Claims:WE CLAIM:

1. A purification process for the preparation of Midodrine hydrochloride, comprising the steps of;

a) Crude compound of Midodrine hydrochloride was dissolved in an organic solvent,
b) heating the obtained suspension at 60-65°C and stir for 30 mins,
c) cooling the solution obtained in step b) at 10-15ºC, and
d) isolating the pure compound of Midodrine hydrochloride.

2. The process as claimed in claim 1, wherein the organic solvent is selected from methanol, ethanol, butanol, propanol and isopropanol.

3. Novel crystalline Form “OP” of Midodrine hydrochloride.

4. Novel crystalline form “OP” of Midodrine hydrochloride as claimed in claim 3, characterized by an X-ray powder diffraction pattern (XRPD) spectrum having peak reflection at about 5.33, 10.7, 11.93, 15.14, 16.1, 17.16, 20.66, 21.54, 22.07, 23.84, 24.12, 26.99 and 43.93±0.2 degrees 2?.

5. Novel crystalline form “OP” of Midodrine hydrochloride as claimed in claim 3 and 4, having a powder X-ray powder diffraction pattern substantially in accordance with Figure-1.

6. Novel crystalline form “OP” of Midodrine hydrochloride as claimed in claim 3, characterized by an Infra-red spectrum (IR) having peak reflections at about 3078.36, 2703.09, 2592.43, 2382.85, 1976.71, 1853.25, 1651.94, 1570.23, 1402.80, 1327.00, 1239.80, 1163.04, 1125.26, 1113.00, 1053.10, 1021.70, 954.79, 928.50, 880.73, 854.84, 770.11, 732.81, 672.44.

7. Novel crystalline form “OP” of Midodrine hydrochloride as claimed in claim 3 and 6, having a Infra-red spectrum (IR) substantially in accordance with Figure-2.

8. Novel crystalline form “OP” of Midodrine hydrochloride as claimed in claim 3, differential scanning calorimetry (DSC) substantially in accordance with Figure-3.

Dated this the seventh (07th) day of May, 2021

, Description:NOVEL CRYSTALLINE FORM OF MIDODRINE HYDROCHLORIDE

FIELD OF THE INVENTION

The present invention relates to purification process for Midodrine hydrochloride and also relates to novel crystalline Form “OP” of Midodrine hydrochloride.

BACKGROUND OF THE INVENTION

Midodrine hydrochloride (trade name; ProAmatine®, Gutron®) is classified as an antihypotensive drug. Midodrine was approved in the United States by the Food and Drug Administration (FDA) in 1996 for the treatment of dysautonomia and orthostatic hypotension. In August 2010, the FDA proposed withdrawing this approval because the manufacturer, Shire plc, failed to complete required studies after the medicine reached the market.

Midodrine is indicated for the treatment of symptomatic orthostatic hypotension. It can reduce dizziness and faints by about a third, but can be limited by troublesome goose bumps, skin itch, gastrointestinal discomfort, chills, elevated blood pressure while lying down, and urinary retention. Midodrine hydrochloride is chemically known as (±)-2-amino-N-[2-(2,5­dimethoxyphenyl)-2-hydroxyethyl]-acetamide monohydrochloride of formula (I) has the following structure.

Midodrine hydrochloride was first described in US 3340298 as a product and its purification process; which comprises the crude compound of Midodrine hydrochloride recrystallized with water / methanol to obtain pure Midodrine hydrochloride with melting point 192 – 193°C. No XRD and DSC are reported.

Polymorphic forms of Midodrine hydrochloride is not reported in the literature.

Polymorphism is defined as "the ability of a substance to exist as two or more crystalline phases that have different arrangement and/or conformations of the molecules in the crystal Lattice. Thus, in the strict sense, polymorphs are different crystalline forms of the same pure substance in which the molecules have different arrangements and/or different configurations of the molecules". Different polymorphs may differ in their physical properties such as melting point, solubility, X-ray diffraction patterns, etc. Although those differences disappear once the compound is dissolved, they can appreciably influence pharmaceutically relevant properties of the solid form, such as handling properties, dissolution rate and stability. Such properties can significantly influence the processing, shelf life, and commercial acceptance of a polymorph. It is therefore important to investigate all solid forms of a drug, including all polymorphic forms, and to determine the stability, dissolution and flow properties of each polymorphic form. Polymorphic forms of a compound can be distinguished in the laboratory by analytical methods such as X-ray diffraction (XRD), Differential Scanning Calorimetry (DSC) and Infrared spectrometry (IR).

