FORM-2
THE PATENTS ACT, 1970 (39 of 1970)
&
THE PATENTS RULE, 2003
COMPLETE SPECIFICATION
[See section 10, rule 13]
A NOVEL PROCESS FOR PREPARATION OF BITTER-LESS ERYTHROMYCIN ETHYL SUCCINATE
APPLICANT:
CALYX CHEMICALS AND PHARMACEUTICALS LTD. 2, Marwah's Complex, Sakivihar Road, Sakinaka, Andheri (E), Mumbai-400 072, Maharashtra, India
Indian Company incorporated under the Companies Act 1956
The following specification particularly describes the invention and the manner in which it is to be performed:

FIELD OF INVENTION
The present invention relates to a novel process for the preparation of bitter-less Erythromycin ethyl succinate from erythromycin base. The present invention also relates to the improved process for the preparation of bitter-less Erythromycin ethyl succinate from erythromycin thiocyanate.
In particular, the present invention relates to the processes for the preparation of Erythromycin ethyl succinate containing less than 2 % of erythromycin base which makes it bitter-less.
BACKGROUND OF INVENTION
Erythromycin is one of the most successful drugs of all time and has been widely used in treatment of bacterial infections. However, the oral administration of erythromycin base is associated with drawback of its bitter taste. This problem is greatly exacerbated by the fact that erythromycin needs to be administrated in large doses. The enteric coated tablets and capsules are used clinically which masks the bitter taste of erythromycin but it becomes difficult to mask taste of erythromycin in liquid formulations used in pediatrics. To overcome this problem, Erythromycin ethyl succinate with structural Formula I, a prodrug of erythromycin which is bitter-less is administered orally.


wherein R is COCH2CH2COOC2H5
The Erythromycin ethyl succinate on hydrolysis in body forms erythromycin base which effectively acts against bacterial infectised in US2967129 wherein the process for preparation of erythromycin ethyons.
Erythromycin ethyl succinate was first disclol succinate is also disclosed. This process involves use of erythromycin free base, sodium bicarbonate and ethyl succinyl chloride in acetone. As is readily apparent from the patent disclosure, the reaction is very slow with low yields.
US4219641 describes a process for preparation of Erythromycin ethyl succinate by reacting erythromycin USP quality free base with ethyl succinyl chloride in a two phase system consisting of organic solvent capable of forming two phases with water and aqueous base. Heavy metal scavenger (sodium citrate) has been used in the process. The patent also reports the use of ethyl acetate as an organic solvent which must be accompanied by the addition of hexane to crystallize the desired product.

None of the known prior art, provides a process for preparation of Erythromycin ethyl succinate without presence of erythromycin base in it. Also, till date, the prior art have not mentioned quantity of unreacted erythromycin base in final product, i.e. Erythromycin ethyl succinate. It is to be noted that if the quantity of erythromycin base is more than 2 % in Erythromycin ethyl succinate, it makes the composition bitter and hence, unpleasant for oral consumption. Hence, there is a need to develop a novel, efficient and industrially viable process for the preparation of bitter-less Erythromycin ethyl succinate.
The inventors of present invention have found out a novel process to obtain bitter-less Erythromycin ethyl succinate containing less than 2 % of erythromycin base using organic solvent selected from ester or ether in formation of Erythromycin ethyl succinate from erythromycin base or in purification of obtained product i.e. Erythromycin ethyl succinate. The organic solvent like ester or ether lowers the amount of erythromycin base in the final product since erythromycin base has selective solubility in ester or ether over Erythromycin ethyl succinate. The inventors of present invention have also rationally designed the process to obtain bitter-less Erythromycin ethyl succinate from erythromycin thiocyanate. The process is cost effective, operationally simple, exploits cheap and commercially available raw material and yields the final product with less than 2 % of erythromycin base.
Thus, the processes of the present invention provide Erythromycin ethyl succinate with less than 2 % of erythromycin base which makes it bitter-less and hence it can be used readily for oral administration.

