FORM 2
THE PATENT ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
"AMORPHOUS HYDRATED FORM OF BENZOTHIOPHENE COMPOUND AND PROCESS FOR PREPARATION THEREOF"


2. APPLICANT
(a) NAME: AARTI DRUGS LIMITED
(b) NATIONALITY: Indian Company incorporated under the Indian Companies
ACT, 1956
(c) ADDRESS: Mahendra Industrial Estate, Ground Floor, Plot No. 109-D,
Road No. 29, Sion (East), Mumbai - 400 022, Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it has to be performed.


Technical field of Invention:
The present invention relates to a novel amorphous hydrated forms of raloxifene hydrochloride, chemically termed as [6-hydroxy-2-(4-hydroxyphenyl)-benzothiophene-3-yl]-[4-[2-(l-piperidyl)ethoxy]phenyl]-methanone hydrochloride and process for preparation thereof. Raloxifene hydrochloride is used in treatment for osteoporosis in postmenopausal women. Osteoporosis is a common and serious disease among postmenopausal women.
Background and Prior Art:
Raloxifene hydrochloride is a Selective Estrogen Receptor Modulator (SERM) that belongs to the benzothiophene class of compounds and it is useful for the prevention of osteoporosis in postmenopausal women. Raloxifene hydrochloride is represented by the following structure

Formula 1
Raloxifene base was disclosed in US 4133814. Other methods of preparing raloxifene base are disclosed in patents WO 9848792, US 4380635.
Raloxifene hydrochloride was first disclosed in US patent 4418068. This patent does not disclose any polymorphic or any amorphous hydrated form of raloxifene hydrochloride. Other methods of preparation of raloxifene hydrochloride are disclosed in
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WO2005003116, EP0875511, US5606076, US5606075, EP842930, WO9848793, WO9849156, EP0693488 and US5523416.
US4358593 discloses a process for the preparation of raloxifene and its salts.
WO9609045 discloses non- solvated, crystalline raloxifene hydrochloride characterized by XRD, DSC and IR.
W09735571 discloses raloxifene, salts and solvates thereof, characterized by XRD.
WO2004029046 discloses raloxifene L-lactate hemi hydrate, DL-lactate hemi hydrate and raloxifene sulphate 2-propanol solvate characterized by XRD and DSC. Process for their preparation is also disclosed.
US20020173645 discloses a series of crystalline polymorphic forms of raloxifene hydrochloride namely Form I ( a 1,2-dichloroethane solvate), Form II ( another 1,2-dichloroethane solvate), Form III ( a chlorobenzene solvate), Form IV ( a chloroform solvate) and a nonsolvated crystalline form, characterized by XRD and the process for preparation thereof.
The advancement of raloxifene, in particular, has been somewhat hampered by its physical characteristics, both as to bioavailability and manufacturing. For example, raloxifene is generally insoluble, which may affect bioavailability. Clearly, any improvement in the physical characteristics of raloxifene and in closely related compounds would potentially offer a more beneficial therapy and enhanced manufacturing capabilities.
WO9808513 discloses a process for preparation of an amorphous form of raloxifene hydrochloride, which comprises preparing a solution of crystalline form of raloxifene hydrochloride in a suitable solvent, and then spray drying the solution to recover an amorphous form.
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EP 826 682 discloses raloxifene in an amorphous form having enhanced solubility.
At present, most commercial available pharmaceutical compositions comprising raloxifene as active ingredient comprises raloxifene hydrochloride, because raloxifene hydrochloride is fairly soluble in aqueous solvents whereas raloxifene as free base is only sparingly soluble in aqueous solvents.
Despite the extensive experimentation of increasing the bioavailability of raloxifene there is still a need for providing the active compound in a form having increased availability of the active compound in order to provide pharmaceutical preparations for oral administration, which composition have a high availability of the active compound Raloxifene from the upper gastrointestinal tract.
Aqueous solubility of raloxifene hydrochloride, however, is far below what would be expected for an organic hydrochloride salt containing two phenolic hydroxy] groups. This poor solubility has somewhat limited the bioavailability of this preferred salt form. Another significant barrier to optimum and consistent absorption of raloxifene hydrochloride is its hydrophobicity.
