DESC:The following specification describes particularly the invention and in the manner in which it is to be performed:
INTRODUCTION
Aspects of the present application relate to solid form of Icotinib hydrochloride and pharmaceutical compositions thereof. Specific aspects relate to the crystalline forms Icotinib hydrochloride salt and processes for their preparation.
Icotinib is the adopted name of compound developed by Hanmi pharma having a chemical name: N-(3-Ethynylphenyl)-7,8,10,11,13,14-hexahydro[1,4,7,10]tetraoxacyclododecino[2,3-g]quinazolin-4-amine and the structure as below.

Icotinib is a highly selective, first generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI).
US 7078409 B2 first discloses Icotinib, its pharmaceutically acceptable salts, preparative process, pharmaceutical composition and their use for treating epidermal growth factor receptor (EGFR) tyrosine kinase or vascular endothelial growth factor receptor (VEGFR) tyrosine kinase-mediated disorders.
Further, US 8822482 B2 discloses Icotinib hydrochloride salt, crystalline form I, Form-II, Form-III and Form-IV of Icotinib hydrochloride characterized through X-ray power diffraction pattern.
The existence and possible numbers of polymorphic forms for a given compound cannot be predicted, and there are no “standard” procedures that can be used to prepare polymorphic forms of a substance. However, new forms of a pharmaceutically useful compound may provide an opportunity to improve the performance characteristics of pharmaceutical products. Further, discovery of additional polymorphic forms, including solvate polymorphs, may help in the identification of the polymorphic content of a batch of an active pharmaceutical ingredient. For example, in some cases, different forms of the same drug can exhibit very different solubility and different dissolution rates. The discovery of new polymorphic forms enlarges selection of materials with which formulation scientists can design a pharmaceutically acceptable dosage form of a drug with a targeted release profile or other desired characteristics. Therefore, there remains a need for preparing new and stable polymorphic forms of Icotinib hydrochloride which can overcome the disadvantages of the prior art and their preparation in a more cost effective and industrially viable manner.
SUMMARY
In an aspect, the present application provides a crystalline Form R of Icotinib hydrochloride, characterized by a PXRD pattern comprising the peaks at about 6.22, 10.16, 14.88, 16.18, 19.55, 20.89, 21.66, 22.47, 23.08, 23.35, 24.00, 25.74, 26.19, 30.73 and 32.27 ± 0.2° 2?.
In an aspect, the present application provides a crystalline Form ICB-1 of Icotinib hydrochloride, characterized by a PXRD pattern comprising the peaks at about 10.08, 12.83, 20.72, 23.42, 26.95 and 28.10 ± 0.2° 2?.
In another aspect, the present application provides a crystalline Form ICB-1 of Icotinib hydrochloride, further characterized by a PXRD pattern comprising the peaks at about 9.80, 10.69, 12.15 and 21.53 ± 0.2° 2?.
In another aspect, the present application provides a crystalline Form ICB-2 of Icotinib hydrochloride, characterized by a PXRD pattern comprising the peaks at about 6.85, 13.212, 21.82 and 26.27± 0.2° 2?.
In another aspect, the present application provides a crystalline Form ICB-2 of Icotinib hydrochloride, further characterized by a PXRD pattern comprising the peaks at about 7.47, 15.86, 16.502 and 22.36 ± 0.2° 2?.
In another aspect, the present application provides a crystalline Form ICB-3 of Icotinib hydrochloride, characterized by a PXRD pattern comprising the peaks at about 7.25, 9.55, 11.81, 13.75, 14.58, 24.23 and 29.73 ± 0.2° 2?.
In another aspect, the present application provides a crystalline Form ICB-4 of Icotinib hydrochloride, characterized by a PXRD pattern comprising the peaks at about 8.31, 9.22, 16.72, 24.61 and 30.24 ± 0.2° 2?.
In another aspect, the present application provides a crystalline Form ICB-4 of Icotinib hydrochloride, further characterized by a PXRD pattern comprising the peaks at about 9.93, 11.31, 14.96 and 22.20 ± 0.2° 2?.
In another aspect, the present application provides a crystalline Form ICB-5 of Icotinib hydrochloride, characterized by a PXRD pattern comprising the peaks at about 4.44, 8.89, 13.31 and 25.83 ± 0.2° 2?.
In another aspect, the present application provides a crystalline Form ICB-5 of Icotinib hydrochloride, further characterized by a PXRD pattern comprising the peaks at about 16.42, 15.63 and 26.89 ± 0.2° 2?.
