DESC:“CRYSTALLINE FORM OF PHENYRAMIDOL HYDROCHLORIDE”

FIELD OF THE INVENTION

The present invention relates to a crystalline form of Phenyramidol hydrochloride. The present invention also relates to process for the preparation of crystalline form of Phenyramidol hydrochloride with high purity and yield.

BACKGROUND OF THE INVENTION

Phenyramidol hydrochloride (also known as Fenyramidol or IN 511 or MJ 5050) is a drug chemically known as 2-(ß-hydroxyphenethylamino) pyridine hydrochloride of formula (I) with a molecular formula C13H14N2O.HCl, attributed for its analgesic and muscle relaxant property.

Preparation of Phenyramidol hydrochloride (I) was first described in Journal of American Chemical Society 81, 4347-4351,1959 and its process for the preparation of Phenyramidol hydrochloride (I) comprises by reacting 2-amino pyridine with sodamide in presence of liquid ammonia, followed by reacted with styrene oxide in presence of ethylene glycol dimethyl ether to get Phenyramidol base and further it is treated with hydrochloric acid to obtain Phenyramidol hydrochloride of formula (I), which is recrystallized from mixture of ethanol / ether, showed m.p. 132-133°C.

US 3,165,527 discloses a process for the preparation of Phenyramidol hydrochloride (I) by reacting 2-amino pyridine is reacted with (dl)-mandelic acid to get 2-mandelamidopyridine, which is converted into Phenyramidol by using lithium aluminium hydride and ethylene glycol dimethyl ether as a solvent. The resultant Phenyramidol base is treated with hydrochloric acid to get Phenyramidol hydrochloride, which is recrystallize from a mixture of isopropyl alcohol / ethyl acetate.

The major disadvantage with the above prior art process is the usage recrystallization with mixture of ethanol / ether and mixture of isopropyl alcohol / ethyl acetate caused for unwanted impurities and that leads to low purity of Phenyramidol hydrochloride.

The present invention has many advantages over the prior art processes, which is industrially friendly such as Phenyramidol hydrochloride is recrystallized with alcohol solvent or mixture of alcohol solvents to get highly pure Phenyramidol hydrochloride with high yield. Similarly, the present invention involves simple steps which are commonly adopted in industrial scale

No crystalline polymorphic forms are disclosed in the literature for Phenyramidol hydrochloride.

Therefore, there is a need for novel crystalline form of Phenyramidol hydrochloride having better physicochemical properties and relatively higher solubilities; there is also a constant need for a low cost and industrial friendly process for preparing the crystalline form of Phenyramidol hydrochloride.

SUMMARY OF THE INVENTION

The present invention relates to a crystalline form of Phenyramidol hydrochloride. The present invention also relates to process for the preparation of crystalline form of Phenyramidol hydrochloride with high purity and yield.

One aspect of the present invention is to provides crystalline form of Phenyramidol hydrochloride, which is characterized by its X-ray powder diffraction (PXRD) pattern having peaks at about 11.60, 14.46, 19.19, 23.28, 25.03, 26.66, 29.18. ± 0.2 degrees of two-theta.

Another aspect of the present invention is to provides a process for the preparation of crystalline form of Phenyramidol hydrochloride, which is characterized by its X-ray powder diffraction (PXRD) pattern having peaks at about 11.60, 14.46, 19.19, 23.28, 25.03, 26.66, 29.18. ± 0.2 degrees of two-theta, comprising the steps of:
a) Phenyramidol hydrochloride is dissolved in an alcohol solvent,
b) optionally treated with activated carbon;
c) recrystallization of product with alcohol solvent or a mixture of alcohol solvent; and
d) isolating the crystalline form of Phenyramidol hydrochloride.

BRIEF DESCRIPTION OF THE DRAWINGS:

Fig. 1: illustrates X-ray powder diffraction (PXRD) pattern of Phenyramidol hydrochloride crystalline form.

Fig 2: illustrates differential scanning calorimetry (DSC) curve of Phenyramidol hydrochloride crystalline form.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a crystalline form of Phenyramidol hydrochloride. The present invention also relates to process for the preparation of crystalline form of Phenyramidol hydrochloride with high purity and yield.

One embodiment of the present invention is to provides crystalline form of Phenyramidol hydrochloride, which is characterized by its X-ray powder diffraction (PXRD) pattern having peaks at about 11.60, 14.46, 19.19, 23.28, 25.03, 26.66, 29.18. ± 0.2 degrees of two-theta.

According to the embodiment of the present invention is further characterised by its X-ray powder diffraction pattern (PXRD) having additional peaks at about 11.60, 14.02, 14.46, 16.53, 19.19, 19.93, 20.54, 23.28, 24.50, 25.03, 26.66, 28.65, 29.18, 32.27, 35.99, 36.31, ± 0.2 degrees of two-theta.

The crystalline form of the present invention is further characterized by the PXRD pattern as substantially as shown in Figure-1.

The crystalline Form of the present invention is further characterized by the DSC as substantially as shown in Figure-2.

Another aspect of the present invention is to provides a process for the preparation of crystalline form of Phenyramidol hydrochloride is characterized by its X-ray powder diffraction (PXRD) pattern having peaks at about 11.60, 14.46, 19.19, 23.28, 25.03, 26.66, 29.18. ± 0.2 degrees of two-theta, comprising the steps of:

a) Phenyramidol hydrochloride is dissolved in an alcohol solvent;
b) optionally treating with activated carbon;
c) recrystallization of product with alcohol solvent or a mixture of alcohol solvent; and
d) isolating the crystalline form of Phenyramidol hydrochloride.

