WO1995007083A1

WO1995007083A1 - Ifosfamide lyophilisate composition

Info

Publication number: WO1995007083A1
Application number: PCT/AU1994/000523
Authority: WO
Inventors: Alan Duncan Robertson; Ross Andrew Shalliker; Jimmy Sosic
Original assignee: FH Faulding and Co Ltd
Current assignee: Mayne Pharma International Pty Ltd
Priority date: 1993-09-10
Filing date: 1994-09-05
Publication date: 1995-03-16
Anticipated expiration: 1996-03-10
Also published as: ZA946967B

Abstract

A pharmaceutical lyophilisate composition including approximately 50 to 80 % by weight, based on the total weight of the pharmaceutical composition of ifosfamide; approximately 20 to 50 % by weight, based on the total weight of the pharmaceutical composition of sodium chloride.

Description

Ifosfamide lyophilisate composition

The present invention relates to an ifosfamide lyophilisate composition and a process for preparing same.

Ifosfamide is a pharmaceutical useful in the treatment of tumour diseases, and has the chemical formula 3-(2-chloroethyl)-2-[(2-chloroethyl)amino]-tetrahydro-2H-l,3 ,2- oxazaphosphorin-2-oxide

Ifosfamide thus belongs to the chemical group of oxazaphosphorins. It was included in a series of cytostatic compounds disclosed and claimed by Arnold et al., in United States Patent No. 3,732,340 which issued

8th May, 1973.

The anhydrous form of ifosfamide is a white crystalline powder having a melting point of between 48°C and 51°C and is highly hygroscopic. Thus contact with moisture in the air must be avoided where possible.

Ifosfamide dissolves in water to the extent of about 10% by weight, and is stable only to a limited extent in aqueous solution, e.g. approximately 3 to 4 hours maximum at around 22°C.

Accordingly, ifosfamide gives rise to numerous difficulties during preparation and processing. When stored for any lengthy period of time, ifosfamide for example in a sterile crystallisation form begins to sinter and the rate of dissolution decreases. This is accompanied by a drop in clear solubility and the pH of the solution, with simultaneous yellow colourisation.

One composition known in the prior art and described in Australian Patent 598,602 to Asta Pharma

Aktiengesellschaft describes a lyophilised preparation containing ifosfamide, 0.1 to 17 parts by weight based on one part by weight ifosfamide of a hexitol, and optionally up to 16.9 parts by weight based on one part by weight ifosfamide of other conventional pharmaceutical auxilliary substances. Whilst this lyophilisate composition has provided some improvement in stability, there remains a need for improvements in the stability and shelf life of ifosfamide products.

It is also known in the prior art, e.g. from United States Patent 4,537,883 to Mead Johnson & Company to form lyophilisate compositions with the related oxazaphosphorin cyclophosfamide in its monohydrate form with sodium chloride. However, as pointed out in Australian Patent 598,602 referred to above, it has heretofore been considered that admixture of sodium chloride with ifosfamide such as is conventional for the dry filling of other oxazaphosphorins, does not yield a lyophilisate.

It is accordingly an object of the present invention to overcome, or at least alleviate, one or more of the difficulties or deficiencies related to the prior art.

Accordingly, in a first aspect there is provided a pharmaceutical lyophilisate composition including approximately 50 to 80% by weight, based on the total weight of the pharmaceutical composition, of ifosfamide; and approximately 20 to 50% by weight, based on the total weight of the pharmaceutical composition, of sodium chloride. It has been found that contrary to the teachings of the prior art, it is possible to form a stable lyophilisate composition utilising sodium chloride. The pharmaceutical lyophilisate composition according to the present invention may be characterised by improved stability and shelf life. The lyophilisate may have the appearance of a good freeze dried plug having the crystalline structure and visual appearance of a dry firm powder. The plug may reconstitute quickly, e.g. in. two to three seconds, to form a solution on addition of a solvent.

The pharmaceutical lyophilisate composition may further include supplementary excipients or conventional pharmaceutical additives such as lactose, dextrose, Na₂C0₃, hexitols such as mannitol, C,, sugars and dextrans or mixtures thereof. The supplementary excipients may be present in the pharmaceutical lyophilisate composition in any suitable amount. The supplementary excipients are preferably present in amounts of from 0 to 10% by weight based on the total weight of the pharmaceutical lyophilisate composition, more preferably approximately 4.0% by weight to 7.5% by weight.

