FIELD OF THE INVENTION
The present invention relates to a ready-to-use pharmaceutical composition comprising the
known compound Pemetrexed that is free from antioxidants, amino acids and chelating
agents; which liquid composition is stable and pharmaceutically elegant.
BACKGROUND OF THE INVENTION
Certain folic acid antimetabolites are known to be antineoplastic agents. These compounds
inhibit enzymatic conversion involving metabolic derivatives of folic acid. One such
compound described by U.S. Pat. No. 5,344,932, known as "Pemetrexed" represented by
Formula-l shown below, is currently formulated into a concentrated liquid for administration
as an infusion dosage form. This member of the folic acid family has been approved for
treatment of malignant pleural mesothelioma and for second-line treatment of non small cell
lung cancer. Pemetrexed disodium salt heptahydrate represented by Formula-ll is marketed
by Eli Lilly and Company under the trade name ALIMTA@ as a sterile lyophilized powder for
intravenous administration. The commercial product is reported to be a lyophilized powder
of heptahydrate Pemetrexed disodium and mannitol. The lyophilized product is available in
strengths of 100mg/vial and 500 mglvial and is reconstituted with 0.9% sodium chloride at a
concentration of 25mg/mL before its administration.
Formula I
Formula I1
The formulation teachings of US. Pat. No. 5,344,932 provides that the compounds claimed
therein can be administered parenterally.
A ready-to-use, stable, ready to reconstitute solution that could be stored at room
temperature is particularly desired for a pharmaceutical such as Pemetrexed, wherein such
ready-to-use pharmaceutical composition provides easier, safer handling, storage, and
distribution. It is particularly desirable if the stable pharmaceutical composition can be
prepared without the use of freeze drying techniques. The disadvantage of lyophilized drugs
is that they have to be reconstituted, usually by injecting diluent through the septum into the
vial. The drug is drawn up into a new syringe, the needle changed before finally being
injected into the patient. The multiple steps make it inconvenient for use and provide an
opportunity for injury from exposed needles. The desired liquid formulation can offer
enhanced safety for caregiver handling of the cytotoxic materials. Further, a stable, readyto-
use pharmaceutical composition is more acceptable to the customer.
It was discovered that a simple, isotonic saline solution of Pemetrexed is not
pharmaceutically acceptable for commercial purposes due to degradation of the solution to
form unacceptable related substances. The chemical instability of Pemetrexed is mainly
attributed to their oxidative degradation. Hence, the main challenge lies in formulating a
stable pharmaceutical composition of Pemetrexed that has the minimum concentration of
oxidative degradation impurities. All the prior arts mainly provide solutions to the problem
related to oxidative degradation of the drug by using an antioxidant or an amino acid or a
chelating agent in their pharmaceutical composition.
1. Bernd et a1 in US Patent No. 6,686,365 discloses a stable ready-to-use (RTU) formulation of
Pemetrexed which is developed by using antioxidantslamino acids like L-Cysteine,
Monothioglycerol and Thioglycolic acid. Hence, use of an antioxidant in the formulation is
the key element in developing a stable pharmaceutical composition of Pemetrexed.
2. Yanling et a1 in CN Patent No. 101081305, again discloses a RTU formulation of
Pemetrexed stabilized by using antioxidant like L-arginine, L-glutathione, L-methionine and
L-tryptophan. Hence, use of an antioxidant in the formulation is the key element in
developing a stable pharmaceutical composition of Pemetrexed.
3. Palepu et al in PCT Application No. WO 2012/015810, again claims a RTU solution
formulation of Pemetrexed along with an antioxidant, a chelating agent and dissolved in a
pharmaceutically acceptable fluid. Hence, use of antioxidants and chelating agents in the
formulation is the key element in developing a stable pharmaceutical composition of
Pemetrexed.