OBJECT OF INVENTION
i) An object of the present invention is to provide a novel process for the preparation of bitter-less Erythromycin ethyl succinate from erythromycin base in an organic solvent selected from esters or ethers.
ii) Another object of the present invention is to obtain bitter-less Erythromycin ethyl succinate by purifying or washing the erythromycin ethyl succinate, obtained by using processes of the present invention, with an organic solvent selected from esters or ethers.
iii) Another object of the present invention is to provide the improved processes for the preparation of bitter-less Erythromycin ethyl succinate from erythromycin thiocyanate.
iv) Another object of the present invention is to obtain Erythromycin ethyl succinate with less than 2 % of erythromycin base by using novel and improved processes of the present invention.
v) Yet another object of the present invention is to provide simple, economic and industrially viable processes for the preparation of bitter-less Erythromycin ethyl succinate.
SUMMARY OF INVENTION
According to an aspect of the present invention, there is provided a novel process for the preparation of bitter-less Erythromycin ethyl succinate of Formula I containing less than 2 % of erythromycin base


Formula I
wherein R is COCH2CH2COOC2H5
comprising,
A] reacting erythromycin base with ethyl succinyl chloride in presence of a base in an organic solvent selected from esters or ethers followed by filtering the reaction mass and washing the obtained product with solvent such as esters or ethers to yield bitter-less Erythromycin ethyl succinate containing less than 2 % erythromycin base.
or
B] reacting erythromycin base with ethyl succinyl chloride in presence of a base in an organic solvent selected from halogenated solvents or low molecular weight aliphatic ketones followed by isolating the crude product and purifying it with solvent such as esters or ethers to yield bitter-less Erythromycin ethyl succinate containing less than 2 % erythromycin base.
According to another aspect of the present invention, there is provided a improved process, process A, for preparation of bitter-less Erythromycin ethyl succinate of Formula I from erythromycin thiocyanate


wherein R is COCH2CH2COOC2H5 comprising steps of,
i) treating erythromycin thiocyanate of Formula II

with aqueous base in presence of suitable solvent to obtain erythromycin base ii) reacting erythromycin base obtained in step i) with ethyl succinyl chloride in presence of a base in an organic solvent to obtain product Erythromycin ethyl succinate

iii) purifying or washing the product Erythromycin ethyl succinate with an organic solvent selected from esters or ethers to obtain bitter-less Erythromycin ethyl succinate containing less than 2 % erythromycin base.
According to another aspect of the present invention, there is provided an alternative process, process B for preparation of Erythromycin ethyl succinate of Formula I from erythromycin thiocyanate

wherein R is as defined above, comprises of
a) treating erythromycin thiocyanate of Formula II with aqueous base in
presence of suitable solvent


Formula II
b) optionally adding organic solvent after completion of step a) reaction
c) separating organic layer
d) adding a base and ethyl succinyl chloride to the organic layer of step c) to obtain Erythromycin ethyl succinate
e) purifying or washing erythromycin ethyl succinate obtained in step d) with an organic solvent selected from esters or ethers to obtain bitter-less Erythromycin ethyl succinate containing less than 2 % erythromycin base
In particular, the present invention relates to the novel and improved processes for the preparation of Erythromycin ethyl succinate containing less than 2 % of erythromycin base which makes it bitter-less.
DETAILED DESCRIPTION OF INVENTION
The present invention provides the novel and improved processes for the preparation of bitter-less Erythromycin ethyl succinate of Formula I, an ester prodrug of erythromycin that is commonly administered. In particular, the present invention relates to the novel and improved processes for the preparation of Erythromycin ethyl succinate containing less than 2 % of erythromycin base which makes it bitter-less.


wherein R is COCH2CH2COOC2H5
In an embodiment of the present invention, there is provided a novel process for preparation of bitter-less Erythromycin ethyl succinate of Formula I with less than 2 % erythromycin base content comprising,
A] reacting erythromycin base with ethyl succinyl chloride in presence of a base in an
organic solvent selected from esters or ethers followed by filtering the reaction
mass and washing the obtained product with solvent such as esters or ethers to
yield bitter-less Erythromycin ethyl succinate containing less than 2 %
erythromycin base
or
B] reacting erythromycin base with ethyl succinyl chloride in presence of a base in
an organic solvent selected from halogenated solvents or low molecular weight
aliphatic ketones followed by isolating the crude product and purifying it with
solvents such as esters or ethers to yield bitter-less Erythromycin ethyl succinate
containing less than 2 % erythromycin base

In another embodiment of the present invention the organic solvent is selected from esters like ethyl acetate, iso-propyl acetate, butyl acetate, amyl acetate, preferably ethyl acetate is used.
In another embodiment of the present invention, the organic solvent is selected from ethers like methyl tert-butyl ether or isopropyl ether, preferably methyl tert-butyl ether is used.
According to yet another embodiment of the present invention, the base used is selected from weak organic or inorganic base, wherein organic base is selected from triethyl amine or pyridine and inorganic base is selected from sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate, preferably sodium bicarbonate or potassium bicarbonate is used.
In another embodiment of the present invention the organic solvent selected from halogenated solvents is preferably methylene chloride.
In yet another embodiment of the present invention the organic solvent selected from low molecular weight aliphatic ketones is preferably acetone.
The erythromycin base used for the above reaction is prepared by the improved processes, process A or process B, of the present invention or erythromycin base can also be prepared by using conventional methods known in the art.

