DESC:CRYSTALLINE FORM S1 OF TAPINAROF

FIELD OF THE INVENTION

The present invention provides a crystalline Form S1 of Tapinarof. The present invention also relates to a process for preparing crystalline Form S1 of Tapinarof.

BACKGROUND OF THE INVENTION

Tapinarof (INN; trade name Vtama®) is a topical drug for treatment of mild to moderate plaque psoriasis and atopic dermatitis. Tapinarof was approved for medical use in the United States in May 2022 and the US Food and Drug Administration (FDA) considers it to be a first-in-class medication. The medication acts as an aryl hydrocarbon receptor agonist.

Tapinarof is chemically known as 3,5-dihydroxy-4-isopropyl-trans-stilbene, having formula (I):

Tapinarof is a white to pale brown powder. Tapinarof is practically insoluble in water and freely soluble in methanol, ethanol and acetone.

WO 2019/094934 and WO 2019/063002 described crystalline forms of Tapinarof. WO2021236709 described the co-crystals of Tapinarof.

Many pharmaceutical solids can exist in different physical forms. Polymorphism is often characterized as the ability of drug substance to exist in two or more crystalline phases that have different arrangement and/or conformations of the molecule in the crystal lattice. Polymorphism refers to occurrence of different crystalline form of the same drug substance. The different crystalline forms have different physical properties like melting point, X-ray diffraction pattern,
infrared spectra and solid state NMR spectrum.

Discovering new solid-state forms and solvates of a pharmaceutical product may yield materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable intermediate crystal forms that facilitate conversion to other polymorphic forms. New solid-state forms of a pharmaceutically useful compound can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. For at least these reasons, there is a need for additional solid-state forms of Tapinarof. Moreover, the processes for preparing such forms should be suitable for industrial production and not cumbersome. The present invention provides such crystalline forms and processes for their preparations.

The difference in physical properties of different crystalline forms results from the orientation and intermolecular interactions of adjacent molecules in the bulk solid. Accordingly, the polymorphs are distinct solids sharing the same molecular formulae, yet having different physical properties compared to other crystalline forms of the same compound.

The different polymorphs, pseudo polymorphs or the amorphous form differ in their physical properties such as melting point, solubility etc. and hence may affect pharmaceutical properties such as dissolution rate and bioavailability of the drug substance. Hence, the discovery of new or different polymorphs is essential. Since a new polymorph may aide in the manufacture of the drug product formulation which may prove to be more effective absorption in gastrointestinal tract.

We have found a crystalline Form S1 of Tapinarof. The crystalline Form S1 of Tapinarof has been found to be stable over time and reproducible. Hence it is suitable for pharmaceutical preparations.

We have also found a process for the preparation of crystalline form S1 of Tapinarof.

OBJECT OF THE INVENTION
The object of the present invention is to provide a novel crystalline form S1 of Tapinarof.
The object of the present invention is to provide a process for the preparation of novel crystalline form S1 of Tapinarof.

SUMMARY OF THE INVENTION

The present invention provides a crystalline Form S1 of Tapinarof. The present invention also relates to a process for preparing crystalline Form S1 of Tapinarof.

In one embodiment of the present invention, it provides a crystalline Form S1 of Tapinarof characterized by an X-ray powder diffraction (XRPD) spectrum having peak reflections at 5.7, 11.4, 15.9, 20.0, 23.8, and 27.1 ±0.2 degrees 2?.

In another embodiment of the present invention, it provides a process for the preparation of crystalline Form S1 of Tapinarof, comprising:

a. Crude Tapinarof was dissolved in a solvent or mixture of solvent,
b. heating the obtained suspension at suitable temperature,
c. cooling the obtained solution in step b),
d. isolating the crystalline Form S1 of Tapinarof.

BRIEF DESCRIPTION OF THE DRAWINGS:

Figure 1: X-ray powder diffraction (PXRD) crystalline Form S1 of Tapinarof.

