DESC:CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of earlier Indian provisional patent application No. IN
201941001230, filed on Jan 10, 2019; the entire contents of each of which are incorporated by reference herein.

FIELD OF THE INVENTION
The present disclosure generally relates to the field of pharmaceutical sciences and more specifically relates to novel polymorphic forms of Larotrectinib sulfate. The present disclosure provides processes for the preparation of amorphous form of Larotrectinib sulfate, an amorphous solid dispersion of Larotrectinib sulfate and its process for the preparation thereof.

BACKGROUND OF THE INVENTION

Larotrectinib sulfate, chemically known as (3S)-N-{5-[(2R)-2-(2,5-difluorophenyl)-1-pyrrolidinyl] pyrazolo[1,5-a] pyrimidin-3-yl}-3-hydroxy-1-pyrrolidinecarboxamide sulfate having the structure shown in Formula-I, is a kinase inhibitor.

Formula-I
Larotrectinib sulfate is approved and is being marketed under the brand name Vitrakvi®
for the treatment of adult and pediatric patients with solid tumors that have a neurotrophic receptor tyrosine kinase (NTRK) gene fusion without a known acquired resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity, and have no satisfactory alternative treatments

United States Pat. No. US 8513263 discloses Larotrectinib, its pharmaceutically acceptable salt and process for the preparation of same.

United States Pat. No. US 9127013 discloses Larotrectinib sulfate and a process for the preparation of amorphous form of Larotrectinib sulfate in methanol, followed by concentration of methanol by the distillation.

The present invention provides to processes for the preparation of amorphous form of Larotrectinib sulfate, an amorphous solid dispersion of Larotrectinib sulfate and their process for the preparation thereof.

OBJECT AND SUMMARY OF THE INVENTION

In one object of the present invention is to provide a process for the preparation of amorphous form of Larotrectinib sulfate comprising the steps of:
a) dissolving Larotrectinib sulfate in a solvent or mixture of solvents,
b) removing the solvent to isolate amorphous form of Larotrectinib sulfate
with the proviso that, wherein the solvent in the step (a) is not a methanol

In another object of the present invention is to provide a process for the preparation of amorphous form of Larotrectinib sulfate comprising the steps of:
a) dissolving Larotrectinib sulfate in an alcoholic solvent,
b) spray drying the alcoholic solvent to isolate amorphous form of Larotrectinib sulfate

In another object the present invention is to provide an amorphous solid dispersion of Larotrectinib sulfate.

In another object of the present invention is to provide an amorphous solid dispersion of Larotrectinib sulfate comprising the steps of:
a) dissolving Larotrectinib sulfate and one or more pharmaceutically acceptable excipients in a solvent to form a solution; and
b) removing the solvent to isolate the solid dispersion of Larotrectinib sulfate

BRIEF DESCRIPTION OF THE DRAWINGS

Further aspects of the present disclosure together with additional features contributing thereto and advantages accruing there from will be apparent from the following description of embodiments of the disclosure which are shown in the accompanying drawing figures wherein:

Figure 1 shows a powder X-ray diffraction pattern of the amorphous Larotrectinib sulfate

Figure 2 is a PXRD pattern of amorphous solid dispersion of Larotrectinib sulfate with hydroxypropyl methylcellulose

Figure 3 is a PXRD pattern of amorphous solid dispersion of Larotrectinib sulfate with Hydroxypropyl beta-cyclodextrin

DETAILED DESCRIPTION OF THE INVENTION

The amorphous form of Larotrectinib sulfate of the present invention may be characterized by their X-ray powder diffraction patterns. Thus, X-ray diffraction patterns of the amorphous Larotrectinib sulfate was measured on BRUKER D-8 Discover powder diffractometer equipped with a goniometer of ?/2? configuration and Lynx Eye detector. The Cu-anode X-ray tube was operated at 40 kV and 30 mA. The experiments were conducted over the 2? range of 2.0°-50.0°, 0.030° step size and 0.4 seconds step time.

The amorphous form of Larotrectinib sulfate is characterized by a powder X-ray diffraction pattern as depicted in Figure 1.