Hence, from all the above mentioned prior art disclosures it is evident that the key element
in all these pharmaceutical compositions of Pemetrexed is that either antioxidants or amino
acids or chelating agents are invariably present in all these formulations. The main role of
these antioxidants or amino acids or chelating agents is to prevent the oxidative degradation
of Pemetrexed and provide chemical stability to the various parenteral formulations. This
clearly indicates that till date a stable liquid pharmaceutical composition of Pemetrexed has
always been obtained by the addition of antioxidants, amino acids and chelating agents in
the formulation. Hence, the presence of antioxidants, amino acids and chelating agents in
the dosage form has been found to be the quintessential element in the formulation of a
stable pharmaceutical composition of Pemetrexed as it reduces the oxidative degradation of
the drug and provides stability to the formulation.
However, a point of mention is that such agents as antioxidants, amino acids and chelating
agents qualify as extraneous agents in the formulation of any pharmaceutical compositions.
It may further be mentioned that Health Authorities all over the world are very concerned
about the level of such extraneous agents as antioxidants, amino acids and chelating agents
in the pharmaceutical compositions. As a consequence, regulatory approval norms today
are very stringent about the nature and level of extraneous agents present in any drug
product. In view of this, the range or freedom available to experiment with various
extraneous agents such as antioxidants, amino acids and chelating agents is minimum and
they cannot be utilized beyond a limited amount. The presence of any unapproved range of
excipients in the pharmaceutical formulations may have harmful effects on the patients and
hence, such formulations are not acceptable to the Health Authorities, even if such
4
formulations are stable. Keeping the aforementioned limitations in mind it is essential for the
formulators to develop a pharmaceutical composition that is stable and contains any
extraneous agents in the formulation in quantities that fall within the regulatory limits.
Hence, there is a need to develop pharmaceutical compositions of Pemetrexed that are both
stable as well as free of any extraneous agents such as antioxidantslamino acidslchelating
agents and hence, such formulations are more patient compliant.
Against this backdrop the inventors of the present Application have surprisingly found that
stable ready-to-use pharmaceutical compositions of Pemetrexed may be developed without
the use of extraneous agents such as antioxidants, amino acids and chelating agents in the
formulation that shows comparable stability to the currently marketed ALIMTA@ lyophilized
formulation and this forms the basis of the present Application.
SUMMARY OF THE INVENTION
The present invention provides stable ready-to-use pharmaceutical compositions of
Pemetrexed that is free from antioxidants, amino acids and chelating agents and shows
comparable stability to the marketed formulation.
The most important aspect of the present invention is to provide stable ready-to-use
pharmaceutical compositions of Pemetrexed that may be suitable for parenteral
administration. Such stable ready-to-use formulation of Pemetrexed can be developed
without the use of antioxidants or amino acids or chelating agents, by controlling the oxygen
content of drug solution and vial headspace with the use of an inert gas viz nitrogen. Such
parenteral formulations do not contain antioxidants , amino acids or chelating agents in their
formulation, however they exhibit comparable stability profile to the currently marketed
ALIMTA@ lyophilized formulation and found to more stable in comparison to the
Pharmaceutical composition using Antioxidants in place of Nitrogen under the same storage
conditions.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to stable ready-to-use pharmaceutical compositions of
Pemetrexed that is free from antioxidants, amino acids and chelating agents and shows
comparable stability to the currently marketed formulation.
The formulations as developed by the Inventors of the present Application are suitable for
parenteral administration. Such stable ready-to-use formulation of Pemetrexed can be
developed without the use of antioxidants , amino acids and chelating agents, by controlling
the oxygen content of drug solution and vial headspace with the use of an inert gas viz
nitrogen. Such parenteral formulations do not contain antioxidants, amino acids and
chelating agents in their formulation; however they exhibit comparable stability to the
currently available lyophilized marketed formulation of Pemetrexed.