We have found a novel crystalline Form “OP” of Midodrine hydrochloride. The crystalline form has been found to be stable over the time and reproducible. Hence it is suitable for pharmaceutical preparations.

SUMMARY OF THE INVENTION

The present invention relates to purification process for Midodrine hydrochloride and also relates to novel crystalline Form “OP” of Midodrine hydrochloride.

One aspect of the present invention, it provides a purification process for the preparation of Midodrine hydrochloride, comprising the steps of;

a. Crude compound of Midodrine hydrochloride was dissolved in an organic solvent,
b. heating the obtained suspension at 60-65°C and stir for 30 mins,
c. cooling the solution obtained in step b) at 10-15ºC, and
d. isolating the pure compound of Midodrine hydrochloride.

The another aspect of the present invention, it provides novel crystalline Form “OP” of Midodrine hydrochloride characterized by an X-ray powder diffraction (XRPD) spectrum having peak reflections at about 5.33, 10.7, 11.93, 15.14, 16.1, 17.16, 20.66, 21.54, 22.07, 23.84, 24.12, 26.99 and 43.93±0.2 degrees 2?.

In another aspect, there is provided a novel crystalline Form “OP” of Midodrine hydrochloride, which is characterized by X-ray powder diffraction pattern substantially as same as depicted in FIG. 1. The novel crystalline Form “OP” of Midodrine hydrochloride is further characterized by infra-red spectrum as shown in FIG. 2. The novel crystalline Form “OP” of Midodrine hydrochloride is further characterized by Differential Scanning calorimetry (DSC) as shown in FIG. 3.

BRIEF DESCRIPTION OF THE DRAWINGS:

Figure 1: X-ray powder diffraction (PXRD) novel crystalline Form “OP” of Midodrine hydrochloride.

Figure 2: Infra-red spectra (IR) novel crystalline Form “OP” of Midodrine hydrochloride.

Figure 3: Differential scanning calorimetry (DSC) novel crystalline Form “OP” of Midodrine hydrochloride

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to purification process for Midodrine hydrochloride and also relates to novel crystalline Form “OP” of Midodrine hydrochloride.

One embodiment of the present invention, it provides a purification process for the preparation of Midodrine hydrochloride, comprising the steps of;

a. Crude compound of Midodrine hydrochloride was dissolved in an organic solvent,
b. heating the obtained suspension at 60-65°C and stir for 30 mins,
c. cooling the solution obtained in step b) at 10-15ºC, and
d. isolating the pure compound of Midodrine hydrochloride.

According to the embodiment of the present invention, it provides purification process for the preparation of Midodrine hydrochloride, which comprises the crude compound of Midodrine hydrochloride is dissolved in organic solvent, heat the reaction mass at 60-65°C and stir for 30 mins then get a clear solution. The reaction mass is cooled to 10-15°C to get a solid. The precipitated solid is filtered and the wet material is dried at 45-50°C for 8 hrs to obtain pure Midodrine hydrochloride.

According to the embodiment of the present invention, wherein the organic solvent is selected from methanol, ethanol, butanol, propanol and isopropanol.

In an embodiment of the present invention provides the novel crystalline form “OP” of Midodrine hydrochloride is characterized by X-Ray powder diffraction spectrum as depicted in Figure 1.

According to the embodiment of the present invention provides the novel crystalline form “OP” of Midodrine hydrochloride is characterized by X-Ray powder diffraction spectrum having peak reflections at about 5.33, 10.7, 11.93, 15.14, 16.1, 17.16, 20.66, 21.54, 22.07, 23.84, 24.12, 26.99 and 43.93±0.2 degrees 2?.

According to the embodiment of the present invention provides the novel crystalline form “OP” of Midodrine hydrochloride is further characterized by X-Ray powder diffraction spectrum having peak reflections at about 5.33, 7.96, 10.7, 11.93, 13.36, 14.54, 15.14, 16.1, 17.16, 19.41, 19.74, 20.18, 20.66, 21.54, 22.07, 22.95, 23.84, 24.12, 24.78, 25.39, 26.58, 26.99, 27.61, 28.68, 29.28, 29.95, 30.59, 31.71, 32.89, 33.26, 34.28, 34.73, 35.52, 36.45, 37.05, 37.8, 39.35, 39.74,40.28, 42.53, 43.93 and 49.78 ±0.2 degrees 2?

