DESC: FIELD OF THE INVENTION

The present invention relates to a process for the purification of Minoxidil sulfate.

The present invention also relates to crystalline form of Minoxidil sulfate.

The present invention also relates to a process for the preparation of crystalline form of Minoxidil sulfate.

BACKGROUND OF THE INVENTION

Minoxidil, chemically known as 2,4-diamino-6-piperidinylpyrimidine-3-oxide is an antihypertensive compound that lowers blood pressure by dilating peripheral arteriolar blood vessels. Later, it is found that Minoxidil effectively stimulates hair growth and is widely used as a therapeutical cosmetic. Minoxidil is the FDA-approved drug to treat male and female pattern hair loss including androgenic alopecia. The chemical structure of Minoxidil is as below:

Minoxidil is a pro-drug converted to its active form, minoxidil sulfate, by sulfotransferase enzymes in the outer root sheath of hair. Minoxidil sulfate is the active form required for both the promotion of hair regrowth and the vasodilatory effects of minoxidil. Minoxidil sulfate is chemically known as (2-amino-6-imino-4-(piperidin-1-yl)pyrimidin-1(6H)-yl hydrogen sulfate having the molecular formula C9H15N5O4S and structurally represented as below:

US 4,287,338 (Assigned to The Upjohn Company) initially disclosed Minoxidil sulfate and the process for the preparation of Minoxidil sulfate is described in example 1 by methods A, B and C. Method A involves reaction of Minoxidil free base with pyridine-sulfur trioxide in the presence of DMF. The obtained solid product is filtered and washed with ether to give Minoxidil sulfate, which is recrystallized from DMF and water. Method B involves reaction of Minoxidil free base with trimethylamine-sulfur trioxide complex in the presence of DMF to obtain Minoxidil sulfate, which is recrystallized from DMF and water. Method C involves recrystallization of Minoxidil sulfate with DMF and ethyl acetate, further crystallized from acetonitrile.

Drawback of the process disclosed in US ‘338 is use of higher boiling solvent DMF, which makes process less favorable at an industrial scale.

The other reported process, for example, J. Med. Chem. 1983, 26, 1791-1793 and CN1566102A (Assigned to Zheng Guobin) also involve purification of Minoxidil sulfate by DMF.

The prior art process involves use of DMF for purification/recrystallization of Minoxidil sulfate, wherein high temperature is required for the removal of residual DMF after completion of reaction. This leads to conversion of Minoxidil sulfate to Minoxidil free base, thus limits the use of DMF for commercial scale preparation of Minoxidil sulfate.

Further, as per ICH guidelines, being class 2 solvent, the residual solvent level of DMF should be kept minimal in stringent manner.

Therefore, there is a need in the art to provide an efficient purification process, which is capable of industrial scale preparation of Minoxidil sulfate. The present invention provides novel, simple and industrially feasible purification process of Minoxidil sulfate.

Crystalline polymorph of a drug substance may display different melting point, hygroscopicity, stability, solubility and/or dissolution rate, crystallinity, crystal habits, bioavailability and formulation handling characteristics, which are among the numerous properties that need to be considered in preparing medicament that can be effectively administered. Therefore, the regulatory agencies require a definitive control of polymorphic form of the active component in pharmaceutical dosage forms.

Polymorph of Minoxidil sulfate is not reported in the literature. Accordingly, there is a need for polymorphic forms of Minoxidil sulfate that offer advantages for preparing reproducible pharmaceutical formulations. The crystalline form of Minoxidil sulfate of the present invention fulfill this criteria.

OBJECTS OF THE INVENTION

The primary object of present invention is to provide a purification process of Minoxidil sulfate.

Another object of the invention is to provide crystalline form of Minoxidil sulfate.

Another object of the invention is to provide a process for the preparation of crystalline form of Minoxidil sulfate.
SUMMARY OF THE INVENTION

The main aspect of present invention is provide a process for purification of Minoxidil sulfate by using water or ketone solvent(s) or mixture thereof.

Ketone solvent(s) for the purpose of this invention are selected from the group including but not limited to acetone, butanone, 2-hexanone, methyl ethyl ketone, methyl isobutyl ketone, methyl isopropyl ketone, ethyl isopropyl ketone or cyclohexanone.

Another aspect of the invention is to provide a process for purification of Minoxidil sulfate by using water or acetone or mixture thereof.