In another aspect, the present application provides a crystalline Form ICB-6 of Icotinib hydrochloride, characterized by a PXRD pattern comprising the peaks at about 9.91 and 21.15 ± 0.2° 2?.
In another aspect, the present application provides a crystalline Form ICB-6 of Icotinib hydrochloride, further characterized by a PXRD pattern comprising the peaks at about 7.56, 15.12, 16.44 and 24.06 ± 0.2° 2?.
In another aspect, the present application provides a crystalline Form ICB-7 of Icotinib hydrochloride, characterized by a PXRD pattern comprising the peaks at about 6.42, 6.71, 7.8, 19.47 and 19.76 ± 0.2° 2?.
In another aspect, the present application provides a crystalline Form ICB-7 of Icotinib hydrochloride, further characterized by a PXRD pattern comprising the peaks at about 15.6 and 21.62 ± 0.2° 2?.
In another aspect, the present application provides a crystalline Form ICB-8 of Icotinib hydrochloride, characterized by a PXRD pattern comprising the peaks at about 7.31, 19.25, 21.23 and 22.58 ± 0.2° 2?.
In another aspect, the present application provides a crystalline Form ICB-8 of Icotinib hydrochloride, further characterized by a PXRD pattern comprising the peaks at about 7.18, 16.68 and 20.43 ± 0.2° 2?.
In another aspect, the present application provides a process for the preparation of crystalline Form R of Icotinib hydrochloride, comprising
a) providing a solution of Icotinib hydrochloride in a solvent,
b) optionally adding water; and
c) isolating the crystalline Form R of Icotinib hydrochloride.
In another aspect, the present application provides a process for the preparation of crystalline Form ICB-1 of Icotinib hydrochloride, comprising
a) providing a solution or suspending Icotinib hydrochloride in ethanol; and
b) isolating the crystalline Form ICB-1 of Icotinib hydrochloride.
In another aspect, the present application provides a process for the preparation of crystalline Form ICB-2 of Icotinib hydrochloride, comprising
a) providing a solution or suspending Icotinib hydrochloride in propionic acid, THF, 1,4-Dioxane, water or mixtures thereof; and
b) isolating the crystalline Form ICB-2 of Icotinib hydrochloride.
In another aspect, the present application provides a process for the preparation of crystalline Form ICB-3 of Icotinib hydrochloride, comprising
a) providing a solution or suspending Icotinib hydrochloride in solvent selected from glycerol, MTBE, ethyl acetate, tetrahydrofuran, 1,4-dioxane, water and mixtures thereof ; and
b) isolating the crystalline Form ICB-3 of Icotinib hydrochloride.
In another aspect, the present application provides a process for the preparation of crystalline Form ICB-4 of Icotinib hydrochloride, comprising
a) providing a solution or suspending Icotinib hydrochloride in methanol; and
b) isolating the crystalline Form ICB-4 of Icotinib hydrochloride.
In another aspect, the present application provides a process for the preparation of crystalline Form ICB-5 of Icotinib hydrochloride, comprising
a) providing a solution or suspending Icotinib hydrochloride in formic acid; and
b) isolating the crystalline Form ICB-5 of Icotinib hydrochloride.
In another aspect, the present application provides a process for the preparation of crystalline Form ICB-6 of Icotinib hydrochloride, comprising
a) providing a solution or suspending Icotinib hydrochloride in dimethylsulfoxide; and
b) isolating the crystalline Form ICB-6 of Icotinib hydrochloride.
In another aspect, the present application provides a process for the preparation of crystalline Form ICB-7 of Icotinib hydrochloride, comprising
a) providing a solution or suspending Icotinib hydrochloride in propylene glycol; and
b) isolating the crystalline Form ICB-7 of Icotinib hydrochloride
In another aspect, the present application provides a process for the preparation of crystalline Form ICB-8 of Icotinib hydrochloride, comprising
a) providing a solution or suspending Icotinib hydrochloride in acetic acid; and
b) isolating the crystalline Form ICB-8 of Icotinib hydrochloride
In another aspect, the present application provides pharmaceutical compositions comprising a one or more crystalline forms selected crystalline form R, crystalline Form ICB-1, Form ICB-2, Form ICB-3, Form ICB-4, Form ICB-5, Form ICB-6, Form ICB-7 and Form ICB-8 of Icotinib hydrochloride and at least one pharmaceutically acceptable excipient.

