WO2026009173A1 - Polymorphic forms of rad1901-2hcl - Google Patents

Abstract

The present invention relates to crystalline forms of RAD1901-2HCL and process for preparation thereof, represented by following structural formula.

Description

POLYMORPHIC FORMS OF RAD1901.2HCL

FIELD OF THE INVENTION

The present invention relates to crystalline Forms of RAD1901.2HC1, process for their preparation and pharmaceutical composition comprising it.

BACKGROUND OF THE INVENTION:

RAD1901.2HC1 (Elacestrant is approved as dihydrochloride) chemically known as (6R)-6-(2-

(N-(4-(2-(ethylamino)ethyl)benzyl)-N-ethylamino)-4-methoxy phenyl)-5, 6,7,8- tetrahydronaphthal en-2-ol compound of Formula I and represented by following structural Formula:

Formula I

Elacestrant was discovered and developed by Eisai R&D Management Co Ltd and marketed by Stemline Therapeutics and it is approved for the treatment of postmenopausal women or adult men, with ER-positive, HER2-negative, ESRI -mutated advanced or metastatic breast cancer with disease progression following at least one line of endocrine therapy. It is approved in USFDA and EMEA and it is marketed under the trade name Orserdu®.

US 7,612,114 B2 (herein after referred as ‘ 114) discloses RAD1901 and its process. RAD1901 was prepared by reacting 7-benzyloxy-3-bromo-l,2-dihydronaphthalene with 4- bromo-3 -nitroanisole in presence of dichlorobis(triphenylphosphine)palladium (II) and copper in dimethyl sulfoxide provides 7-benzyloxy-3-(4-methoxy-2-nitrophenyl)-l,2- dihydronaphthalene, which is reduced in presence of pd/C and concentrated hydrochloric acid in tetrahydrofuran and methanol provides 6-(2-amino-4-methoxyphenyl)-5, 6,7,8- tetrahydronaphthalen-2-ol. The obtained compound is reacted with acetic anhydride in pyridine, and then reduced with lithium aluminum hydride in presence of aluminum chloride in tetrahydrofuran provides 6-(2-ethylamino-4-methoxyphenyl)-5, 6,7,8- tetrahydronaphthalen-2-ol. pivaloylation of obtained compound with 2,2-dimethyl-l-(2- thioxo thiazolidin-3-yl)propan-l-one in presence of sodium hydride in tetrahydrofuran provides racemic 6-(2-ethylamino-4-methoxyphenyl)-5,6,7,8- tetrahydronaphthalen-2-yl ester. Optical resolution of obtained compound using chiral HPLC provides (S) and (R)-isomers. The condensation of (R)-isomer and (4-Formylphenyl) acetic acid in presence of sodium triacetoxyborohydride and acetic acid in 1,2-dichloroethane provides pivalic acid (R)-6-{2-[(4-carboxymethylbenzyl)ethylamino]-4-methoxyphenyl}- 5,6,7,8-tetrahydronaphthalen-2-yl ester, which is converted into acid chloride using oxalyl chloride in N,N-dimethylFormamide and tetrahydrofuran and followed by reaction with ethylamine in tetrahydrofuran.

Further the preparation method is represented schematically as below:

US 10,385,008 B2 (herein after referred as ‘008) discloses the preparation of RAD1901.2HC1 and its crystalline Forms designated as Form 1, Form 2, Form 3 and amorphous Form.

RAD1901.2HC1 has been prepared by reacting RAD 1901 with hydrochloric acid in ethanol and ethyl acetate; Form 1 has been prepared from water, ethanol and ethyl acetate; Form 2 has been prepared from water/methanol (wherein ratio of water upto 2%); Form 3 has been prepared from water/methanol (ratio of water is above 2%); amorphous Form has been prepared by lyophilization from water or t-butanol/water (1 : 1).

US ‘008 in Figure 1 shows that Form 1 transforms into Form 3 under high humidity conditions, Form 2 changes to Form 3 when the humidity is below 40%RH, and Form 3 changes to Form 2 when the humidity is above 40%RH. US 11,643,385 B2 discloses crystalline Forms of RAD1901.2HC1 designated as Form IB; wherein Form IB has been prepared from 2-ethoxy ethanol. US ‘385 in Table 17 shows that Form IB can remain stable at humidity above 90%RH. However, Form IB is a very small flaky particle and is predominantly agglomerate. The uneven particle size distribution of the easily agglomerated crystal Form will increase the risk of uneven content of pharmaceutical preparations.

