WO2014060959A1

WO2014060959A1 - Crystalline pemetrexed dipotassium process

Info

Publication number: WO2014060959A1
Application number: PCT/IB2013/059384
Authority: WO
Inventors: Vimal Kumar Shrawat; Rafiuddin .; Vinod Kumar Singh; Bhagat Raj PIPAL; Akshay Kant CHATURVEDI
Original assignee: Shilpa Medicare Ltd
Current assignee: Shilpa Medicare Ltd
Priority date: 2012-10-17
Filing date: 2013-10-16
Publication date: 2014-04-24
Anticipated expiration: 2015-04-17

Abstract

The present invention provides crystalline pemetrexed dipotassium hemiheptahydrate (I) - characterized by X-ray powder diffraction pattern comprising at least 5 characteristic 29° peaks selected from the XRPD peak set of 5.00, 13.70, 14.90, 15.20, 16.90, 20.00, 20.50, 21.40, 23.6, 24.2, 25.10, 27.5 and 28.30 ± 0.20 29°, DSC isotherm comprising the endothermic peaks ranging between 65 to 85°C (Peak -1), 86 to 105°C (Peak -2), 120 to 132°C (Peak -3), 250 to 265°C (Peak -4), and IR absorption characteristic peaks at approximately 2936 cm^-1, 2857 cm^-1, 1396 cm^-1, 1184 cm^-1, 1158 cm^-1, 1092 cm^-1, 1076 cm^-1, 819 cm^-1 and 788 cm^-1 useful as active pharmaceutical ingredient in pharmaceutical compositions for the treatment of cancer. The invention also provides process for preparing pemetrexed dipotassium hemiheptahydrate (I) and its pharmaceutical composition thereof.

Description

CRYSTALLINE PEMETREXED DIPOTASSIUM PROCESS

The following specification particularly describes the invention and the manner in which it is to be performed.

INTRODUCTION

Pemetrexed's chemical name is (S)-2-(4-(2-(2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3- d]pyrimidin-5-yl)ethyl)benzamido)pentanedioic acid and has the following chemical structure:

Pemetrexed disodium is the most common salt of pemetrexed di acid. It has the chemical name L-Glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-lH-pyrrolo[2,3-d]pyrimidin-5-yl)- ethyl]benzoyl]-, disodium salt. Pemetrexed disodium heptahydrate is the active ingredient of Eli Lilly and Company's ALIMTA® injectable composition. Pemetrexed disodium heptahydrate has the following chemical structure:

Pemetrexed disodium is a multi-targeted antifolate that strongly inhibits various folate-dependent enzymes, including thymidylate synthase (TS), dihydrofolate reductase (DHFR) and glycinamide ribonucleotide formyltransferase (GARFT). Pemetrexed disodium has been proved effective on a wide variety of solid tumors in clinical trials. Currently, pemetrexed disodium is commercial available in USA, European Union, Canada, Japan and China etc. for treatment of malignant pleural stromal tumor as a first-line drug, and local advanced and metastatic non-small cell lung cancer as a second-line drug. In the treatment of malignant pleural stromal tumor, pemetrexed disodium is a unique chemotherapeutic agent in the market currently. In the second-line treatment of non-small cell lung cancer, pemetrexed disodium has a comparative efficacy and reduced toxicities compared with the standard drug Docetaxel. Hence, it is likely for pemetrexed disodium to become a new standard treatment of the second-line treatment for non-small cell lung cancer. In addition, the clinical studies of pemetrexed disodium in the treatment of breast, bowel, pancreatic, head and neck, gastric and bladder cancers are still ongoing.

Various methods for preparing pemetrexed and pemetrexed disodium are disclosed in the art, such as WO2001014379A , WO1999016742, EP432677, EP589720, WO001 1004, EP549886 and CN1778797. Luo Jie et al in US20100305319A1 ( Equivalent: EP 2213674B 1) describes a method of purifying a s

by salting-out, wherein if M₃ is H , then each of Mi and M2 is independently H , Li , Na or K⁺, provided that both of them are not H⁺; if M₃ ⁺ is Li⁺, Na⁺ or K⁺, then each of Mi⁺ and M2⁺ is independently Li⁺, Na⁺ or K⁺. In example 16 and 17, it provides mention of purification of potassium pemetrexed, however, it appears that it does not refer to other than mono potassium salt of pemetrexed with no characterization details of the said salt. Further, in our attempt to reproduce the said example disclosure, no material could be recovered. Pemetrexed being an important anticancer therapeutic agent, additional and improved ways of preparing pemetrexed pharmaceutically acceptable salt may be of immense value to pharmaceutical science and the healthcare of cancer patients. Hence, there exists a need for the development of new stable crystalline form and economically viable processes, which may be industrially amenable to scalable up, viable, safer for handling, less time consuming and with better and consistent quality parameters.