BRIEF DESCRIPTION OF THE DRAWING
Figure 1 is an illustrative X-ray powder diffraction pattern of crystalline Form ICB-1 of Icotinib hydrochloride, prepared by the method of Example-1.
Figure 2 is an illustrative X-ray powder diffraction pattern of crystalline Form ICB-2 of Icotinib hydrochloride, prepared by the method of Example-2.
Figure 3 is an illustrative X-ray powder diffraction pattern of crystalline Form ICB-3 of Icotinib hydrochloride, prepared by the method of Example-3.
Figure 4 is an illustrative X-ray powder diffraction pattern of crystalline Form ICB-4 of Icotinib hydrochloride, prepared by the method of Example-4.
Figure 5 is an illustrative X-ray powder diffraction pattern of crystalline Form ICB-5 of Icotinib hydrochloride, prepared by the method of Example-5.
Figure 6 is an illustrative X-ray powder diffraction pattern of crystalline Form ICB-6 of Icotinib hydrochloride, prepared by the method of Example-6.
Figure 7 is an illustrative X-ray powder diffraction pattern of crystalline Form ICB-7 of Icotinib hydrochloride, prepared by the method of Example-7.
Figure 8 is an illustrative X-ray powder diffraction pattern of crystalline Form ICB-8 of Icotinib hydrochloride, prepared by the method of Example-8.
Figure 9 is an illustrative X-ray powder diffraction pattern of crystalline Form R of Icotinib hydrochloride, prepared by the method of Example No 9.