Another aspect of the invention is to provide crystalline form of Minoxidil sulfate.

Another aspect of the invention is to provide crystalline form of Minoxidil sulfate having diffraction peak at diffraction angle (2?±0.2°) of 16.95° in a powder X-ray diffraction.

Another aspect of the invention is to provide a process for the preparation of crystalline form of Minoxidil sulfate by purification or recrystallization of Minoxidil sulfate with water or ketone solvent(s) or mixture thereof.

DETAILED DESCRIPTION OF THE DRAWINGS

Fig. 1 illustrates an XRPD pattern of Minoxidil sulfate as prepared by Example 2.

DETAILED DESCRIPTION OF THE INVENTION

The main embodiment of the invention is to provide a process for purification of Minoxidil sulfate. In a preferred embodiment, process for purification of Minoxidil sulfate by using water or ketone solvent(s) or mixture thereof.

Ketone solvent(s) for the purpose of this invention are selected from the group including but not limited to acetone, butanone, 2-hexanone, methyl ethyl ketone, methyl isobutyl ketone, methyl isopropyl ketone, ethyl isopropyl ketone or cyclohexanone.

Another embodiment of the invention is to provide a process for purification of Minoxidil sulfate by using water or acetone or mixture thereof.

The process for the preparation of Minoxidil sulfate is depicted in following reaction scheme.

The starting material used in the process i.e. Minoxidil can be prepared by any known prior art process.

Another embodiment of the invention is to provide crystalline form of Minoxidil sulfate.

In another embodiment, the present invention provides crystalline form of Minoxidil sulfate having diffraction peak at diffraction angle (2?±0.2°) of 10.68° in a powder X-ray diffraction.

In another embodiment, the present invention provides crystalline form of Minoxidil sulfate having diffraction peak at diffraction angle (2?±0.2°) of 12.1° in a powder X-ray diffraction.

In another embodiment, the present invention provides crystalline form of Minoxidil sulfate having diffraction peak at diffraction angle (2?±0.2°) of 16.53° in a powder X-ray diffraction.

In another embodiment, the present invention provides crystalline form of Minoxidil sulfate having diffraction peak at diffraction angle (2?±0.2°) of 16.95° in a powder X-ray diffraction.

In another embodiment, the present invention provides crystalline form of Minoxidil sulfate having diffraction peak at diffraction angle (2?±0.2°) of 18.22° in a powder X-ray diffraction.

In another embodiment, the present invention provides crystalline form of Minoxidil sulfate having diffraction peak at diffraction angle (2?±0.2°) of 18.4° in a powder X-ray diffraction.

In another embodiment, the present invention provides crystalline form of Minoxidil sulfate having diffraction peak at diffraction angle (2?±0.2°) of 20.2° in a powder X-ray diffraction.

In another embodiment, the present invention provides crystalline form of Minoxidil sulfate having diffraction peak at diffraction angle (2?±0.2°) of 23.29° in a powder X-ray diffraction.
In another embodiment, the present invention provides crystalline form of Minoxidil sulfate having diffraction peak at diffraction angle (2?±0.2°) of 23.53° in a powder X-ray diffraction.

In another embodiment, the present invention provides crystalline form of Minoxidil sulfate having diffraction peak at diffraction angle (2?±0.2°) of 24.23° in a powder X-ray diffraction.

In another embodiment, the present invention provides crystalline form of Minoxidil sulfate having diffraction peak at diffraction angle (2?±0.2°) of 24.8° in a powder X-ray diffraction.

The powder X-ray diffraction pattern of the Minoxidil sulfate crystals obtained in Example 2 is shown in FIG 1. The peaks and intensities of the diffraction angles (2?) for the crystals obtained in Example 2 are listed in Table 1.

