HYDROCHLORIDE

FIELD OF THE INVENTION

The present invention relates to novel polymorphs of 4-hydroxy Atomoxetine hydrochloride and process for the preparation thereof.

The present invention also relates to crystalline monohydrate and anhydrate forms of 4-hydroxy Atomoxetine hydrochloride.

BACKGROUND OF THE INVENTION

Atomoxetine, designated chemically as (-)-N-methyl-3-phenyl-3-(0-tolyloxy)- propylamine hydrochloride, is structurally represented by the compound of Formula-I and is indicated for the potential treatment of attention-deficit hyperactivity disorder (ADHD). This compound is manufactured, marketed and sold in the United States under the brand name Strattera.

Formula-I Atomoxetine was first disclosed in US Patent No 4314081. The said patent disclosed Atomoxetine, its pharmaceutically acceptable salts and composition containing them.

4-hydroxy Atomoxetine, chemically known as R-(-)-N-methyl-3-(2-methyl-4- hydroxyphenyl)oxy)-3 -phenyl- 1-aminopropane, structurally represented by Formula-II, is a metabolite of Atomoxetine.

Fomnula-ll

4-hydroxy Atomoxetine hydrochloride was first disclosed in US Patent No 7384983, wherein 4-hydroxy Atomoxetine free base was dissolved in ethylacetate, treated the solution with 0.1N HC1; followed by lyophilization yielded a yellow solid which was dissolved in methanol and passed through a short column of activated carbon; the solvent was removed and finally the hydrochloride salt was recrystallized from water to afford 4-hydroxy Atomoxetine hydrochloride. However, this patent does not mention about the nature of the polymorph obtained through this process.

Polymorphism, the occurrence of different crystal forms, is a property of some molecules and molecular complexes. A single molecule may give rise to a variety of polymorphs having distinct crystal structures and physical properties like melting point, X-ray diffraction pattern, infrared absorption fingerprint, and solid state NMR spectrum. One polymorph may give rise to thermal behavior different from that of another polymorph. Thermal behavior can be measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis ("TGA"), and differential scanning calorimetry ("DSC"), which have been used to distinguish polymorphic forms.

The difference in the physical properties of different polymorphs results from the orientation and intermolecular interactions of adjacent molecules or complexes in the bulk solid. Accordingly, polymorphs are distinct solids sharing the same molecular formula yet having distinct advantageous physical properties compared to other polymorphs of the same composition or complex. No polymorphs were reported in the literature till date for 4-hydroxy Atomoxetine hydrochloride. Hence there remains a need for polymorphic forms which have properties suitable for pharmaceutical processing on a commercial scale.

The present invention relates to novel polymorphs of 4-hydroxy Atomoxetine hydrochloride and process for preparing them.

SUMMARY AND OBJECT OF THE INVENTION

The present invention provides novel polymorphs of 4-hydroxy Atomoxetine hydrochloride and process for preparation thereof.

One aspect of the present invention provides crystalline 4-hydroxy Atomoxetine hydrochloride monohydrate.

Another aspect of the present invention provides process for the preparation of crystalline 4-hydroxy Atomoxetine hydrochloride monohydrate which comprises the steps of: a) dissolving 4-hydroxy Atomoxetine hydrochloride in solvent, and b) isolating crystalline 4-hydroxy Atomoxetine hydrochloride monohydrate.

Yet another aspect of the present invention further provides crystalline 4-hydroxy Atomoxetine hydrochloride anhydrate.

Yet another aspect of the present invention provides process for the preparation of crystalline 4-hydroxy Atomoxetine hydrochloride anhydrate which comprises the steps of: a) dissolving 4-hydroxy Atomoxetine hydrochloride in acetonitrile, and b) isolating crystalline 4-hydroxy Atomoxetine hydrochloride anhydrate. Yet another aspect of the present invention provides a composition comprising crystalline 4-hydroxy Atomoxetine hydrochloride and a pharmaceutically acceptable excipient/carrier. BRIEF DESCRIPTION OF THE DRAWINGS

Fig. l depicts an X-ray powder diffraction pattern of 4-hydroxy Atomoxetine hydrochloride monohydrate.

Fig.2 depicts a DSC thermogram of 4-hydroxy Atomoxetine hydrochloride monohydrate.

Fig.3 depicts a TGA thermogram of 4-hydroxy Atomoxetine hydrochloride monohydrate.

Fig.4 depicts an X-ray powder diffraction pattern of 4-hydroxy Atomoxetine hydrochloride anhydrate.

Fig.5 depicts a DSC thermogram of 4-hydroxy Atomoxetine hydrochloride anhydrate.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides novel polymorphs of 4-hydroxy Atomoxetine hydrochloride and process for preparation thereof.

One embodiment of the present invention provides crystalline 4-hydroxy Atomoxetine hydrochloride monohydrate.

Another embodiment of the present invention provides crystalline 4-hydroxy Atomoxetine hydrochloride monohydrate characterized by X-ray powder diffraction pattern as shown in Figure 1 with peaks at 10.1, 10.3 and 17.6 ± 0.2 2 theta values.

Yet another embodiment of the present invention provides crystalline 4-hydroxy Atomoxetine hydrochloride monohydrate further characterized by X-ray powder diffraction pattern as shown in Figure 1 with peaks at 10.1, 10.3, 17.6, 19.5, 19.9, 21.1, 22.8, 25.0, 25.5 and 27.3 ± 0.2 2 theta values. Yet another embodiment of the present invention provides crystalline 4-hydroxy Atomoxetine hydrochloride monohydrate characterized by DSC as shown in Figure

2 with two endothermic peaks at 80°C and 144°C.

