DESC:FIELD OF THE INVENTION

The present invention relates to liquid bendamustine parenteral compositions and the process for preparation thereof. The present invention also relates to liquid bendamustine hydrochloride pharmaceutical composition comprising (i) bendamustine hydrochloride, (ii) a pharmaceutically acceptable solvent system consisting of diethylene glycol monoethyl ether, and a (iii) pH adjusting agent.

BACKGROUND OF THE INVENTION

Bendamustine hydrochloride is an alkylating agent and is structurally represented as

Bendamustine hydrochloride is used in the treatment of a number of cancers including leukemia’s, Hodgkin’s disease and multiple myelomas. Bendamustine HCl is the active ingredient of the commercial product TreandaTM, a lyophilized powder 25mg/Vial & 100mg/Vial for reconstitution; BendekaTM, a ready to dilute solution 100mg/4mL (25mg/mL) in a multiple-dose clear glass vial and BelrapzoTM, a ready to dilute solution 100mg/4mL (25mg/mL) in a multiple-dose clear glass vial. TreandaTM lyophilized injection is intended for intravenous infusion over a period of 30 minutes after reconstitution with sterile water for injection and after further dilution with either 0.9% sodium chloride injection or 2.5% dextrose/0.45% sodium chloride injection; and each vial of 25mg and 100mg contains bendamustine hydrochloride and mannitol. BendekaTM, is a ready to dilute solution intended for intravenous infusion over a period of 10 minutes after dilution into 50mL of 0.9% saline, or 0.45% saline/2.5% dextrose or 5% dextrose; and each milliliter contains 25mg of bendamustine hydrochloride, 0.1mL of propylene glycol, 5mg of monothioglycerol in polyethylene glycol 400, sodium hydroxide may have been used to adjust the acidity of polyethylene glycol 400. BelrapzoTM is intended for intravenous infusion over a period of 30 minutes after dilution with 0.9% sodium chloride injection, USP, or 2.5% dextrose/0.45% sodium chloride injection; and each milliliter of the injection contains 25 mg of bendamustine hydrochloride, 0.1 mL of propylene glycol, 5 mg of monothioglycerol, NF and q.s. to 1 mL polyethylene glycol 400, NF.

US Patent No. 8,436,190 discloses the lyophilized pharmaceutical compositions of bendamustine.

US Patent No. 8,344,006 discloses stable, non-aqueous liquid formulations comprising bendamustine solubilized in dimethyl acetamide and propylene glycol.

US Patent No. 8,609,707 discloses a bendamustine HCl liquid formulation is prepared by solubilizing the drug in polyethylene glycol (PEG) and propylene glycol (PG). The patent discloses that the stability of the resulting formulation is improved by adding an antioxidant.

US Patent No. 9,603,930 discloses a stable liquid pharmaceutical composition comprising bendamustine hydrochloride, and a pharmaceutically acceptable solvent system comprising N, N-dimethyl acetamide and glycerin, wherein the pharmaceutically acceptable solvent system comprises about 5% (v/v) of glycerin to about 15% v/v of glycerin.

US Publication No. 2017/0304451 A1 discloses a ready to use parenteral composition comprising bendamustine hydrochloride, diethylene glycol monoethyl ether, and a polar solvent selected from N-methyl-2-pyrrolidone.

There exists a need for liquid bendamustine hydrochloride formulations which have better stability and impurity profiles than the liquid bendamustine formulations currently available.

SUMMARY OF THE INVENTION

The present invention provides a novel liquid bendamustine hydrochloride formulation with good stability and impurity profile, which is particularly suitable for long term storage, wherein the formulation is free of antioxidants.

In embodiments of the invention, the present invention provides a stable liquid bendamustine pharmaceutical composition comprising: (i) bendamustine, a pharmaceutically acceptable salt, and/or a hydrate thereof, (ii) diethylene glycol monoethyl ether, and (iii) a pH adjusting agent.

