for...

Details Hydrate forms of alendronate sodium, processes for... Hydrate forms of alendronate sodium, processes for...

2001-07-03

2004-02-24

Vollano, Jean F. (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Phosphorus acids or salts thereof

Reexamination Certificate

active

06696601

ABSTRACT:

FIELD OF THE INVENTION
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-1-hydroxybutylidene-1,1-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 &agr;-Hydroxyalkylidene-diphosphonic Acids, Izv. Akad. Nauk USSR, Ser. Khim, 2,433 (1978) and in U.S. Pat. Nos. 4,407,761, 4,621,077, 4,705,651, 5,039,819 and 5,159,108.
U.S. Pat. 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 forms of alendronate sodium, having water content of 1.3 to 11.7 percent, and processes for their manufacture. Moreover, the present invention provides new crystalline forms of alendronate sodium, 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 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.
The present invention provides a new crystalline Form B of alendronate sodium, having a powder X-ray diffractogram substantially as depicted in
FIG. 1
a
, 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 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
−1
, 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%).
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. 4
a,
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.
4
c
has significant IR bands at 662 cm
−1
, 919 cm
−1
, 934 cm
−1
, 954 cm
−1
, 1054 cm
−1
, 1072 cm
−1
1297 cm
−1
and 1318 cm
−1
. The TGA curve, as depicted in
FIG. 4
b,
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. 5
a,
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±0.2, 19.4±0.2 degrees 2 theta. Form E has significant IR bands as depicted in
FIG. 5
c
at 660 cm
−1
, 897 cm
−1
, 924 cm
−1
, 953 cm
−1
, 970 cm
−1
, 1017 cm
−1
, 1040 cm
−1
, 1093 cm
−1
1149 cm
−1
, 1177 cm
−1
, 1252 cm
−1
1293 cm
−1
1337 cm
−1
, 1535 cm
−1
, 1606 cm
−1
, and 1639 cm
−1
. The TGA curve, as depicted in
FIG. 5
b,
shows a gradual loss on drying of 3.7% up to 150° C.
A still further embodiment of the invention is a new crystalline Form F of alendronate sodium, having a powder X-ray diffractograrn substantially as depicted in
FIG. 6
a
, 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
c
at 660 cm
−1
, 893 cm
−1
, 930 cm
−1
, 953 cm
−1
, 970 cm
−1
, 982 cm
−1
, 1010 cm
−1
, 1033 cm
−1
1052 cm
−1
, 1060 cm
−1
, 1069 cm
−1
, 1109 cm
−1
and 1169 cm
−1
, 1251 cm
−1
, 1338 cm
−1
, 1498 cm
−1
, 1544 cm
−1
, 1603 cm
−1
, 1637 cm
−1
, 1664 cm
−1
. The TGA
FIG. 6
b
curve shows a gradual loss on drying of 1.3% 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. 7
a,
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±0.2, 20.4±0.2, 20.9±0.2, 22.1±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. 7
c
at 665 cm
−1
, 751 cm
−1
, 856 cm
−1
, 895 cm
−1
, 913 cm
−1
, 939 cm
−1
, 1011 cm
−1
, 1021 cm
−1
, 1050 cm
−1
, 1091 cm
−1
, 1155 cm
−1
, 1273 cm
−1
, 1305 cm
−1
, 1337 cm
−1
, 1510 cm
−1
, and 1639 cm
−1
. The TGA curve,
FIG. 7
b,
shows a loss on drying of 6.5% which indicates 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 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. 8
a,
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±0.2, 22.4±0.2, degrees two theta. Form H has significant IR bands, as depicted in
FIG. 8
c,
of 664 cm
−1
, 688 cm
−1
, 722 cm
−1
, 751 cm
−1
, 863 cm
−1
, 893 cm
−1
, 918 cm
−1
, 936 cm
−1
, 984 cm
−1
, 1010 cm
−1
, 1036 cm
−1
, 1052 cm
−1
, 1092 cm
−1
, 1157 cm
−1
, 1273 cm
−1
, 1303 cm
−1
and 1338 cm
−1
, 1499 cm
−1
, 1598 cm
−1
, 1636 cm
−1
, and 1664 cm
−1
. The TGA curve
FIG. 8
b
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%.
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%.
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