(EXTRACTED FROM WIPO)
STABILIZATION OF PHENOBARBITAL SODIUM FOR INJECTION

FIELD OF THE INVENTION

[0001] The present invention relates to a lyophilized pharmaceutical composition of hydrolytically unstable pharmaceutical compounds, such as phenobarbital or salts thereof. The present invention also relates to an aqueous solution for injection of phenobarbital or salts thereof that is reconstituted from the lyophilized pharmaceutical composition. The pharmaceutical compositions of the present disclosure have an ethanol content in the range from about 5000 ppm to about 70000 ppm. The composition of the present disclosure, in certain embodiments, is stable following two years of storage, wherein the total impurities do not exceed 0.5%. The pharmaceutical compositions of the present disclosure may be used for the treatment of neonatal seizures.

BACKGROUND OF THE INVENTION

[0002] Phenobarbital is an anti-epileptic drug which has been used for many years in the treatment of neonatal seizures. One of the problems associated with a phenobarbital composition, however, is its instability due to hydrolysis, which causes it to possess a higher level of impurities. While the compound is freely soluble in water, with solubility reported to be as high as 333 mg/ml to 1 g/ml, the presence of hydroxyl ions from the water in the composition results in a hydrolysis pathway that can destroy the phenobarbital ring complex. This destruction results in the possible formation of impurities including harmful degradants or precipitates.

[0003] One known method of improving the stability of phenobarbital sodium involves the use of a lower pH and the use of a mixture of water and generic solvents such as alcohol, propylene glycol, glycerin, benzyl alcohol, or polyethylene glycol. Currently, marketed compositions of phenobarbital sodium injections contain benzyl alcohol, alcohol, and propylene glycol, which pose a higher toxicity risk to neonates and therefore present a potential safety risk when used in the treatment of neonatal seizures.

Nevertheless, neonatologists have no choice but to give benzyl alcohol-, alcohol-, and propylene glycol-containing compositions to neonates. The use of a combination of various cosolvents at a higher concentrations also causes a higher osmolality (>500 mOsm) of the product. This is of particular concern for preterm infants, who are particularly vulnerable to the adverse effects of intravenous administration of hypertonic substances, as their infusions have been associated with increased risk of intraventricular hemorrhage, hepatic necrosis and necrotizing enterocolitis. Studies have shown that hyperosmolality and metabolic acidosis, then renal dysfunction and finally acute renal failure and clinical deterioration are major effects of increasing doses and serum concentrations of propylene glycol in neonates. In addition, several case reports of intoxication have pointed out the potential CNS (lethargy, coma, seizures) or local vascular affects (including hemolysis) most probably associated to higher plasma levels of propylene glycol and hyperosmolality following acute toxicity.

[0004] Propylene glycol is an example of a compound used commercially as a diluent or stabilizer in some extremely hypertonic preparations for intravenous use, including phenytoin, phenobarbital, diazepam, digoxine, and multivitamin solutions. Although it is considered to be a relatively safe substance, serum hyperosmolality and other harmful effects to newborns and infants have been reported, including secondary to transdermal absorption of propylene glycol from topical pharmaceutical preparations. In addition, the toxicity of propylene glycol to newborns and infants may be particularly acute because infants and newborns may have a delayed development of mechanisms to eliminate propylene glycol from their systems. All of these issues with propylene glycol has thus encouraged the search for alternatives to propylene glycol for use as a diluent for substances for intravenous use in neonates.

[0005] U.S. Patent Application Publication No. 20210085608 relates to phenobarbital sodium formulations and lyophilization. According to this publication, lyophilization may result to the stability in a phenobarbital sodium formulation. However, this publication fails to disclose or suggest the role that ethanol may play in the stability of a phenobarbital formulation.

[0006] U.S. Patent No. 9,901,576 relates to phenobarbital formulations. However, the examples of this patent contains higher amount ethanol for the stability. According to regulatory guidelines (for example European Medicines Agency guidance and The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use), the formulations having the solvent amount of over 50000 ppm are unsuitable for use in neonates.

SUMMARY OF THE INVENTION

[0007] The present inventors have developed stable pharmaceutical compositions of the hydrolytically unstable drug phenobarbital or salts thereof. The pharmaceutical compositions of the present disclosure provide stability over a lengthy shelf life, as measured by the amount of total impurities formed over time and that does not generate any significant amount of impurities during extended storage. The present inventors have also observed that the presence of higher levels of alcohol alone is not sufficient to control the level of impurities. Thus, embodiments of the present disclosure relate to pharmaceutical compositions of phenobarbital or salts thereof and methods of preparing the same by utilizing a combination of a certain level of alcohol and lyophilization.

[0008] In the first aspect, the present disclosure relates to a pharmaceutical composition of phenobarbital or salts thereof that has been reconstituted from a lyophilized pharmaceutical composition of phenobarbital or salts thereof, wherein the amount of total impurities in the pharmaceutical composition does not exceed 0.2% following 12 hours of storage at 20-25°C or 36 hours of storage at 2-8°C.

[0009] In the second aspect, the present disclosure relates to a pharmaceutical composition of phenobarbital or salts thereof, wherein the pharmaceutical composition has an alcohol content in the range from about 5000 ppm to 66000 ppm or alternatively from about 5000 ppm to 70000 ppm.

[0010] In the third aspect, the present disclosure relates to a lyophilized pharmaceutical composition of phenobarbital or salts thereof, wherein the composition has an alcohol content in the range from about 5000 ppm to about 66000 ppm or alternatively from about 5000 ppm to about 70000 ppm.

[0011] In the fourth aspect, the present disclosure relates to a pharmaceutical composition of phenobarbital or salts thereof that has been reconstituted from a lyophilized pharmaceutical composition of phenobarbital or salts thereof, wherein the pharmaceutical composition has an alcohol content in the range from about 5000 ppm to about 66000 ppm or alternatively from about 5000 ppm to about 70000 ppm.

[0012] In the fifth aspect, the present disclosure relates to a process of preparing a lyophilized pharmaceutical composition of phenobarbital or salts thereof having an alcohol content in the range from about 5000 ppm to about 66000 ppm or about 70000 ppm, wherein the process comprises dissolving phenobarbital or salts thereof in water to obtain an aqueous solution of phenobarbital or salts thereof in a concentration of 10-200 mg/ml and lyophilizing the aqueous solution to obtain the lyophilized pharmaceutical composition of phenobarbital or salts thereof.

[0013] In the sixth aspect, the present disclosure relates to a process of preparing a pharmaceutical composition of phenobarbital or salts thereof that has been reconstituted from a lyophilized pharmaceutical composition of phenobarbital or salts thereof, wherein the pharmaceutical composition has an alcohol content in the range from about 5000 ppm to about 66000 ppm or about 70000 ppm, the process comprises dissolving phenobarbital or salts thereof in water to obtain an aqueous solution having a concentration 10-200 mg/ml; lyophilizing the aqueous solution to obtain a lyophilized pharmaceutical composition of phenobarbital or salts thereof; and reconstituting the lyophilized pharmaceutical composition to obtain the pharmaceutical composition of phenobarbital or salts thereof.

[0014] In the seventh aspect, the present disclosure relates to a lyophilized pharmaceutical composition of phenobarbital or salts thereof having an alcohol content in the range from about 5000 ppm to about 66000 ppm or alternatively from about 5000 ppm to about 70000 ppm, wherein the lyophilized pharmaceutical composition is obtained by a process comprising: dissolving phenobarbital or salts thereof in water to obtain an aqueous solution having a concentration 10-200 mg/ml and lyophilizing the aqueous solution to obtain the lyophilized pharmaceutical composition of phenobarbital or salts thereof.

[0015] In the eighth aspect, the present disclosure relates to a pharmaceutical composition of phenobarbital or salts thereof that has been reconstituted from a lyophilized pharmaceutical composition of phenobarbital or salts thereof having an alcohol content in the range from about 5000 ppm to about 66000 ppm or alternatively from about 5000 ppm to about 70000 ppm, wherein the pharmaceutical composition is obtained by a process comprising: dissolving phenobarbital or salts thereof in water to obtain an aqueous solution having a concentration 10-200 mg/ml; lyophilizing the aqueous solution to obtain a lyophilized pharmaceutical composition of phenobarbital or salts thereof; and reconstituting the lyophilized pharmaceutical composition to obtain the pharmaceutical composition of phenobarbital or salts thereof.

[0016] In the ninth aspect, the present disclosure relates to a lyophilized pharmaceutical composition comprising phenobarbital sodium and ethanol, wherein ethanol is present in an amount sufficient to inhibit degradation of phenobarbital sodium, such that the amount of total impurities present following 36 months of storage at 20-25°C does not exceed 0.2%.

[0017] In the tenth aspect, the present disclosure relates to an aqueous solution for injection comprising phenobarbital sodium and ethanol, wherein ethanol is present in an amount sufficient to inhibit degradation of phenobarbital sodium, such that the amount of total impurities present following 12 hours of storage at 20-25°C or following 36 hours of storage at 2-8°C does not exceed 0.2%.

[0018] In the eleventh aspect, the present disclosure relates to a process for the preparation of a pharmaceutical composition of phenobarbital or salts thereof, wherein the process comprises dissolving phenobarbital or a salt thereof in water to obtain an aqueous solution having a concentration of 10-200 mg/ml and lyophilizing the aqueous solution to obtain a lyophilized pharmaceutical composition, wherein phenobarbital or salts thereof has an alcohol content in the range from about 9000 ppm to about 66000 ppm or alternatively from about 9000 ppm to about 70000 ppm or alternatively from about 9000 ppm to about 90000 ppm.

[0019] In another aspect, the present disclosure relates to a lyophilized pharmaceutical composition of phenobarbital sodium, wherein the composition has an ethanol content in the range from about 12000 ppm to about 25000 ppm; wherein the composition is stable up to 36 months of storage at 20-25°C such that the amount of total impurities present following 36 months of storage at 20-25°C does not exceed 0.2%; and wherein the composition is free of benzyl alcohol and propylene glycol.

[0020] In another aspect, the present disclosure relates to an aqueous solution for injection of phenobarbital sodium, wherein the aqueous solution has an ethanol content in the range from about 12000 ppm to about 25000 ppm; wherein the aqueous solution is stable up to 12 hours of storage at 20-25 °C or 36 hours of storage at 2-8 °C such that the amount of total impurities present following 12 hours of storage at 20-25°C or following 36 hours of storage at 2-8°C does not exceed 0.2%; wherein the aqueous solution is

reconstituted from a lyophilized pharmaceutical composition of phenobarbital sodium; and wherein the aqueous solution is free of benzyl alcohol and propylene glycol.

[0021] In another aspect, the present disclosure relates to a lyophilized pharmaceutical composition of phenobarbital or salts thereof, wherein the amount of alcohol in the lyophilized pharmaceutical composition following 36 months of storage at 20-25 °C, is in the range from about 5000 ppm to about 66000 ppm or alternatively from about 5000 ppm to about 70000 ppm.

[0022] In another aspect, the present disclosure relates to a pharmaceutical composition of phenobarbital or salts thereof that has been reconstituted from a lyophilized pharmaceutical composition of phenobarbital or salts thereof, wherein the amount of alcohol in the pharmaceutical composition following 12 hours of storage at 20-25°C or 36 hours of storage at 2-8°C, is in the range from about 5000 ppm to 66000 ppm or alternatively from about 5000 ppm to about 70000 ppm.

[0023] In another aspect, the present disclosure relates to a method of preventing degradation of phenobarbital or salts thereof, wherein the method comprises dissolving phenobarbital or salts thereof in water to obtain an aqueous solution having a concentration of 10-200 mg/ml; and lyophilizing the aqueous solution to obtain a lyophilized pharmaceutical composition of phenobarbital or salts thereof, wherein the phenobarbital or salts thereof has an alcohol content in the range from about 9000 ppm to about 66000 ppm or alternatively from about 9000 ppm to about 70000 ppm or alternatively from about 9000 ppm to about 90000 ppm.

DETAILED DESCRIPTION OF THE INVENTION

DEFINITIONS

[0024] The “phenobarbital or salts thereof’ that may be used according to the present disclosure may be phenobarbital base or a phenobarbital salt. The particular salt form of phenobarbital is not particularly limited, and in non-limiting examples, may be, for example, phenobarbital sodium, phenobarbital potassium, phenobarbital benzathine, phenobarbital betaine, or phenobarbital choline. Preferred embodiments utilize a phenobarbital sodium salt.

[0025] The term “reconstitution” as used herein, includes the addition of vehicle/diluent in to the lyophilized phenobarbital. In preferred embodiments, the

vehicle/diluent is water for injection, an aqueous saline solution or an aqueous dextrose solution. In an additional preferred embodiments, the vehicle/diluent is water for injection or a 0.9% aqueous saline solution.

[0026] The terms "about" as used herein refers to as modifying a term or value such that it is not an absolute. Such terms will be defined by the circumstances and the terms that they modify as those terms are understood by those of skill in the art. This includes, at very least, the degree of expected experimental error, technique error and instrument error for a given technique used to measure a value. The term "about" when used in the present application preceding a number and referring to it, is meant to designate any value which lies within the range of ±10%.

[0027] The term “total impurities” as used herein, includes known and unknown impurities, either present from the active pharmaceutical ingredient (API) or generated by the degradation of phenobarbital or salts thereof during the manufacturing or stability of the pharmaceutical compositions of the present disclosures. These total impurities include, but are not limited to, 2-phenyl-2-ethyl acetyl urea, 2-phenyl-2-ethyl-malonamide, a-phenylbutyrylguanidine, 2-phenylbutyric acid and 5-methyl-5-phenylbarbituric acid, and can be represented by following structural formulas:

2-phenyl-2 -ethyl acetyl urea 2 -phenyl-2 -ethyl- a-phenylbutyrylguanidine malonamide

5-methyl-5-phenylbarbituric acid

[0028] The term “correctable abnormalities” as used herein is defined as any abnormality which can be corrected by medication. The correctable abnormalities include hypoglycemia or hypocalcemia.

[0029] The term “C1-C3 alcohol” as used herein means an alkanol having 1-3 carbon atoms, which includes methanol, ethanol, 1 -propanol, or isopropyl alcohol.

[0030] In an embodiment, the present disclosure relates to a pharmaceutical composition of phenobarbital or salts thereof that has been reconstituted from a lyophilized pharmaceutical composition of phenobarbital or salts thereof.

[0031] In one embodiment, the pharmaceutical composition of phenobarbital or salts thereof is an aqueous solution for injection.

[0032] In one embodiment, the amount of total impurities in the pharmaceutical composition does not exceed 0.2% following 12 hours of storage at 20-25°C or 36 hours of storage at 2-8°C, alternatively, the total impurities does not exceed 0.15% following 12 hours of storage at 20-25°C or 36 hours of storage at 2-8°C, alternatively, the total impurities does not exceed 0.1% following 12 hours of storage at 20-25°C or 36 hours of storage at 2-8°C, alternatively, the total impurities does not exceed 0.05% following 12 hours of storage at 20-25°C or 36 hours of storage at 2-8°C.

[0033] In one embodiment, the present disclosure relates to a pharmaceutical composition of phenobarbital or salts thereof that has been reconstituted from a lyophilized pharmaceutical composition of phenobarbital or salts thereof, wherein the amount of total impurities in the pharmaceutical composition does not exceed 0.2% following 12 hours of storage at 20-25°C or 36 hours of storage at 2-8°C, alternatively, the total impurities does not exceed 0.15% following 12 hours of storage at 20-25°C or 36 hours of storage at 2-8°C, alternatively, the total impurities does not exceed 0.1% following 12 hours of storage at 20-25°C or 36 hours of storage at 2-8°C, alternatively, the total impurities does not exceed 0.05% following 12 hours of storage at 20-25°C or 36 hours of storage at 2-8°C.

[0034] In one embodiment, the total impurities are selected from 2-phenyl-2 -ethyl acetyl urea, 2-phenyl-2-ethyl-malonamide, a-phenylbutyrylguanidine, 2-phenylbutyric acid and 5 -methyl-5 -phenylbarbituric acid.

[0035] In one embodiment, the lyophilized pharmaceutical composition of phenobarbital or salts thereof is reconstituted with water for injection, an aqueous saline or an aqueous dextrose solution. In one embodiment, the lyophilized pharmaceutical composition of phenobarbital or salts thereof is reconstituted with 0.9% of aqueous saline.

[0036] In one embodiment, phenobarbital or salts thereof is present in a concentration of 10-200 mg/ml. In one embodiment, phenobarbital or salts thereof is present in a concentration of 10 mg/ml, 20 mg/ml, 30 mg/ml, 40 mg/ml, 50 mg/ml, 60 mg/ml, 70 mg/ml, 80 mg/ml, 90 mg/ml, 100 mg/ml, 110 mg/ml, 120 mg/ml, 130 mg/ml, 140 mg/ml, 150 mg/ml, 160 mg/ml, 170 mg/ml, 180 mg/ml, 190 mg/ml and 200 mg/ml.

[0037] In one embodiment, phenobarbital or salts thereof is phenobarbital base or phenobarbital sodium, preferably phenobarbital sodium.

[0038] In one embodiment, the pharmaceutical composition has an alcohol content in the range from about 5000 ppm to about 66000 ppm or alternatively from about 5000 ppm to about 70000 ppm. In one embodiment, the alcohol content is at least about 5000 ppm, about 10000 ppm, about 15000 ppm, about 20000 ppm, about 25000 ppm, about 30000 ppm, about 35000 ppm, about 40000 ppm, about 45000 ppm, about 50000 ppm, about 55000 ppm, about 60000 ppm, about 65000 ppm, about 66000 ppm or about 70000 ppm. In another embodiment, the alcohol content is in the range from about 12000 ppm to about 70000 ppm, about 12000 ppm to about 66000 ppm, about 12000 ppm to about 65000 ppm, about 12000 ppm to about 60000 ppm, about 12000 ppm to about 55000 ppm, about 12000 ppm to about 50000 ppm, about 12000 ppm to about 45000 ppm, about 12000 ppm to about 40000 ppm, about 12000 ppm to about 35000 ppm, about 12000 ppm to about 30000 ppm, about 12000 ppm to about 25000 ppm, about 12000 ppm to about 20000 ppm or about 12000 ppm to about 15000 ppm. In another embodiment, the alcohol content is in the range from about 15000 ppm to about 70000 ppm, about 15000 ppm to about 66000 ppm, about 25000 ppm to about 66000 ppm, about 35000 to about 66000 ppm, about 45000 ppm to about 66000 ppm, about 55000 ppm to about 66000 ppm, about 35000 ppm to about 55000 ppm or about 30000 ppm to about 50000 ppm.

[0039] In another embodiment, the alcohol content is in the range from about

12000 ppm to about 25000 ppm. In one embodiment, the alcohol content is in the range from about 35000 to about 66000 ppm.

[0040] In one embodiment, the alcohol is a C1-C3 alcohol.

[0041] In one embodiment, the alcohol is ethanol.

[0042] In one embodiment, the osmolality of said pharmaceutical composition is below 500 mOsm/kg. In one embodiment, the osmolality of said pharmaceutical composition is about 300-400 mOsm/kg.

[0043] In one embodiment, the pharmaceutical composition is free of benzyl alcohol.

[0044] In one embodiment, the pharmaceutical composition is also free of propylene glycol.

[0045] In a preferred embodiment, the pharmaceutical composition is free of benzyl alcohol and propylene glycol.

