Novel process for preparation of isotonic aqueous injection of ropivacaine
The preparation of an injectable solution of ropivacaine by dissolving ropivacaine base in aqueous acidic solution having a molar ratio of acid to ropivacaine base greater than 1:1 eliminates the need for a hydrochloride or hydrochloride monohydrate intermediate in the manufacture of the injectable. The osmolality can be adjusted as needed. The excess acid is neutralized with a base.
1 . A process for making a solution of ropivacaine base in an aqueous medium comprising:
(a) providing ropivacaine base or a suspension of ropivacaine base in an aqueous medium;
(b) mixing said ropivacaine base or suspension with hydrochloric acid wherein the acid is present in an extramolar amount effective to dissolve said ropivacaine; and
(c) adjusting the pH of the solution with sodium hydroxide to a range of about 3.9 to about 6.5.
2 . The process of claim 1 , wherein the content of ropivacaine base after step (b) is between about 0.05% wt/vol and about 7.0 % wt/vol.
3 . The process of claim 2 , wherein the content of ropivacaine base after step (b) is between about 0.05% wt/vol and about 2.0% wt/vol.
4 . The process of claim 3 , wherein the content of ropivacaine base after step (b) is between about 0.1% wt/vol and about 1.5% wt/vol.
5 . The process of claim 4 , wherein the content of ropivacaine base after step (b) is between about 0.2% wt/vol and about 1.0% wt/vol.
6 . The process of claim 1 , further comprising the step of adjusting the osmolality of the solution by the addition of a salt.
7 . The process of claim 6 , wherein the osmolality is adjusted to be between about 270 mOsM/kg to about 320 mOsM/kg.
8 . The process of claim 6 , wherein the osmolality is adjusted prior to step (b).
9 . The process of claim 6 , wherein the osmolality is adjusted between step (b) and step (c).
10 . The process of claim 6 , wherein the osmolality is adjusted after step (c).
11 . The process of claim 1 , further comprising diluting the solution obtained after step (b) to contain about 1.5% wt/vol to about 4.5% wt/vol of ropivacaine base.
12 . The process of claim 1 , wherein the molar ratio of ropivacaine base to acid after step (b) is at least about 1 to 1.1.
13 . The process of claim 12 , wherein the molar ratio of ropivacaine base to acid after step (b) is at least about 1 to 1.25.
14 . The process of claim 13 , wherein the molar ratio of ropivacaine base to acid after step (b) is at least about 1 to 1.5.
15 . The process of claim 14 , wherein the molar ratio of ropivacaine base to acid after step (b) is at about 1 to 3.
16 . The process of claim 6 , wherein the chloride concentration is in the range of from about 0.3% wt/vol to about 0.7% wt/vol.
17 . The process of claim 1 , wherein the pH is about 5.
18 . The process of claim 1 , wherein sodium chloride is added during step (b).
19 . The process of claim 1 , wherein sodium chloride is added between steps (b) and (c).
20 . The process of claim 1 , wherein sodium chloride is added during step (c).