In an embodiment of the present invention, a solution of Phenyramidol hydrochloride is dissolved in alcohol solvent and then treated with activated charcoal, filtered the reaction mass threw hy-flow bed and evaporation of solvent to get off white solid followed by recrystallization of product from a mixture of alcohol solvent, filter the product and dried to get crystalline form of Phenyramidol hydrochloride.

According to an embodiment of the present invention, wherein the alcohol solvent or mixture selected from C1-C6 alcoholic solvents, preferably methanol, ethanol, isopropyl alcohol or 2-propanol, n-butanol, 2-butanol, tert-butanol and mixtures thereof.

The following examples illustrate the present invention, but should not be construed as limiting the scope of the invention.

EXAMPLES

Example 1: Preparation of Phenyramidol hydrochloride

Styrene oxide (127.60 gm, 1.06 mol), suspension of 2-aminopyridine (100.0 gm, 1.06 mol), and potassium tert-butoxide (119.4 gm, 1.06 mol) in toluene (600.0 ml) were added into a reaction flask at below 10oC. The obtained reaction mixture was stirred at ambient conditions for 10-12 hrs. Followed by slowly addition of water (600.0 ml) and separate the organic layer. The obtained organic layer was treated with water (300.0 ml), followed by evaporation of solvent to yield thick residue. The resultant residue was dissolved in 2-propanol (200.0 ml) and acidified with anhydrous HCl in 2-propanol (150.0 ml) up to pH~2.0. Filtered and washed the solid with 2-propanol to yield Phenyramidol hydrochloride.

Yield: 150.0 gm

Purity: 98.6% (by HPLC)

Example 2: Preparation of crystalline form of Phenyramidol hydrochloride

Crude Phenyramidol hydrochloride (150.0 gm) was dissolved in methanol (400.0 ml), followed by treated with activated charcoal in the reaction flask. The obtained reaction mixture was filtered threw hy-flow bed and evaporation of solvent to yield off white solid. The resultant solid was recrystallized with a mixture of methanol (50.0 ml) and 2-propanol (400.0 ml). Filtered and then dried at 50-60oC to yield crystalline form of Phenyramidol hydrochloride.

Yield: 120.0 gm

Purity: 99.96% (by HPLC)

Example 3: Preparation of crystalline form of Phenyramidol hydrochloride

Crude Phenyramidol hydrochloride (150.0 gm) was dissolved in methanol (400.0 ml), followed by treated with activated charcoal in the reaction flask. The obtained reaction mixture was filtered threw hy-flow bed and evaporation of solvent to yield off white solid. The resultant solid was recrystallized with 2-propanol (600.0 ml). Filtered and then dried at 50-60oC to yield crystalline form of Phenyramidol hydrochloride.

Yield: 128.0 gm

Purity: by HPLC: 99.90%

Example 4: Preparation of crystalline form of Phenyramidol hydrochloride

Crude Phenyramidol hydrochloride (150.0 gm) was dissolved in methanol (400.0 ml), followed by treated with activated charcoal in the reaction flask. The obtained reaction mixture was filtered threw hy-flow bed and evaporation of solvent to yield off white solid. The resultant solid was recrystallized with ethanol (600.0 ml). Filtered and then dried at 50-60oC to yield crystalline form of Phenyramidol hydrochloride.

Yield: 121.0 gm.

Purity: 99.97% (by HPLC)

Example 5: Preparation of crystalline form of Phenyramidol hydrochloride

Crude Phenyramidol hydrochloride (150.0 gm) was dissolved in methanol (400.0 ml) followed by treated with activated charcoal in the reaction flask. The obtained reaction mixture was filtered threw hy-flow bed and evaporation of solvent to yield off white solid. The resultant solid was recrystallized with mixture of methanol (50.0ml) / ethanol (300.0 ml). Filtered and then dried at 50-60oC to yield crystalline form of Phenyramidol hydrochloride.

Yield: 119.0 gm

Purity: 99.98% (by HPLC)
,CLAIMS:WE CLAIM:

1. A crystalline form of Phenyramidol hydrochloride, which is characterized by its X-ray powder diffraction (PXRD) pattern having peaks at about 11.60, 14.46, 19.19, 23.28, 25.03, 26.66, 29.18. ± 0.2 degrees of two-theta.

2. The crystalline form of Phenyramidol hydrochloride as claimed in claim 1, which is further characterized by powder diffraction pattern (PXRD) having additional peaks at about 11.60, 14.02, 14.46, 16.53, 19.19, 19.93, 20.54, 23.28, 24.50, 25.03, 26.66, 28.65, 29.18, 32.27, 35.99, 36.31, ± 0.2 degrees of two-theta.

3. The crystalline form of Phenyramidol hydrochloride as claimed in claim 1, wherein the PXRD pattern as substantially shown in figure-1.

4. The crystalline form of Phenyramidol hydrochloride as claimed in claim 1, wherein the DSC curve as substantially shown in figure-2.

5. A process for the preparation of crystalline form of Phenyramidol hydrochloride, which is characterized by its X-ray powder diffraction (PXRD) pattern having peaks at about 11.60, 14.46, 19.19, 23.28, 25.03, 26.66, 29.18. ± 0.2 degrees of two-theta, comprising the steps of:

a) Phenyramidol hydrochloride is dissolved in an alcohol solvent;
b) optionally treated with activated carbon;
c) recrystallization of product with alcohol solvent or a mixture of alcohol solvent; and
d) isolating the crystalline form of Phenyramidol hydrochloride.

6. The process as claimed in claim 3, wherein the alcohol solvent or mixture selected from C1-C6 alcoholic solvents, preferably methanol, ethanol, isopropyl alcohol or 2-propanol, n-butanol, 2-butanol, tert-butanol and mixtures thereof.