In another embodiment of the invention, the present invention provides the liquid bendamustine hydrochloride pharmaceutical composition comprising (i) bendamustine hydrochloride, (ii) a pharmaceutically acceptable solvent system consisting of diethylene glycol monoethyl ether, and (iii) a pH adjusting agent.

In still another embodiment of the invention, the present invention provides the stable liquid bendamustine pharmaceutical composition comprising: (i) bendamustine, a pharmaceutically acceptable salt, and/or a hydrate thereof, (ii) diethylene glycol monoethyl ether, and (iii) a pH adjusting agent, wherein the pharmaceutical composition is free of antioxidants.

In a further embodiment, the present invention provides the liquid bendamustine hydrochloride pharmaceutical composition comprising (i) bendamustine hydrochloride, (ii) a pharmaceutically acceptable solvent system consisting of diethylene glycol monoethyl ether, and (iii) a pH adjusting agent, wherein the pharmaceutical composition is free of antioxidants.
In another embodiment, the present invention provides the stable liquid bendamustine pharmaceutical composition comprising: (i) bendamustine, a pharmaceutically acceptable salt, and/or a hydrate thereof, (ii) diethylene glycol monoethyl ether, and (iii) a pH adjusting agent, wherein the pH of the pharmaceutical composition is of about 3.0 to about 4.0.

In a further embodiment, the present invention provides the liquid bendamustine hydrochloride pharmaceutical composition comprising (i) bendamustine hydrochloride, (ii) diethylene glycol monoethyl ether and (iii) a pH adjusting agent, wherein the pH of the pharmaceutical composition is of about 3.0 to about 4.0.

In a still further embodiment, the present provides the stable liquid bendamustine pharmaceutical composition comprising: (i) bendamustine, a pharmaceutically acceptable salt, and/or a hydrate thereof, (ii) diethylene glycol monoethyl ether, and (iii) a pH adjusting agent, wherein the pH of the pharmaceutical composition is of about 3.0 to about 4.0 and wherein the pharmaceutical composition is free of antioxidants.

In embodiments of the present invention, the invention provides a stable liquid bendamustine pharmaceutical composition comprising: (i) about 25 mg/ml of bendamustine hydrochloride, (ii) diethylene glycol monoethyl ether, (iii) about 0.25 mg/ml of sodium hydroxide, wherein the pH of the pharmaceutical composition is of about 3.0 to about 4.0.

In further embodiments of the present invention, the invention provides a stable liquid bendamustine pharmaceutical composition comprising: (i) about 25 mg/ml of bendamustine hydrochloride, (ii) diethylene glycol monoethyl ether, (iii) about 0.25 mg/ml of sodium hydroxide, wherein the pH of the pharmaceutical composition is of about 3.0 to about 4.0 and wherein the pharmaceutical composition is free of antioxidants.

In another embodiment, the present invention provides the stable liquid bendamustine pharmaceutical composition comprising: (i) about 25 mg/ml of bendamustine hydrochloride, (ii) diethylene glycol monoethyl ether, (iii) about 0.25 mg/ml of sodium hydroxide, and (iv) hydrochloric acid, wherein the pH of the pharmaceutical composition is of about 3.0 to about 4.0.

In a still further embodiment, the present invention provides the stable liquid bendamustine pharmaceutical composition comprising: (i) about 25 mg/ml of bendamustine hydrochloride, (ii) diethylene glycol monoethyl ether, (iii) about 0.25 mg/ml of sodium hydroxide, and (iv) hydrochloric acid, wherein the pH of the pharmaceutical composition is of about 3.0 to about 4.0 and wherein the pharmaceutical composition is free of antioxidants.

In a further embodiment, the present invention provides the stable liquid bendamustine pharmaceutical composition consisting of: (i) about 25 mg/ml of bendamustine hydrochloride, (ii) diethylene glycol monoethyl ether, (iii) about 0.25 mg/ml of sodium hydroxide, and (iv) hydrochloric acid, wherein the pH of the pharmaceutical composition is of about 3.0 to about 4.0.