In one embodiment of the present invention provide a process for the preparation of amorphous form of Larotrectinib sulfate comprising the steps of:
a) dissolving Larotrectinib sulfate in a solvent or mixture of solvents,
b) removing the solvent to isolate amorphous form of Larotrectinib sulfate
with the proviso that, wherein the solvent in the step (a) is not a methanol

According to this embodiment, Larotrectinib sulfate may be dissolved in a solvent at a temperature of about 40°C to about 80°C. Within the context of this embodiment, Larotrectinib sulfate starting material may be any polymorphic form.

According to the present embodiment, the term “solvent,” unless otherwise indicated, refers to an C2-C5 alcohol solvent, ketone solvent, ether, water or a mixture thereof. As used herein, C2-C5 alcohol solvents include, but are not limited to, ethanol, n-propanol, isopropanol, n-butanol, 2-butanol, isobutanol, t-butanol, n-pentanol, or mixtures thereof; ketone solvents include, but are not limited to, acetone, methylethyl ketone, methylisobutyl ketone, or mixtures thereof; As used herein, ethereal solvents include, but not limited to, 1,4-dioxane, diethyl ether, diisopropyl ether, cyclopentyl methyl ether, ethyl tert-butyl ether, methyl tert-butyl ether, tetrahydrofuran or mixtures thereof. In some particularly useful embodiments, water, 1,4-dioxane or a mixture of water and 1,4-dioxane is used as the solvent. In particularly useful embodiments, Larotrectinib sulfate is dissolved in water or a mixture of water and 1,4-dioxane at a temperature of about 55°C to about 65°C.

Next, the solution may be filtered, for example, through HYFLO®, to remove any undissolved particulates.
Next, according to this embodiment, solvent may be removed to isolate amorphous Larotrectinib sulfate. This may be carried out by well-known techniques, for example, evaporation, distillation, spray drying, lyophilization, agitated thin film drying, or combinations thereof. In certain embodiments, lyophilization, spray drying, or distillation is used to remove the solvent.

In another embodiment of the present invention provide a process for the preparation of amorphous form of Larotrectinib sulfate comprising the steps of:
a) dissolving Larotrectinib sulfate in an alcoholic solvent,
b) spray drying the alcoholic solvent to isolate amorphous form of Larotrectinib sulfate

According to this embodiment, Larotrectinib sulfate may be dissolved in an alcoholic solvent is selected from methanol ethanol, n-propanol, isopropanol, n-butanol, 2-butanol, isobutanol, t-butanol, n-pentanol, or mixtures thereof, preferably methanol; at a temperature of about 50°C to about 70°C. Within the context of this embodiment, Larotrectinib sulfate starting material may be any polymorphic form.
Next, the solution may be filtered, for example, through HYFLO®, to remove any undissolved particulates.
Next, according to this embodiment, alcoholic solvent may be removed by spray drying to isolate amorphous Larotrectinib sulfate.
In another embodiment of the present invention provide an amorphous solid dispersion of Larotrectinib sulfate

As used herein, the term solid dispersion means any solid composition having at least two components. In certain embodiments, a solid dispersion as disclosed herein includes an active ingredient Larotrectinib sulfate dispersed among at least one pharmaceutical carrier or excipient.