Figure 2: Differential scanning calorimetry (DSC) crystalline Form S1 of Tapinarof.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a crystalline Form S1 of Tapinarof. The present invention also relates to a process for preparing crystalline Form S1 of Tapinarof.

In one embodiment of the present invention, the crystalline Form S1 of Tapinarof is characterized by X-Ray powder diffraction spectrum as depicted in Figure 1.

In one another embodiment of the present invention, it provides a crystalline Form S1 of Tapinarof characterized by an X-ray powder diffraction (XRPD) spectrum having peak reflections at 5.7, 11.4, 15.9, 20.0, 23.8, and 27.1 ±0.2 degrees 2?.
In yet another embodiment of the present invention, it provides a process for the preparation of crystalline Form S1 of Tapinarof, comprising:

a. Crude Tapinarof was dissolved in a solvent or mixture of solvent,
b. heating the obtained suspension at suitable temperature,
c. cooling the obtained solution in step b),
d. isolating the crystalline Form S1 of Tapinarof.

According to the embodiment of the present invention, the preparation of crystalline Form S1 of Tapinarof is comprises by dissolving crude Tapinarof in a solvent or mixture of solvent. The reaction mixture was heated to 30 ºC to 60ºC, stir for 30 minutes and it’s allowed to cool at -5 to 10ºC and stir for 1-4 hours. The obtain solid filtered and washed with solvent.
According to the embodiment of the present invention, wherein the solvent is selected from alcohols such as methanol, ethanol, propanol, butanol, n-propyl alcohol, isopropyl alcohol, and t-butyl alcohol; nitriles such as acetonitrile and propionitrile; amides such as N,N-dimethylformamide and N,N-dimethylacetamide; sulfoxides such as dimethyl sulfoxide and diethyl sulfoxide; and aromatic hydrocarbons such as toluene and xylene; aliphatic hydrocarbons such as n-heptane and n-hexane; esters such as ethylacetate, methylacetate, butyl acetate, isopropyl acetate, methoxy ethyl acetate; ketones such as acetone, methylisobutyl ketone, 2-pentanone, ethylmethylketone, diethylketone; halogenated hydrocarbons such as chloroform, dichloromethane; ethers such as methyl tert-butyl ether, diethyl ether, tetrahydrofuran, dioxane or water and or mixtures thereof.
According to the embodiment of the present invention, the suitable temperature is between 30 ºC to 60ºC.
According to the embodiment of the present invention, the cooling is between -5 ºC to 10ºC.
In yet another embodiment, the present invention provides a pharmaceutical composition comprising crystalline form S1 of Tapinarof and one or more pharmaceutically acceptable excipients.
In yet another embodiment of the present invention, there is provided pharmaceutical compositions comprising a therapeutically effective amount of crystalline Form S1 of Tapinarof in combination with a pharmaceutically acceptable carrier and along with pharmaceutically acceptable excipients, and at least one pharmaceutically acceptable excipient. The crystalline Form S1 of Tapinarof in combination with a pharmaceutically acceptable carrier may preferably be formulated into tablets, capsules, suspensions, dispersions, injectables or other pharmaceutical forms.

The process details of the invention are provided in the examples given below, which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention.

