FIELD OF THE INVENTION
The present inventioh relates to an improved process for the preparation of
succinylcholine chloride of Formula I or its hydrates.
O
CI
Formula I
The present invention relates to the. use of succinylcholine chloride of Formula I
or its hydrates as skeletal muscle relaxant in anesthesia and intensive care, usually
for facilitation of endotracheal intubation
BACKGROUND OF THE INVENTION
Succinylcholine chloride is sold under the trade names Anectine, Quelicin, and
Scoline. The chemical name of succinylcholine chloride is 2,2'-[(l,4-dioxobutanel,
4-diyl)bis(oxy)]bis (N,N,N-trimethylethanaminium) chloride represented by
Formula I,
Formula I ,
U.S. Pat. No. 2,858,329 describes a process for the preparation of bisdimethylaminoethylsuccinate
by heating succinic anhydride and N,Ndimethylaminoethanol
at 135-145° C in benzene for 12-18 hr. The obtained
succinylcholine is further purified by high vacuum distillation at very high
temperature. The obtained succinylcholine is then purged with molar equivalent of -
methylchloride in isopropyl alcohol (IPA) and water at 40-50° C to obtain
succinylcholine chloride.
GB706215 describes a process for the preparation of succinyl choline chloride.
hydrate in acetone and methyl chloride followed by purification in absolute ethanol,
which on heating at 163-165 °C gives succinylcholine chloride.
U.S. Pat. No. 5,206,420 describes a process for the preparation of succinyl choline
halide. According to this patent, dialkyl succinate is reacted with large excess of
dimethyl amino ethanol, in presence of a base catalyst viz. alkali metal alcoholate
or amide as catalyst. The bis(2-dimethylaminoethylj succinate obtained is then
reacted with methyl halide in benzene to yield succinyl choline halide. The prior art
processes involve purification of bis-dimethylaminoethyl succinate using high
vacuum distillation at very high temperature. Since the product is highly heat
sensitive, substantial portion is decomposed during high vacuum distillation. Those
processes need special heating facility, which is not desired at industrial level. The
high vacuum distillation further poses a safety risk. The prior art reaction is carried
out in benzene which is carcinogenic, and thus, is not desired at industrial level.
CN1062346A discloses a process for the preparation of succinylcholine chloride by
reacting succinic acid or its anhydride with thionyl chloride by adding DMF in
catalytic amount and heating to produce succinyl chloride, which was used directly
in the esterification reaction, with a chlorinating choline, in acetone to produce
succinylcholine chloride of Formula I. . •
Thionyl chloride degrades into volatile side products, like SO2 which creates air
and water pollution arid also other impurities. Therefore, there is need to develop a
process free from volatile side products and other impurities. Reaction with oxalyl
chloride does not produce volatile or hazardous by products. Further, reaction with
oxalyl chloride does not require the higher temperature therefore reaction is easy to
handle. Further, the workup and isolation of product is not cumbersome compared
to the reaction conducted with thionyl chloride.
OBJECT OF THE INVENTION
• l4.-.-&.9--2-OIs8* I > ' : i l 3
1
The main object of the present invention is to provide an improved, cost effective
and environment friendly process for the preparation of succinylcholine chloride of
Formula I, to overcome the above stated drawbacks.
SUMMARY OF THE INVENTION
The main aspect of the present invention is to provide an improved process for the
preparation of succinylcholine chloride of Formula I,
o
Formula I
wherein said process comprising of:
a) refluxing the succinic anhydride of Formula III with oxalyl chloride in the presence
of catalytic amount of dimethylformamide (DMF) and suitable solvent to obtain
succinyl chloride of Formula IV;
o^cyo
Formula III
Oxalyl chloride
DMF, Solvent
Reflux
- ~
o
0
Formula IV
CI
b) coupling the succinyl chloride of Formula IV with choline chloride of Formula V
in suitable solvent, optionally in presence of base, to obtain. succinylcholine
chloride of Formula I.
