DESC:FIELD OF THE INVENTION:
The present invention relates to a novel crystalline form of Risdiplam of structural formula-1 and process for preparation thereof. The present invention further relates to pharmaceutical composition comprising the said crystalline form and their use as pharmaceutically active compounds. Particularly, the present invention relates to novel crystalline Risdiplam polymorph Form H, process for preparation and pharmaceutical composition thereof.

BACKGROUND OF THE INVENTION:
7-(4,7-Diazaspiro[2,5] octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-pyrido[1,2-a]pyrimidin-4-one (Formula-1) is commonly known as Risdiplam. Risdiplam is a medication used to treat spinal muscular atrophy (SMA) and the first oral medication approved to treat this disease. Risdiplam is approved by the US Food and Drug Administration (FDA) and by European Medicines Agency under the brand name of Evrysdi for the treatment of SMA in patients of 2 months of age and older.

US9969754B2 discloses Risdiplam and its process for the preparation thereof. However, this process results in Risdiplam very poor yields. The process is shown in below scheme 1. According to this process compound (a) is reacted with compound (b) in presence of Pd(Ph3P)4 to obtain 2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-7-fluoro-pyrido[1,2-a]pyrimidin-4-one, which is reacted with 4,7-diazaspiro[2.5]octane hydrochloride to yield Risdiplam.

Scheme 1

US11390632B2 disclosed the following route of synthesis of Risdiplam, as shown in scheme 2. According to this synthetic scheme, the compound of formula III reacted with compound of formula III’ in the presence of a palladium catalyst or nickel catalyst to form the compound of formula (II); and reacting the compound of formula (II) with a strong acid to obtain a compound of formula (I).

Scheme 2
The processes described in the above prior arts resulted in poor yields and they require multiple chromatographic purifications for the isolation of Risdiplam and its intermediates which are considered to be very expensive for commercial scale preparations.

Further, WO2020079203 discloses the crystalline Form A of Risdiplam. WO2021021775 discloses crystalline form 1, form 2, form 3, form 4 and form 5 of Risdiplam. WO2022162107 describes the crystalline Form 1 of Risdiplam.

However, there is need in art to provide a novel crystalline form of Risdiplam with high purity and yield, to overcome the problems associated with the prior arts as described above.

SUMMARY OF THE INVENTION:
The primary object of the present invention is to provide a novel crystalline Form H of 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido-4H-[1,2-a]pyrimidin-4-one (Risdiplam) of structural formula-1 with high yield and purity.

In an aspect, the crystalline Form H of Risdiplam is characterized by a PXRD data having peaks at 5.94, 11.05, 15.99, 20.27, 23.59 2?±0.2?.

In another aspect, the crystalline Form H of Risdiplam comprises the additional PXRD peaks at 15.41, 17.23, 24.74, 26.53, 27.07 2?±0.2?. The PXRD peaks for Risdiplam Form H is illustrated in Fig 1.
In yet another aspect, the crystalline Form H of Risdiplam is characterized by the IR spectrum at 834 cm-1, 880cm-1, 926 cm-1, 1210 cm-1, 1227cm-1, 1674cm-1, 2824cm-1, 3283cm-1; as illustrated in Figure 2A and 2B. The IR spectrum of Risdiplam Form H was conducted after 6 months of storage.

In another aspect, the crystalline Form H of Risdiplam is characterized by the DSC comprising two endotherms (i) a broad endothermic peak at 242-248ºC and an endothermic peak with an onset at 280.55ºC and a peak at temperature of about 286ºC as illustrated in Figure 3A-3C.

In an aspect, the crystalline Form H of the present invention is in anhydrous form having water content less than 2.0% as determined by thermogravimetric analysis (TGA) in table below.

In yet another aspect, the present invention provides a process for preparation of crystalline Form H of Risdiplam of structural formula-1.