These formulations are presented as a single vial presentation having Pemetrexed
concentrations in the range of 2.5 to 50 mglml, of which the preferred concentration is 25
mglml. These pharmaceutical compositions are then administered via intravenous infusion
to treat patients suffering from malignant pleural mesothelioma and for second-line
treatment of non small cell lung cancer which is the approved indication of Pemetrexed.
As used herein, the term "pemetrexed" refers to the stable salts, acids and free base forms
thereof. The term includes, for example, the free acid, the pharmaceutically acceptable alkali
metal, alkaline earth metal, non-toxic metal, ammonium, and substituted ammonium salts,
such as for example, the sodium, potassium, lithium, calcium, magnesium, aluminum, zinc,
ammonium, trimethylammonium, triethylammonium, monoethanolammonium,
triethanolammonium, pyridinium, substituted pyridinium, and the like.
The stable ready-to-use pharmaceutical composition of Pemetrexed is usually solvated in an
aqueous solvent comprising water for injection.
In one embodiment of the present invention, the ready-to-use pharmaceutical composition of
Pemetrexed has a pH between about 4 and about 9, preferably between about 5 and about
8 and more preferably in the range of about 6.6 and about 7.8. The pH of such ready-to-use
pharmaceutical compositions of Pemetrexed may be adjusted with a pharmacologically
acceptable pH adjusting agent such as an acid, base, buffer or their combination thereof. In
an embodiment of the present invention the pH adjusting agent is hydrochloric acid or
sodium hydroxide, or their combination thereof. The hydrochloric acid or sodium hydroxide
may be in any suitable form, such as a 1N solution.
In another embodiment of the present invention, so as to minimize oxidation of the sensitive
material it is also desirable to remove headspace oxygen and moisture or both from the
sealable vessel as quickly as possible. This may be aided by, for example, purging the
sealable container with a gas which is substantially oxygen-free, or substantially moisture
free, or substantially oxygen and moisture free before, during or after step, or any
combination thereof. Purging can be expected to reduce the oxygen level in the sealable
container to a level of from about 0.5% to about lo%, typically about 5% or lower,
depending on the efficiency of flushing and how quickly the container is sealed after
flushing.
The gas used for purging the sealable container may be any appropriate inert gas known to
those in the art, the most commonly used gases being argon, helium or nitrogen, or mixtures
thereof. However the most preferred inert gas is nitrogen.
In another embodiment of the present invention, so as to increase the storage stability of the
aqueous parenteral preparation, optionally it may be desirable to add antimicrobial agent to
inhibit the growth of microbial organism which may occur accidently and contaminate the
product during use. The antimicrobial agents selected are stable and effective in the
parenteral formulations, the most commonly used being benzalkonium chloride, benzyl
alcohol, phenol, chlorocresol, phenylmercuric salts, methylhydroxybenzoate,
propylhydroxybenzoate. However the most preferred antimicrobial agents are
methylhydroxybenzoate, propylhydroxybenzoate and benzalkonium chloride.
The invention is further illustrated by way of the following example, which in no way should
be construed as limiting the scope of the invention.
EXAMPLES
Various embodiments of the pharmaceutical formulations according to the present invention
were prepared and studied for their stability and impurity profile when stored under
accelerated stability conditions, which are illustrated below:
Example 1: The pharmaceutical composition as provided in this example is a Stable readyto-
use pharmaceutical composition of Pemetrexed that is free from antioxidants, amino
acids and chelating agents.
The ready-to-use pharmaceutical composition of Pemetrexed comprises of Pemetrexed
disodium as the active ingredient, wherein Pemetrexed disodium was prepared from
Pemetrexed diacid by taking suitable quantity of water for injection in a manufacturing
vessel. Nitrogen was purged into water for injection until dissolved oxygen content of water
for injection comes to less than 7 mgIL, preferably less than 3 mgIL. Pemetrexed Diacid
was then added in water for injection to make a slurry. Fixed quantity of sodium hydroxide
(4.7mglmL) in the form of 10% wlv solution was added to dissolve Pemetrexed Diacid. The
pH was adjusted to 6.6-7.8 with either 10% wlv sodium hydroxide solution or IN
hydrochloric acid solution. Nitrogen purging was continued throughout the entire procedure.
