WO2016207443A1

WO2016207443A1 - Pharmaceutical composition comprising pemetrexed

Info

Publication number: WO2016207443A1
Application number: PCT/EP2016/064889
Authority: WO
Inventors: Elena BIRSAN; Rotaru MARIA; Cornelia Stancu
Original assignee: Actavis Group Ptc Ehf
Priority date: 2015-06-25
Filing date: 2016-06-27
Publication date: 2016-12-29
Also published as: GB201511246D0

Abstract

This invention relates to a stable solution pharmaceutical formulation containing pemetrexed. The solution formulation is obtainable from pemetrexed diacid or a pharmaceutically acceptable salt thereof and glucose.

Description

PHARMACEUTICAL COMPOSITION COMPRISING PEMETREXED

This invention relates to a pharmaceutical formulation and in particular to a stable solution formulation obtainable by dissolving pemetrexed or a pharmaceutically acceptable salt thereof in water.

Pemetrexed ((2S)-2-{[4-[2-(2-amino-4-oxo-1 ,7-dihydro pyrrolo[2,3-d]pyrimidin-5- yl)ethyl]benzoyl]amino}-pentanedioic acid) (I) is a folate antimetabolite used in the treatment of malignant pleural mesothelioma and non-small cell lung cancer:

By inhibiting thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyl transferase (GARFT), and hence the formation of precursor purine and pyrimidine nucleotides, pemetrexed prevents the formation of the DNA and RNA required for the growth and survival of both normal cells and cancer cells.

Pemetrexed is disclosed in EP 0 432 677. Different crystalline forms and/or amorphous form are described in EP 1 259 513, EP 2 072 518 and WO 2008/124485. Pemetrexed diacid and its preparation are disclosed in US 5,416,21 1 , US 6,262,262, and WO 2008/021410. Certain formulations of pemetrexed are disclosed in WO 2012/015810.

Pemetrexed is commercially available as the disodium salt under the trade name ALIMTA® (Eli Lilly). ALIMTA® is a lyophilised powder comprising 100mg or 500 mg pemetrexed disodium, mannitol, hydrochloric acid and sodium hydroxide.

A liquid concentrate formulation formed from ALIMTA® is prepared by reconstituting the lyophilised powder with the appropriate volume of sodium chloride solution for injection (9mg/ml; 0.9%) to provide a clear (colourless to yellow or green-yellow) solution comprising 25 mg/ml pemetrexed and having a pH between 6.6 and 7.8. The liquid concentrate formulation is then further reconstituted in 100ml with sodium chloride solution for injection (9mg/ml; 0.9%) to give a solution for infusion which is administered intravenously to the patient over 10 minutes. However, the current commercially available formulations are limited by a high rate of degradation of the drug. Thus pemetrexed solutions are single use products which cannot be stored for longer than 24 hours at 2°C to 8°C.

There remains a need to provide further and/or improved pemetrexed solution formulations with long-term stability.

Accordingly in a first aspect, the invention provides a pharmaceutical formulation obtainable by dissolving:

(i) pemetrexed diacid or a pharmaceutically acceptable salt thereof; and

(ii) glucose;

in water.

For the avoidance of doubt, this definition covers the compositions per se. By "obtainable" is meant that the formulation can be prepared by any method, as long as it could have been prepared by the defined steps. Therefore, for example, this definition includes compositions prepared by dissolving pemetrexed diacid or a pharmaceutically acceptable salt thereof in water, and then adding a solution of glucose.

In a second aspect the invention provides a process for preparing a pharmaceutical formulation comprising:

(i) taking a composition obtainable by dissolving pemetrexed diacid or a pharmaceutically acceptable salt thereof in water; and

(ii) diluting that composition with an aqueous solution of glucose.

The applicant has found that a solution containing pemetrexed for infusion containing glucose is surprisingly stable, and can be kept for more prolonged periods of time without physical or chemical degradation.

The pharmaceutical formulations typically contain glucose at a concentration of 1 -20% w/v, preferably 2-10% w/v, more preferably 4-6 w/v e.g. 5% w/v.

The pharmaceutical formulations typically have a volume of from 10 to 1250 mL, preferably from 75 mL to 125 ml. For example, the pharmaceutical formulation can have a volume of 10 mL, 25 mL, 50 mL, 100 mL, 125 mL, 250 mL or 1000 mL.

