INTRODUCTION:
Present invention relates to novel polymorphic forms of ibandronate, particularly ibandronate monosodium monohydrate, process for their preparation and pharmaceutical compositions containing them.
Patent DE3623397 (corresponding US Pat 4,927,814) describes preparation of diphosphonate derivatives, pharmaceutical compositions and methods of use. Notable among them is [ 1 -Hydroxy-3 -(methylpentylamino)propylidene]bisphosphonic acid monosodium monohydrate of formula-I,

Monosodium monohydrate salt of ibandronic acid known as boniva is available in the market as bone resorption inhibitor.
The aforesaid US patent describes the preparation of ibandronic acid from the corresponding p-aminopropionic acid by reductive bisphosphonylation. However, no process for the preparation of pharmaceutically acceptable monosodium monohydrate salt of ibandronic acid is disclosed. There is a need to produce ibandronate monosodium monohydrate in a reproducible, pure and crystalline form to enable formulations to meet exact pharmaceutical requirements and specifications. It is known that pharmaceutical substances can exhibit polymorphism. Polymorphism is commonly defined as the ability of any substance to have two or more different crystal structures. Pharmaceutical substances may also encapsulate water or solvent molecules when crystallized. These solvates or hydrates are referred to as pseudo polymorphs. It is also possible that the drug substance can exist in amorphous form. Different polymorphs, pseudo polymorphs, or the amorphous form differ in their physical properties such as melting point, solubility, etc. These physical properties can appreciably influence the pharmaceutical properties such as

dissolution rate and bioavailability. It is desirable that the drug substance is stable for extended periods of time without any need for specialized storage conditions. It is therefore important to evaluate a polymorphism of drug substance. Also, the identification of polymorphic form of a drug substance enlarges the repertoire of materials that a formulation scientist has with which to design a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristics.
We have found that ibandronate monosodium in its hydrate form exhibits polymorphism and two novel crystalline forms and one amorphous form of ibandronate monosodium can be synthesized by changing the crystallization conditions such as solvent, temperature, etc. These novel forms are found to be stable, reproducible, and suitable for pharmaceutical preparations. Water content in these forms is 4-6% w/w, preferably close to 5.0% w/w indicating for monohydrate form.
Accordingly the main objective of the present invention is to provide stable, novel crystalline forms of ibandronate monosodium designated as Form I and Form II, process for preparation of the said novel crystalline forms and pharmaceutical compositions containing these novel crystalline forms. Water content in these forms is 4-6% w/w, preferably 4.8-5.2% w/w indicating for monohydrate form.
Another objective of the present invention is to provide stable, novel amorphous ibandronate monosodium designated as Form III, process for the said amorphous form and pharmaceutical compositions containing the said form. Water content in this form is 4.8-5.2% as monohydrate.
DESCRIPTION OF THE INVENTION:
According to one aspect of the present invention there is provided a novel crystalline form of ibandronate monosodium monohydrate, designated as Form I, characterized by an X-ray powder diffraction pattern having peaks expressed as 20 (intensity in %) 2.99 (1.2), 6.02 (100), 9.79 (1.6), 12.29 (2.2), 14.28 (1.4), 14.99 (1.1), 16.78 (2.7), 17.17 (4.9), 18.03 (1.9), 18.42 (1.4), 19.59 (3.3), 20.12 (2.9), 20.54 (2.0), 21.42 (3.7), 23.67 (1.1),

24.21 (1.3), 24.73 (2.5), 25.18 (3.5), 25.96 (1.0), 26.73 (1.9), 28.58 (2.0), 28.95 (1.9), 30.49 (3.1), 31.12 (1.0), 34.26 (1.3), 35.72 (1.6), 36.49 (1. 9), and 43.81 (1.1) degrees.
According to another aspect of the present invention there is provided a process for preparation of Form I of ibandronate monosodium monohydrate. Thus, ibandronate monosodium monohydrate prepared according to the process disclosed in our pending Indian patent application 996/CHE/05 is dissolved in a suitable aqueous solvent at elevated temperature. The resultant solution is cooled to ambient temperature and filtered to get Form I crystals of ibandronate monosodium monohydrate. The suitable solvent is selected from a group consisting of water miscible solvents such as acetone, methanol, acetonitrile, and tetrahydrofuran.
According to one aspect of the present invention there is provided a novel crystalline form of ibandronate monosodium monohydrate, designated as Form II, characterized by an X-ray powder diffraction pattern having peaks expressed as 20 (intensity in %) at about 4.94 (100.0), 11.05 (0.7), 14.11 (0.9), 17.17 (1.8), 18.60 (1.4), 19.95 (1.7), 25.90 (1.3), and 36.39 (0.9) degrees.
According to another aspect of the present invention there is provided a process for the preparation of Form II of ibandronate monosodium monohydrate. Thus, ibandronate monosodium monohydrate prepared according to the process disclosed in our pending Indian patent application 996/CHE/05 is dissolved in aqueous isopropanol at elevated temperature. The resultant solution is cooled to ambient temperature and the crystals of Form II ibandronate monosodium monohydrate are isolated by filtration.
According to one aspect there is provided a novel amorphous form designated as Form III of ibandronate monosodium monohydrate. The amorphous ibandronate monosodium monohydrate according to the present invention is characterized by powder X-ray diffraction and microscopic examination. The XRD diffractogram is characterized by the absence of well-defined peaks, which are an essential feature of a crystalline compound.