[0046] In another aspect, the present disclosure relates to a method for the treatment of neonatal seizure in newborn infants in need thereof, comprising administering the pharmaceutical composition of phenobarbital or salts thereof that has been reconstituted from a lyophilized pharmaceutical composition of phenobarbital or salts thereof, wherein the amount of total impurities in the pharmaceutical composition does not exceed 0.2% following 12 hours of storage at 20-25°C or 36 hours of storage at 2-8°C, alternatively, the total impurities does not exceed 0.15% following 12 hours of storage at 20-25°C or 36 hours of storage at 2-8°C, alternatively, the total impurities does not exceed 0.1% following 12 hours of storage at 20-25°C or 36 hours of storage at 2-8°C, alternatively, the total impurities does not exceed 0.05% following 12 hours of storage at 20-25°C or 36 hours of storage at 2-8°C.

[0047] In one embodiment, the newborn infants is 2 weeks of age or younger.

[0048] In one embodiment, the present disclosure relates to a method for the treatment of neonatal seizure in newborn infants 2 weeks of age or younger in need thereof, comprising administering a pharmaceutical composition of phenobarbital or salts thereof that has been reconstituted from a lyophilized phenobarbital or salts thereof composition, wherein the amount of total impurities in the pharmaceutical composition does not exceed 0.2% following 12 hours of storage at 20-25°C or 36 hours of storage at 2-8°C, alternatively, the total impurities does not exceed 0.15% following 12 hours of storage at 20-25°C or 36 hours of storage at 2-8°C, alternatively, the total impurities does not exceed 0.1% following 12 hours of storage at 20-25°C or 36 hours of storage at 2-8°C, alternatively, the total impurities does not exceed 0.05% following 12 hours of storage at 20-25°C or 36 hours of storage at 2-8°C.

[0049] In one embodiment, the method comprises administering the pharmaceutical composition to neonates in whom correctable abnormalities have been excluded or corrected. In one embodiment, the correctable abnormalities are hypoglycemia or hypocalcemia.

[0050] In one embodiment, the pharmaceutical composition is administered intravenously by infusion at a dose of 20mg/kg over a course of 15 minutes. In one embodiment, the method comprises administration of the pharmaceutical composition at an initial loading dose of 20mg/kg over a course of 15 minutes and measuring the electrographic seizures, wherein if the electrographic seizures persist or recur after completion of the initial loading dose, a second dose 20 mg/kg is administered over the subsequent 15 minutes for a total loading dose of 40 mg/kg. Electrographic seizures can be measured by any means and instruments known in the art like electroencephalogram (EEG) or using 2-channel EEG with amplitude-integrated EEG.

[0051] In one embodiment, the present invention discloses a method for the treatment of neonatal seizure in newborn infants comprising administering a pharmaceutical composition of phenobarbital or salts thereof that has been reconstituted from a lyophilized pharmaceutical composition of phenobarbital or salts thereof.

[0052] In one embodiment, the total impurities are selected from 2-phenyl-2 -ethyl acetyl urea, 2-phenyl-2-ethyl-malonamide, a-phenylbutyrylguanidine, 2-phenylbutyric acid and 5 -methyl-5 -phenylbarbituric acid.

[0053] In one embodiment, the pharmaceutical composition of phenobarbital or salts thereof is an aqueous solution for injection.

[0054] In one embodiment, the lyophilized pharmaceutical composition of phenobarbital or salts thereof is reconstituted with water for injection, an aqueous saline or an aqueous dextrose solution. In one embodiment, the lyophilized pharmaceutical composition of phenobarbital or salts thereof is reconstituted with 0.9% of aqueous saline.

[0055] In one embodiment, phenobarbital or salts thereof is present in a concentration of 10-200 mg/ml. In one embodiment, phenobarbital or salts thereof is present in a concentration of 10 mg/ml, 20 mg/ml, 30 mg/ml, 40 mg/ml, 50 mg/ml, 60 mg/ml, 70 mg/ml, 80 mg/ml, 90 mg/ml, 100 mg/ml, 110 mg/ml, 120 mg/ml, 130 mg/ml, 140 mg/ml, 150 mg/ml, 160 mg/ml, 170 mg/ml, 180 mg/ml, 190 mg/ml and 200 mg/ml.

[0056] In one embodiment, phenobarbital or salts thereof is phenobarbital base or phenobarbital sodium, preferably phenobarbital sodium.

[0057] In one embodiment, the pharmaceutical composition has an alcohol content in the range from about 5000 ppm to about 66000 ppm or alternatively from about 5000 ppm to about 70000 ppm. In one embodiment, the alcohol content is at least about 5000 ppm, about 10000 ppm, about 15000 ppm, about 20000 ppm, about 25000 ppm, about 30000 ppm, about 35000 ppm, about 40000 ppm, about 45000 ppm, about 50000 ppm, about 55000 ppm, about 60000 ppm, about 65000 ppm, about 66000 ppm, or about 70000 ppm. In another embodiment, the alcohol content is in the range from about 12000 ppm to about 70000 ppm, about 12000 ppm to about 66000 ppm, about 12000 ppm to about 65000 ppm, about 12000 ppm to about 60000 ppm, about 12000 ppm to about 55000 ppm, about 12000 ppm to about 50000 ppm, about 12000 ppm to about 45000 ppm, about 12000 ppm to about 40000 ppm, about 12000 ppm to about 35000 ppm, about 12000 ppm to about 30000 ppm, about 12000 ppm to about 25000 ppm, about 12000 ppm to about 20000 ppm or about 12000 ppm to about 15000 ppm. In another embodiment, the alcohol content is in the range from about 15000 ppm to about 70000 ppm, about 15000 ppm to about 66000 ppm, about 25000 ppm to about 66000 ppm, about 35000 to about 66000 ppm, about 45000 ppm to about 66000 ppm, about 55000 ppm to about 66000 ppm, about 35000 ppm to about 55000 ppm or about 30000 ppm to about 50000 ppm.

[0058] In another embodiment, the alcohol content is in the range from about

12000 ppm to about 25000 ppm. In one embodiment, the alcohol content is in the range from about 35000 to about 66000 ppm.

[0059] In one embodiment, the alcohol is a C1-C3 alcohol.

[0060] In one embodiment, the alcohol is ethanol.

[0061] In one embodiment, the osmolality of said pharmaceutical composition is below 500 mOsm/kg. In one embodiment, the osmolality of said pharmaceutical composition is about 300-400 mOsm/kg.

[0062] In one embodiment, the pharmaceutical composition is free of benzyl alcohol.

[0063] In one embodiment, the pharmaceutical composition is also free of propylene glycol.

[0064] In a preferred embodiment, the pharmaceutical composition is free of benzyl alcohol and propylene glycol.

[0065] In another embodiment, the present disclosure relates to a pharmaceutical composition of phenobarbital or salts thereof, wherein the pharmaceutical composition has an alcohol content in the range from about 5000 ppm to 66000 ppm or, alternatively, from about 5000 ppm to about 70000 ppm.

[0066] In one embodiment, the pharmaceutical composition has an alcohol content in the range from about 5000 ppm to about 66000 ppm, or, alternatively, from about 5000 ppm to about 70000 ppm. In one embodiment, the alcohol content is at least about 5000 ppm, about 10000 ppm, about 15000 ppm, about 20000 ppm, about 25000 ppm, about 30000 ppm, about 35000 ppm, about 40000 ppm, about 45000 ppm, about 50000 ppm, about 55000 ppm, about 60000 ppm, about 65000 ppm, about 66000 ppm, or about 70000 ppm. In another embodiment, the alcohol content is in the range from about 12000 ppm to about 70000 ppm, about 12000 ppm to about 66000 ppm, about 12000 ppm to about 65000 ppm, about 12000 ppm to about 60000 ppm, about 12000 ppm to about 55000 ppm, about 12000 ppm to about 50000 ppm, about 12000 ppm to about 45000 ppm, about 12000 ppm to about 40000 ppm, about 12000 ppm to about 35000 ppm, about 12000 ppm to about 30000 ppm, about 12000 ppm to about 25000 ppm, about 12000 ppm to about 20000 ppm or about 12000 ppm to about 15000 ppm. In another embodiment, the alcohol content is in the range from about 15000 ppm to about 70000 ppm, about 15000 ppm to about 66000 ppm, about 25000 ppm to about 66000 ppm, about 35000 to about 66000

ppm, about 45000 ppm to about 66000 ppm, about 55000 ppm to about 66000 ppm, about 35000 ppm to about 55000 ppm or about 30000 ppm to about 50000 ppm.

[0067] In another embodiment, the alcohol content is in the range from about

12000 ppm to about 25000 ppm. In one embodiment, the alcohol content is in the range from about 35000 to about 66000 ppm.

[0068] In one embodiment, the alcohol is a C1-C3 alcohol.

[0069] In one embodiment, the alcohol is ethanol.

[0070] In one embodiment, phenobarbital or salts thereof is phenobarbital base or phenobarbital sodium, preferably phenobarbital sodium.

[0071] In another embodiment, the pharmaceutical composition is a lyophilized pharmaceutical composition of phenobarbital or salts thereof.

[0072] In one embodiment, the lyophilized pharmaceutical composition is stable up to 36 months of storage at 20-25°C.

[0073] In one embodiment, the amount of total impurities present in the lyophilized pharmaceutical composition following 36 months of storage at 20-25 °C does not exceed 0.5%. In one embodiment, the amount of total impurities present in the lyophilized pharmaceutical composition following 36 months of storage at 20-25 °C does not exceed 0.2%, alternatively, the total impurities does not exceed 0.15% following 36 months of storage at 20-25°C, alternatively, the total impurities does not exceed 0.1% following 36 months of storage at 20-25°C, alternatively, the total impurities does not exceed 0.05% following 36 months of storage at 20-25°C.

[0074] In one embodiment, the total impurities are selected from 2-phenyl-2 -ethyl acetyl urea, 2-phenyl-2-ethyl-malonamide, a-phenylbutyrylguanidine, 2-phenylbutyric acid and 5 -methyl-5 -phenylbarbituric acid.

[0075] In another embodiment, the pharmaceutical composition is an aqueous solution for injection of phenobarbital or salts thereof.

[0076] In one embodiment, the aqueous solution is reconstituted from the lyophilized pharmaceutical composition of phenobarbital or salts thereof. In one

embodiment, the lyophilized pharmaceutical composition is reconstituted with water for injection, an aqueous saline or an aqueous dextrose solution. In another embodiment, the lyophilized pharmaceutical composition is reconstituted with 0.9% of aqueous saline.

[0077] In one embodiment, the aqueous solution comprises phenobarbital or salts thereof in a concentration of 10-200 mg/ml. In one embodiment, phenobarbital or salts thereof is present in a concentration of 10 mg/ ml, 20 mg/ ml, 30 mg/ ml, 40 mg/ ml, 50 mg/ ml, 60 mg/ ml, 70 mg/ ml, 80 mg/ ml, 90 mg/ ml, 100 mg/ ml, 110 mg/ ml, 120 mg/ ml, 130 mg/ ml, 140 mg/ ml, 150 mg/ ml, 160 mg/ ml, 170 mg/ ml, 180 mg/ ml, 190 mg/ ml and 200 mg/ ml.

[0078] In one embodiment, the aqueous solution is stable up to 12 hours of storage at 20-25 °C.

[0079] In one embodiment, the amount of total impurities present in the aqueous solution following 12 hours of storage at 20-25°C does not exceed 0.5%. In one embodiment, the amount of total impurities present in the aqueous solution following 12 hours of storage at 20-25°C does not exceed 0.2%, alternatively, the total impurities does not exceed 0.15% following 12 hours of storage at 20-25 °C, alternatively, the total impurities does not exceed 0.1% following 12 hours of storage at 20-25°C, alternatively, the total impurities does not exceed 0.05% following 12 hours of storage at 20-25°C.

[0080] In one embodiment, the aqueous solution is stable up to 36 hours of storage at 2-8°C.

[0081] In one embodiment, the amount of total impurities present in the aqueous solution following 36 hours of storage at 2-8°C does not exceed 0.5%. In one embodiment, the amount of total impurities present in the aqueous solution following 36 hours of storage at 2-8°C does not exceed 0.2%, alternatively, the total impurities does not exceed 0.15% following 36 hours of storage at 2-8°C, alternatively, the total impurities does not exceed 0.1% following 36 hours of storage at 2-8°C, alternatively, the total impurities does not exceed 0.05% following 36 hours of storage at 2-8°C.

[0082] In one embodiment, the total impurities are selected from 2-phenyl-2 -ethyl acetyl urea, 2-phenyl-2-ethyl-malonamide, a-phenylbutyrylguanidine, 2-phenylbutyric acid and 5 -methyl-5 -phenylbarbituric acid.

[0083] In one embodiment, the osmolality of said composition is below 500 mOsm/kg. In one embodiment, the osmolality of said aqueous solution is about 300-400 mOsm/kg.

[0084] In one embodiment, the pharmaceutical composition is free of benzyl alcohol.

[0085] In one embodiment, the pharmaceutical composition is also free of propylene glycol.

[0086] In a preferred embodiment, the pharmaceutical composition is free of benzyl alcohol and propylene glycol.

[0087] In another aspect, the present disclosure relates to a method for the treatment of neonatal seizure in newborn infants in need thereof, comprising administering the pharmaceutical composition of phenobarbital or salts thereof, wherein the pharmaceutical composition has an alcohol content in the range from about 5000 ppm to about 66000 ppm or alternatively from about 5000 ppm to about 70000 ppm.

[0088] In one embodiment, the newborn infants is 2 weeks of age or younger.

[0089] In one embodiment, the present disclosure relates to a method for the treatment of neonatal seizure in newborn infants 2 weeks of age or younger in need thereof, comprising administering the pharmaceutical composition of phenobarbital or salts thereof, wherein the pharmaceutical composition has an alcohol content in the range from about 5000 ppm to about 66000 ppm or alternatively from about 5000 ppm to about 70000 ppm.

[0090] In one embodiment, the method comprises administering the pharmaceutical composition to neonates in whom correctable abnormalities have been excluded or corrected. In one embodiment, the correctable abnormalities are hypoglycemia or hypocalcemia.

[0091] In one embodiment, the pharmaceutical composition is administered intravenously by infusion at a dose of 20mg/kg over a course of 15 minutes.

[0092] In one embodiment, the method comprises administration of the pharmaceutical composition at an initial loading dose of 20mg/kg over a course of 15 minutes and measuring the electrographic seizures, wherein if the electrographic seizures persist or recur after completion of the initial loading dose, a second dose 20 mg/kg is administered over the subsequent 15 minutes for a total loading dose of 40 mg/kg.

[0093] In one embodiment, the present invention discloses a method for the treatment of neonatal seizure in newborn infants comprising administering a pharmaceutical composition of phenobarbital or salts thereof, wherein the pharmaceutical composition has an alcohol content in the range from about 5000 ppm to 66000 ppm or, alternatively, from about 5000 ppm to about 70000 ppm.

[0094] In one embodiment, the pharmaceutical composition has an alcohol content in the range from about 5000 ppm to about 66000 ppm, or, alternatively, from about 5000 ppm to about 70000 ppm. In one embodiment, the alcohol content is at least about 5000 ppm, about 10000 ppm, about 15000 ppm, about 20000 ppm, about 25000 ppm, about 30000 ppm, about 35000 ppm, about 40000 ppm, about 45000 ppm, about 50000 ppm, about 55000 ppm, about 60000 ppm, about 65000 ppm, about 66000 ppm, or about 70000 ppm. In another embodiment, the alcohol content is in the range from about 12000 ppm to about 70000 ppm, about 12000 ppm to about 66000 ppm, about 12000 ppm to about 65000 ppm, about 12000 ppm to about 60000 ppm, about 12000 ppm to about 55000 ppm, about 12000 ppm to about 50000 ppm, about 12000 ppm to about 45000 ppm, about 12000 ppm to about 40000 ppm, about 12000 ppm to about 35000 ppm, about 12000 ppm to about 30000 ppm, about 12000 ppm to about 25000 ppm, about 12000 ppm to about 20000 ppm or about 12000 ppm to about 15000 ppm. In another embodiment, the alcohol content is in the range from about 15000 ppm to about 70000 ppm, about 15000 ppm to about 66000 ppm, about 25000 ppm to about 66000 ppm, about 35000 to about 66000 ppm, about 45000 ppm to about 66000 ppm, about 55000 ppm to about 66000 ppm, about 35000 ppm to about 55000 ppm or about 30000 ppm to about 50000 ppm.

[0095] In another embodiment, the alcohol content is in the range from about

12000 ppm to about 25000 ppm. In one embodiment, the alcohol content is in the range from about 35000 to about 66000 ppm.

[0096] In one embodiment, the alcohol is a C1-C3 alcohol.

[0097] In one embodiment, the alcohol is ethanol.

[0098] In one embodiment, phenobarbital or salts thereof is phenobarbital base or phenobarbital sodium, preferably phenobarbital sodium.

[0099] In one embodiment, the pharmaceutical composition is free of benzyl alcohol.

[0100] In one embodiment, the pharmaceutical composition is also free of propylene glycol.

[0101] In a preferred embodiment, the pharmaceutical composition is free of benzyl alcohol and propylene glycol.

[0102] In another embodiment, the pharmaceutical composition is a lyophilized pharmaceutical composition of phenobarbital or salts thereof.

[0103] In one embodiment, the lyophilized pharmaceutical composition is stable up to 36 months of storage at 20-25°C.

[0104] In one embodiment, the amount of total impurities present in the lyophilized pharmaceutical composition following 36 months of storage at 20-25 °C does not exceed 0.5%. In one embodiment, the amount of total impurities present in the lyophilized pharmaceutical composition following 36 months of storage at 20-25 °C does not exceed 0.2%, alternatively, the total impurities does not exceed 0.15% following 36 months of storage at 20-25°C, alternatively, the total impurities does not exceed 0.1% following 36 months of storage at 20-25°C, alternatively, the total impurities does not exceed 0.05% following 36 months of storage at 20-25°C.

[0105] In another embodiment, the pharmaceutical composition is an aqueous solution for injection of phenobarbital or salts thereof.

[0106] In one embodiment, the aqueous solution is reconstituted from the lyophilized pharmaceutical composition of phenobarbital or salts thereof. In one embodiment, the lyophilized pharmaceutical composition is reconstituted with water for injection, an aqueous saline or an aqueous dextrose solution. In another embodiment, the lyophilized pharmaceutical composition is reconstituted with 0.9% of aqueous saline. [0107] In one embodiment, the aqueous solution comprises phenobarbital or salts thereof in a concentration of 10-200 mg/ml. In one embodiment, phenobarbital or salts thereof is present in a concentration of 10 mg/ ml, 20 mg/ ml, 30 mg/ ml, 40 mg/ ml, 50 mg/ ml, 60 mg/ ml, 70 mg/ ml, 80 mg/ ml, 90 mg/ ml, 100 mg/ ml, 110 mg/ ml, 120 mg/ ml, 130 mg/ ml, 140 mg/ ml, 150 mg/ ml, 160 mg/ ml, 170 mg/ ml, 180 mg/ ml, 190 mg/ ml and 200 mg/ ml.

[0108] In one embodiment, the aqueous solution is stable up to 12 hours of storage at 20-25 °C.

[0109] In one embodiment, the amount of total impurities present in the aqueous solution following 12 hours of storage at 20-25°C does not exceed 0.5%. In one embodiment, the amount of total impurities present in the aqueous solution following 12 hours of storage at 20-25°C does not exceed 0.2%, alternatively, the total impurities does not exceed 0.15% following 12 hours of storage at 20-25 °C, alternatively, the total impurities does not exceed 0.1% following 12 hours of storage at 20-25°C, alternatively, the total impurities does not exceed 0.05% following 12 hours of storage at 20-25°C.

[0110] In one embodiment, the aqueous solution is stable up to 36 hours of storage at 2-8°C.