Final volume was made upto 100% with water for injection and drug solution was then
filtered through a suitable 0 . 2 ~filt er. The filtered solution was then filled into vials and vials
headspace was blanketed with nitrogen to achieve headspace oxygen content less than 8%,
preferably less than 2%. The vials were stoppered and sealed.
The obtained Pemetrexed disodium was then used to prepare stable ready-to-use
pharmaceutical composition, wherein the parenteral formulation as provided may be
prepared and presented as a Single Vial formulation. The pharmaceutical composition was
prepared by purging nitrogen into water for injection until dissolved oxygen content of water
for injection comes to less than less than 7 mgIL, preferably less than 3 mgIL. Prepared
Pemetrexed disodium was then added and stirred in water for injection. The pH of bulk
solution was adjusted in between 6.6 to 7.8 with 10%wlv sodium hydroxide solution.
Continued stirring was done to dissolve the Pemetrexed disodium. Final volume was made
upto 100% with water for injection and drug solution was then filtered through a suitable
0 . 2 ~filt er. Nitrogen purging was continued throughout the entire process.. Filtered solution
was then filled into vials and vial headspace was blanketed with nitrogen to achieve
headspace oxygen content less than 8%, preferably less than 2%. The vials were then
stoppered and sealed. The unit Composition Formula of the pharmaceutical composition
prepared by the present inventors is provided in Table- A:
Table- A: Unit Composition Formula of the Stable ready-to-use formulation of
Pemetrexed
* Nitrogen is used for purging in bulk solution and blanketing in vial headspace
** Antimicrobial agent is used to increase the storage stability and may be added optionally.
Sr. No.
1
2
3
4
5
The ready-to-use formulation of Pemetrexed as presented in Table-A and thus prepared by
the abovementioned process does not contain any antioxidants or amino acids or chelating
agents in the formulation and yet exhibits comparable stability profile with that of the
currently available marketed formulation of Pemetrexed.
Stability data of the pharmaceutical composition of the present invention and its
comparison with the stability data of the Innovator AlimtaB (Pemetrexed for Injection,
MIS. Eli Lilly)
Ingredients
Pemetrexed Diacid
Sodium Hydroxide / Hydrochloric acid
Water for Injection
Nitrogen*
Antimicrobial agent**
Stability of the pharmaceutical composition of the present invention was tested at initial
stage and by subjecting the samples under various storage conditions: 40°C/75%RH for 1
month and 2 month, 25"C/60%RH for 3 months and 6 months and 2-8°C for 3 months and 6
months. Impurity analysis of formulation was done during initial stage and after storage
under various conditions for various time periods. Samples of commercially available
lyophilized product ~limta@wa s also analyzed at initial stage, 40°C/75%RH for 1 month 3
month and 6 month, 25"C/60%RH for upto 6 months. The stability data of pharmaceutical
composition of present invention and commercially available formulation are presented in
Table 01 and 02 respectively. Table 03 shows the comparative stability data of
pharmaceutical composition of the present invention and marketed formulation AlimtaO.