We have found that surprisingly, it is possible to form a stable lyophilisate composition utilising sodium chloride that does not include mannitol.

Accordingly in a further aspect there is provided a pharmaceutical lyophilisate composition including approximately 50 to 80% by weight, based on the total weight of the pharmaceutical composition, of ifosfamide, and approximately 20 to 50% by weight, based on the total weight of the pharmaceutical composition, of sodium chloride wherein said composition excludes mannitol.

It has been further found that improvements in stability may be achieved by control of the pH of the composition on reconstitution. The pH of the composition should be within the range of approximately 6.0 to 7.2, preferably approximately 6.5 to 7.1, on reconstitution.

It has been also found that even further improvements in stability may be achieved by including both sodium chloride and a buffer in the pharmaceutical lyophilisate composition.

Accordingly, in a further preferred aspect of the present invention, there is provided a pharmaceutical lyophilisate composition including approximately 50 to 80% by weight, based on the total weight of the pharmaceutical lyophilisate composition, of ifosfamide; approximately 20 to 50% by weight, based on the total weight of the pharmaceutical composition, of sodium chloride; and a buffer in an amount sufficient to provide a pH of the composition on reconstitution in the range of approximately 6.0 to 7.2.

The buffer may be added to the pharmaceutical lyophilisate composition in any suitable amount. The buffer is preferably present in an amount effective to maintain the pH on reconstitution within the range of approximately 6.5 to 7.1. The buffer is preferably present in amounts of up to approximately 15% by weight, based on the total weight of the pharmaceutical composition, more preferably approximately 10 to 15% by weight.

Preferably the buffer is a phosphate buffer. A phosphate buffer such as disodium hydrogen phosphate

(Na_HP0₄), sodium dihydrogen phosphate (NaH„P0₄), potassium dihydrogen phosphate (KH„P0₄) or dipotassium hydrogen phosphate (K_?HP0₄) has been found to be suitable. Na2-HPO4. is preferred.

The pharmaceutical lyophilisate composition may further include supplementary excipients or conventional pharmaceutical additives such as lactose, dextrose, Na„CO_, hexitols such as mannitol, C.. sugars and cyclodextrans or mixtures thereof. The supplementary excipients may be present in the pharmaceutical lyophilisate composition in any suitable amount. The supplementary excipients are preferably present in amounts of from 0 to 10% by weight based on the total weight of the pharmaceutical lyophilisate composition, more preferably approximately 4.0% by weight to 7.5% by weight.

In a particularly preferred aspect of the present invention, there is provided a pharmaceutical lyophilisate composition including approximately 50 to 80% by weight, based on the total weight of the pharmaceutical lyophilisate composition of ifosfamide; approximately 20 to 50% by weight, based on the total weight of the pharmaceutical composition, of sodium chloride; approximately 5 to 15% by weight, based on the total weight of the pharmaceutical composition, of a phosphate buffer.

It has been found that a lyophilisate composition falling within the scope of the preferred ranges specified above may exhibit significantly improved stability, such that after storage at approximately 40°C, for at least a month, no change in appearance is apparent. The lyophilisate composition is also readily reconstituted to a colourless solution for injection, having a pH in the range of approximately 6.0 to 7.2.

Accordingly, in a preferred aspect there is provided a stable pharmaceutical lyophilisate composition suitable for parenteral administration on reconstitution including approximately 50 to 80% by weight, based on the total weight of the pharmaceutical composition of ifosfamide; approximately 20 to 50% by weight, based on the total weight of the pharmaceutical composition of sodium chloride; a buffer in an amount sufficient to provide a pH of the composition on reconstitution in the range of approximately 6.0 to 7.2; wherein mannitol is not present in the composition.

In a further aspect, it has been found that still further improvements may be achieved wherein the lyophilisate is formed utilising a thermal cycling process such that a crystalline product is produced. The thermal cycling or annealing process may function as follows.