. 0 ,C1\ J |/Cf
C I ^ ^ V 0 1 + H 0 ~ ^ Solvent % ^ Q ^ ^
O Y^N
O " T>ci
Formula IV Formula V Formula I
In another aspect, the present invention provides an improved process for the
preparation of succinylcholine chloride dihydrate of Formula II,
f^o^vS 2H2o
o • ' L1 . ' . , ,
Formula II
wherein said process comprising of:
a) refluxing the succinic anhydride of Formula III with oxalyl chloride in the presence
of catalytic amount of DMF and suitable solvent to obtain succinyl chloride of
Formula IV;
cwcyo
Formula III
Oxalyl chloride
DMF, Solvent
Reflux
" ^ -
0
Formula IV
b) coupling the succinyl chloride of Formula IV with choline chloride of Formula V
in suitable solvent, optionally in presence of base, to obtain succinylcholine
chloride of Formula I;
J l ^ Tl '/Solvent r ^ C T ^ • ^
FormuialV Formula V Formula I
c) treating the succinyl choline chloride of Formula I with alcohol and water;
° i cr x ^ i'cr
X / v ^ N ^ Alcohol-Water ^ O ^ ^ O .2H20
o '
Formula I Formula II ^fr
d) isolating the succinyl choline chloride dihydrate of Formula IL
DETAILED DESCRIPTION
Brief Description of the accompanying drawing
FIG. 1, represents the X-ray (powder) diffraction (XRPD) pattern of the crystalline
fohii of succinylcholine chloride dihydrate. •„ '
FIG. 2, represents the differential scanning calorimetry (DSC) pattern of the
crystalline form of succinylcholine chloride dihydrate. .
FIG. 3, represents the thermo gravimetric analysis (TGA) pattern of the crystalline
form of succinylcholine chloride dihydrate.
In one embodiment, the present invention is provide an improved process for the
preparation of succinylcholine chloride of Formula I,
ll '• Cf
V^^cr
Formula I
wherein said process comprising of:
a) refluxing the succinic anhydride of Formula III with oxalyl chloride in the
presence of catalytic amount of dimethylformamide (DMF) and suitable solvent
to obtain succinyl chloride of Formula IV;
•.n:-Q:-^R^w.ir i/ •* li -6 . - *
O^°Y6
Formula III
Oxalyl chloride.
DMF, Solvent
Reflux
- * *
0
Formula IV
b) coupling the succinyl chloride of Formula IV with choline chloride of Formula
V in suitable solvent, optionally in presence of base, to obtain succinylcholine
chloride of Formula I;
- o I ri-
O iCI A /\ lTCI
IT r. '/ Solvent r ^ C T ^ • ^
o T NXCI
Formula IV Formula V Formula I
In another embodiment, the present invention provides an improved process for the
preparation of succinylcholine.chloride dihydrate of Formula II,
f ^ V ^ ? ^ .2H20
Formula II
wherein said process comprising of:
a) refluxing succinic anhydride of Formula III with oxalyl chloride in the presence of
catalytic amount of dimethylformamide (DMF) and suitable solvent to obtain
succinyl chloride of Formula IV;
O ^ ^ V ^ 0 Oxalyl chloride
v_7 ™,* «.....•» cr ^ Y w- <
o
.CI
DMF, Solvent
Reflux O
Formula III Formula IV
b) coupling the succinyl chloride of Formula IV with choline chloride of Formula V
in suitable solvent, optionally in: presence of base, to obtain succinylcholine
chloride of Formula I:
o i cf • A ^ N"CI
I ^ - Solvent f O — *^
o T Y^ci
o Formula IV Formula V Formula I
c) treating the succinyl choline chloride of Formula I with Alcohol-water.
J L X ^ ^ N C Alcohol-Water r ^ T ^ + N .2H?0
o '
Formula I Formula II and*
d) Isolating the succinyl choline chloride dihydrate of Formula II.
In another embodiment, the suitable solvent used in step a) is selected from the
group consisting of dichloromethane (DCM), chloroform (CHCI3) and carbon
tetrachloride (CCU). The most preferred solvent is dichloromethane.
In another embodiment, the suitable solvent used in step b) is selected from the
group consisting of acetone, dichloroethane (DCM), methylisobutylketone
(MIBK), cyclohexanone, methylethylketone (MEK), methylbutylketone (MBK)
and chloroform (CHCI3). The most preferred solvent is acetone.
In another embodiment, the base used in step b) is selected from Pyridine, Triethyl
Amine, Diisopropyl ethyl amine, Dicyclohexyl amine. The most preferred base is
Pyridine.
In another embodiment, the alcohol used in step c) is selected from the group
consisting of Ethanol, Isopropyl alcohol, n-Butanol, ferf-Butanol. The most
preferred alcohol is isopropyl alcohol.
In another embodiment, the ratio of alcohol and water in step c) is selected from
from 5:1 to 30:1. The most preferred ratio is 5:1.
r=r&w--'£'&Jt#-x.kt-. ii s
Q .
CD
O
CN
^ ,
O
CO
CO £-
CO
o
CN
In one embodiment, succinic choline chloride dehydrates of Formula II obtained
herein is crystalline in nature.
In one another embodiment, succinic choline chloride dehydrates of Formula II
obtained herein is amorphous in nature.