[0111] In one embodiment, the amount of total impurities present in the aqueous solution following 36 hours of storage at 2-8°C does not exceed 0.5%. In one embodiment, the amount of total impurities present in the aqueous solution following 36 hours of storage at 2-8°C does not exceed 0.2%, alternatively, the total impurities does not exceed 0.15% following 36 hours of storage at 2-8°C, alternatively, the total impurities does not exceed 0.1% following 36 hours of storage at 2-8°C, alternatively, the total impurities does not exceed 0.05% following 36 hours of storage at 2-8°C.

[0112] In one embodiment, the osmolality of said composition is below 500 mOsm/kg. In one embodiment, the osmolality of said aqueous solution is about 300-400 mOsm/kg.

[0113] In one embodiment, the total impurities are selected from 2-phenyl -2 -ethyl acetyl urea, 2-phenyl-2-ethyl-malonamide, a-phenylbutyrylguanidine, 2-phenylbutyric acid and 5 -methyl-5 -phenylbarbituric acid.

[0114] In yet another embodiment, the present disclosure relates to a lyophilized pharmaceutical composition of phenobarbital or salts thereof, wherein the composition has an alcohol content in the range from about 5000 ppm to about 66000 ppm or, alternatively, from about 5000 ppm to about 70000 ppm.

[0115] In one embodiment, the lyophilized pharmaceutical composition has an alcohol content in the range from about 5000 ppm to about 66000 ppm or, alternatively, from about 5000 ppm to about 70000 ppm. In one embodiment, the alcohol content is at least about 5000 ppm, about 10000 ppm, about 15000 ppm, about 20000 ppm, about 25000 ppm, about 30000 ppm, about 35000 ppm, about 40000 ppm, about 45000 ppm, about 50000 ppm, about 55000 ppm, about 60000 ppm, about 65000 ppm, about 66000 ppm, or about 70000 ppm. In another embodiment, the alcohol content is in the range from about 12000 ppm to about 70000 ppm, about 12000 ppm to about 66000 ppm, about 12000 ppm to about 65000 ppm, about 12000 ppm to about 60000 ppm, about 12000 ppm to about 55000 ppm, about 12000 ppm to about 50000 ppm, about 12000 ppm to about 45000 ppm, about 12000 ppm to about 40000 ppm, about 12000 ppm to about 35000 ppm, about 12000 ppm to about 30000 ppm, about 12000 ppm to about 25000 ppm, about 12000 ppm to about 20000 ppm or about 12000 ppm to about 15000 ppm. In another embodiment, the alcohol content is in the range from about 15000 ppm to about 70000 ppm, about 15000 ppm to about 66000 ppm, about 25000 ppm to about 66000 ppm, about 35000 to about 66000 ppm, about 45000 ppm to about 66000 ppm, about 55000 ppm to about 66000 ppm, about 35000 ppm to about 55000 ppm or about 30000 ppm to about 50000 ppm.

[0116] In another embodiment, the alcohol content is in the range from about

12000 ppm to about 25000 ppm. In one embodiment, the alcohol content is in the range from about 35000 to about 66000 ppm.

[0117] In one embodiment, the alcohol is a C1-C3 alcohol.

[0118] In one embodiment, the alcohol is ethanol.

[0119] In one embodiment, phenobarbital or salts thereof is phenobarbital base or phenobarbital sodium, preferably phenobarbital sodium.

[0120] In one embodiment, the lyophilized pharmaceutical composition is stable up to 36 months of storage at 20-25°C.

[0121] In one embodiment, the amount of total impurities present in the lyophilized pharmaceutical composition following 36 months of storage at 20-25 °C does not exceed 0.5%. In one embodiment, the amount of total impurities present in the lyophilized pharmaceutical composition following 36 months of storage at 20-25 °C does not exceed 0.2%, alternatively, the total impurities does not exceed 0.15% following 36 months of storage at 20-25°C, alternatively, the total impurities does not exceed 0.1% following 36 months of storage at 20-25°C, alternatively, the total impurities does not exceed 0.05% following 36 months of storage at 20-25°C.

[0122] In one embodiment, the total impurities are selected from 2-phenyl -2 -ethyl acetyl urea, 2-phenyl-2-ethyl-malonamide, a-phenylbutyrylguanidine, 2-phenylbutyric acid and 5 -methyl-5 -phenylbarbituric acid.

[0123] In one embodiment, the lyophilized pharmaceutical composition is free of benzyl alcohol.

[0124] In one embodiment, the lyophilized pharmaceutical composition is also free of propylene glycol.

[0125] In a preferred embodiment, the lyophilized pharmaceutical composition is free of benzyl alcohol and propylene glycol.

[0126] In another aspect, the present disclosure relates to a method for the treatment of neonatal seizure in newborn infants in need thereof, comprising administering the lyophilized pharmaceutical composition of phenobarbital or salts thereof, and wherein the lyophilized pharmaceutical composition has an alcohol content in the range from about 5000 ppm to about 66000 ppm or, alternatively, from about 5000 ppm to about 70000 ppm.

[0127] In one embodiment, the newborn infants is 2 weeks of age or younger.

[0128] In one embodiment, the present disclosure relates to a method for the treatment of neonatal seizure in newborn infants 2 weeks of age or younger in need thereof, comprising administering the lyophilized pharmaceutical composition of

phenobarbital or salts thereof, and wherein the lyophilized pharmaceutical composition has an alcohol content in the range from about 5000 ppm to about 66000 ppm or alternatively from about 5000 ppm to about 70000 ppm.

[0129] In one embodiment, the method comprises reconstituting the lyophilized pharmaceutical composition of phenobarbital or salts thereof immediately prior to the administration.

[0130] In one embodiment, the lyophilized pharmaceutical composition is reconstituted with water for injection, an aqueous saline or an aqueous dextrose solution to obtain the aqueous solution for injection of phenobarbital or salts thereof.

[0131] In one embodiment, the method comprises administering the aqueous solution to neonates in whom correctable abnormalities have been excluded or corrected. In one embodiment, the said correctable abnormalities are hypoglycemia or hypocalcemia.

[0132] In one embodiment, the aqueous solution is administered intravenously by infusion at a dose of 20mg/kg over a course of 15 minutes.

[0133] In one embodiment, the method comprises administration of the aqueous solution at an initial loading dose of 20mg/kg over a course of 15 minutes and measuring the electrographic seizures, wherein if the electrographic seizures persist or recur after completion of the initial loading dose, a second dose of 20 mg/kg is administered over the subsequent 15 minutes for a total loading dose of 40 mg/kg.

[0134] In one embodiment, the present invention discloses a method for the treatment of neonatal seizure in newborn infants comprising administering a lyophilized pharmaceutical composition of phenobarbital or salts thereof, wherein the composition has an alcohol content in the range from about 5000 ppm to about 66000 ppm or, alternatively, from about 5000 ppm to about 70000 ppm.

[0135] In one embodiment, the lyophilized pharmaceutical composition has an alcohol content in the range from about 5000 ppm to about 66000 ppm or, alternatively, from about 5000 ppm to about 70000 ppm. In one embodiment, the alcohol content is at least about 5000 ppm, about 10000 ppm, about 15000 ppm, about 20000 ppm, about 25000 ppm, about 30000 ppm, about 35000 ppm, about 40000 ppm, about 45000 ppm,

about 50000 ppm, about 55000 ppm, about 60000 ppm, about 65000 ppm, about 66000 ppm, or about 70000 ppm. In another embodiment, the alcohol content is in the range from about 12000 ppm to about 70000 ppm, about 12000 ppm to about 66000 ppm, about 12000 ppm to about 65000 ppm, about 12000 ppm to about 60000 ppm, about 12000 ppm to about 55000 ppm, about 12000 ppm to about 50000 ppm, about 12000 ppm to about 45000 ppm, about 12000 ppm to about 40000 ppm, about 12000 ppm to about 35000 ppm, about 12000 ppm to about 30000 ppm, about 12000 ppm to about 25000 ppm, about 12000 ppm to about 20000 ppm or about 12000 ppm to about 15000 ppm. In another embodiment, the alcohol content is in the range from about 15000 ppm to about 70000 ppm, about 15000 ppm to about 66000 ppm, about 25000 ppm to about 66000 ppm, about 35000 to about 66000 ppm, about 45000 ppm to about 66000 ppm, about 55000 ppm to about 66000 ppm, about 35000 ppm to about 55000 ppm or about 30000 ppm to about 50000 ppm.

[0136] In another embodiment, the alcohol content is in the range from about

12000 ppm to about 25000 ppm. In one embodiment, the alcohol content is in the range from about 35000 to about 66000 ppm.

[0137] In one embodiment, the alcohol is a C1-C3 alcohol.

[0138] In one embodiment, the alcohol is ethanol.

[0139] In one embodiment, phenobarbital or salts thereof is phenobarbital base or phenobarbital sodium, preferably phenobarbital sodium.

[0140] In one embodiment, the lyophilized pharmaceutical composition is stable up to 36 months of storage at 20-25°C.

[0141] In one embodiment, the amount of total impurities present in the lyophilized pharmaceutical composition following 36 months of storage at 20-25 °C does not exceed 0.5%. In one embodiment, the amount of total impurities present in the lyophilized pharmaceutical composition following 36 months of storage at 20-25 °C does not exceed 0.2%, alternatively, the total impurities does not exceed 0.15% following 36 months of storage at 20-25°C, alternatively, the total impurities does not exceed 0.1% following 36 months of storage at 20-25°C, alternatively, the total impurities does not exceed 0.05% following 36 months of storage at 20-25°C.

[0142] In one embodiment, the total impurities are selected from 2-phenyl -2 -ethyl acetyl urea, 2-phenyl-2-ethyl-malonamide, a-phenylbutyrylguanidine, 2-phenylbutyric acid and 5 -methyl-5 -phenylbarbituric acid.

[0143] In one embodiment, the lyophilized pharmaceutical composition is free of benzyl alcohol.

[0144] In one embodiment, the lyophilized pharmaceutical composition is also free of propylene glycol.

[0145] In a preferred embodiment, the lyophilized pharmaceutical composition is free of benzyl alcohol and propylene glycol.

[0146] In still yet another embodiment, the present disclosure relates to a pharmaceutical composition of phenobarbital or salts thereof that has been reconstituted from a lyophilized pharmaceutical composition of phenobarbital or salts thereof, wherein the pharmaceutical composition has an alcohol content in the range from about 5000 ppm to about 66000 ppm or, alternatively, from about 5000 ppm to about 70000 ppm.

[0147] In one embodiment, the pharmaceutical composition has an alcohol content in the range from about 5000 ppm to about 66000 ppm or, alternatively, from about 5000 ppm to about 70000 ppm. In one embodiment, the alcohol content is at least about 5000 ppm, about 10000 ppm, about 15000 ppm, about 20000 ppm, about 25000 ppm, about 30000 ppm, about 35000 ppm, about 40000 ppm, about 45000 ppm, about 50000 ppm, about 55000 ppm, about 60000 ppm, about 65000 ppm, about 66000 ppm, or about 70000 ppm. In another embodiment, the alcohol content is in the range from about 12000 ppm to about 70000 ppm, about 12000 ppm to about 66000 ppm, about 12000 ppm to about 65000 ppm, about 12000 ppm to about 60000 ppm, about 12000 ppm to about 55000 ppm, about 12000 ppm to about 50000 ppm, about 12000 ppm to about 45000 ppm, about 12000 ppm to about 40000 ppm, about 12000 ppm to about 35000 ppm, about 12000 ppm to about 30000 ppm, about 12000 ppm to about 25000 ppm, about 12000 ppm to about 20000 ppm or about 12000 ppm to about 15000 ppm. In another embodiment, the alcohol content is in the range from about 15000 ppm to about 70000 ppm, about 15000 ppm to about 66000 ppm, about 25000 ppm to about 66000 ppm, about 35000 to about 66000 ppm, about 45000 ppm to about 66000 ppm, about 55000 ppm to about 66000 ppm, about 35000 ppm to about 55000 ppm or about 30000 ppm to about 50000 ppm.

[0148] In another embodiment, the alcohol content is in the range from about

12000 ppm to about 25000 ppm. In one embodiment, the alcohol content is in the range from about 35000 to about 66000 ppm.

[0149] In one embodiment, the alcohol is a C1-C3 alcohol.

[0150] In one embodiment, the alcohol is ethanol.

[0151] In one embodiment, phenobarbital or salts thereof is phenobarbital base or phenobarbital sodium, preferably phenobarbital sodium.

[0152] In one embodiment, the lyophilized pharmaceutical composition is reconstituted with water for injection, an aqueous saline or an aqueous dextrose solution.

In one embodiment, the lyophilized pharmaceutical composition is reconstituted with 0.9% aqueous saline.

[0153] In one embodiment, the pharmaceutical composition is an aqueous solution for injection of phenobarbital or salts thereof.

[0154] In one embodiment, the pharmaceutical composition comprises phenobarbital or salts thereof in a concentration of 10-200 mg/ml. In one embodiment, phenobarbital or salts thereof is present in a concentration of 10 mg/ml, 20 mg/ml, 30 mg/ml, 40 mg/ml, 50 mg/ml, 60 mg/ml, 70 mg/ml, 80 mg/ml, 90 mg/ml, 100 mg/ml, 110 mg/ml, 120 mg/ml, 130 mg/ml, 140 mg/ml, 150 mg/ml, 160 mg/ml, 170 mg/ml, 180 mg/ml, 190 mg/ml and 200 mg/ml.

[0155] In one embodiment, the pharmaceutical composition is stable up to 12 hours of storage at 20-25 °C.

[0156] In one embodiment, the amount of total impurities present in the pharmaceutical composition following 12 hours of storage at 20-25°C does not exceed 0.5%. In one embodiment, the amount of total impurities present in the pharmaceutical composition following 12 hours of storage at 20-25°C does not exceed 0.2%, alternatively, the total impurities does not exceed 0.15% following 12 hours of storage at 20-25°C, alternatively, the total impurities does not exceed 0.1% following 12 hours of storage at 20-25°C, alternatively, the total impurities does not exceed 0.05% following 12 hours of storage at 20-25 °C.

[0157] In one embodiment, the pharmaceutical composition is stable up to 36 hours of storage at 2-8°C.

[0158] In one embodiment, the amount of total impurities present in the pharmaceutical composition following 36 hours of storage at 2-8°C does not exceed 0.5%. In one embodiment, the amount of total impurities present in the pharmaceutical composition following 36 hours of storage at 2-8°C does not exceed 0.2%, alternatively, the total impurities does not exceed 0.15% following 36 hours of storage at 2-8°C, alternatively, the total impurities does not exceed 0.1% following 36 hours of storage at 2-8°C, alternatively, the total impurities does not exceed 0.05% following 36 hours of storage at 2-8°C.

[0159] In one embodiment, the total impurities are selected from 2-phenyl -2 -ethyl acetyl urea, 2-phenyl-2-ethyl-malonamide, a-phenylbutyrylguanidine, 2-phenylbutyric acid and 5 -methyl-5 -phenylbarbituric acid.

[0160] In one embodiment, the osmolality of said pharmaceutical composition is below 500 mOsm/kg. In one embodiment, the osmolality of said aqueous solution is about 300-400 mOsm/kg.

[0161] In one embodiment, the pharmaceutical composition is free of benzyl alcohol.

[0162] In one embodiment, the pharmaceutical composition is also free of propylene glycol.

[0163] In a preferred embodiment, the pharmaceutical composition is free of benzyl alcohol and propylene glycol.

[0164] In another aspect, the present disclosure relates to a method for the treatment of neonatal seizure in newborn infants in need thereof, comprising administering the pharmaceutical composition of phenobarbital or salts thereof that has been reconstituted from a lyophilized pharmaceutical composition of phenobarbital or salts thereof, and wherein the pharmaceutical composition has an alcohol content in the range from about 5000 ppm to about 66000 ppm or, alternatively, from about 5000 ppm to about 70000 ppm.

[0165] In one embodiment, the newborn infants is 2 weeks of age or younger.

[0166] In one embodiment, the present disclosure relates to a method for the treatment of neonatal seizure in newborn infants 2 weeks of age or younger in need thereof, comprising administering the pharmaceutical composition of phenobarbital or salts thereof that has been reconstituted from a lyophilized pharmaceutical composition of phenobarbital or salts thereof, and wherein the pharmaceutical composition has an alcohol content in the range from about 5000 ppm to about 66000 ppm or, alternatively, from about 5000 ppm to about 70000 ppm.

[0167] In one embodiment, the method comprises administering the pharmaceutical composition to neonates in whom correctable abnormalities have been excluded or corrected. In one embodiment, the correctable abnormalities are hypoglycemia or hypocalcemia.

[0168] In one embodiment, the pharmaceutical composition is administered intravenously by infusion at a dose of 20mg/kg over a course of 15 minutes.

[0169] In one embodiment, the method comprises administration of the pharmaceutical composition at an initial loading dose of 20mg/kg over a course of 15 minutes and measuring the electrographic seizures, wherein if the electrographic seizures persist or recurs after completion of the initial loading dose, a second dose of 20 mg/kg is administered over the subsequent 15 minutes for a total loading dose of 40 mg/kg.

[0170] In one embodiment, the present invention discloses a method for the treatment of neonatal seizure in newborn infants comprising administering a pharmaceutical composition of phenobarbital or salts thereof that has been reconstituted from a lyophilized pharmaceutical composition of phenobarbital or salts thereof, wherein the pharmaceutical composition has an alcohol content in the range from about 5000 ppm to about 66000 ppm or, alternatively, from about 5000 ppm to about 70000 ppm.

[0171] In one embodiment, the pharmaceutical composition has an alcohol content in the range from about 5000 ppm to about 66000 ppm or, alternatively, from about 5000 ppm to about 70000 ppm. In one embodiment, the alcohol content is at least about 5000 ppm, about 10000 ppm, about 15000 ppm, about 20000 ppm, about 25000 ppm, about 30000 ppm, about 35000 ppm, about 40000 ppm, about 45000 ppm, about 50000 ppm,

about 55000 ppm, about 60000 ppm, about 65000 ppm, about 66000 ppm, or about 70000 ppm. In another embodiment, the alcohol content is in the range from about 12000 ppm to about 70000 ppm, about 12000 ppm to about 66000 ppm, about 12000 ppm to about 65000 ppm, about 12000 ppm to about 60000 ppm, about 12000 ppm to about 55000 ppm, about 12000 ppm to about 50000 ppm, about 12000 ppm to about 45000 ppm, about 12000 ppm to about 40000 ppm, about 12000 ppm to about 35000 ppm, about 12000 ppm to about 30000 ppm, about 12000 ppm to about 25000 ppm, about 12000 ppm to about 20000 ppm or about 12000 ppm to about 15000 ppm. In another embodiment, the alcohol content is in the range from about 15000 ppm to about 70000 ppm, about 15000 ppm to about 66000 ppm, about 25000 ppm to about 66000 ppm, about 35000 to about 66000 ppm, about 45000 ppm to about 66000 ppm, about 55000 ppm to about 66000 ppm, about 35000 ppm to about 55000 ppm or about 30000 ppm to about 50000 ppm.

[0172] In another embodiment, the alcohol content is in the range from about

12000 ppm to about 25000 ppm. In one embodiment, the alcohol content is in the range from about 35000 to about 66000 ppm.

[0173] In one embodiment, the alcohol is a C1-C3 alcohol.

[0174] In one embodiment, the alcohol is ethanol.

[0175] In one embodiment, phenobarbital or salts thereof is phenobarbital base or phenobarbital sodium, preferably phenobarbital sodium.

[0176] In one embodiment, the lyophilized pharmaceutical composition is reconstituted with water for injection, an aqueous saline or an aqueous dextrose solution.

In one embodiment, the lyophilized pharmaceutical composition is reconstituted with 0.9% aqueous saline.

[0177] In one embodiment, the pharmaceutical composition is an aqueous solution for injection of phenobarbital or salts thereof.