WO 2023064519 Al discloses crystalline Forms of RAD1901.2HC1 designated as Form 6, Form 7 and Form 9, wherein Form 6 is dimethylsulfoxide solvate and prepared from anhydrous dimethylsulfoxide and methyl isobutyl ketone; Form 7 is 1-propanol solvate and prepared from 1-propanol; Form 9 is prepared by exposing Amorphous RAD1901.2HC1 to 75% of relative humidity on 40°C for 6 days.

WO 2023227029 discloses crystalline Form of RAD1901.2HC1 designated as Form CS II, wherein Form CS II has been prepared Form chloroform solvent.

It is known in the art that drug polymorphism is a common phenomenon in drug development, which affects the drug quality. Polymorphism refers to the phenomenon that a compound exists in multiple crystal Forms. Different crystal Forms of APIs have different physical and chemical properties, including chemical stability, thermal stability, solubility, hygroscopicity and/or particle size, which may lead to different dissolution and absorption of the drug in the body, thereby affecting to a certain extent Clinical efficacy of drugs. In addition, different crystal Forms of APIs have different manufacturability, including yield, purification properties, filtration properties, drying properties and grinding properties. The stability relative to pressure during tableting may have an impact on the production of APIs. Processing during the process has an impact. Therefore, polymorphism is an important part of drug research and drug quality control.

RAD1901.2HC1 can exist in different polymorphic Forms, which may differ from each other in terms of stability, physical properties, spectral data as well as process for the preparation thereof. However, there is still a need for crystalline forms which are stable, reproducible, free of other polymorphic forms and suitable for pharmaceutical composition. In view of this the present inventors have now found crystalline forms, which are stable, reproducible, free of other polymorphic forms and suitable for pharmaceutical composition.

OBJECTIVES OF THE INVENTION

The objective of present invention is to provide crystalline Forms of RAD1901.2HC1.

Another objective of the present invention is to provide process for the preparation of crystalline Forms of RAD1901.2HC1 and pharmaceutical composition comprising it.

Another objective of the present invention is to provide RAD1901.2HC1, which yields industrially acceptable yields, purity, economical, commercially feasible.

SUMMARY OF THE INVENTION

The present invention relates to RAD1901.2HC1 crystalline Form Hl, which is characterized by Powder X-Ray diffraction pattern as shown in figure 1.

In another embodiment, the present invention provides a process for the preparation of RAD1901.2HC1 crystalline Form Hl, which comprises: a. dissolving RAD 1901 in ester solvent or mixture of ester solvent and alcoholic solvent; b. adding alcoholic hydrochloride solution; c. maintaining the reaction mixture at 25-30°C; and d. isolating RAD1901.2HC1 crystalline Form Hl.

In another embodiment, the present invention provides RAD1901.2HC1 crystalline Form H2, which is characterized by Powder X-ray diffractogram as shown in figure 2.

In another embodiment, the present invention provides a process for preparation of RAD1901.2HC1 crystalline Form H2, which comprises: a. exposing RAD1901.2HC1 crystalline Form Hl to less than 40%RH for 24 hours; and b. isolating RAD1901.2HC1 crystalline Form H2.

In another embodiment, the present invention provides RAD1901.2HC1 crystalline Form H3, which is characterized by Powder X-ray diffractogram as shown in figure 3. In another embodiment, the present invention provides a process for preparation of RAD1901.2HC1 crystalline Form H3, which comprises: a. heating RAD 1901.2HC1 crystalline Form Hl to 105-110°C; and b. isolating RAD1901.2HC1 crystalline Form H3.

BRIEF DESCRIPTION OF THE DRAWINGS:

Figure 1. Powder X-ray diffractogram of RAD1901.2HC1 crystalline Form Hl

Figure 2. Powder X-ray diffractogram of RAD1901.2HC1 crystalline Form H2

Figure 3 Powder X-ray diffractogram of RAD1901.2HC1 crystalline Form H3

X-ray powder diffraction spectrum was measured on a bruker axs D8 advance X- ray powder diffractometer having a copper- a radiation. Adequate sample was gently flattered on a sample holder and scanned from 2 to 50 degrees two-theta, at 0.02 increment and scan speed of 0.2 Sec/Step. The sample was simply placed on the sample holder. The sample was rotated at 30 rpm at a voltage 40 KV and current 35 mA.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to RAD1901.2HC1 crystalline Form Hl, which is characterized by Powder X-Ray diffraction pattern as shown in figure 1.

