Example 4: Preparation of Ready to Use Aqueous Solution of Bortezomib (Form 1) at 60° C.

Approximately 5.00 g of Mannitol was weighed and added into 180.0 g of water with continuous stirring. To the solution 1.80 g of weighed quantity of sodium chloride was added and stirred continuously to obtain a clear solution. The solution was heated to a temperature of 60° C. To the heated solution, Bortezomib (Form 1) API 0.5 g was added under continuous stirring to form a clear solution. The solution was cooled down to room temperature and final volume of the solution was made up to 200 g. All the operations were performed under sodium vapor lamp to minimize photo degradation. The solution was filtered through 0.2μ filter.

TABLE 3

Condition
Specification
Initial

Assay
90%-110%
97.8

Impurity-E
NMT 1.0%
0.02

Impurity-L
NMT 1.0%
0.23

Impurity-J
NMT 1.0%
0.06

Impurity-F
NMT 1.0%
0.08

Impurity-I
NMT 1.0%
ND

Impurity-U
NMT 1.0%
ND

Highest Unknown
NMT 0.5%
0.01

Total impurities
NMT 3.0%
0.45

Example 5: Preparation of Ready to Use Aqueous Solution of Bortezomib (Form 2) at 50° C.

Approximately 2.50 g of Mannitol was weighed and added into 90.0 g of water with continuous stirring. To the solution 0.9 g of weighed quantity of sodium chloride was added and stirred continuously to obtain a clear solution. The solution was purged with Nitrogen to maintain the dissolved oxygen below 2 ppm. The solution was heated to a temperature of 50° C. To the heated solution, Bortezomib (Form 2) API 0.25 g was added under continuous stirring to form a clear solution. The solution was cooled down to room temperature and final volume of the solution was made up to 100 g. All the operations were performed under sodium vapor lamp to minimize photo degradation. The solution was filtered through 0.2μ filter. 1.4 mL of solution was filled into each vial, stoppered with rubber stopper and sealed with flip off seals.

TABLE 4

Condition
Specification
Initial
2-8° C. (2 week)

Assay
90%-110%
100.9
101.4

Impurity-E
NMT 1.0%
0.07
0.07

Impurity-L
NMT 1.0%
0.06
0.11

Impurity-J
NMT 1.0%
0.06
0.07

Impurity-F
NMT 1.0%
0.07
0.07

Impurity-I
NMT 1.0%
ND
0.03

Impurity-U
NMT 1.0%
ND
ND

Highest Unknown
NMT 0.5%
0.01
0.01

Total impurities
NMT 3.0%
0.35
0.39

Example 6: Preparation of Ready to Use Aqueous Solution of Bortezomib (Form 2) at 40° C.

Approximately 2.50 g of Mannitol was weighed and added into 90.0 g of water with continuous stirring. To the solution 0.9 g of weighed quantity of sodium chloride was added and stirred continuously to obtain a clear solution. The solution was purged with Nitrogen to maintain the dissolved oxygen below 2 ppm. The solution was heated to a temperature of 40° C. To the heated solution, Bortezomib (Form 2) API 0.25 g was added under continuous stirring to form a clear solution. The solution was cooled down to room temperature and final volume of the solution was made up to 100 g. All the operations were performed under sodium vapor lamp to minimize photo degradation. The solution was filtered through 0.2μ filter. 1.4 mL of solution was filled into each vial, stoppered with rubber stopper and sealed with flip off seals.

TABLE 5

Condition
Specification
Initial
2-8° C. (2 week)

Assay
90%-110%
99.7
101.3

Impurity-E
NMT 1.0%
0.03
0.07

Impurity-L
NMT 1.0%
0.03
0.14

Impurity-J
NMT 1.0%
0.06
0.12

Impurity-F
NMT 1.0%
0.08
0.12

Impurity-I
NMT 1.0%
0.02
0.02

Impurity-U
NMT 1.0%
ND
0.01

Highest Unknown
NMT 0.5%
0.01
0.01

Total impurities
NMT 3.0%
0.23
0.53

Example 7: Preparation of Ready to Use Aqueous Solution of Bortezomib (Form 2) at RT

Approximately 2.5 g of Mannitol was weighed and added into 90.0 g of water with continuous stirring. To the solution 0.9 g of weighed quantity of sodium chloride was added and stirred continuously to obtain a clear solution. The solution was purged with Nitrogen to maintain the dissolved oxygen below 2 ppm. To the solution, Bortezomib (Form 2) API 0.25 g was added under continuous stirring to form a clear solution. The solution was cooled down to room temperature and final volume of the solution was made up to 100 g. All the operations were performed under sodium vapor lamp to minimize photo degradation. The solution was filtered through 0.2μ filter.

