Claims:We Claim:
1. A novel crystalline Form-AB of Liothyronine sodium (I) characterized by a powder X-ray diffraction pattern comprising one or more powder X-ray diffraction peaks selected from the group consisting of: 5.97, 20.96 and 22.81 ± 0.2° 2?.

2. A novel crystalline Form-AB of Liothyronine sodium (I) as claimed in claim 1 further characterized by a powder X-ray diffraction pattern comprising one or more powder X-ray diffraction peaks selected from the group consisting of: 16.05, 16.46, 21.33, 22.00, 24.04, 27.88 and 30.21± 0.2° 2?.

3. A novel crystalline Form-AB of Liothyronine sodium (I), characterized by Figure 1.

4. A novel crystalline Form-AB of Liothyronine sodium (I), characterized by DSC having thermal event at 203°C ± 2°C.

5. A process for the preparation of novel crystalline Form-AB of Liothyronine sodium (I), comprising,
a) providing solution of Liothyronine in an alcoholic solvent;
b) adding sodium carbonate to the solution obtained in step-i;
c) optionally, filtration of the mixture obtained in step-ii and distillation of filtrate;
d) optionally, adding second solvent to the compound obtained in step-iii;
e) isolating novel crystalline Form-AB of Liothyronine sodium (I).

6. The process as claimed in claim 4, wherein alcoholic solvent used in step-a) is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol and tert-butanol.

7. The process as claimed in claim 5, wherein alcoholic solvent is methanol.

8. The process as claimed in claim 4, wherein second solvent is selected from the group comprising water, methanol, ethanol, propanol, isopropanol, butanol, isobutanol, toluene, benzene, o-xylene, m-xylene, p-xylene, acetone, acetonitrile, ethyl acetate, methylene chloride, chloroform, dioxane, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, methyl tert-butyl ether, diethyl ether, hexane, cyclohexane, heptanes or mixture thereof.

9. The process as claimed in claim 7, wherein second solvent is ethanol. , Description:FIELD OF INVENTION

The present invention relates to a novel crystalline polymorph Form-AB of Liothyronine Sodium (I) and process of preparation thereof.

Formula I

BACKGROUND OF THE INVENTION

Liothyronine sodium (I) is the sodium salt of a synthetic form of the natural thyroid hormone L-triiodothyronine (T3) useful in the treatment of thyroid disorders and is available in the market under the brand names CYTOMEL®, LEVOTHROID®, LEVOXYL®, TIROSINT®, LEVO-T®. Liothyronine sodium (I) is chemically described as O-(4-hydroxy-3-iodophenyl)-3,5-diiodo-L-tyrosine sodium salt.

IT 1302201 discloses solid crystalline form of Liothyronine sodium, but not disclosed the X-ray powder diffraction (XRPD) pattern or 2? values.

IN 1400/MUM/2009 discloses a novel process for preparing Liothyronine sodium, and also discloses the powder X-ray diffraction (PXRD) diffractogram of the product obtained via the process described therein having XRPD pattern with peaks at about 6.59, 16.47, 18.24, 19.63, 21.31, 22.05, 23.62 and 25.42 ± 0.2° 2?.

IN 201641023206 discloses Amorphous Form and crystalline Form APO-I of Liothyronine sodium.

Polymorphism, the occurrence of different crystal forms, is a property of some molecules. A single compound, like Liothyronine sodium (I), may give rise to a variety of polymorphs having distinct crystal structures and physical properties like melting point (mp), thermal behaviors (e.g. measured by thermogravimetric analysis - "TGA", or differential scanning calorimetry - "DSC"), X-ray powder diffraction (XRPD) pattern, infrared absorption fingerprint, Raman absorption fingerprint, and solid state (13C-) NMR spectrum. One or more of these techniques may be used to distinguish different polymorphic forms of a compound.

Different solid state forms of an active pharmaceutical ingredient may possess different properties. Such variations in the properties of different solid state forms may provide a basis for improving formulation, for example, by facilitating better processing or handling characteristics, improving the dissolution profile, or improving stability (polymorph as well as chemical stability) and shelf-life. These variations in the properties of different solid state forms may also provide improvements to the final dosage form, for instance, if they serve to improve bioavailability. Different solid state forms of an active pharmaceutical ingredient may also give rise to a variety of polymorphs or crystalline forms, which may in turn provide additional opportunities to use variations in the properties and characteristics of a solid active pharmaceutical ingredient for providing an improved product.

New polymorphic forms of a pharmaceutically useful compound can also provide an opportunity to improve the performance characteristics of a pharmaceutical product (dissolution profile, bioavailability, etc.). It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, e.g., a different crystal habit, higher crystallinity or polymorphic stability which may offer better processing or handling characteristics, improved dissolution profile, or improved shelf-life. For at least these reasons, there is a need for additional solid state forms of Liothyronine sodium (I).

After numerous trials and earnest efforts, the present inventors surprisingly found novel crystalline polymorph Form-AB of Liothyronine Sodium (I) having advantageous properties which is useful and well suitable for the preparation of various pharmaceutical compositions.

