| HS Code | 557802 |
| Chemical Name | Penicillin G (Benzylpenicillin) |
| Cas Number | 61-33-6 (free acid); 113-98-4 (potassium salt); 69-57-8 (sodium salt) |
| Molecular Formula | C16H18N2O4S (free acid); C16H17KN2O4S (potassium salt); C16H17N2NaO4S (sodium salt) |
| Molecular Weight | 334.39 g/mol (free acid); 372.48 g/mol (potassium salt); 356.37 g/mol (sodium salt) |
| Appearance | White to off-white crystalline powder |
| Solubility | Freely soluble in water for potassium/sodium salts; sparingly soluble in alcohol; practically insoluble in fixed oils |
| Melting Point | Decomposes above 120°C (free acid); salt forms decompose at higher temperatures |
| Ph Range | Aqueous solution typically pH 5.0 to 7.5 |
| Storage Temperature | 2°C to 8°C, protected from moisture and light |
| Shelf Life | 24 months under recommended storage conditions |
As an accredited Penicillin G(Benzylpenicillin) Veterinary Grade API for Tablets / Injections / Capsules / Powders / Granules / Premix / Solutions factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | Packaged in sealed, moisture-resistant polyethylene-lined fiber drums, 25 kg net each, ensuring stability and safety for veterinary pharmaceutical manufacturing. |
| Container Loading (20′ FCL) | 20′ FCL: drummed veterinary penicillin G API loaded securely, dry, no cross-contamination, with palletized stow and proper ventilation for transport. |
| Shipping | Shipments of Penicillin G Veterinary Grade API are packed in sealed, moisture-resistant containers with appropriate hazard and handling labels. Transport is completed under cool, dry conditions, protected from direct light. International logistics include veterinary API documentation, safety data sheets, and temperature monitoring to ensure stability and regulatory compliance. |
| Storage | Store in tightly sealed, original containers in a cool, dry, well-ventilated area, protected from light, moisture, and heat. Avoid temperatures above 25°C; refrigeration may extend stability but prevent freezing. Keep away from acids, oxidizing agents, and disinfectants. Ensure container is undamaged and use first-in, first-out inventory. |
| Shelf Life | Shelf life is typically 2–3 years when stored in a cool, dry place, protected from moisture and light. |
In mass medication programs for broilers, turkeys, and nursery swine, benzylpenicillin potassium is formulated as a water-soluble powder with a target finished strength of 100 mg/g (10.0% w/w) on an anhydrous glucose monohydrate or lactose monohydrate carrier. The addition ratio in the drinking water line is calibrated to deliver 20–30 mg/kg body weight per day, usually through a 1:100 proportioner pump when the stock solution is prepared at 1 g powder per 1 L water, with final concentration corrected for daily water intake. The dry-blending line is maintained at <40% RH because the API is hygroscopic and residual moisture above 0.5% accelerates beta-lactam hydrolysis during storage; a 500 L twin-shell V-blender operating at 60% fill for 15 min is typical after the penicillin potassium is passed through a 20-mesh stainless steel screen. Packaging in double-laminated aluminum foil sachets of 100 g, 500 g, and 1 kg is specified to maintain water vapor transmission below 0.5 g/m²/24 h. Compliance follows the current Ph. Eur. monograph for benzylpenicillin potassium, EU GMP Chapter 5 beta-lactam containment, VICH GL3 stability testing in moisture-impermeable packaging, and Commission Regulation (EU) No 37/2010 for residue control in treated poultry and swine. Reconstitution water must be free of sodium hypochlorite and acidic water acidifiers; aqueous solution hydrolysis accelerates below pH 4 and above 25°C, so the medicated stock solution is consumed or replaced within 12 h to avoid potency loss. Terminal finished product types are water-soluble powder sachets for drinking-water administration in bell drinkers and nipple systems fitted with a proportioner pump.
