DESC:FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

"AN IMPROVED PROCESS FOR THE PREPARATION OF ZINC SULFATE HEPTAHYDRATE"

Biophore India Pharmaceuticals Pvt Ltd.
An Indian company having its registered office at Plot # 92, 1-98/2/92, Kavuri hills Phase II, Jubilee Hills, Hyderabad, India

The following specification particularly describes the invention and the manner in which it is to be performed (For Complete):
FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of zinc sulfate heptahydrate (I), having quality specifications as per new FDA-imposed quality standards and the ICH Q3D guidelines.

BACKGROUND OF THE INVENTION
Zinc sulfate heptahydrate is a heptahydrate form of zinc sulfate. It is a hydrate and a metal sulfate. It contains a zinc sulfate. Zinc Sulfate Injection, USP is a sterile, non-pyrogenic, clear, colourless, and odourless solution intended for use as a trace element and an additive to intravenous solutions for parenteral nutrition. Its empirical formula is ZnSO4. 7H2O. Its structure is as depicted below.

(I)
The synthesis of zinc sulfate heptahydrate (I) has been reported in few patents and non-patent literatures, the contents of which are hereby incorporated as reference in their entirety.

US 1,922,902 discloses zinc sulfate heptahydrate, wherein zinc Sulphate is usually produced for commerce as one of the hydrates containing 6 or 7 mols of water of crystallization. Attempts to produce zinc sulphate with a lower Water content, such as would correspond to about 4 or 5 mols of water of crystallization, have resulted in obtaining products in lump form which dissolve only with difficulty in water.

The zinc sulfate crystallizes in a hydrate row with 1, 2, 3, 5, 6 and 7 molecules of water of crystallization; the technical products are the heptahydrate ZnSO4.7H2O and the monohydrate Zn SO4.H2O.

Still, there lies a need for the preparation of zinc sulfate heptahydrate (I) having quality specifications as per new FDA-imposed quality standards and the ICHQ3 guidelines. Hence, the present inventors provide an improved process for the preparation of the same.

OBJECTIVE OF THE INVENTION
Accordingly, an objective of the present invention provides an improved process for the preparation of zinc sulfate heptahydrate (I).

Yet in another objective, the present invention provides a process for the preparation of zinc sulfate heptahydrate (I), having quality specifications as per new FDA-imposed quality standards and the ICH Q3D guidelines.

SUMMARY OF THE INVENTION
Accordingly, in one aspect of the present invention is to provide a process for the preparation of zinc sulfate heptahydrate (I) as shown in scheme 1, comprising:
a) reacting zinc (II) oxide with sulfuric acid and water to obtain zinc sulfate heptahydrate crude (Ia); and
b) purifying crude zinc sulfate heptahydrate (Ia) to obtain zinc sulfate heptahydrate (I).

Yet in another aspect, the present invention is to provide a process for the preparation of zinc sulfate heptahydrate (I), having quality specifications as per new FDA-imposed quality standards and the ICH Q3D guidelines.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 illustrates X-Ray Diffraction (XRD) pattern of crystalline Zinc sulfate heptahydrate (I).
Figure 2 illustrates Differential Scanning Calorimetry (DSC) of crystalline form of Zinc sulfate heptahydrate (I).

DETAILED DESCRIPTION OF THE INVENTION
Accordingly, in one embodiment of the present invention provides a process for the preparation of zinc sulfate heptahydrate (I) as illustrated in scheme I.

Scheme 1
In another embodiment, the steps involved in the preparation of zinc sulfate heptahydrate (I) as shown in scheme I are as follows:

In an embodiment of the present invention proceeds with concentrated sulfuric acid was slowly added at below 60 °C to the de-mineralized water at room temperature. Zinc (II) oxide was added to the above reaction mass at 40-45 °C. Temperature was raised to 50-55 °C and cooled to 45-50 °C. Filtered the mass at 45-50°C. pH of the reaction mass was adjusted to 4.7 to 4.9 using 1M sulfuric acid at 25-30°C. 80% of water was distilled off under vacuum at 55-60 °C and cooled the reaction mass to room temperature. Filtered the solid and dried to get Zinc sulfate hepta hydrate (I).

In another embodiment, zinc sulfate forms different hydrates viz-a-viz., monohydrate, hexahydrates and heptahydrate. Preferably forms zinc sulfate heptahydrate.

In another embodiment, the present invention provides a process for the preparation of zinc sulfate heptahydrate (I), having quality specifications as per new FDA-imposed quality standards and the ICH Q3D guidelines.

