DESC:FIELD OF THE INVENTION
The present invention relates to novel crystalline form AL of erythromycin ethyl succinate and its process for preparation.
BACKGROUND OF THE INVENTION
Erythromycin ethyl succinate is chemically described as 4-O- [(2S,3R,4S,6R)-4-(dimethylamino)-2-[[(3R,4S,5S,6R,7R,9R,11R,12R,13S,14R)- 14-ethyl-7,12,13-trihydroxy-4-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6- dimethyloxan-2-yl]oxy-3,5,7,9,11,13-hexamethyl-2,10-dioxo-oxacyclotetradec-6-yl]oxy]-6-methyloxan-3-yl] 1-O-ethyl butanedioate having the structural Formula I.

It has only been reported in the literature: erythromycin ethylsuccinate [C43H75NO16, with a molecular weight of 862.07, CAS No.: 1264-62-6], and its use. So far, there is no report in the literature the crystalline form of macrolide derivatives-erythromycin ethylsuccinate and the preparation method thereof.
US2967129A discloses the preparation method of the compound of Formula I wherein the compound of Formula I is obtained by recrystallization from acetone and water.
US2014128583A1 discloses a crystalline hydrates {C43H75NO16.nH2O, n=0.2 to 0.6}, of the compound of Formula I.
It has been the endeavor of pharmaceutical scientists to provide novel and stable form of drug substances, which would have the strengths of thermodynamic stability, enhanced solubility, rapid onset of action and an enhanced bioavailability. However, it is well known in the art that polymorphism is unpredictable, both as regards the uncertainty that any new forms will be found, and the lack of any standard methods for preparing a new form. This has been discussed in the literature, such as A. Goho, "Tricky Business," Science News, Vol. 166(8), August 21, 2004, and A. M. Rouhi, "The Right Stuff," Chemical and Engineering News, February 24, 2003, pages 32-35.
Therefore, it would be desirable to provide stable polymorph of erythromycin ethylsuccinate and processes for their preparation, which are commercially viable.
OBJECT OF THE INVENTION
It is an object of the present invention to provide novel crystalline form AL of erythromycin ethylsuccinate of Formula I.
It is an object of the present invention to provide an improved process for the preparation of novel crystalline form AL of erythromycin ethylsuccinate of Formula I which is operationally simple and easy to handle at commercial scale.
SUMMARY OF THE INVENTION
In one aspect of the present invention encompasses process for the preparation of erythromycin ethylsuccinate of Formula I.

In another aspect of the present invention encompasses the crystalline of form AL of erythromycin ethylsuccinate.
In another aspect of the present invention encompasses process for the preparation of crystalline form AL of erythromycin ethylsuccinate.
In another aspect of the present invention encompasses the process for the preparation of crystalline form AL of erythromycin ethylsuccinate comprising the steps of;
a) providing the solution of erythromycin ethylsuccinate in suitable solvent or mixture of suitable solvents,
b) heating the reaction mass,
c) cooling the reaction mass to obtain crystalline form AL of erythromycin ethylsuccinate.
In another aspect, the present invention provides a process for the preparation of the crystalline form AL of erythromycin ethylsuccinate comprising the steps of;
a) providing a solution of erythromycin ethylsuccinate in a suitable solvent or mixture of suitable solvents,
b) isolating the crystalline form AL of erythromycin ethylsuccinate.
In another aspect of the present invention encompasses process for the preparation of erythromycin ethylsuccinate of Formula I comprising the steps of;

a) reaction of compound of formula II with suitable base and suitable solvent to give erythromycin base,

b) reaction of erythromycin base with ethyl succinyl chloride in the presence of suitable base and suitable solvent to give compound of formula I.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure-1: shows the X-ray powder diffraction pattern of crystalline form AL of erythromycin ethylsuccinate.

DETAILED DESCRIPTION OF THE INVENTION
Erythromycin ethylsuccinate used for process of present invention can be prepared by any process known in the art or any method known perse and includes crystalline, amorphous hydrates and solvated forms thereof.
In one embodiment of the present invention encompasses process for the preparation of erythromycin ethylsuccinate of Formula I.