The inventors of this application have found a new form of Pemetrexed i.e. Pemetrexed dipotassium hemiheptahydrate (I) designated as Form-SPl, which is stable and free from any contamination along with a process for preparation thereof.

SUMMARY OF INVENTION

Particular aspects of the present application relate to the Pemetrexed dipotassium

hemiheptahydrate (I)

(I)

and process/es for preparation thereof .

Individual aspects of the application relate to Pemetrexed dipotassium hemiheptahydrate (I) , process for preparation of Pemetrexed dipotassium hemiheptahydrate (I) and its stable crystalline polymorphic form designated as Form-SPl, which is substantially free from process related impurities. The crystalline polymorphic form of Pemetrexed dipotassium hemiheptahydrate (I) obtained by the processes according to the present invention is useful as active pharmaceutical ingredient in pharmaceutical compositions for treating hyper-proliferative disorders, such as cancer, by administering the compound in a composition. Different aspects of the present application are summarized herein below individually.

In one aspect of the present application, it relates to crystalline Pemetrexed dipotassium hemiheptahydrate (I)

Crystalline Form-SPl of Pemetrexed dipotassium hemiheptahydrate is characterized by X-ray powder diffraction pattern comprising at least 5 characteristic 29° peaks selected from the XRPD peak set of 5.00, 13.70, 16.90, 20.00, 21.40, 23.6, 24.2 and 28.30 ± 0.20 2Θ°. A few further characterizing XRPD diffraction angle peaks include 14.90, 15.20, 20.50, 25.10 and 27.5 ± 0.20 2Θ°.

Crystalline Pemetrexed dipotassium hemiheptahydrate (I) Form- SP 1 is further characterized by DSC isotherm comprising at least three endothermic peaks ranging between- a. Peak - 1 - Between 65 to 85°C

b. Peak -2- Between 86 to 105°C

c. Peak -3- Between 120 to 132°C

d. Peak -4- Between 250 to 265°C

In a further aspect, it relates to Crystalline Pemetrexed dipotassium hemiheptahydrate (I) Form- SPl, which has an IR absorption spectrum having characteristic peaks expressed in cm^"1 at approximately 2936 cm^"1, 2857 cm^"1, 1396 cm^"1, 1 184 cm^"1, 1 158 cm^"1, 1092 cm^"1, 1076 cm^"1, 819 cm^"1 and 788 cm^"1.

Crystalline Pemetrexed dipotassium hemiheptahydrate (I) Form- SP 1 of the present invention is further characterized by X-ray powder diffraction pattern substantially according to Fig-1, DSC isothermal pattern substantially according to Fig-2 and IR absorption spectrum substantially according to Fig-3.

In yet another aspect of the present invention, it relates to a process for preparing Crystalline Pemetrexed dipotassium hemiheptahydrate (I) Form- SP1 characterized by X-ray powder diffraction pattern comprising at least 5 characteristic 29°peaks selected from the XRPD peak set of 5.00, 13.70, 14.90, 15.20, 16.90, 20.00, 20.50, 21.40, 23.6, 24.2, 25.10, 27.5 and 28.30 ± 0.20 29°, DSC isotherm comprising the endothermic peaks ranging between 65 to 85°C (Peak -1), 86 to 105°C (Peak -2), 120 to 132°C (Peak -3), 250 to 265°C (Peak -4), and IR absorption characteristic peaks at approximately 2936 cm^"1, 2857 cm^"1, 1396 cm^"1, 1 184 cm^"1, 1 158 cm^"1, 1092 cm^"1, 1076 cm^"1, 819 cm^"1 and 788 cm^"1, comprising the steps of- a. combining N-[4-[2-(2-amino-4,7-dihydro-4-oxo-lH-pyrrolo[2,3-d]pyrimidin-5- yl) ethyl] benzoyl] -L-glutamic dipotassium with water or aqueous organic solvent mixture at temperature ranging between 15-30 deg C.

b. optionally filtering the solution

c. cooling the solution or filtrate upto 0-10°C

d. adding aliphatic alcohol solvent within 30-120 minutes

e. optionally raising the temperature between to 20-35°C under stirring

f. stir and maintain the reaction mass for time upto 1-4 hours

g. filtering and isolating the crystalline material

In the process for preparing Crystalline Pemetrexed dipotassium hemiheptahydrate (I) final step of filtering and isolating the crystalline material comprise the steps of-

1. Subjecting crystalline solid recovered to washing with aliphatic alcohol solvent (CI to C5);

2. Drying the crystalline material under vacuum

3. Recovering the Crystalline Pemetrexed dipotassium hemiheptahydrate having purity greater than 99.2% w/w and water content in the range between 9.5 to 12.0% w/w

In yet another aspect, the Crystalline Pemetrexed dipotassium hemiheptahydrate (I) Form-SPl obtained by the process/es of the present application may be formulated as solid compositions for oral administration in the form of lyophilized powder, capsules, tablets, pills, powders or granules useful in the treatment of hyper-pro liferative disorders, such as cancer.