Table 1
Angle
(2?±0.2°) d value Relative intensity (%)
8.05 10.97 12.7
10.64 8.30 24.1
10.68 8.27 34.5
12.10 7.30 45.5
13.45 6.57 16.7
13.94 6.34 24.0
16.05 5.51 21.6
16.53 5.35 55.2
16.95 5.22 100
18.22 4.86 56.3
18.40 4.81 39.0
18.51 4.78 23.6
18.90 4.69 29.0
20.20 4.39 49.5
21.07 4.21 17.6
21.55 4.11 8.0
23.29 3.81 87.5
23.53 3.77 34.2
24.21 3.67 27.6
24.23 3.66 32.1
24.80 3.58 41.1
26.28 3.38 29.9
26.74 3.33 26.0
27.00 3.29 12.5
28.09 3.17 12.1
29.32 3.04 8.5
29.42 3.03 6.4
30.38 2.93 9.8
35.04 2.55 6.0

Another embodiment of the invention is to provide process for the preparation of crystalline form of Minoxidil sulfate. In a preferred embodiment, purification or recrystallization of Minoxidil sulfate with water or ketone solvent(s) or mixture thereof.

Ketone solvent(s) for the purpose of this invention are selected from the group including but not limited to acetone, butanone, 2-hexanone, methyl ethyl ketone, methyl isobutyl ketone, methyl isopropyl ketone, ethyl isopropyl ketone or cyclohexanone.

Another embodiment of the invention is to provide process for the preparation of crystalline form of Minoxidil sulfate comprising purification or recrystallization of Minoxidil sulfate with water or acetone or mixture thereof.

The following example(s) are intended to illustrate the present invention. It should be understood that the invention is not limited to those specific examples. Numerous changes and modifications may be made to the embodiments of the invention without departing from actual scope of the invention.
Example 1: Process for the preparation of 2-amino-6-imino-4-(piperidin-1-yl)pyrimidin-1(6H)-yl hydrogen sulfate (Minoxidil sulfate crude)

Methylene chloride (1600 ml) and triethylamine (190 gm) were added into RBF at 25-35°C under nitrogen atmosphere and cooled the reaction mass to 0-5°C. To this reaction mass, chlorosulfonic acid solution, which is prepared by Chlorosulfonic acid (110 gm) in methylene chloride (800 ml) and Minoxidil (100 gm) were added and raise temperature 25-35°C for 3 hrs. After completion of the reaction, sodium bicarbonate solution (2000 ml) was slowly added to the reaction mixture, stirred at 25-35°C for 1 hour, filtered the solid and washed the wet cake with purified water to give 220 gm of crude Minoxidil sulfate.

Example 2: Purification of 2-amino-6-imino-4-(piperidin-1-yl)pyrimidin-1(6H)-yl hydrogen sulfate (Minoxidil sulfate)

The crude Minoxidil sulfate (220 gm) obtained from the example 1 and Acetone (850 ml) were added into RBF, stirred at 25-35°C for 15-20 min. Thus, obtained reaction mass was filtered and washed with acetone (50 ml). To this filtrate, chilled purified water (1800 ml) was added at 5-15°C for 1 hour, filtered and dried at 25-30oC for 10 hours to give 100 gm of pure Minoxidil sulfate. ,CLAIMS:We claim:

1. A process for purification of Minoxidil sulfate by using water or ketone solvent or mixture thereof.

2. A process as claimed in claim 1, wherein ketone solvent is selected from acetone, butanone, 2-hexanone, methyl ethyl ketone, methyl isobutyl ketone, methyl isopropyl ketone, ethyl isopropyl ketone or cyclohexanone.

3. A process as claimed in claim 1, wherein ketone solvent is acetone.

4. A crystalline form of Minoxidil sulfate having diffraction peak at diffraction angle (2?±0.2°) of 12.10° in a powder X-ray diffraction.

5. A crystalline form of Minoxidil sulfate having diffraction peak at diffraction angle (2?±0.2°) of 16.53° in a powder X-ray diffraction.

6. A crystalline form of Minoxidil sulfate having diffraction peak at diffraction angle (2?±0.2°) of 16.95° in a powder X-ray diffraction.

7. A crystalline form of Minoxidil sulfate having diffraction peak at diffraction angle (2?±0.2°) of 18.22° in a powder X-ray diffraction.

8. A crystalline form of Minoxidil sulfate having diffraction peak at diffraction angle (2?±0.2°) of 20.20° in a powder X-ray diffraction.

9. A crystalline form of Minoxidil sulfate having diffraction peak at diffraction angle (2?±0.2°) of 23.29° in a powder X-ray diffraction.

10. The crystalline form of Minoxidil sulfate, which is characterized by a powder X-ray diffraction in which the peak positions are substantially in accordance with the peak positions of the pattern shown in Fig. 1.