The recommended dose of pemetrexed is 500 mg/m2 of body surface area (BSA) administered as an intravenous infusion over 10 minutes on the first day of each 21 -day cycle. Thus the amount of pemetrexed included in the aqueous solution is calculated on a patient-by-patient basis depending on their body size. Typically, the pharmaceutical formulation is obtainable from an amount of pemetrexed diacid or a pharmaceutically acceptable salt thereof which is from 0.02 mmol to 4.67 mmol, for example 0.21 mmol to 0.26 mmol, or 1.05 mmol to 1 .29 mmol, or 2.22 mmol to 2.46 mmol.

In other words, the pharmaceutical formulations are obtainable from an amount of pemetrexed diacid which is 10 mg to 2000 mg, for example 90 mg to 1 10 mg, or 450 mg to 550 mg, or 950 mg to 1050 mg, of pemetrexed diacid or an equivalent number of mols of a pharmaceutically acceptable salt thereof.

In preferred examples, the pharmaceutical formulations are as follows (wherein in each case pemetrexed diacid also refers to the corresponding number of mols of a pharmaceutically acceptable salt of pemetrexed):

100 mg pemetrexed diacid dissolved in 10 ml of solution; or

100 mg pemetrexed diacid dissolved in 25 ml of solution; or

500 mg pemetrexed diacid dissolved in 50 ml of solution; or

500 mg pemetrexed diacid dissolved in 125 ml of solution; or

1000 mg pemetrexed diacid dissolved in 100 ml of solution; or

1000 mg pemetrexed diacid dissolved in 250 ml of solution.

Preferably the pharmaceutical formulation has a concentration of 3-5 mg/mL (e.g. 4 mg/mL) or 8-1 1 mg/mL (e.g. 10 mg/mL) pemetrexed diacid or when the formulation includes a base an anion thereof.

The pemetrexed may be used in any pharmaceutically acceptable form. In one embodiment, the aqueous solution is obtainable from pemetrexed diacid. In another embodiment, the aqueous solution is obtainable from a pharmaceutically acceptable salt of pemetrexed.

In one embodiment the pharmaceutically acceptable salt is a disodium salt i.e. the salt is pemetrexed disodium, which can be formed by reacting pemetrexed diacid with two equivalents of sodium hydroxide.

In the embodiment wherein the pharmaceutical formulation is obtainable from a pharmaceutically acceptable salt of pemetrexed, typically the pharmaceutically acceptable salt is a basic addition salt i.e. a salt formed by adding a base or alkali to the pemetrexed diacid.

The salts may be formed by adding the base to an aqueous solution obtainable from pemetrexed diacid, or dissolving the base and pemetrexed diacid in water and then isolating the salt from the solution. Usually, at least two equivalents of the base relative to the amount of pemetrexed diacid are used i.e. the base is used in an amount sufficient to deprotonate both acidic sites in pemetrexed diacid. For example, the base can be present in an amount of from about 2 mol to about 8 mol, for example from 3 mol to 6 mol e.g. 4 mol to 5.5 mol, in each case relative to the number of mols of pemetrexed diacid present.

In particular, the amine is selected from the group consisting of diethanolamine, tris(hydroxymethyl)-aminomethane and meglumine, preferably the amine is tris(hydroxymethyl)aminomethane.

Tris(hydroxymethyl)aminomethane is shown in formula (II) and is also referred to as TRIS, tromethamine, trometamol and trisamine. It is widely used as a buffer component. It is a primary amine and a weak base with a pKa of 8.07 at 25°C.

Meglumine is shown by formula (III) and has the chemical name (2R,3R,4R,5S)-6- (Methylamino)-hexane-1 ,2,3,4,5-pentol (and is also referred to as emthylglucamin, 1 -Deoxy- 1 -(methylamino)-D-glucitol or N-methylsorbitylamine). It is an amino sugar derived from sorbitol.

Diethanolamine is shown in formula (IV) and is also referred to as DEA or DEOA, iminodiethanol, N-ethylethanamine or 2,2'-dihydroxydiethylamine. It is a polyfunctional compound which is miscible in water.

(II) (III) (IV)

The formulation may comprise a single basic organic amine, or a combination of two or three amines.

The unit dose may also include further excipients which are pharmaceutically acceptable, and in particular are suitable for intravenous administration. The excipients used must be sufficiently soluble to dissolve in the intravenous solution.