The pharmaceutical carriers or excipients include but are not limited to starches, lactose, mannitol (Pearlitol™ SD200), cellulose derivatives, confectioner's sugar and the like. Different grades of lactose include but are not limited to lactose monohydrate, lactose DT (direct tableting), and lactose anhydrous. Different starches include but are not limited to maize starch, potato starch, rice starch, wheat starch, pregelatinized starch and starch 1500, starch 1500 LM grade, fully pregelatinized starch and others. Different cellulose compounds that can be used include crystalline celluloses and powdered celluloses. Examples of crystalline cellulose products include but are not limited to CEOLUS™ KG801, Avicel™PH101, PH102, PH301, PH302 and PH-F20, microcrystalline cellulose PHI 12 microcrystalline cellulose 114, and microcrystalline cellulose 112. Hydroxypropylcelluloses, also called HPC (Klucel™ LF, Klucel EXF) and useful in various grades, hydroxypropylmethylcelluloses, also called hypromelloses or HPMC (Methocel™) and useful in various grades, polyvinylpyrrolidones or povidones (such as grades PVP-K25, PVP-K29, PVP-K30, and PVP-K90), Plasdone™ S-630 (copovidone), powdered acacia, gelatin, guar gum, carbomers (Carbopol™), methylcelluloses, polymethacrylates, carmellose calcium, carboxymethylstarch sodium, croscarmellose sodium, crospovidones, examples of commercially available crospovidone products including but not limited to crosslinkedpovidone, Kollidon™CL, Polyplasdone™ XL, XI- 10, and INF- 10 and low-substituted hydroxypropylcelluloses. Examples of low-substituted hydroxypropylcelluloses include but are not limited to low-substituted hydroxypropylcellulose LHl l, LH21, LH31, LH22, LH32, LH20, LH30, LH32 and LH33, sodium starch glycolate, colloidal silicon dioxide. Active agents such as ethylene glycol stearates, propylene glycol stearates, diethylene glycol stearates, glycerol stearates, sorbitan esters (SPAN™) and polyhydroxyethylenically treated sorbitan esters (TWEEN™), aliphatic alcohols and PEG ethers, phenol and PEG ethers, quaternary ammonium salts (e.g. cetyltrimethylammonium bromide) and amine salts (e.g. octadecylamine hydrochloride). sodium stearate, potassium stearate, ammonium stearate, and calcium stearate, triethenolamine stearate, magnesium stearate, sodium lauryl sulphate, magnesium lauryl sulfate, calcium soaps, zinc stearate, polyoxyethylenemonostearates sodium dioctylsulphosuccinate, and sodium dodecylbenzenesulphonate, glycerylmonostearates, palmitic acid, talc, carnauba wax, calcium stearate sodium, sodium or calcium soaps, silicate, silicon dioxide, hydrogenated vegetable oils and fats, stearic acid and combinations thereof. Phospholipids, e.g. diacylphosphatidylglycerols, diaceylphosphatidylcholines, and diaceylphosphatidic acids, the precursors and derivatives thereof, such as for example soybean lecithin and egg yolk. Pigments such as Titanium oxide, silicon dioxide, iron oxides, zinc oxide, combinations thereof. Plasticizers such as castor oil, diacetylatedmonoglycerides, dibutylsebacate, diethyl phthalate, glycerin, polyethylene glycol, propylene glycol, triacetin, and triethyl citrate. Basic inorganic salts of sodium, potassium, magnesium and calcium. Examples of basic inorganic salts of sodium are sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, and the like. Examples of basic inorganic salts of potassium are potassium carbonate, calcium carbonate, magnesium carbonate, dibasic calcium phosphate, tribasic calcium phosphate potassium hydrogen carbonate, potassium hydroxide, and the like. Examples of basic inorganic salts of magnesium are heavy magnesium carbonate, magnesium, [Mg6Al2(OH)16.C03.4H2O], aluminum hydroxide-magnesium [2.5MgO.Al203.xH2O], and the like. Examples of basic inorganic salts of calcium include precipitated calcium carbonate, calcium hydroxide, and the like. And also, antiadherents, opacifiers, solvents, and optionally colorants, lubricants, pigments, antifoam agents, and polishing agents. Preferably the excipients for the present invention is hydroxypropyl methylcellulose; hydroxypropyl beta-cyclodextrin in solvent or a mixture thereof.

In another object of the present invention is to provide an amorphous solid dispersion of Larotrectinib sulfate comprising the steps of:
a) dissolving Larotrectinib sulfate and one or more pharmaceutically acceptable excipients in a solvent to form a solution; and
b) removing the solvent to isolate the solid dispersion of Larotrectinib sulfate

According to this embodiment, Larotrectinib sulfate and a pharmaceutical excipient may be first dissolved in a solvent at a temperature of about 40°C to about 80°C. Within the context of this embodiment, Larotrectinib sulfate starting material may be any polymorphic form.

According to the present embodiment, the term “solvent,” unless otherwise indicated, refers to an C2-C5 alcohol solvent, ketone solvent, ether, water or a mixture thereof. As used herein, C2-C5 alcohol solvents include, but are not limited to, ethanol, n-propanol, isopropanol, n-butanol, 2-butanol, isobutanol, t-butanol, n-pentanol, or mixtures thereof; ketone solvents include, but are not limited to, acetone, methylethyl ketone, methylisobutyl ketone, or mixtures thereof; As used herein, ethereal solvents include, but not limited to, 1,4-dioxane, diethyl ether, diisopropyl ether, cyclopentyl methyl ether, ethyl tert-butyl ether, methyl tert-butyl ether, tetrahydrofuran or mixtures thereof. In some particularly useful embodiments, water, 1,4-dioxane or a mixture of water and 1,4-dioxane is used as the solvent. In particularly useful embodiments, Larotrectinib sulfate is dissolved in water or a mixture of water and 1,4-dioxane at a temperature of about 55 °C to about 65°C.