DETAILED DESCRIPTION
In an aspect, the present application provides a crystalline Form R of Icotinib hydrochloride, characterized by a PXRD pattern comprising the peaks at about 6.22, 10.16, 14.88, 16.18, 19.55, 20.89, 21.66, 22.47, 23.08, 23.35, 24.00, 25.74, 26.19, 30.73 and 32.27 ± 0.2° 2?.
In an aspect, the present application provides a crystalline Form ICB-1 of Icotinib hydrochloride, characterized by a PXRD pattern comprising the peaks at about 10.08, 12.83, 20.72, 23.42, 26.95 and 28.10 ± 0.2° 2?.
In another aspect, the present application provides a crystalline Form ICB-1 of Icotinib hydrochloride, further characterized by a PXRD pattern comprising the peaks at about 9.80, 10.69, 12.15 and 21.53 ± 0.2° 2?.
In another aspect, the present application provides a crystalline Form ICB-2 of Icotinib hydrochloride, characterized by a PXRD pattern comprising the peaks at about 6.85, 13.212, 21.82 and 26.27± 0.2° 2?.
In another aspect, the present application provides a crystalline Form ICB-2 of Icotinib hydrochloride, further characterized by a PXRD pattern comprising the peaks at about 7.47, 15.86, 16.502 and 22.36 ± 0.2° 2?.
In another aspect, the present application provides a crystalline Form ICB-3 of Icotinib hydrochloride, characterized by a PXRD pattern comprising the peaks at about 7.25, 9.55, 11.81, 13.75, 14.58, 24.23 and 29.73 ± 0.2° 2?.
In another aspect, the present application provides a crystalline Form ICB-4 of Icotinib hydrochloride, characterized by a PXRD pattern comprising the peaks at about 8.31, 9.22, 16.72, 24.61 and 30.24 ± 0.2° 2?.
In another aspect, the present application provides a crystalline Form ICB-4 of Icotinib hydrochloride, further characterized by a PXRD pattern comprising the peaks at about 9.93, 11.31, 14.96 and 22.20 ± 0.2° 2?.
In another aspect, the present application provides a crystalline Form ICB-5 of Icotinib hydrochloride, characterized by a PXRD pattern comprising the peaks at about 4.44, 8.89, 13.31 and 25.83 ± 0.2° 2?.
In another aspect, the present application provides a crystalline Form ICB-5 of Icotinib hydrochloride, further characterized by a PXRD pattern comprising the peaks at about 16.42, 15.63 and 26.89 ± 0.2° 2?.
In another aspect, the present application provides a crystalline Form ICB-6 of Icotinib hydrochloride, characterized by a PXRD pattern comprising the peaks at about 9.91 and 21.15 ± 0.2° 2?.
In another aspect, the present application provides a crystalline Form ICB-6 of Icotinib hydrochloride, further characterized by a PXRD pattern comprising the peaks at about 7.56, 15.12, 16.44 and 24.06 ± 0.2° 2?.
In another aspect, the present application provides a crystalline Form ICB-7 of Icotinib hydrochloride, characterized by a PXRD pattern comprising the peaks at about 6.42, 6.71, 7.8, 19.47 and 19.76 ± 0.2° 2?.
In another aspect, the present application provides a crystalline Form ICB-7 of Icotinib hydrochloride, further characterized by a PXRD pattern comprising the peaks at about 15.6 and 21.62 ± 0.2° 2?.
In another aspect, the present application provides a crystalline Form ICB-8 of Icotinib hydrochloride, characterized by a PXRD pattern comprising the peaks at about 7.31, 19.25, 21.23 and 22.58 ± 0.2° 2?.
In another aspect, the present application provides a crystalline Form ICB-8 of Icotinib hydrochloride, further characterized by a PXRD pattern comprising the peaks at about 7.18, 16.68 and 20.43 ± 0.2° 2?.
In another aspect, the present application provides a process for the preparation of crystalline Form R of Icotinib hydrochloride, comprising
c) providing a solution of Icotinib hydrochloride in a solvent,
d) optionally adding water; and
c) isolating the crystalline Form R of Icotinib hydrochloride.