In a still further embodiment, the present invention provides the stable liquid bendamustine pharmaceutical composition consisting of: (i) about 25 mg/ml of bendamustine hydrochloride, (ii) diethylene glycol monoethyl ether, (iii) about 0.25 mg/ml of sodium hydroxide, and (iv) hydrochloric acid, wherein the pH of the pharmaceutical composition is of about 3.0 to about 4.0 and wherein the pharmaceutical composition is free of antioxidants.

In a specific embodiment, the present invention relates to the liquid bendamustine hydrochloride pharmaceutical composition consisting of (i) about 25 mg/ml of bendamustine hydrochloride, (ii) a pharmaceutically acceptable solvent system consisting of diethylene glycol monoethyl ether, (iii) about 0.25 mg/ml of sodium hydroxide, and (iv) hydrochloric acid to adjust the pH, wherein the pH of the pharmaceutical composition is of about 3.0 to about 4.0.

In a further specific embodiment, the present invention relates to the liquid bendamustine hydrochloride pharmaceutical composition consisting of (i) about 25 mg/ml of bendamustine hydrochloride, (ii) a pharmaceutically acceptable solvent system consisting of diethylene glycol monoethyl ether, (iii) about 0.25 mg/ml of sodium hydroxide, and (iv) hydrochloric acid to adjust the pH; wherein the pH of the pharmaceutical composition is of about 3.0 to about 4.0 and wherein the pharmaceutical composition is free of antioxidants.

Further the stable liquid bendamustine formulation have the individual impurity less than 1.0% and total impurities less than 2.0% of total impurities after 6 months storage at 2 - 8°C.

BRIEF DESCRIPTION OF THE INVENTION

The present invention provides a liquid bendamustine pharmaceutical composition comprising bendamustine, a pharmaceutically acceptable salt, and/or hydrate thereof, and a pharmaceutically acceptable solvent system consisting of diethylene glycol monoethyl ether, wherein the pharmaceutical composition is free of antioxidants.

As used herein in connection with numerical values, the terms “about” mean +/- 5% of the indicated value, including the indicated value.

Bendamustine hydrochloride is the most preferably used salt in the present invention. Bendamustine hydrochloride is present in the concentration of about 10 mg/mL to about 100 mg/mL, more preferably of about 20 mg/mL to about 60 mg/mL and most preferably of about 25 mg/mL based on the weight of the pharmaceutical composition.

In embodiments of the invention, the solvent system consists of diethylene glycol monoethyl ether.

The present invention provides a stable liquid bendamustine pharmaceutical composition comprising: (i) bendamustine, a pharmaceutically acceptable salt, and/or a hydrate thereof, (ii) diethylene glycol monoethyl ether, and (iii) a pH adjusting agent.

The pH adjusting agents used in the present invention are selected from group consisting of sodium hydroxide and hydrochloric acid.

In another embodiment of the invention, the present invention provides the liquid bendamustine hydrochloride pharmaceutical composition comprising (i) bendamustine hydrochloride, (ii) a pharmaceutically acceptable solvent system consisting of diethylene glycol monoethyl ether, and (iii) a pH adjusting agent.

In still another embodiment of the invention, the present invention provides the stable liquid bendamustine pharmaceutical composition comprising: (i) bendamustine, a pharmaceutically acceptable salt, and/or a hydrate thereof, (ii) diethylene glycol monoethyl ether, and (iii) a pH adjusting agent, wherein the pharmaceutical composition is free of antioxidants.

In a further embodiment, the present invention provides the liquid bendamustine hydrochloride pharmaceutical composition comprising (i) bendamustine hydrochloride, (ii) a pharmaceutically acceptable solvent system consisting of diethylene glycol monoethyl ether, and (iii) a pH adjusting agent, wherein the pharmaceutical composition is free of antioxidants.

