Field of the Invention:
The present invention relates to novel crystalline forms of methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula-1, represented by the following structural formula.
Background of the Invention:
Riociguat, also known as methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b] pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula-1. Riociguat is the first of a new class of guanylatecyclase (sGC) agonist, directly activates sGC and increases low levels of NO sensitivity, for treating pulmonary hypertension and chronic obstructive pulmonary hypertension.
US Patent No. 7173037 B2 (herein after referred as US’037) discloses methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula-1 and process for its preparation. The said US’037 patent does not discuss about its polymorphic form.
WO2014/128109 A1 discloses crystalline modification I, modification II, mono-DMSO solvate, sesqui-DMSO solvate, ¼ ethyl acetate solvate and amorphous forms of methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula-1.
WO2015/055124 A1 discloses crystalline Form I, Form II, Form III and Form IV and amorphous forms of methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula-1.

The crystalline form of a drug compound may have different chemical and physical properties, including appearances, melting point, chemical reactivity, apparent solubility, dissolution rate, stability, optical and mechanical properties, vapor pressure and density. These properties may have a direct effect on the ability to process and/or manufacture the drug compound and the drug product, as well as on drug product stability, dissolution, and bioavailability. Thus the crystalline forms of the compound of formula-1 may affect the quality, safety, and efficacy of a drug product comprising the compound of formula-1. So it is very important to think through the situation of different crystal forms in drug development.
The present invention relates to novel crystalline forms of methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula-1.
Brief description of the Invention:
The first aspect of the present invention is to provide a novel crystalline form of methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl) carbamate compound of formula-1, herein after designated as form-M.
The second aspect of the present invention is to provide a process for the preparation of crystalline form-M of methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula-1.
The third aspect of the present invention is to provide a novel crystalline form of methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl) carbamate compound of formula-1, herein after designated as form-S.
The fourth aspect of the present invention is to provide a process for the preparation of crystalline form-S of methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl] -5-pyrimidinyl(methyl)carbamate compound of formula-1.
Brief description of the Drawings:
Figure 1: Illustrates the PXRD pattern of crystalline form-A of methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula-1 obtained according to reference example-1.

Figure 2: Illustrates the PXRD pattern of crystalline form-M of methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula-1.
Figure 3: Illustrates the DSC thermogram of crystalline form-M of methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula-1.
Figure 4: Illustrates the PXRD pattern of crystalline form-S of methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula-1.
Figure 5: Illustrates the DSC thermogram of crystalline form-S of methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula-1.
Detailed description of the Invention:
The present invention provides novel crystalline forms of methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula-1, and process for the preparation thereof.
As used herein the term “suitable solvent” used in the present invention refers to “hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, pet ether, toluene, pentane, cycloheptane, methylcyclohexane, m-, o-, or p-xylene, and the like; “ether solvents” such as dimethoxy methane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, t-butyl methyl ether, 1,2-dimethoxy ethane and the like; “ester solvents” such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate and the like; “polar-aprotic solvents such as dimethylacetamide (DMA), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP) and the like; “chloro solvents” such as dichloro methane, dichloroethane, chloroform, carbon tetrachloride and the like; “ketone solvents” such as acetone, methyl ethyl ketone, methyl isobutylketone and the like; “nitrile solvents” such as acetonitrile, propionitrile, isobutyronitrile and the like; “alcoholic solvents” such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 2-methoxyethanol, l, 2-ethoxyethanol, diethylene glycol, 1, 2, or 3-pentanol, neo-pentyl alcohol, t-