The formulation of procaine benzylpenicillin and benzathine benzylpenicillin into injectable suspensions is governed by a process conflict between particle size reduction for syringeability and dissolution-rate control for duration of action. A common finished strength is 300,000 IU/mL procaine benzylpenicillin as a single salt, while fixed-dose repository products are formulated at 150,000 IU/mL benzathine plus 150,000 IU/mL procaine benzylpenicillin. The API is dispersed in an aqueous vehicle containing a suspending agent such as 0.5–1.0% w/v sodium carboxymethylcellulose or methylcellulose, and a wetting agent such as 0.1–0.2% w/v polysorbate 80; these concentrations are adjusted so that the suspension passes through an 18-gauge needle at 20°C while retaining a sedimentation volume capable of uniform redispersion after 10 inversions. Aseptic manufacturing is required because benzylpenicillin degrades in aqueous suspension under terminal steam sterilization; the process uses sterile API micronized to Dv90 ≤ 20 µm, a sterile-filtered vehicle, and continuous rotor-stator mixing in a closed stainless steel vessel under Grade A unidirectional airflow. Filling into 100 mL and 250 mL multidose vials is performed on a peristaltic-dosing line with in-line particle size monitoring to reject batches exceeding Dv99 > 50 µm, a threshold correlated with needle blockage and caking.
Compliance anchors include USP <71> sterility testing, USP <85> bacterial endotoxins testing, USP <788> particulate matter in injections, and the current Ph. Eur. monographs for procaine benzylpenicillin and benzathine benzylpenicillin. Withdrawal periods for cattle and swine are set according to Commission Regulation (EU) No 37/2010, with benzylpenicillin MRL values of 50 µg/kg in muscle, fat, and liver, 100 µg/kg in kidney, and 4 µg/kg in milk; meat withdrawal is determined by the marketing authorization and is typically not less than 3–5 days depending on species and dose. Process bottlenecks reported on production lines include resuspension failure in open tanks when mixing is interrupted, and procaine particle dissolution during wet milling, which generates fines that increase the initial plasma peak but shorten release duration. The terminal finished product types are single-ingredient injectable suspensions and fixed-dose procaine/benzathine suspensions in 100 mL and 250 mL multidose vials for intramuscular injection in cattle, horses, and swine.
| Parameter | Procaine benzylpenicillin | Benzathine benzylpenicillin |
|---|---|---|
| Water solubility profile | Sparingly soluble; dissolution at the injection site controls early plasma release | Very low solubility; repository effect prolongs absorption |
| Typical intramuscular strength | 300,000 IU/mL | 150,000 IU/mL in fixed-dose combination |
| Particle size control for syringeability | Dv90 ≤ 20 µm | Dv90 ≤ 25 µm |
| Release duration class | 24–48 h | 72–96 h |
Dry-cow therapy syringes containing 600 mg procaine benzylpenicillin per 5 g intramammary dose (12.0% w/w) are manufactured as sterile oil-based or aqueous-gel suspensions, with the API dispersed in a thixotropic vehicle of aluminum monostearate in vegetable oil or a methylcellulose aqueous gel. The manufacturing sequence involves sterilization of the vehicle at 121°C for 15 min, aseptic addition of micronized procaine benzylpenicillin at Dv90 ≤ 25 µm, and high-shear dispersion under −0.8 bar vacuum to reduce entrapped air; the suspension is then filled into single-dose 5 g intramammary syringes under Grade A aseptic conditions. The syringe-type finished product requires a viscosity profile that retains the suspension in the teat cistern but does not exceed a plunger force of 50 N during administration. Sterility is verified according to USP <71>, bacterial endotoxins according to USP <85>, and particulate matter according to USP <788>. Milk withdrawal is anchored to the benzylpenicillin MRL of 4 µg/kg in milk under Commission Regulation (EU) No 37/2010; actual withdrawal is product-specific and validated in lactating cows, with dry-cow labels commonly specifying a milk discard time of 72–96 h after calving. Terminal finished product types are 5 g and 10 g single-dose intramammary syringe/plunger assemblies for dairy cattle dry-cow therapy.