Further aspects of the present invention are demonstrated in detailed description section as well as examples. BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 is Illustration of X-ray powder diffraction (XRPD) pattern of Crystalline Pemetrexed dipotassium hemiheptahydrate (I) Form-SPl, prepared according to Example-2

Fig. 2 is an Illustration of a differential scanning calorimetric ("DSC") curve of Pemetrexed dipotassium hemiheptahydrate (I) Form-SPl, prepared according to Example-2

Fig. 3 is an Illustration of a IR spectrum of Pemetrexed dipotassium hemiheptahydrate (I) Form- SPl, prepared according to Example-2

Fig. 4 is an Illustration of a TGA thermogram of Pemetrexed dipotassium hemiheptahydrate (I) Form-SPl, prepared according to Example-2

Fig. 5 is Illustration of X-ray powder diffraction (XRPD) pattern of Crystalline Pemetrexed dipotassium hemiheptahydrate (I) Form-SP2

DETAILED DESCRIPTION

As set forth herein, embodiments of the present invention provide crystalline Pemetrexed dipotassium hemiheptahydrate (I) Form-SPl and processes for preparation thereof. Individual embodiments of the present invention are detailed herein below separately.

In one embodiment of the present application, it provides crystalline Pemetrexed dipotassium hemiheptahydrate (I) Form-SPl.

(I)

Crystalline Form-SPl of Pemetrexed dipotassium hemiheptahydrate is characterized by X-ray powder diffraction pattern comprising at least 5 characteristic 29° peaks selected from the XRPD peak set of 5.00, 13.70, 16.90, 20.00, 21.40, 23.6, 24.2 and 28.30 ± 0.20 2Θ°. A few further characterizing XRPD diffraction angle peaks include 14.90, 15.20, 20.50, 25.10 and 27.5 ± 0.20 2Θ°. Crystalline Pemetrexed dipotassium hemiheptahydrate (I) Form- SP 1 is further characterized by DSC isotherm comprising at least three endothermic peaks ranging between- a. Peak -1- Between 65 to 85°C

b. Peak -2- Between 86 to 105°C

c. Peak -3- Between 120 to 132°C

d. Peak -4- Between 250 to 265°C

The characteristic peaks and their d spacing values of the novel Crystalline Pemetrexed dipotassium hemiheptahydrate (I) Form- SP 1 for a particular batch material are tabulated in the Table- 1.

20 21.38 4.153

21 21.73 4.086

22 22.01 4.036

23 22.38 3.970

24 22.68 3.918

25 23.05 3.855

26 23.21 3.829

27 23.67 3.755

28 24.17 3.679

29 25.122 3.54189

30 25.597 3.47724

31 26.191 3.39979

32 26.369 3.37717

33 26.833 3.31987

34 27.524 3.23805

35 28.361 3.14437

36 29.377 3.03785

37 30.197 2.95723

38 30.959 2.88613

39 31.704 2.82007

40 31.921 2.80133

41 32.992 2.71282

42 34.174 2.62166

43 35.798 2.50634

44 40.522 2.22441

Table-1 : Characteristic XRPD Peaks of Crystalline Pemetrexed dipotassium

hemiheptahydrate (T) Form- SP1 In another embodiment, Crystalline Pemetrexed dipotassium hemiheptahydrate (I) Form- SP1, which has an IR absorption spectrum having characteristic peaks expressed in cm^"1 at approximately 2936 cm^"1, 2857 cm^"1, 1396 cm^"1, 1 184 cm^"1, 1 158 cm^"1, 1092 cm^"1, 1076 cm^"1, 819 cm^"1 and 788 cm^"1.

Crystalline Pemetrexed dipotassium hemiheptahydrate (I) Form- SP 1 of the present invention is characterized by X-ray powder diffraction pattern substantially according to Fig-1, DSC isothermal pattern substantially according to Fig-2 and IR absorption spectrum substantially according to Fig-3.