In another embodiment, the present invention provides the stable liquid bendamustine pharmaceutical composition comprising: (i) bendamustine, a pharmaceutically acceptable salt, and/or a hydrate thereof, (ii) diethylene glycol monoethyl ether, and (iii) a pH adjusting agent, wherein the pH of the pharmaceutical composition is of about 3.0 to about 4.0.

In a further embodiment, the present invention provides the liquid bendamustine hydrochloride pharmaceutical composition comprising (i) bendamustine hydrochloride, (ii) diethylene glycol monoethyl ether and (iii) a pH adjusting agent, wherein the pH of the pharmaceutical composition is of about 3.0 to about 4.0.

In a still further embodiment, the present provides the stable liquid bendamustine pharmaceutical composition comprising: (i) bendamustine, a pharmaceutically acceptable salt, and/or a hydrate thereof, (ii) diethylene glycol monoethyl ether, and (iii) a pH adjusting agent, wherein the pH of the pharmaceutical composition is of about 3.0 to about 4.0 and wherein the pharmaceutical composition is free of antioxidants.

In embodiments of the present invention, the invention provides a stable liquid bendamustine pharmaceutical composition comprising: (i) about 25 mg/ml of bendamustine hydrochloride, (ii) diethylene glycol monoethyl ether, (iii) about 0.25 mg/ml of sodium hydroxide, wherein the pH of the pharmaceutical composition is of about 3.0 to about 4.0.

In further embodiments of the present invention, the invention provides a stable liquid bendamustine pharmaceutical composition comprising: (i) about 25 mg/ml of bendamustine hydrochloride, (ii) diethylene glycol monoethyl ether, (iii) about 0.25 mg/ml of sodium hydroxide, wherein the pH of the pharmaceutical composition is of about 3.0 to about 4.0 and wherein the pharmaceutical composition is free of antioxidants.

In another embodiment, the present invention provides the stable liquid bendamustine pharmaceutical composition comprising: (i) about 25 mg/ml of bendamustine hydrochloride, (ii) diethylene glycol monoethyl ether, (iii) about 0.25 mg/ml of sodium hydroxide, and (iv) hydrochloric acid, wherein the pH of the pharmaceutical composition is of about 3.0 to about 4.0.

In a still further embodiment, the present invention provides the stable liquid bendamustine pharmaceutical composition comprising: (i) about 25 mg/ml of bendamustine hydrochloride, (ii) diethylene glycol monoethyl ether, (iii) about 0.25 mg/ml of sodium hydroxide, and (iv) hydrochloric acid, wherein the pH of the pharmaceutical composition is of about 3.0 to about 4.0 and wherein the pharmaceutical composition is free of antioxidants.

In a further embodiment, the present invention provides the stable liquid bendamustine pharmaceutical composition consisting of: (i) about 25 mg/ml of bendamustine hydrochloride, (ii) diethylene glycol monoethyl ether, (iii) about 0.25 mg/ml of sodium hydroxide, and (iv) hydrochloric acid, wherein the pH of the pharmaceutical composition is of about 3.0 to about 4.0.

In a still further embodiment, the present invention provides the stable liquid bendamustine pharmaceutical composition consisting of: (i) about 25 mg/ml of bendamustine hydrochloride, (ii) diethylene glycol monoethyl ether, (iii) about 0.25 mg/ml of sodium hydroxide, and (iv) hydrochloric acid, wherein the pH of the pharmaceutical composition is of about 3.0 to about 4.0 and wherein the pharmaceutical composition is free of antioxidants.

In a specific embodiment, the present invention relates to the liquid bendamustine hydrochloride pharmaceutical composition consisting of (i) about 25 mg/ml of bendamustine hydrochloride, (ii) a pharmaceutically acceptable solvent system consisting of diethylene glycol monoethyl ether, (iii) about 0.25 mg/ml of sodium hydroxide, and (iv) hydrochloric acid to adjust the pH, wherein the pH of the pharmaceutical composition is of about 3.0 to about 4.0.