Further, there is ample literature available on improved delivery of hydrophobic drugs such as raloxifene hydrochloride in pharmaceutical compositions using solid carriers/surfactants as described in US6569463 and US 5811120 respectively.
Thus, it would be a significant contribution to the art to provide amorphous forms of raloxifene in hydrated forms which have increased solubility, and to provide methods of preparation.
Summary of the Invention:
Therefore, to overcome the limited bioavailability of raloxifene hydrochloride, the present invention provides novel amorphous raloxifene hydrochloride in hydrated forms which has the following formula
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conditions specified whereby an amorphous raloxifene hydrochloride dihydrate is obtained.
Thus according to the another aspects of the present invention, amorphous hydrated material is prepared by dissolving a crystalline form of a compound of formula I in a suitable solvent or a solvent mixture for example, methanol and water, followed by recovery of the material by any suitable means. Techniques which may be employed to recover amorphous hydrated compounds of formula II from the solution include those wherein the solvent is removed from the solution, preferably rapidly, and the product deposited, and those wherein the product is precipitated from a solution. Methods involving the use of these procedures which have been found to be satisfactory include spray drying, roller drying, solvent precipitation, rotary evaporation and freeze drying.
Detailed description of the invention:
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.
The term "amorphous dihydrate" as mentioned herein includes a physical state which may be verified by X-Ray Diffraction; Karl Fisher method; TGA and other means including but not limited to observation with a polarized light microscope and differential scanning calorimetry.
In accordance with the above, the present invention provides amorphous raloxifene hydrochloride dihydrate of compound of formula II as shown below.
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wherein n is an integer of 0.5 to 3.0. Preferably, n is 2 i.e. amorphous raloxifene hydrochloride dihydrate.
In a preferred embodiment, the invention provides amorphous raloxifene hydrochloride dihydrate, which is characterized by XRD, TGA and DSC and Karl Fisher method. The amorphous nature of the compound of formula II is confirmed by the XRD as shown in Fig 1.
According to the invention, the compound of formula II is further characterized by Thermo Gravimetric Analysis (TGA) as shown in Fig 2, and found that the loss in weight in relation to change in temperature is about 6-8 %, indicating loss of two water molecules, confirming that the compound of formula II is in dehydrated form.
Further, the compound of invention is characterized by Differential Scanning Calorimetry. The DSC thermogram as shown in Fig 3 exhibits significant endothermic peaks at 133°C, 202°C and 264°C.
The DSC thermogram as shown in Fig 3 includes three characteristic peaks. The first peak is an endothermic peak at an extrapolated onset temperature ranging 128 to 133°C which is attributed to loss of one mole of water confirming product is hydrated. Another peak is an endothermic peak at an extrapolated onset temperature range of 176 to 202°C corresponding to the loss of another mole of water confirming that the product is dihydrate.The endothermal peak at an extrapolated on set temperature of 267 to 271°C corresponds to melting point of the amorphous product.
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In yet another aspect, the amorphous raloxifene hydrochloride dihydrate is characterized by Karl Fisher method and found that the bound water content of the compound of invention is in the range of 6 to 8 %.
The compound of formula II according to the present invention is conveniently prepared by a process which constitutes a further feature of the present invention, and which comprises recovering a compound of formula II from a solution thereof under the conditions specified whereby an amorphous raloxifene hydrochloride dihydrate is obtained.
Thus according to the another preferred embodiment of the present invention, amorphous hydrated material is prepared by dissolving a crystalline form of a compound of formula I in a suitable solvent or a solvent mixture, for example, methanol and water, followed by recovery of the material by any suitable means. Techniques which may be employed to recover amorphous hydrated compounds of formula II from the solution include those wherein the solvent is removed from the solution, preferably rapidly, and the product deposited, and those wherein the product is precipitated from a solution. Methods involving the use of these procedures which have been found to be satisfactory include spray drying, roller drying, solvent precipitation, rotary evaporation and freeze drying. Particularly preferred for the practice of the present invention is the method of spray drying. Solvents which may be employed in the practice of the present invention will be chosen according to the technique and conditions to be employed, and include water, methanol, ethanol, dimethylformamide, including mixtures thereof, if desired. In general, the compounds of formula 1 have sufficient heat stability to withstand spray drying and the like, and accordingly, spray drying is the preferred method of recovery. Spray drying systems may be operated in a known manner to obtain an amorphous hydrated product essentially free from crystalline material as well as free from particulate contaminations. Closed cycle spray drying systems in which the drying medium is recycled and particularly safe and economic for use in obtaining the product of the present invention.