Examples of pharmaceutically acceptable excipients include but are not limited to sugar alcohols, sugars, pH-adjusting agents and antioxidants. Suitable sugar alcohols include mannitol, sorbitol and erythritol. The sugar alcohol is typically present in an amount equivalent to from 0.1 mg to 2.0 mg, preferably from 0.5 mg to 1.5 mg per mg of pemetrexed diacid (or when a pharmaceutically acceptable salt of pemetrexed is used, relative to amount of pemetrexed diacid to which that base is equivalent).

Suitable ph -adjusting agents include hydrochloric acid, sodium hydroxide, acetic acid, citric acid and malonic acid, or salts thereof.

In one embodiment, the pH-adjusting agent is trisodium citrate or citric acid, which stabilise the active ingredient and prevent degradation. The citrate/citric acid is preferably added in a molar ratio to pemetrexed in the range from 1 :2 to 3: 1 , preferably 1 :1 to 2: 1 , such as about 1 :1 to 1 :1.2 or 1 :1 to 1 :1.5. A desired ratio can be obtained with adding about 10 mg citric acid anhydrous per 25 mg of pemetrexed diacid used in making the formulation.

In one embodiment, the formulation is obtainable from pemetrexed diacid, tromethamine (which deprotonates the pemetrexed diacid) and citric acid. In particular, the formulations are obtainable from, relative to 25 mg of pemetrexed diacid (or the corresponding molar amount of a pharmaceutically acceptable salt thereof), from 30 mg to 40 mg tromethamine (e.g. 33 mg to 38 mg tromethamine) and from 7.5 mg to 15 mg citric acid (e.g. from 8 mg to 12 mg citric acid). In addition, the formulation preferably comprises an antioxidant such as L- cysteine, preferably in the form L-cysteine hydrochloride monohydrate (or a solution made therefrom), in an amount of from about 0.1 mg/mL to 0.5 mg/mL, preferably in an amount of about 0.5 mg/mL. Alternatively, the formulation may additionally comprise a sulphur- containing compound, preferably in the form of monothioglycerol and methionine, preferably in an amount of about 0.2 mg/mL to 0.5 mg/mL. The liquid formulation should preferably have a pH in the range of about 7 to 8, such as about 7.5, or preferably have a pH in the range of about 7.5 to 8.5, such as about 8.

In another preferred embodiment, the formulation is obtainable from pemetrexed disodium, mannitol, hydrochloric acid and sodium hydroxide.

The invention also provides the pharmaceutical formulation for use in treating cancers, in particular malignant pleural mesothelioma and non-small cell lung cancer.

The pharmaceutical formulation is typically prepared by a process comprising:

(ii) diluting that composition with an aqueous solution of glucose. In one embodiment, the aqueous solution of glucose contains glucose at a concentration of 1- 20% w/v, preferably 2-10% w/v e.g. 5% w/v.

In one embodiment, the composition obtainable by dissolving pemetrexed diacid or a pharmaceutically acceptable salt thereof in water is a liquid concentrate formulation, for example wherein:

- the liquid concentrate formulation is obtainable from pemetrexed diacid or a pharmaceutically acceptable salt thereof in an amount of which is equivalent to from 80 mg to 120 mg (e.g. 100 mg) of pemetrexed diacid and the liquid formulation has a volume of from 3.5 to 4.5 ml_ (e.g. 4 mL); or

- the liquid concentrate formulation is obtainable from pemetrexed diacid or a pharmaceutically acceptable salt thereof in an amount of which is equivalent to from 450 to 550 mg (e.g. 500 mg) of pemetrexed diacid and the liquid formulation has a volume of from 17.5 to 22.5 mL (e.g. 20 mL); or

- the liquid concentrate formulation is obtainable from pemetrexed diacid or a pharmaceutically acceptable salt thereof in an amount of which is equivalent to from 900 mg to 1 100 mg (e.g. 1000 mg) of pemetrexed diacid and the liquid formulation has a volume of from 37.5 mL to 42.5 mL (e.g. 40 mL).

In another embodiment, the composition obtainable by dissolving pemetrexed diacid or a pharmaceutically acceptable salt thereof in water is a liquid concentrate formulation, for example wherein:

- the liquid concentrate formulation is obtainable from pemetrexed diacid or a pharmaceutically acceptable salt thereof in an amount of from 0.18 mmol to 0.28 mmol (e.g. 0.23 mmol) and the liquid formulation has a volume of from 3.5 to 4.5 mL (e.g. 4 mL); or

- the liquid concentrate formulation is obtainable from pemetrexed diacid or a pharmaceutically acceptable salt thereof in an amount of from 1.05 mmol to 1 .29 mmol (e.g. 1 .17 mmol) and the liquid formulation has a volume of from 17.5 to 22.5 mL (e.g. 20 mL); or

- the liquid concentrate formulation is obtainable from pemetrexed diacid or a pharmaceutically acceptable salt thereof in an amount of from 2.1 1 mmol to 2.57 mmol (e.g. 2.34 mmol) and the liquid formulation has a volume of from 37.5 mL to 42.5 mL (e.g. 40 mL).