Examples of suitable pharmaceutical excipients include polysaccharides, polyvinylpyrrolidone, polyvinyl acetate (PVAC), polyvinyl alcohol (PVA), polymers of acrylic acid and their salts, silicon dioxide (e.g., AEROPERL® 300 sold by Evonik), polyacrylamide, polymethacrylates, vinylpyrrolidone-vinyl acetate copolymers (e.g., those sold under the PLASDONE® tradename), C1-C6 polyalkylene glycols (e.g., polypropylene glycol, polyethylene glycol), copolymers of polyethylene glycol and polypropylene glycol (e.g., the families of block copolymers based on ethylene oxide and propylene oxide sold under the PLURONIC® tradename), and mixtures thereof.
Suitable polysaccharides include, for example, microcrystalline cellulose, microcrystalline cellulose pH 101, microcrystalline cellulose pH 102, hydroxypropyl methylcellulose (HPMC), croscarmellose, carboxymethyl cellulose (CMC) and salts thereof, methyl cellulose, hydroxyethyl cellulose, ethyl hydroxyethyl cellulose, hydroxypropyl cellulose (HPC), optionally substituted a-cyclodextrins, optionally substituted ß-cyclodextrins (e.g., hydroxypropyl ß-cyclodextrin), optionally substituted ?-cyclodextrins (e.g., hydroxypropyl ?-cyclodextrin) and mixtures thereof. As used herein, the term “substituted” with respect to cyclodextrin means the addition of side chain groups such as hydroxyl, hydroxypropyl, or other C1-C6 alkyl and C1-C6 hydroxyalkyl groups.
In particularly useful embodiments of the present disclosure, vinylpyrrolidone-vinyl acetate copolymers (e.g., PLASDONE S-630), granulated silicon dioxide (e.g., AEROPERL® 300), microcrystalline cellulose pH 101, or microcrystalline cellulose pH 102 is used as the pharmaceutically acceptable excipient. In particularly useful embodiments, these excipients are incorporated into the solid dispersion at a weight percent of 50% w/w with respect to the total weight of the composition. Preferably the excipients for the present invention is hydroxypropyl methylcellulose; hydroxypropyl beta-cyclodextrin in solvent or a mixture thereof.

Next, the solution may be filtered, for example, through HYFLO®, to remove any undissolved particulates.
Next, according to the present embodiment, the solvent may be removed to isolate an amorphous solid dispersion of Larotrectinib sulfate. This may be carried out by techniques well-known in the art, for example, by evaporation, distillation, spray drying, or agitated thin film drying, or any combination thereof. In certain embodiments, lyophilization spray drying or distillation is used to remove the solvent.

Stability:

In yet another embodiment, the physical stability of Larotrectinib sulfate amorphous form was determined by storing the samples at 40°C and 75% relative humidity (RH), 25°C and 60% relative humidity (RH) for six months and the samples were analyzed by PXRD. The results are shown in below Table 1. The Larotrectinib amorphous form was found to be physically stable at 40°C and 75% relative humidity (RH) and at 25°C and 60% relative humidity (RH) conditions up to six months.

In view of the above description and the examples below, one of ordinary skill in the art will be able to practice the invention as claimed without undue experimentation. The foregoing will be better understood with reference to the following examples that detail certain procedures for the preparation of molecules according to the present invention. All references made to these examples are for the purposes of illustration. The following examples should not be considered exhaustive, but merely illustrative of only a few of the many aspects and embodiments contemplated by the present disclosure.

