Field of the Invention
The present invention relative to an improved process for the preparation of beta
lactamase inhibitor‘ More predominantly, this invention further relates to a process for the
preparation of Avibactam Sodium of formula (I) in its crystalline form. The present invention
also relates to the improved process for the preparation of Avibactam sodium in its crystalline
form B. Additionally, the present invention also relates to an improved process for the
preparation of Avibactam sodium in its crystalline form which is industrially viable.
Avibactam Sodium, is a non B-lactam, B-lactamase inhibitor and is used in
combination with Ceflazidime pentahydrate buffered with sodium carbonate for the ‘treatment
I
of complicated urinary tract infections and complicated intm-abdominal infections in cases
where such infections are reportedly due to the microorganisms which have developed
antibiotic resistance, more specifically resistance towards Cephalosporin antibiotics This is
widely prevalent in the Gram Negative bacteria which produce beta lactamase enzymes that
inhibit the antibiotic properties of Cephalosporin drugs Avibactam Sodium is known to inhibit
the beta lactamase ehzymes which in turn keeps the antibiotic activity of the Cephalosporin
drug intact. The Chemical Name of Avibactam Sodium is sodium [(1R,ZS,5R)-2-carbamoyl-7-
oxo-l,6-cyclopedia[3 .2. 1 ]octane-6—yl] sulfate.
US 8969566B2 discloses a process for the preparation of Avibactam Sodium which
involve the conversion of piperidine compound with source of ammonia or ammonia proxy to
convent into piperidine carboxamide compound and its conversion to bi cyclic amide with
carbohylating agent followed by treatment with source of tetra-n-butylammonium ion and its
subsequent conversion into sodium salt by treating it with source of sodium,
US 928431482 discloses similar process for the preparation of Avibactam sodium.
However, such conversion was effected from carbonyl compound as starting material instead of
ester compound as disclosed in US 896956682 with the same sequence involving conversion
of piperidine carbonyl compound into piperidine amide compound and carbonylating the
resulting compound into bicyclic compound
EP3269717B9 discloses Avibactam Sodium in different poly morphs viz., Form-A,
Form-B, Form-C, Form—D and Form-E of Avibactam sodium and also the application mentions
that Form B is not easy to prepare in the absence of seed, if water is merely excluded, or under
rapid crystallization then kinetic Form D may be produced rather than Form B, This patent
further discloses the preferred example 1 and 2 for preparation of form B with a single solvent,
ethanol and temperature is preferably 25-30 °C.
.
Therefore, it is evident that there are various conditions which restrict the stable scaleup
of the preparation of form B‘ Therefore, reliable industrial preparation of anhydrous form B
appears to be very challenging.
’
If crystalline forms are made with polymorphic impurities, this may cause instability
and it can accelerate significant interconversion to another polymorphic form‘ Therefore, it is
advantageous to produce crystalline forms with high polymorphic bfirity.
7
There is an existing and continual_need in the art for new and improved methods for
preparing polymorphic form B of Avibactam Sodium. The present invention provides an
improved process for preparing compound Avibactam Sodium in its crystalline form B.
The preparation of crystalline form B of Avibactam Sodium of the instant invention
can solve the problems of difficulty in industrialization and stable production of crystalline
form B of Avibactam Sodium.
The present invention relates to the process for the preparation of sodium salt of
(1R,ZS,5R)-7-oxo-6-sulfooxy-1,6-diazabicycld[3.2.l]octane-2-carboxamide in its crystalline
form, especially polymorphic ally pure Form B or essentially polymorphically pure Form B as
well as to an industrially applicable, reliable and robust process for its preparation and to
pharmaceutical composition thereof.
Objective of the Invention
The primary objective of the present invention is to provide an improved process for
the preparation of polymorphic form B of Avibactam sodium of formula (I).
Another objective of the present invention is to provide an improved process for the
preparation of Avibactam sodium of formula (I) in its polymorphic form B which is industrially
viable‘
Summary of the Invention
Accordingly, the present invention provides an improved process for the preparation
of polymorphic form B of Avibactam sodium of formula (I).
Th; mixture of solvents propranolol and methanol have been used in the process for
the preparation of Avibactam Sodium polymorphic form B. The operating temperature for
reactive crystallization of Avibactam Sodium form B is also 502t2 °C.