For pre-ruminant calves and foals receiving benzylpenicillin orally in milk replacer or via oral bolus, the formulation must minimize acid degradation in the gastric compartment and reduce segregation during direct compression. Benzylpenicillin potassium is incorporated at 250 mg or 500 mg per bolus or tablet, with 100 mg per unit used for smaller neonatal animals. The addition ratio in the final tablet is adjusted with spray-dried lactose monohydrate, microcrystalline cellulose, and crospovidone disintegrant at 2–5% w/w, plus magnesium stearate at 0.5% w/w, to achieve disintegration within 15 min per USP <701> and content uniformity per USP <905>. Direct compression is preferred over wet granulation because benzylpenicillin potassium is thermolabile and moisture-sensitive; the tableting line runs below <40% RH, with a compression force of 10–20 kN on a rotary tablet press and a friability target of <1.0% after 100 rotations per USP <1216>. For oral boluses, a larger elongated punch produces the 500 mg unit, and hydroxypropyl methylcellulose film coating is applied to mask bitterness and provide moisture protection. Compliance is based on the current Ph. Eur. monograph for benzylpenicillin potassium, EU GMP Chapter 5 beta-lactam containment, and stability data generated under VICH GL3 at 25°C/60% RH and 40°C/75% RH. Terminal finished product types are 100 mg, 250 mg, and 500 mg oral tablets and 500 mg oral boluses for pre-ruminant calves; published industrial data for the 100 mg unit in foals is limited.
The incorporation of benzylpenicillin potassium into medicated feed premix and granulated premix formulations requires stepwise dilution to avoid segregation between the API particle, typically Dv50 20–40 µm, and mineral or organic carriers. A common premix addition ratio is 10.0% w/w benzylpenicillin potassium on a light calcium carbonate or spray-dried whey carrier, with the premix then added to the final feed at 10–20 kg/tonne to achieve a target dose of 20–30 mg/kg body weight per day. The manufacturing line uses a horizontal ribbon mixer with a coefficient of variation CV ≤ 5.0% for premix homogeneity; a first geometric dilution step at 1:10 API-to-carrier is followed by a second 1:10 dilution before final blending. Granulated premix, which reduces dust and segregation in bulk bins, is produced in a fluid-bed dryer with top-spray binder solution of pregelatinized starch or povidone at 3–5% w/w dry solids, and inlet air temperature is limited to 50°C because benzylpenicillin potassium potency loss accelerates above this threshold during prolonged drying. Compliance anchors are Regulation (EU) 2019/6 for medicated feed, the current Ph. Eur. benzylpenicillin potassium monograph, and Codex Alimentarius benzylpenicillin maximum residue limits where applicable. Regulatory authorization for penicillin G in feed differs by jurisdiction; EU growth-promotion use is banned, and EU medicated feed authorizations with penicillin G are limited, while some non-EU markets register therapeutic feed premixes under national dossiers, for which published industrial batch data remains limited. Production lines report electrostatic adhesion of micronized penicillin to mixer walls when relative humidity drops below 30%, and segregation in bins when carrier particle size distribution is not matched to API Dv90 within a ratio of 2:1. Terminal finished product types are 10% w/w feed premix powders and granulated premixes in 20 kg and 25 kg bags, intended for licensed feed mills.
Because registered commercial penicillin G capsules are not marketed for companion animals in most jurisdictions, veterinary compounding pharmacies produce oral capsules from benzylpenicillin potassium when a prescribed strength is unavailable. Capsule strengths of 100 mg and 250 mg are prepared by geometric dilution of the API with lactose monohydrate in a porcelain or glass mortar, and the final powder is filled into hard gelatin capsules size 0 or size 1 using a manual filling machine or an electronic capsule filler with weight verification at ≥95% of the target fill weight. The addition ratio is typically 10–40% w/w API depending on target capsule fill weight and excipient compatibility; because benzylpenicillin potassium is hygroscopic, the compounding environment is maintained at <40% RH and finished capsules are packaged in amber vials with desiccant. Compliance is anchored to USP <795> Pharmaceutical Compounding—Nonsterile Preparations, USP <905> uniformity of dosage units, and the current Ph. Eur. benzylpenicillin potassium monograph for potency input. Beyond-use dates follow USP <795> default rules at 14 days for dry powder capsules stored at controlled room temperature unless stability data support a longer period. This route is not suitable for food-producing animals because MRL compliance and withdrawal cannot be established under extemporaneous compounding. Terminal finished product types are 100 mg and 250 mg oral gelatin capsules for veterinarian-prescribed companion animal therapy; published multi-batch potency data for this specific veterinary configuration is limited because compounding activity is site-specific.