In another embodiment of the present invention, there is provided an imrpoved processes, process A and process B for the preparation of bitter-less Erythromycin ethyl succinate of Formula I from erythromycin thiocyanate of Formula II

Process A comprises the steps of,
i) treating erythromycin thiocyanate of Formula II with aqueous base in
presence of suitable solvent to obtain erythromycin base
ii) reacting erythromycin base obtained in step i) with ethyl succinyl chloride
in presence of a base in an organic solvent to obtain product Erythromycin
ethyl succinate
iii) purifying or washing the product Erythromycin ethyl succinate with an
organic solvent selected from esters or ethers to obtain bitter-less
Erythromycin ethyl succinate containing less than 2 % erythromycin base
Process B comprises the steps of,
a) treating erythromycin thiocyanate of Formula II with aqueous base in presence of suitable solvent
b) optionally adding organic solvent after completion of step a) reaction
c) separating organic layer

d) adding a base and ethyl succinyl chloride to the organic layer of step c) to
obtain Erythromycin ethyl succinate
e) purifying or washing erythromycin ethyl succinate obtained in step d) with an
organic solvent selected from esters or ethers to obtain bitter-less
Erythromycin ethyl succinate containing less than 2 % erythromycin base
The process of the present invention for preparation of Erythromycin ethyl succinate of Formula I from erythromycin thiocyanate of Formula II is depicted in following Scheme 1


Formula I
SCHEME 1
wherein R is COCH2CH2COOC2H5
The compound of Formula II is prepared by the well known prior art processes.
According to an embodiment of the present invention, in step i) and in step a) the erythromycin thiocyanate of Formula H is first converted to a compound of Formula HI i.e. erythromycin base, using aqueous base.

The aqueous base used in the step i) and step a) is selected from sodium hydroxide, potassium hydroxide, liquid ammonia, sodium bicarbonate or potassium bicarbonate, preferably sodium hydroxide is used.
In another embodiment of the present invention, the range of suitable stoichiometrics of base with respect to erythromycin thiocyanate is between 2-12 equivalents, preferably 8.5.
According to another embodiment of the present invention, step i) and step a) is carried out in a suitable solvent selected from water or organic solvents such as halogenated solvents preferably methylene dichloride or low molecular weight aliphatic ketones preferably acetone or esters like ethyl acetate, isopropyl acetate, butyl acetate, amyl acetate or ethers like methyl tert-butyl ether or iso-propyl ether.
The step i) and step a) is carried out at a temperature between room temperature to reflux temperature.
In yet another embodiment of the present invention, erythromycin base obtained in step i) reaction is isolated by processing organic layer by separating it, washing it with water and reducing organic solvent to obtained reaction mass. The obtained reaction mass is then chilled, filtered and dried to get erythromycin base.
In yet another embodiment of present invention, in the alternative process, process B, after step a) reaction is completed, the organic solvent is optionally added in step b). After addition of organic solvent, the reaction mass is stirred for 5 to 30 minutes and then the organic layer is separated in step c). The separated organic layer is then processed by washing it with water to remove the unreacted base and reducing its

moisture content by known methods in prior arts. The moisture content is reduced to the extent wherein KF is below 0.5 %. The organic layer thus obtained is then taken further for the step d) reaction without isolating erythromycin base.

In further embodiment of the present invention, organic solvent added in step b) is selected from esters like ethyl acetate, isopropyl acetate, butyl acetate, amyl acetate or ethers like methyl tert-butyl ether or isopropyl ether or halogenated solvents, preferably methylene dichloride or low molecular weight aliphatic ketones, preferably acetone, preferably solvent used is ethyl acetate.
According to yet another embodiment of the present invention, a base used in step ii) and in step d) is selected from weak organic or inorganic base, wherein organic base is selected from triethyl amine or pyridine and inorganic base is selected from sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate, preferably sodium bicarbonate or potassium bicarbonate is used.
According to another embodiment of the present invention, in step ii) and in step d) ethyl succinyl chloride is added portionwise.
In another embodiment of the present invention, the range of suitable stoichiometrics of ethyl succinyl chloride with respect to erythromycin thiocyanate is between 1 to 2.5 equivalents, preferably 1.2
In another embodiment of the present invention, the step ii) and step d) is carried out at temperature ranging from 25 °C to 35 °C.
In yet another embodiment of the present invention, the step ii) and step d) is carried out in a solvent selected from organic solvents like ester, ether, halogenated solvents, preferably methylene dichloride or low molecular weight aliphatic ketones preferably