Step a) Avibactam Tetrabutylammonium salt dissolution:
To the methanol and isopropanol mixture, Avibactam Tetrabutylammofiium salt was added, the .
resulted solution was stirred to get clear solution, stirred and the resulted solution was filtered
and washed with isopropanol, methanol and acetic acid mixture to yield dissoluted Avibactam
Tetrabutylammonium salt.
Experiment 1:
Isopropanol was used as a solvent for reactive crystallization of Avibactarh Sodium
from Tetrabutylammonium salt of Avibactam with 20 timms dilution in the absence of water
at 25-30°C. The impurities were observed at RRT 0‘31 -1 ~49%; RRT 0.34 - 0.08%, RRT 0.39
- 1.03% and RT 1.12 - 0.40%. The yield (70.67%) is also observed to be very less due to
high solubility of Avibactam Sodium in methanoL The pXRD diffractogram (figure-1)
indicates that the use of solvent isopropanol rmulted in an entirely different polymorphic
form apart from the forms A to E of Avibactam Sodium. The HPLC chromatogram (figure-
10) indicates the degradation of Avibactam Sodium.
Experiment 2:
Isopropanol was used as a solvent for reactive crystallization of Avibactam Sodium
from Tetrabutylammonium salt of Avibactam with 10 tima dilution in the absence of water
at 25-30°C. The impurities were observed at 0.3]RRT: 0,35%; 0.39RRT: 0.16%. The yield
(42.40%) is also observed to be very less. The pXRD diffractogram (Figure-2) indicates that
the use of solvent isopropanol resulted in predominantly Form D of Avibactam Sodium with
additional 29 values‘
Experiment 3:
Methanol was used as a solvent for reactive crystallization of Avibactam Sodium
from Tetrabutylammonium salt of Avibactam with 10 times dilution in'the absehce of water
at 25-30°C. The yield (14.13%) is also observed to be very less due to high solubility of
Avibactam Sodium in methanol, The pXRD diffractogram (figure-3) indicates that the use
of solvent methanol resulted in the mixturas of Form B and E of Avibactam Sodium with
additional 29 values. The HPLC chromatogram (figure-11) indicates the degradation of
Avibactam Sodium.
Experiment 4:
Isobutanol was used as the solvent for reactive crystallization of Avibactam
Sodium from Tetrabutylammonium salt of Avibactam with 20 times dilution in the absence
of water at 25-30°C. Less yield (42.40 %) and the pXRD pallem does not match with Form B. The
pXRD diffractogram (figure-4) indicates that the use of solvent isobutanol resulted in the
mixtures of Form B and D of Avibactam Sodium with additional 29 values observed.
Experiment 5:
l-Butanol was used as a solvent for reactive crystalliiation of Avibactam Sodium
from Tetrabutylammonium salt of Avibactam with 20 timm dilution in the absence of water
at 25-30°C. The yield (70.67%) was less due to the hardness of the material. The pXRD
diffractogram (figure-5) indicates that the use of solvent 1-butanol resulted in predominantly
Form D of Avibactam Sodium with additional 29 values.
Experiment 6:
n-Propanol was used as a solvent for reactive crystallization of Avibactam Sodium
from Tetrabutylammonium salt of Avibactam with 20 times dilution in the absence of water
at 25-30°C. The material is pasty in nature and the filtration is also very slow and the yield in
84.50 %‘ The pXRD difi'ractogram (figure-6) indicates that the use of solvent n-propanol
resulted in predominantly Form D of Avibactam Sodium with additional 29 valum
observed
Experiment 7:
Isopropanol (17 times) and Methanol (3 times) mixture was used as a solvent for
reactive crystallization of Avibactam Sodium from Tetrabutylammonium salt of Avibactam
with water (016 times) at 25-30 °C‘ The pXRD diffiacfogram (figure-7) indicates that the
use of solvent isopropanol (17 times) and methanol (3 times) mixture resulted in Form B of
Avibactam Sodium with additional 29 values. The residual solvent content is more when
the experiment is carried out at 25-30 °C.
Experiment 8:
Isopropanol (17 times) and Methanol (3 times) mixture was used as a solvent for
reactive crystallization of Avibactam Sodium from Tetrabutylammonium salt of Avibactam
with water (0.16 times) at elevated temperature, 40t2 °C. The pXRD diffractogram (figure-8)
indicates_that the use of solvent isopropanol (17 times) and methanol (3 times) mixture
resulted in Form B of Avibactam Sodium with additional 20 values. The residual solvent
content is more when the experiment is carried out at 40i2 °C.