Accordingly, the process for preparation of crystalline Form H of Risdiplam of structural formula-1, comprising:
a. Adding Risdiplam in a mixture of solvent(s);
b. Stirring at temperature ranging between 25 to 400C; and
c. Precipitating the crystalline solid obtained in step b) followed by filtering, washing and drying.

In an aspect, the said process for preparation of crystalline Form H of Risdiplam does not employ multiple chromatographic purifications for isolation.

In yet another aspect, the crystalline Form H of Risdiplam of structural formula-1 prepared according to the above process is in high yield, purity and is substantially free of chemical impurities.

In an aspect, the present invention provides a pharmaceutical composition comprising of crystalline Form H of Risdiplam prepared by the present process as an active ingredient together with pharmaceutically acceptable carrier.

BRIEF DESCRIPTIONS OF THE DRAWINGS:

Fig 1 illustrates PXRD data of crystalline Form H of Risdiplam of structural formula-1
Fig 2A illustrates infrared spectrum (IR) of crystalline Form H of Risdiplam of structural formula-1; and 2B illustrates infrared spectrum (IR) of crystalline Form H of Risdiplam after 6 month storage.
Fig 3A-C illustrates differential scanning calorimetry (DSC) of Risdiplam of structural formula-1.

DETAILED DESCRIPTION OF THE INVENTION:
The present invention will now be explained in detail with reference to its preferred and optional embodiments but should not be construed to limit the scope of the invention.

The terms which are introduced in the complete specification retain those definitions throughout the description and the claims.

Accordingly, the term “Crystalline” and “Polymorphs” refer to the particular compound in the particular crystalline form that is distinct from another crystalline form but shares the same chemical formula. Further, the crystalline state is irrespective of whether the chemical compound is solvated or not.

With regards to the “Polymorphic Purity” the crystalline polymorph Form H of Risdiplam is substantially free of chemical impurities (generated during preparation of the polymorphs) and of other polymorphic crystalline forms. “Substantially free” of chemical impurities for the purposes of this invention means less than or equal to about 5%w/w of chemical impurities, preferably less than or equal to 3%w/w of chemical impurities, more preferably less than or equal to about 2%w/w of chemical impurities, most preferably less than or equal to about 1%w/w of chemical impurities. The term “purified” or “in purified form” of the polymorph Form refers to the product obtained by the present process of preparation and which does not employ multiple chromatographic purifications for isolation.

In an embodiment, the present invention is directed to a crystalline Form H of 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido-4H-[1,2-a]pyrimidin-4-one (Risdiplam) of structural formula-1 with high yield and purity.

In an embodiment, the crystalline Form H of Risdiplam is characterized by a PXRD data having peaks at 5.94, 11.05, 15.99, 20.27, 23.59 2?±0.2?.

In another embodiment, the crystalline Form H of Risdiplam comprises the additional PXRD peaks at 15.41, 17.23, 24.74, 26.53, 27.07 2?±0.2?.

The PXRD peaks for Risdiplam Form H is illustrated in Fig 1.

In yet another embodiment, the crystalline Form H of Risdiplam is characterized by the IR spectrum at 834cm-1, 880cm-1,926 cm-1, 1210cm-1, 1227cm-1, 1674cm-1, 2824cm-1, 3283cm-1 as illustrated in Figure 2A and 2B. The IR spectrum of Risdiplam Form H illustrated in Fig 2B was conducted after 6 months of storage. No change in the IR spectrum was observed indicating the stability of the crystalline Form H of Risdiplam.

In another embodiment, the crystalline Form H of Risdiplam is characterized by the DSC comprising two endotherms (i) a broad endothermic peak at 242-248ºC and an endothermic peak with an onset at 280.55ºC and a peak at temperature of about 286ºC as illustrated in Figure 3A-3C.

In an embodiment, the crystalline Form H of the present invention is in anhydrous form having water content less than 2.0% as determined by thermogravimetric analysis (TGA) shown in table below.

In yet another embodiment, the present invention discloses a process for preparation of crystalline Form H of Risdiplam of structural formula-1.