In a further specific embodiment, the present invention relates to the liquid bendamustine hydrochloride pharmaceutical composition consisting of (i) about 25 mg/ml of bendamustine hydrochloride, (ii) a pharmaceutically acceptable solvent system consisting of diethylene glycol monoethyl ether, (iii) about 0.25 mg/ml of sodium hydroxide, and (iv) hydrochloric acid to adjust the pH; wherein the pH of the pharmaceutical composition is of about 3.0 to about 4.0 and wherein the pharmaceutical composition is free of antioxidants.

The inventors of the invention have surprisingly found that the stable liquid bendamustine hydrochloride pharmaceutical composition have individual impurity less than 1.0% and total impurities less than 2.0% after 6 months storage at 2-8°C, when the stable liquid bendamustine hydrochloride composition comprises diethylene glycol monoethyl ether as solvent, of about 0.25 mg/ml of sodium hydroxide and hydrochloric acid, wherein the pH of the pharmaceutical composition is of about 3.0 to about 4.0.

In another embodiment, the present invention provides the liquid bendamustine hydrochloride pharmaceutical composition consisting essentially of (i) about 25 mg/ml of bendamustine hydrochloride, (ii) a pharmaceutically acceptable solvent system consisting of diethylene glycol monoethyl ether, and (iii) about 0.25 mg/ml of sodium hydroxide; wherein the pH of the pharmaceutical composition is of about 3.0 to about 4.0.

In still further embodiment, the present invention provides the liquid bendamustine hydrochloride pharmaceutical composition consisting essentially of (i) about 25 mg/ml of bendamustine hydrochloride, (ii) a pharmaceutically acceptable solvent system consisting of diethylene glycol monoethyl ether, and (iii) about 0.25 mg/ml of sodium hydroxide; wherein the pH of the pharmaceutical composition is of about 3.0 to about 4.0 and wherein the pharmaceutical composition is free of antioxidants.

In another embodiment, the present invention provides the liquid bendamustine hydrochloride pharmaceutical composition consisting essentially of (i) about 25 mg/ml of bendamustine hydrochloride, (ii) a pharmaceutically acceptable solvent system consisting of diethylene glycol monoethyl ether, and (iii) about 0.25 mg/ml of sodium hydroxide; wherein the pH of the pharmaceutical composition is of about 3.0 to about 4.0.

In a still further embodiment, the present invention provides the liquid bendamustine hydrochloride pharmaceutical composition consisting essentially of (i) about 25 mg/ml of bendamustine hydrochloride, (ii) a pharmaceutically acceptable solvent system consisting of diethylene glycol monoethyl ether, and (iii) about 0.25 mg/ml of sodium hydroxide; wherein the pH of the pharmaceutical composition is of about 3.0 to about 4.0 and wherein the pharmaceutical composition is free of antioxidants.

An impurity level of the liquid bendamustine formulation is determined by use of high performance liquid chromatography-mass spectrometry (HPLC-MS or LC-MS). For long term storage, the liquid bendamustine hydrochloride pharmaceutical compositions are typically stored under a refrigerated condition (2 to 8° C.) with very low humidity. In some embodiments, bendamustine total degradation impurities in the final product are less than about 2.0% under the refrigerated storage condition for six months and the individual impurity is less than 1.0%.

In a still further embodiment, the present invention provides the stable liquid bendamustine hydrochloride pharmaceutical composition consisting essentially of (i) about 25 mg/ml of bendamustine hydrochloride, (ii) diethylene glycol monoethyl ether, and (iii) about 0.25 mg/ml of sodium hydroxide, wherein the pH of the pharmaceutical composition is of about 3.0 to about 4.0, wherein the pharmaceutical composition is free of antioxidants and wherein an individual impurity present in the said composition is less than 1.0% and total amount of impurities present in the said composition is less than 2.0%.