In another aspect of the present invention provides a process for the preparation of RAD1901.2HC1 crystalline Form Hl, which comprises dissolving RAD1901 in ester solvent or mixture of ester solvent and alcoholic solvent, wherein ester solvent is selected from group consisting of methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate or isobutyl acetate and alcoholic solvent is selected from group consisting of methanol, ethanol, propanol, isopropanol, butanol or isobutanol; adding alcoholic hydrochloride solution; stirring the reaction mixture at 25-30°C; and isolating RAD1901.2HC1 crystalline Form Hl.

In another aspect of the present invention the reaction mixture is stirred for 1-12 hours, preferably 2-3 hours. In another aspect of the present invention, alcoholic hydrochloride used is about 3.5 equivalents per 1 equivalent of RAD 1901.

In another aspect of the present invention, alcoholic hydrochloride solution is selected from methanolic hydrochloride, ethanolic hydrochloride, propanolic hydrochloride, isopropanolic hydrochloride, butanolic hydrochloride or isobutanolic hydrochloride.

In another aspect of the present invention, isolation is carried out by known conventional methods.

In another aspect the present invention provides RAD1901.2HC1 crystalline Form H2, which is characterized by Powder X-ray diffractogram as shown in figure 2.

In another aspect of the present invention provides RAD1901.2HC1 crystalline Form H2, which is further characterized by monoclinic crystal parameters having a= 31.015, b=11.822, c= 8.854 A°.

In another aspect the present invention provides a process for preparation of RAD1901.2HC1 crystalline Form H2, which comprises exposing RAD1901.2HC1 crystalline Form Hl to less than 40%RH for 24 hours and isolating RAD1901.2HC1 crystalline Form H2 having crystal parameters a= 31.015, b=11.822, c= 8.854 A°.

In another aspect the present invention RAD1901.2HC1 crystalline Form H3, which is characterized by Powder X-ray diffractogram as shown in figure 3.

In another aspect the present invention provides a process for preparation of RAD1901.2HC1 crystalline Form H3, which comprises heating RAD1901.2HC1 crystalline Form Hl at 105- 110°C for 24 hours and isolating RAD1901.2HC1 crystalline Form H3.

In another aspect of the present invention RAD 1901 has been prepared by following the process known in the prior art.

According to another aspect of the present invention, there is provided a pharmaceutical composition comprising crystalline Form Hlof RAD1901.2HC1 and pharmaceutically acceptable excipients, and optionally other therapeutic ingredients. RAD1901.2HC1 crystalline Form HI may preferably be formulated into tablets or other pharmaceutical forms.

According to another aspect of the present invention, there is provided a pharmaceutical composition comprising crystalline Form H2of RAD1901.2HC1 and pharmaceutically acceptable excipients, and optionally other therapeutic ingredients. RAD1901.2HC1 crystalline Form H2 may preferably be formulated into tablets or other pharmaceutical forms.

According to another aspect of the present invention, there is provided a pharmaceutical composition comprising crystalline Form H3 of RAD1901.2HC1 and pharmaceutically acceptable excipients, and optionally other therapeutic ingredients. RAD1901.2HC1 crystalline Form H3 may preferably be formulated into tablets or other pharmaceutical forms.

The invention of the present application will be explained in more detail with reference to the following examples, which should not be construed as limiting the scope of the invention in any manner.

Examples:

Reference example: Preparation of RAD1901.2HC1

Step 1: Preparation of N-(2-(6-(benzyloxy)-3,4-dihydronaphthalen-2-yl)-5-methoxy phenyl) acetamide

A solution of 7-Benzyloxy-3-bromo-l,2-dihydronaphthalene (1 eq.) and bis(pinacolato)diboron (1.3 eq.) were dissolved in 1,2-dimethoxy ethane (7 volumes), treated with potassium acetate (3.1 eq.) and PdC12(PPh3)2 (2 mol %), and heated at 85° C. The reaction was then monitored for completion by HPLC. The solution was cooled to 20 °C and treated with 25 wt % potassium bicarbonate (aqueous, 3 volumes) and 2-bromo-5- methoxyacetanilide (1 eq), then heated to 85 °C and monitored for completion by HPLC. The reaction was then cooled to 55 °C and the mixture filtered and the solids washed with 1,2- dimethoxyethane. The water layer was separated off and the remaining organic layer cooled to 20 °C and diluted with water (6.9 volumes). The mixture was then agitated for >1 hour and the Formed solids filtered and washed with water (3.1 volumes) and the cake dried at <55 °C. The combined solids were treated with dichloromethane (10 volumes) and carbon (0.25 wt equivalents) and the resulting mixture was stirred and heated to reflux for >6 hours. The mixture was then cooled to 20° C, the solid filtered, and washed with dichloromethane (3 volumes). The resulting filtrate solution was concentrated to 3 volumes under vacuum at <45° C and treated with ethanol (6 volumes) and concentrated under vacuum at <45° C to 4.9 volumes. An additional ethanol (6 volumes) was added and the volume once again concentrated under vacuum at <45° C to 4.9 volumes and ethanol (1 volume) added and cooled to 20° C and the product collected by filtration and rinsed with ethanol (1 volume) and dried under N2 at <50° C to get title compound.