Minor variations in the observed 2 θ° angles values may be expected based on the analyst, the specific XRPD diffractometer employed and the sample preparation technique. Further possible variations may also be expected for the relative peak intensities, which may be largely affected by the non-uniformity of the particle size of the sample. Hence, identification of the exact crystalline form of a compound should be based primarily on observed 2 theta angles with lesser importance attributed to relative peak intensities. The 2 theta diffraction angles and corresponding d-spacing values account for positions of various peaks in the X-ray powder diffraction pattern. D-spacing values are calculated with observed 2 theta angles and copper K a wavelength using the Bragg equation well known to those of having skill in the art of XRPD diffractometry science. In view of possibility of marginal error in the assigning 2 theta angles and d-spacing, the preferred method of comparing X-ray powder diffraction patterns in order to identify a particular crystalline form is to overlay the X-ray powder diffraction pattern of the unknown form over the X-ray powder diffraction pattern of a known form. For example, one skilled in the art can overlay an X-ray powder diffraction pattern of an unidentified crystalline form of Pemetrexed dipotassium hemiheptahydrate over FIG. 1 and readily determine whether the X-ray diffraction pattern of the unidentified form is substantially the same as the X-ray powder diffraction pattern of the crystalline form of this invention. If the X-ray powder diffraction pattern is substantially the same as FIG. 1, the previously unknown crystalline form of Pemetrexed dipotassium hemiheptahydrate can be readily and accurately identified as the crystalline Form SP1 of this invention.

The crystalline Form-SPl of Pemetrexed dipotassium is a hemiheptahydrate, which is evident from the Fig-3 i.e. the DSC thermogram. A sample of the crystalline Form SP1 prepared by the inventors of this application showed moisture content up to about 1 1.2% w/w by KF method, which also confirms the hemiheptahydrate (theoretical water content as calculated 1 1.12% w/w) nature of the compound. While the invention is not limited to any specific theory, it should be understood however that the crystalline form SP1 of Pemetrexed dipotassium may contain additional residual or unbound moisture without losing its hemiheptahydrate character and/or its hemiheptahydrate crystalline form-SPl characteristics. Nevertheless, person having skill in the art should be able to determine whether they are same crystalline forms or not, by looking at the overall shape of the X-ray powder diffraction pattern optionally with help of other thermal data like DSC or TGA. In yet another embodiment of the present invention, it provide process/es for preparing Crystalline Pemetrexed dipotassium hemiheptahydrate (I) Form- SP1 characterized by X-ray powder diffraction pattern comprising at least 5 characteristic 29°peaks selected from the XRPD peak set of 5.00, 13.70, 14.90, 15.20, 16.90, 20.00, 20.50, 21.40, 23.6, 24.2, 25.10, 27.5 and 28.30 ± 0.20 29°, DSC isotherm comprising the endothermic peaks ranging between 65 to 85°C (Peak -1), 86 to 105°C (Peak -2), 120 to 132°C (Peak -3), 250 to 265°C (Peak -4), and IR absorption characteristic peaks at approximately 2936 cm^"1, 2857 cm^"1, 1396 cm^"1, 1 184 cm^"1, 1 158 cm^"1, 1092 cm^"1, 1076 cm^"1, 819 cm^"1 and 788 cm^"1 comprising the steps of- a. combining N-[4-[2-(2-amino-4,7-dihydro-4-oxo-lH-pyrrolo[2,3-d]pyrimidin-5- yl) ethyl] benzoyl] -L-glutamic dipotassium with water or aqueous organic solvent mixture at temperature ranging between 15-30 deg C.

b. optionally filtering the solution

c. cooling the solution or filtrate upto 0-10°C

d. adding aliphatic alcohol solvent within 30-120 minutes

e. optionally raising the temperature between to 20-35°C under stirring

f. stir and maintain the reaction mass for time upto 1-4 hours

g. filtering and isolating the crystalline material

2. Drying the crystalline material under vacuum

3. Recovering the Crystalline Pemetrexed dipotassium hemiheptahydrate having purity greater than 99.2% w/w and water content in the range between 9.5 to 12.0% w/w Step of combining N-[4-[2-(2-amino-4,7-dihydro-4-oxo-lH-pyrrolo[2,3-d]pyrimidin-5-yl) ethyl] benzoyl] -L-glutamic dipotassium with water or aqueous organic solvent mixture at temperature ranging between 15-30 deg C comprise either mixing or suspending or making solution of Pemetrexed dipotassium obtained by any process /any form with DM water or freshly prepared/already prepared aqueous organic solvent mixture in appropriate proportions (containing predominately water i.e. alteast > 50% water). Water miscible organic solvents, are selected from but not limited to ketone, alcohol solvent, DMF or DMSO. In the process of preparing mixed solvent solution, alcohol solvent is selected from C 1 to C5 alcohol and ketone solvent may be selected from C3 to CIO ketone.

During combining Pemetrexed dipotassium with a water or aqueous organic solvent mixture, ratio of Pemetrexed dipotassium w.r.t. water or aqueous organic solvent mixture is important in order to obtain the specifics of the crystalline polymorph to meet, which comprise a range between 1 : 3-8 (w/v). More preferably, this range may be 1 : 4 (w/v).