[0178] In one embodiment, the pharmaceutical composition comprises phenobarbital or salts thereof in a concentration of 10-200 mg/ml. In one embodiment, phenobarbital or salts thereof is present in a concentration of 10 mg/ml, 20 mg/ml, 30 mg/ml, 40 mg/ml, 50 mg/ml, 60 mg/ml, 70 mg/ml, 80 mg/ml, 90 mg/ml, 100 mg/ml, 110

mg/ml, 120 mg/ml, 130 mg/ml, 140 mg/ml, 150 mg/ml, 160 mg/ml, 170 mg/ml, 180 mg/ml, 190 mg/ml and 200 mg/ml.

[0179] In one embodiment, the pharmaceutical composition is stable up to 12 hours of storage at 20-25 °C.

[0180] In one embodiment, the amount of total impurities present in the pharmaceutical composition following 12 hours of storage at 20-25°C does not exceed 0.5%. In one embodiment, the amount of total impurities present in the pharmaceutical composition following 12 hours of storage at 20-25°C does not exceed 0.2%, alternatively, the total impurities does not exceed 0.15% following 12 hours of storage at 20-25°C, alternatively, the total impurities does not exceed 0.1% following 12 hours of storage at 20-25°C, alternatively, the total impurities does not exceed 0.05% following 12 hours of storage at 20-25 °C.

[0181] In one embodiment, the pharmaceutical composition is stable up to 36 hours of storage at 2-8°C.

[0182] In one embodiment, the amount of total impurities present in the pharmaceutical composition following 36 hours of storage at 2-8°C does not exceed 0.5%. In one embodiment, the amount of total impurities present in the pharmaceutical composition following 36 hours of storage at 2-8°C does not exceed 0.2%, alternatively, the total impurities does not exceed 0.15% following 36 hours of storage at 2-8°C, alternatively, the total impurities does not exceed 0.1% following 36 hours of storage at 2-8°C, alternatively, the total impurities does not exceed 0.05% following 36 hours of storage at 2-8°C.

[0183] In one embodiment, the total impurities are selected from 2-phenyl -2 -ethyl acetyl urea, 2-phenyl-2-ethyl-malonamide, a-phenylbutyrylguanidine, 2-phenylbutyric acid and 5 -methyl-5 -phenylbarbituric acid.

[0184] In one embodiment, the osmolality of the pharmaceutical composition is below 500 mOsm/kg. In one embodiment, the osmolality of the pharmaceutical composition is about 300-400 mOsm/kg.

[0185] In one embodiment, the pharmaceutical composition is free of benzyl alcohol.

[0186] In one embodiment, the pharmaceutical composition is also free of propylene glycol.

[0187] In a preferred embodiment, the pharmaceutical composition is free of benzyl alcohol and propylene glycol.

[0188] In another embodiment, the present disclosure relates to a process of preparing a lyophilized pharmaceutical composition of phenobarbital or salts thereof having an alcohol content in the range from about 5000 ppm to about 66000 ppm or, alternatively, from about 5000 ppm to about 70000 ppm, wherein the process comprises dissolving phenobarbital or salts thereof in water to obtain an aqueous solution of phenobarbital or salts thereof in a concentration of 10-200 mg/ml and lyophilizing the aqueous solution to obtain the lyophilized pharmaceutical composition of phenobarbital or salts thereof.

[0189] In one embodiment, the process comprises measuring the alcohol content of an aqueous solution of phenobarbital or salts thereof. In one embodiment, if the alcohol content of the aqueous solution is below 5000 ppm then the process further comprises a step of adding an alcohol in a quantity that is sufficient to achieve the alcohol content of at least about 5000 ppm.

[0190] In one embodiment, the process comprises measuring the alcohol content of the lyophilized pharmaceutical composition of phenobarbital or salts thereof. In one embodiment, the process may comprises repeating steps of lyophilization to achieve the alcohol content not more than about 66000 ppm or about 70000 ppm. In one embodiment, if the alcohol content is above 66000 ppm or 70000 ppm (whichever is desired), the process further comprises repeating the lyophilization step till the alcohol content of the lyophilized pharmaceutical composition is not more than about 66000 ppm or not more than about 70000 ppm. It is understood that even a single additional cycle of lyophilization would be sufficient or it has to be repeated n number of times to obtain the desired alcohol level.

[0191] In another aspect, the present disclosure relates to a process of preparing a lyophilized pharmaceutical composition of phenobarbital or salts thereof having an alcohol content in the range from about 5000 ppm to about 66000 ppm or, alternatively, from about 5000 ppm to about 70000 ppm, wherein the process comprises dissolving phenobarbital or salts thereof in water to obtain an aqueous solution having a concentration of 10-200 mg/ml; measuring the alcohol content of the aqueous solution; if the alcohol content is below 5000 ppm, adding an alcohol to achieve the alcohol content of at least about 5000 ppm; lyophilizing the aqueous solution to obtain a lyophilized pharmaceutical composition; measuring the alcohol content of the lyophilized pharmaceutical composition; if the alcohol content is above 66000 ppm or above about 70000 ppm (whichever is desired), repeating the lyophilization step multiple times until the alcohol content of the lyophilized pharmaceutical composition is not more than about 66000 ppm or is not more than about 70000 ppm.

[0192] In one embodiment, the process comprises addition of a pH modifier to the aqueous solution of phenobarbital or salts thereof to achieve a pH in a range of 8-12, preferably in a range of 9-11, more preferably in a range of 9-10.5.

[0193] In one embodiment, the pH modifier is selected from HC1 and/or NaOH. In one embodiment, the pH modifier is aqueous HC1 solution.

[0194] In one embodiment, the lyophilized pharmaceutical composition is stable up to 36 months of storage at 20-25°C.

[0195] In one embodiment, the lyophilized pharmaceutical composition has an alcohol content of at least about 5000 ppm, about 10000 ppm, about 15000 ppm, about 20000 ppm, about 25000 ppm, about 30000 ppm, about 35000 ppm, about 40000 ppm, about 45000 ppm, about 50000 ppm, about 55000 ppm, about 60000 ppm, about 65000 ppm, about 66000 ppm, or about 70000 ppm. In another embodiment, the alcohol content is in the range from about 12000 ppm to about 70000 ppm, about 12000 ppm to about 66000 ppm, about 12000 ppm to about 65000 ppm, about 12000 ppm to about 60000 ppm, about 12000 ppm to about 55000 ppm, about 12000 ppm to about 50000 ppm, about 12000 ppm to about 45000 ppm, about 12000 ppm to about 40000 ppm, about 12000 ppm to about 35000 ppm, about 12000 ppm to about 30000 ppm, about 12000 ppm to about 25000 ppm, about 12000 ppm to about 20000 ppm or about 12000 ppm to about 15000

ppm. In another embodiment, the alcohol content is in the range from about 15000 ppm to about 70000 ppm, about 15000 ppm to about 66000 ppm, about 25000 ppm to about 66000 ppm, about 35000 to about 66000 ppm, about 45000 ppm to about 66000 ppm, about 55000 ppm to about 66000 ppm, about 35000 ppm to about 55000 ppm or about 30000 ppm to about 50000 ppm.

[0196] In another embodiment, the alcohol content is in the range from about

12000 ppm to about 25000 ppm. In one embodiment, the alcohol content is in the range from about 35000 to about 66000 ppm.

[0197] In one embodiment, the alcohol is a C1-C3 alcohol.

[0198] In one embodiment, the alcohol is ethanol.

[0199] In one embodiment, phenobarbital or salts thereof is phenobarbital base or phenobarbital sodium, preferably phenobarbital sodium.

[0200] In one embodiment, the lyophilized pharmaceutical composition is stable up to 36 months of storage at 20-25°C.

[0201] In one embodiment, the amount of total impurities present in the lyophilized pharmaceutical composition following 36 months of storage at 20-25 °C does not exceed 0.5%. In one embodiment, the amount of total impurities present in the lyophilized pharmaceutical composition following 36 months of storage at 20-25 °C does not exceed 0.2%, alternatively, the total impurities does not exceed 0.15% following 36 months of storage at 20-25°C, alternatively, the total impurities does not exceed 0.1% following 36 months of storage at 20-25°C, alternatively, the total impurities does not exceed 0.05% following 36 months of storage at 20-25°C.

[0202] In one embodiment, the total impurities are selected from 2-phenyl-2 -ethyl acetyl urea, 2-phenyl-2-ethyl-malonamide, a-phenylbutyrylguanidine, 2-phenylbutyric acid and 5 -methyl-5 -phenylbarbituric acid.

[0203] In one embodiment, the lyophilized pharmaceutical composition is free of benzyl alcohol.

[0204] In one embodiment, the lyophilized pharmaceutical composition is also free of propylene glycol.

[0205] In a preferred embodiment, the lyophilized pharmaceutical composition is free of benzyl alcohol and propylene glycol.

[0206] In the another aspect, the present disclosure relates to a process of preparing a pharmaceutical composition of phenobarbital or salts thereof that has been reconstituted from a lyophilized pharmaceutical composition of phenobarbital or salts thereof, wherein the pharmaceutical composition has an alcohol content in the range from about 5000 ppm to about 66000 ppm or, alternatively, from about 5000 ppm to about 70000 ppm, wherein the process comprises dissolving phenobarbital or salts thereof in water to obtain an aqueous solution having a concentration of 10-200 mg/ml; lyophilizing the aqueous solution to obtain a lyophilized pharmaceutical composition of phenobarbital or salts thereof; and reconstituting the lyophilized pharmaceutical composition to obtain the pharmaceutical composition of phenobarbital or salts thereof.

[0207] In one embodiment, the process comprises measuring the alcohol content of an aqueous solution of phenobarbital or salts thereof. In one embodiment, if the alcohol content of the aqueous solution is below 5000 ppm then the process further comprises a step of adding an alcohol in a quantity that is sufficient to achieve the alcohol content of at least about 5000 ppm.

[0208] In one embodiment, the process comprises measuring the alcohol content of the lyophilized pharmaceutical composition of phenobarbital or salts thereof. In one embodiment, the process may comprises additional steps of lyophilization to achieve the alcohol content not more than about 66000 ppm or not more than about 70000 ppm (whichever is desired). In one embodiment, if the alcohol content is above 66000 ppm or about 70000 ppm, the process further comprises repeating the lyophilization step until the alcohol content of the lyophilized pharmaceutical composition is not more than about 66000 ppm or not more than about 70000 ppm. It is understood that even a single additional cycle of lyophilization would be sufficient or it has to be repeated n number of times to obtain the desired alcohol level.

[0209] In another aspect, the present disclosure relates to a process of preparing a pharmaceutical composition of phenobarbital or salts thereof that has been reconstituted

from a lyophilized pharmaceutical composition of phenobarbital or salts thereof, wherein the pharmaceutical composition has an alcohol content in the range from about 5000 ppm to about 66000 ppm or, alternatively, from about 5000 ppm to about 70000 ppm, wherein the process comprises dissolving phenobarbital or salts thereof in water to obtain an aqueous solution having a concentration of 10-200 mg/ml; measuring the alcohol content of aqueous solution; if the alcohol content is below 5000 ppm, adding an alcohol to achieve the alcohol content of at least about 5000 ppm; lyophilizing the aqueous solution to obtain a lyophilized pharmaceutical composition; measuring the alcohol content of the lyophilized pharmaceutical composition; if the alcohol content is above 66000 ppm or about 70000 ppm (whichever is desired), repeating the lyophilization step multiple times until the alcohol content of the lyophilized pharmaceutical composition is not more than about 66000 ppm or not more than about 70000 ppm (whichever is desired); and reconstituting the lyophilized pharmaceutical composition to obtain the pharmaceutical composition of phenobarbital or salts thereof.

[0210] In one embodiment, the process comprises addition of a pH modifier to the aqueous solution of phenobarbital or salts thereof to achieve a pH in a range of 8-12, preferably in a range of 9-11, more preferably in a range of 9-10.5. In one embodiment, the pH modifier is selected from HC1 and/or NaOH. In one embodiment, the pH modifier is aqueous HC1 solution.

[0211] In one embodiment, the lyophilized pharmaceutical composition is reconstituted with water for injection, an aqueous saline or an aqueous dextrose solution.

In one embodiment, the lyophilized pharmaceutical composition is reconstituted with 0.9% aqueous saline.

[0212] In one embodiment, the pharmaceutical composition has an alcohol content in the range from about 5000 ppm to about 66000 ppm or alternatively from about 5000 ppm to about 70000 ppm. In one embodiment, the alcohol content is at least about 5000 ppm, about 10000 ppm, about 15000 ppm, about 20000 ppm, about 25000 ppm, about 30000 ppm, about 35000 ppm, about 40000 ppm, about 45000 ppm, about 50000 ppm, about 55000 ppm, about 60000 ppm, about 65000 ppm, about 66000 ppm, or about 70000 ppm. In another embodiment, the alcohol content is in the range from about 12000 ppm to about 70000 ppm, about 12000 ppm to about 66000 ppm, about 12000 ppm to about 65000 ppm, about 12000 ppm to about 60000 ppm, about 12000 ppm to about 55000 ppm,

about 12000 ppm to about 50000 ppm, about 12000 ppm to about 45000 ppm, about 12000 ppm to about 40000 ppm, about 12000 ppm to about 35000 ppm, about 12000 ppm to about 30000 ppm, about 12000 ppm to about 25000 ppm, about 12000 ppm to about 20000 ppm or about 12000 ppm to about 15000 ppm. In another embodiment, the alcohol content is in the range from about 15000 ppm to about 70000 ppm, about 15000 ppm to about 66000 ppm, about 25000 ppm to about 66000 ppm, about 35000 to about 66000 ppm, about 45000 ppm to about 66000 ppm, about 55000 ppm to about 66000 ppm, about 35000 ppm to about 55000 ppm or about 30000 ppm to about 50000 ppm.

[0213] In another embodiment, the alcohol content is in the range from about

12000 ppm to about 25000 ppm. In one embodiment, the alcohol content is in the range from about 35000 to about 66000 ppm.

[0214] In one embodiment, the alcohol is a C1-C3 alcohol.

[0215] In one embodiment, the alcohol is ethanol.

[0216] In one embodiment, phenobarbital or salts thereof is phenobarbital base or phenobarbital sodium, preferably phenobarbital sodium.

[0217] In one embodiment, the pharmaceutical composition is an aqueous solution for injection of phenobarbital or salts thereof.

[0218] In one embodiment, the pharmaceutical composition comprises phenobarbital or salts thereof in a concentration of 10-200 mg/ml. In one embodiment, phenobarbital or salts thereof is present in a concentration of 10 mg/ml, 20 mg/ml, 30 mg/ml, 40 mg/ml, 50 mg/ml, 60 mg/ml, 70 mg/ml, 80 mg/ml, 90 mg/ml, 100 mg/ml, 110 mg/ml, 120 mg/ml, 130 mg/ml, 140 mg/ml, 150 mg/ml, 160 mg/ml, 170 mg/ml, 180 mg/ml, 190 mg/ml and 200 mg/ml.

[0219] In one embodiment, the pharmaceutical composition is stable up to 12 hours of storage at 20-25 °C.

[0220] In one embodiment, the amount of total impurities in the pharmaceutical composition present following 12 hours of storage at 20-25°C does not exceed 0.5%. In one embodiment, the amount of total impurities present in the pharmaceutical composition following 12 hours of storage at 20-25°C does not exceed 0.2%, alternatively, the total impurities does not exceed 0.15% following 12 hours of storage at 20-25°C, alternatively, the total impurities does not exceed 0.1% following 12 hours of storage at 20-25 °C, alternatively, the total impurities does not exceed 0.05% following 12 hours of storage at 20-25°C.

[0221] In one embodiment, the pharmaceutical composition is stable up to 36 hours of storage at 2-8°C.

[0222] In one embodiment, the amount of total impurities present in the pharmaceutical composition following 36 hours of storage at 2-8°C does not exceed 0.5%. In one embodiment, the amount of total impurities present in the pharmaceutical composition following 36 hours of storage at 2-8°C does not exceed 0.2%, alternatively, the total impurities does not exceed 0.15% following 36 hours of storage at 2-8°C, alternatively, the total impurities does not exceed 0.1% following 36 hours of storage at 2-8°C, alternatively, the total impurities does not exceed 0.05% following 36 hours of storage at 2-8°C.

[0223] In one embodiment, the total impurities are selected from 2-phenyl-2 -ethyl acetyl urea, 2-phenyl-2-ethyl-malonamide, a-phenylbutyrylguanidine, 2-phenylbutyric acid and 5 -methyl-5 -phenylbarbituric acid.

[0224] In one embodiment, the osmolality of the pharmaceutical composition is below 500 mOsm/kg. In one embodiment, the osmolality of the pharmaceutical composition is about 300-400 mOsm/kg.

[0225] In one embodiment, the pharmaceutical composition is free of benzyl alcohol.

[0226] In one embodiment, the pharmaceutical composition is also free of propylene glycol.

[0227] In a preferred embodiment, the pharmaceutical composition is free of benzyl alcohol and propylene glycol.

[0228] In another aspect, the present disclosure relates to a lyophilized pharmaceutical composition of phenobarbital or salts thereof having an alcohol content in the range from about 5000 ppm to about 66000 ppm or, alternatively, from about 5000

ppm to about 70000 ppm, wherein the lyophilized pharmaceutical composition is obtained by a process comprising: dissolving phenobarbital or salts thereof in water to obtain an aqueous solution having a concentration of 10-200 mg/ml and lyophilizing the aqueous solution to obtain the lyophilized pharmaceutical composition of phenobarbital or salts thereof.

[0229] In one embodiment, the process comprises measuring the alcohol content of an aqueous solution of phenobarbital or salts thereof. In one embodiment, if the alcohol content of the aqueous solution is below 5000 ppm then the process further comprises a step of adding an alcohol in a quantity that is sufficient to achieve the alcohol content of at least about 5000 ppm.

[0230] In one embodiment, the process comprises measuring the alcohol content of the lyophilized pharmaceutical composition of phenobarbital or salts thereof. In one embodiment, the process may comprises an additional step of lyophilization to achieve the alcohol content of not more than about 66000 ppm or not more than 70000 ppm (whichever is desired). In one embodiment, if the alcohol content is above 66000 ppm or about 70000 ppm, the process further comprises repeating the lyophilization step till the alcohol content of the lyophilized pharmaceutical composition is not more than about 66000 ppm or not more than about 70000 ppm (whichever is desired). It is understood that even a single additional cycle of lyophilization would be sufficient or it has to be repeated n number of times to obtain the desired alcohol level.

[0231] In one embodiment, the process comprises addition of a pH modifier to the aqueous solution of phenobarbital or salts thereof to achieve a pH in a range of 8-12, preferably in a range of 9-11, more preferably in a range of 9-10.5.

[0232] In one embodiment, the pH modifier is selected from HC1 and/or NaOH. In one embodiment, the pH modifier is aqueous HC1 solution.

[0233] In one embodiment, the lyophilized pharmaceutical composition has an alcohol content of at least about 5000 ppm, about 10000 ppm, about 15000 ppm, about 20000 ppm, about 25000 ppm, about 30000 ppm, about 35000 ppm, about 40000 ppm, about 45000 ppm, about 50000 ppm, about 55000 ppm, about 60000 ppm, about 65000 ppm, about 66000 ppm, or about 70000 ppm. In another embodiment, the alcohol content is in the range from about 12000 ppm to about 70000 ppm, about 12000 ppm to about

66000 ppm, about 12000 ppm to about 65000 ppm, about 12000 ppm to about 60000 ppm, about 12000 ppm to about 55000 ppm, about 12000 ppm to about 50000 ppm, about 12000 ppm to about 45000 ppm, about 12000 ppm to about 40000 ppm, about 12000 ppm to about 35000 ppm, about 12000 ppm to about 30000 ppm, about 12000 ppm to about 25000 ppm, about 12000 ppm to about 20000 ppm or about 12000 ppm to about 15000 ppm. In another embodiment, the alcohol content is in the range from about 15000 ppm to about 70000 ppm, about 15000 ppm to about 66000 ppm, about 25000 ppm to about 66000 ppm, about 35000 to about 66000 ppm, about 45000 ppm to about 66000 ppm, about 55000 ppm to about 66000 ppm, about 35000 ppm to about 55000 ppm or about 30000 ppm to about 50000 ppm.