In further embodiment, the present invention provides the stable liquid bendamustine hydrochloride pharmaceutical composition consisting essentially of (i) about 25 mg/ml of bendamustine hydrochloride, (ii) a pharmaceutically acceptable solvent system consisting of diethylene glycol monoethyl ether, and (iii) about 0.25 mg/ml of sodium hydroxide, wherein the pH of the pharmaceutical composition is of about 3.0 to about 4.0, wherein the pharmaceutical composition is free of antioxidants and wherein an individual impurity present in the said composition is less than 1.0% and total amount of impurities present in the said composition is less than 2.0%.

In a still further embodiment the present invention provides the stable liquid bendamustine hydrochloride pharmaceutical composition consisting of (i) about 25mg/ml of bendamustine hydrochloride, (ii) a pharmaceutically acceptable solvent system consisting of diethylene glycol monoethyl ether, and (iii) about 0.25mg/ml of sodium hydroxide; wherein the pH of the pharmaceutical composition is of about 3.0 to about 4.0, wherein the pharmaceutical composition is free of antioxidants and wherein an individual impurity present in the said composition is less than 1.0% and total amount of impurities present in the said composition is less than 2.0%.

In another embodiment the present invention provides the stable liquid bendamustine hydrochloride pharmaceutical composition consisting of (i) about 25 mg/ml of bendamustine hydrochloride, (ii) a pharmaceutically acceptable solvent system consisting of diethylene glycol monoethyl ether, and (iii) about 0.25 mg/ml of sodium hydroxide, wherein the pH of the pharmaceutical composition is of about 3.0 to about 4.0, wherein the pharmaceutical composition is free of antioxidants and wherein an individual impurity present in the said composition is less than 1.0% and total amount of impurities present in the said composition is less than 2.0%.

In another embodiment the present invention provides the stable liquid bendamustine hydrochloride pharmaceutical composition consisting essentially of (i) about 25mg/ml of bendamustine hydrochloride, (ii) diethylene glycol monoethyl ether, (iii) about 0.25mg/ml of sodium hydroxide, (iv) hydrochloric acid, wherein the pH of the pharmaceutical composition is of about 3.0 to about 4.0, wherein the pharmaceutical composition is free of antioxidants and wherein an individual impurity present in the said composition is less than 1.0% and total amount of impurities present in the said composition is less than 2.0%.

In a still further embodiment the present invention provides the stable liquid bendamustine hydrochloride pharmaceutical composition consisting of (i) about 25mg/ml of bendamustine hydrochloride, (ii) diethylene glycol monoethyl ether, (iii) about 0.25mg/ml of sodium hydroxide, (iv) hydrochloric acid, wherein the pH of the pharmaceutical composition is of about 3.0 to about 4.0, wherein the pharmaceutical composition is free of antioxidants and wherein an individual impurity present in the said composition is less than 1.0% and total amount of impurities present in the said composition is less than 2.0%.

Another embodiment of the present invention provides the process for the preparation of stable liquid bendamustine hydrochloride pharmaceutical composition comprising, consisting essentially of, or consisting the steps of:
(a) adding the weighed quantity of sodium hydroxide to diethylene glycol monoethyl ether in a vessel under nitrogen purging,
(b) adding the bendamustine hydrochloride to the contents of step a, adjusting the pH to about 3.0 to about 4.0, with hydrochloric acid for the bendamustine hydrochloride solution,
(c) adding the final volume to 100% using diethylene glycol monoethyl ether,
(d) filtering the solution and filling the filtered solution into vials and
(e) stoppering the vials, sealing the vials and storing the vials at 2-8°C.

Compositions of the present invention can preferably be diluted using 0.9% sodium chloride injection, 2.5% dextrose/0.45% sodium chloride injection before the parenteral administration.

In another embodiment, the composition of the present invention is useful for the treatment of chronic lymphocytic leukemia and B-cell non-Hodgkin lymphoma.

The present invention further provides methods of producing such liquid bendamustine formulations. A general procedure for preparing a liquid formulation of bendamustine is set forth below. However, a person skilled in the art would understand that modifications to the procedure or process may be made.