Providing a solution in step a) includes:
i) direct use of a reaction mixture containing Icotinib hydrochloride that is obtained in the course of its synthesis that comprises alcohol, polar aprotic solvents, water or mixture thereof, or by alcohol, polar aprotic solvents, water or mixture thereof to a reaction mixture; or
ii) dissolving Icotinib hydrochloride in a solvent selected from alcohol, polar aprotic solvents, water or mixture thereof
In another aspect, the present application provides a process for the preparation of crystalline Form ICB-1 of Icotinib hydrochloride, comprising
a) providing a solution or suspending Icotinib hydrochloride in ethanol; and
b) isolating the crystalline Form ICB-1 of Icotinib hydrochloride.
In another aspect, the present application provides a process for the preparation of crystalline Form ICB-2 of Icotinib hydrochloride, comprising
a) providing a solution or suspending Icotinib hydrochloride in propionic acid, THF, 1,4-Dioxane, water or mixtures thereof; and
b) isolating the crystalline Form ICB-2 of Icotinib hydrochloride.
In another aspect, the present application provides a process for the preparation of crystalline Form ICB-3 of Icotinib hydrochloride, comprising
a) providing a solution or suspending Icotinib hydrochloride in solvent selected from glycerol, MTBE, ethyl acetate, tetrahydrofuran, 1,4-dioxane, water and mixtures thereof ; and
b) isolating the crystalline Form ICB-3 of Icotinib hydrochloride.
In another aspect, the present application provides a process for the preparation of crystalline Form ICB-4 of Icotinib hydrochloride, comprising
a) providing a solution or suspending Icotinib hydrochloride in methanol; and
b) isolating the crystalline Form ICB-4 of Icotinib hydrochloride.
In another aspect, the present application provides a process for the preparation of crystalline Form ICB-5 of Icotinib hydrochloride, comprising
a) providing a solution or suspending Icotinib hydrochloride in formic acid; and
b) isolating the crystalline Form ICB-5 of Icotinib hydrochloride.
In another aspect, the present application provides a process for the preparation of crystalline Form ICB-6 of Icotinib hydrochloride, comprising
a) providing a solution or suspending Icotinib hydrochloride in dimethylsulfoxide; and
b) isolating the crystalline Form ICB-6 of Icotinib hydrochloride.
In another aspect, the present application provides a process for the preparation of crystalline Form ICB-7 of Icotinib hydrochloride, comprising
a) providing a solution or suspending Icotinib hydrochloride in propylene glycol; and
b) isolating the crystalline Form ICB-7 of Icotinib hydrochloride
In another aspect, the present application provides a process for the preparation of crystalline Form ICB-8 of Icotinib hydrochloride, comprising
a) providing a solution or suspending Icotinib hydrochloride in acetic acid; and
b) isolating the crystalline Form ICB-8 of Icotinib hydrochloride