[0234] In another embodiment, the alcohol content is in the range from about

12000 ppm to about 25000 ppm. In one embodiment, the alcohol content is in the range from about 35000 to about 66000 ppm.

[0235] In one embodiment, the alcohol is a C1-C3 alcohol.

[0236] In one embodiment, the alcohol is ethanol.

[0237] In one embodiment, phenobarbital or salts thereof is phenobarbital base or phenobarbital sodium, preferably phenobarbital sodium.

[0238] In one embodiment, the lyophilized pharmaceutical composition is stable up to 36 months of storage at 20-25°C.

[0239] In one embodiment, the amount of total impurities present in the lyophilized pharmaceutical composition following 36 months of storage at 20-25 °C does not exceed 0.5%. In one embodiment, the amount of total impurities present in the lyophilized pharmaceutical composition following 36 months of storage at 20-25 °C does not exceed 0.2%, alternatively, the total impurities does not exceed 0.15% following 36 months of storage at 20-25°C, alternatively, the total impurities does not exceed 0.1% following 36 months of storage at 20-25°C, alternatively, the total impurities does not exceed 0.05% following 36 months of storage at 20-25°C.

[0240] In one embodiment, the total impurities are selected from 2-phenyl-2 -ethyl acetyl urea, 2-phenyl-2-ethyl-malonamide, a-phenylbutyrylguanidine, 2-phenylbutyric acid and 5 -methyl-5 -phenylbarbituric acid.

[0241] In one embodiment, the lyophilized pharmaceutical composition is free of benzyl alcohol.

[0242] In one embodiment, the lyophilized pharmaceutical composition is also free of propylene glycol.

[0243] In a preferred embodiment, the lyophilized pharmaceutical composition is free of benzyl alcohol and propylene glycol.

[0244] In order to achieve a desired stability, the lyophilized pharmaceutical composition should have an alcohol content in the range from about 5000 ppm to 66000 ppm or, alternatively, from about 5000 ppm to about 70000 ppm, and thus the process may include the steps as discussed above for measuring the alcohol content, adding alcohol or removing additional alcohol by repeating the lyophilization step and ensuring that the alcohol content is achieved as described above.

[0245] In yet another aspect, the present disclosure relates to a pharmaceutical composition of phenobarbital or salts thereof that has been reconstituted from a lyophilized pharmaceutical composition of phenobarbital or salts thereof having an alcohol content in the range from about 5000 ppm to about 66000 ppm or, alternatively, from about 5000 ppm to about 70000 ppm, wherein the pharmaceutical composition is obtained by a process comprising: dissolving phenobarbital or salts thereof in water to obtain an aqueous solution having a concentration of 10-200 mg/ml; lyophilizing the aqueous solution to obtain the lyophilized pharmaceutical composition of phenobarbital or salts thereof; and reconstituting the lyophilized pharmaceutical composition to obtain the pharmaceutical composition of phenobarbital or salts thereof.

[0246] In one embodiment, the process comprises measuring the alcohol content of an aqueous solution of phenobarbital or salts thereof. In one embodiment, if the alcohol content of the aqueous solution is below 5000 ppm then the process further comprises a step of adding an alcohol in a quantity that is sufficient to achieve the alcohol content of at least about 5000 ppm.

[0247] In one embodiment, the process comprises measuring the alcohol content of the lyophilized pharmaceutical composition of phenobarbital or salts thereof. In one embodiment, the process may comprise an additional step of lyophilization to achieve the alcohol content not more than about 66000 ppm or not more than about 70000 ppm (whichever is desired). In one embodiment, if the alcohol content is above about 66000 ppm or above about 70000 ppm, the process further comprises repeating the lyophilization step until the alcohol content of the lyophilized pharmaceutical composition is not more than about 66000 ppm or not more than about 70000 ppm (whichever is desired). It is understood that even a single additional cycle of lyophilization would be sufficient or it has to be repeated n number of times to obtain the desired alcohol level.

[0248] In one embodiment, the process comprises addition of a pH modifier to the aqueous solution of phenobarbital or salts thereof to achieve a pH in a range of 8-12, preferably in a range of 9-11, more preferably in a range of 9-10.5.

[0249] In one embodiment, the pH modifier is selected from HC1 and/or NaOH. In one embodiment, the pH modifier is aqueous HC1 solution.

[0250] In one embodiment, the lyophilized pharmaceutical composition is reconstituted with water for injection, an aqueous saline or an aqueous dextrose solution.

In one embodiment, the lyophilized pharmaceutical composition is reconstituted with 0.9% aqueous saline.

[0251] In one embodiment, the pharmaceutical composition has an alcohol content in the range from about 5000 ppm to about 66000 ppm, or, alternatively, from about 5000 ppm to about 70000 ppm. In one embodiment, the alcohol content is at least about 5000 ppm, about 10000 ppm, about 15000 ppm, about 20000 ppm, about 25000 ppm, about 30000 ppm, about 35000 ppm, about 40000 ppm, about 45000 ppm, about 50000 ppm, about 55000 ppm, about 60000 ppm, about 65000 ppm, about 66000 ppm, or about 70000 ppm. In another embodiment, the alcohol content is in the range from about 12000 ppm to about 70000 ppm, about 12000 ppm to about 66000 ppm, about 12000 ppm to about 65000 ppm, about 12000 ppm to about 60000 ppm, about 12000 ppm to about 55000 ppm, about 12000 ppm to about 50000 ppm, about 12000 ppm to about 45000 ppm, about 12000 ppm to about 40000 ppm, about 12000 ppm to about 35000 ppm, about 12000 ppm to about 30000 ppm, about 12000 ppm to about 25000 ppm, about 12000 ppm to about

20000 ppm or about 12000 ppm to about 15000 ppm. In another embodiment, the alcohol content is in the range from about 15000 ppm to about 70000 ppm, about 15000 ppm to about 66000 ppm, about 25000 ppm to about 66000 ppm, about 35000 to about 66000 ppm, about 45000 ppm to about 66000 ppm, about 55000 ppm to about 66000 ppm, about 35000 ppm to about 55000 ppm or about 30000 ppm to about 50000 ppm.

[0252] In another embodiment, the alcohol content is in the range from about

12000 ppm to about 25000 ppm. In one embodiment, the alcohol content is in the range from about 35000 to about 66000 ppm.

[0253] In one embodiment, the alcohol is a C1-C3 alcohol.

[0254] In one embodiment, the alcohol is ethanol.

[0255] In one embodiment, phenobarbital or salts thereof is phenobarbital base or phenobarbital sodium, preferably phenobarbital sodium.

[0256] In one embodiment, the pharmaceutical composition is an aqueous solution for injection of phenobarbital or salts thereof.

[0257] In one embodiment, the pharmaceutical composition comprises phenobarbital or salts thereof in a concentration of 10-200 mg/ml. In one embodiment, phenobarbital or salts thereof is present in a concentration of 10 mg/ml, 20 mg/ml, 30 mg/ml, 40 mg/ml, 50 mg/ml, 60 mg/ml, 70 mg/ml, 80 mg/ml, 90 mg/ml, 100 mg/ml, 110 mg/ml, 120 mg/ml, 130 mg/ml, 140 mg/ml, 150 mg/ml, 160 mg/ml, 170 mg/ml, 180 mg/ml, 190 mg/ml and 200 mg/ml.

[0258] In one embodiment, the pharmaceutical composition is stable up to 12 hours of storage at 20-25 °C.

[0259] In one embodiment, the amount of total impurities present in the pharmaceutical composition following 12 hours of storage at 20-25°C does not exceed 0.5%. In one embodiment, the amount of total impurities present in the pharmaceutical composition following 12 hours of storage at 20-25°C does not exceed 0.2%, alternatively, the total impurities does not exceed 0.15% following 12 hours of storage at 20-25°C, alternatively, the total impurities does not exceed 0.1% following 12 hours of storage at 20-25°C, alternatively, the total impurities does not exceed 0.05% following 12 hours of storage at 20-25 °C.

[0260] In one embodiment, the pharmaceutical composition is stable up to 36 hours of storage at 2-8°C.

[0261] In one embodiment, the amount of total impurities present in the pharmaceutical composition following 36 hours of storage at 2-8°C does not exceed 0.5%. In one embodiment, the amount of total impurities present in the pharmaceutical composition following 36 hours of storage at 2-8°C does not exceed 0.2%, alternatively, the total impurities does not exceed 0.15% following 36 hours of storage at 2-8°C, alternatively, the total impurities does not exceed 0.1% following 36 hours of storage at 2-8°C, alternatively, the total impurities does not exceed 0.05% following 36 hours of storage at 2-8°C.

[0262] In one embodiment, the total impurities are selected from 2-phenyl-2 -ethyl acetyl urea, 2-phenyl-2-ethyl-malonamide, a-phenylbutyrylguanidine, 2-phenylbutyric acid and 5 -methyl-5 -phenylbarbituric acid.

[0263] In one embodiment, the osmolality of the pharmaceutical composition is below 500 mOsm/kg. In one embodiment, the osmolality of the pharmaceutical composition is about 300-400 mOsm/kg.

[0264] In one embodiment, the pharmaceutical composition is free of benzyl alcohol.

[0265] In one embodiment, the pharmaceutical composition is also free of propylene glycol.

[0266] In a preferred embodiment, the pharmaceutical composition is free of benzyl alcohol and propylene glycol.

[0267] In order to achieve a desired stability, the pharmaceutical composition should have an alcohol content in the range from about 5000 ppm to 66000 ppm or, alternatively, from about 5000 ppm to about 70000 ppm, and thus the process may include the steps as discussed above for measuring the alcohol content, adding alcohol or

removing additional alcohol by repeating the lyophilization step and ensuring that the alcohol content is achieved as described above.

[0268] In still yet another aspect, the present disclosure relates to a lyophilized pharmaceutical composition comprising phenobarbital or salts thereof and an alcohol.

[0269] In one embodiment, the alcohol is present in an amount sufficient to inhibit phenobarbital degradation, such that the amount of total impurities present in the lyophilized pharmaceutical composition following 36 months of storage at 20-25 °C does not exceed 0.5%. In one embodiment, the amount of total impurities present in the lyophilized pharmaceutical composition following 36 months of storage at 20-25 °C does not exceed 0.2%, alternatively, the total impurities does not exceed 0.15% following 36 months of storage at 20-25°C, alternatively, the total impurities does not exceed 0.1% following 36 months of storage at 20-25°C, alternatively, the total impurities does not exceed 0.05% following 36 months of storage at 20-25°C.

[0270] In one embodiment, the total impurities are selected from 2-phenyl -2 -ethyl acetyl urea, 2-phenyl-2-ethyl-malonamide, a-phenylbutyrylguanidine, 2-phenylbutyric acid and 5 -methyl-5 -phenylbarbituric acid.

[0271] In one embodiment, the amount of alcohol sufficient to inhibit phenobarbital degradation is in the range from about 5000 ppm to about 66000 ppm or, alternatively, from about 5000 ppm to about 70000 ppm. In one embodiment, the alcohol content is at least about 5000 ppm, about 10000 ppm, about 15000 ppm, about 20000 ppm, about 25000 ppm, about 30000 ppm, about 35000 ppm, about 40000 ppm, about 45000 ppm, about 50000 ppm, about 55000 ppm, about 60000 ppm, about 65000 ppm, about 66000 ppm, or about 70000 ppm. In another embodiment, the alcohol content is in the range from about 12000 to about 70000 ppm, about 12000 ppm to about 66000 ppm, about 12000 ppm to about 65000 ppm, about 12000 ppm to about 60000 ppm, about 12000 ppm to about 55000 ppm, about 12000 ppm to about 50000 ppm, about 12000 ppm to about 45000 ppm, about 12000 ppm to about 40000 ppm, about 12000 ppm to about 35000 ppm, about 12000 ppm to about 30000 ppm, about 12000 ppm to about 25000 ppm, about 12000 ppm to about 20000 ppm or about 12000 ppm to about 15000 ppm. In another embodiment, the alcohol content is in the range from about 15000 ppm to about 70000 ppm, about 15000 ppm to about 66000 ppm, about 25000 ppm to about 66000 ppm, about 35000 to about 66000 ppm, about 45000 ppm to about 66000 ppm, about 55000 ppm to about 66000 ppm, about 35000 ppm to about 55000 ppm or about 30000 ppm to about 50000 ppm.

[0272] In another embodiment, the alcohol content is in the range from about

12000 ppm to about 25000 ppm. In one embodiment, the alcohol content is in the range from about 35000 to about 66000 ppm.

[0273] In one embodiment, the alcohol is a C1-C3 alcohol.

[0274] In one embodiment, the alcohol is ethanol.

[0275] In one embodiment, phenobarbital or salts thereof is phenobarbital base or phenobarbital sodium, preferably phenobarbital sodium.

[0276] In one embodiment, the lyophilized pharmaceutical composition is stable up to 36 months of storage at 20-25°C.

[0277] In one embodiment, the lyophilized pharmaceutical composition is free of benzyl alcohol.

[0278] In one embodiment, the lyophilized pharmaceutical composition is also free of propylene glycol.

[0279] In a preferred embodiment, the lyophilized pharmaceutical composition is free of benzyl alcohol and propylene glycol.

[0280] In one embodiment, the present disclosure relates to a lyophilized pharmaceutical composition comprising phenobarbital sodium and ethanol, wherein ethanol is present in an amount sufficient to inhibit degradation of phenobarbital sodium, such that the amount of total impurities present in the lyophilized pharmaceutical composition following 36 months of storage at 20-25 °C does not exceed 0.2%, alternatively, the total impurities does not exceed 0.15%, alternatively, the total impurities does not exceed 0.1%, alternatively, the total impurities does not exceed 0.05%; wherein the amount of ethanol sufficient to inhibit degradation of phenobarbital sodium is in the range from about 12000 ppm to about 25000 ppm; and

wherein the pharmaceutical composition is free of benzyl alcohol and propylene glycol.

[0281] In another aspect, the present disclosure relates to an aqueous solution for injection comprising phenobarbital or salts thereof and an alcohol.

[0282] In one embodiment, the aqueous solution for injection is reconstituted from a lyophilized pharmaceutical composition of phenobarbital or salts thereof.

[0283] In one embodiment, the lyophilized pharmaceutical composition is reconstituted with water for injection, an aqueous saline or an aqueous dextrose solution.

[0284] In one embodiment, the alcohol is present in an amount sufficient to inhibit phenobarbital degradation, such that the amount of total impurities present in the aqueous solution following 12 hours of storage at 20-25°C does not exceed 0.5%. In one embodiment, the amount of total impurities present in the aqueous solution following 12 hours of storage at 20-25°C does not exceed 0.2%, alternatively, the total impurities does not exceed 0.15%, alternatively, the total impurities does not exceed 0.1%, alternatively the total impurities does not exceed 0.05%.

[0285] In one embodiment, the alcohol is present in an amount sufficient to inhibit phenobarbital degradation, such that the amount of total impurities present in the aqueous solution following 36 hours of storage at 2-8°C does not exceed 0.5%. In one embodiment, the amount of total impurities present in the aqueous solution following 36 hours of storage at 2-8°C does not exceed 0.2%, alternatively, the total impurities does not exceed 0.15%, alternatively, the total impurities does not exceed 0.1%, alternatively, the total impurities does not exceed 0.05%.

[0286] In one embodiment, the total impurities are selected from 2-phenyl-2 -ethyl acetyl urea, 2-phenyl-2-ethyl-malonamide, a-phenylbutyrylguanidine, 2-phenylbutyric acid and 5 -methyl-5 -phenylbarbituric acid.

[0287] In one embodiment, the amount of alcohol sufficient to inhibit phenobarbital degradation is in the range from about 5000 ppm to about 66000 ppm or, alternatively, from about 5000 ppm to about 70000 ppm. In one embodiment, the alcohol content is at least about 5000 ppm, about 10000 ppm, about 15000 ppm, about 20000 ppm, about 25000 ppm, about 30000 ppm, about 35000 ppm, about 40000 ppm, about 45000

ppm, about 50000 ppm, about 55000 ppm, about 60000 ppm, about 65000 ppm, about 66000 ppm, or about 70000 ppm. In another embodiment, the alcohol content is in the range from about 12000 ppm to about 70000 ppm, about 12000 ppm to about 66000 ppm, about 12000 ppm to about 65000 ppm, about 12000 ppm to about 60000 ppm, about 12000 ppm to about 55000 ppm, about 12000 ppm to about 50000 ppm, about 12000 ppm to about 45000 ppm, about 12000 ppm to about 40000 ppm, about 12000 ppm to about 35000 ppm, about 12000 ppm to about 30000 ppm, about 12000 ppm to about 25000 ppm, about 12000 ppm to about 20000 ppm or about 12000 ppm to about 15000 ppm. In another embodiment, the alcohol content is in the range from about 15000 ppm to about 70000 ppm, about 15000 ppm to about 66000 ppm, about 25000 ppm to about 66000 ppm, about 35000 to about 66000 ppm, about 45000 ppm to about 66000 ppm, about 55000 ppm to about 66000 ppm, about 35000 ppm to about 55000 ppm or about 30000 ppm to about 50000 ppm.

[0288] In another embodiment, the alcohol content is in the range from about

12000 ppm to about 25000 ppm. In one embodiment, the alcohol content is in the range from about 35000 to about 66000 ppm.

[0289] In one embodiment, the alcohol is a C1-C3 alcohol.

[0290] In one embodiment, the alcohol is ethanol.

[0291] In one embodiment, phenobarbital or salts thereof is phenobarbital base or phenobarbital sodium, preferably phenobarbital sodium.

[0292] In one embodiment, the aqueous solution comprises phenobarbital or salts thereof in a concentration of 10-200 mg/ml. In one embodiment, phenobarbital or salts thereof is present in a concentration of 10 mg/ml, 20 mg/ml, 30 mg/ml, 40 mg/ml, 50 mg/ml, 60 mg/ml, 70 mg/ml, 80 mg/ml, 90 mg/ml, 100 mg/ml, 110 mg/ml, 120 mg/ml,

130 mg/ml, 140 mg/ml, 150 mg/ml, 160 mg/ml, 170 mg/ml, 180 mg/ml, 190 mg/ml and 200 mg/ml.

[0293] In one embodiment, the aqueous solution is stable up to 12 hours of storage at 20-25 °C.

[0294] In one embodiment, the aqueous solution is stable up to 36 hours of storage at 2-8°C.

[0295] In one embodiment, the osmolality of the aqueous solution is below 500 mOsm/kg. In one embodiment, the osmolality of the aqueous solution is about 300-400 mOsm/kg.

[0296] In one embodiment, the aqueous solution is free of benzyl alcohol.

[0297] In one embodiment, the aqueous solution is also free of propylene glycol.

[0298] In a preferred embodiment, the aqueous solution is free of benzyl alcohol and propylene glycol.