Any form of Crude or Pure Pemetrexed dipotassium salt obtained by any process may be used for preparing Form-SPl . The solution may be optionally filtered through hyflow bed or any similar silica based material. As per requirement, other known techniques of filtration for e.g. filtering through micron filter paper may also be used. In the step of cooling the solution or filtrate in the range about 0- 10°C, it is preferred to cool the solution gradually followed by continued stirring of the solution at same temperature up to a time ranging between 15 to 60 minutes.

In step of adding aliphatic alcohol solvent, it comprises slow addition of alcohol solvent, wherein addition is preferably completed within 30-120 minutes time. After combining this alcohol mixture, the solution may optionally be maintained under stirring for a time ranging between 10- 60 minutes in order to retain the desired hemiheptahydrate level with unreacted Pemetrexed dipotassium present if any. The temperature of the reaction mass may be optionally raised to about 20-35°C as per need to attain the crystalline material precipitated out with no or minimal possible degradation if any. Simultaneously, it is also essentially required to cool the solution in the successive lower rate of cooling in order to retain the characteristics of Form-SPl, while achieving the pure crystal formation. The process related impurities, including unreacted intermediates, side products, degradation products and other medium dependent impurities, that appears in the impurity profile of the Pemetrexed dipotassium hemiheptahydrate can substantially be removed by the process of the present invention resulting in the formation pure crystalline form-SPl. A substantially pure product having purities more than 99.2% (by HPLC) can be obtained by the process of the present invention. In view of maintaining the equilibrium to the impurity profile compliance, the process requires quality checks, while raising the temperature, wherever required up to 20-35°C.

Inventors of the present application also observed during the ongoing experimentation that initially the crystalline product obtained shows XRPD pattern slightly different from the XRPD pattern of Form-SPl . This was, in fact confirmed as another polymorphic form, which is designated hereinafter as Form-SP2. It was further confirmed by inventors during experimentation, that said form is a metastable and transitory form, which on storage for about a week at temperature below 20 °C, eventually gets converted to the more stable polymorphic form i.e. Form-SPl . Polymorphic Form-SP2 of Pemetrexed dipotassium hemiheptahydrate is characterized by presence of one or more additional characteristic 29° diffraction angle XRPD peaks at 5.5, 8.2, 9.4, 12.6, 13.4, 14.7, 15.0, 17.3, 24.9 and 28.0 ± 0.20 2Θ°, besides the presence of characteristic peaks of Form-SPl (Fig. 5). More particularly peaks present at 5.5, 8.2, 24.8 and 28.0 ± 0.20 29° appear to provide distinction of metastable Form-SP2 with respect to Stable Form-SPl .

During stability studies, it was observed that, the additional peaks present in the XRPD pattern of Form-SP2, start re-appearing at the above ambient temperatures - particularly above the temperatures of ~ 25 °C. At lower temperature of 10 °C and below, Form-SPl of Pemetrexed dipotassium hemiheptahydrate retains its characteristic XRPD pattern. It was also observed that while storing for prolong durations above the ambient temperature of ~ 25 °C - the Form-SP2 starts rapidly changing towards amorphous characteristics and XRPD sharp peaks start disappearing from the XRPD pattern of crystalline Form-SP2. Thus, Pemetrexed dipotassium hemiheptahydrate exists as a stable polymorphic Form- SP1 at temperature below 10 °C or any temperatures below 20°C. When exposed to moisture and higher temperatures like 25 °C or above Form- SP1 gets converted to Form-SP2. Due to phenomenon of hydration, dehydration and rehydration, Form SP1 and Form SP2 of Pemetrexed dipotassium hemiheptahydrate may get reversibly converted into each other, depending upon the storage temperature and relative humidity parameters. In one embodiment of the present invention, any reference to Form-SPl of Pemetrexed dipotassium hemiheptahydrate shall be construed to cover Form-SP2 as well.

The product may be isolated from the reaction mass by conventional processes including filtering and optional drying, which may be carried out at room temperature for the suitable durations to retain the crystalline polymorphic form characteristics. Crystalline Form-SPl can be recovered by conventional processes, which are not limited to scrapping, breaking, triturating and if required conventional drying. Crystalline Pemetrexed dipotassium hemiheptahydrate (I) Form-SPl obtained according to present invention may be dried under vacuum to attain water content in the range between 9.5 to 12.0 % w/w. Crystalline Pemetrexed dipotassium hemiheptahydrate (I) Form-SPl of the present invention may have one or more advantageous and desirable properties compared to the known Crystalline Pemetrexed disodium salt, which are not limited to better stability, solubility and quality parameter leading to improved storage and distribution.