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The drying gas employed in the process may be selected from air or inert gases for example, nitrogen, argon and carbon dioxide. The preferred would be air. The gas inlet temperature to the spray dryer is chosen according to the solvent employed, but would be, for example, in the range of from about 75°C to about 150 C.
The presence of amorphous hydrated form of a compound is characterized by XRD. A compound of formula II in accordance with the present invention is preferably essentially free from the crystalline form of the material.
Long term studies have indicated that the amorphous hydrated form of the present invention is very stable.
Solubility of the amorphous hydrated form was demonstrated to be approximately 250-280 times higher than the crystalline form while tested for their intrinsic solubility. Advantage of increased solubility include but are not limited to ease in processing the amorphous hydrated material, which includes equipment cleaning issues, ease in formulation and delivery of the material, and the like.
Compounds of formula II which are amorphous hydrated forms have been demonstrated to have several advantages, including but not limited to a high degree of bioavailability, as well as being in a form for effective methods of administration.
Based on the above, the invention further provides pharmaceutical compositions comprising amorphous Raloxifene hydrochloride dihydrate together with pharmaceutically acceptable carrier/carriers. These carriers are added in the composition for a variety of purposes.
Thus according to another embodiment, the amorphous Raloxifene hydrochloride dihydrate of the present invention can be used in pharmaceutical preparations as the same is having high aqueous stability/solubility. The pharmaceutical preparations can be selected from Various dosage forms such as solid dosage form like tablets, capsules, pellets, powders, soft gelatin capsules, and the like and oral liquids. The tablets can be
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prepared as conventional dosage forms such as immediate release, sustained release, modified release or controlled release.
The pharmaceutical compositions can be prepared using conventional techniques well known In the art.
According to another embodiment, the invention provides use of amorphous Raloxifene hydrochloride dihydrate in pharmaceutical preparations.
According to another embodiment, the invention provides method for treating osteoporosis in postmenopausal women, wherein said method comprises administering therapeutically effective amounts of Raloxifene hydrochloride dihydrate of the present invention or pharmaceutical composition comprising the same. The compound of the present invention can also be administered optionally with other actives depending on the disease conditions.
The quantity of the compound used in pharmaceutical compositions of the present invention will vary depending upon the body weight of the patient and the mode of administration and can be of any effective amount to achieve the desired therapeutic effect.
The invention further describes a method for inhibiting bone resorption or bone loss, or
treating or preventing osteoporosis in post menopausal women; wherein, said method
comprises administering compounds of the present invention.
The following examples, which include preferred embodiments, will serve to illustrate
the practice of this invention, it being understood that the particulars shown are by way of
example and for purpose of illustrative discussion of preferred embodiments of the
invention.
Examples:
Example 1
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Preparation of amorphous raloxifene hydrochloride dihydrate
The amorphous dihydrate form of raloxifene hydrochloride of the instant invention was
prepared by dissolving 10 gm of crystalline raloxifene hydrochloride in 160 ml of
methanol and 25 ml of water at 60-70°C. The amorphous dihydrated material was
recovered by spray drying the solution under the following conditions: equilibrium inlet
temp - 80-85°C, equilibrium outlet temp - 45-50°C, feed rate - 2.0-2.5 ml/min, aspirator
setting - 30-35. air flow indicator - 500-600, atomization pressure - 35-40 psi. The
process was completed in approx 1 to 2 hrs.
Yield : >96 %
HPLC purity : >99.0 %
Melting Point: 263-266°C
Water content : 6-8 %
The product was analyzed by XRD(Figure I), TGA(Figure II) and DSC(Figure III)
Example 2
10 gms of crystalline raloxifene hydrochloride is dissolved in 900 ml of methanol and
100 ml of water at 30-32°C. The amorphous diydrated material was recovered by spray
drying the solution under following conditions: equilibrium inlet temp - 70-75°C,
equilibrium outlet temp - 35-45°C, feed rate - 3.5-5.0 ml/min, aspirator setting - 25-30,
air flow indicator - 500-600, atomization pressure - 30-35 psi. The process was
completed in approx 4 to 5 hrs.