[0299] In one embodiment, the present disclosure relates to an aqueous solution for injection comprising phenobarbital sodium and ethanol, wherein ethanol is present in an amount sufficient to inhibit degradation of phenobarbital sodium, such that the amount of total impurities present in the aqueous solution following 12 hours of storage at 20-25°C or following 36 hours of storage at 2-8°C does not exceed 0.2%, alternatively, does not exceed 0.15%, alternatively, does not exceed 0.1%, alternatively, does not exceed 0.05%;

wherein the amount of ethanol sufficient to inhibit degradation of phenobarbital sodium is in the range from about 12000 ppm to about 25000 ppm;

wherein phenobarbital sodium is present in a concentration from 10-200 mg/ml; wherein the aqueous solution is reconstituted from a lyophilized pharmaceutical composition of phenobarbital sodium; and

wherein the aqueous solution is free of benzyl alcohol and propylene glycol.

[0300] In yet another aspect, the present disclosure relates to a process for the preparation of a pharmaceutical composition of phenobarbital or salts thereof, wherein the process comprises dissolving phenobarbital or salt thereof in water to obtain an aqueous solution having a concentration of 10-200 mg/ml and lyophilizing the aqueous solution to obtain a lyophilized pharmaceutical composition, wherein phenobarbital or salts thereof has an alcohol content in the range from about 9000 ppm to about 66000 ppm, or,

alternatively, from about 9000 ppm to about 70000 ppm, or, alternatively, from about 9000 ppm to about 90000 ppm.

[0301] In one embodiment, the process comprises phenobarbital or salts thereof having an alcohol content in the range from about 9000 ppm to about 66000 ppm, or, alternatively, from about 9000 ppm to about 70000 ppm, or, alternatively, from about 9000 ppm to about 90000 ppm. In one embodiment, the active pharmaceutical ingredient of phenobarbital or salts thereof for the purpose of this embodiment is having an alcohol content in the range from about 9000 ppm to about 66000 ppm, or, alternatively, from about 9000 ppm to about 70000 ppm, or, alternatively, from about 9000 ppm to about 90000 ppm.

[0302] In one embodiment, the process further comprises reconstitution of a lyophilized pharmaceutical composition. In one embodiment, a lyophilized pharmaceutical composition is reconstituted with water for injection, an aqueous saline or an aqueous dextrose solution. In one embodiment, a lyophilized pharmaceutical composition is reconstituted with 0.9% aqueous saline.

[0303] In one embodiment, phenobarbital or salts thereof has an alcohol content of at least about 9000 ppm, about 10000 ppm, about 15000 ppm, about 20000 ppm, about 25000 ppm, about 30000 ppm, about 35000 ppm, about 40000 ppm, about 45000 ppm, about 50000 ppm, about 55000 ppm, about 60000 ppm, about 65000 ppm, about 66000 ppm, about 70000 ppm, or about 90000 ppm. In another embodiment, the alcohol content is in the range from about 12000 ppm to about 90000 ppm, about 12000 ppm to about 70000 ppm, about 12000 ppm to about 66000 ppm, about 12000 ppm to about 65000 ppm, about 12000 ppm to about 60000 ppm, about 12000 ppm to about 55000 ppm, about 12000 ppm to about 50000 ppm, about 12000 ppm to about 45000 ppm, about 12000 ppm to about 40000 ppm, about 12000 ppm to about 35000 ppm, about 12000 ppm to about 30000 ppm, about 12000 ppm to about 25000 ppm, about 12000 ppm to about 20000 ppm or about 12000 ppm to about 15000 ppm. In another embodiment, the alcohol content is in the range from about 15000 ppm to about 90000 ppm, about 15000 ppm to about 70000 ppm, about 15000 ppm to about 66000 ppm, about 25000 ppm to about 66000 ppm, about 35000 to about 66000 ppm, about 45000 ppm to about 66000 ppm, about 55000 ppm to about 66000 ppm, about 35000 ppm to about 55000 ppm or about 30000 ppm to about 50000 ppm.

[0304] In another embodiment, the alcohol content is in the range from about

12000 ppm to about 25000 ppm. In one embodiment, the alcohol content is in the range from about 35000 to about 66000 ppm.

[0305] In one embodiment, the alcohol is a C1-C3 alcohol.

[0306] In one embodiment, the alcohol is ethanol.

[0307] In one embodiment, phenobarbital or salts thereof is phenobarbital base or phenobarbital sodium, preferably phenobarbital sodium.

[0308] In one embodiment, the pharmaceutical composition is free of benzyl alcohol.

[0309] In one embodiment, the pharmaceutical composition is also free of propylene glycol.

[0310] In a preferred embodiment, the pharmaceutical composition is free of benzyl alcohol and propylene glycol.

[0311] In one embodiment, the pharmaceutical composition is a lyophilized pharmaceutical composition of phenobarbital or salts thereof.

[0312] In one embodiment, the lyophilized pharmaceutical composition is stable up to 36 months of storage at 20-25°C.

[0313] In one embodiment, the amount of total impurities present in the lyophilized pharmaceutical composition following 36 months of storage at 20-25 °C does not exceed 0.5%. In one embodiment, the amount of total impurities present in the lyophilized pharmaceutical composition following 36 months of storage at 20-25°C does not exceed 0.2%, alternatively, the total impurities does not exceed 0.15% following 36 months of storage at 20-25°C, alternatively, the total impurities does not exceed 0.1% following 36 months of storage at 20-25°C, alternatively, the total impurities does not exceed 0.05% following 36 months of storage at 20-25°C.

[0314] In one embodiment, the pharmaceutical composition is an aqueous solution for injection of phenobarbital or salts thereof.

[0315] In one embodiment, the aqueous solution comprises phenobarbital or salts thereof in a concentration of 10-200 mg/ml. In one embodiment, phenobarbital or salts thereof is present in a concentration of 10 mg/ ml, 20 mg/ ml, 30 mg/ ml, 40 mg/ ml, 50 mg/ ml, 60 mg/ ml, 70 mg/ ml, 80 mg/ ml, 90 mg/ ml, 100 mg/ ml, 110 mg/ ml, 120 mg/ ml, 130 mg/ ml, 140 mg/ ml, 150 mg/ ml, 160 mg/ ml, 170 mg/ ml, 180 mg/ ml, 190 mg/ ml and 200 mg/ ml.

[0316] In one embodiment, the aqueous solution is stable up to 12 hours of storage at 20-25 °C.

[0317] In one embodiment, the amount of total impurities present in the aqueous solution following 12 hours of storage at 20-25°C does not exceed 0.5%. In one embodiment, the amount of total impurities present in the aqueous solution following 12 hours of storage at 20-25°C does not exceed 0.2%, alternatively, the total impurities does not exceed 0.15% following 12 hours of storage at 20-25 °C, alternatively the total impurities does not exceed 0.1% following 12 hours of storage at 20-25°C, alternatively, the total impurities does not exceed 0.05% following 12 hours of storage at 20-25°C.

[0318] In one embodiment, the aqueous solution is stable up to 36 hours of storage at 2-8°C.

[0319] In one embodiment, the amount of total impurities present in the aqueous solution following 36 hours of storage at 2-8°C does not exceed 0.5%. In one embodiment, the amount of total impurities present in the aqueous solution following 36 hours of storage at 2-8°C does not exceed 0.2%, alternatively, the total impurities does not exceed 0.15% following 36 hours of storage at 2-8°C, alternatively, the total impurities does not exceed 0.1% following 36 hours of storage at 2-8°C, alternatively, the total impurities does not exceed 0.05% following 36 hours of storage at 2-8°C.

[0320] In one embodiment, the osmolality of the aqueous solution is below 500 mOsm/kg. In one embodiment, the osmolality of the aqueous solution is about 300-400 mOsm/kg.

[0321] In one embodiment, the total impurities are selected from 2-phenyl-2 -ethyl acetyl urea, 2-phenyl-2-ethyl-malonamide, a-phenylbutyrylguanidine, 2-phenylbutyric acid and 5 -methyl-5 -phenylbarbituric acid.

[0322] In another aspect, the present disclosure relates to a lyophilized pharmaceutical composition of phenobarbital or salts thereof, wherein the lyophilized pharmaceutical composition has: (i) an amount of alcohol present following 36 months of storage at 20-25°C in the range from about 5000 ppm to about 66000 ppm or, alternatively, from about 5000 ppm to about 70000 ppm; or (ii) an amount of total impurities present following 36 months of storage at 20-25°C does not exceed 0.2%, alternatively, does not exceed 0.15%, alternatively, does not exceed 0.1%, or, alternatively, does not exceed 0.05%.

[0323] In one embodiment, the lyophilized pharmaceutical composition has an amount of alcohol present following 36 months of storage at 20-25°C in the range from about 5000 ppm to about 66000 ppm or, alternatively, from about 5000 ppm to about 70000 ppm. In one embodiment, the alcohol content is at least about 5000 ppm, about 10000 ppm, about 15000 ppm, about 20000 ppm, about 25000 ppm, about 30000 ppm, about 35000 ppm, about 40000 ppm, about 45000 ppm, about 50000 ppm, about 55000 ppm, about 60000 ppm, about 65000 ppm, about 66000 ppm, or about 70000 ppm. In another embodiment, the alcohol content is in the range from about 12000 ppm to about 70000 ppm, about 12000 ppm to about 66000 ppm, about 12000 ppm to about 65000 ppm, about 12000 ppm to about 60000 ppm, about 12000 ppm to about 55000 ppm, about 12000 ppm to about 50000 ppm, about 12000 ppm to about 45000 ppm, about 12000 ppm to about 40000 ppm, about 12000 ppm to about 35000 ppm, about 12000 ppm to about 30000 ppm, about 12000 ppm to about 25000 ppm, about 12000 ppm to about 20000 ppm or about 12000 ppm to about 15000 ppm. In another embodiment, the alcohol content is in the range from about 15000 ppm to about 70000 ppm, about 15000 ppm to about 66000 ppm, about 25000 ppm to about 66000 ppm, about 35000 to about 66000 ppm, about 45000 ppm to about 66000 ppm, about 55000 ppm to about 66000 ppm, about 35000 ppm to about 55000 ppm or about 30000 ppm to about 50000 ppm.

[0324] In another embodiment, the alcohol content is in the range from about

12000 ppm to about 25000 ppm. In one embodiment, the alcohol content is in the range from about 35000 to about 66000 ppm.

[0325] In one embodiment, the alcohol is a C1-C3 alcohol.

[0326] In one embodiment, the alcohol is ethanol.

[0327] In one embodiment, phenobarbital or salts thereof is phenobarbital base or phenobarbital sodium, preferably phenobarbital sodium.

[0328] In one embodiment, the lyophilized pharmaceutical composition is stable up to 36 months of storage at 20-25°C.

[0329] In one embodiment, the total impurities are selected from 2-phenyl-2 -ethyl acetyl urea, 2-phenyl-2-ethyl-malonamide, a-phenylbutyrylguanidine, 2-phenylbutyric acid and 5 -methyl-5 -phenylbarbituric acid.

[0330] In one embodiment, the lyophilized pharmaceutical composition is free of benzyl alcohol.

[0331] In one embodiment, the lyophilized pharmaceutical composition is also free of propylene glycol.

[0332] In a preferred embodiment, the lyophilized pharmaceutical composition is free of benzyl alcohol and propylene glycol.

[0333] In another aspect, the present disclosure relates to a pharmaceutical composition of phenobarbital or salts thereof that has been reconstituted from a lyophilized pharmaceutical composition of phenobarbital or salts thereof, wherein the pharmaceutical composition has: (i) an amount of alcohol present following 12 hours of storage at 20-25°C or 36 hours of storage at 2-8°C in the range from about 5000 ppm to about 66000 ppm or, alternatively, from about 5000 ppm to about 70000 ppm; or (ii) an amount of total impurities present following 12 hours of storage at 20-25°C or 36 hours of storage at 2-8°C does not exceed 0.2%, alternatively, does not exceed 0.15%, alternatively, does not exceed 0.1%, or, alternatively, does not exceed 0.05%.

[0334] In one embodiment, the pharmaceutical composition has an amount of alcohol present following 12 hours of storage at 20-25°C or 36 hours of storage at 2-8°C in the range from about 5000 ppm to about 66000 ppm or, alternatively, from about 5000 ppm to about 70000 ppm. In one embodiment, the alcohol content is at least about 5000 ppm, about 10000 ppm, about 15000 ppm, about 20000 ppm, about 25000 ppm, about 30000 ppm, about 35000 ppm, about 40000 ppm, about 45000 ppm, about 50000 ppm, about 55000 ppm, about 60000 ppm, about 65000 ppm, about 66000 ppm, or about 70000

ppm. In another embodiment, the alcohol content is in the range from about 12000 ppm to about 70000 ppm, about 12000 ppm to about 66000 ppm, about 12000 ppm to about 65000 ppm, about 12000 ppm to about 60000 ppm, about 12000 ppm to about 55000 ppm, about 12000 ppm to about 50000 ppm, about 12000 ppm to about 45000 ppm, about 12000 ppm to about 40000 ppm, about 12000 ppm to about 35000 ppm, about 12000 ppm to about 30000 ppm, about 12000 ppm to about 25000 ppm, about 12000 ppm to about 20000 ppm or about 12000 ppm to about 15000 ppm. In another embodiment, the alcohol content is in the range from about 15000 ppm to about 70000 ppm, about 15000 ppm to about 66000 ppm, about 25000 ppm to about 66000 ppm, about 35000 to about 66000 ppm, about 45000 ppm to about 66000 ppm, about 55000 ppm to about 66000 ppm, about 35000 ppm to about 55000 ppm or about 30000 ppm to about 50000 ppm.

[0335] In another embodiment, the alcohol content is in the range from about

12000 ppm to about 25000 ppm. In one embodiment, the alcohol content is in the range from about 35000 to about 66000 ppm.

[0336] In one embodiment, the alcohol is a C1-C3 alcohol.

[0337] In one embodiment, the alcohol is ethanol.

[0338] In one embodiment, phenobarbital or salts thereof is phenobarbital base or phenobarbital sodium, preferably phenobarbital sodium.

[0339] In one embodiment, the lyophilized pharmaceutical composition is reconstituted with water for injection, an aqueous saline or an aqueous dextrose solution.

In one embodiment, the lyophilized pharmaceutical composition is reconstituted with 0.9% aqueous saline.

[0340] In one embodiment, the pharmaceutical composition is an aqueous solution for injection of phenobarbital or salts thereof.

[0341] In one embodiment, the pharmaceutical composition comprises phenobarbital or salts thereof in a concentration of 10-200 mg/ml. In one embodiment, phenobarbital or salts thereof is present in a concentration of 10 mg/ml, 20 mg/ml, 30 mg/ml, 40 mg/ml, 50 mg/ml, 60 mg/ml, 70 mg/ml, 80 mg/ml, 90 mg/ml, 100 mg/ml, 110

mg/ml, 120 mg/ml, 130 mg/ml, 140 mg/ml, 150 mg/ml, 160 mg/ml, 170 mg/ml, 180 mg/ml, 190 mg/ml and 200 mg/ml.

[0342] In one embodiment, the pharmaceutical composition is stable up to 12 hours of storage at 20-25 °C.

[0343] In one embodiment, the pharmaceutical composition is stable up to 36 hours of storage at 2-8°C.

[0344] In one embodiment, the total impurities are selected from 2-phenyl-2 -ethyl acetyl urea, 2-phenyl-2-ethyl-malonamide, a-phenylbutyrylguanidine, 2-phenylbutyric acid and 5 -methyl-5 -phenylbarbituric acid.

[0345] In one embodiment, the osmolality of said pharmaceutical composition is below 500 mOsm/kg. In one embodiment, the osmolality of said aqueous solution is about 300-400 mOsm/kg.

[0346] In one embodiment, the pharmaceutical composition is free of benzyl alcohol.

[0347] In one embodiment, the pharmaceutical composition is also free of propylene glycol.

[0348] In a preferred embodiment, the pharmaceutical composition is free of benzyl alcohol and propylene glycol.

[0349] In another aspect, the present disclosure relates to a lyophilized pharmaceutical composition of phenobarbital sodium, wherein the composition has an ethanol content in the range from about 12000 ppm to about 25000 ppm; wherein the composition is stable up to 36 months of storage at 20-25°C such that the amount of total impurities present following 36 months of storage at 20-25°C does not exceed 0.2%, alternatively, does not exceed 0.15%, alternatively, does not exceed 0.1%, or, alternatively, does not exceed 0.05%; and wherein the composition is free of benzyl alcohol and propylene glycol.

[0350] In another aspect, the present disclosure relates to an aqueous solution for injection of phenobarbital sodium, wherein the aqueous solution has an ethanol content in the range from about 12000 ppm to about 25000 ppm; wherein the aqueous solution is stable up to 12 hours of storage at 20-25 °C or 36 hours of storage at 2-8 °C such that the amount of total impurities present following 12 hours of storage at 20-25°C or following 36 hours of storage at 2-8°C does not exceed 0.2%, alternatively, does not exceed 0.15%, alternatively, does not exceed 0.1%, or, alternatively, does not exceed 0.05%; wherein the aqueous solution is reconstituted from a lyophilized pharmaceutical composition of phenobarbital sodium; and wherein the aqueous solution is free of benzyl alcohol and propylene glycol.

[0351] In another aspect, the present disclosure relates to a method of preventing degradation of phenobarbital or salts thereof, wherein the method comprises dissolving phenobarbital or salts thereof in water to obtain an aqueous solution having a concentration of 10-200 mg/ml; and lyophilizing the aqueous solution to obtain a lyophilized pharmaceutical composition of phenobarbital or salts thereof, wherein the method comprises presence of alcohol, in an amount sufficient to inhibit the degradation of phenobarbital or salts thereof.

CLAIMS:

1. A pharmaceutical composition of phenobarbital or salts thereof that has been reconstituted from a lyophilized pharmaceutical composition of phenobarbital or salts thereof, wherein the amount of total impurities in the pharmaceutical composition does not exceed 0.2% following 12 hours of storage at 20-25°C or 36 hours of storage at 2- 8°C.

2. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition has an alcohol content in the range from about 5000 ppm to about 70000 ppm.

3. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition has an alcohol content is in the range from about 12000 ppm to about 66000 ppm.

4. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition has an alcohol content is in the range from about 12000 ppm to about 25000 ppm.

5. The pharmaceutical composition of claims 2-4, wherein the alcohol is a C1-C3 alcohol.

6. The pharmaceutical composition of claim 1, wherein phenobarbital or salts thereof is phenobarbital sodium.

7. The pharmaceutical composition of claim 1, wherein the total impurities are selected from 2-phenyl-2-ethyl acetyl urea, 2-phenyl-2-ethyl-malonamide, a- phenylbutyrylguanidine, 2-phenylbutyric acid and 5 -methyl-5 -phenylbarbituric acid.

8. The pharmaceutical composition of claim 1, wherein the lyophilized pharmaceutical composition is reconstituted with water for injection, an aqueous saline or an aqueous dextrose solution.

9. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is an aqueous solution for injection of phenobarbital or salts thereof.

10. The pharmaceutical composition of claim 9, wherein phenobarbital or salts thereof is present in a concentration of 10-200 mg/ml.

11. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is free of benzyl alcohol.

12. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is free of propylene glycol.

13. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition has an osmolality below 500 mOsm/kg.

14. A method for the treatment of neonatal seizure in newborn infants 2 weeks of age or younger in need thereof, comprising administering a pharmaceutical composition of phenobarbital or salts thereof that has been reconstituted from a lyophilized

pharmaceutical composition of phenobarbital or salts thereof, wherein the amount of total impurities in the pharmaceutical composition does not exceed 0.2% following 12 hours of storage at 20-25°C or 36 hours of storage at 2-8°C.

15. The method of claim 14, wherein the pharmaceutical composition is administered intravenously by infusion at a dose of 20mg/kg over a course of 15 minutes.