Qtylm L
25mg
qs to pH 6.6 - 7.8
qs to 1 mL
q S
Table 01: Stability Data of the ready-to-use formulation of Pemetrexed of the present
Invention
Table 02: Stability Data of Marketed ALIMTA~ Lyophilized Formulation
Initial
40°C/75%RH 1 Month
40°C/75%RH 2Month
25"C/60%RH 3Month
25"C/60%RH 6Month
2"-8°C 3Month
2"-8°C 6Month
40°C/75%RH 6 Month
7.52
7.68
7.72
7.25
7.50
7.57
7.54
101.8
102.2
102.6
97.9
101.1
96.7
101.7
0.30
0.50
0.87
0.44
0.65
0.37
0.45
Table 03: Stability data of the pharmaceutical composition of the present invention
and its comparison with the stability data of the Marketed ~limta@(L yophilized
Formulation, Mls. Eli Lilly)
Prior to any comparison it should be kept in mind that exact comparison of the stability data
cannot be done for the ready-to-use solution formulation of Pemetrexed of the present
lnvention and Marketed ALIMTAB Lyophilized Formulation, the reason being that the
pharmaceutical composition of the present invention is a ready-to-use solution formulation,
whereas ~limta@is a lyophilized formulation. Thus both the dosage forms are different from
each other and storage stability conditions for both the compositions are different. For
example normal storage condition in case of the ready-to-use solution formulation is at
refrigerated temperature i.e. 2-8°C and therefore, accelerated stability testing is established
at 25"C/60%RH. However, in the case of Lyophilized formulation such as Alimta@ , storage
condition is at room temperature i.e. at 25°C and Accelerated stability testing is established
at 40°C/75%RH.
Therefore considering this, below mentioned is the comparison between ALIMTA@
Lyophilized Formulation and the ready-to-use solution formulation of Pemetrexed of the
present lnvention at initial stage and at various storage conditions.
25"C/60%RH 3Month
25"C/60%RH 6Month
2"-8°C 6Month
ALIMTAB Lyophilized Formulation
Initial 7.16 104.75 0.16
From the stability data provided in the abovementioned Tables 01, 02 and 03, it may be
mentioned that the ready-to-use solution formulation of Pemetrexed of the present lnvention
was found to be stable at various storage conditions: i.e at normal storage conditions at 2-
8°C for 3 months and 6 months, at accelerated storage conditions at 25"C/60%RH for 3
months and 6 months and further at 40°C/75%RH for 1 month and 2 months and the
impurity levels were also found to be under control during this time. Also the stability results
at initial stages, normal storage conditions and also under accelerated storage conditions
were found to be comparable with the stability data of commercially available ALIMTAB
Lyophilized Formulation.
40°C/75%RH 1 Month
40°C/75%RH 3 Month
40°C/75%RH 6 Month
25"C/60%RH 6 Month
Further as mentioned above, the stability of the pharmaceutical composition of the present
invention has been achieved by controlling the total oxygen content in the drug solution and
vial headspace with the use of Nitrogen. The effect of controlling the oxygen content in the
ready-to-use solution formulation of Pemetrexed of the present lnvention was evaluated by
comparing it to a formulation where no nitrogen was used to control the oxygen content of
the formulation. Both the formulations were analyzed at initial stage and after subjecting
them to storage for 14 days at 40°C/75%RH. The stability data obtained is presented in
Table 04.
Table 04: Stability data comparison of the Pharmaceutical composition of the readyto-
use solution formulation of Pemetrexed of the present lnvention and
Pharmaceutical composition without using nitrogen
-
-
-
-
-
-
-
-
0.23
0.25
0.34
0.23
Hence, as seen from Table-04, at 14 days 40°C/75%RH accelerated stability storage
condition, in the pharmaceutical composition without using nitrogen, a significant fall in assay
and very high level of impurities were observed, whereas in the pharmaceutical composition
of the present invention at same storage condition no such fall in assay or development of
impurities was observed. Hence the data presented in Table 04 demonstrates the
stabilization of the ready-to-use solution formulation of Pemetrexed of the present lnvention
by controlling the oxygen content in the pharmaceutical and headspace with the use of
Nitrogen.