The ingredients are subjected to a first freezing step as is standard in the art to induce glass formation. This may be followed by a second step in which the temperature is raised slightly. The temperature may be raised above the collapse temperature to permit a vitreous transformation and crystallisation. The temperature may then be lowered again to permit complete solidification.

The pharmaceutical lyophilisate compositions of the present invention may be prepared by dissolving ifosfamide and other components in a suitable solvent. The solvent may be an aqueous or alcoholic solvent or mixtures thereof. An aqueous solvent is preferred. Water of suitable quality, for example Water for Injection ("W.F.I."), is particularly preferred.

Preferably, the components are added to the solvent in the following order:

(1) ifosfamide,

(2) buffer,

(3) supplementary comρonent(s) (if any),

(4) sodium chloride, (5) acid or base if required to adjust the pH of the final solution.

The pre-lyophilization solution may be purified in a conventional manner, for example by filtration using microbial retentive filters and nitrogen gas for pre-filter pressure. The sterilized solution may be then aseptically filled into sterile packaging of appropriate size to allow reconstitution to give an intended volume of solution of desired ifosfamide concentration for administration. Typically, vials are used and may contain sufficient fill solution to provide from approximately 0.5 to 5 g of ifosfamide per vial.

Following the filling operation, the contents of the vials may be lyophilised.

In a still further aspect of the present invention there is provided a process for preparing a pharmaceutical lyophilisate composition, which process includes providing a pharmaceutical formulation including an effective amount of ifosfamide; sodium chloride; a buffer in amount sufficient to provide a pH of the formulation in the range of approximately 6.0 to 7.2; optionally supplementary excipients; and a solvent therefor; and cooling the pharmaceutical formulation to a temperature of approximately -50°C to -20°C; subjecting the cooled pharmaceutical formulation to a first drying step at elevated pressure and at a temperature of approximately -30°C to approximately -10°C; and subjecting the partially dried product to a second drying step at a lower pressure and at a temperature of approximately 0 to 10°C to form a pharmaceutical lyophilisate.

It has been surprisingly found that utilising the process according to this aspect of the presention, a lyophilisate may be formed from ifosfamides utilising sodium chloride as the principal adjuvant.

Preferably the ifosfamide is present in an amount sufficient to provide a concentration of approximately 50% to 80% by weight, in the final pharmaceutical lyophilisate composition formed, and the sodium chloride is present in an amount of approximately 20% to 50% by weight, in the pharmaceutical lyophilisate composition formed.

More preferably the buffer is a phosphate buffer present in an amount sufficient of approximately 5% to 15% in the final pharmaceutical composition formed.

Preferably the pharmaceutical lyophilisate so formed includes approximately 50 to 80% by weight, based on the total weight of the pharmaceutical lyophilisate composition, of ifosfamide; approximately 20 to 50% by weight, based on the total weight of the pharmaceutical composition, of sodium chloride; approximately 5 to 15% by weight, based on the total weight of the pharmaceutical composition, of a phosphate buffer.

The solvent may be an aqueous or alcoholic solvent or mixtures thereof. An aqueous solvent is preferred. Water of suitable quality, for example Water for Injection ("W.F.I."), is particularly preferred. Preferably the process is carried out in a freeze drying apparatus.

In a further preferred embodiment, the freeze drying process may include a thermal cycling or annealing process. Accordingly, the process may include the preliminary step of pre-chilling the freeze drying apparatus to a temperature of approximately -20°C to -5°C, prior to loading the pharmaceutical formulation for a period of up to about 1 hour.

The preliminary step may subsequently include cooling the * pharmaceutical formulation to a temperature of approximately -55°C to -40°C for a period of approximately 1 to 2 hours; raising the temperature of the freeze drying apparatus to approximately -25°C to -15°C for approximately 1 to 5 hours; and recooling the pharmaceutical apparatus to a temperature of approximately -55°C to -40°C for approximately 1 to 5 hours.

The first drying step may be conducted in a range of pressures of approximately 150 to 350 μ bars. The first drying step may be conducted at a temperature of approximately -20°C to -30°C and may continue for approximately 12 to 48 hours. The shelf temperature may then be raised to a temperature of approximately -10°C to -20°C and maintained for a further 6 to 15 hours.