16. The method of claim 14, wherein the method comprises administering the pharmaceutical composition at an initial loading dose of 20mg/kg over a course of 15 minutes and measuring the electrographic seizures; and if electrographic seizures persist or recur after completion of the initial loading dose, a second dose of 20 mg/kg is administered over subsequent 15 minutes for a total loading dose of 40 mg/kg.

17. The method of claim 14, wherein the method comprises administering the pharmaceutical composition to neonates in whom correctable abnormalities have been excluded or corrected.

18. The method of claim 17, wherein the correctable abnormalities are selected from hypoglycemia or hypocalcemia.

19. The method of claim 14, wherein the pharmaceutical composition has an alcohol content in the range from about 5000 ppm to about 70000 ppm.

20. The method of claim 14, wherein the pharmaceutical composition has an alcohol content is in the range from about 12000 ppm to about 66000 ppm.

21. The method of claim 14, wherein the pharmaceutical composition has an alcohol content is in the range from about 12000 ppm to about 25000 ppm.

22. The method of claims 19-21, wherein the alcohol is a C1-C3 alcohol.

23. The method of claim 14, wherein phenobarbital or salts thereof is phenobarbital sodium.

24. The method of claim 14, wherein the total impurities are selected from 2 -phenyl -2- ethyl acetyl urea, 2-phenyl-2-ethyl-malonamide, a-phenylbutyrylguanidine, 2- phenylbutyric acid and 5 -methyl-5 -phenylbarbituric acid.

25. The method of claim 14, wherein the lyophilized pharmaceutical composition is reconstituted with water for injection, an aqueous saline or an aqueous dextrose solution.

26. The method of claim 14, wherein the pharmaceutical composition is an aqueous solution for injection of phenobarbital or salts thereof.

27. The method of claim 26, wherein phenobarbital or salts thereof is present in a concentration of 10-200 mg/ml.

28. The method of claim 14, wherein the pharmaceutical composition is free of benzyl alcohol.

29. The method of claim 14, wherein the pharmaceutical composition is free of propylene glycol.

30. The method of claim 14, wherein the pharmaceutical composition has an osmolality below 500 mOsm/kg.

31. A pharmaceutical composition of phenobarbital or salts thereof, wherein the pharmaceutical composition has an alcohol content in the range from about 5000 ppm to about 70000 ppm.

32. The pharmaceutical composition of claim 31, wherein the composition has an alcohol content in the range from about 12000 ppm to about 66000 ppm.

33. The pharmaceutical composition of claim 31, wherein the composition has an alcohol content in the range from about 12000 ppm to about 25000 ppm.

34. The pharmaceutical composition of claim 31-33, wherein alcohol is a C1-C3 alcohol.

35. The pharmaceutical composition of claim 31 , wherein phenobarbital or salts thereof is phenobarbital sodium.

36. The pharmaceutical composition of claim 31 , wherein the pharmaceutical composition is a lyophilized pharmaceutical composition of phenobarbital or salts thereof.

37. The pharmaceutical composition of claim 36, wherein the lyophilized pharmaceutical composition is stable up to 36 months of storage at 20-25 °C.

38. The pharmaceutical composition of claim 37, wherein the amount of total impurities present following 36 months of storage at 20-25°C does not exceed 0.5%.

39. The pharmaceutical composition of claim 37, wherein the amount of total impurities present following 36 months of storage at 20-25°C does not exceed 0.2%.

40. The pharmaceutical composition of claim 31 , wherein the pharmaceutical composition is an aqueous solution for injection of phenobarbital or salts thereof.

41. The pharmaceutical composition of claim 40, wherein the aqueous solution is reconstituted from the lyophilized pharmaceutical composition of phenobarbital or salts thereof.

42. The pharmaceutical composition of claim 41, wherein the lyophilized pharmaceutical composition of phenobarbital or salts thereof is reconstituted with water for injection, an aqueous saline or an aqueous dextrose solution.

43. The pharmaceutical composition of claim 42, wherein phenobarbital or salts thereof is present in a concentration of 10-200 mg/ml.

44. The pharmaceutical composition of claim 40, wherein the aqueous solution is stable up to 12 hours of storage at 20-25°C.

45. The pharmaceutical composition of claim 44, wherein the amount of total impurities present following 12 hours of storage at 20-25°C does not exceed 0.5%.

46. The pharmaceutical composition of claim 44, wherein the amount of total impurities present following 12 hours of storage at 20-25°C does not exceed 0.2%.

47. The pharmaceutical composition of claim 40, wherein the aqueous solution is stable up to 36 hours of storage at 2-8°C.

48. The pharmaceutical composition of claim 47, wherein the amount of total impurities present following 36 hours of storage at 2-8°C does not exceed 0.5%.

49. The pharmaceutical composition of claim 47, wherein the amount of total impurities present following 36 hours of storage at 2-8°C does not exceed 0.2%.

50. The pharmaceutical composition of claim 40, wherein the aqueous solution has an osmolality below 500 mOsm/kg.

51. The pharmaceutical composition of claims 38-39, 45-46 and 48-49, wherein the total impurities are selected from 2-phenyl-2-ethyl acetyl urea, 2-phenyl-2-ethyl- malonamide, a-phenylbutyrylguanidine, 2-phenylbutyric acid and 5-methyl-5- phenylbarbituric acid.

52. The pharmaceutical composition of claim 31 , wherein the pharmaceutical composition is free of benzyl alcohol.

53. The pharmaceutical composition of claim 31 , wherein the pharmaceutical composition is free of propylene glycol.

54. A method for the treatment of neonatal seizure in newborn infants 2 weeks of age or younger in need thereof, comprising administering a pharmaceutical composition of phenobarbital or salts thereof, wherein the pharmaceutical composition has an alcohol content in the range from about 5000 ppm to about 70000 ppm.

55. The method of claim 54, wherein the pharmaceutical composition is administered intravenously by infusion at a dose of 20mg/kg over a course of 15 minutes.

56. The method of claim 54, wherein the method comprises administering the pharmaceutical composition at an initial loading dose of 20mg/kg over a course of 15 minutes and measuring the electrographic seizures; and if the electrographic seizures persist or recur after completion of the initial loading dose, a second dose 20 mg/kg is administered over the subsequent 15 minutes for a total loading dose of 40 mg/kg.

57. The method of claim 54, wherein the method comprises administering the pharmaceutical composition to neonates in whom correctable abnormalities have been excluded or corrected.

58. The method of claim 57, wherein the correctable abnormalities are selected from hypoglycemia or hypocalcemia.

59. The method of claim 54, wherein the pharmaceutical composition has an alcohol content in the range from about 12000 ppm to about 66000 ppm.

60. The method of claim 54, wherein the pharmaceutical composition has an alcohol content in the range from about 12000 ppm to about 25000 ppm.

61. The method of claims 54, 59-60, wherein alcohol is a C1-C3 alcohol.

62. The method of claim 54, wherein phenobarbital or salts thereof is phenobarbital sodium.

63. The method of claim 54, wherein the pharmaceutical composition is a lyophilized pharmaceutical composition of phenobarbital or salts thereof.

64. The method of claim 63, wherein the lyophilized pharmaceutical composition is stable up to 36 months of storage at 20-25°C.

65. The method of claim 64, wherein the amount of total impurities present following 36 months of storage at 20-25°C does not exceed 0.5%.

66. The method of claim 64, wherein the amount of total impurities present following 36 months of storage at 20-25 °C does not exceed 0.2%.

67. The method of claim 54, wherein the pharmaceutical composition is an aqueous solution for injection of phenobarbital or salts thereof.

68. The method of claim 67, wherein the aqueous solution is reconstituted from a lyophilized pharmaceutical composition of phenobarbital or salts thereof.

69. The method of claim 68, wherein the lyophilized pharmaceutical composition is reconstituted with water for injection, an aqueous saline or an aqueous dextrose solution.

70. The method of claim 67, wherein the aqueous solution is stable up to 12 hours of storage at 20-25°C.

71. The method of claim 70, wherein the amount of total impurities present following 12 hours of storage at 20-25 °C does not exceed 0.2%.

72. The method of claim 67, wherein the aqueous solution is stable up to 36 hours of storage at 2-8°C.

73. The method of claim 72, wherein the amount of total impurities present following 36 hours of storage at 2-8°C does not exceed 0.2%.

74. The method of claim 67, wherein the aqueous solution has an osmolality below 500 mOsm/kg.

75. The method of claim 54, wherein the pharmaceutical composition is free of benzyl alcohol.

76. The method of claim 54, wherein the pharmaceutical composition is free of propylene glycol.

77. A lyophilized pharmaceutical composition of phenobarbital or salts thereof, wherein the composition has an alcohol content in the range from about 5000 ppm to about 70000 ppm.

78. The lyophilized pharmaceutical composition of claim 77, wherein the lyophilized pharmaceutical composition has an alcohol content in the range from about 12000 ppm to about 66000 ppm.

79. The lyophilized pharmaceutical composition of claim 77, wherein the lyophilized pharmaceutical composition has an alcohol content in the range from about 12000 ppm to about 25000 ppm.

80. The lyophilized pharmaceutical composition of claims 77-79, wherein alcohol is a Ci- C3 alcohol.

81. The lyophilized pharmaceutical composition of claim 77, wherein phenobarbital or salts thereof is phenobarbital sodium.

82. The lyophilized pharmaceutical composition of claim 77 is stable up to 36 months of storage at 20-25°C.

83. The lyophilized pharmaceutical composition of claim 82, wherein the amount of total impurities present following 36 months of storage at 20-25 °C does not exceed 0.5%.

84. The lyophilized pharmaceutical composition of claim 82, wherein the amount of total impurities present following 36 months of storage at 20-25°C does not exceed 0.2%.

85. The lyophilized pharmaceutical composition of claims 83-84, wherein the total impurities are selected from 2-phenyl-2-ethyl acetyl urea, 2-phenyl-2-ethyl- malonamide, a-phenylbutyrylguanidine, 2-phenylbutyric acid and 5-methyl-5- phenylbarbituric acid.

86. The lyophilized pharmaceutical composition of claim 77, wherein the lyophilized pharmaceutical composition is free of benzyl alcohol.

87. The lyophilized pharmaceutical composition of claim 77, wherein the lyophilized pharmaceutical composition is free of propylene glycol.

88. A method for the treatment of neonatal seizure in newborn infants 2 weeks of age or younger in need thereof, comprising administering a lyophilized pharmaceutical composition of phenobarbital or salts thereof, wherein the lyophilized pharmaceutical composition has an alcohol content in the range from about 5000 ppm to about 70000 ppm.

89. The method of claim 88, wherein the method comprises reconstituting the lyophilized pharmaceutical composition of phenobarbital or salts thereof immediately prior to the administration.

90. The method of claim 89, wherein the lyophilized pharmaceutical composition is reconstituted with water for injection, an aqueous saline or an aqueous dextrose solution to obtain the aqueous solution for injection of phenobarbital or salts thereof.

91. The method of claim 90, wherein the aqueous solution is administered intravenously by infusion at a dose of 20mg/kg over a course of 15 minutes.

92. The method of claims 88 and 89, wherein the method comprises administering the aqueous solution at an initial loading dose of 20mg/kg over a course of 15 minutes and measuring the electrographic seizures; and if the electrographic seizures persist or recur after completion of the initial loading dose, a second dose 20 mg/kg is administered over the subsequent 15 minutes for a total loading dose of 40 mg/kg.

93. The method of claim 88, wherein the method comprises administering to neonates in whom correctable abnormalities have been excluded or corrected.

94. The method of claim 93, wherein the correctable abnormalities are selected from hypoglycemia or hypocalcemia.

95. The method of claim 88, wherein the lyophilized pharmaceutical composition has an alcohol content in the range from about 12000 ppm to about 66000 ppm.

96. The method of claim 88, wherein the lyophilized pharmaceutical composition has an alcohol content in the range from about 12000 ppm to about 25000 ppm.

97. The method of claims 88, and 95-96, wherein alcohol is a C1-C3 alcohol.

98. The method of claim 88, wherein phenobarbital or salts thereof is phenobarbital sodium.

99. The method of claim 88, wherein the lyophilized pharmaceutical composition is stable up to 36 months of storage at 20-25°C.

100. The method of claim 99, wherein the amount of total impurities present following 36 months of storage at 20-25°C does not exceed 0.5%.

101. The method of claim 99, wherein the amount of total impurities present following 36 months of storage at 20-25 °C does not exceed 0.2%.

102. The method of claims 100-101, wherein the total impurities are selected from 2- phenyl-2 -ethyl acetyl urea, 2-phenyl-2-ethyl-malonamide, a-phenylbutyrylguanidine, 2-phenylbutyric acid and 5 -methyl-5 -phenylbarbituric acid.

103. The method of claim 88, wherein the lyophilized pharmaceutical composition is free of benzyl alcohol.

104. The method of claim 88, wherein the lyophilized pharmaceutical composition is free of propylene glycol.

105. A pharmaceutical composition of phenobarbital or salts thereof that has been reconstituted from a lyophilized pharmaceutical composition of phenobarbital or salts thereof, wherein the pharmaceutical composition has an alcohol content in the range from about 5000 ppm to about 70000 ppm.

106. The pharmaceutical composition of claim 105, wherein the pharmaceutical composition has an alcohol content in the range from about 12000 ppm to about 66000 ppm.

107. The pharmaceutical composition of claim 105, wherein the pharmaceutical composition has an alcohol content in the range from about 12000 ppm to about 25000 ppm.

108. The pharmaceutical composition of claim 105-107, wherein the alcohol is a C1-C3 alcohol.

109. The pharmaceutical composition of claim 105, wherein phenobarbital or salts thereof is phenobarbital sodium.

110. The pharmaceutical composition of claim 105, wherein the lyophilized pharmaceutical composition is reconstituted with water for injection, an aqueous saline or an aqueous dextrose solution.

111. The pharmaceutical composition of claim 105, wherein the pharmaceutical composition is an aqueous solution for injection of phenobarbital or salts thereof.

112. The pharmaceutical composition of claim 105, wherein phenobarbital or salts thereof is present in a concentration of 10-200 mg/ml.

113. The pharmaceutical composition of claim 105, wherein the pharmaceutical composition is stable up to 12 hours of storage at 20-25°C.

114. The pharmaceutical composition of claim 113, wherein the amount of total impurities present following 12 hours of storage at 20-25°C does not exceed 0.5%.

115. The pharmaceutical composition of claim 113, wherein the amount of total impurities present following 12 hours of storage at 20-25°C does not exceed 0.2%.

116. The pharmaceutical composition of claim 105, wherein the pharmaceutical composition is stable up to 36 hours of storage at 2-8°C.

117. The pharmaceutical composition of claim 116, wherein the amount of total impurities present following 36 hours of storage at 2-8°C does not exceed 0.5%.

118. The pharmaceutical composition of claim 116, wherein the amount of total impurities present following 36 hours of storage at 2-8°C does not exceed 0.2%.

119. The pharmaceutical composition of claims 114-115 and 117-118, wherein the total impurities are selected from 2-phenyl-2-ethyl acetyl urea, 2-phenyl-2-ethyl- malonamide, a-phenylbutyrylguanidine, 2-phenylbutyric acid and 5-methyl-5- phenylbarbituric acid.

120. The pharmaceutical composition of claim 105, wherein the pharmaceutical composition has an osmolality below 500 mOsm/kg.

121. The pharmaceutical composition of claim 105, wherein the pharmaceutical composition is free of benzyl alcohol.

122. The pharmaceutical composition of claim 105, wherein the pharmaceutical composition is free of propylene glycol.

123. A method for the treatment of neonatal seizure in newborn infants 2 weeks of age or younger in need thereof, comprising administering a pharmaceutical composition of phenobarbital or salts thereof that has been reconstituted from a lyophilized pharmaceutical composition of phenobarbital or salts thereof, and wherein the pharmaceutical composition has an alcohol content in the range from about 5000 ppm to about 70000 ppm.

124. The method of claim 123, wherein the pharmaceutical composition is administered intravenously by infusion at a dose of 20mg/kg over a course of 15 minutes.

125. The method of claim 123, wherein the method comprises administering the pharmaceutical composition at an initial loading dose of 20mg/kg over a course of 15 minutes and measuring the electrographic seizures; and if the electrographic seizures persist or recur after completion of the initial loading dose, a second dose 20 mg/kg is administered over the subsequent 15 minutes for a total loading dose of 40 mg/kg.

126. The method of claim 123, wherein the method comprises administering the pharmaceutical composition to neonates in whom correctable abnormalities have been excluded or corrected.

127. The method of claim 126, wherein the correctable abnormalities are selected from hypoglycemia or hypocalcemia.

128. The method of claim 123, wherein the pharmaceutical composition has an alcohol content in the range from about 12000 ppm to about 66000 ppm.

129. The method of claim 126, wherein the pharmaceutical composition has an alcohol content in the range from about 12000 ppm to about 25000 ppm.

130. The method of claims 123, and 128-129, wherein alcohol is a C1-C3 alcohol.

131. The method of claim 123, wherein phenobarbital or salts thereof is phenobarbital sodium.

132. The method of claim 123, wherein the lyophilized pharmaceutical composition is reconstituted with water for injection, an aqueous saline or an aqueous dextrose solution.

133. The method of claim 123, wherein the pharmaceutical composition is an aqueous solution for injection of phenobarbital or salts thereof.

134. The method of claim 123, wherein phenobarbital or salts thereof is present in a concentration of 10-200 mg/ml.

135. The method of claim 123, wherein the pharmaceutical composition is stable up to 12 hours of storage at 20-25 °C.

136. The method of claim 135, wherein the amount of total impurities present following 12 hours of storage at 20-25 °C does not exceed 0.2%.

137. The method of claim 123, wherein the pharmaceutical composition is stable up to 36 hours of storage at 2-8°C.

138. The method of claim 137, wherein the amount of total impurities present following 36 hours of storage at 2-8°C does not exceed 0.2%.

139. The method of claims 136 and 138, wherein the total impurities are selected from 2- phenyl-2 -ethyl acetyl urea, 2-phenyl-2-ethyl-malonamide, a-phenylbutyrylguanidine, 2-phenylbutyric acid and 5 -methyl-5 -phenylbarbituric acid.

140. The method of claim 123, wherein the pharmaceutical composition has an osmolality below 500 mOsm/kg.

141. The method of claim 123, wherein the pharmaceutical composition is free of benzyl alcohol.

142. The method of claim 123, wherein the pharmaceutical composition is free of propylene glycol.

143. A process of preparing a lyophilized pharmaceutical composition of phenobarbital or salts thereof having an alcohol content in the range from about 5000 ppm to about 70000 ppm, wherein the process comprises dissolving phenobarbital or salts thereof in water to obtain an aqueous solution of phenobarbital or salts thereof in a concentration of 10-200 mg/ml and lyophilizing the aqueous solution to obtain the lyophilized pharmaceutical composition of phenobarbital or salts thereof.

144. The process of claim 143, wherein the process comprises measuring the alcohol content of the aqueous solution of phenobarbital or salts thereof and if the alcohol content is below 5000 ppm then the process further comprises a step of adding alcohol to achieve the alcohol content of at least about 5000 ppm.

145. The process of claim 143, wherein the process comprises measuring the alcohol content of the lyophilized pharmaceutical composition of phenobarbital or salts thereof and if the alcohol content is above 70000 ppm, the process further comprises repeating the lyophilization step multiple times until the alcohol content of the lyophilized pharmaceutical composition is not more than about 70000 ppm.

146. The process of claim 143 further comprising adding a pH modifier to the aqueous solution of phenobarbital or salts thereof to achieve a pH in a range of 9-10.5.

147. The process of claim 143, wherein the lyophilized pharmaceutical composition has an alcohol content in the range from about 12000 ppm to about 66000 ppm.

148. The process of claim 143, wherein the lyophilized pharmaceutical composition has an alcohol content in the range from about 12000 ppm to about 25000 ppm.