TABLE 6

Condition
Specification
Initial

Assay
90%-110%
98.3

Impurity-E
NMT 1.0%
0.03

Impurity-L
NMT 1.0%
0.02

Impurity-J
NMT 1.0%
0.05

Impurity-F
NMT 1.0%
0.09

Impurity-I
NMT 1.0%
ND

Impurity-U
NMT 1.0%
ND

Highest Unknown
NMT 0.5%
0.01

Total impurities
NMT 3.0%
0.21

Example 8: Preparation of Ready to Use Aqueous Solution of Bortezomib (Form 1) at 80° C. Without Sodium Chloride

Approximately 2.5 g of Mannitol was weighed and added into 90.0 g of water with continuous stirring. The solution was heated to a temperature of 80° C. To the heated solution, Bortezomib (Form 1) API 0.25 g was added under continuous stirring to form a clear solution. The solution was cooled down to room temperature and final volume of the solution was made up to 100 g. The solution was filtered through 0.2μ filter. 1.0 mL of solution was filled into each vial, stoppered with rubber stopper and sealed with flip off seals.

TABLE 7

Condition
Specification
Initial
2-8° C. (3 M)

Assay
90%-110%
95.8
97.3

Impurity-E
NMT 1.0%
0.02
0.02

Impurity-L
NMT 1.0%
0.19
0.26

Impurity-J
NMT 1.0%
0.06
0.09

Impurity-F
NMT 1.0%
0.06
0.07

Impurity-I
NMT 1.0%
ND
ND

Impurity-U
NMT 1.0%
ND
ND

Highest Unknown
NMT 0.5%
ND
ND

Total impurities
NMT 3.0%
0.38
0.49

Example 9: Preparation of Ready to Use Aqueous Solution of Bortezomib (Form 1) with Vacuum Evaporation Process with 0.9% Sodium Chloride
Preparation of Concentrate:

- Step 1: Approximately 330 g of water was taken and to it added 24.75 g of mannitol under continuous stirring to form a clear solution. The solution obtained was then purged with nitrogen to obtain DO level below 2%
- Step 2: Approximately 171.6 g Tertiary butyl alcohol was taken and added 2.556 of Bortezomib was added under stirring at a temperature of 50° C. to obtain a clear solution.
- Step 3: Both step 1 and step 2 were mixed together and charged for vacuum evaporation in Buchi Rotavap at vacuum of 300 mbar and gradually reduced to 150 mbar and then to 60 mbar.

Preparation of Final Formulation:

- Step 4: 207.65 g of concentrate was taken and made up to 1000 g. The batch was divided into two parts and to 1 part 0.9% sodium chloride was added. The solution was filtered through 0.2μ filter.

TABLE 8

Condition
Specification
Initial
2-8° C. (3 M)

Assay
90%-110%
97.9
97.5

Impurity-E
NMT 1.0%
0.01
0.01

Impurity-L
NMT 1.0%
0.03
0.08

Impurity-J
NMT 1.0%
0.06
0.11

Impurity-F
NMT 1.0%
0.10
0.12

Impurity-I
NMT 1.0%
ND
ND

Impurity-U
NMT 1.0%
ND
ND

Highest Unknown
NMT 0.5%
0.01
0.01

Total impurities
NMT 3.0%
0.20
0.32

Example 10: Preparation of Ready to Use Aqueous Solution of Bortezomib (Form 1) with Vacuum Evaporation Process without Sodium Chloride
Preparation of Concentrate:

- Step 1: Approximately 57.798 g of water was taken and to it added 5.032 g of mannitol under continuous stirring to form a clear solution. The solution obtained was then purged with nitrogen to obtain DO level below 2%
- Step 2: Approximately 32.002 g Tertiary butyl alcohol was taken and added 0.501 of Bortezomib was added under stirring at a at a temperature of 50° C. to obtain a clear solution.
- Step 3: Both step 1 and step 2 were mixed together and charged for vacuum evaporation in Buchi Rotavap at vacuum of 300 mbar and gradually reduced to 150 mbar and then to 60 mbar.

Preparation of Final Formulation:

- Step 4: 10.014 g of concentrate was taken and made up to 24.879 g. The solution was filtered through 0.2μ filter.

TABLE 9

Condition
Specification
Initial
2-8° C. (3 M)

Assay
90%-110%
100.5
99.8

Impurity-E
NMT 1.0%
0.04
0.05

Impurity-L
NMT 1.0%
0.09
0.17

Impurity-J
NMT 1.0%
0.01
0.09

Impurity-F
NMT 1.0%
0.11
0.39

Impurity-I
NMT 1.0%
ND
ND

Impurity-U
NMT 1.0%
ND
ND

Highest Unknown
NMT 0.5%
0.01
0.01

Total impurities
NMT 3.0%
0.39
0.91

Example 11: Preparation of Ready to Use Aqueous Solution of Bortezomib (Form 2) with Only Light Control and No DO Control at 40° C.

Approximately 5.00 g of Mannitol was weighed and added into 180.0 g of water with continuous stirring. To the solution 1.8 g of weighed quantity of sodium chloride was added and stirred continuously to obtain a clear solution. The solution was heated to a temperature of 40° C. To the heated solution, Bortezomib (Form 2) API 0.50 g was added under continuous stirring to form a clear solution. The solution was cooled down to room temperature and final volume of the solution was made up to 200 g. All the operations were performed under sodium vapor lamp. The solution was filtered through 0.2μ filter. 1.4 mL of solution was filled into each vial, stoppered with rubber stopper and sealed with flip off seals.