In one another embodiment succinyl choline chloride dihydrate of Formula II is
characterized by its XRPD having peaks at diffraction angles 2-theta of about 15.68,
19.89; 20.01, 21.89, 23.54 and 27.51 ±0.2
In another embodiment succinyl choline chloride dihydrate of Formula II is
characterized by its XRPD having peaks at diffraction angles 2-theta of 10.71,
11.73, 13.73, 14.54, 15.68, 17.19, 18.21, 18.89, 19.24, 19.89, 19.24, 19.89, 20.01,
21.59, 21.89, 23.33, 23.54, 24.97, 26;27, 26.52, 26.88, 27.51, 28.02, 28.25, 28.46,
29.16,29.28, 30.19, 30.79, 31.14, 31.38, 31.83, 32.75, 33.11, 33.60, 34.73, 35.25,
35.62, 36.7, 36.44, 36.87, 37.71, 38.28, 38.72 and 39.33 ±0.2.
In yet another embodiment succinyl choline chloride dihydrate of Formula II is
characterized by its XRPD as depicted in FIG-1.
ST

CO
o
CN
In one embodiment succinyl choline chloride dihydrate of Formula II obtained
herein has water content of about 9.0 to 9.5 % w/w by the KF method.
In a preferred embodiment, the present invention provides a substantially pure
amorphous form of succinylcholine. chloride of Formula I, wherein said amorphous
form is substantially free of any crystalline form.
In a preferred embodiment, the present invention provides a substantially pure
crystalline form of succinylcholine chloride of Formula I, wherein said crystalline
form is substantially free of any crystalline form.
In other embodiment, the present invention provides succinylcholine chloride of
Formula I, wherein succinylcholine chloride of Formula I is the mixture of
amorphous and crystallineform.
In a preferred embodiment, the succinyl choline chloride dihydrate of Formula II
may be isolated- from the reaction mixture by purification, centrifugation,
crystallization, filtration, extraction or evaporation.
* » •
In furthermore embodiment, there is provided a substantially pure succinylcholine
chloride dihydrate, wherein said succinylcholine chloride dihydrate is substantially
free of impurities of Formula A, B, C, D and E, and wherein each impurity is less
c? than about 0.15% w/w or total impurity less than about 1 % w/w, more specifically
less than about 0.15% w/w of any impurity;
- C D -
CO fePjB^afcLiJ^I. ;LA=JGfc9-' - 2-&3s 9 • I ^ - I O ; ie.0.
1 I
Formula A Formula B Formulae
+ C1
o
AoH
o
Formula D Formula E
In further embodiment, the present invention provides succinylcholine chloride
dihydrate of Formula II characterized by particle size distribution wherein, dw is
between 0.1 (im to 200jam.
In a preferred embodiment, the succinylcholine chloride dihydrate of Formula II is
characterized by particle size distribution wherein, dgo is between 2.0 jim to 150^m.
In one another embodiment, the succinylcholine chloride dihydrate of Formula II
prepared as per the process of the present invention is characterized with purity
above 99%, preferably above 99.5%, and more preferably above 99.9%.
In a preferred embodiment, the present invention provides a substantially pure
crystalline form of suecinylcholirie chloride dihydrate of Formula II, wherein said
crystalline form is substantially free of amorphous form.
In one another embodiment, the present invention further provides a composition
comprising succinylcholine chloride dihydrate of Formula II and one or more
pharmaceutical acceptable excipients.
The present invention can be illustrated by the following examples, which are not
to limit the scope of invention.
Example-1 Synthesis of Succinyl chloride of Formula IV: .
Charged succinic anhydride (10 g) dichloromethane (25ml) and catalytic amount of.
DMF (0.09g) in to a round bottom flask. Added drop-wise bxalyl chloride (25.4g).
Reaction mixture was stirred for 10 hours at temperature 20-25°C. Distilled out the
solvent under vacuum at temperature range 40-45°C to get succinyl chloride (7.7
g) of Formula III.
Example-2 Synthesis of Succinyl choline chloride of Formula I:
Charged choline chloride (41.7 g) of Formula V) in separate round bottom flask,
added acetone (20 ml) at temperature range 20-25°C. To this, added the solution of
succinyl chloride of Formula IV in to acetone (50 ml) at temperature 20-25°C for
20-30 min. Add methanol (15 ml) and stirred for 5 min followed by the addition of
acetone (50 ml) and stirred for 2-3 hours at temperature.range 30-35°C. Filter the
reaction mixture to get crude succinylcholine chloride (25 g) of Formula I.
Example-3 Synthesis of Succinyl choline chloride of Formula I:
Charged choline chloride (41.7 g) of Formula V in separate round bottom flask,
added acetone (20 ml) at temperature range 20-25°C. To this, added the solution of
succinyl chloride of Formula IV in to acetone (50 ml) at temperature 20-25°C and
stir for 20-30 min. Added Pyridine (5 ml) and stir the mass for 5 min. Added
methanol (15 ml) and stirred for 5 min followed by the addition of acetone (50 ml)
and stirred for 2-3 hours at temperature range 30-35°C. Filter the reaction mixture
to get crude succinylcholine chloride. (25 g) of Formula I.