In one embodiment, the liquid concentrate formulation is obtainable from pemetrexed diacid or a pharmaceutically acceptable salt thereof in an amount of which is equivalent to a concentration of from 10 to 50 mg/mL, preferably from 20 to 30 mg/mL, most preferably from 23 to 27 mg/mL e.g. 25 mg/mL of pemetrexed diacid.

In another embodiment, the liquid concentrate formulation is obtainable from pemetrexed diacid or a pharmaceutically acceptable salt thereof in a concentration of from 23 mM to 1 17 mM, preferably from 47 mM to 70 mM, most preferably from 54 mM to 63 mM e.g. 58 mM.

In one embodiment the liquid concentrate formulation is supplied in a glass vial (e.g. a Type I glass vial according to the European Pharmacopoeia 3.2.1 ) with a rubber stopper.

Conventionally, pemetrexed (e.g. pemetrexed disodium) and the excipients are supplied to the medical profession as a lyophilised formulation. The reconstituted liquid concentrate formulation is then prepared by the medical professional immediately prior to its use by adding an aqueous fluid. Typically, the aqueous fluid is water for injection or aqueous solutions of sodium chloride (for example 1 -20 mg/mL, preferable 5-15 mg/mL e.g. 9 mg/mL aqueous sodium chloride).

However, the applicant has previously discovered that the amine-based excipients of pemetrexed discussed herein are especially advantageous because they are highly stable, soluble and prove easy to mix, lyophilise and reconstitute (see WO 2014/167585, the contents of which are included by reference in their entirety).

The liquid concentrate solutions obtainable from pemetrexed in the form of an amine salt can be formed in two ways.

First, the liquid concentrate solutions can be prepared by dissolving pemetrexed salts in aqueous solutions. Second, the amine base can be added to an aqueous solution obtainable from pemetrexed diacid. In one preferred embodiment, the liquid concentrate formulation is prepared by forming a pemetrexed diacid-tromethamine salt, and then dissolving that salt in an aqueous solution.

Alternatively, the liquid concentrate solutions obtainable from the salts can be prepared by dissolving pemetrexed diacid in an aqueous solution including the appropriate base, for example a buffer including the base. In one preferred embodiment, the liquid concentrate formulation is prepared by dissolving pemetrexed diacid in an aqueous solution including tromethamine, for example a tromethamine-containing buffer.

The liquid concentrate formulations comprising the basic organic amines can therefore be prepared in batch and supplied to the medical profession such that there is no need for the initial reconstitution step. In one embodiment, the liquid concentrate formulation is prepared by adding pemetrexed diacid and the other excipients to water for injection and bubbling nitrogen though the solution. The bulk liquid concentrate formulation is then added to suitably sized and stoppered vials. In particular, the vials are clear plastic vials sealed with fluoropolymer-coated bromobutylic rubber stoppers.

Examples

Preparation of liquid concentrate formulation

Bulk liquid concentrate formulation containing the equivalent of 25 mg/ml pemetrexed diacid were prepared having the following unit formula:

Preparation

Nitrogen was bubbled through the water for 20 minutes and then approximately 80% of water for injection was transferred into the preparation vessel. Nitrogen was continuously bubbled through the water during the following steps. Tromethamine powder (7.0322 g) was added and the container was rinsed with water for injection. The solution was stirred for approximately five minutes until complete dissolution. Pemetrexed diacid (5.4989 g) was added and the container was rinsed with water for injection. The stirring was continued for about five minutes until complete dissolution. The pH of the solution was 8.53. A solution of citric acid monohydrate (2.0167 g) in 5 ml water was added and the stirring was continued for five minutes. The pH of the solution was 7.12. A solution of L- cysteine hydrochloride monohydrate (100.4 mg) in about 1 ml water was added and the stirring was continued for 5 minutes. The pH of the solution was 6.99. The pH of the solution was adjusted to 7.50 using a solution of 5 M tromethamine. The remaining water for injection was added and the solution was stirred for 5 minutes.