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Benzylpenicillin veterinary-grade active pharmaceutical ingredient is supplied as the free acid or as crystalline potassium, sodium, procaine, or benzathine salts. The free acid has molecular formula C16H18N2O4S, molar mass 334.39 g/mol, and CAS 61-33-6. The sodium salt is normally selected for injectable solutions and dry premix formulations requiring rapid dissolution; the potassium salt is preferred in oral powders, capsules, and tablets where water activity is controlled. This material is a veterinary-grade active pharmaceutical ingredient intended exclusively for further manufacture into tablets, injections, capsules, powders, granules, premix, and solutions. It is not a finished pharmaceutical dosage form and is not compounded for direct administration. Production occurs under veterinary good manufacturing practice in closed stainless-steel crystallizers, followed by solvent recovery, filtration, drying, and mill sizing. Potency is assigned by the zero-time chemical assay and is traceable to the current international standard for benzylpenicillin.
Compendial compliance is assessed against Ph. Eur. 0113 and USP benzylpenicillin sodium monograph. Appearance is white or almost white crystalline powder. Identification relies on infrared absorption spectrophotometry and the penicillin chromogenic reaction. A 10 g/L aqueous solution of the sodium salt should show pH 5.5–7.5. Water content by Karl Fischer titration is controlled to ≤1.0%. Assay on the anhydrous basis is typically 96.0–100.5% for the sodium salt. Related substances are determined by liquid chromatography with ultraviolet detection, using benzylpenicilloic acid and benzylpenilloic acid as marker impurities. Residual solvent limits follow Ph. Eur. 5.4 and VICH GL18. For injectable-grade powder, bacterial endotoxin control is assigned from the finished product risk assessment and may require ≤0.01 IU/mg depending on dose. Particle size is measured by laser diffraction per ISO 13320:2020; the target D90 depends on the intended suspension, dry blend, or solution.
| Attribute | Typical acceptance boundary | Analytical reference |
|---|---|---|
| Appearance | White or almost white crystalline powder | Ph. Eur. 0113 |
| pH of 10 g/L aqueous solution | 5.5–7.5 | Ph. Eur. 0113 |
| Water content | ≤1.0% | Karl Fischer, Ph. Eur. 2.5.32 |
| Assay on anhydrous basis | 96.0–100.5% | Pharmacopoeial HPLC method |
| Related substances | Specific and total limits per monograph | LC-UV using marker impurities |
| Residual solvents | Class 2 solvents within monograph limits | Ph. Eur. 5.4 / VICH GL18 |
| Bacterial endotoxins, injectable grade | Assigned by finished product; often ≤0.01 IU/mg | Ph. Eur. 2.6.14 / USP <85> |
| Particle size | D90 assigned to formulation | ISO 13320:2020 |
Before dry blending for premix, benzylpenicillin potassium is passed through a stainless-steel cone mill fitted with a 0.5 mm screen. At relative humidity below 30%, micronized sodium salt generates electrostatic cohesion that reduces flow through rotary tablet press feed frames; production suites are therefore maintained at 40–55% RH when particle size is below 20 µm D50. If the powder is not pre-dried after exposure to RH greater than 60%, moisture can enter the crystal lattice and alter compressibility during slugging or roller compaction. Aqueous solution stability is strongly temperature dependent; injectable filling terminals operate below 15°C and target dissolved oxygen below 2 mg/L to limit β-lactam hydrolysis. Published data for specific dry-processing configurations of this veterinary API are limited, so each blend must be qualified by bulk density, flow function, and potency uniformity studies.
The free acid is acid-labile. Exposure to gastric fluid with pH 1.0–3.0 accelerates β-lactam ring opening and formation of benzylpenicilloic acid. In monogastric species, absorption of unbuffered benzylpenicillin from oral capsules and tablets is variable and generally low. Oral veterinary formulations are therefore usually restricted to potassium salt in enteric-coated pellets, or to granules and premix buffered with citrate or phosphate carriers. Formulators should validate gastric survival using biorelevant media at 37°C and pH 1.2 for 30 min before evaluating intestinal transfer. In ruminating calves, milk replacer or abomasal delivery can bypass forestomach dilution and improve systemic exposure. This distinguishes benzylpenicillin from phenoxymethylpenicillin, which is acid-stable and better absorbed after oral administration in horses and pigs.