EXAMPLES

Example 1: Preparation of amorphous Larotrectinib Sulfate
Larotrectinib Sulfate (1g) was dissolved in water (20mL) at 60±5°C. The resulting clear solution was filtered through hyflo to remove any undissolved particulates and subjected to lyophilization using Labocon lyophilizer (Model: LFD-BT-104) to yield amorphous form of Larotrectinib Sulfate.
Yield: 0.9g

Example 2: Preparation of amorphous Larotrectinib Sulfate
Larotrectinib Sulfate (3g) was dissolved in a mixture of 1,4-dioxane (60mL) and water (60mL) at 60±5°C. The resulting clear solution was filtered through hyflo to remove any undissolved particulates and subjected to lyophilization using Labocon lyophilizer (Model: LFD-BT-104) to yield amorphous form of Larotrectinib Sulfate.
Yield: 3g

Example 3: Preparation of amorphous Larotrectinib Sulfate
Larotrectinib Sulfate (2g) was dissolved in methanol (50mL) at 60±5°C. The clear solution was filtered through hyflo to remove any undissolved particulates and the resulting clear solution was subjected to spry drying (Model: Buchi B-290) with feed rate of solution 15 mL/minute and inlet temperature at 70°C to yield Larotrectinib sulfate amorphous form.
Yield: 0.4g

Example 4: Preparation of amorphous solid dispersion of Larotrectinib Sulfate
Larotrectinib Sulfate (1g) and hydroxypropyl methylcellulose (HPMC, 1g) were dissolved in a mixture of 1,4-Dioxane (20mL) and water (20mL) at 60±5°C. The resulting clear solution was filtered through hyflo to remove any undissolved particulates and subjected to lyophilization using Labocon lyophilizer (Model: LFD-BT-104) to yield amorphous solid dispersion of Larotrectinib Sulfate with HPMC.
Yield: 2g

Example 5: Preparation of amorphous solid dispersion of Larotrectinib Sulfate
Larotrectinib Sulfate (900mg) and hydroxypropyl beta-cyclodextrin (HPBCD, 100mg) were dissolved in a mixture of 1,4-Dioxane (20mL) and water (20mL) at 60±5°C. The resulting clear solution was filtered through hyflo to remove any undissolved particulates and subjected to lyophilization using Labocon lyophilizer (Model: LFD-BT-104) to yield amorphous solid dispersion of Larotrectinib Sulfate with HPBCD.
Yield: 1g
,CLAIMS:1. An amorphous solid dispersion of Larotrectinib sulfate with at least one pharmaceutically acceptable excipient.

2. A process for the preparation of an amorphous solid dispersion of Larotrectinib sulfate comprising the steps of:
a) dissolving Larotrectinib sulfate and one or more pharmaceutically acceptable excipients in a solvent to form a solution; and
b) removing the solvent to isolate the solid dispersion of Larotrectinib sulfate

3. The amorphous solid dispersion as claimed in claim 1 and 2, wherein the pharmaceutically acceptable excipient is selected from hydroxypropyl methylcellulose, hydroxypropyl beta-cyclodextrin,

4. A process for the preparation of Amorphous Larotrectinib sulfate comprising the steps of:
a) dissolving Larotrectinib sulfate in a solvent or mixture of solvents,
b) removing the solvent to isolate amorphous form of Larotrectinib sulfate
with the proviso that, wherein the solvent in the step (a) is not a methanol

5. The process, as claimed in claim 2 and 4, where in the solvent or mixture of solvents are selected from C2-C5 alcohol solvent, ketone solvent, ether and/or water.

6. The process as claimed in claim 5, wherein the C2-C5 alcohol solvent selected from ethanol, n-propanol, isopropanol, n-butanol, 2-butanol, isobutanol, t-butanol, n-pentanol, or mixtures thereof.

7. The process as claimed in claim 5, wherein the ketone solvents selected from cetone, methylethyl ketone, methylisobutyl ketone, or mixtures thereof.

8. The process as claimed in claim 5, wherein the etheral solvents are selected from 1,4-dioxane, diethyl ether, diisopropyl ether, cyclopentyl methyl ether, ethyl tert-butyl ether, methyl tert-butyl ether, tetrahydrofuran or mixtures thereof.

9. A process for the preparation of amorphous form of Larotrectinib sulfate comprising the steps of:
a) dissolving Larotrectinib sulfate in an alcoholic solvent,
b) spray drying the alcoholic solvent to isolate amorphous form of Larotrectinib sulfate.

10. The process as claimed in claim 9, wherein the alcoholic solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, 2-butanol, isobutanol, t-butanol and n-pentanol.