Yield : >97 %
HPLC purity : >99.0 %
Melting Point : 264-267°C
Water content: 6-8 %
The product was characterized by XRD, TGA and DSC
Example 3
16 gms of crystalline raloxifene hydrochloride is dissolved in 700 ml of methanol and 300 ml of water at 30-32°C. The amorphous diydrated material was recovered by spray drying the solution under following conditions: equilibrium inlet temp - 95-100°C,
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equilibrium outlet temp - 45-50°C, feed rate - 2.5-3.0 ml/min. aspirator setting - 45-50,
air flow indicator - 550-650, atomization pressure - 45-50 psi The process was
completed in approx 5 to 6 Hrs.
Yield : >95%
HPLC purity : >99.0 %
Melting Point : 264-267°C
Water content: 6-8 %
The product was characterized by XRD, TGA and DSC
Example 4
10 gms of crystalline raloxifene hydrochloride is dissolved in 460 ml of methanol at 60-
65°C. The amorphous dihdrated material was recovered by spray drying the solution
under following conditions: equilibrium inlet temp - 75-80°C, equilibrium outlet temp -
40-45°C, feed rate - 3.5-4.0 ml/min, aspirator setting - 40-45, air flow indicator - 500-
600, atomization pressure - 40-45 psi The process was completed in approx 2 to 3 Hrs.
Yield : >97%
HPLC purity : >99.0 %
Melting Point :265-268°C
Water content : 6-8 %
The product was characterized by XRD, TGA and DSC
Example 5
10 gms of crystalline raloxifene hydrochloride is dissolved in 70 ml of
dimethylformamide. The amorphous dihydrated material was recovered by spray drying
the solution under following conditions: equilibrium inlet temp - 135-145 equilibrium
outlet temp - 65-75°C, feed rate - 2.0-2.5 ml/min, aspirator setting - 60-65, air flow
indicator - 600-700, atomization pressure - 55-65 psi The process was completed in
approx 1 Hr.
Yield : >95% ...
HPLC purity : >99.0 %
Melting Point: 267-269C
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Water content: 6-8 %
The product was characterized by XRD. TGA and DSC
It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative examples and that the present invention may be embodied in other specific forms without departing from the essential attributes thereof, and it is therefore desired that the present embodiments and examples be considered in all respects as illustrative and not restrictive, reference being made to the appended claims, rather than to the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein
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We claim,
1. An amorphous compound of formula II

Formula II wherein n is an integer of 0.5 to 3.0
2. The amorphous compound as claimed in claim 1, which is a dihydate.
3. The amorphous compound as claimed in claim I, which has a moisture content of about 6-8 %.
4. The compound as claimed in claim 2, wherein said compound is characterized by TGA showing corresponding loss in weight of about 6 - 8 %.
5. The compound as claimed in claim 2. wherein said compound is characterized by Karl Fisher method showing the bound water content in the range of 6 to 8%.
6. The compound as claimed in claim 2, wherein said compound is characterized by DSC exhibiting a significant endothermic peaks at I33°C, 202°C and 264°C in DSC thermogram.
7. A process for preparing an amorphous hydrated form of a compound of claim 1 in greater than 96 % recovery comprising the steps of:
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a) preparing a solution of a crystalline form of a compound of formula 1 in a suitable solvent or solvent mix, and
b) spray drying said solution to recover an amorphous dihydrate form of a compound of formula II.
8. The process as claimed in claim 7 wherein said suitable solvent or solvent mix is
selected from methanol, water, dimethylformamide either alone or in
combinations thereof.
9. The process as claimed in claim 7. wherein said gas used is air at an inlet
temperature in the range of from about 75°C to about 150°C and out let
temperature of 40-65°C
10. A pharmaceutical composition comprising a compound according to claim 1
together with one or more pharmaceutical excipients.
11. A method for inhibiting bone resorption or bone loss, or treating or preventing
osteoporosis in post menopausal women; wherein, said method comprises
administering a compound of claim 1.
Dated this 12th day of November 2008

Dr. Gopakumar G. Nair Agent for the Applicant
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