iT^uiumg IU miuuier aspeci 01 tne present invention there is provided a process for the preparation of ibandronate monosodium monohydrate. The amorphous form of ibandronate monosodium monohydrate can be made by conventional techniques such as lyophilisation or evaporation (under vacuum) of a solution, preferably aqueous solution. Preferred method for amorphous form is to use spray-drying technique. This is a well-known and very efficient process suitable for commercial scale operation.
The invention further includes pharmaceutical compositions comprising the polymorphic form of ibandronate monosodium monohydrate disclosed herein and a pharmaceutical^ acceptable carrier. These compositions may be in any suitable form such as tablets or capsules.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is an X-ray powder diffraction pattern of Form I crystals of ibandronate
monosodium monohydrate.
Figure 2 is an X-ray powder diffraction pattern of Form II crystals of ibandronate
monosodium monohydrate.
Figure 3 is an X-ray powder diffraction pattern of Form III amorphous ibandronate
monosodium monohydrate.
Figure 4 is an X-ray powder diffraction pattern of 150mg tablet prepared from Form I
crystals of ibandronate monosodium monohydrate.
X-ray powder diffraction spectrum was recorded on a Siemens D5000 X-ray powder diffractometer having a copper-Ka radiation.
The details of the process of the invention are provided in the Examples given below which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention.

Example 1
(i) Preparation of ibandronate
Into a 1L four-necked RB flask equipped with mechanical stirrer and reflux condenser was charged lOOg of 3-(N-Methyl-N-pentylamino)propionic acid hydrochloride and 49g of crystalline phosphorous acid. The reaction mass was heated to 75°C and started the addition of phosphorous trichloride slowly over a period of 2hr. Reaction mass was maintained at reflux for 4hr without stirring. Reaction mass was cooled to 30°C and added 80ml of water. Reaction mass was heated to reflux temperature and maintained at reflux for 7hr. Water (150ml was added to the reaction mass and adjusted the pH to 4.3-4.4 using aqueous sodium hydroxide. Reaction mass was diluted with 560ml of methanol and kept under stirring for 2hr. Crystallization of ibandronate began after 30min. Reaction mass was filtered and the wet cake washed with 50ml of 1:4 aqueous methanol. The wet solid was dried in the oven at 60°C to get 145g of ibandronate as white solid.
(ii) Preparation of Form I crystals of ibandronate monosodium monohydrate:
Above prepared ibandronate (25g) was taken into a 250ml three-necked RB flask and dissolved in 200ml of water. Water was distilled of from the reaction mass and added 100ml of fresh water. The reaction mass was treated with 2g of carbon and filtered. The filtrate was taken into a RB flask and added 200ml of acetone at 50-60°C. Crystallization of ibandronate began immediately. The reaction mass was cooled to 25 °C and maintained for lhr before filtration. The wet solid was washed with 50ml of acetone and dried at 60°C to get 20g of Form I crystals of ibandronate monosodium monohydrate.
Example 2
Preparation of Form I crystals of ibandronate monosodium monohydrate:
Ibandronate (5g) prepared as per the process described in step (i) of example 1 above was taken into a RB flask and dissolved in 40ml of water. Water was distilled of from the reaction mass and added 20ml of fresh water. The reaction mass was treated with O.lg of carbon and filtered. The filtrate was taken into a RB flask and added 5ml of ethanol at 70°C. The reaction mass was cooled to 25°C and filtered. The wet solid was washed with

5ml of aqueous ethanol (4:1) and dried at 60°C to get 4.1g of Form I crystals of ibandronate monosodium monohydrate.
Example 3
Preparation of Form I crystals of ibandronate monosodium monohydrate:
Ibandronate (5g) prepared as per the process described in step (i) of example 1 above was taken into a RB flask and dissolved in 40ml of water. Water was distilled of from the reaction mass and added 20ml of fresh water. The reaction mass was treated with O.lg of carbon and filtered. The filtrate was taken into a RB flask and added 10ml of THF at 60°C. The reaction mass was cooled to 25°C and filtered. The wet solid was washed with 50ml of aqueous THF (4:1) and dried at 60°C to get 4.0g of Form I crystals of ibandronate monosodium monohydrate.
Example 4
Preparation of Form I crystals of ibandronate monosodium monohydrate:
Ibandronate (5g) prepared as per the process described in step (i) of example 1 above was taken into a RB flask and dissolved in 40ml of water. Water was distilled of from the reaction mass and added 20ml of fresh water. The reaction mass was treated with O.lg of carbon and filtered. The filtrate was taken into a RB flask and added 10ml of acetonitrile at 50°C. The reaction mass was cooled to 25°C and filtered. The wet solid was washed with 50ml of aqueous THF (4:1) and dried at 60°C to get 3.8g of Form I crystals of ibandronate monosodium monohydrate.
Example 5
Preparation of Form II crystals of ibandronate monosodium monohydrate:
Ibandronate (5g) prepared as per the process described in step (i) of example 1 above was taken into a RB flask and dissolved in 40ml of water. Water was distilled of from the reaction mass and added 10ml of fresh water. The reaction mass was treated with O.lg of carbon and filtered. The filtrate was taken into a RB flask and added 10ml of acetonitrile at 60°C. The reaction mass was cooled to 25°C and filtered. The wet solid was washed