OBJECTIVE OF THE INVENTION

The main objective of the present invention is to provide a novel crystalline polymorph Form-AB of Liothyronine Sodium (I) and process of preparation thereof.
SUMMARY OF THE INVENTION

The main embodiment of the present invention is to provide a novel crystalline polymorph Form-AB of Liothyronine Sodium (I).

Formula I
Another embodiment of the present invention is to provide a process for the preparation of novel crystalline polymorph Form-AB of Liothyronine Sodium (I), comprising,
i. providing solution of Liothyronine in an alcoholic solvent;
ii. adding sodium carbonate to the solution obtained in step-i;
iii. optionally, filtration of the mixture obtained in step-ii and distillation of filtrate;
iv. optionally, adding second solvent to the compound obtained in step-iii;
v. isolating crystalline polymorph Form-AB of Liothyronine Sodium (I).

BRIEF DESCRIPTION OF THE DRAWINGS

Fig 1 shows the X-ray powder diffractogram ("XRPD") pattern of novel crystalline polymorph Form-AB of Liothyronine Sodium (I).

Fig 2 shows the Differential scanning calorimetry ("DSC") pattern of novel crystalline polymorph Form-AB of Liothyronine Sodium (I).

Fig 3 shows the thermal gravimetric analysis ("TGA") pattern of novel crystalline polymorph Form-AB of Liothyronine Sodium (I).

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a novel crystalline polymorph Form-AB of Liothyronine Sodium (I).

In an embodiment of the invention, novel crystalline polymorph Form-AB of Liothyronine Sodium (I) is characterized by 2-theta peak(s) (XRPD) selected from 5.97, 16.05, 16.46, 20.96, 21.33, 22.00, 22.81, 24.04, 27.88 and 30.21 (± 0.2 ?).

In another embodiment of the present invention, novel crystalline polymorph Form-AB of Liothyronine Sodium (I) is characterized by having XRPD peaks as shown in Fig-1.

The XRPD analysis of Liothyronine Sodium (I) of the present invention was carried out using Empyrean Cu LFF HR (9430 033 7310x) DK 426771 X-ray diffractometer using CuKa radiation of wavelength 1.540598 Ao and at a continuous scan speed of 0.03o/min.

In another embodiment of the present invention, novel crystalline polymorph Form-AB of Liothyronine Sodium (I) is characterized by having DSC as shown in Fig-2 with thermal event at 203oC. TGA as shown in Fig.-3 shows a loss of approximately 5.34% mass over the temperature range up to 105oC, 7.11% mass over the temperature range 105-190oC.

The present invention also relates to a process for the preparation of novel crystalline polymorph Form-AB of Liothyronine Sodium (I) comprising;
i. providing solution of Liothyronine in an alcoholic solvent;
ii. adding sodium carbonate to the solution obtained in step-i;
iii. optionally, filtration of the mixture obtained in step-ii;
iv. optionally, adding second solvent to the compound obtained in step-iii;
v. isolating crystalline polymorph Form-AB of Liothyronine Sodium (I).

Alcoholic solvent used in step-i is selected from the methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, preferably methanol.

Second solvent is selected from the group comprising water, methanol, ethanol, propanol, isopropanol, butanol, isobutanol, toluene, benzene, o-xylene, m-xylene, p-xylene, acetone, acetonitrile, ethyl acetate, methylene chloride, chloroform, dioxane, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, methyl tert-butyl ether, diethyl ether, hexane, cyclohexane, heptanes or mixture thereof, preferably ethanol.

The isolation is performed by any conventional methods such as cooling, filtration or combination thereof.

The isolation further comprises optionally washing with a suitable solvent and drying.

Suitable solvent used in above isolation is selected from the group comprising water, methanol, ethanol, propanol, isopropanol, butanol, isobutanol, acetone, acetonitrile, ethyl acetate, dioxane, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, methyl tert-butyl ether, diethyl ether, hexane, cyclohexane, heptanes or mixture thereof.
The process details of the invention are provided in the examples given below, which are provided by way of illustration only and therefore should not be constructed to limit the scope of the invention.

Examples:

Example-1: Preparation of 3,5-Diiodo L- Tyrosine copper Complex

RBF was charged with 1600ml of water and 16gms of sodium hydroxide at 20-25°C and stirred to get clear solution. 100g of 3,5 diiodo tyrosine dihydrate was added to the above reaction mass and stirred for an hour to get clear solution .Copper sulphate solution (36.34gms dissolved in 225ml of water at 40-45°C,and maintain for 30-45min at 40-45°C) was then added in to the reaction mixture over a period of 15-30 min at 20-25°C and maintained for 2 - 2.5 hrs at 20-25°C. The resultant reaction mixture was filtered and washed with 250ml of DM water and the wet cake was proceed to next step without drying.