Example-4 Preparation of succinylcholine. chloride dihydrate of Formula II:
Crude succinylcholine chloride {25 g) taken in mixture of Isopropyl alcohol (125
ml) and water (25 ml) in ratio range (5:1). Stirred at temperature range 60-70°C for
8-10 h. Filtered the solid material to get pure material.
Yield 20 g
Purity: 99.5%
Water content: 9.3%

WE CLAIM
1. An improved process for the preparation of succinylcholine chloride of Formula
I,
A^cc r
Formula I
wherein said process comprising of:
a) refluxing the succinic anhydride of Formula Illwith oxalyl chloride in the presence
of catalytic amount of DMF and suitable solvent to obtain succinyl chloride of
Formula IV;
(wr~ + HO A ^
O iCI" A /\ N>Ci
I ^ ci + X\.N; Solvent f^Or^?*^
o o» 7xcf
Formula IV Formula V Formula I
2. An improved process for the preparation of succinylcholine chloride dihydrate
of Formula II,
o , cf A > ^ O ^ + ^ .2H20
M i o <"C1
Formula II
wherein said process comprising of:
a) refluxing the succinic anhydride of Formula III with oxalyl chloride in the presence
of catalytic amount of DMF and suitable solvent to obtain succinyl chloride of
Formula IV;
O ^ / O ^ O Oxalyl chloride
•\—' DMF, Solvent U Jf
Reflux °
Formula III Formula IV
b), coupling the succinyl chloride of Formula IV with choline chloride of Formula V
in suitable solvent, optionally in presence of base, to obtain succinylcholine
chloride of Formula I; and
o ,ci -ft J-a
CI^.^JT Solvent
. 0 J I^Cl
FormulaTV Formula V Formula I
c) treating the succinyl choline chloride of Formula I with alcohol-water;
X ^ N^ Alcohol-Water r ^ ^ O ^^ + x 2B>0
L S * V0--Sr
o
Formula I Formula II and;
d) isolating the succinyl choline chloride dihydrate of Formula II.
3. The process as claimed in claim 1, wherein said solvent used in step a) and b) is
selected from dichloromethane (DCM), chloroform (CHCI3) and carbon
tetrachloride (CCU), acetone, Methylisobutylketone (MIBK), Cyclohexanone,
Methylethylketone (MEK), Methylbutylketone (MBK) and Chloroform (CHCI3).
1
4. The process as claimed in claim 2, wherein said solvent used in step a) and b) is
selected from dichloromethane (DCM), chloroform (CHCI3) and carbon
tetrachloride (CCU), acetone, Methylisobutylketone (MIBK), Cyclohexanone,
Methylethylketone (MEK), Methylbutylketone (MBK) and Chloroform (CHCb).
5. The process as claimed in claim 2, wherein base is selected from Ethanol, Isopropyl
alcohol, n-Butanol, tert-Butanol.
6. The process as claimed in claim 2, wherein base is selected from Pyridine, Triethyl
Amine, Diisopropyl ethyl amine, Dicyclohexyl amine.
V
7. The process as claimed in claim 2, wherein the ratio of alcohol and water is from
5:1 to 30:1.
8. The process as-claimed in claim 2, wherein succinyl choline chloride dihydrate of
' Formula II is crystalline in nature and characterized by atleast one of:
a) an X-ray powder diffraction (XRD) pattern having peaks at 15.68, 19.89,
20.01,21.89, 23.54 and 27.51 ±0.2±0.2 degrees two-theta,
b) an X-ray powder diffraction (XRD) pattern as depicted in FIG. 1,
c) a weight loss of about 8.35% w/w, as measured by a Thermo gravimetric
analysis (TGA). >
I d) melting endotherms of 161.52°C as measured by differential scanning
calorimetry.
CD
G)
co
Q.
CD
CN
O
CN
CO
^ -
CO o
00
9. The process as claimed in claim 2, wherein succinyl choline chloride dihydrate of
Formula II is substantially free of impurities of Formula A, B, C, D and E, o wherein
CN
g each impurity is less than about 0.15% w/w,
CO
£:
CO
o
CN
"• 1 f* &• l ^ f e l N: -JL 1 fr~ B% - 2B-1 #•• Jf /' - 1 1 ~ ^
o o
O'
o
Formula A
or
OH
O -
Formula B
O
O'
OH
O
Formula C
+ G1
/ \ .
O
OH
OH
O
Formula D
HO'
+ C1
Formula £