As mentioned above and also as seen from the data provided in Table 04, the stability of the
pharmaceutical composition of the present invention has been achieved by controlling the
total oxygen content in the drug solution and vial headspace with the use of Nitrogen. The
effect of controlling the oxygen content by using Nitrogen in the ready-to-use solution
formulation of Pemetrexed of the present lnvention was evaluated by comparing it to a
formulation where Nitrogen was not used to control the oxygen content in the formulation
and in its place antioxidants were used to control the oxygen content of the formulation. Both
the formulations were analyzed at initial stage and after subjecting them to one month of
storage at 40°C/75%RH. The stability data obtained is presented in Table 05.
Conditions
Table 05: Stability data comparison of the Pharmaceutical composition of the readyto-
use solution formulation of Pemetrexed of the present lnvention and
Pharmaceutical composition using Antioxidants in place of Nitrogen
PH
Assay
(%I
Total Related Substance
Ready-to-use solution formulation of Pemetrexed of the present lnvention (Using
Nitrogen)
0.3
0.3
Initial
40°C/ 75%RH/14 days
101.6
101 . I
Pharmaceutical composition without using nitrogen
7.6
7.9
Initial
40°C/ 75%RH/14 days
103.2
91 .I
7.3
-
0.5
8.6
As seen from Table-05, it may be mentioned that results of the pharmaceutical composition
of the ready-to-use solution formulation of Pemetrexed of the present lnvention (using
Nitrogen) at the initial time points and after subjecting them to 1 month at 40°C/75%RH were
found to be more stable in comparison to the Pharmaceutical composition using Antioxidants
in place of Nitrogen under the same storage conditions.
Pharmaceutical composition of the ready-to-use solution formulation of Pemetrexed of
the present lnvention (using Nitrogen)
Hence, as seen above, the pharmaceutical composition of the ready-to-use solution
formulation of Pemetrexed of the present lnvention as illustrated in the abovementioned
example is free of antioxidants or amino acids or chelating agents and is found to exhibit
comparable stability profile to the currently marketed ALIMTA@ lyophilized formulation and
found to more stable in comparison to the Pharmaceutical composition using Antioxidants in
place of Nitrogen under the same storage conditions.
Initial
4OoC/75%RH 1 Month
101.8
102.2
7.52
7.68
0.30
0.50
Pharmaceutical composition using Antioxidants in place of Nitrogen
Initial
4OoC/75%RH 1 Month
7.25
6.76
100.12
72.52
3.10
20.13
ABSTRACT
STABLE READY-TO-USE PHARMACEUTICAL COMPOSITION OF PEMETREXED
A stable ready-to-use pharmaceutical composition comprising pemetrexed or
pharmaceutically acceptable salts thereof, wherein the composition is free from
antioxidants, amino acids and chelating agents. Also provided is a process for
preparing a stable ready-to-use pharmaceutical composition comprising the steps: i)
purging inert gas into a parenterally acceptable aqueous solvent until the dissolved
oxygen content of the solvent comes to less than 7 mgIL, preferably less than 3
mg1L; ii) adding pemetrexed disodium under stirring; iii) adjusting the pH of the
resulting solution to between 4 to 9; iv) optionally adding additional aqueous solvent;
wherein the composition is purged with inert gas throughout the entire process.

WE CLAIM:
1. A stable ready-to-use pharmaceutical composition comprising pemetrexed or
pharmaceutically acceptable salts thereof, wherein the composition is free from
antioxidants, amino acids and chelating agents.
2. A pharmaceutical composition according to claim 1, wherein the composition has a
dissolved oxygen content of less than 7 mgIL, preferably less than 3 mg1L.
3. A pharmaceutical composition according to claims 1 or 2, wherein pemetrexed is
present at a concentration of about 2.5 to about 50 mglml, preferably about 25
mglml.
4. A pharmaceutical composition according to any of the preceding claims comprising a
parenterally acceptable aqueous solvent.
5. A pharmaceutical composition according to claim 4, wherein the parenterally
acceptable aqueous solvent is water for injection.
6. A pharmaceutical composition according to any of the preceding claims, having a pH
in the range of 4 to 9.
