# US 9,872,873 B2 · Process for preparing stable pharmaceutical compositions of compounds susceptible to hydrolysis

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- Number: US 9,872,873 B2
- Document ID: US9872873B2
- Status: Granted
- Kind: B2
- Application number: 14/377,047
- Filed: 2012-03-29
- Published: 2014-12-25
- Granted: 2018-01-23
- Earliest claimed: 2012-02-06
- Assignees: Fresenius Kabi Oncology Limited
- Applicants: Dhiraj Khattar; Rajesh Khanna; Sanjay Motwani; Minakshi Garg; Vikas Chandel; Mukti Yadav; Vijay Kumar Kyama; Vikas Bhandari
- Inventors: Dhiraj Khattar; Rajesh Khanna; Sanjay Motwani; Minakshi Garg; Vikas Chandel; Mukti Yadav; Vijay Kumar Kyama; Vikas Bhandari
- Web page: https://patentgrep.com/patent/US9872873B2

## CPC

- A61K 31/706: containing six-membered rings with nitrogen as a ring hetero atom
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 9/19: lyophilised {, i.e. freeze-dried, solutions or dispersions (lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00)}
- A61K 31/4184: condensed with carbocyclic rings, e.g. benzimidazoles
- A61K 47/02: Inorganic compounds
- A61K 47/26: Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)

## Abstract

The present invention relates to a process of preparing a stable pharmaceutical composition of compounds which are susceptible to hydrolysis comprising a. Addition of required quantity of pharmaceutically acceptable lyophilization excipients optionally in Water for Injection in a formulation vessel; b. Addition of organic solvent to form a appropriate proportion of aqueous and organic solvent; c. Maintaining the temperature of the formulation vessel from the range −5±1° C. to −5±3° C.; d. Addition of required quantity of compound susceptible to hydrolysis to form a solution and lyophilizing the solution.

## Claims

### Claim 1

A process of preparing a stable pharmaceutical composition of bendamustine, wherein the process comprises:
(a) combining a required quantity of a pharmaceutically acceptable lyophilization excipient in water for injection (WFI) with acetonitrile in a formulation vessel to generate a mixture, wherein the proportion of water to acetonitrile in the mixture is 80:20 (v:v);
(b) maintaining a temperature within the formulation vessel in a range of −5±3° C.;
(c) adding a required quantity of bendamustine to the formulation vessel in order to form a solution; and
(d) lyophilizing the solution.

### Claim 2 (depends on 1)

The process of claim 1, wherein the pharmaceutically acceptable lyophilization excipient is sodium dihydrogen phosphate, potassium dihydrogen phosphate, mannitol, gelatin, glycerin, dextrose, dextran, citric acid, ascorbic acid, tartaric acid, sodium hydrogen sulfite or sodium hydroxide.

### Claim 3 (depends on 2)

The process of claim 2, wherein the pharmaceutically acceptable lyophilization excipient is mannitol, potassium dihydrogen phosphate, sodium dihydrogen phosphate, or sodium hydroxide.

### Claim 4 (depends on 1)

The process of claim 1, wherein the temperature within the formulation vessel is −5±2° C.

### Claim 5

A process of preparing a stable pharmaceutical composition of azacitidine or decitabine wherein the process comprises:
(a) combining a required quantity of a pharmaceutically acceptable lyophilization excipient in water for injection (WFI) with acetonitrile in a formulation vessel to generate a mixture, wherein the proportion of water to acetonitrile in the mixture is in a ratio of 80:20 (v:v);
(b) maintaining a temperature within the formulation vessel in a range of −5±2° C.;
(c) adding a required quantity of azacitidine or decitabine to the formulation vessel in order to form a prelyophilized solution; and
(d) lyophilizing the solution.

### Claim 6 (depends on 1)

The process of claim 1, wherein the process consists of step (a)-step (d).

### Claim 7 (depends on 5)

The process of claim 5, wherein the process consists of step (a)-step (d).