pentyl alcohol, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol and the like; “polar solvents” such as water or mixtures thereof.
The first aspect of the present invention provides a novel crystalline form-M of methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl) carbamate compound of formula-1, characterized by its powder X-ray diffraction pattern having peaks at 7.1, 8.2, 8.6, 10.8, 12.9, 13.5, 14.2, 15.4, 17.7, 19.2, 20.1, 23.3, 24.1, 25.0 and 26.5 ±0.2 degrees two theta.
The crystalline form-M of methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula-1 is further characterized by 13.1, 16.2, 19.5, 20.7, 22.8, 26.0, 27.5, 27.8, 29.0, 29.8 and 31.6 ±0.2 degrees two theta.
The crystalline form-M of methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b] pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula-1 is further characterized by powder X-ray diffraction pattern as depicted in figure-2 and differential scanning calorimetry (DSC) thermogram as depicted in figure-3 respectively.
The second aspect of the present invention provides a process for the preparation of crystalline form-M of methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula-1, comprising of:
a) Dissolving methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula-1 in a suitable solvent,
b) adding the solution obtained in step-a) to a suitable solvent at a suitable temperature,
c) stirring the reaction mixture,
d) adding a suitable solvent to the reaction mixture at a suitable temperature,
e) stirring the reaction mixture,
f) filtering the precipitated solid and drying to get crystalline form-M of methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl) carbamate compound of formula-1.
Wherein,

in step-a), b) and d) the suitable solvent is selected from alcohol solvents, ketone solvents, ester
solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents and polar solvents like
water or mixture thereof;
in step-b) the suitable temperature is ranging from -50°C to 25-30°C;
in step-d) the suitable temperature is ranging from -30°C to 25-30°C.
The preferred embodiment of the present invention provides a process for the preparation of crystalline form-M of methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula-1, comprising of:
a) Dissolving methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula-1 in dimethyl acetamide,
b) adding the solution obtained in step-a) to methyl tertiary butyl ether at -50°C,
c) stirring the reaction mixture,
d) adding acetone to the reaction mixture at -20°C,
e) stirring the reaction mixture,
f) filtering the precipitated solid and drying to get crystalline form-M of methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl) carbamate compound of formula-1.
The another preferred embodiment of the present invention provides a process for the preparation of crystalline form-M of methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula-1, comprising of,
a) Dissolving methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula-1 in dimethyl acetamide,
b) adding the solution obtained in step-a) to toluene at -50°C,
c) stirring the reaction mixture,
d) adding acetone to the reaction mixture at -20°C,
e) stirring the reaction mixture,
f) filtering the precipitated solid and drying to get crystalline form-M of methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl) carbamate compound of formula-1.

The another preferred embodiment of the present invention provides process for the preparation of crystalline form-M of methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo [3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula-1, comprising of,
a) Dissolving methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula-1 in dimethyl acetamide,
b) adding the solution obtained in step-a) to a mixture of acetone and water at -30°C,
c) stirring the reaction mixture,
d) adding methyl tertiary butyl ether and followed by n-heptane to the reaction mixture at -25 to -15°C,
e) stirring the reaction mixture,
f) filtering the precipitated solid and drying to get crystalline form-M of methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl) carbamate compound of formula-1.
The third aspect of the present invention provides a novel crystalline form-S of methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl) carbamate compound of formula-1, characterized by its powder X-ray diffraction pattern having peaks at 6.7, 8.0, 8.2, 11.2, 11.8, 13.2, 13.5, 14.3, 15.4, 15.9, 16.4, 17.7, 19.4, 20.2, 21.5, 23.4, 24.2, 25.1, 25.5, 26.6, 27.9 and 28.6 ±0.2 degrees two theta.
The crystalline form-S of methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b] pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula-1 is further characterized by 7.1, 8.6, 8.9, 10.6, 18.1, 22.9, 29.0, 29.8, 30.9, 32.1, 32.7, 34.4 and 35.9 ±0.2 degrees two theta.
The crystalline form-S of methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b] pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula-1 is further characterized by powder X-ray diffraction pattern as depicted in figure-4 and differential scanning calorimetry (DSC) thermogram as depicted in figure-5.
The fourth aspect of the present invention provides a process for the preparation of crystalline form-S of methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula-1, comprising of:

a) Dissolving methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula-1 in a suitable solvent,
b) adding the solution obtained in step-a) to a suitable solvent at a suitable temperature,
c) cooling the reaction mixture to a suitable temperature,
5 d) stirring the reaction mixture,
e) filtering the precipitated solid and drying to get crystalline form-S of methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl) carbamate compound of formula-1.
10 Wherein,
in step-a) and b) the suitable solvent is selected from alcohol solvents, ketone solvents, ester
solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents and polar solvents like
water or mixture thereof;
in step-b) the suitable temperature was ranging from 0°C to 30°C;
15 in step-c) the suitable temperature is ranging from -40°C to 0°C.
The preferred embodiment of the present invention provides a process for the preparation
of crystalline form-S of methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-
yl]-5-pyrimidinyl(methyl)carbamate compound of formula-1, comprising of:
20 a) Dissolving methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-
5-pyrimidinyl(methyl)carbamate compound of formula-1 in dimethyl acetamide,
b) adding the solution obtained in step-a) to water at 25-30°C,
c) cooling the reaction mixture to -30°C,
d) stirring the reaction mixture,
25 e) filtering the precipitated solid and drying to get crystalline form-S of methyl 4,6-
diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl) carbamate compound of formula-1.
Crystalline forms of methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]
30 pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula-1 produced by the present
invention can be further micronized or milled in a conventional techniques to get the desired
particle size to achieve desired solubility profile based on different forms of pharmaceutical
composition requirements. Techniques that may be used for particle size reduction include, but
8

not limited to ball, roller and hammer mills, and jet mills. Milling or micronization may be performed before drying, or after the completion of drying of the product.
The starting material, methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]
5 pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula-1 used in the present
invention can be prepared according to any of the process known in the art.
The present invention also encompasses pharmaceutical compositions comprising novel
crystalline forms compound of formula-1. As used herein, the term "pharmaceutical
10 compositions" or "pharmaceutical formulations" include tablets, pills, powders, liquids,
suspensions, emulsions, granules, capsules, suppositories, or injection preparations.
The process disclosed in example-8 of US7173037 B2 was into-to repeated and the
obtained solid methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-
15 pyrimidinyl(methyl)carbamate compound of formula-1 was characterized with P-XRD and it
has been designated herein as Form-A. The P-XRD pattern of the crystalline form-A of methyl
4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)
carbamate compound of formula-1 is depicted in figure-1.
20 P-XRD Method of Analysis:
PXRD analysis of compounds produced by the present invention were carried out using BRUKER/AXS X-Ray diffractometer using Cu Kα radiation of wavelength 1.5406 A° and continuous scan speed of 0.03°/min.
DSC method of Analysis:
25 Differential scanning calorimetric (DSC) analysis was performed with Q10 V9.6 Build
290 calorimeter. Samples of about 2 to 3 milligrams held in a closed pan were analyzed at a heating rate of 10° per minute.
The process described in the present invention was demonstrated in examples illustrated
30 below. These examples are provided as illustration only and therefore should not be construed as
limitation of the scope of the invention.
Examples:
Example-1: Preparation of crystalline Form-M of methyl 4,6-diamino-2-[1-(2-fluoro
benzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate (Formula-1)
9

Dimethyl acetamide (70 ml) was added to methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-
pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate (500 mg) at 25-30°C and stirred
for 10 minutes at the same temperature. The reaction mixture was added to a pre-cooled methyl
tert-butyl ether (30 ml) at -45°C to -50°C and stirred for 10 minutes at the same temperature.
5 Slowly raised the temperature of the reaction mixture to -10°C to -5°C. Acetone (10 ml) was
added to the reaction mixture at -10°C to -5°C. Slowly raised the temperature of the reaction
mixture to 25-30°C and stirred for 20 minutes at the same temperature. Filtered the precipitated
solid and dried to get the title compound. Yield: 400 mg.
The P-XRD pattern of the obtained compound is depicted in figure-2.
10 Example-2: Preparation of crystalline Form-M of methyl 4,6-diamino-2-[1-(2-fluoro
benzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate (Formula-1)
Dimethyl acetamide (70 ml) was added to methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate (500 mg) at 25-30°C and stirred for 10 minutes at the same temperature. The reaction mixture was added to a pre-cooled toluene
15 at -45°C to -50°C and stirred for 10 minutes at the same temperature. Slowly raised the
temperature of the reaction mixture to -10°C to -5°C. Acetone (10 ml) was added to the reaction mixture at -10°C to -5°C. Slowly raised the temperature of the reaction mixture to 25-30°C and stirred for 30 minutes at the same temperature. Filtered the precipitated solid and dried to get the title compound. Yield: 350 mg.
20 The P-XRD pattern of the obtained compound is depicted in figure-2.
Example-3: Preparation of crystalline Form-M of methyl 4,6-diamino-2-[1-(2-fluoro benzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate (Formula-1)
Dimethyl acetamide (10 ml) was added to methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate (300 mg) at 25-30°C and stirred
25 for 10 minutes at the same temperature. The reaction mixture was added to pre-cooled aqueous
acetone at -30°C to -35°C and stirred for 10 minutes at the same temperature. Slowly raised the temperature of the reaction mixture to -20°C to -15°C. Methyl tertiary butyl ether (50 ml) and followed by n-Heptane (50 ml) were added to the reaction mixture at -20°C to -15°C. Slowly raised the temperature of the reaction mixture to 25-30°C and stirred for 20 minutes at the same
30 temperature. Filtered the precipitated solid and dried to get the title compound. Yield: 220 mg.
The P-XRD pattern of the obtained compound is depicted in figure-2.
10

