The present invention provides a process for the preparation of crystalline lyophilized sodium bicarbonate.
Sodium bicarbonate is used as an inactive ingredient in injectable pharmaceutical preparations such as ertapenem, octreotide acetate, fomivirsen sodium, mannitol, and poractant alfa and in oral tablets such as ESTRATEST® (Esterified Estrogens and Methyltestosterone) and terfenadine. Sterile water for injection containing sodium bicarbonate is used for reconstituting certain drugs such as ceftizoxime, cefazolin, cimetidine hydrochloride, cefoxitin sodium and ceftriaxone sodium. Sodium bicarbonate is also used in the preparation of sodium salts of the drugs such as cilastatin and cefotetan. Sodium bicarbonate is also an ingredient in oral solutions for gastrointestinal lavage such as COLYTE®. It is also used for pH neutralization of drugs such as metronidazole and ascorbic acid prior to parenteral administration.
Sodium bicarbonate of higher purity is commercially produced by injecting gaseous carbondioxide into a solution sodium carbonate of such composition that results in crystallization of sodium bicarbonate as the solution becomes fully saturated with carbon dioxide. The crystals are separated by centrifuging and filtering, and then dried to remove the traces of moisture.
As detailed in PCT Patent Publication No WO 94/14705, sodium bicarbonate wet cake is traditionally dried by using conventional rotary steam tube dryers. Such methods involve high temperature dehydration and steam pressure up to thirty five atmosphere. The dried material usually has high bulk density and the crystals resulting from this process usually have irregular particle size distribution and dendritic structures, which are physically weak and readily disintegrate into finer fragments on handling. Further, at higher temperatures sodium bicarbonate tends to be converted into sodium carbonate.
US Patent No 3,647,365 provides a method to obtain hollow beads sodium bicarbonate having bulk density of 25 - 32 pounds per cubic foot, wherein the process involves drying of the product by warming under carbondioxide environment. Such
methods of drying by warming consume considerable time for complete removal of the moisture. US Patent No 5,290,322 provides a method to prepare sodium bicarbonate crystals having regular particle size distribution by mobile bed crystallization method. However, the method needs to be operated at a temperature of about 70°C under carbondioxide environment and results in a mean particle size of about 900 microns.
The present inventors have now surprisingly found that crystalline sodium bicarbonate with high purity; optimum bulk density and uniform particle size distribution can be prepared in comparatively a shorter reaction time by lyophilizing a solution of sodium bicarbonate. The method does not require carbon dioxide atmosphere, high pressure or temperature conditions, and yet results in a sterile product with moisture content less than about 0.25 % w/w. The present method is suitable for industrial preparation of pharmaceutical grade crystalline sodium bicarbonate.
A first aspect of the present invention provides a crystalline lyophilized sodium bicarbonate. The crystalline lyophilized sodium bicarbonate of the present invention has bulk density ranging from about 0.10 to about 0.25 g/ml and tapped density ranging from 0.30 to about 0.40 g/ml.
A second aspect of the invention provides crystalline lyophilized sodium bicarbonate having particle size wherein 90% of the particles (do.g) have particle diameter 40 microns or less.
A third aspect of the present invention provides a process for the preparation of crystalline sodium bicarbonate, wherein the said process comprises
a) lyophilizing the solution of sodium bicarbonate in lyophilizer having tray thickness of about 15 mm or less,
b) isolating crystalline sodium bicarbonate from the reaction mass thereof.
Sodium bicarbonate of any morphology or particle size range prepared by any of the prior art methods can be used as a starting substrate. The sodium bicarbonate is dissolved in water at a temperature of about 5° to about 15°C. The solution is
optionally filtered through a micron filter and transferred to lyophilizer trays having the temperature of about 0° to about -10°C. The thickness of the solution layer on the lyophilizer trays is less than about 15 millimeter. The solution is cooled to a temperature of-20°C or less under vacuum. Then the temperature is raised to about 0°C, and then to about 10°C. The product can further be dried at a temperature of about 15°C or above.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
EXAMPLE 1
PREPARATION OF CRYSTALLINE LYOPHILIZED SODIUM BICARBONATE:
Deionised water (3.5 L) was cooled at a temperature of 5° to 10°C. Sodium bicarbonate (250 g) was added slowly to the deionised water at a temperature of 5° to 10°C and stirred until complete dissolution of the solid. The solution was filtered using 0.45 micron filter and transferred to lyophilizer trays, pre-cooled to 0° to -5°C, to form a layer of 8 to 10 millimeter thickness. The solution was frozen to -40°C and held at the same temperature for 180 minutes, followed by the application of vacuum (150 mTorr). The temperature was raised to 0°C in 300 minutes and held at the same temperature for 600 minutes. The temperature was further raised to 10°C in 120 minutes and held at the same temperature for 600 minutes. The temperature of the reaction mixture so obtained was raised to 15°C in 60 minutes and held at the same temperature for 360 minutes. The temperature was further raised to 25°C in 120 minutes and held at the same temperature for 300 minutes, followed by the release of vacuum to obtain the title compound.
Yield: 225 g Purity: 99.6 % w/w

Loss on Drying: 0.08%
Bulk Density: 0.24 g/ml
Tapped Bulk Density: 0.34 g/ml
Particle Size (measured by Malvern Mastersizer):
D(0.1) D(0.5) D(0.9)
3(j, 15ji 37p,

WE CLAIM:
1. A crystalline lyophilized sodium bicarbonate.
2. A crystalline lyophilized sodium bicarbonate having a bulk density ranging from about 0.10 to about 0.25 g/ml.
3. A crystalline lyophilized sodium bicarbonate having a tapped density ranging from about 0.30 to about 0.40 g/ml.
4. A crystalline lyophilized sodium bicarbonate having particle size wherein 90% of the particles (dog) have particle diameter of 40 microns or less.
5. A process for the preparation of crystalline lyophilized sodium bicarbonate, wherein the said process comprises,

a) lyophilizing the solution of sodium bicarbonate in lyophilizer having tray thickness of about 15 mm or less,
b) isolating crystalline sodium bicarbonate from the reaction mass thereof.

6. A process as claimed in claim 5, wherein the solution of sodium bicarbonate is obtained by dissolving sodium bicarbonate in water.
7. A process as claimed in claim 6, wherein sodium bicarbonate is dissolved at a temperature of about 15°C or less.
8. A process as claimed in claim 5, wherein step a) is carried out at a temperature of about -20°C or less.
9. A process as claimed in claim 5, wherein the reaction mixture is filtered before lyophilizing.
10. A process as claimed in claim 5, wherein step a) is carried out under vacuum.