Procaine benzylpenicillin (non-injectable)

Procaine benzylpenicillin, sterile

Molecular formula. C₁₆H₁₈N₂O₄S,C₁₃H₂₀N₂O₂,H₂O

Relative molecular mass. 588.7

Graphic formula.

Chemical name. 2-(Diethylamino)ethyl p-aminobenzoate compound with (2S,5R,6R)-3,3-dimethyl-7-oxo-6-(2-phenylacetamido)-4-thia-1-azabicyclo-[3.2.0]heptane-2-carboxylic acid (1:1) monohydrate; 2-(diethylamino)ethyl 4-aminobenzoate compound with [2S-(2α,5α,6β)]-3,3-dimethyl-7-oxo-6-[(phenyl-acetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid (1:1) monohydrate; CAS Reg. No. 6130-64-9 (monohydrate).

Other names. Penicillin G procaine, Procaine penicillin.

Description. A white or almost white, crystalline powder; odourless or almost odourless.

Solubility. Slightly soluble in water; soluble in ethanol (~750 g/l) TS.

Category. Antibacterial drug.

Storage. Procaine benzylpenicillin should be kept in a tightly closed container and protected from light.

Labelling. The designation sterile Procaine benzylpenicillin indicates that the substance complies with the additional requirements for sterile Procaine benzylpenicillin and may be used for parenteral administration or for other sterile applications.

Additional information. Solutions of Procaine benzylpenicillin are dextrorotatory. It is readily decomposed by acids, alkalis, and oxidizing agents. Even in the absence of light, it is gradually degraded on exposure to a humid atmosphere, the decomposition being faster at higher temperatures.

Requirements

Definition. Procaine benzylpenicillin contains not less than 96.0% and not more than 100.5% of total penicillins calculated as C₁₆H₁₈N₂O₄S,C₁₃H₂₀N₂O₂ and not less than 38.5% and not more than 41.5% of C₁₃H₂₀N₂O₂, both calculated with reference to the anhydrous substance.

Identity tests

A. To 2 mg in a test-tube add 0.05 mL of water followed by 2 mL of sulfuric acid (~1760 g/l) TS and mix; the solution is almost colourless. Immerse the test-tube for 1 minute in a water-bath; the solution remains almost colourless. Place 2 mg in a second test-tube, add 1 drop of water and 2 mL of formaldehyde/sulfuric acid TS and mix; the solution is almost colourless, but after a few minutes the colour changes to yellow-brown. Immerse the test-tube for 1 minute in a water-bath; a reddish brown colour is produced.

B. Dissolve 10 mg in 10 mL of water and add 0.5 mL of neutral red/ethanol TS. Add sufficient sodium hydroxide (0.01 mol/l) VS to give a permanent orange colour and then add 1.0 mL of penicillinase TS; the colour changes rapidly to red.

C. About 0.05 g yields the reaction described for the identification of primary aromatic amines under 2.1 General identification tests, producing a bright, orange-red precipitate.

Water. Determine as described under 2.8 Determination of water by the Karl Fischer method, Method A, using about 0.5 g of the substance; the water content is not less than 28 mg/g and not more than 42 mg/g.

pH value. pH of a saturated solution containing about 3.0 g in 10 mL of carbon-dioxide-free water R, 5.0-7.5.

Assay

For total penicillins. Dissolve about 0.045 g, accurately weighed, in sufficient water to produce 1000 mL. Transfer two 2.0-mL aliquots of this solution into separate stoppered tubes. To one tube add 10.0 mL of imidazole/mercuric chloride TS, mix, stopper the tube and place in a water-bath at 60°C for exactly 25 minutes. Cool the tube rapidly to 20°C (solution A). To the second tube add 10.0 mL of water and mix (solution B).

Without delay measure the absorbance of a 1-cm layer at the maximum at about 314 nm against a solvent cell containing a mixture of 2.0 mL of water and 10.0 mL of imidazole/mercuric chloride TS for solution A and water for solution B.

From the difference between the absorbance of solution A and that of solution B, calculate the amount of C₁₆H₁₈N₂O₄S,C₁₃H₂₀N₂O₂ in the substance being tested by comparison with 0.050 g of benzylpenicillin sodium RS similarly and concurrently examined, taking into account that each mg of benzylpenicillin sodium RS (C₁₆H₁₇N₂NaO₄S) is equivalent to 1.601 mg of C₁₆H₁₈N₂O₄S,C₁₃H₂₀N₂O₂. In an adequately calibrated spectrophotometer the absorbance of the reference solution should be 0.62 ± 0.03.

For procaine. Dissolve about 0.5 g, accurately weighed, in 10 mL of water, add 5 mL of sodium carbonate (75 g/l) TS and extract with four successive quantities, each of 25 mL of chloroform R, filter the chloroform extracts, and evaporate to a small volume on a water-bath. Add 20.0 mL of hydrochloric acid (0.1 mol/l) VS and distil off the remaining chloroform. Cool, add 0.25 mL of methyl red/ethanol TS and titrate with sodium hydroxide (0.1 mol/l) VS. Each mL of hydrochloric acid (0.1 mol/l) VS is equivalent to 23.63 mg of C₁₃H₂₀N₂O₂.

Additional Requirements for Procaine Benzylpenicillin for sterile use

Bacterial endotoxins. Carry out the test as described under 3.4 Test for bacterial endotoxins; contains not more than 0.01 IU of endotoxin RS per mg of benzylpenicillin.

Sterility. Complies with 3.2 Test for sterility.