The second drying step may be conducted at a pressure of approximately 10 to 15 μ bar, and at a temperature of approximately 0 to 10°C, and may continue for an extended period for example approximately 3 to 24 hours.

Dosage forms according to the present invention may comprise a pharmaceutical lyophilisate composition as hereinbefore described, contained in a suitable container, usually a vial but also an ampoule, syringe, or other container commonly used for packaging, reconstitution and, optionally, delivery of intravenous or other parenteral solutions. By suitable container is meant a container capable of maintaining a sterile environment such as a vial capable of being hermetically sealed by a stopper means. Additionally, suitable container implies appropriateness of size, considering the volume of solution to be held upon reconstitution of the improved ifosfamide lyophilizate composition. While such containers are usually glass, generally type I glass; they may also be of other suitable materials which do not interact with the lyophilisate components. The closure, typically a stopper and preferably a sterile rubber stopper or an equivalent which gives a hermetic seal, and capable of maintaining a sterile environment will also allow entry for the purpose of introduction of diluent such as sterile water for reconstitution of the ifosfamide solution. Preferred dosage forms containing the ifosfamide lyophilisate compositions may be vials from about 10 to 250 ml and preferably about 25 to 200 ml in capacity. It will be recognized that larger or smaller dosage forms may be readily accommodated as part of the present invention. The pharmaceutical lyophilisate compositions of the present invention are intended to be reconstituted with common diluents, such as W.F.I. , USP, to provide appropriate solutions of ifosfamide for parenteral administration, preferably intravenous administration. The compositions of the present invention may be characterised by rapid reconstitution in standard solvents, for example, within approximately 1 minute or ' less. The reconstituted products may exhibit . minimal foaming.

The present invention will now be more fully described with reference to the accompanying examples. It should be understood, however, that the description following is illustrative only and should not be taken in any way as a restriction on the generality of the invention described above.

EXAMPLE 1 FORMULATION 1

Ifosfamide 66.67 mg/mL

NaCl 20.00 mg/mL —> 40.00 mg/mL

Fill Volume 15 mL

Vial 30 mL, 20 mm

Mixing Instructions:

(a) Add approximately 75% of required W.F.I, into a clean mixing vessel. (b) Add NaCl while stirring, mix and dissolve.

(c) Slurry ifosfamide with W.F.I. , add slurry while stirring, mix and dissolve.

(d) Adjust volume with W.F.I.

(e) Check and adjust pH range, if necessary.

Cycle:

l.(a) Pre-chill shelves to -10°C before loading freeze dryer with product. (b) Load freeze dryer with product and cool shelves to -50°C and hold for 2 hours.

(c) Heat shelves to -20°C and hold for 2 hours.

(d) Cool shelves to -50°C and hold for 90 minutes.

2. (a) Primary dry for 34 hours at Maximum pressure of 255.5 μ bar and minimum pressure of 159.1 μ bar. Shelf temperature is -25°C. 3. (a) Secondary dry at 159.1 μ bar and at shelf temperature of -20°C for 12 hours.

EXAMPLE 2

FORMULATION 2

Ifosfamide 66.67 mg/mL

NaCl 40.00 mg/mL

Mannitol 6.0 mg/mL Fill volume 15 ml Vial 30 ml, 20 mm

Mixing instructions with disodium hydrogen phosphate: (a) Add approximately 75% of required W.F.I, into a clean mixing vessel.

(b) Add Dibasic Sodium Phosphate while stirring, mix and dissolve.

(c) Slurry ifosfamide with W.F.I., add slurry while stirring, mix and dissolve.

(d) Add Mannitol while stirring, mix and dissolve.

(e) Add Sodium Chloride while stirring, mix and dissolve.

(f) Adjust the pH into the range 6.9 to 7.1 with 5N

(g) Adjust to volume with W.F.I.

(h) Check and readjust pH if necessary, into the range

6.9 to 7.1 with either 5N H 3,PO4. or l.in NaOH.

Cvcle:

l.a) Pre-chill shelves to -10°C before loading freeze dryer with product, (b) Load freeze dryer with product and cool shelves to -50°C and hold for 2 hours. (c) Heat shelves to -20°C and hold for 2 hours.

