PROCESS FOR THE MANUFACTURE OF SNAC (SALCAPROZATE SODIUM)

Abstract

Disclosed are improved methods for the synthesis of N-(8-[2-hydroxybenzoyl]- amino) caprylic acid. Certain compounds have been found useful for preventing the formation of a colored impurity when included in an ester hydrolysis reaction. Conducting ester hydrolysis in anaerobic conditions has also been found to minimize the formation of the color impurity. Also disclosed are improved methods for synthesizing the sodium salt of N-(8-[2-hydroxybenzoyl]-amino) caprylic acid.

Claims

1-9. (canceled)

10. A composition comprising a compound of formula: ##STR00004## or an anion or salt thereof, wherein the composition is essentially free of pink color bodies.

11. A pharmaceutical formulation comprising the composition of claim 10.

12. The pharmaceutical formulation of claim 11, further comprising a pharmaceutically active drug and one or more pharmaceutically acceptable carriers or excipients.

13. The pharmaceutical formulation of claim 11, wherein the formulation is in a form suitable for oral administration.

14. The pharmaceutical formulation of claim 13, wherein the form suitable for oral administration is a tablet form.

15. The pharmaceutical formulation of claim 13, wherein the drug is present in an amount that is not therapeutically effective when the drug is orally administered alone.

16. The pharmaceutical formulation of claim 13, wherein the compound is present in an amount effective to facilitate absorption of the drug in the gastrointestinal tract such that the amount of drug in the oral dosage form is therapeutically effective.

17. The pharmaceutical formulation of claim 11, comprising a sodium salt of the compound of formula ##STR00005##

Description

EXAMPLES

Example 1

Production of SNAC Free Acid

[0041] ##STR00002##

A dry, clean, 500 ml half jacketed, 4-neck round bottom flask, equipped with a mechanic stirrer, thermo couple, chiller, and an addition funnel, was charged with 153 g of water, 22 mg of EDTA (0.08 mmol), and 30 g of 2,4-dioxo-1,3-benzoazinyl-octanoic acid ethyl ester (76.49 mmol). The mixture was stirred for 30 minutes at 205 C. Then 29.22 g of 40% NaOH solution (292.18 mmol) was added to the mixture. The mixture was heated to 97 C. and held for 20 hours. The mixture was then cooled to 205 C. The batch was charged to an addition funnel, and the flask was charged with 29 g of acetone and 36.25 g of 31% HCl. The batch in the first flask was transferred to the acetone/HCl solution over 40 minutes while maintaining temperature <30 C. After the transfer, the pH of the batch was adjusted to 4.5 with 20% NaOH solution. The mixture was heated to 60 C., held for 0.5 h, and then cooled to 205 C. The batch was held at 205 C. for at least 2 hours. The solid was filtered, washed with water, and dried at 805 C. under vacuum overnight to give 20.4 g (95% yield) of SNAC free acid.

Example 2

Formation of SNAC Sodium Salt

[0042] ##STR00003##

[0043] A 1L, halt jacketed, 4-neck round bottom tlask equipped with a mechanical stirrer, a thermo couple, an additional funnel, and a condenser, was charged with 46.35 g of SNAC free acid (165.9 mmol), and 180 ml of iPrOH and stirred at room temperature (rt). The suspension was heated to 40 C. To the resulting suspension was added 33.84 g of 20% NaOH (169.2 mmol) solution over a span of 30 minutes. The suspension has become a clear solution when about only half of the base was added. After the full amount of base was added, the clear solution was at pH=9.0. The reaction temperature was then raised to 50 C. and was stirred at 50 C. for 30 minutes. The almost colorless clear solution was cooled to 35 C. in one hour. The clear solution was then seeded with 100 mg of crystalline SNAC sodium salt (0.33 mol) and stirred at 35 C. for one hour. The clear solution has become a milky light suspension. The suspension was further cooled to 30 C. in one hour and hold at 30 C. for one hour, it has become a very thick white suspension. 180 ml of i-PrOH was added over a span of one hour. The internal temperature was kept at 30 C. through out the addition. The stirring actually became easier after the addition. The suspension was then cooled to 0 C. in a span of one hour and was aged at that temperature for 18 hours. The solid was filtered on a coarse sintered glass funnel and filtration was very fast. The solid was air-dried for one hour. The resulting white solid was transferred to a crystallization dish and was dried at 35 C. for 6 hours and at 90 C. with nitrogen bleeding for additional 18 hours. It was cooled in an oven to rt under vacuum (needs to be less than 40 C.) before removal from the oven. In total 46.8 g (93.6% yield) white solid was collected, which was found to by anhydrous SNAC sodium salt, with a monomodal particle size distribution. The water content was found to be 0.52%, as judged by Karl Fischer titration. The aqueous solution of the salt has pH=7.0. Water content needs to be carefully monitored during drying process to make sure the water level is below 1%, preferably below 0.5%. Before filtration, the reaction content may be aged at 0 C. overnight. No quality deterioration was observed. The anhydrous monomodal SNAC sodium salt product has good solubility in water, significantly higher than that of a trihydrate form.