149. The process of claims 143, 147-148, wherein alcohol is a C1-C3 alcohol.

150. The process of claim 143, wherein phenobarbital or salts thereof is phenobarbital sodium.

151. The process of claim 143, wherein the lyophilized pharmaceutical composition is stable up to 36 months of storage at 20-25 °C.

152. The process of claim 151, wherein the amount of total impurities present following 36 months of storage at 20-25°C does not exceed 0.5%.

153. The process of claim 151, wherein the amount of total impurities present following 36 months of storage at 20-25°C does not exceed 0.2%.

154. The process of claims 152-153, wherein the total impurities are selected from 2- phenyl-2 -ethyl acetyl urea, 2-phenyl-2-ethyl-malonamide, a-phenylbutyrylguanidine, 2-phenylbutyric acid and 5 -methyl-5 -phenylbarbituric acid.

155. The process of claim 143, wherein the lyophilized pharmaceutical composition is free of benzyl alcohol.

156. The process of claim 143, wherein the lyophilized pharmaceutical composition is free of propylene glycol.

157. A process of preparing a lyophilized pharmaceutical composition of phenobarbital or salts thereof having an alcohol content in the range from about 5000 ppm to about 70000 ppm, the process comprising dissolving phenobarbital or salts thereof in water to obtain an aqueous solution having a concentration of 10-200 mg/ml; measuring the alcohol content of the aqueous solution; if the alcohol content of the aqueous solution is below 5000 ppm, adding an alcohol to achieve the alcohol content of at least about 5000 ppm; lyophilizing the aqueous solution to obtain the lyophilized pharmaceutical composition; measuring the alcohol content of the lyophilized pharmaceutical composition; if the alcohol content of the lyophilized pharmaceutical composition is above 70000 ppm, repeating the lyophilization step until the alcohol content of the lyophilized pharmaceutical composition is not more than about 70000 ppm.

158. The process of claim 157 further comprising adding a pH modifier to the aqueous solution of phenobarbital or salts thereof to achieve a pH in a range of 9-10.5.

159. The process of claim 157, wherein the lyophilized pharmaceutical composition has an alcohol content in the range from about 12000 ppm to about 66000 ppm.

160. The process of claim 157, wherein the lyophilized pharmaceutical composition has an alcohol content in the range from about 12000 ppm to about 25000 ppm.

161. The process of claims 157, 159-160, wherein alcohol is a C1-C3 alcohol.

162. The process of claim 157, wherein phenobarbital or salts thereof is phenobarbital sodium.

163. The process of claim 157, wherein the lyophilized pharmaceutical composition is stable up to 36 months of storage at 20-25 °C.

164. The process of claim 163, wherein the amount of total impurities present following 36 months of storage at 20-25°C does not exceed 0.5%.

165. The process of claim 163, wherein the amount of total impurities present following 36 months of storage at 20-25°C does not exceed 0.2%.

166. The process of claims 164-165, wherein the total impurities are selected from 2- phenyl-2 -ethyl acetyl urea, 2-phenyl-2-ethyl-malonamide, a-phenylbutyrylguanidine, 2-phenylbutyric acid and 5 -methyl-5 -phenylbarbituric acid.

167. The process of claim 157, wherein the lyophilized pharmaceutical composition is free of benzyl alcohol.

168. The process of claim 157, wherein the lyophilized pharmaceutical composition is free of propylene glycol.

169. A process of preparing a pharmaceutical composition of phenobarbital or salts thereof that has been reconstituted from a lyophilized pharmaceutical composition of phenobarbital or salts thereof, wherein the pharmaceutical composition has an alcohol content in the range from about 5000 ppm to about 70000 ppm, the process comprising dissolving phenobarbital or salts thereof in water to obtain an aqueous solution having a concentration 10-200 mg/ml; lyophilizing the aqueous solution to obtain the lyophilized pharmaceutical composition of phenobarbital or salts thereof; and reconstituting the lyophilized pharmaceutical composition to obtain the pharmaceutical composition of phenobarbital or salts thereof.

170. The process of claim 169, wherein the process comprises measuring the alcohol content of the aqueous solution of phenobarbital or salts thereof and if the alcohol content is below 5000 ppm then the process further comprises a step of adding alcohol to achieve the alcohol content of at least about 5000 ppm.

171. The process of claim 169, wherein said process comprises measuring the alcohol content of the lyophilized pharmaceutical composition of phenobarbital or salts thereof and if the alcohol content is above 70000 ppm, the process further comprises repeating the lyophilization step until the alcohol content of the lyophilized pharmaceutical composition is not more than about 70000 ppm.

172. The process of claim 169 further comprising adding a pH modifier to the aqueous solution of phenobarbital or salts thereof to achieve a pH in a range of 9-10.5.

173. The process of claim 169, wherein the lyophilized pharmaceutical composition is reconstituted with water for injection, an aqueous saline or an aqueous dextrose solution.

174. The process of claim 169, wherein the pharmaceutical composition is an aqueous solution for injection of phenobarbital or salts thereof.

175. The process of claim 169, wherein the pharmaceutical composition has an alcohol content in the range from about 12000 ppm to about 66000 ppm.

176. The process of claim 169, wherein the pharmaceutical composition has an alcohol content in the range from about 12000 ppm to about 25000 ppm.

177. The process of claims 169, and 175-176, wherein alcohol is a C1-C3 alcohol.

178. The process of claim 169, wherein phenobarbital or salts thereof is phenobarbital sodium.

179. The process of claim 169, wherein the pharmaceutical composition is stable up to 12 hours of storage at 20-25 °C.

180. The process of claim 179, wherein the amount of total impurities present following 12 hours of storage at 20-25 °C does not exceed 0.2%.

181. The process of claim 169, wherein the pharmaceutical composition is stable up to 36 hours of storage at 2-8°C.

182. The process of claim 181, wherein the amount of total impurities present following 36 hours of storage at 2-8°C does not exceed 0.2%.

183. The process of claims 180 and 182, wherein the total impurities are selected from 2- phenyl-2 -ethyl acetyl urea, 2-phenyl-2-ethyl-malonamide, a-phenylbutyrylguanidine, 2-phenylbutyric acid and 5 -methyl-5 -phenylbarbituric acid.

184. The process of claim 169, wherein the pharmaceutical composition has an osmolality below 500 mOsm/kg.

185. The process of claim 169, wherein the pharmaceutical composition is free of benzyl alcohol.

186. The process of claim 169, wherein the pharmaceutical composition is free of propylene glycol.

187. A process of preparing a pharmaceutical composition of phenobarbital or salts thereof that has been reconstituted from a lyophilized pharmaceutical composition of phenobarbital or salts thereof, wherein the pharmaceutical composition has an alcohol content in the range from about 5000 ppm to about 70000 ppm, wherein the process comprises dissolving phenobarbital or salts thereof in water to obtain an aqueous solution having a concentration of 10-200 mg/ml; measuring the alcohol content of aqueous solution; if the alcohol content is below 5000 ppm, adding an alcohol to achieve the alcohol content of at least about 5000 ppm; lyophilizing the aqueous solution to obtain the lyophilized pharmaceutical composition; measuring the alcohol content of the lyophilized pharmaceutical composition; if the alcohol content is above 70000 ppm, repeating the lyophilization step until the alcohol content of the lyophilized pharmaceutical composition is not more than about 70000 ppm; and

reconstituting the lyophilized pharmaceutical composition to obtain the pharmaceutical composition of phenobarbital or salts thereof.

188. The process of claim 187 further comprising adding a pH modifier to the aqueous solution of phenobarbital or salts thereof to achieve a pH in a range of 9-10.5.

189. The process of claim 187, wherein the lyophilized pharmaceutical composition is reconstituted with water for injection, an aqueous saline or an aqueous dextrose solution.

190. The process of claim 187, wherein the pharmaceutical composition is an aqueous solution for injection of phenobarbital or salts thereof.

191. The process of claim 187, wherein the pharmaceutical composition has an alcohol content in the range from about 12000 ppm to about 66000 ppm.

192. The process of claim 187, wherein the pharmaceutical composition has an alcohol content in the range from about 12000 ppm to about 25000 ppm.

193. The process of claims 187, and 191-192, wherein alcohol is a C1-C3 alcohol.

194. The process of claim 187, wherein phenobarbital or salts thereof is phenobarbital sodium.

195. The process of claim 187, wherein the pharmaceutical composition is stable up to 12 hours of storage at 20-25 °C.

196. The process of claim 195, wherein the amount of total impurities present following 12 hours of storage at 20-25 °C does not exceed 0.2%.

197. The process of claim 187, wherein the pharmaceutical composition is stable up to 36 hours of storage at 2-8°C.

198. The process of claim 197, wherein the amount of total impurities present following 36 hours of storage at 2-8°C does not exceed 0.2%.

199. The process of claims 196 and 198, wherein the total impurities are selected from 2- phenyl-2 -ethyl acetyl urea, 2-phenyl-2-ethyl-malonamide, a-phenylbutyrylguanidine, 2-phenylbutyric acid and 5 -methyl-5 -phenylbarbituric acid.

200. The process of claim 187, wherein the pharmaceutical composition has an osmolality below 500 mOsm/kg.

201. The process of claim 187, wherein the pharmaceutical composition is free of benzyl alcohol.

202. The process of claim 187, wherein the pharmaceutical composition is free of propylene glycol.

203. A lyophilized pharmaceutical composition of phenobarbital or salts thereof having an alcohol content in the range from about 5000 ppm to about 70000 ppm, wherein the lyophilized pharmaceutical composition is obtained by a process comprising: dissolving phenobarbital or salts thereof in water to obtain an aqueous solution having a concentration of 10-200 mg/ml and lyophilizing the aqueous solution to obtain the lyophilized pharmaceutical composition of phenobarbital or salts thereof.

204. The lyophilized pharmaceutical composition of claim 203, wherein the lyophilized pharmaceutical composition has an alcohol content in the range from about 12000 ppm to about 66000 ppm.

205. The lyophilized pharmaceutical composition of claim 203, wherein the lyophilized pharmaceutical composition has an alcohol content in the range from about 12000 ppm to about 25000 ppm.

206. The lyophilized pharmaceutical composition of claims 203-205, wherein alcohol is ethanol.

207. The lyophilized pharmaceutical composition of claim 203, wherein phenobarbital or salts thereof is phenobarbital sodium.

208. The lyophilized pharmaceutical composition of claim 203, wherein the lyophilized pharmaceutical composition is stable up to 36 months of storage at 20-25°C.

209. The lyophilized pharmaceutical composition of claim 208, wherein the amount of total impurities present following 36 months of storage at 20-25 °C does not exceed 0.5%.

210. The lyophilized pharmaceutical composition of claim 208, wherein the amount of total impurities present following 36 months of storage at 20-25°C does not exceed 0.2%.

211. The lyophilized pharmaceutical composition of claims 209-210, wherein the total impurities are selected from 2-phenyl-2-ethyl acetyl urea, 2-phenyl-2-ethyl- malondiamide, a-phenylbutyrylguanidine, 2-phenylbutyric acid and 5-methyl-5- phenylbarbituric acid.

212. The lyophilized pharmaceutical composition of claim 203, wherein the lyophilized pharmaceutical composition is free of benzyl alcohol.

213. The lyophilized pharmaceutical composition of claim 203, wherein the lyophilized pharmaceutical composition is free of propylene glycol.

214. The lyophilized pharmaceutical composition of claim 203, wherein the process comprises measuring the alcohol content of the aqueous solution of phenobarbital or salts thereof and if the alcohol content is below 5000 ppm then the process further comprises a step of adding alcohol to achieve the alcohol content of at least about 5000 ppm.

215. The lyophilized pharmaceutical composition of claim 203, wherein said process comprises measuring the alcohol content of the lyophilized pharmaceutical composition of phenobarbital or salts thereof and if the alcohol content is above 70000 ppm, the process further comprises repeating the lyophilization step until the alcohol content of the lyophilized pharmaceutical composition is not more than about 70000 ppm.

216. A pharmaceutical composition of phenobarbital or salts thereof that has been reconstituted from a lyophilized pharmaceutical composition of phenobarbital or salts thereof having an alcohol content in the range from about 5000 ppm to about 70000 ppm, wherein the pharmaceutical composition is obtained by a process comprising: dissolving phenobarbital or salts thereof in water to obtain an aqueous solution having a concentration of 10-200 mg/ml; lyophilizing the aqueous solution to obtain the lyophilized pharmaceutical composition of phenobarbital or salts thereof; and reconstituting the lyophilized pharmaceutical composition to obtain the pharmaceutical composition of phenobarbital or salts thereof.

217. The pharmaceutical composition of claim 214, wherein the pharmaceutical composition has an alcohol content in the range from about 12000 ppm to about 66000 ppm.

218. The pharmaceutical composition of claim 214, wherein the pharmaceutical composition has an alcohol content in the range from about 12000 ppm to about 25000 ppm.

219. The pharmaceutical composition of claims 214-216, wherein alcohol is ethanol.

220. The pharmaceutical composition of claim 214, wherein phenobarbital or salts thereof is phenobarbital sodium.

221. The pharmaceutical composition of claim 214, wherein the lyophilized pharmaceutical composition is reconstituted with water for injection, an aqueous saline or an aqueous dextrose solution.

222. The pharmaceutical composition of claim 214, wherein the pharmaceutical composition is an aqueous solution for injection of phenobarbital or salts thereof.

223. The pharmaceutical composition of claim 214, wherein the pharmaceutical composition is stable up to 12 hours of storage at 20-25°C.

224. The pharmaceutical composition of claim 221, wherein the amount of total impurities present following 12 hours of storage at 20-25°C does not exceed 0.5%.

225. The pharmaceutical composition of claim 221, wherein the amount of total impurities present following 12 hours of storage at 20-25°C does not exceed 0.2%.

226. The pharmaceutical composition of claim 214, wherein the pharmaceutical composition is stable up to 36 hours of storage at 2-8°C.

227. The pharmaceutical composition of claim 224, wherein the amount of total impurities present following 36 hours of storage at 2-8°C does not exceed 0.5%.

228. The pharmaceutical composition of claim 224, wherein the amount of total impurities present following 36 hours of storage at 2-8°C does not exceed 0.2%.

229. The pharmaceutical composition of claims 222-223 and 225-226, wherein the total impurities are selected from 2-phenyl-2-ethyl acetyl urea, 2-phenyl-2-ethyl- malondiamide, a-phenylbutyrylguanidine, 2-phenylbutyric acid and 5-methyl-5- phenylbarbituric acid.

230. The pharmaceutical composition of claim 214, wherein the pharmaceutical composition has an osmolality below 500 mOsm/kg.

231. The pharmaceutical composition of claim 214, wherein the pharmaceutical composition is free of benzyl alcohol.

232. The pharmaceutical composition of claim 214, wherein the pharmaceutical composition is free of propylene glycol.

233. The pharmaceutical composition of claim 214, wherein the process comprises measuring the alcohol content of the aqueous solution of phenobarbital or salts thereof and if the alcohol content is below 5000 ppm then the process further comprises a step of adding alcohol to achieve the alcohol content of at least about 5000 ppm.

234. The pharmaceutical composition of claim 214, wherein said process comprises measuring the alcohol content of the lyophilized pharmaceutical composition of phenobarbital or salts thereof and if the alcohol content is above 70000 ppm, the process further comprises repeating the lyophilization step till the alcohol content of the lyophilized pharmaceutical composition is not more than about 70000 ppm.

235. A lyophilized pharmaceutical composition comprising phenobarbital sodium and ethanol, wherein the ethanol is present in an amount sufficient to inhibit degradation of phenobarbital sodium, such that the amount of total impurities present following 36 months of storage at 20-25 °C does not exceed 0.2%;

wherein the amount of ethanol sufficient to inhibit degradation of phenobarbital sodium is in the range from about 12000 ppm to about 25000 ppm; and wherein the pharmaceutical composition is free of benzyl alcohol and propylene glycol.

236. An aqueous solution for injection comprising phenobarbital sodium and ethanol, wherein the ethanol is present in an amount sufficient to inhibit degradation of the phenobarbital sodium, such that the amount of total impurities present following 12 hours of storage at 20-25°C or following 36 hours of storage at 2-8°C does not exceed 0.2%;

wherein the amount of ethanol sufficient to inhibit degradation of the phenobarbital sodium is in the range from about 12000 ppm to about 25000 ppm;

wherein the phenobarbital sodium is present in a concentration from 10-200 mg/ml; wherein the aqueous solution is reconstituted from a lyophilized pharmaceutical composition of phenobarbital sodium; and

wherein the aqueous solution is free of benzyl alcohol and propylene glycol.

237. A process for the preparation of a pharmaceutical composition of phenobarbital or salts thereof, the process comprising dissolving phenobarbital or salt thereof in water to obtain an aqueous solution having a concentration of 10-200 mg/ml and lyophilizing the aqueous solution to obtain a lyophilized pharmaceutical composition, wherein phenobarbital or salts thereof has an alcohol content in the range from about 9000 ppm to about 90000 ppm.

238. A lyophilized pharmaceutical composition of phenobarbital sodium, wherein the composition has an ethanol content in the range from about 12000 ppm to about 25000 ppm; wherein the composition is stable up to 36 months of storage at 20-25°C such that the amount of total impurities present following 36 months of storage at 20-25°C does not exceed 0.2%; and wherein the composition is free of benzyl alcohol and propylene glycol.

239. An aqueous solution for injection of phenobarbital sodium, wherein the aqueous solution has an ethanol content in the range from about 12000 ppm to about 25000 ppm; wherein the aqueous solution is stable up to 12 hours of storage at 20-25 °C or 36 hours of storage at 2-8°C such that the amount of total impurities present following 12 hours of storage at 20-25°C or following 36 hours of storage at 2-8°C does not exceed 0.2%; wherein the aqueous solution is reconstituted from a lyophilized

pharmaceutical composition of phenobarbital sodium; and wherein the aqueous solution is free of benzyl alcohol and propylene glycol.

240. A lyophilized pharmaceutical composition of phenobarbital sodium having an ethanol content in the range from about 5000 ppm to about 70000 ppm, wherein the lyophilized pharmaceutical composition is obtained by a process comprising: dissolving phenobarbital or salts thereof in water to obtain an aqueous solution having a concentration of 10-200 mg/ml; measuring the alcohol content of the aqueous solution; if the alcohol content is below 5000 ppm, adding an alcohol to achieve the alcohol content of at least about 5000 ppm; lyophilizing the aqueous solution to obtain the lyophilized pharmaceutical composition; measuring the alcohol content of the lyophilized pharmaceutical composition; if the alcohol content is above 70000 ppm, repeating the lyophilization step until the alcohol content of the lyophilized pharmaceutical composition is not more than about 70000 ppm.

241. A pharmaceutical composition of phenobarbital sodium that has been reconstituted from a lyophilized pharmaceutical composition of phenobarbital sodium having an alcohol content in the range from about 5000 ppm to about 70000 ppm, wherein the pharmaceutical composition is obtained by a process comprising: dissolving phenobarbital or salts thereof in water to obtain an aqueous solution having a concentration of 10-200 mg/ml; measuring the alcohol content of the aqueous solution; if the alcohol content is below 5000 ppm, adding an alcohol to achieve the alcohol content of at least about 5000 ppm; lyophilizing the aqueous solution to obtain the lyophilized pharmaceutical composition; measuring the alcohol content of the lyophilized pharmaceutical composition; if the alcohol content is above 70000 ppm, repeating the lyophilization step until the alcohol content of the lyophilized pharmaceutical composition is not more than about 70000 ppm; and reconstituting the lyophilized pharmaceutical composition to obtain the pharmaceutical composition of phenobarbital or salts thereof.