(d) Cool shelves to -50°C and hold for 90 minutes. 2. (a) Primary dry at maximum pressure of 255.5 μbar and a minimum pressure of 159.1 μbar. The shelf temperature is held at -25°C for 23 hours. The shelf temperature is then raised to -20°C and held for 9 hours. The shelf temperature is then raised to -10°C and held for 150 minutes.

3. (a) Secondary dry at 11.2 μbar and at a shelf temperature of +10°C for 4 hours.

EXAMPLE 3 FORMULATION 3

Ifosfamide 66.67 mg/mL

NaCl 40.00 mg/mL

NaH₂P0₄ 14.00 mg/mL

Mannitol 6 mg/mL Fill Volume 15 ml

Vial 30 ml, 20 mm

Mixing instructions with sodium dihydrogen phosphate: (a) Add approximately 75% of required W.F.I, into a clean mixing vessel.

(b) Add Monobasic Sodium Phosphate while stirring, mix and dissolve. Adjust pH to 6.5 with l.ON NaOH.

(d) Add Mannitol while stirring, mix and dissolve.

(e) Add Sodium Chloride while stirring, mix and dissolve.

(f) Adjust the pH into the range 6.9 to 7.1 with 5N

(g) Adjust to volume with W.F.I.

(h) Check and readjust pH if necessary, into the range 6.9 to 7.1 with either 5N H₃P0₄ or l.ON NaOH. Cycle: l.(a) Pre-chill shelves to -10°C before loading freeze dryer with product, (b) Load freeze dryer with product and cool shelves to -50°C and hold for 2 hours, (c) Heat shelves to -20°C and hold for 2 hours, (c) Cool shelves to -50°C and hold for 90 minutes.

2. (a) Primary dry at a maximum pressure of 255.5 μ bar and minimum pressure of 159.1 μ bar. The shelf temperature is held at -25°C for 25 hours. The shelf temperature is then raised to -15°C and held for 13 hours.

3. (a) Secondary dry at 11.2 μ bar and at a shelf temperature of +5.0°C for 4 hours.

EXAMPLE 4 FORMULATION 4

Ifosfamide 66.67 mg/mL NaCl 30.00 mg/mL

Na₂HP0₄ 14.00 mg/mL

Fill Volume 15 mL

Vial 30 mL, 20mm

Mixing instructions:

(a) Add approximately 90% of the required WFI into a clean mixing vessel.

(b) Add slurried ifosfamide while stirring, mix and dissolve.

(c) Add dibasic sodium phosphate while stirring, mix and dissolve.

(d) Add sodium chloride while stirring, mix and dissolve. (e) Check and record pH.

(f) Adjust pH into the range 6.7-6.9 with either 5.0 N

(g) Adjust batch to volume with WFI.

(h) Check pH and readjust if necessary into the range 6.7-6.9 with either 5.0 N H₃P0₄ or 1.0 N NaOH. Cyc le :

1(a) Pre-chill shelves to -10°C before loading freeze dryer with product.

(b) Load freeze dryer with product and cool shelves to -45°C and hold for 1.5 hours.

(c) Heat shelves to -20°C and hold for 4 hours.

(d) Cool shelves to -45°C and hold for 3.5 hours.

2(a) Primary dry at a maximum pressure of 318 μ bar and minimum pressure 195 μ bar. The shelf temperature is held at -20°C for 30 hours. The shelf temperature is then raised to -10°C and held for 18 hours. 3(a) Secondly, dry at 11.2 μ bar and at a shelf temperature of 10.0°C for 1.5 hours.

EXAMPLE 5

Ifosfamide 66.67 mg/mL

NaCl 30.00 mg/mL NaH₂P0₄ 14.00 mg/mL

Fill Volume 15 mL

Vial 30 mL, 20 mm

Mixing instructions:

(a) Add approximately 90% of the required WFI into a clean mixing vessel.

(b) Add slurried ifosfamide while stirring, mix and dissolve. (c) Add monobasic sodium phosphate while stirring, mix and dissolve.

(d) Add sodium chloride while stirring, mix and dissolve. Adjust pH to 6.5 with l.ON NaOH.

(e) Check and record pH. (f) Adjust pH into the range 6.7-6.9 with either 5.0 N

(g) Adjust batch to volume with WFI. (g) Adjust batch to volume with WFI.