Accordingly, the process for preparation of crystalline Form H of Risdiplam having structural formula-1 comprises the steps of:
a. Adding Risdiplam in a mixture of solvent(s);
b. Stirring at a temperature ranging between 25 to 400C; and
c. Precipitating the crystalline solid obtained in step b) followed by filtering, washing and drying.

In an embodiment, the solvents are selected from polar, non-polar, protic or aprotic solvents selected from the groups consisting of alcohols, acids, esters hydrocarbons and such like alone or mixtures thereof.

The solvent for the process is particularly selected from lower C1-C4 alcohols, acids such as acetic acid, alone or mixtures thereof.

In an embodiment, the said process for preparation of crystalline Form H of Risdiplam does not employ multiple chromatographic purifications for isolation.

In an embodiment, the crystalline Form H of Risdiplam prepared according to the present invention is obtained in a yield of about more than 60 %, preferably about more than 70% and more preferably about more than 80% and with the purity in the range of 99.3 to 99.7%.

In an embodiment, the crystalline Form H of Risdiplam prepared according to the present invention is characterized by a PXRD data having peaks at 5.94, 11.05, 15.99, 20.27, 23.59 2?±0.2?.

In another embodiment, the crystalline Form H of Risdiplam prepared by the present process comprises the additional PXRD peaks at 15.41, 17.23, 24.74, 26.53, 27.07 2?±0.2? as depicted in Fig 1.

The crystalline Form H of Risdiplam prepared according to the present invention is characterized by an infrared spectrum (IR) having peaks at about 834 cm-1, 880 cm-1, 926 cm-1, 1210 cm-1 and 1227 cm-1, 1674cm-1, 2824cm-1, 3283cm-1 illustrated in Figure 2A and 2B. No substantial change in the IR spectrum was observed after 6 month storage indicating the stability of the crystalline Form H of Risdiplam.

In yet another embodiment, the crystalline Form H of Risdiplam prepared by the present process was characterized by a differential calorimetry thermogram (DSC) comprising two endotherms (i) a broad endothermic peak at 242-248ºC and an endothermic peak with an onset at 280.55ºC and a peak at temperature of 286ºC as illustrated in Figure 3A-3C.

In yet another embodiment, the present invention discloses a pharmaceutical composition comprising of crystalline Form H of Risdiplam prepared by the present process together with pharmaceutically acceptable excipient.

The pharmaceutical composition may be formulated in solid form which include but not limited to powders, tablets, capsules, granules, pellets and the like; the liquid forms include but not limited to solutions, suspensions and emulsions; parenteral forms. The pharmaceutically acceptable carriers include but not limited to diluents, binders, preservatives, disintegrating agents, encapsulating agents, solubilizing agents, surfactants, flavorants and colorants.

In yet another embodiment, the crystalline Form H of Risdiplam obtained in the present invention is used as a medicament for treatment of spinal muscular atrophy (SMA).

In another embodiment, the present invention relates to a method of treating spinal muscular atrophy (SMA) by administering therapeutically effective amount to a subject in need thereof the crystalline Form H of Risdiplam prepared by the present process.

In another embodiment, the crystalline Form H of Risdiplam is stable up to a period of 6 months as illustrated by IR spectrum in Fig 2.

The following examples, which include preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of examples and for purpose of illustrative discussion of preferred embodiments of the invention.
Example-1: Preparation of Crystalline Risdiplam Form H
Process: To a mixture of Acetic acid (2.0 ml) and Methanol (20.0 ml) was added Risdiplam (2.0 g) under stirring at 30 ± 5°C so that it dissolves completely and precipitated out as crystalline solid which was filtered, washed with Methanol (4.0 ml) and dried to get title compound. Yield = 1.8 g; % Yield = 90.0%; Purity 99.54%.
Example-2: Preparation of Crystalline Risdiplam Form H
To a mixture of Acetic acid (1.0 ml) and tertiary butanol (10.0 ml) was added Risdiplam (1.0 g) under stirring at 30± 5°C so that it dissolves completely and precipitated out as crystalline solid which was filtered, washed with tertiary butanol (2.0ml) and dried to get title compound. Yield = 0.82 g; %Yield = 82.0%; purity 99.34%.