The bulk liquid concentrate formulation was filtered through a sterilizing filter of 0.2 μιη porosity, and divided into stoppered vials. The vials contain 4 ml liquid concentrate formulation (obtainable from 100 mg pemetrexed diacid), 20 ml liquid concentrate formulation (obtainable from 500 mg pemetrexed diacid), or 40 ml liquid concentrate formulation (obtainable from 1000 mg pemetrexed diacid).

A 4 mL liquid concentrate formulation comprising 25 mg/mL pemetrexed is obtainable from the following components:

Further examples of 1 mL liquid concentrate formulations comprising 25 mg/mL pemetrexed are obtainable from the following components:

Stability studies

Preparation of solution for infusion

The liquid concentrate formulations were diluted with 5% w/v glucose solution to give a solution for infusion having a concentration of 4.0 mg/mL or 10 img/mL pemetrexed.

1. Stability of solution for infusion

The obtained diluted solutions were kept in PVC bags under the following storage conditions:

The solutions for infusion were tested for their appearance (colour, clarity), pH, visible particles, sub-visible particles, assay and related substances.

Results obtained for pemetrexed 100 mq/4 mL diluted to 4 mq/ml pemetrexed in 5% glucose at 15-3Q^°C, in normal lighting conditions

Impurity B: (2S,2'S)-2,2'-[[(5R)-2,2'-diamino-4,4\6-trra^

diylcarbonylimino)]dipentanedioic acid,

Impurity D: (2S)-2-[[(4S)-4-[[4-[2-(2-amino-4-oxo-4J-dihydro acid, Impurity C: (2S,2'S)-2,2'-[[(5S)-2,2^,-diamino-4,4\6-trioxo-1 ,4,4 6,7,7'-hexahydro-1H5H-5,6'-bipyrrolo[2,3-^

diylcarbonylimino)]dipentanedioic acid.

Results obtained for pemetrexed 100 mp/4 mL diluted to 4 mq/ml pemetrexed in 5% glucose at 2-8^°C, in the absence of light

Results obtained for pemetrexed 100 mp/4 mL diluted to 10 mq/ml pemetrexed in 5% glucose at 15-30^°C, in normal lighting conditions

Results obtained for pemetrexed 100 mp/4 mL diluted to 10 mq/ml pemetrexed in 5% glucose at 2-8^°C, in the absence of light

Results obtained for pemetrexed 1000 mp/40 mL diluted to 4 mq/ml pemetrexed in 5% glucose at 15-30'C, in normal lighting conditions

Results obtained for pemetrexed 1000 mq/40 mL diluted to 4 mq/ml pemetrexed in 5% glucose at 2-8^°C, in the absence of light

Results obtained for pemetrexed 1000 mp/40 mL diluted to 10 mg/ml pemetrexed in 5% glucose at 15-30^°C, in normal lighting conditions

Results obtained for pemetrexed 1000 mq/40 mL diluted to 10 mg/ml pemetrexed in 5% glucose at 2-8'C, in the absence of light

Conclusion

The chemical and physical in-use stability of diluted solutions containing pemetrexed 25 mg/mL concentrate for solution for infusion has been demonstrated for 3 and 7 days at room temperature and 28 days at 2-8^°C

2. Stability of solution for infusion prepared 18 months after preparation of batch

The obtained diluted solutions were kept in PE bottles under the following storage conditions:

Results obtained for pemetrexed 100 mq/4 mL diluted to 4 mq/ml pemetrexed in 5% glucose at 25°C, in normal lighting conditions

Results obtained for pemetrexed 100 mq/4 mL diluted to 4 mq/ml pemetrexed in 5% glucose at 2-8 C, in the absence of light

Results obtained for pemetrexed 100 mq/4 mL diluted to 10 mq/ml pemetrexed in 5% glucose at 25°C, in normal lighting conditions

Results obtained for pemetrexed 100 mq/4 mL diluted to 10 mq/ml pemetrexed in 5% glucose at 2-8°C, in the absence of light

Results obtained for pemetrexed 500 mq/20 mL diluted to 4 mq/ml pemetrexed in 5% glucose at 25°C, in normal lighting conditions

Results obtained for penietrexed 500 mq/20 mL diluted to 4 mg/ml pemetrexed in 5% glucose at 2-8°C, in the absence of light

Results obtained for pemetrexed 500 mq/20 mL diluted to 10 mq/ml pemetrexed in 5% glucose at 25°C, in normal lighting conditions