(h) Check pH and readjust if necessary into the range

6.7-6.9 with either 5.0 N H 3,PO4„ or 1.0 N NaOH.

Cvcle:

1(a) Pre-chill shelves to -10°C before loading freeze dryer with product, (b) Load freeze dryer with product and cool shelves to -45°C and hold for 1.5 hours. (c) Heat shelves to -20°C and hold for 4 hours.

(d) Cool shelves to -45°C and hold for 3.5 hours. 2(a) Primary dry at a maximum pressure of 318 μ bar and minimum pressure 195 μ bar. The shelf temperature is held at -20°C for 30 hours. The shelf temperature is then raised to -10°C and held for 18 hours. 3(a) Secondly, dry at 11.2 μ bar and at a shelf temperature of 10.0°C for 1.5 hours.

EXAMPLE 6

Ifosfamide 66.67 mg/mL and

Sodium Chloride 12.00 mg/mL

Fill Volume 15 mL Vial 30 mL, 20 mm

Mixing Instructions:

(a) Add approximately 75% of required W.F.I, into a clean mixing vessel.

(b) Add NaCl while stirring, mix and dissolve.

(d) Adjust volume with W.F.I. (e) Check and adjust pH range, if necessary. Cycle :

(c) Heat shelves to -20°C and hold for 2 hours.

(d) Cool shelves to -50°C and hold for 90 minutes.

2. (a) Primary dry for 34 hours at Maximum pressure of 255.5 μ bar and minimum pressure of 159.1 μ bar. Shelf temperature is -25°C.

3. (a) Secondary dry at 159.1 μ bar and at a shelf temperature of -20°C for 12 hours.

Finally, it is to be understood that various other modifications and/or alterations may be made without departing from the spirit of the present invention as outlined herein.

Claims

CLAIMS :

1. A pharmaceutical lyophilisate composition including approximately 50 to 80% by weight, based on the total weight of the pharmaceutical composition of ifosfamide; approximately 20 to 50% by weight, based on the total weight of the pharmaceutical composition of sodium chloride.

2. A pharmaceutical lyophilisate composition according to claim 1 further including one or more supplementary excipient(s) and/or conventional pharmaceutical additive(s).

3. A pharmaceutial lyophilisate composition according to claim 2 wherein the supplementary excipient(s) is selected from the group consisting of lactose, dextrose, Na₂CO,, a hexitol, a C,₂ sugar, and a dextran or mixtures thereof.

4. A pharmaceutical lyophilisate composition according to claim 2 or claim 3 wherein the excipient or additive is present in an amount of approximately 4.0% to 7.5% by weight, based on the total weight of the pharmaceutical lyophilisate composition.

5. A pharmaceutical lyophilisate composition according to any one of the preceding claims in which mannitol is not present in the composition.

6. A pharmaceutical lyophilisate composition according to any one of claims 1 to 5 further including a buffer in an amount sufficient to provide a pH of the composition on reconstitution in the range of approximately 6.0 to 7.2.

7. A pharmaceutical lyophilisate composition according to claim 6 wherein the buffer is present in an amount effective to maintain the pH of the reconstituted composition in the range of approximately 6.5 to 7.1.

8. A pharmaceutical lyophilisate composition according to claim 6 wherein the buffer is a phosphate buffer and is present in an amount . of approximately 5 to 15% by weight, based on the total weight of the pharmaceutical composition.

9. A pharmaceutical lyophilisate composition according to claim 8 wherein the phosphate buffer is selected from disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate and dipotassium hydrogen phosphate.

10. A pharmaceutical lyophilisate composition according to any one of the preceding claims in unit dosage form.

11. A pharmaceutical lyophilisate composition according to claim 10 which is in a form suitable for parenteral administration on reconstitution.

12. A pharmaceutical lyophilisate composition according to claim 11 wherein the lyophilisate is formed utilising a thermal cycling process such that a crystalline product is produced.

13. A pharmaceutical lyophilisate composition suitable for parenteral administration on reconstitution including approximately 50 to 80% by weight, based on the total weight of the pharmaceutical composition of ifosfamide; approximately 20 to 50% by weight, based on the total weight of the pharmaceutical composition of sodium chloride; a buffer in an amount sufficient to provide a pH of the composition on reconstitution in the range of approximately 6.0 to 7.2; and wherein mannitol is not present in the composition.