Yet another embodiment of the present invention provides crystalline 4-hydroxy Atomoxetine hydrochloride monohydrate characterized by TGA as shown in Figure

3 with a weight loss of about 5.2% due to loss one molecule of water, which is analogous to the theoretical weight loss of 5.5% for monohydrate.

Yet another embodiment of the present invention provides a process for the preparation of crystalline 4-hydroxy Atomoxetine hydrochloride monohydrate, which comprising the steps of:

a) dissolving 4-hydroxy Atomoxetine hydrochloride in solvent, and

b) isolating crystalline 4-hydroxy Atomoxetine hydrochloride monohydrate.

According to the present invention 4-hydroxy Atomoxetine hydrochloride is dissolved in solvent selected from water, chlorinated solvents such as chloroform or dichloromethane; aqueous alcohols such as aqueous methanol, aqueous ethanol, aqueous propanol or aqueous butanol; hydrocarbons such as cyclohexane, heptane, toluene or mixtures thereof and heated to 40-50°C to form a clear solution. Cooled the solution to 25-30°C and left for about 2-5 days. The obtained solid is filtered to give crystalline 4-hydroxy Atomoxetine hydrochloride monohydrate.

Yet another embodiment of the present invention provides crystalline 4-hydroxy Atomoxetine hydrochloride anhydrate.

Yet another embodiment of the present invention provides crystalline 4-hydroxy Atomoxetine hydrochloride anhydrate characterized by X-ray powder diffraction pattern as shown in Figure 4 with peaks at 9.6 and 18.7 ± 0.2 2 theta values. Yet another embodiment of the present invention provides crystalline 4-hydroxy Atomoxetine hydrochloride anhydrate further characterized by X-ray powder diffraction pattern as shown in Figure 4 with peaks at 9.6, 13.2, 14.9, 16.7, 18.7, 19.3, 19.6, 19.9, 21.4, 21.6, 22.9, 23.7, 24.4, 26.6 and 32.7 ± 0.2 2 theta values.

Yet another embodiment of the present invention provides crystalline 4-hydroxy Atomoxetine hydrochloride anhydrate characterized by DSC as shown in Figure 5 with a single endotherrnic peak at 144°C. »

Yet another embodiment of the present invention provides a process for the preparation of crystalline 4-hydroxy Atomoxetine hydrochloride anhydrate, which comprising the steps of:

a) dissolving 4-hydroxy Atomoxetine hydrochloride in acetonitrile, and b) isolating crystalline 4-hydroxy Atomoxetine hydrochloride anhydrate.

According to the present invention 4-hydroxy Atomoxetine hydrochloride is dissolved in acetonitrile and heated to 40-60°C to form a clear solution. Cooled the solution to 25-30°C and left for about 2-5 days. The obtained solid is filtered to give crystalline 4-hydroxy Atomoxetine hydrochloride anhydrate.

Yet another embodiment of the present invention provides compositions comprising crystalline 4-hydroxy Atomoxetine hydrochloride and a pharmaceutically acceptable excipient/carrier.

The 4-hydroxy Atomoxetine hydrochloride used as starting material in the following examples may be prepared according to the process disclosed in our co-pending Indian patent application 1800/CHE/2009.

POWDER X-RAY DIFFRACTION (PXRD) The PXRD measurements were carried out using PANalytical, X'Pert PRO powder diffractometer equipped with goniometer of Θ/Θ configuration and X'Celerator detector. The Cu- anode X-ray tube is operated at 40kV and 30mA. The experiments were conducted over the 2Θ range of 2.0°-50.0°, 0.030° step size and 50 seconds step time.

DIFFERENTIAL SCANNING CALORIMETRY (DSC)

The DSC measurements were carried out on Mettler Toledo 822 Stare and TA Q1000 of TA instruments. The experiments were performed at a heating rate of 10.0°C/minute over a temperature range of 30°C-300°C purging with nitrogen at a flow rate of 50ml/minute. Standard aluminum crucibles covered by lids with three pin holes were used.

THERMOGRAVIMETRIC ANALYSIS (TGA)

TGA is carried out using instrument TGA/SDTA 851. The experiments were performed at a heating rate of 10.0°C/minute over a temperature range of 30-250°C purging with nitrogen at a flow rate of 25ml/minute.

The following examples are provided for illustrative purposes only and are not intended to limit the scope of the invention in any way.

EXPERIMENTAL SECTION Example-1:

4-hydroxy Atomoxetine hydrochloride (lOOmg) was dissolved in mixture of chloroform (8.0ml) and aqueous methanol (2.0ml) at 40-50°C to form a clear solution. Cooled the solution to 25-30°C and left for about 4 days. The obtained solid was filtered to give crystals of 4-hydroxy Atomoxetine hydrochloride monohydrate. Crystalline 4-hydroxy Atomoxetine hydrochloride monohydrate can also be obtained from the solvents given in Table- 1.

TABLE !

S.No Solvents used

1. Water

2. Chloroform+ aqueous Methanol

3. Aqueous Methanol

4. Cyclohexane+ aqueous Methanol

5. Toluene+ aqueous Methanol

6. n-Heptane+ aqueous Methanol Example-2:

4-hydroxy Atomoxetine hydrochloride (lOOmg) was dissolved in acetonitrile (8.0ml) at 40-50°C to form a clear solution. Cooled the solution to 25-30°C and left for about 4 days. The obtained solid is filtered to give crystals of 4-hydroxy Atomoxetine hydrochloride anhydrate.