Lyophilized compositions of phenobarbital sodium salt
A composition of, method for producing, and use of an amorphous lyophilized Phenobarbital Sodium having high purity are presented. The amorphous lyophilized Phenobarbital Sodium is storage-stable being essentially void of impurities (e.g., phenylethylacetylurea (PEAU), 2-ethyl-2-phenylmalonamide (2EPMM), and/or alpha-phenylbutyrylguanidine (PBG)) upon reconstitution in water.
1. A method of producing a storage-stable form of lyophilized amorphous phenobarbital sodium composition, comprising:
adding phenobarbital sodium to water to form a phenobarbital sodium solution having a pH of between 9.2 and 10.2, wherein the phenobarbital sodium solution does not contain an organic solvent, and wherein the phenobarbital sodium solution optionally further comprises sodium chloride;
lyophilizing the phenobarbital sodium solution in a container under a protocol comprising a freezing step, a primary drying step, and a secondary drying step to thereby produce the lyophilized amorphous phenobarbital sodium composition;
wherein the freezing step comprises freezing the lyophilized amorphous phenobarbital sodium to a temperature of about −50° C. without application of vacuum;
wherein the primary drying step comprises application of vacuum at a pressure of between about 50 mTorr and 75 mTorr at a temperature of between about −50° C. and about 0° C. for at duration of at least 1,000 minutes;
wherein the secondary drying step comprises application of vacuum at a pressure of between about 50 mTorr and 75 mTorr at a temperature of between about 25° C. and about 50° C. for at duration of at least 200 minutes;
wherein the lyophilized amorphous phenobarbital sodium has an initial moisture content of equal or less than 1.5%; and
wherein the lyophilized amorphous phenobarbital sodium forms, upon storage over 3 months, no more than 0.2% phenylethylacetylurea (PEAU) when reconstituted in an aqueous solution.
2. The method of claim 1 , wherein the sodium chloride is present in the phenobarbital sodium solution in an amount that, upon reconstitution of the lyophilized amorphous phenobarbital sodium in the aqueous solution, yields a sodium chloride concentration of 0.9% in the reconstituted solution.
3. The method of claim 1 , wherein the phenobarbital sodium solution in the container is present in an amount of about 65 mg, or about 100 mg, or about 130 mg, or about 200 mg.
4. The method of claim 1 , wherein the water is sparged with nitrogen.
5. The method of claim 1 , wherein the phenobarbital sodium solution does not contain a preservative.
6. The method of claim 1 , wherein the primary drying step is performed using at increasing temperatures that increase from about −50° C. to about 0° C. when the amount of phenobarbital sodium in the container is between 65 mg and 130 mg.
7. The method of claim 1 , wherein the primary drying step is performed using at constant temperature of about −42° C. when the amount of phenobarbital sodium in the container is 200 mg.
8. The method of claim 1 , wherein the secondary drying step is performed using at decreasing temperatures that decrease from about 50° C. to about 25° C. when the amount of phenobarbital sodium in the container is between 65 mg and 130 mg.
9. The method of claim 1 , wherein the secondary drying step is performed using at constant temperature of about 35° C. when the amount of phenobarbital sodium in the container is 200 mg.
10. The method of claim 1 , wherein the lyophilized amorphous phenobarbital sodium has an initial moisture content of equal or less than 1.2%.
11. The method of claim 1 , wherein the lyophilized amorphous phenobarbital sodium has an initial moisture content of equal or less than 1.0%.
12. The method of claim 1 , wherein the lyophilized amorphous phenobarbital sodium forms, upon storage over 3 months, no more than 0.1% phenylethylacetylurea (PEAU) when reconstituted in an aqueous solution.
13. The method of claim 1 , wherein the lyophilized amorphous phenobarbital sodium forms, upon storage over 3 months, no detectable quantities of 2-ethyl-2-phenylmalonamide (2EPMM) or alpha-phenylbutyrylguanidine (PBG) when reconstituted in an aqueous solution.
14. The method of claim 1 , wherein the storage is at 40° C. and 75% relative humidity.
15. The method of claim 1 , wherein the lyophilized amorphous phenobarbital sodium composition contains at least 98% lyophilized amorphous phenobarbital sodium.