14. A pharmaceutical lyophilisate composition according to claim 13 wherein the lyophilisate is formed utilising a thermal cycling process such that a crystalline product is formed.

15. A process for preparing a pharmaceutical lyophilisate composition which process includes providing a pharmaceutical -formulation including an effective amount of ifosfamide; sodium chloride; a buffer in an amount sufficient to provide a pH of the formulation on reconstitution in the range of approximately 6.0 to 7.2%; optionally one or more supplementary excipients or pharmaceutical additives; and a solvent therefor; cooling the pharmaceutical formulation to a temperature of approximately -50°C to -20°C; subjecting the cooled pharmaceutical formulation to a first drying step under reduced pressure at a temperature of approximately -30°C to approximately -10°C; and subjecting the partially dried product to a second drying step at a lower pressure and at a temperature of 0°C to approximately 10°C to form a pharmaceutical lyophilisate.

16. A process according to claim 15 wherein the pharmaceutical formulation is subjected to a thermal cycling step, prior to the first drying step.

17. A process according to claim 16 including, prior to the first drying step, the steps of cooling the pharmaceutical formulation to a temperature of approximately -55°C to -40°C for a period of approximately 1 to 2 hours; heating the pharmaceutical formulation to a temperature of approximately -25°C to -15°C for approximately 1 to 5 hours; cooling the pharmaceutical formulation to a temperature of approximately -55°C to -40°C for approximately 1 to 5 hours.

18. A process according to any one of claims 15 to 17 wherein the ifosfamide is present in an amount sufficient to provide a concentration of approximately 50% to 80% by weight, in the final pharmaceutical lyophilisate composition formed, and the sodium chloride is present in an amount sufficient to provide a concentration of approximately 20% to 50% by weight, in the pharmaceutical lyophilisate composition formed.

19. A process according to any one of claims 15 to 18 wherein the buffer is a phosphate buffer present in an amount sufficient of approximately 5% to 15%, in the final pharmaceutical composition formed.

20. A process according to any one of claims 15 to 19 including one or more supplementary excipients selected from the groups consisting of from lactose, dextrose, Na₂C0₃, a hexitol, a C₁₂ sugar, and a dextran or mixtures thereof.

21. A process according to any one of claims 15 to 20 wherein the supplementary excipient(s) or pharmaceutical additive(s) is present in an amount sufficient to provide a concentration of approximately 4.0% to 7.5% by weight, in the final pharmaceutical lyophisilate composition formed.

22. A process according to any one of claims 15 to 21 wherein mannitol is not present in the pharmaceutical formulation.

23. A process according to any one of claims 15 to 22 wherein the solvent is selected from an aqueous or alcoholic solvent.

24. A process according to any one of claims 15 to 23 wherein the process is carried out in a freeze drying apparatus which is prechilled to a temperature of approximately -20°C to -5°C for a period up to about 1 hour prior to loading the pharmaceutical formulation.

25. A process according to any one of claims 15 to 24 wherein the first drying step is conducted at a pressure of approximately 150 to 350 μ bars and a temperature of approximately -20°C to -30°C for approximately 12 to 48 hours.

26. A process according to any one of claims 15 to 25 wherein the second drying step is conducted at a pressure of approximately 10 to 15 μ bar and a temperature of approximately 0 to 10°C for approximately 3 to 24 hours.

27. A process according to any one of claims 15 to 26 wherein the pharmaceutical formulation is formed by adding to the solvent

(i) the ifosfamide;

(ii) the buffer; (iii) optionally the supplementary component(s) or pharmaceutical additive(s);

(iv) the sodium chloride; and

(v) if necessary, acid or base to adjust pH.

28. A process according to claim 27 wherein the ifosfamide is added as a slurry in the solvent.

29. A pharmaceutical lyophilisate composition produced by the process of any one of claims 15 to 28.

30. A method for the treatment of a tumour disease in a human or animal subject, said method including administering to the subject an effective amount of a reconstituted pharmaceutical lyophilisate composition according to any one of claims 1 to 14 or claim 29.