Providing a solution or suspension of Icotinib hydrochloride includes:
i) direct use of a reaction mixture containing Icotinib hydrochloride that is obtained in the course of its synthesis; or
ii) dissolving or suspending Icotinib hydrochloride in a solvent
Any physical form of Icotinib hydrochloride may be utilized for providing or suspending the solution of Icotinib hydrochloride. In embodiments, Icotinib hydrochloride can be dissolved or suspended in a solvent or mixture of one or more solvents. The dissolution or suspension temperatures may range from about 0°C to about the reflux temperature of the solvent, or less than about 100°C, less than about 70°C, less than about 40°C, less than about 30°C, less than about 20°C, less than about 10°C, or any other suitable temperatures without affecting its quality.
Isolation of crystalline forms of Icotinib hydrochloride may involve methods including cooling, concentrating the mass, adding an anti-solvent, adding seed crystals to induce crystallization, or the like. Stirring or other alternate methods such as shaking, agitation, or the like, may also be employed for the isolation.
The crystalline forms of Icotinib hydrochloride may be recovered by methods including decantation, centrifugation, gravity filtration, suction filtration, agitated nutsche filter & dryer or any other technique for the recovery of solids under pressure or under reduced pressure. The recovered solid may optionally be dried. Drying may be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, agitated nutsche filter & dryer or the like.
The drying may be carried out at temperatures less than about 100°C, less than about 80°C, less than about 60°C, less than about 50°C, less than about 30°C, or any other suitable temperatures, at atmospheric pressure or under a reduced pressure, as long as the Icotinib hydrochloride is not degraded in quality. The drying may be carried out for any desired times until the required product quality is achieved.
The dried product may optionally be subjected to a size reduction procedure to produce desired particle sizes. Milling or micronization may be performed before drying, or after the completion of drying of the product. Techniques that may be used for particle size reduction include, without limitation, ball, roller and hammer milling, and jet milling.
One or more crystalline forms of the present application may be anhydrous or solvates or hydrates or mixtures thereof.
In another aspect, the present application provides crystalline forms of Icotinib hydrochloride according to instant application and pharmaceutical compositions thereof, wherein the chemical purity of Icotinib hydrochloride may be more than 99% by HPLC or more than 99.5% by HPLC or more than 99.9% by HPLC.
In another aspect, the present application provides pharmaceutical compositions comprising a one or more crystalline forms selected crystalline Form R, crystalline Form ICB-1, Form ICB-2, Form ICB-3, Form ICB-4, Form ICB-5, Form ICB-6, Form ICB-7 and Form ICB-8 of Icotinib hydrochloride and at least one pharmaceutically acceptable excipient.
Crystalline forms of the Icotinib hydrochloride disclosed in the present application is more stable when compared with the crystalline forms reported in the literature. In particular, crystalline forms of the Icotinib hydrochloride disclosed in the present application is more stable when compared with the stable crystalline I reported in US 8822482 B2.
Crystalline Form Exposed to Time period Result
Form-I 25 °C/60 %RH & 30 °C/75 %RH 15 days Form-I converted to mixture of Form-I with other crystalline form
Form R 25 °C/60 %RH & 30 °C/75 %RH 15 days Form R retained
ICB-1 25 °C/60 %RH & 30 °C/75 %RH 15 days ICB-1 retained
ICB-3 25 °C/60 %RH & 30 °C/75 %RH 15 days ICB-3 retained
Crystalline Form R, Form ICB-1 and ICB-3 are stable when open Exposed to 25 °C/60 %RH & 30 °C/75 %RH For 15 days
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Variations of the described procedures, as will be apparent to those skilled in the art, are intended to be within the scope of the present application.
Definitions
The term "about" when used in the present application preceding a number and referring to it, is meant to designate any value which lies within the range of ±10%, preferably within a range of ±5%, more preferably within a range of ±2%, still more preferably within a range of ±1 % of its value. For example, "about 10" should be construed as meaning within the range of 9 to 11 , preferably within the range of 9.5 to 10.5, more preferably within the range of 9.8 to 10.2, and still more preferably within the range of 9.9 to 10.1.
The following definitions are used in connection with the present application unless the context indicates otherwise. In general, the number of carbon atoms present in a given group or compound is designated “Cx-Cy”, where x and y are the lower and upper limits, respectively. For example, a group designated as “C1-C6” contains from 1 to 6 carbon atoms. The carbon number as used in the definitions herein refers to carbon backbone and carbon branching, but does not include carbon atoms of the substituents, such as alkoxy substitutions or the like.
An “alcohol” is an organic compound containing a carbon bound to a hydroxyl group. “C1-C6 alcohols” include methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1-propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, cyclohexanol, phenol, glycerol and the like.
A “polar aprotic solvents” include N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, sulfolane, N-methylpyrrolidone and the like;
EXAMPLES
Example-1: Preparation of crystalline form ICB-1 of Icotinib hydrochloride
Icotinib hydrochloride (1 g) was suspended in ethanol (50 mL), the resulting slurry was stirred at 50° C for 23 hours. Solid was filtered and dried to afford the title compound.
Water content: 0.22%, Loss on drying by TGA: 0.73%
XRPD: Crystalline form ICB-1, as depicted in Figure-1.

Example-2: Preparation of crystalline form ICB-2 of Icotinib hydrochloride
Icotinib hydrochloride (0.8 g) was suspended in propionic acid (12 mL), the resulting slurry was stirred at 40° C for 11 hours. Solid was filtered and dried to afford the title compound.
XRPD: Crystalline form ICB-2, as depicted in Figure-2.

Example-3: Preparation of crystalline form ICB-3 of Icotinib hydrochloride
Icotinib hydrochloride (0.8 g) was suspended in Glycerol-MTBE mixture (2 mL glycerol and 18 mL MTBE), the resulting slurry was stirred at 40° C for 11 hours. Ethyl acetate (20 mL) was added and stirred at ambient temperature for 90 minutes. Ethyl acetate solution was decanted, water (10 mL) was added and stirred for 45 minutes at ambient temperature. Solid was filtered and dried to afford the title compound.
XRPD: Crystalline form ICB-3, as depicted in Figure-3.