Yield: 70%.

Step 2: Preparation of (+/-)N-(2-(6-hydroxy- 1,2,3, 4-tetrahydronaphthalen-2-yl)-5- methoxyphenyl)acetamide

A solution of N-(2-(6-(benzyloxy)-3,4-dihydronaphthalen-2-yl)-5-methoxyphenyl)acetamide (1 eq.), Palladium hydroxide on carbon (0.1 weight equivalents), tetrahydrofuran (7 volumes) and methanol (7 volumes) was purged with N2 and then H2 at 20° C The reaction mixture was agitated under 100 psi H2 for >12 hours at 20° C and the reaction monitored for completion. After purging the reaction with N2 at 20° C, the reaction mixture was heated at 40° C for >1 hour, filtered and rinsed with tetrahydrofuran (1.5 volumes) and methanol (1.5 volumes). The solution was concentrated to 2.4 volumes under vacuum at <45° C and treated with ethyl acetate (12 volumes), concentrated to 2.4 volumes under vacuum at <45° C, treated again with ethyl acetate (12 volumes) and concentrated to 2.4 volumes under vacuum at <45° C and treated with ethyl acetate (3.3 volumes) and the temperature adjusted to 20° C and agitated at 20° C>1 hour, the product collected by filtration and washed with ethyl acetate (1.4 volumes). The solid can be recrystallized in methanol/ethyl acetate to get title compound.

Step 3: Preparation of (+/-)6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronapthalen- 2-ol

A solution of (+/-)N-(2-(6-hydroxy-l,2,3,4-tetrahydronaphthalen-2-yl)-5-methoxypheny) acetamide (1 eq.) in methanol (9 volumes) and concentrated hydrochloric acid (1.5 wt equivalents) was heated and agitated at reflux >16 hours and monitored for completion. The reaction was cooled to <35° C and concentrated under vacuum at <45° C to 3.8 volumes, charged with 2-methyl tetrahydrofuran (3 volumes) and concentrated under vacuum at <45° C to 3.8 volumes, charged with 2-methyl tetrahydrofuran (3 volumes) and concentrated under vacuum at <45° C to 3.8 volumes, charged with 2-methyl tetrahydrofuran (12 volumes) IM sodium hydroxide (then 10 volumes) followed by 1.5 weight equivalents of 25% potassium bicarbonate while maintaining the internal temperatures at <35° C The internal temperature was adjusted to 20° C and stirred for >15 minutes. The pH was adjusted/maintained to between 8-10 using IM hydrochloric acid or IM sodium hydroxide. The agitation was stopped and the aqueous layer separated out after settling and water (1 volume) added and the solution stirred >15 minutes and the aqueous layer removed after settling and one additional volume of water added and the aqueous layer separated out after settling. The organic layer was concentrated under vacuum to 3 volumes at <45° and the solution treated with heptane (3 volumes) and agitated for 12 hours at 20° C. The solids were collected by filtration and the filter cake rinsed with heptane (2 volumes). The solvents were evaporated at <50° C to get title compound.

Yield: 90%.

Step 4: Preparation of (R)-6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronapthalen- 2-ol