acetone., preferably ester or ether is used. The solvent is selected from esters like, ethyl acetate, iso-propyl acetate, butyl acetate, amyl acetate, preferably ethyl acetate is used or from ethers like methyl tert-butyl ether or /so-propyl ether.
In further embodiment of the present invention, Erythromycin ethyl succinate obtained in step ii) and step d) is purified or washed, in step iii) and step e), with organic solvent selected from esters or ethers to obtained bitter-less Erythromycin ethyl succinate containing less than 2 % of erythromycin base.
In another embodiment of the present invention ,the organic solvent used in step iii) and step e) are selected from esters like ethyl acetate, wo-propyl acetate, butyl acetate, amyl acetate, preferably ethyl acetate is used and from ethers like methyl tert-butyl ether or wo-propyl ether, preferably methyl tert-butyl ether is used.
The inventors of the present invention have observed that the solubility of the erythromycin base is more than solubility of Erythromycin ethyl succinate in esters and ethers, preferably in ester like ethyl acetate and ether like methyl tart-butyl ether. Hence, product Erythromycin ethyl succinate containing lower amount of erythromycin base i.e. less then 2% (by HPLC analysis) is obtained when reaction of erythromycin base with ethyl succinyl chloride in presence of base is carried out in ester or in ether, or when the product obtained after reaction of erythromycin base with ethyl succinyl chloride in presence of base, is purified or washed with ester or ether. This process thus provides a bitter-less erythromycin ethyl succinate.
In another aspect of the present invention, there is also provided an improved process for preparation of bitter-less Erythromycin ethyl succinate, using a single organic solvent selected from esters like ethyl acetate, iso-propyl acetate, butyl acetate, amyl acetate, preferably ethyl acetate is used through out the process.

The detail of the invention provided in the following example is given by the way of illustration only and should not be construed to limit the scope of the present invention.
EXAMPLES AND COMPARATIVE EXAMPLES
Comparative Example 1
For comparison purposes. Erythromcyanate (100 gm, active) and acetone (350 ml), a solution of Na2C03 (30 g in 20ycin ethyl succinate was prepared by process known in the art
To a suspension of Erythromycin thio0 ml water) was added at 25-28°C to obtain a pH of 10.3 to 10.5. This reaction mixture was maintained for 1 hour and then chilled water (584 ml) was added to it. The reaction mass was chilled to 0-5 °C, filtered and then washed with water to obtain Erythromycin base. The wet Erythromycin base obtained was reslurried in 1000 ml of water at 40 °C. The slurry was again filtered and washed with water. The product was dried at 50-55 °C to get Erythromycin base (92 gm). The erythromycin base obtained was further suspended in acetone and sodium bicarbonate (92 gm) was added to it, at 30-32 °C. The mixture was stirred followed by addition of ethyl succinyl chloride (38.18 gm) in lots. After completion of reaction, the reaction mixture was filtered. To the filtrate, bicarbonate solution (13 gm in 24 lit of water) was added slowly over a period of 1 hour at 30-35 °C. The resultant product was filtered out and washed with water. The product obtained was dried at 50-55 oC. Yield: 99gm
Erythromycin Base content-3- 4 % (by HPLC analysis)

Experimental Example 1
Preparation of Erythromycin ethyl succinate according to present invention in methylene chloride and using ethyl acetate as purification solvent.
To a suspension of Erythromycin thiocyanate (100 gm, active) and methylene dichloride (560 ml) at 25-28 °C, a solution of NaOH (8.8 g inl54 ml water) was added. The mixture was then refluxed for 1 hour. After completion of reaction, the organic layer of reaction mixture was separated and washed with water to assure complete removal of alkali. The organic layer was then distilled atmospherically to distill out around 160mi of methylene dichloride. The reaction mass was then chilied, filtered and dried at 50-55 °C to obtain Erythromycin base (92 gm). The dried erythromycin base was suspended in methylene dichloride (644 ml), to this was added sodium bicarbonate (92 gm) at 30-35 °C. The reaction mixture was stirred followed by addition of ethyl succinyl chloride (38.18 gm) in lots. The reaction was monitored on TLC and after the completion of reaction, water (1000 ml) was added to reaction mass. The organic layer was separated from aqueous layer. The organic was then distilled to obtain crude mass. The crude mass was given a slurry wash with ethyl acetate to obtain pure Erythromycin ethyl succinate which was filtered, washed with water and was dried at 50-55 °C. Yield: 78 gm
Erythromycin Base content-0.08-0.2 % (by HPLC analysis)
Experimental Example 2
Preparation of Erythromycin ethyl succinate according to present invention using methylene chloride and ethyl acetate as a solvents.
To a suspension of Erythromycin thiocyanate (100 gm, active) and methylene