In another embodiment of the present invention present invention the novel crystalline form “OP” of Midodrine hydrochloride is characterized by Infra-red spectra (IR) as depicted in Figure 2.

According to the embodiment of the present invention provides the novel crystalline form “OP” of Midodrine hydrochloride is further characterized by Infra-red spectrum (IR) having peak reflections at about 3078.36, 2703.09, 2592.43, 2382.85, 1976.71, 1853.25, 1651.94, 1570.23, 1402.80, 1327.00, 1239.80, 1163.04, 1125.26, 1113.00, 1053.10, 1021.70, 954.79, 928.50, 880.73, 854.84, 770.11, 732.81, 672.44.
According to the embodiment of the present invention provides the novel crystalline form “OP” of Midodrine hydrochloride is further characterized by Infra-red spectrum (IR) having peak reflections at about 3336.54, 3078.36, 2996.85, 2975.19, 2950.51, 2881.17, 2703.09, 2592.43, 2382.85, 1976.71, 1853.25, 1651.94, 1570.23, 1499.82, 1471.67, 1435.54, 1402.80, 1359.90, 1327.00, 13.8.13, 1296.88, 1273.32, 1239.80, 1215.26, 1193.73, 1183.84, 1163.04, 1134.87, 1125.26, 1113.00, 1069.05, 1053.10, 1039.81, 1021.70, 954.79, 928.50, 903.91, 880.73, 854.84, 811.74, 770.11, 732.81, 705.27, 672.44.

The an another embodiment of the present invention, the novel crystalline form “OP” of Midodrine hydrochloride differential scanning calorimetry (DSC) as depicted in Figure 3.

In yet another embodiment of the present invention, there is provided pharmaceutical compositions comprising a therapeutically effective amount of novel crystalline form “OP” solid dispersion of Midodrine hydrochloride in combination with a pharmaceutically acceptable carrier and along with pharmaceutically acceptable excipients, and at least one pharmaceutically acceptable excipient. The novel crystalline form “OP” solid dispersion of Midodrine hydrochloride in combination with a pharmaceutically acceptable carrier may preferably be formulated into cream, 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.

EXAMPLES

Example-1:
Purification process of Midodrine hydrochloride:

100 g (0.34 moles) of crude Midodrine hydrochloride is taken in methanol (150 ml) at 25-30°C and reaction mass temperature is raised to 60-65°C to get clear solution. Then, activated charcoal (5 gm) is added and stir the reaction mass for 30 min at 60-65°C. After that, reaction mass is filtered through hyflo bed and the filtrate is cooled to 10-15°C to get solid. The precipitated solid is filtered and the wet material is dried at 45-50°C for 8 hrs to get titled compound.
HPLC Purity: 99.8%
Yield: 75%

Example-2:
Purification process of Midodrine hydrochloride

100 g (0.34 moles) of crude Midodrine hydrochloride is taken in ethanol (200 ml) at 25-30°C and reaction mass temperature is raised to 70-75°C to get clear solution. Then, activated charcoal (5 gm) is added and stir the reaction mass for 30 min at 70-75°C. After that, reaction mass is filtered through hyflo bed and the filtrate is cooled to 10-15°C to get solid. The precipitated solid is filtered and the wet material is dried at 45-50°C for 8 hrs to get titled compound.
HPLC Purity: 99.6%
Yield: 70%

Example-3:
Purification process of Midodrine hydrochloride

100g (0.34 moles) of crude Midodrine hydrochloride is taken in 2-propanol (200 ml) at 25-30°C and reaction mass temperature is raised to 75-80°C to get clear solution. Then, activated charcoal (5 gm) is added and stir the reaction mass for 30 min at 75-80°C. After that, reaction mass is filtered through hyflo bed and the filtrate is cooled to 10-15°C to get solid. The precipitated solid is filtered and the wet material is dried at 45-50°C for 8 hrs to get titled compound.
HPLC Purity: 99.4%
Yield: 77%