Example 3: Comparative table of the present Risdiplam Form H and Form A disclosed in WO2020079203A1
IR DSC TGA Form
WO2020079203A1 (Form A) 848 885 939 1218 298 Form-A
011/DS-C/V/118/032
(Form A Prepared By Harman) 848 885 939 1217 291.22 0.006% Matches with Form-A
011/DS-C/IV/118/048 834 880 926 1210 1227 286.14 0.172% Matches with Form-H
011/DS-C/IV/118/049 834 880 926 1210 1227 284.9 0.025% Matches with Form-H
011/DS-C/IV/118/050 834 880 926 1210 1227 286.11 0.047% Matches with Form-H
011/DS-C/V/138/005 834 880 926 1210 1226 283.82 0.18% Matches with Form-H

Example 4: Risdiplam solubility Data
Batch No Water Ethanol Form
STD < 0.1 mg/ml < 1 mg/ml
011/DS-C/V/118/032 0.003 mg/ml 1.3 mg/ml Form-A
011/DS-C/IV/118/048 0.006 mg/ml 1.4 mg/ml Form-H

Although the invention has been described in detail in the foregoing for the purpose of illustration, it is to be understood that such detail is solely for that purpose and that variations can be made therein by those skilled in the art without departing from the spirit and scope of the invention except as it may be limited by the claims.
,CLAIMS:1. A crystalline Form H of Risdiplam of formula

wherein said crystalline Form is characterized by

(i) X-ray powder diffraction pattern containing at least one of the following 2 theta values (±0.2?) at 5.94, 11.05, 15.41, 15.99, 17.23, 20.27, 23.59 24.74, 26.53, 27.07 2?±0.2?;
(ii) An infrared spectrum (IR) having peaks at about 834 cm-1, 880 cm-1, 926 cm-1, 1210 cm-1 and 1227 cm-1, 1674cm-1, 2824cm-1, 3283cm-1;
(iii) A broad endothermic peak at 242-248ºC and an endothermic peak with an onset at 280.55ºC and a peak at temperature of 286ºC as measured by differential scanning calorimetry (DSC).

2. The crystalline Form H, as claimed in claim 1, wherein said crystalline form is an anhydrous form with water content less than 2%.

3. The crystalline Form H, as claimed in claim 2, wherein the water content ranges between 0.17 to 0.05% as determined by thermogravimetric analysis (TGA).

4. A process for preparing the crystalline Form H, as claimed in any one of the claims 1 to 3, comprising;
a. Adding Risdiplam in a mixture of solvent(s);
b. Stirring at a temperature ranging between 25 to 400C; and
c. Precipitating the crystalline solid obtained in step b) followed by filtering, washing and drying.
5. The process as claimed in claim 4, wherein the solvent is selected from polar, non-polar, protic or aprotic solvents selected from the groups consisting of alcohols, acids, esters hydrocarbons and such like alone or mixtures combinations thereof.

6. The process as claimed in claim 4, wherein the solvent is selected from lower C1-C4 alcohols, acids such as acetic acid, alone or mixtures thereof.

7. The process as claimed in claim 4, wherein the process is free of chromatographic purification.

8. A pharmaceutical composition comprising the crystalline polymorph Form H of any one of claims 1 to 7 and pharmaceutically acceptable excipient.

9. The use of the crystalline polymorph Form H as claimed in any one of the preceding claims 1 to 7 for spinal muscular atrophy (SMA).

10. The method of treating spinal muscular atrophy (SMA) comprising administering the crystalline polymorph Form H as claimed in any one of the preceding claims 1 to 7 in therapeutically effective amount to a subject in need thereof.