Example-4: Preparation of crystalline form ICB-4 of Icotinib hydrochloride
Icotinib hydrochloride (0.8 g) was suspended in methanol (20 mL), the resulting slurry was stirred at 40° C for 10 hours. Solid was filtered and dried to afford the title compound.
XRPD: Crystalline form ICB-4, as depicted in Figure-4.

Example-5: Preparation of crystalline form ICB-5 of Icotinib hydrochloride
Icotinib hydrochloride (0.8 g) was suspended in formic acid (1 mL), the resulting solution was stirred at 40° C for 9 hours. Separated solid was scrapped and collected to afford the title compound.
XRPD: Crystalline form ICB-5, as depicted in Figure-5.

Example-6: Preparation of crystalline form ICB-6 of Icotinib hydrochloride
Icotinib hydrochloride (0.8 g) was suspended in dimethylsulfoxide (4 mL), the resulting solution was stirred at 40° C for 9 hours. Solid was filtered and dried to afford the title compound.
XRPD: Crystalline form ICB-6, as depicted in Figure-6.

Example-7: Preparation of crystalline form ICB-7 of Icotinib hydrochloride
Icotinib hydrochloride (0.8 g) was suspended in propylene glycol (4 mL), the resulting solution was stirred at 40° C for 8 hours. Solid was filtered, washed with ethyl acetate (20 mL) and dried to afford the title compound.
XRPD: Crystalline form ICB-7, as depicted in Figure-7.

Example-8: Preparation of crystalline form ICB-8 of Icotinib hydrochloride
Icotinib hydrochloride (0.8 g) was suspended in acetic acid (2 mL), the resulting solution was stirred at 40° C for 2 hours. Separated solid was filtered and dried to afford the title compound.
XRPD: Crystalline form ICB-8, as depicted in Figure-8.

Example-9: Preparation of crystalline form R of Icotinib hydrochloride
A mixture of 4-chloro-7,8,10,11,13,14-hexahydro-[1,4,7,10] tetraoxacyclododecino[2,3-g]quinazoline (50 g) in ethanol (1200 mL) and DMF (60 mL) was stirred at 28 °C for 15 minutes. 3-ethynylaniline (21.68 g) in IPA (480 mL) was slowly added to the reaction mixture and then heated to 72 °C for 3 hours under nitrogen atmosphere. The reaction mixture was cooled to ambient temperature and stirred for 30 minutes. Separated solid was filtered, washed with isopropanol, and dried at 53 °C under reduced pressure to obtain the title compound.
Purity by HPLC: 99.6%, Water content: 2.3%, melting point: 236 °C
XRPD: Crystalline form R, as depicted in Figure-9.

Example-10: Preparation of crystalline form R of Icotinib hydrochloride
Icotinib hydrochloride (1 g), ethanol (24 mL; water content (by KF): 6.46%), DMF (1.2 mL) and IPA (9.6 mL) charged into flask, heated to 73 °C and stirred for 3 hours under nitrogen atmosphere. The reaction mixture was cooled to ambient temperature and stirred for 30 minutes. Separated solid was filtered, washed with isopropanol (5 mL), and dried at 48 °C under reduced pressure to obtain the title compound.

Example-11: Preparation of crystalline form R of Icotinib hydrochloride
A mixture of 4-chloro-7,8,10,11,13,14-hexahydro-[1,4,7,10] tetraoxacyclododecino[2,3-g]quinazoline (220 g) in ethanol (5280 mL; water content:6.25%) and DMF (264 mL) was stirred at 28 °C for 15 minutes. 3-ethynylaniline (95.38 g) in IPA (2112 mL) was slowly added to the reaction mixture and then heated to 72 °C for 3 hours under nitrogen atmosphere. The reaction mixture was cooled to ambient temperature and stirred for 30 minutes. Separated solid was filtered, washed with isopropanol (1100 mL), and dried at 48 °C under reduced pressure to obtain the title compound.
Purity by HPLC: 99.6%, Water content: 2.04%, melting point: 235 °C
XRPD: Crystalline form R, as depicted in Figure-9.
Ethanol content: 215 ppm; Isopropanol content: 114 ppm; DMF content: Not detected

Example-12: Preparation of crystalline form ICB-1 of Icotinib hydrochloride
Icotinib hydrochloride (135 g mixture of Form ICB-I and Form R) was suspended in ethanol (500 mL), the resulting slurry was stirred at 40° C for 9 hours. Solid was filtered and dried to afford the title compound.