dichloride (560 ml) at 25-28°C, a solution of NaOH (8.8 g in 154 ml water) was added. The mixture was then refluxed for 1 hour, After completion of reaction, the organic layer of reaction mixture was separated and washed with water, to assure complete removal of alkali. The organic layer was then distilled atmospherically to distill out around 160 ml of methylene dichloride. The reaction mass was then chilled, filtered and dried at 50-55 °C to obtain Erythromycin base (92 gm). The dried erythromycin base was suspended in ethyl acetate (644 ml), to this was added sodium bicarbonate (92 gm) at 30-35 °C. The reaction mixture was stirred followed by addition of ethyl succinyl chloride (38.18 gm) in lots. The reaction was monitored on TLC and after the completion of reaction, reaction mixture was filtered. The filtrate obtained was chilled to obtain solid product. The solid was filtered, washed with chilled ethyl acetate (46 ml) and dried at 50-55 °C under vaccum. Yield : 92 gm.
Erythromycin Base content-0.1-0.5 % (by HPLC analysis)
Experimental Example 3
Preparation of Erythromycin ethyl succinate according to present invention in a single organic solvent i.e. ethyl acetate
To the solution of sodium hydroxide (42.8g in 360 ml water) was added erythromycin thiocyanate (100 gm, active) at 25-28°C. After the completion of the reaction, to the reaction mixture was added ethyl acetate (600 ml). The organic layer was separated and washed with water to remove alkali. The moisture content of the organic layer was then reduced below 0.5% and then sodium bicarbonate (100 gm) was added at 30-35 °C. The reaction mixture was stirred followed by addition of ethyl succinyl chloride (43.5 gm) in lots. The reaction was monitored on TLC and after the completion of reaction, reaction mixture was filtered. The filtrate obtained was

chilled to obtain solid product. The solid was filtered, washed with chilled ethyl acetate (46 ml) and dried at 50-55 °C under vacuum. Yield: 100 gm.
Erythromycin Base content-0.1-0.5 % (by HPLC analysis)
Experimental Example 4
Preparation of Erythromycin ethyl succinate according to present invention in methylene dichloride and using methyl tert-butyl ether as a purification solvent,
To a suspension of erythromycin thiocyanate (100 gm, active) and methylene dichloride (560 ml) was added a solution of sodium hydroxide (8.8 g inl54 ml water) at 25-28 °C. The mixture was then refluxed for 1 hour. After completion of reaction, the organic layer of reaction mixture was separated and washed with water to assure complete removal of alkali. To the organic layer was then added sodium bicarbonate (100 gm) at 30-35 °C. The reaction mixture was stirred followed by addition of ethyl succinyl chloride (41.5 gm) in lots. The reaction was monitored on TLC and after the completion of reaction; water (1000 ml) was added to the reaction mixture and the organic layer was separated. The organic layer was then distilled off to obtain a crude mass of Erythromycin ethyl succinate. The crude mass was then given a slurry wash with methyl tert-butyl ether to obtain bitter-less Erythromycin ethyl succinate. The solid was filtered, washed with water and dried at 50-55 °C under vacuum. Yield: 76 gm
Erythromycin Base content -0.53 % (by HPLC analysis)

We claim
1. A novel process for the preparation of bitter-less Erythromycin ethyl succinate of Formula I containing less than 2 % of erythromycin base

wherein, R is COCH2CH2COOC2H5
comprising,
A] reacting erythromycin base with ethyl succinyl chloride in presence of a base in an organic solvent selected from esters or ethers followed by filtering the reaction mass and washing the obtained product with solvent such as esters or ethers to yield bitter-less Erythromycin ethyl succinate containing less than 2 % erythromycin base
or
B] reacting erythromycin base with ethyl succinyl chloride in presence of a base in an organic solvent selected from halogenated solvents or low molecular weight aliphatic ketones followed by isolating the crude product and purifying it with solvent such as esters or ethers to yield bitter-less Erythromycin ethyl succinate containing less than 2 % erythromycin base