In another embodiment, the solid zinc sulfate heptahydrate (I) obtained according to the present invention is crystalline powder.

In another embodiment, the present invention provides crystalline form of Zinc sulfate heptahydrate (I) obtained according to the present invention is characterised by X-ray powder diffractions (XRD) pattern as illustrated in figure 1 and 2 theta values as provided in Table 1:

Table 1:
Two theta (2T) values Relative Intensity (I/Io)
14.9 11.9
16.3 56.3
16.5 40.5
17.7 15.6
19.6 25.9
19.7 29.6
20.0 100
20.8 75.3
21.0 56.7
21.3 11.8
21.9 26.0
23.5 19.8
25.5 16.5
30.3 10.2
30.6 15.5
30.9 34.1
33.1 18.0
33.5 17.4
39.6 14.1
40.9 25.5
45.9 10.3

In another embodiment, the zinc sulfate heptahydrate (I) obtained according to the present invention has water content of not more than 46% (w/w), preferably not more than 44% (w/w), more preferably not more than 43%.

In another embodiment, the solid zinc sulfate heptahydrate (I) obtained according to the present invention which on drying is anhydrous.

In another embodiment, the present invention provides zinc sulfate heptahydrate (I), is having a heavy metal content of no greater than about 5 ppm, specifically no greater than about 1.5 ppm of Arsenic, no greater than about 0.5 ppm of lead, no greater than about 0.3 ppm of Mercury, no greater than about 0.3 ppm of cobalt, no greater than about 0.3 ppm of nickel, no greater than about 6 ppm of copper.

In another embodiment, the present invention provides zinc sulfate heptahydrate (I), is having no greater than about 0.2 ppm of cadmium.

In another embodiment, the present invention provides zinc sulfate heptahydrate (I), is having no greater than about 160 ppm of Aluminium, no greater than about 100 ppm of Iron.

In another embodiment, the present invention provides zinc sulfate heptahydrate (I), is having no greater than about 300 ppm of chloride, no greater than about 5.0 mg of alkaline and alkaline earths.

The following examples further illustrate the present invention but should not be construed in any way as to limit its scope.

EXAMPLES
Example-1: Process for the preparation of Zinc sulfate heptahydrate (I)
64.9 ml of concentrated sulfuric acid was added at below 60 °C to the11.0 volumes of water at 25 to 30 °C and stirred for 5-10 minutes at 40-45 °C. 100 g of Zinc (II) oxide was added to the reaction mass at the same temperature. The reaction temperature was raised to 50-55°C and stirred for 14-16 hours. After completion of the reaction, the reaction mass was cooled to 45-50°C and filtered. pH of the reaction mass was adjusted to 4.7 to 4.9 using 1M sulfuric acid at 25-30°C. Distilled off water from the reaction mass at 50-60°C under vacuum. The reaction mass was transferred to plastic trays at 55-58 °C, cooled gradually to 25-30°C and hold for 60-70 hours at 25-30°C. Filtered the solid and dried to get the title compound. Yield: 50-55 %. XRD: figure 1.
,CLAIMS:We claim:
1. A process for the preparation of zinc sulfate heptahydrate (I)

wherein the process comprising:
a) reacting zinc (II) oxide with sulfuric acid and water to obtain zinc sulfate heptahydrate crude (Ia); and

a) purifying crude zinc sulfate heptahydrate (Ia) to obtain zinc sulfate heptahydrate (I).
2. The process as claimed in claim1, wherein the zinc sulfate heptahydrate (I), is having the water content is less than 46% (w/w).
3. The process as claimed in claim1, wherein the zinc sulfate heptahydrate (I), is having no greater than about 1.5 ppm of Arsenic, no greater than about 0.5 ppm (w/w) Lead, no greater than about 0.3 ppm of Mercury; no greater than about 0.2 ppm of Cadmium.
4. The process as claimed in claim1, wherein the zinc sulfate heptahydrate (I), is having no greater than about 160 ppm of Aluminium.
5. The process as claimed in claim1, wherein the zinc sulfate heptahydrate (I), is having no greater than about 100 ppm of Iron.
6. The process as claimed in claim1, wherein the zinc sulfate heptahydrate (I), is having no greater than about 300 ppm of chloride.
7. The process as claimed in claim1, wherein the zinc sulfate heptahydrate (I), is having no greater than about 5.0 mg of alkaline and alkaline earths.

Dated this 12th day of October 2023.
Manik Reddy Pullagurla
Chief Scientific Officer
Biophore India Pharmaceuticals Pvt Ltd.