Mannitol → Bendamustine Mannitol

HRID 631038

Reaction equation

HRID 631038 reaction equation
[CH2:1]([OH:12])[C@H:2]([C@H:4]([C@@H:6]([C@@H:8]([CH2:10][OH:11])[OH:9])[OH:7])[OH:5])[OH:3].[CH3:13][N:14]1[C:22]([CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[N:21][C:20]2[CH:19]=[C:18]([N:29]([CH2:33][CH2:34][Cl:35])[CH2:30][CH2:31][Cl:32])[CH:17]=[CH:16][C:15]1=2.CN1C(CCCC(O)=O)=NC2C=C(N(CCCl)CCCl)C=CC1=2.Cl.C(O)C.CN1C(CCCC(O)=O)=NC2C=C(N(CCCl)CCCl)C=CC1=2>O.C(O)CC.C(O)C>[CH3:13][N:14]1[C:22]([CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[N:21][C:20]2[CH:19]=[C:18]([N:29]([CH2:30][CH2:31][Cl:32])[CH2:33][CH2:34][Cl:35])[CH:17]=[CH:16][C:15]1=2.[CH2:10]([OH:11])[C@H:8]([C@H:6]([C@@H:4]([C@@H:2]([CH2:1][OH:12])[OH:3])[OH:5])[OH:7])[OH:9]

Participants

8

Reactant 4

HCID 6251Mannitol2×HCID 65628BendamustineHCID 77082Bendamustine HydrochlorideHCID 131735415Ethanol bendamustine

Product 1

HCID 131735414Bendamustine Mannitol

Reagents, catalysts & solvents 3

HCID 702EthanolSolventHCID 962WaterSolvent2×HCID 10311-PropanolSolvent

Procedure

Two batches (Batch 1 and Batch2) each one with a different pharmaceutical composition comprising solid dispersions in the form of dry powder and substantially free of hydrolysis degradants were produced. For each batch, two pre-drying intermediate compositions were formulated in separate containers. For Batch 1, the aqueous pre-drying composition was formulated consisting of 2380 mg of mannitol dissolved in 70 ml of water. The non-aqueous pre-drying composition was formulated by dissolving 1400 mg of bendamustine in 70 ml of n-propanol. For Batch 2, the aqueous pre-drying composition consisted of 1190 mg of mannitol dissolved in 70 ml of water. The non-aqueous pre-drying composition was formulated by dissolving 700 mg of bendamustine hydrochloride in 70 ml of ethanol. The ethanol/bendamustine solution could be cooled to minimize the extent of possible side reactions. Both feed pumps (see FIG. 10) were set in such a way that the ratio of excipient to API was 1.8 for Batch 1 and 1.9 for Batch 2. Tables 2 and 3 show the process parameters for Batch 1 and Batch 2.

Workup

  1. customTwo batches (Batch 1 and Batch2) each one with a different pharmaceutical composition comprising solid dispersions in the form of dry powder and substantially free of hydrolysis degradants
  2. customwere produced

Sources & evidence

ORD record
ord-1ca2d6f0ffff47bfafbea48a9b07efc3
Source dataset
uspto-grants-2016_04
Patent number
US09320730B2

Linked notes

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