2. The improved processes for the preparation of bitter-less Erythromycin ethyl succinate of Formula I from erythromycin thiocyanate of Formula II

Formula I
wherein, R is COCH2CH2COOC2H5
Process A comprises the steps of,
i) treating erythromycin thiocyanate of Formula II
O
H3p0 OCH3
CH3 Formula II

with aqueous base in presence of suitable solvent to obtain erythromycin base ii) reacting erythromycin base obtained in step i) with ethyl succinyl chloride in presence of a base in an organic solvent to obtain product Erythromycin ethyl succinate
iii) purifying or washing the product Erythromycin ethyl succinate with an organic solvent selected from esters or ethers to obtain bitter-less Erythromycin ethyl succinate containing less than 2 % erythromycin base
Process B comprises the steps of, a) treating erythromycin thiocyanate of Formula II with aqueous base in presence of suitable solvent

Formula II
b) optionally adding organic solvent after completion of step a) reaction
c) separating organic layer
d) adding a base and ethyl succinyl chloride to the organic layer of step c) to obtain Erythromycin ethyl succinate

e) purifying or washing erythromycin ethyl succinate obtained in step d) with an organic solvent selected from esters or ethers to obtain bitter-less Erythromycin ethyl succinate containing less than 2 % erythromycin base
3. The process for preparation of bitter-less Erythromycin ethyl succinate as claimed in claim 1 or 2, wherein organic solvent ester is selected from ethyl acetate, wo-propyl acetate, butyl acetate, amyl acetate, preferably ethyl acetate or ether is selected from methyl tert-butyl ether or isopropyl ether, preferably methyl tert-butyl ether
4. The process for preparation of bitter-less Erythromycin ethyl succinate as claimed in claim 1 or 2, wherein a base used is selected from weak organic or inorganic base, organic base is selected from triethyl amine or pyridine and inorganic base is selected from sodium bicarbonate, potassium bicarbonate, sodium carbonate, or potassium carbonate, preferably base used is sodium bicarbonate or potassium bicarbonate
5. The process for preparation of bitter-less Erythromycin ethyl succinate as claimed in claim 1, wherein organic solvent selected from halogenated solvents is preferably methylene dichloride or low molecular weight aliphatic ketones is preferably acetone
6. The process for preparation of bitter-less Erythromycin ethyl succinate as claimed in claim 2, wherein the range of suitable stoichiometrics of ethyl succinyl chloride with respect to erythromycin thiocyanate is between 1 to 2.5 equivalents, preferably about 1.2
7. The process for preparation of bitter-less Erythromycin ethyl succinate as claimed in claim 2, wherein aqueous base used in step i) and step a) is selected

from sodium hydroxide, potassium hydroxide, liquid ammonia, sodium bicarbonate or potassium bicarbonate, preferably sodium hydroxide
8. The process for preparation of bitter-less Erythromycin ethyl succinate as claimed in claim 2 or 7, wherein the range of suitable stoichiometries of the base with respect to the erythromycin thiocyanate is between 2-12 equivalents, preferably about 8.5
9. The process for preparation of bitter-less Erythromycin ethyl succinate as claimed in claim 2, wherein organic solvent in step ii) and step b) is selected from esters like ethyl acetate, isopropyl acetate, butyl acetate, amyl acetate, preferably ethyl acetate or ethers like methyl tert-butyl ether, zso-propyl ether or halogenated solvents, preferably methylene dichloride or low molecular weight aliphatic ketones, preferably acetone

10. The process for preparation of bitter-less Erythromycin ethyl succinate as claimed in claim 2, wherein suitable solvent used in step i) or step a) is selected from water, organic solvent such as halogenated solvents preferably, methylene dichloride or low molecular weight aliphatic ketones preferably, acetone or esters like ethyl acetate, wo-propyl acetate, butyl acetate, amyl acetate or ethers like methyl tert-butyl ether or wo-propyl ether
11. The process for preparation of bitter-less Erythromycin ethyl succinate as claimed in claim 2, wherein step i) and step a) is carried out at a temperature between room temperature to reflux temperature of the respective solvent

12. The process for preparation of bitter-less Erythromycin ethyl succinate as claimed in claim 1 or 2, wherein reaction of erythromycin base with ethyl succinyl chloride is carried out at 25 °C to 35 °C