In another aspect of the present invention encompasses the crystalline of form AL of erythromycin ethylsuccinate.
In another embodiment of the present invention encompasses crystalline form AL of erythromycin ethylsuccinate characterized by X-ray powder diffraction pattern as shown in Figure 1.
In another embodiment of the present invention encompasses crystalline form AL of erythromycin ethylsuccinate having an X-ray diffraction pattern comprising peaks at 2-theta angles of 5.05, 6.69, 8.74, 9.03, 10.11, 15.28, and 17.62 ±2 Ø.
In another embodiment of the present invention encompasses process for the preparation of crystalline form AL of erythromycin ethylsuccinate.
In another embodiment of the present invention encompasses the process for the preparation of crystalline form AL of erythromycin ethylsuccinate comprising the steps of;
a) providing the solution of erythromycin ethylsuccinate in suitable solvent or mixture of suitable solvents,
b) heating the reaction mass,
c) cooling the reaction mass to obtain crystalline form AL of erythromycin ethylsuccinate.
In another embodiment of the present invention encompasses the process for the preparation of crystalline form AL of erythromycin ethylsuccinate comprising the steps of;
a) providing the solution of erythromycin ethylsuccinate in acetone, ethyl acetate and water,
b) heating the reaction mass,
c) cooling the reaction mass to obtain crystalline form AL of erythromycin ethylsuccinate.
In another embodiment, the present invention provides a process for the preparation of the crystalline form AL of erythromycin ethylsuccinate comprising the steps of;
a) providing a solution of erythromycin ethylsuccinate in a suitable solvent or mixture of suitable solvents,
b) isolating the crystalline form AL of erythromycin ethylsuccinate.
In another embodiment, the present invention provides a process for the preparation of the crystalline form AL of erythromycin ethylsuccinate comprising the steps of;
a) providing a solution of erythromycin ethylsuccinate in acetone, ethyl acetate and water,
b) isolating the crystalline form AL of erythromycin ethylsuccinate .
In another embodiment of the present invention encompasses process for the preparation of erythromycin ethylsuccinate of Formula I comprising the steps of;

a) reaction of compound of formula II with suitable base and suitable solvent to give erythromycin base,

b) reaction of erythromycin base with ethyl succinyl chloride in the presence of suitable base and suitable solvent to give compound of formula I.

In another embodiment of the present invention encompasses process for the preparation of erythromycin ethylsuccinate of Formula I comprising the steps of;
a) reaction of compound of formula II with sodium hydroxide and ethyl acetate to give erythromycin base,

b) reaction of erythromycin base with ethyl succinyl chloride in the presence of sodium bicarbonate and acetone to give compound of formula I.

The term "solvent" includes any solvent or solvent mixture, for example, water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof.
The suitable solvent of the present invention may be selected from the group consisting of water, alcohols, esters, ketones, ethers, polar aprotic solvents, or mixtures thereof. Examples of alkanols include those primary, secondary, and tertiary alcohols having from one to six carbon atoms.
Suitable alcohol solvents include methanol, ethanol, n-propanol, 2-propanol, ethylene glycol, PEG and butanol. Examples of ester solvents include ethyl acetate, n-propyl acetate, isopropyl acetate, and n-butyl acetate. Examples of ketones include acetone, methyl ethyl ketone, and the like. Examples of ethers include tetrahydrofuran and the like. A suitable polar aprotic solvent includes N,N-dimethylformamide, ?,?-dimethylacetamide, dimethylsulphoxide, acetonitrile, and N-methylpyrrolidone. Examples of halogenated hydrocarbons include dichloromethane, chloroform, and 1,2-dichloroethane. A solvent may preferably be a mixture of ketone with water and esters, for example, a mixture of acetone with water and ethyl acetate.
Suitable base of the present invention includes but not limited to an inorganic base or organic base selected from the group comprising of carbonates, bicarbonates, hydroxides, hydrides and alkoxides of alkali or alkaline earth metals and the like, phosphates such as dipotassium monohydrogen phosphate, potassium dihydrogen phosphate, tripotassium phosphate, disodium monohydrogen phosphate, sodium dihydrogen phosphate, trisodium phosphate, diammonium monohydrogen phosphate, ammonium dihydrogen phosphate and triammonium phosphate; acetates such as potassium acetate, sodium acetate and ammonium acetate; formates such as potassium formate and sodium formate; n-butyllithium, n-hexyllithium, sodium hydride and lithium diisopropylamide. These inorganic bases may be used singly, or in combination of two or more kinds thereof. The organic base is selected from the group comprising of lutidine, diisopropylethylamine, dimethylaminopyridine, triethylamine, tri-n-propylamine, tri-n-butylamine, piperidine, pyridine, 2-picoline, 3-picoline, 2,6-lutidine, N-methylmorpholine, N-ethylmorpholine, N,N-15 diethylaniline, N-ethyl-N-methylaniline, diisopropylethylamine, 3-methylimidazole, 1,8-diazabicyclo[5.4.0]-7-undecene, 1,4-diazabicyclo[2.2.2]octane and 4-dimethylaminopyridine; and metal alcoholates such as sodium methoxide and sodium ethoxide. Other bases are known to the person skilled in the art.