The Crystalline Pemetrexed dipotassium hemiheptahydrate (I) Form-SPl described herein is characterized by X-ray powder diffraction pattern (XRPD) and IR absorption spectra and Thermal techniques such as differential scanning calorimetric (DSC) Analysis and TGA. The samples of Crystalline Pemetrexed dipotassium hemiheptahydrate (I) Form-SPl were analyzed by XRPD on a Bruker AXS D8 Advance Diffractometer using X-ray source - Cu Ka radiation using the wavelength 1.5418 A, however, DSC analysis were carried out on a Perkin Elmer Jade instrument and TGA analysis were carried out on Perkin Elmer Pyris 1.0 instrument. Illustrative examples of analytical data for the Crystalline Pemetrexed dipotassium hemiheptahydrate (I) Form-SPl obtained in the Examples are set forth in the Figs. 1-4.

In yet further embodiment, it provides that the Crystalline Pemetrexed dipotassium hemiheptahydrate (I) Form-SPl obtained by the processes of the present application may be formulated as lyophilized powder composition as injectable or solid compositions for oral administration in the form of capsules, tablets, pills, powders or granules useful in the treatment of hyper-proliferative disorders, such as cancer. In these compositions, the active product is mixed with one or more pharmaceutically acceptable excipients. The drug substance can be formulated as liquid compositions for oral administration including solutions, suspensions, syrups, elixirs and emulsions, containing solvents or vehicles such as water, sorbitol, glycerine, propylene glycol or liquid paraffin.

The compositions for parenteral administration can be lyophilized powder, suspensions, emulsions or aqueous or non-aqueous sterile solutions. In a particular embodiment of the present invention, a process for preparing lyophilized pharmaceutical composition of Crystalline Pemetrexed dipotassium hemiheptahydrate (I) Form-SPl comprising the steps of-

1. Combining Water for injection purged with nitrogen with Mannitol,

2. Stirring the solution until clear

3. Adding crystalline Pemetrexed dipotassium hemiheptahydrate SP1 and stirring for about

5- 30 min

4. Adjusting the pH ranging between 6.5 and 8.5 using diluted aqueous Sodium hydroxide/ Hydrochloric acid solution

5. Making up the volume with water for injection

6. Filtering through micron filter ( ~ 0.2μ ) and filling the vials

7. Loading into Lyophilizer with freezing cycle temperature ranging between -15 to -40 °C for 60 to 240 minutes.

8. After lyophilization fully stoppering the vials and sealing with aluminium flip-off seals. In other compositions, as a solvent or vehicle, propylene glycol, polyethylene glycol, vegetable oils, especially olive oil, and injectable organic esters, e.g. ethyl oleate, may be employed. These compositions can contain adjuvants, especially wetting, emulsifying and dispersing agents. The sterilization may be carried out in several ways, e.g. using a bacteriological filter, by incorporating sterilizing agents in the composition, by irradiation or by heating. They may be prepared in the form of sterile compositions, which can be dissolved at the time of use in sterile water or any other sterile injectable medium.

Pharmaceutically acceptable excipients used in the compositions comprising Crystalline Pemetrexed dipotassium hemiheptahydrate (I) Form-SPl of the present application include, but are but not limited to diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, pre-gelatinized starch and the like; disintegrants such as starch, sodium starch glycolate, pregelatinized starch, Croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants, waxes and the like. Other pharmaceutically acceptable excipients that are of use include but not limited to film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants and the like.

Pharmaceutically acceptable excipients used in the compositions derived from Crystalline Pemetrexed dipotassium hemiheptahydrate (I) Form-SPl of the present application may also comprise to include the pharmaceutically acceptable carrier used for the preparation of solid dispersion, wherever utilized in the desired dosage form preparation.

Certain specific aspects and embodiments of the present application will be explained in more detail with reference to the following examples, which are provided by way of illustration only and should not be construed as limiting the scope of the invention in any manner.

EXPERIMENTAL DETAILS

The preparation of Crystalline Pemetrexed dipotassium hemiheptahydrate (I) Form-SPl according to process of the present invention may be demonstrated by examples as given below. Example-1

Preparation of N-[4-[2-(2-amino-4,7-dihydro-4-oxo-lH-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl] benzoyl] -L-glutamic diacid dipotassium salt (Pemetrexed dipotassium hemiheptahydrate)

The process for preparing pemetrexed dipotassium salt comprise of two steps-

Step- 1 : Pemetrexed dimethyl ester

To a mixture of 4-(2-(2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5- yl)ethyl)benzoic acid (200 g, 0.67 mol) and 2-chloro-4,6-dimethoxy-l,3,5-triazine (129.4 g g, 0.74 mol) in dimethylformamide was added N-methylmorpholine (203.46 g, 2.01 mol) at 0-5 °C under stirring and the mixture was stirred at 0-5 °C for 1 ₂ hour. Added slowly the solution of L- glutamic acid dimethylester hydrochloride (206.0 g, 0.97 mol) in dimethylformamide at 0-5 °C under stirring and the mixture maintained at 25-30 °C for 2-3 hours, when the reaction was found to be complete. The reaction mixture was poured into 4000 ml of DM water followed by addition of potassium bicarbonate and dichloromethane. The dichloromethane layer separated and washed successively two times with water (4 L each). The dichloromethane layer was evaporated to dryness under reduced pressure. The residue was dissolved in isopropyl alcohol (1L) at 80-85 °C under stirring. Cooled the dissolved solution slowly to rt under stirring. The mass was stirred at rt for 3-4 hours and solid was filtered, washed with isopropyl alcohol (200 ml) and dried to give the title compound (200 g, 65.5%) with purity of 98.56%.