EXPERIMENTAL PROCEDURE:
Example-1:
Preparation of (E)-2-isopropyl-5-styrylbenzene-1,3-diol (Tapinarof)
Charge Toluene (700ml), Aluminium chloride (212gm) into RBF, cool the reaction mass to 5-100C and add Triethylamine (161.2gm) to form complex. Add a solution of (E)-2-isopropyl-1,3-dimethoxy-5-styrylbenzene (100g) and toluene (300ml) into the reaction mass at same temperature. The obtained reaction mass heated to 90-950C and stir for 4-5hrs. After completion of the reaction checked by HPLC and its allowed cool to 5-100C. Charge purified water (1000ml) and Conc.HCl (100ml) and ethyl acetate (600ml) into another RBF, cool the reaction mass to 5-100C and add above reaction mass at same temperature and stir for 5-10 min. The reaction was heated to room temperature, separate the layers, and extract the material again with ethyl acetate (300m) and combine the organic layers wash with 5% of sodium chloride solution, followed by carbon treatment, distillation. Obtained crude material isolation with MTBE (150ml) and n-heptane (250ml), followed by crystalized with MTBE (150ml) to obtain title of the compound.
Example 2:
Purification Crystalline Form S1 of Tapinarof
Crude Tapinarof (100 g) HPLC purity (99.08%) in MTBE (200mL), heat to 45-50 0C, stir for 30 minutes and filter through micron filter. The reaction mixture was allowed to cool at 0-5ºC and stir for 1-2 hours, filter the sold wash with MTBE (25 mL) and dried at 40-50ºC for 8-10 hours to obtain pure crystalline Form S1 of Tapinarof.
Yield: 85% (85g)
HPLC purity: 99.97%
Example 3:
Purification Crystalline Form S1 of Tapinarof
Crude Tapinarof (100 g) HPLC purity (99.10%) in MTBE (150mL), heat to 45-50 0C stir for 30 minutes and filter through micron filter. The reaction mixture was allowed to cool at 0-5ºC and stir for 1-2 hours, filter the sold wash with MTBE (30 mL) and dried at 40-50ºC for 8-10 hours to obtain pure crystalline Form S1 of Tapinarof.
Yield: 85.2% (85.2g)
HPLC purity: 99.96%
Example 4:
Purification Crystalline Form S1 of Tapinarof
Crude Tapinarof (100 g) HPLC purity (99.08%) in MTBE (150mL), heat to 45-50 0C stir for 30 minutes and filter through micron filter. The reaction mixture was allowed to cool at 25-30ºC and add n-Heptane (300ml), cool the reaction mass to 0-5ºC and stir for 1-2 hours. The obtained solid was washed with MTBE and n-heptane (25+25 mL) and dried at 40-50ºC for 8-10 hours to obtain pure crystalline Form S1 of Tapinarof.
Yield: 84% (84g)
HPLC purity: 99.96%
,CLAIMS:We Claim:

1. A Crystalline Form S1 of Tapinarof characterized by an X-ray powder diffraction (XRPD) spectrum having peak reflections at 5.7, 11.4, 15.9, 20.0, 23.8, and 27.1 ±0.2 degrees 2?.

2. A Crystalline Form S1 of Tapinarof as claimed in claim 1, characterized by X-Ray powder diffraction spectrum as depicted in Figure 1.

3. A process for the preparation of crystalline Form S1 of Tapinarof, comprising:

a. Dissolving tapinarof in a solvent or mixture of solvent,
b. heating the obtained suspension at suitable temperature,
c. cooling the obtained solution in step b),
d. isolating the crystalline Form S1 of Tapinarof.

4. The process as claimed in claim 3, wherein the solvent is selected from alcohols such as methanol, ethanol, propanol, butanol, n-propyl alcohol, isopropyl alcohol, and t-butyl alcohol; nitriles such as acetonitrile and propionitrile; amides such as N,N-dimethylformamide and N,N-dimethylacetamide; sulfoxides such as dimethyl sulfoxide and diethyl sulfoxide; and aromatic hydrocarbons such as toluene and xylene; aliphatic hydrocarbons such as n-heptane and n-hexane; esters such as ethylacetate, methylacetate, butyl acetate, isopropyl acetate, methoxy ethyl acetate; ketones such as acetone, methylisobutyl ketone, 2-pentanone, ethylmethylketone, diethylketone; halogenated hydrocarbons such as chloroform, dichloromethane; ethers such as methyl tert-butyl ether, diethyl ether, tetrahydrofuran, dioxane or water and or mixtures thereof.

5. The process as claimed in claim 3, wherein the suitable temperature is between 30 ºC to 60ºC and cooling temperature is between -5 ºC to 10ºC