Experiment 9:
Isopropanol (17 times) and Methanol (3 timas) mixture was used as a solvent for
reactive crystallization of Avibactam Sodium from Tetrabutylammonium salt of Avibactam
with water (0.16 times) at elevated temperature, 5012 °C. The pXRD diffractogram (figure-9)
indicates that the use of solvent isopropanol (17 times) and methanol (3 times) mixture
resulted in pure Form B of Avibactam Sodium‘ The residual solvent content is less when the
experiment is carried out at 50i2 °C.
The experiments 1—6 carried out indicates that the use of single solvents such as
isopropanol, methanol, l-butane, n-propanol and Istanbul for reactive crystallization
resulted in the formation of mixture of poly morphs of Avibactam Sodium or degradation of
Avibactam Sodium and also the yield is also lfis‘
The experiments 7-8 carried out indicates that the use of mixture of isopropanol
and methanol, for reactive Crystallization which resulted in the formation of mixture of
polymorphs of Avibactam Sodium when carried out at 25-30°C and 40:1:2°C.
The experiment 9 carried out indicates that the use of mixture of isopropanol and
methanol, for reactive crystallization which resulted in the formation of pure polymorphic
form B of Avibactam Sodium when carried out at 50i2°C.
The experiments were carried out using individual solvent, ethanol and mixture of
solvents isopropanol and methanol and the residual solvents content was determined by
using Gas chromatography and the results are tabulated below in Table-2,
Table-2: Residual solvents content at various temperature conditions:
We Claim:
1. A process for preparation of polymorphic form B of Avibactam Sodium of formula (I) which
comprising:
reacting the compound of formula (II), tetrabutyl ammonium salt of Avibactam with sodium-2-
ethyl hexanoate in isopropanol, methanol and water mixture;
2. The process for preparation of polymorphic form B of Avibactam Sodium of formula (1)
according to claim 1 comprising of:
reacting the compound of formula (H), tetrabutyl ammonium salt of Avibactam with sodium-2-
ethyl hexanoate in isopropanol, methanol and water mixture in the presence or absence of seed
crystals;
3. The process for preparation of polymorphic for B of Avibactam Sodium of formula (I)
according to claim I comprising of:
reacting the compound of formula (II), tetrabutyl ammonium salt of Avibactam with sodium-2- ethyl hexanoate in isopropanol, methanol and water mixture in the presence or absence of seed
crystals by raising the temperature to about 45-50°C i2 °C;
4. The process for preparation of polymorphic form B of Avibactam sodium of formula (I), as
claimed in claims 1 to 3, characterized in that it is carried out at a temperature of 505:2 °C,
5. The process as claimed in claims 1 to 4, characterized in that it is carried out in the presence
of Acetic acid‘
6. The process for preparation of polymorphic form B of Avibactam sodium of formula (I), as
claimed in claim 1 to 5 comprising of:
step a) tetrabutyl ammonium salt of Avibactam dissolution comprising of:
adding isopropano! and methanol mixture;
adding tetrabutyl ammonium salt of Avibactam of Formula (II);
adding isopropanol, methanol and acetic acid mixture;
step b) sodium-Z-ethyl hexanoate solution comprising of:
adding isopropanol and water mixture;
adding sodium-Z-ethyl hexanoate and stirring;
adding isopropanol;
step c) crystallization comprising of:
raising the temperature of tetmbutyl ammonium salt filtrate to 50i2 °C;
seeding with Avibactam sordiurm Form B crystals at 50:4:2 °C;
adding sodium-Z-ethyl hexanoale solution and stirring;
cooling to 25-27 °C and stining;
adding chilled isopropanol and water mixture.
7. The polymorphic-form B of Avibactam Sodium of formula (I) prepared according to the
claims 1 to 6.
8. The pharmaceutical composition comprising po
9‘ The pharmaceutical composition comprising polymorphic form B of Avibactam sodium of
formula (1) prepared according to claims 1 to 8 and further comprising a fi-lactamine antibiotic
Ceftazidime.
10‘ The pharmaceutical composition comprising polymorphic form B of Avibactam sodium of
formula (I) prepared according to claims 1 to 9 and further comprising a B-lactamine antibiotic
Ceftazidime pentahydrate buffered with sodium carbonate.