Example-2: Preparation of 3,5-Diiodothyronine

RBF was charged with above wet cake and 2000ml of DM water to which 1600ml of methanol was added over a period of 15-20min at 15-20°C. RBF was then charged with 32gm of triethyl amine at 20°C and 200g of of Bis (P-anisyl)iodonium iodide was added into the reaction mixture at 20-25°C. The reaction mixture was maintained for 1-1hr 30 min at 20-25°C and slowly raised the reaction mass temperature to 65-70°C and maintained for 5-6hrs at 65-70°C. Cooled the reaction mass temperature to 25-30°C, and maintained for 45 min at 25-30°C followed by filtered and washed with100 ml of DM water and 100ml of Methanol (wash the wet material twice with methanol and DM water) and the wet cake was proceed to next step without drying.

The above wet cake was stirred with 1000ml of DM water and 1000ml of Toluene at 20-25°C followed by slowly added dil HCl solution for 30-45min at 25-30°C (add 150gms of HCl in 130ml of DM water), stirred the reaction mass for 2-2hrs 30 min at 25-30°C. Filtered the reaction mass and washed with 150ml of Toluene (twice), 175ml of Methyl isobutyl ketone (twice) and hydrochloric acid solution (take 58gms of HCl and 250ml of DM water). The wet cake was proceed to next step without drying.

The above wet cake was stirred with 830ml of DM water and 207gms of HCl for 2-3hrs at 25-30°C, filtered and washed with mixture of 834ml of DM water and 207gms HCl.

RBF was charged with 420g acetic acid and above wet compound, stirred the reaction mass at 25-30°C for 15- 30 min. 500g of aq. hydro iodic acid was added then raised the reaction mass temperature to 60-65°C, further raised the reaction mass temperature to 103-108°C and maintained for 6-8hrs at 103-108°C, then cooled the reaction mass to 20-25°C. The reaction mixture was quenched with aq. sodium bisulphite solution (100g of Sodium bisulphite in 2000ml DM). The pH of the reaction mixture was adjusted to 3-5 with sodium hydroxide solution (208.3gms of NaOH dissolved in 416ml of DM water at 20-25°C) and maintained for 30-45min at 20-25°C. Filtered the reaction mass and washed with 500ml of DM water (thrice) followed by 200ml of methanol (twice). The wet cake was proceed to next step without drying.

Example-3: Preparation of Liothyronine
In a 5 Liter three necked round bottom flask, 3,5-Diiodothyronine (100g) and aqueous mono methylamine was added and stirred until formation clear solution at 25-30°C. Cooled the reaction mass to -2 to 2°C and slowly added iodine solution at -2 to 2°C over a period of 4 to 5h (preparation of iodine solution: a solution of water (200ml), potassium iodide (169g) and iodine (53.0g) stirred to obtain clear solution at 25-30°C for 10-15 min followed by addition DM water (640 ml) and stirred the reaction mass for more 10-15 min at 25-30°C). After completion of addition of iodine solution, reaction mass was stirred at -2 to 2°C for 15-20 min and raised the reaction mass temperature to 20-25°C and then slowly added sodium bisulphate (200 gr) and sodium acetate (600.0gr) over a period of 15-20 min at 20-25°C and maintained the reaction mass for 45-60 min at 20-25°C. Filtered the reaction mass and washed with acetonitrile (2x200ml) and unloaded the wet compound.
Charged 1000ml of DM water and above wet compound in to RBF. Adjusted the reaction mass pH to 6.3-6.8 with dil HCl solution (150 ml of DM water and 50 ml of con HCl), stirred the reaction mass for 30-45 mins at 25-30°C. Filtered the reaction mass and washed with water (2x500 ml) followed by acetonitrile (2x200 ml). Dried the solid for 7-8 hr under vacuum at 50-55°C until MC complies.
RBF was charged with methanol (1000 ml) and above solid and stirred for 10-15 min at 25-30°C, cooled the reaction mass to 0-5°C and slowly charged 23g of HCl to get clear solution. To this solution, Norit carbon (10g) was added and stirred for 20-30 min at 0-5°C. Filtered the reaction mass through hyflo and washed with chilled methanol (100 ml). Filtrate was taken into RBF and cooled to 10-15°C then PH adjusted 7.5-8.0 with aq. ammonia. Raised the reaction mass temperature to 60-65°C and maintained 60-90 min. Filtered the reaction mass at 40-45°C and washed with hot methanol (100 ml). The wet material is then taken to RBF and added water (1000ml) and stirred for 30-40 min then filtered the reaction mass and washed with water (300ml) and acetonitrile (300ml) and dried the material for 7-8hr at 50-55°C under vacuum to get pure Liothyronine.
Example-4: Preparation of novel crystalline Form-AB of Liothyronine sodium
Liothyronine (100g) was added to methanol (1500ml) and stirred for 10-15min at 25-30°C followed by addition of sodium carbonate (11.5 gr) and stirred for 10-15 min at 25-30°C. Raised the reaction mass temperature to 63-67°C and stirred for 3-4hr. cooled the reaction mass temperature to RT and charged with norit carbon (15g) and stirred for 20-30 min, filtered through hyflow bed and washed with methanol (200ml). Filtrate was taken into RBF and distilled out methanol completely under vacuum at below 45°C then charged ethanol (100ml), cooled the reaction mass to 0-5°C and maintained for 60min. Filtered the reaction mass and washed with ethanol (50ml) and dried the material under vacuum at 25-30°C for 75-80 hr.