EXAMPLES

Example 1: Parenteral Compositions of Bendamustine

Ingredients Qty/mL
Bendamustine Hydrochloride 25mg
Diethylene glycol monoethyl ether q.s to 1mL
Sodium hydroxide q.s to pH 2.75

Brief Manufacturing Process:
1. Weighed quantity of bendamustine hydrochloride was added to approximately 90% of Diethylene glycol monoethyl ether in a vessel and stirred until the bendamustine hydrochloride is dissolved completely,
2. The pH is adjusted to 2.5 with sodium hydroxide solution (prepared by dissolving required amount of sodium hydroxide in water for injection),
3. The final volume was adjusted to 100% batch size using Diethylene glycol monoethyl ether,
4. The solution of step 3 was pre-filtered using 0.45µ sterile grade filters,
5. The pre-filtered solution of step 4 was filtered through 0.22µ sterile grade filters,
6. The filtered bulk solution of step 5 was stoppered, sealed and stored at 2°C to 8°C.

Example 2: Parenteral Compositions of Bendamustine

Ingredients Qty/mL
Bendamustine Hydrochloride 25mg
Diethylene glycol monoethyl ether q.s to 1mL
Sodium hydroxide q.s to pH 4.5

Brief Manufacturing Process:
1. Weighed quantity of bendamustine hydrochloride was added to approximately 90% of Diethylene glycol monoethyl ether in a vessel and stirred until the bendamustine hydrochloride is dissolved completely,
2. The pH is adjusted to 4.5 with sodium hydroxide solution (prepared by dissolving required amount of sodium hydroxide in water for injection),
3. The final volume was adjusted to 100% batch size using Diethylene glycol monoethyl ether,
4. The solution of step 3 was pre-filtered using 0.45µ sterile grade filters,
5. The pre-filtered solution of step 4 was filtered through 0.22µ sterile grade filters,
6. The filtered bulk solution of step 5 was stoppered, sealed and stored at 2°C to 8°C.

Example 3: Parenteral Compositions of Bendamustine

Ingredients Qty/mL
Bendamustine Hydrochloride 25mg
Sodium hydroxide 0.24mg
Diethylene glycol monoethyl ether q.s to 1mL
Hydrochloric acid q.s to pH 3.5

Brief Manufacturing Process:
1. Weighed quantity of sodium hydroxide was added to approximately 90% of Diethylene glycol monoethyl ether in a vessel under nitrogen purging and stirred until the sodium hydroxide is dissolved completely,
2. Bendamustine hydrochloride was added to the contents of step 1 under nitrogen purging and stirred to dissolve the bendamustine hydrochloride completely,
3. The pH is adjusted to 3.5 using hydrochloric acid solution (dissolving concentrated hydrochloric acid in water for injection,
4. The final volume was adjusted to 100% batch size using Diethylene glycol monoethyl ether,
5. The solution of step 4 was pre-filtered using 0.45µ sterile grade filters,
6. The pre-filtered solution of step 5 was filtered through 0.22µ sterile grade filters,
7. The filtered bulk solution of step 6 was stoppered, sealed and stored at 2°C to 8°C.

Example 4: Parenteral Compositions of Bendamustine

Ingredients Qty/mL
Bendamustine Hydrochloride 25mg
Sodium hydroxide 0.24mg
Diethylene glycol monoethyl ether q.s to 1mL
Hydrochloric acid q.s to pH 4.0

Brief Manufacturing Process:
1. Weighed quantity of sodium hydroxide was added to approximately 90% of Diethylene glycol monoethyl ether in a vessel under nitrogen purging and stirred until the sodium hydroxide is dissolved completely,
2. Bendamustine hydrochloride was added to the contents of step 1 under nitrogen purging and stirred to dissolve the bendamustine hydrochloride completely,
3. The pH is adjusted to 4.0 using hydrochloric acid solution (dissolving concentrated hydrochloric acid in water for injection,
4. The final volume was adjusted to 100% batch size using Diethylene glycol monoethyl ether,
5. The solution of step 4 was pre-filtered using 0.45µ sterile grade filters,
6. The pre-filtered solution of step 5 was filtered through 0.22µ sterile grade filters,
7. The filtered bulk solution of step 6 was stoppered, sealed and stored at 2°C to 8°C