(+/-)6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronapthalen-2-ol (1 equivalent) in acetonitrile (14.2 volumes) and dichloromethane (4.8 volumes) was heated to 40 °C To this was added (+)-2, 3 -dibenzoyl -D-tartaric acid [0.5 eq.] and heated to reflux. The reactor was cooled to 50° C for approximately 1 hour, cooled to 40 °C for approximately 1 hour and cooled to 25° C for approximately 1 hour. The slurry was filtered and the filter cake washed with dichloromethane (2 volumes). The wet filter cake was refluxed in dichloromethane (8 volumes) for >1 h. The solution was cooled to 25° C at a rate of 15° C/h and stirred at 25° C for >1 hour. The slurry was filtered and washed with di chloromethane (2 volumes) and the cake was again slurried with dichloromethane (8 volumes) for 1 hour at ambient temperature and then filtered and washed with dichloromethane (2 volumes) and dried. (The chiral purity was assayed at this point, providing an enantiomeric excess of >90%). A solution containing the (+)-Dibenzoyl-L-tartaric acid salt, water (15 volumes) and methanol (3 volumes) was treated with 25% potassium bicarbonate aqueous solution (4.6 volumes) and agitated at 25° C for >1 h. The solids were collected by filtration and rinsed with water (4 volumes). The aqueous layer was adjusted to a pH of >8 using 25% potassium bicarbonate as needed, and the resulting solids were collected by filtration. The filter cake was washed with water (4 volumes). The combined solids were added to water (4 volumes), the resulting slurry was stirred for >1 h, and the solids were then collected by filtration. The filter cake was washed with water (4 volumes) and heptane (4 volumes) and was dried at <50°C to provide the title compound.

Yield: 90% and ee: 90%. Step 5: Preparation of (R)-N-ethyl-3-(4-((ethyl(2-(6-hydroxy-l,2,3,4-tetrahydro napthalen-2-yl)-5-methoxyphenyl)amino)methyl)propanamide

A mixture containing (R)-6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronapthalen-2-ol (1 equivalent) together with activated molecular sieves (1 wt equivalent) and anhydrous tetrahydrofuran was agitated at ambient temperature for >2 hours. The mixture was filtered through THF-compacted celite and rinsed with tetrahydrofuran (10 volumes). The solution was charged with N-ethyl-2-(4-Formylphenyl)acetamide (1.2 eq.) and heptane (7.5 volumes) and Dibenzoyl-L-tartaric acid (0.1%) and heated to reflux. The mixture was atmospherically distilled to 10 volumes at reflux. The reaction was monitored for completion via TLC. Heptane (2.9 volumes) and tetrahydrofuran (7.1 volumes) were added and the reaction was atmospherically distilled to 10 volumes at reflux and monitored for completion by TLC. The solution was cooled to 20° C and agitated for >5 hours to ensure that crystallization had occurred. The solid product was collected by filtration, rinsed with heptane (2 volumes) and dissolved in anhydrous Tetrahydrofuran (40 volumes) and treated with Sodium triacetoxyborohydride (4.5 equivalents). The mixture was heated to 50° C for >16 hours and monitored by TLC. An additional Sodium triacetoxyborohydride (4.5 equivalents) was added. The reaction was cooled to 20° C and quenched with 3M sodium hydroxide (15 volumes). The solution/mixture was agitated for >30 minutes and the pH adjusted to 8-9 with 9% aqueous sodium bicarbonate (14 volumes) if necessary. The aqueous layer was separated out and the organic layer concentrated to 5 volumes under vacuum at <45° C The resulting solution was diluted with ethyl acetate (10 volumes) and concentrated to 5 volumes under vacuum at <45° C. The solution was treated with ethyl acetate (10 volumes) and 5.6% brine solution (5 volumes), stirred and then allowed to settle and the aqueous layer removed. The mixture was dried with sodium sulfate (4 wt) and filtered and concentrated to 5 volumes under vacuum at <45° C, treated with heptane (10 volumes) and concentrated to 5 volumes under vacuum at <45° C, treated with heptane (10 volumes) and concentrated to 5 volumes under vacuum at <45 °C and treated with heptane (10 volumes) and concentrated to 5 volumes under vacuum at <45° C The solution was then treated with tetrahydrofuran (10 volumes) and dried under vacuum at <45° C and treated again with tetrahydrofuran (10 volumes) and dried to 5 volumes under vacuum at <45° C and treated with tetrahydrofuran (5 volumes) and residual heptane evaluated by GC (<4%) and the THF solution carried forward to the next reaction.

Yield: 90%.