Example-4: Preparation of crystalline Form-S of methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo [3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate (Formula-1)
Dimethyl acetamide (70 ml) was added to methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-
pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate (500 mg) at 25-30°C and stirred
5 for 10 minutes at the same temperature. Water (50 ml) was cooled to -30°C to -35°C. The
reaction mixture was added to water at -30 to -35°C and stirred for 10 minutes at the same
temperature. Slowly raised the temperature of the reaction mixture to 25-30°C and stirred for 30
minutes at the same temperature. Filtered the precipitated solid and dried to get the title
compound. Yield: 400 mg.
10 The P-XRD pattern of the obtained compound is depicted in figure-4.
Reference example-1:
Preparation of methyl 4,6-diamino-2-[1-(2-fluoro benzyl)-1H-pyrazolo [3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate (Formula-1)
Methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimid-
15 inylcarbamate 20.0 g (49.0 m mol) is dissolved in tetrahydrofuran (257 ml) and cooled to 0°C.
Lithium bis(trimethylsilyl)amide solution 53.9 ml (49.0 m mol of a 1M solution in tetrahydro
furan) was added drop wise over the course of 15 minutes. After stirring at 0°C for 20 minutes,
iodomethane 6.95 g (53.9 m mol) was added. After one hour, the mixture is allowed to warm to
room temperature, and the reaction is stopped by adding saturated aqueous ammonium chloride
20 solution. The phases are separated. The aqueous phase is extracted several times with ethyl
acetate and dichloromethane. The combined organic phases are concentrated in vacuo. The
residue obtained in this way is suspended in a mixture of dichloromethane and tetrahydrofuran
(1:1). The insoluble crystals are filtered off with suction and taken up in methanol. The mixture
is refluxed for one hour. After cooling, the precipitate which has separated out is filtered off. The
25 red solid obtained in this way is suspended in a mixture of dioxane and dichloromethane (1:1)
100 ml and, while boiling, methanol (20 ml) was added until a clear solution forms. Activated
carbon is added, and the mixture is boiled briefly and filtered hot through kieselguhr. The
solution obtained in this way is evaporated to dryness. The suspension after taking up in
methanol is stirred at room temperature for one hour. The white crystals are filtered off with
30 suction. Yield: 14.8 gms.
The P-XRD pattern of the obtained compound was depicted in figure-1.
11

We Claim:
1. Novel crystalline form-M of methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b] pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula-1, characterized by its powder X-ray diffraction pattern having peaks at 7.1, 8.2, 8.6, 10.8, 12.9, 13.1, 13.5, 14.2, 15.4, 16.2, 17.7, 19.2, 19.5, 20.1, 20.7, 22.8, 23.3, 24.1, 25.0, 26.0, 26.5, 27.5, 27.8, 29.0, 29.8 and 31.6 ±0.2 degrees two theta as depicted in figure-2.
2. A process for the preparation of crystalline form-M of methyl 4,6-diamino-2-[1-(2-fluoro benzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula-1, comprising of:

a) Dissolving methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula-1 in a suitable solvent,
b) adding the solution obtained in step-a) to a suitable solvent at a suitable temperature,
c) stirring the reaction mixture,
d) adding a suitable solvent to the reaction mixture at a suitable temperature,
e) stirring the reaction mixture,
f) filtering the precipitated solid and drying to get crystalline form-M of methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl) carbamate compound of formula-1.
3. The process according to claim-2 wherein,
in step-a), the suitable solvent is selected from polar aprotic solvents;
in step-b) and d) the suitable solvent is selected from ether solvents, hydrocarbon solvents,
ketone solvents, ester solvents and polar solvents like water or mixture thereof;
in step-b) the suitable temperature is ranging from -50°C to 25-30°C;
in step-d) the suitable temperature is ranging from -30°C to 25-30°C.
4. A process for the preparation of crystalline form-M of methyl 4,6-diamino-2-[1-(2-fluoro
benzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of
formula-1, comprising of:
a) Dissolving methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula-1 in dimethyl acetamide,
b) adding the solution obtained in step-a) to methyl tertiary butyl ether at -50°C,

c) stirring the reaction mixture,
d) adding acetone to the reaction mixture at -20°C,
e) stirring the reaction mixture,
f) filtering the precipitated solid and drying to get crystalline form-M of methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl) carbamate compound of formula-1.
5. A process for the preparation of crystalline form-M of methyl 4,6-diamino-2-[1-(2-fluoro
benzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of
formula-1, comprising of,
a) Dissolving methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula-1 in dimethyl acetamide,
b) adding the solution obtained in step-a) to toluene at -50°C,
c) stirring the reaction mixture,
d) adding acetone to the reaction mixture at -20°C,
e) stirring the reaction mixture,
f) filtering the precipitated solid and drying to get crystalline form-M of methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl) carbamate compound of formula-1.
6. A process for the preparation of crystalline form-M of methyl 4,6-diamino-2-[1-(2-fluoro
benzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of
formula-1, comprising of,
a) Dissolving methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula-1 in dimethyl acetamide,
b) adding the solution obtained in step-a) to a mixture of acetone and water at -30°C,
c) stirring the reaction mixture,
d) adding methyl tertiary butyl ether and followed by n-heptane to the reaction mixture at -25 to -15°C,

f) filtering the precipitated solid and drying to get crystalline form-M of methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl (methyl)carbamate compound of formula-1.
7. Novel crystalline form-S of methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b] pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula-1, characterized by its powder X-ray diffraction pattern having peaks at 6.7, 7.1, 8.0, 8.2, 8.6, 8.9, 10.6, 11.2, 11.8, 13.2, 13.5, 14.3, 15.4, 15.9, 16.4, 17.7, 18.1, 19.4, 20.2, 21.5, 22.9, 23.4, 24.2, 25.1, 25.5, 26.6, 27.9, 28.6, 29.0, 29.8, 30.9, 32.1, 32.7, 34.4 and 35.9 ±0.2 degrees two theta as depicted in figure-4.
8. A process for the preparation of crystalline form-S of methyl 4,6-diamino-2-[1-(2-fluoro benzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula-1, comprising of:

a) Dissolving methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula-1 in a suitable solvent,
b) adding the solution obtained in step-a) to a suitable solvent at a suitable temperature,
c) cooling the reaction mixture to a suitable temperature,
d) stirring the reaction mixture,
e) filtering the precipitated solid and drying to get crystalline form-S of methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl (methyl)carbamate compound of formula-1.
9. The process according to claim-8 wherein,
in step-a) and b) the suitable solvent is selected from polar aprotic solvents and polar solvents
like water or mixture thereof;
in step-b) the suitable temperature was ranging from 0 to 30°C;
in step-c) the suitable temperature is ranging from - 40°C to 0°C.
10. A process for the preparation of crystalline form-S of methyl 4,6-diamino-2-[1-(2-fluoro
benzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of
formula-1, comprising of:

a) Dissolving methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula-1 in dimethyl acetamide,
b) adding the solution obtained in step-a) to water at 25-30°C,
c) cooling the reaction mixture to -30°C,
d) stirring the reaction mixture,
e) filtering the precipitated solid and drying to get crystalline form-S of methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula-1.