Results obtained for pem'etrexed 500 mq/20 mL diluted to 10 mq/ml pemetrexed in 5% glucose at 2-8^°C, in the absence of light

Results obtained for pemetrexed 1000 mq/40 ml_ diluted to 4 mq/ml pemetrexed in 5% glucose at 25°C, in normal lighting conditions

Results obtained for perrietrexed 1000 mq/40 mL diluted to 4 mq/ml pemetrexed in 5% glucose at 25°C, at 2-8°C, in the absence of light

Results obtained for pertietrexed 1000 mq/40 mL diluted to 10 mg/ml pemetrexed in 5% glucose at 25°C, in normal lighting conditions

Results obtained for pemetrexed 1000 mq/40 mL diluted to 10 mq/ml pemetrexed in 5% glucose at 25°C, at 2-8^°C, in the absence of light

Conclusion

The chemical and physical in-use stability of diluted solutions containing pemetrexed 25 mg/mL concentrate for solution for infusion has been demonstrated for 3 and 7 days at room temperature and over 28 days at 2-8^°C

Claims

1 . A pharmaceutical formulation obtainable by dissolving:

(i) pemetrexed diacid or a pharmaceutically acceptable salt thereof; and

(ii) glucose;

in water.

2. A pharmaceutical formulation according to claim 1 , wherein the aqueous solution contains glucose at a concentration of 1 -20% w/v, preferably 2-10% w/v e.g. 5% w/v.

3. A pharmaceutical formulation according to claim 1 or 2, wherein the aqueous solution has a volume of from 50 to to 1250 ml_, preferably from 75 mL to 125 ml, for example, the pharmaceutical formulation can have a volume of 10 mL, 25 mL, 50 mL, 100 mL, 125 mL, 250 mL or 1000 mL.

4. A pharmaceutical formulation according to any one of claims 1 to 3, wherein the aqueous solution is obtainable from pemetrexed diacid or a pharmaceutically acceptable salt thereof in an amount of which is equivalent to from 10 mg to 2000 mg, preferably from 50 mg to 1500 mg, for example from 80 mg to 120 mg (e.g. 100 mg), from 450-550 mg (e.g. 500 mg) or 900-1 100 mg (e.g. 1000 mg) of pemetrexed diacid.

5. A pharmaceutical formulation according to any one of claims 1 to 4, wherein the aqueous solution is obtainable from pemetrexed diacid.

6. A pharmaceutical formulation according to any one of claims 1 to 4, wherein the aqueous solution is obtainable from a pharmaceutically acceptable salt of pemetrexed.

7. A pharmaceutical formulation according to claim 6, wherein the pemetrexed is in the form of a pharmaceutically acceptable salt which is a basic addition salt formed with an amine.

8. A pharmaceutical formulation according to claim 7, wherein the amine is selected from the group consisting of diethanolamine, tromethamine and meglumine, preferably wherein the amine is tromethamine.

9. A pharmaceutical formulation according to claim 6, wherein the pemetrexed is in the form of a pharmaceutically acceptable salt which is a disodium salt.

10. A pharmaceutical formulation according to any one of claims 1 to 8, wherein the formulation additionally comprises one or more further pharmaceutically acceptable excipients e.g. pharmaceutically acceptable excipients selected from sugar alcohols, sugars, pH- adjusting agents and antioxidants.

1 1 . A process for preparing a pharmaceutical formulation comprising:

(ii) diluting that composition with an aqueous solution of glucose.

12. A process according to claim 1 1 wherein the aqueous solution of glucose contains glucose at a concentration of 1 -20% w/v, preferably 2-10% w/v e.g. 5% w/v.

13. A process according to claim 1 1 or 12, wherein the composition comprising pemetrexed and water is a liquid concentrate formulation.

14. A process according to claim 13, wherein:

- the liquid concentrate formulation is obtainable from pemetrexed diacid or a pharmaceutically acceptable salt thereof in an amount of which is equivalent to from 900 to 1 100 mg (e.g. 1000 mg) of pemetrexed diacid and the liquid formulation has a volume of from 37.5 mL to 42.5 mL (e.g. 40 mL).

15. A process according to claim 13, wherein the liquid concentrate formulation is obtainable from pemetrexed diacid or a pharmaceutically acceptable salt thereof in an amount of which is equivalent to a concentration of from 10 to 50 mg/mL, preferably from 20 to 30 mg/mL, most preferably from 23 to 27 mg/mL e.g. 25 mg/mL of pemetrexed diacid.