7. A pharmaceutical composition according to any of the preceding claims, wherein the
pH is in the range of 5 to 8.
8. A pharmaceutical composition according to any of the preceding claims, wherein the
pH is in the range of 6.6 to 7.8.
9. A pharmaceutical composition according to any of the preceding claims, wherein the
composition contains a pH adjusting agent.
10. A pharmaceutical composition according to claim 11, wherein the pH adjusting agent
is hydrochloric acid andlor sodium hydroxide.
11. A pharmaceutical composition according to any of the preceding claims, further
comprising at least one antimicrobial agent.
A pharmaceutical composition according to claim 11, wherein the antimicrobial agent
is selected from the group consisting of benzalkonium chloride, benzyl alcohol,
phenol, chlorocresol, phenylmercuric salts, methylhydroxybenzoate,
propylhydroxybenzoate.
A phamaceutical composition according to claims 11 or 12, wherein the antimicrobial
agent is selected from the group consisting of methylhydroxybenzoate,
propylhydroxybenzoate and benzalkonium chloride.
A pharmaceutical composition according to any of the preceding claims, wherein the
composition is provided in a sealed vial with a gaseous headspace, the headspace
having an oxygen content of less than 8%, preferably less than 2% by volume.
A ready-to-use pharmaceutical composition consisting of pemetrexed or
pharmaceutically salts thereof, water for injection, at least one pH adjusting agent
and optionally at least one antimicrobial agent, characterized in that the composition
has a dissolved oxygen content of less than 7 mg/L, preferably less than 3 mg/L.
A pharmaceutical composition according to any of the preceding claims for use as a
medicament.
A pharmaceutical composition for use as a medicament according to claim 16,
wherein the composition is for the treatment of malignant pleural mesothelioma or
refractory non small cell lung cancer.
A pharmaceutical composition for use as a medicament according to claims 16 or 17,
wherein the composition is administered parenterally.
A pharmaceutical composition for use as a medicament according to any of claims
16-18, wherein the parenteral administration is by intravenous injection.
A process for preparing a stable ready-to-use pharmaceutical composition according
to any of claims 1-1 5, comprising the steps:
i purging inert gas into a parenterally acceptable aqueous solvent until the
dissolved oxygen content of the solvent comes to less than 7 mg/L, preferably
less than 3 mgIL,
ii) adding pemetrexed disodium under stirring,
iii) adjusting the pH of the resulting solution to between 4 to 9,
iv) optionally adding additional aqueous solvent,
wherein the composition is purged with inert gas throughout the entire
process.
21. The process according to claim 20, wherein pemetrexed disodium is produced by
adding a predetermined quantity of sodium hydroxide to a slurry of pemetrexed
diacid in a parenterally acceptable aqueous solvent while purging with inert gas.
22. The process according to claims 20 or 21, wherein the composition is subsequently
filtered through a 0.2 pm filter.
23. The process according to any of claims 20-22, wherein the composition is
subsequently filled into a vial, wherein the vial headspace is flushed with an inert gas
to achieve a headspace oxygen content of less than 8%, preferably less than 2% by
volume, followed by sealing the vials.
24. The process according to any of claims 20-23, wherein the inert gas is selected from
the group consisting of argon, helium and nitrogen, or mixtures thereof.
25. The process according to any of claims 20-24, wherein the inert gas is nitrogen.
26. The process according to any of claims 20-25, wherein in step iii) the pH is adjusted
with a pH adjusting agent such as hydrochloric acid andlor sodium hydroxide .
27. The process according to any of claims 20-26, further comprising the addition of at
least one antimicrobial agent.
28. The process according to claim 27, wherein the antimicrobial agent is selected from
the group consisting of benzalkonium chloride, benzyl alcohol, phenol, chlorocresol,
phenylmercuric salts, methylhydroxybenzoate and propylhydroxybenzoate.
Dated this 25'h day of March 201 3