Step-2: Pemetrexed dipotassium hemiheptahydrate

To a mixture of N-[4-[2-(2-amino-4,7-dihydro-4-oxo-lH-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl] benzoyl] -L-glutamic dimethylester (50.0 g, O. l lmol) and dichloromethane (500 ml) was added slowly aqueous solution of 18.47 g of potassium hydroxide in 200 ml of DM water at 0-5 °C under stirring and the mixture was continued to stir at 0-5 °C for 1 hour after complete addition. Dichloromethane layer was separated. Fresh dichloromethane (100 ml) was added to aqueous layer and separated after 15 min stirring and settling each. Dichloromethane layer is separated. pH of aqueous layer was adjusted to 7.5 - 8.5 by using 50% hydrochloric acid solution. Activated carbon (5.0 g) is added to reaction mass and stirred for 15 min. Reaction mass filtered and residue washed with 50 ml of DM water. Cool the filtrate to 0- 10°C under stirring. Add slowly the filtered ethanol (1.2L) within 60-80 minutes at 0- 10°C under stirring. Temperature is raised to 20-25°C slowly under stirring and maintained for 3-4 hours at 20-25°C. Solid filtered, washed with ethyl alcohol (50 ml) and dried to give the title compound.

Yield: 22 g, 39.79%

HPLC purity: 99.28%.

Moisture content (by KF): 1 1.14%

Example-2:

Preparation of crystalline Pemetrexed dipotassium hemiheptahydrate (I) Form-SPl

N-[4-[2-(2-amino-4,7-dihydro-4-oxo-lH-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl] benzoyl]-L- glutamic dipotassium (20.0 g) was dissolved in DM water (80 ml) under stirring at rt and filtered through hyflow bed. Cool the filtrate to 0- 10°C under continuous stirring. Add slowly the filtered ethanol (320 ml) within 60-80 minutes at 0-10°C under stirring. Temperature is raised to 20- 25°C slowly under stirring and maintained for 3-4 hours at 20-25°C. Solid material obtained was then filtered, washed with ethyl alcohol (40 ml) and dried to obtain the title compound.

Yield: 15 g, 75.0%

Purity (by HPLC): 99.53% Water content (by KF): 1 1.00%

Example-3:

Preparation of crystalline Pemetrexed dipotassium hemiheptahydrate (I) Form-SPl

160 ml of DM water and 40 g of N-[4-[2-(2-amino-4,7-dihydro-4-oxo-lH-pyrrolo[2,3- d]pyrimidin-5-yl)ethyl] benzoyl] -L-glutamic dipotassium were charged into a one liter reaction flask at rt. The reaction mixture was stirred for 15 minutes to make clear solution, which was then filtered through micron filter paper. The filtrate obtained was transferred to a clean reaction flask and cooled to 0-5°C under stirring. At same temperature, 560 ml of ethanol was added drop-wise within 45-60 mins to the reaction mixture, under stirring. Stirring was continued for 3 hours. The compound obtained was filtered and suck dried for 10 minutes, followed by washing with 80 ml of chilled ethanol. The obtained wet solid material was then suck dried for 30 minutes, followed by vacuum drying at 40-45°C for 12-14 hours, to obtain the title compound.

Yield: 32 g, 80.0 %

Purity (by HPLC): 99.78%

Water content (by KF): 10.90 % The abovementioned examples, which are provided by way of illustration, should not be construed as limiting the scope of the invention with respect to parameter/s, ingredient/s and quantities used in any manner.

Literature, references, including publications, issued patents and patent applications, cited in the specification are hereby incorporated by reference to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein.