Example 5: Stability Studies
The compositions prepared as in examples 1, 2,3 and 4 are stored at 2°C – 8°C and was tested for impurities at specific intervals. The results of examples 1, 2, 3 and 4 are as tabulated in tables 1 to 4 respectively.
Table -1 (Example -1)

Time Assay Imp - A Imp - B Imp - C Unspecified impurity at RRT 1.80 Total Impurity
Initial 100.5 0.06 ND ND 0.012 0.214
1 M 99.8 0.079 ND ND 0.090 0.572
3 M 99.4 0.115 ND ND 0.246 1.174
6 M 90.7 0.120 ND ND 1.528 3.63

Table -2 (Example -2)

Time Assay Imp - A Imp - B Imp - C Unspecified impurity at RRT 1.80 Total Impurity
Initial 100.7 0.072 ND ND 0.014 0.23
1 M 99.6 0.08 ND ND 0.094 0.516
3 M 98.9 0.1 ND ND 0.267 1.262
6 M 90.3 0.11 ND ND 3.16 5.929

Table - 3 (Example - 3)

Time Assay Imp - A Imp - B Imp - C Unspecified impurity at RRT 1.80 Total Impurity
Initial 100.8 0.070 ND ND 0.012 0.22
1 M 101.2 0.056 ND ND 0.052 0.280
3 M 100.5 0.090 ND ND 0.070 0.546
6 M 100.2 0.075 ND ND 0.1 0.92

Table - 4 (Example - 4)

Time Assay Imp - A Imp - B Imp - C Unspecified impurity at RRT 1.80 Total Impurity
Initial 100.2 0.040 ND ND 0.010 0.15
1 M 101.6 0.051 ND ND 0.048 0.26
3 M 100.4 0.08 ND ND 0.060 0.34
6 M 102.1 0.072 ND ND 0.070 0.53
,CLAIMS:1. A stable liquid bendamustine pharmaceutical composition comprising:
(i) bendamustine, a pharmaceutically acceptable salt, and/or a hydrate thereof,
(ii) diethylene glycol monoethyl ether, and
(iii) a pH adjusting agent, wherein the pharmaceutical composition has a pH of about 3.0 to about 4.0.

2. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises bendamustine hydrochloride.

3. The pharmaceutical composition of claim 1, wherein the bendamustine concentration is of about 10 mg/mL to about 100 mg/mL.

4. The pharmaceutical composition of claim 3, wherein the bendamustine concentration is of about 20 mg/mL to about 60 mg/mL.

5. The pharmaceutical composition of claim 4, wherein the bendamustine concentration is about 25 mg/mL.

6. The pharmaceutical composition of claim 1, wherein the pH adjusting agent is selected from group consisting of sodium hydroxide and hydrochloric acid.

7. The pharmaceutical composition of claim 6, wherein the sodium hydroxide concentration is of about 0.25 mg/mL.

8. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is free of antioxidants.

9. A stable liquid bendamustine pharmaceutical composition comprising:
(i) about 25 mg/ml of bendamustine hydrochloride,
(ii) diethylene glycol monoethyl ether,
(iii) about 0.25 mg/ml of sodium hydroxide, wherein the pH of the pharmaceutical composition is of about 3.0 to about 4.0 and wherein the pharmaceutical composition is free of antioxidants.

10. A stable liquid bendamustine pharmaceutical composition consisting of:
(i) about 25 mg/ml of bendamustine hydrochloride,
(ii) diethylene glycol monoethyl ether,
(iii) about 0.25 mg/ml of sodium hydroxide,
(iv) hydrochloric acid, wherein the pH of the pharmaceutical composition is of about 3.0 to about 4.0 and wherein the pharmaceutical composition is free of antioxidants.