Example-13: Preparation of crystalline form ICB-2 of Icotinib hydrochloride
Icotinib hydrochloride Form R (0.8 g) was suspended in mixture of THF (40 mL) and water (2 mL), the resulting slurry was stirred at 40° C for 8 hours. Solid was filtered and dried to afford the title compound.

Example-14: Preparation of crystalline form ICB-2 of Icotinib hydrochloride
Icotinib hydrochloride Form R (0.8 g) was suspended in mixture of 1,4-Dioxane (40 mL) and water (2 mL), the resulting slurry was stirred at 40° C for 8 hours. Solid was filtered and dried to afford the title compound.

Example-15: Preparation of crystalline form ICB-2 of Icotinib hydrochloride
Icotinib hydrochloride Form R (145 g) was suspended in 0.1 N HCl (3 L), the resulting slurry was stirred at 40° C for 20 hours. Solid was filtered and dried to afford the title compound.
,CLAIMS:CLAIMS

1. Crystalline Form R of Icotinib hydrochloride, characterized by a PXRD pattern comprising the peaks at about 6.22, 10.16, 14.88, 16.18, 19.55, 20.89, 21.66, 22.47, 23.08, 23.35, 24.00, 25.74, 26.19, 30.73 and 32.27 ± 0.2° 2?.
2. Crystalline Form R of Icotinib hydrochloride according to claim 1, characterized by PXRD pattern illustrated in Fig. 9.

3. A process for the preparation of crystalline Form R of Icotinib hydrochloride, comprising
a) providing a solution of Icotinib hydrochloride in a solvent,
b) optionally adding water; and
c) isolating the crystalline Form R of Icotinib hydrochloride.

4. The process according to claim 3, wherein the solvent is selected from alcohol, polar aprotic solvent, water or mixture thereof.

5. The process according to claim 3, wherein the solvent is selected from ethanol, dimethylformamide and water or mixture thereof.

6. The process according to claim 3, wherein the solvent selected from mixture of ethanol, dimethylformamide and water.

7. The process according to claim 3, wherein the solvent selected from mixture of ethanol and water.

8. A crystalline Form ICB-1 of Icotinib hydrochloride, characterized by a PXRD pattern comprising the peaks at about 10.08, 12.83, 20.72, 23.42, 26.95 and 28.10 ± 0.2° 2?.

9. Crystalline Form ICB-1 of Icotinib hydrochloride according to claim 8, further characterized by a PXRD pattern comprising the peaks at about 9.80, 10.69, 12.15 and 21.53 ± 0.2° 2?.

10. A process for the preparation of crystalline Form ICB-1 of Icotinib hydrochloride according to claim 8, comprising
a) providing a solution or suspending Icotinib hydrochloride in ethanol; and
b) isolating the crystalline Form ICB-1 of Icotinib hydrochloride.

11. A crystalline Form ICB-3 of Icotinib hydrochloride, characterized by a PXRD pattern comprising the peaks at about 7.25, 9.55, 11.81, 13.75, 14.58, 24.23 and 29.73 ± 0.2° 2?.

12. A process for the preparation of crystalline Form ICB-3 of Icotinib hydrochloride, comprising
a) providing a solution or suspending Icotinib hydrochloride in solvent selected from glycerol, MTBE, ethyl acetate, tetrahydrofuran, 1,4-dioxane, water and mixtures thereof ; and
b) isolating the crystalline Form ICB-3 of Icotinib hydrochloride.