with 5ml of aqueous acetonitrile (1:1) and dried at 60°C to get 4.0g of Form II crystals of ibandronate monosodium monohydrate.
Example 6
Preparation of Amorphous Form III ibandronate monosodium monohydrate:
Ibandronate (5g) prepared as per the process described in step (i) of example 1 above was taken into a RB flask and dissolved in 40ml of water. Water was distilled of from the reaction mass and added 50ml of fresh water. The reaction mass was heated to 60°C and treated with lg of carbon. The reaction mass was filtered while hot. The filtrate was taken into a RB flask and freeze dried to get amorphous Form III ibandronate monosodium monohydrate.
Example 7
Form I crystals of ibandronate monosodium monohydrate prepared according to the process given in Example 1 is employed in an amount equivalent to 150mg of ibandronic acid per single dosage unit. Composition of one tablet is as given below.


Above prepared tablet was taken and powdered using a mortar and pestle. The resultant powder was subjected for powder XRD.
Advantages of Present Invention:
1. Present invention discloses novel polymorphic forms of ibandronate monosodium monohydrate designated as Form I, Form II, and Form III.
2. Present invention discloses a commercially viable process for the reparation of novel polymorphic forms of ibandronate monosodium monohydrate.
3. The novel polymorphic forms of ibandronate monosodium monohydrate are suitable for pharmaceutical formulations such as tablets or capsules.

We Claim:
1. Novel and stable crystalline Form I of ibandronate monosodium monohydrate of the
formula I,
characterized by an X-ray powder diffraction pattern having peaks expressed as 20 (intensity in %) 2.99 (1.2), 6.02 (100), 9.79 (1.6), 12.29 (2.2), 14.28 (1.4), 14.99 (1.1), 16.78 (2.7), 17.17 (4.9), 18.03 (1.9), 18.42 (1.4), 19.59 (3.3), 20.12 (2.9), 20.54 (2.0), 21.42 (3.7), 23.67 (1.1), 24.21 (1.3), 24.73 (2.5), 25.18 (3.5), 25.96 (1.0), 26.73 (1.9), 28.58 (2.0), 28.95 (1.9), 30.49 (3.1), 31.12 (1.0), 34.26 (1.3), 35.72 (1.6), 36.49 (1. 9), and 43.81 (1.1) degrees as shown in Fig 1 of the drawings accompanying this specification.
2. Novel and stable crystalline Form II of ibandronate monosodium monohydrate of the formula I given in claim 1 characterized by an X-ray powder diffraction pattern having peaks expressed as 29 (intensity in %) 4.94 (100.0), 11.05 (0.7), 14.11 (0.9), 17.17 (1.8), 18.60 (1.4), 19.95 (1,7), 25.90 (1.3), and 36.39 (0.9) degrees as shown in Figure 2 of the drawings accompanying this specification.
3. Novel and stable amorphous Form III ibandronate monosodium monohydrate of the formula I given in claim 1 characterized by an X-ray powder diffraction pattern as shown in figure 3 of drawings.
4. A process for preparation of novel, stable & crystalline Form I of ibandronate monosodium monohydrate having the formula I and characteristics given in Fig 1 which comprises dissolving ibandorate in water and diluting the mass with an organic solvent and filtering the resultant crystals to get the Form I ibandronate monosodium monohydrate.

5. A process as claimed in claim 4 wherein the organic solvent used is selected from
acetone, methanol, ethanol, acetonitrile and tetrahydrofixran.
6. A process according to claims 4 and 5 wherein the ratio between water and organic
solvent is 1:0.5 to 1:10, preferably 1: 2.
7. A process for the preparation of novel Form II of ibandronate monosodium
monohydrate of the formula I having the characteristics given above which comprises
crystallizing ibandronate from an aqueous isopropanol.
8. A process according to claim 7 wherein the ratio between water and isopropanol is
1:0.5 to 1:10, preferably 1:2.
9. A process for the preparation of novel amorphous Form III ibandronate monosodium
monohydrate of formula I having the characteristics as shown in figure 3 which
comprises dissolving ibandronate in water and freeze drying or spray drying to get
amorphous ibandronate monosodium monohydrate.
10. A pharmaceutical composition comprising the crystalline Form I of ibandronate
monohydrate as defined in claim 1 and a pharmaceutically acceptable carrier having
powder X-ray diffraction pattern as shown in figure 3.