Step 6: Preparation of RAD1901.2HC1 A reactor was charged with tetrahydrofuran (7 volumes) and sodium borohydride (2.5 equivalents) and cooled to from -10° C to 0° C. The solution was charged with the tetrahydrofuran solution carried over from step 6 (1 equivalent of (R)-N-ethyl-3-(4-((ethyl(2- (6-hydroxy- 1 ,2,3,4-tetrahydronapthalen-2-yl)-5-methoxy phenyl) amino) methyl)propanamide) while maintaining the reactor temperature at <5° C. The solution was stirred with an internal temperature adjusted to -25° C. 1 Equivalent of 12 in 1 volume of tetrahydrofuran was added to the solution while maintaining the temperature at <-10° C. The mixture was agitated for >30 minutes at <-10° C. then heated to reflux and stirred at reflux for at 4 hours and monitored by HPLC for completion. The reaction mixture was cooled to <5° C. and quenched with concentrated hydrochloric acid (0.5 volumes) while maintaining the reaction mixture temperature of <-10° C., and then treated with water (15 volumes). The pH was checked and adjusted to less than 1.5 as needed. The solution was then heated to reflux and atmospherically distilled until the internal temperature reaches 80° C. The reaction mixture was cooled to 15-25° C, stirred for 6 hours and the solid isolated by filtration. The solid was charged back into the reactor along with ethyl acetate (10 volumes) and IM sodium hydroxide (5 volumes) and the mixture agitated for up to 30 minutes at 10-20° C. The pH was checked and adjusted to 8-9 as needed. The organic and aqueous layers were allowed to separate and the aqueous layer removed and washed with ethyl acetate (10 volumes). The aqueous layer was removed and the combined organic layers were washed with 5% sodium thiosulfate solution (10 volumes). The organic layer was washed with 1% NaCl solution (40 volumes). The aqueous layer was removed and the organic layer concentrated to 3 volumes at an external temperature of up to 45° C. Three times, the residue was dissolved in ethanol (10 volumes) and concentrated to 3 volumes at <45° C. The solution was dried with sodium sulfate and filtered and the filtrate charged to a reactor where it wastreated with ethyl acetate (1 volume) and stirred and charged with 3.3M hydrochloric acid in ethanol (1.4 volumes) and the mixture agitated at 15-25° C for >2 hours and then concentrated to 4.6 volumes at <45° C. The solution was treated with 12.4 volumes of ethyl acetate and agitated at 15-25° C for >2 hours to ensure that crystallization had occurred. The solids were collected by filtration and rinsed with 3.1 volumes of ethylacetate. The filter cake was dried at <50° C. The material can be assayed for purity and recrystallized from methanol/ ethyl acetate if desired to get title compound.

Yield: 50%; purity: 90%.

Example 1. Preparation of Crystalline Form Hl of RAD1901.2HC1 Isopropanolic hydrochloride solution (238 ml) was added to a solution of RAD 1901 (100 g), ethyl acetate (3780 ml) and Isopropanol (220 ml) at 20-25°C and stirred for 4 hours. Filtered the solid and dried to get crystalline Form Hl of RAD1901.2HC1.

Yield: 100 grams.

PXRD of the obtained compound is shown in figure 1.

Example 2. Preparation of Crystalline Form H2 of RAD1901.2HC1

RAD1901.2HC1 crystalline Form Hl was exposed to less than 40%RH for 24 hours to obtain title compound having monoclinic crystal parameter a= 31.015, b=11.822, c= 8.854 A° Yield: 100 grams.

PXRD of the obtained compound is shown in figure 2.

Example 3. Preparation of crystalline Form H3 of RAD1901.2HC1

RAD1901.2HC1 crystalline Form Hl was heated at 105-110°C for 24 hours to obtain title compound.

PXRD of the obtained compound is shown in figure 3.

Claims

We claim:

1. RAD1901.2HC1 crystalline Form Hl, which is characterized by Powder X-ray diffractogram as shown in figure 1.

2. A process for preparation of RAD1901.2HC1 crystalline Form Hl, which comprises: a. dissolving RAD 1901 in ester solvent or mixture of ester solvent and alcoholic solvent; b. adding alcoholic hydrochloride solution; c. maintaining the reaction mixture at 25-30°C; and d. isolating RAD1901.2HC1 crystalline Form Hl.

3. RAD1901.2HC1 crystalline Form H2, which is characterized by Powder X-ray diffractogram as shown in figure 2.

4. A process for preparation of RAD1901.2HC1 crystalline Form H2, which comprises a. exposing RAD1901.2HC1 crystalline Form Hl to less than 40%RH for 24 hours; and b. isolating RAD1901.2HC1 crystalline Form H2.

5. RAD1901.2HC1 crystalline Form H3, which is characterized by Powder X-ray diffractogram as shown in figure 3.

6. A process for preparation of RAD1901.2HC1 crystalline Form H3, which comprises: a. heating RAD 1901.2HC1 crystalline Form Hl to 105-110°C; and b. isolating RAD1901.2HC1 crystalline Form H3.