Usage of the terms "a" and "an" and "the" and similar referents in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The terms "comprising," "having," "including," and "containing" are to be construed as open-ended terms (i.e., meaning "including, but not limited to,") unless otherwise noted. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. The term wt % refers to percent by weight. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples or exemplary language (e.g. "such as") provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

Preferred embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Variations of those preferred embodiments may become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

Claims

CLAIMS im: Crystalline Pemetrexed dipotassium hemiheptahydrate (I) Form-SPl characterized by X- ray powder diffraction pattern comprising at least 5 characteristic 20° diffraction angle peaks selected from the XRPD peak set of 5.00, 13.70, 16.90, 20.00, 21.40, 23.6, 24.2 and 28.30 + 0.20 2Θ°. Crystalline Pemetrexed dipotassium hemiheptahydrate (I) Form-SPl according to claim- 1, further characterized by XRPD diffraction angles at 14.90, 15.20, 20.50, 25.10 and 27.5 + 0.20 2Θ0. Crystalline Pemetrexed dipotassium hemiheptahydrate (I) Form-SPl according to claim- 1 , which is further characterized by DSC isotherm comprising at least three endothermic peaks ranging ; between- a. Peak -1- Between 65 to 85°C b. Peak -2- Between 86 to 105°C c. Peak -3- Between 120 to 132°C d. Peak -4- Between 250 to 265°C 4) . Crystalline Pemetrexed dipotassium hemiheptahydrate (I) Form-SPl according to claim-1, which has an IR absorption spectrum having characteristic peaks expressed in cm"1 at approximately 2936 cm"1, 2857 cm"1, 1396 cm"1, 1184 cm"1, 1158 cm"1, 1092 cm"1, 1076 cm"1, 819 cm"1 and 788 cm"1. 5) . Crystalline Pemetrexed dipotassium hemiheptahydrate (I) Form-SPl characterized by X- ray powder diffraction pattern comprising at least 5 characteristic 20°peaks selected from the XRPD peak set of 5.00, 13.70, 14.90, 15.20, 16.90, 20.00, 20.50, 21.40, 23.6, 24.2, 25.10, 27.5 and 28.30 + 0.20 20°, DSC isotherm comprising the endothermic peaks ranging between 65 to 85°C (Peak -1), 86 to 105°C (Peak -2), 120 to 132°C (Peak -3), 250 to 265°C (Peak -4), and IR absorption characteristic peaks at approximately 2936 cm" 2857 cm"1, 1396 cm"1, 1184 cm"1, 1158 cm"1, 1092 cm"1, 1076 cm"1, 819 cm"1 and 788 cm -1. 6) . Crystalline Pemetrexed dipotassium hemiheptahydrate (I) Form-SPl according to claim 1 characterized by water content (by KF) in the range between 9.5 to 12.0% w/w. 7) . Crystalline Pemetrexed dipotassium hemiheptahydrate (I) according to claim -1, characterized by X-ray powder diffraction pattern substantially according to Fig-1, DSC isothermal pattern substantially according to Fig-2 and IR absorption spectrum substantially according to Fig-3 . 8) . A process for preparing Crystalline Pemetrexed dipotassium hemiheptahydrate (I) characterized by X-ray powder diffraction pattern comprising at least 5 characteristic 20° peaks selected from the XRPD peak set of 5.00, 13.70, 14.90, 15.20, 16.90, 20.00, 20.50, 21.40, 23.6, 24.2, 25.10, 27.5 and 28.30 + 0.20 20°, DSC isotherm comprising the endothermic peaks ranging between 65 to 85°C (Peak -1), 86 to 105°C (Peak -2), 120 to 132°C (Peak -3), 250 to 265 °C (Peak -4), and IR absorption characteristic peaks at approximately 2936 cm"1, 2857 cm"1, 1396 cm"1, 1184 cm"1, 1158 cm"1, 1092 cm"1, 1076 cm"1, 819 cm"1 and 788 cm"1 comprising the steps of- a. combining N-[4-[2-(2-amino-4,7-dihydro-4-oxo-lH-pyrrolo[2,3-d]pyrimidin-5- yl) ethyl] benzoyl] -L-glutamic dipotassium with water or aqueous organic solvent mixture at temperature ranging between 15-30 deg C. b. optionally filtering the solution c. cooling the solution or filtrate upto 0-10°C d. adding aliphatic alcohol solvent within 30-120 minutes e. optionally raising the temperature between to 20-35 °C under stirring f. stirring and maintaining the reaction mass for time upto 1-4 hours g. filtering and isolating the crystalline material 9) . A process for preparing Crystalline Pemetrexed dipotassium hemiheptahydrate (I) according to claim 8, wherein aqueous organic solvent mixture comprises of water miscible solvents selected from alcohol (CI to C5), ketone (C3-C10), DMF or DMSO or water. 10) . A process for preparing Crystalline Pemetrexed dipotassium hemiheptahydrate (I) according to claim 8, wherein step g. of filtering and isolating the crystalline material comprises the steps of-

2. Drying the crystalline material under vacuum

11) . A process for preparing Crystalline Pemetrexed dipotassium hemiheptahydrate (I) according to claim 8, wherein aliphatic alcohol solvent is selected from CI to C5 alcohol.

12) . A pharmaceutical composition comprising Crystalline Pemetrexed dipotassium hemiheptahydrate (I) according to claim- 1 and a pharmaceutically acceptable excipient, diluent, or carrier.