Benzylpenicillin displays hydrolysis kinetics strongly dependent on pH and solvent. Phosphate buffers above pH 7.0 accelerate degradation; citrate buffers below pH 3.0 also promote conversion to benzylpenillic acid. Maximum aqueous stability occurs near pH 6.0–6.8 for the sodium salt. Injectable solutions prepared from benzylpenicillin sodium should be reconstituted immediately before use; storage beyond 24 h at 2–8°C may result in discolouration and potency loss unless stability data support longer holding. Degradation products can increase immunogenicity risk in horses and cattle. The API should be stored at 2–8°C or below 25°C depending on salt form, protected from moisture and light. The sodium and potassium salts are hygroscopic; bulk containers should be sealed under nitrogen and opened only in low-humidity dispensing suites.
Wet granulation of benzylpenicillin for feed premix and granules is performed in high-shear mixers with impeller speeds of 100–400 rpm and chopper speeds of 1,500–3,000 rpm. Water or aqueous binder is added at 5–12% wet mass increase, followed by fluid-bed drying to loss-on-drying ≤2.0%. Drying air temperature is kept below 45°C because benzylpenicillin degrades more rapidly above this threshold. The granules are then sieved through 0.8–1.25 mm screens. If granules exceed 2.0% moisture, tablet ejection force may rise and edge chipping occurs during compression. Dry compaction in roller compactors requires feed screw torque monitoring; flooding of the nip zone with poorly flowing micronized API can produce density variation that shifts tablet potency. For premix, the API is diluted with lactose or calcium carbonate carrier in a ribbon blender; geometric dilution is required because the active fraction may be as low as 1–10% of the final blend.
Compared with phenoxymethylpenicillin, benzylpenicillin is more active against susceptible Gram-positive cocci and spirochetes but less acid-stable. Compared with amoxicillin, benzylpenicillin has a narrower Gram-negative spectrum and greater susceptibility to β-lactamase hydrolysis; β-lactamase-producing staphylococci are inherently resistant unless a β-lactamase inhibitor is co-formulated. When added to drinking water, benzylpenicillin solutions degrade more quickly than amoxicillin trihydrate because of pH and mineral content; stock solutions should be prepared at pH 6.0–6.8 and protected from sunlight. The API is not approved for all species or all countries; prescribing is governed by national veterinary regulations and residue withdrawal periods.
Benzylpenicillin procaine and benzathine salts are low-solubility forms used for intramuscular suspensions and intramammary syringes in cattle, sheep, and swine. Procaine benzylpenicillin supplies a rapid initial release together with a depot fraction; benzathine benzylpenicillin provides prolonged plasma activity beyond 24 h in cattle. These salts are not suitable for intravenous administration because of particulate embolism risk. The milled solids are suspended in aqueous vehicles containing preservatives and stabilizers; injection-site irritation and needle plugging are controlled by particle size below 25 µm D99. Benzylpenicillin sodium or potassium should not be combined with alcohol-based vehicles, oxidizing agents, or heavy-metal ions because β-lactam ring opening is accelerated. Aminoglycoside antibiotics in the same solution may form inactive complexes or precipitates; separate injection sites or sequential administration is required.
| Salt form | Solubility behaviour | Principal veterinary application | Key constraint |
|---|---|---|---|
| Benzylpenicillin sodium | Freely soluble in water; hygroscopic | Injectable solutions, oral powders, premix | Moisture control during dry handling |
| Benzylpenicillin potassium | Freely soluble; less hygroscopic than sodium salt | Tablets, capsules, granules | Static charge at low relative humidity |
| Benzylpenicillin procaine | Sparingly soluble; forms suspensions | Intramuscular injection, intramammary suspension | Particle size controls syringeability |
| Benzylpenicillin benzathine | Very slightly soluble; depot release | Prolonged-release injection | Not for intravenous use; residue persistence in milk |
Residue control and withdrawal periods are assigned under national and regional frameworks. In the European Union, benzylpenicillin is included in the residue status for food-producing species under Regulation (EU) No 37/2010; analytical method validation follows Commission Decision 2002/657/EC or equivalent. Manufacturers must verify maximum residue limit tolerance and withdrawal period against the target market. Sterile injectable-grade material is dispensed in controlled environments with filtered air, and subsequent filling of finished injectable products is performed under aseptic conditions or with terminal sterilisation where formulation stability permits. Penicillin residues require dedicated air handling and validated cleaning procedures; swab limits are derived from health-based exposure limits, and β-lactam products must be segregated from non-β-lactam lines to prevent cross-contamination. Low nanogram-level cross-contact can trigger hypersensitivity in non-target species; published residue thresholds for specific veterinary formulations are limited and are established within individual regulatory submissions.
