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Ibandronate sodium propylene glycol solvate and processes for the preparation thereof

a technology of ibandronate and propylene glycol, which is applied in the field of new solvated form of ibandronate sodium, can solve the problems of toxic types of solvating agents, and achieve the effect of easy and safe scale-up to industrial levels and superior results

Inactive Publication Date: 2008-06-12
APOTEX PHARMACHEN INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0014]During our process optimization work to find novel, cost-effective and robust synthetic procedures to Ibandronate sodium and improved forms of the active ingredient, we surprisingly discovered that a diol, namely propylene glycol (1,2-propanediol), forms a crystalline 1:1 solvate with Ibandronate sodium that can be easily purified and, thereafter, formulated into effective dosage forms.
[0015]The use of propylene glycol as a solvating agent has many advantages. These include that it is inexpensive and widely-available, having many industrial applications including use as a moisturizer for medicines, cosmetics, food and tobacco products and as a humectant food additive. Furthermore, it has an established safety and can be purchased as pharmaceutically acceptable NF-grade material. For instance, it is listed as a Food Additive in FDA's “Everything” Added to Food in the United States (EAFUS)” database (http: / / www.cfsan.fda.gov / ˜dms / eafus.html).
[0016]The Ibandronate sodium propylene glycol solvate of this invention is easily made and crystalline. This form has many desirable characteristics including that it is non-hygroscopic, free-flowing, and is chemically and polymorphically stable. Another benefit is that it is easily dried, even on industrial scale, since it retains very little residual solvent.
[0018]In another aspect of the invention, the phosphorylation of 3-(N-methyl-N-pentylamino)propanoic acid (or its hydrochloride salt) using phosphorous acid and phosphorous trichloride in the presence of polyethylene glycol led to superior results. Most significantly, it allowed for the reaction to be accomplished with effective stirring throughout thereby permitting facile and safe scale-up to industrial levels.

Problems solved by technology

Of note is that many of the types of solvating agents are toxic at higher doses and therefore would have to be removed before they could be used as an active ingredient.

Method used

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  • Ibandronate sodium propylene glycol solvate and processes for the preparation thereof
  • Ibandronate sodium propylene glycol solvate and processes for the preparation thereof
  • Ibandronate sodium propylene glycol solvate and processes for the preparation thereof

Examples

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example 1

Preparation of Sodium Ibandronate Propylene Glycolate from 3-(N-Methyl-N-Pentylamino)Propanoic Acid Hydrochloride

[0031]3-(N-Methyl-N-pentylamino)propanoic acid hydrochloride (100 g) was suspended in toluene (300 mL) and polyethylene glycol 400 (120 mL). Phosphorous acid (43.01 g 1.1 eq.) was added to the mixture. The mixture was warmed and phosphorous trichloride (98.22 g, 1.5 eq.) was added at a rate such that the temperature remained below 60° C. The mixture was stirred for 10 hours at 55-60° C. whereupon it was quenched by adding water (450 mL). The water addition was controlled to maintain a reaction temperature below 70° C. The layers were separated and the aqueous layer was refluxed for 6 hours. The mixture was cooled to 40-45° C. to provide Ibandronic acid in solution and the pH was adjusted to 4.3-4.5 using 50% aqueous sodium hydroxide. Propylene glycol (150 mL) was then added to the reaction mixture at 60-65° C. and stirred for 4-5 hours. The mixture was cooled to 20-25° C....

example 2

Preparation of Sodium Ibandronate Propylene Glycolate from Ibandronic Acid

[0039]Ibandronic acid (6.30 g, 19.7 mmol) was suspended in water (18.0 mL) and heated to dissolution (42° C.). The pH was adjusted to 4.4 using 50% aqueous sodium hydroxide. 1,2-Propanediol was added to the reaction mixture at 56° C. and the mixture was stirred for 2.5 hours. The mixture was cooled to 20-25° C. over a period of 2.5 hours and stirred for another 15 hours. The mixture was filtered, washed with ethyl acetate (2 ×10 mL). The damp solid was suspended in 30 mL of ethyl acetate and stirred at 20-25 ° C. for 1 hour, filtered, rinsed with ethyl acetate (2×10 mL) and dried in vacuo at 65° C. for 8 hours to yield sodium Ibandronate propylene glycolate (4.54 g).

example 3

Preparation of Sodium Ibandronate R-Propylene Glycolate by Recrystallization

[0040]Sodium Ibandronate (2.0 g) was suspended in 6 mL (3.0 vol) of water in a round bottom flask. The flask was heated to dissolution (55-65° C.) at which point 2 mL R-propylene glycol (1.0 vol) was added to the flask. The temperature of the flask was held at 60-65° C. for 2 hours, then cooled to 20-25° C. and held at this temperature for 0.5 hours. Acetone (4 mL, 2.0 vol) was added and the flask was stirred at 20-25° C. for 0.5 hours. The precipitated solid was isolated by filtration, rinsed with acetone and dried in a vacuum oven at 60-65° C. This provided 1.97 grams of Ibandronate sodium R-propylene glycolate.

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Abstract

A novel form of Ibandronate sodium which is particularly suitable for pharmaceutical applications, and a process for preparing said novel form.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This is a divisional application of U.S. application Ser. No. 11 / 639,204, filed on Dec. 15, 2006.FIELD OF THE INVENTION[0002]The present invention relates to a new solvated form of Ibandronate sodium (Boniva®) by formation of a 1:1 Ibandronate sodium propylene glycol solvate, and a method for its preparation. This form is particularly well-suited for pharmaceutical applications.BACKGROUND OF THE INVENTION[0003]Ibandronate sodium (1,3-(N-methyl-N-pentyl)amino-1-hydroxypropane-1,1-diphosphonic acid, monosodium salt) is a third-generation member of the bis-phosphonate class of drugs effective for the treatment of bone disorders such as osteoporosis. It is marketed under the brand name Bonivae and its mode of action is to inhibit osteoclast-mediated bone resorption. An advantage of this pharmaceutical is that it can be used as a once-monthly treatment. [0004]The use of Ibandronate sodium as a medicine was originally disclosed in U.S. Pat. No....

Claims

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Application Information

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IPC IPC(8): C07F9/38
CPCC07F9/3873A61K31/663A61P19/10
Inventor STRADIOTTO, DAVID A.REY, ALLAN W.DATTA, PROBAL KANTITRAYNOR, KRISTA LYNMCPHAIL, CAMERON L.
Owner APOTEX PHARMACHEN INC
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