In the foregoing section, embodiments are described by way of an 20 example to illustrate the process of the invention. However, this is not intended in any way to limit the scope of the present invention. Several variants of the example would be evident to persons ordinarily skilled in the art which are within the scope of the present invention.

Examples
Example 1: Preparation of Erythromycin ethyl succinate
Erythromycin Thiocyanate (100gm) in ethyl acetate (450 ml) was charged in to the round bottomed flask equipped with a mechanical stirrer at 30°C-35°C.The reaction mixture was stirred 25°C-35°C. Process water (100ml) was added to the reaction mixture at 30°C-35°C and was stirred for 5-10 mins at 25-35°C. Ethyl acetate was distilled under vacuum. Acetone(560 ml) was charged to the mass below 60°C.The reaction mass was cooled to 30-40 °C and sodium bicarbonate(25.6 g)was added. Ethyl Succinyl Chloride(33.6 g) and Acetone (40 ml) was added at 30-40°C. The reaction mass was stirred for 5 hrs at 30±40°C.The obtained solid was dried to obtain erythromycin ethyl succinate (250 gm,95%, purity: >80 %).

Example 2: Preparation of crystalline Form AL of Erythromycin ethyl succinate
Acetone (275 ml) was added to a reaction vessel containing Erythromycin ethyl succinate (100 gm) at about 25°C to 35°C. The reaction mixture was stirred for 30- to 40 min till the solid was dissolved. Ethyl acetate (100 ml) was added to the reaction mass and slowly water (900 ml) was added. The reaction mixture was stirred for 2 hours at 25-35°C and was filtered through Buchner funnel. The solid formed was dried to obtain crystalline Form AL of Erythromycin ethyl succinate (80.0 gm, purity: 99.5 %, 95%).
,CLAIMS:Claims

We claim,

1. The process for the preparation of crystalline form AL of erythromycin ethylsuccinate.
comprising the steps of :
a) providing a solution of erythromycin ethylsuccinate in a suitable solvent or
mixture of suitable solvents,
b) isolating the crystalline form AL of erythromycin ethylsuccinate.

2. The process according to the claim 1, wherein the suitable solvent is selected from water,
ethyl acetate, n-propyl acetate, isopropyl acetate, acetone, and methyl ethyl ketone.

3. The process for the preparation of crystalline form AL of erythromycin ethylsuccinate.
comprising the steps of :
a) providing a solution of erythromycin ethylsuccinate in acetone, ethyl acetate and water,
b) isolating the crystalline form AL of erythromycin ethylsuccinate.

4. Crystalline form AL of erythromycin ethylsuccinate having an X-ray diffraction pattern
comprising peaks at 2-theta angles of 5.05, 6.69, 8.74, 9.03, 10.11, 15.28, and 17.62 ±2 Ø.

Dated this 15th day of September, 2017
Dr. Subramaniam Ganesan