| HS Code | 710644 |
| Product Name | Cimetidine Veterinary Grade API |
| Grade | Veterinary Grade |
| Api | Cimetidine |
| Chemical Name | 1-cyano-2-methyl-3-[2-[(5-methyl-1H-imidazol-4-yl)methylsulfanyl]ethyl]guanidine |
| Molecular Formula | C10H16N6S |
| Molecular Weight | 252.34 g/mol |
| Cas Number | 51481-61-9 |
| Appearance | White to off-white crystalline powder |
| Solubility | Slightly soluble in water; soluble in dilute mineral acids; sparingly soluble in alcohol |
| Mechanism Of Action | Histamine H2-receptor antagonist; inhibits gastric acid secretion |
| Target Species | Cattle, pigs, horses, dogs, cats |
| Dosage Forms | Tablets, Injections, Capsules, Powders, Granules, Premix, Solutions |
| Purity Assay | 98.0% to 101.0% on dried basis |
| Storage Conditions | Keep container tightly closed in a cool, dry place |
| Shelf Life | 24 months when stored properly |
As an accredited Cimetidine 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 25 kg sealed drums with double polyethylene liners, labeled, and suitable for veterinary pharmaceutical formulations. |
| Container Loading (20′ FCL) | Cimetidine Veterinary Grade API is packed securely in sealed containers, loaded into a 20′ FCL, protected from moisture and damage. |
| Shipping | Cimetidine Veterinary Grade API is shipped in sealed, inert, moisture-proof drums or bags, protected from light and heat. Transport follows veterinary pharmaceutical safety regulations, with complete documentation and temperature-controlled logistics to preserve stability. Customs harmonized classification and handling protocols ensure safe delivery for tablets, injections, powders, and premix formulations. |
| Storage | Store Cimetidine Veterinary Grade API in a cool, dry, well-ventilated area, ideally below 25°C. Keep in tightly sealed, light-resistant original containers, protected from moisture and direct sunlight. Avoid exposure to heat, humidity, and oxidizing agents. Maintain strict hygiene and ensure containers are closed immediately after use to preserve stability and potency. |
| Shelf Life | Shelf life is 24 months when stored in tightly sealed, light-protected containers under cool, dry conditions. |
Cimetidine base exhibits a pKa of 6.8 and a needle-like crystal habit that contributes to poor flow and segregation risk under direct compression; therefore cGMP oral solid dose lines for companion-animal tablets and capsules use high-shear wet granulation in animal drug facilities operating under FDA 21 CFR 210/211. A typical tablet core contains cimetidine active at 55–70% w/w, microcrystalline cellulose 20–30% w/w, croscarmellose sodium 2–4% w/w, povidone K30 3–5% w/w, and magnesium stearate 0.5–0.75% w/w. The granulation endpoint is defined by impeller torque increase of 1.5–2.5 N·m in a high-shear granulator with impeller speed 250–400 rpm and chopper speed 1500–3000 rpm. Drying in a fluid-bed dryer at inlet air 55–65°C and product temperature 35–40°C proceeds until loss-on-drying reaches 1.5–2.0%; dry milling through a 0.8 mm screen follows. Compression on a rotary tablet press uses 12–20 kN force; tablet hardness is 60–120 N, friability is not more than 1.0% under USP <1216>, and disintegration is not more than 15 min in 0.1 N hydrochloric acid under USP <701>. Dissolution acceptance under USP <711> apparatus 2 in 0.1 N hydrochloric acid at 50–100 rpm is not less than 80% released at 30 min. Content uniformity follows USP <905> or Ph. Eur. 2.9.40 with acceptance value not greater than 15. Capsule filling uses the same milled granulate in hard gelatin capsules size 1–3 after blending with colloidal silicon dioxide 0.5% w/w and, if wetting adjustment is required, sodium lauryl sulfate. Terminal finished product types are scored tablets of 100 mg, 200 mg, and 300 mg cimetidine, and capsules in equivalent strengths. Process failure data on rotary presses with turret speeds above 45 rpm show picking and capping when granulate moisture exceeds 2.5%; compression suite relative humidity is therefore maintained below 60%, and pre-drying is required when excipient moisture exceeds 3.0%.
In sterile injectable manufacturing for veterinary hospital use, cimetidine hydrochloride is dissolved in water for injection in a 316 L stainless-steel jacketed vessel at 20–25°C under nitrogen overlay to reduce dissolved oxygen below 0.5 mg/L. The active is adjusted as cimetidine hydrochloride equivalent to 100 mg cimetidine base per mL; sodium chloride 0.9% w/v is added for isotonicity, and pH is adjusted with 0.1 M hydrochloric acid or sodium hydroxide to 5.0–6.0. The solution is filtered through a 0.22 µm PVDF sterilizing filter into depyrogenated Type I glass vials under EU GMP Annex 1:2022 Grade A conditions equivalent to ISO 14644-1:2015 Class 5. Terminal sterilization in a steam autoclave at 121°C for 15 min with F0 not less than 12 is the standard cycle; aseptic filling is reserved for packaging configurations that cannot survive moist heat. Sterility is verified under USP <71>, bacterial endotoxins under USP <85>, and subvisible particulate matter under USP <788>. Multi-dose veterinary vials include preservative systems validated under USP <51>. Residual solvents are controlled under VICH GL18(R), and elemental impurities under ICH Q3D(R2). Terminal finished product types are sterile single-dose and multi-dose veterinary vials at 100 mg/mL in 10 mL, 20 mL, and 50 mL presentations for intravenous, intramuscular, or subcutaneous administration in companion animals and non-food equine patients. A known incompatibility is precipitation of cimetidine free base at pH above 7.0, which causes filter blocking on 0.22 µm membranes; alkaline vehicles should not be used for dilution. Published data for diluted cimetidine stability in polyvinyl chloride infusion bags beyond 24 h is limited, so admixtures are specified as freshly prepared. For food-producing animals, residue depletion and MRL status must be confirmed with national regulators because cimetidine is not generally authorized for food animal species.
Because multidose HDPE bottles for non-food equine patients may be stored at farm ambient temperatures cycling from 5°C to 30°C, cimetidine base oral suspension is formulated at 20–50 mg/mL (2.0–5.0% w/v), with the higher end selected for large-volume doses delivered by oral syringe. The suspending matrix uses xanthan gum 0.25–0.40% w/v and microcrystalline cellulose/carboxymethylcellulose sodium 0.6–1.2% w/v, hydrated for 30–45 min in a high-shear rotor-stator mixer at 1500–3000 rpm, producing target viscosity 300–600 mPa·s at 25°C under Ph. Eur. 2.2.10 or USP <911>. Cimetidine base is micronized to D90≤80 µm to reduce sedimentation; pH is adjusted with citrate buffer to 5.5–6.5, where the base remains suspended. Preservatives methylparaben 0.18% w/v and propylparaben 0.02% w/v are used, with sorbitol 10–20% w/w as sweetener. Deaeration under vacuum at −0.8 bar for 15 min prevents foam-induced volume inaccuracies during filling. Terminal finished product types are oral suspension bottles of 100 mL and 250 mL and prefilled oral syringes at 20 mg/mL or 40 mg/mL cimetidine base. Release tests include pH, viscosity, density, content uniformity under USP <905>, and sedimentation volume after 72 h. The process limitation is that anionic suspending agents such as carbomer, when not fully neutralized and hydrated under defined pH conditions, can cause pH-dependent flocculation with cimetidine’s basic sites; substitution into the formulation without trial is not recommended. Suspensions are restricted to non-food equine patients; use in food-producing horses requires residue assessment under applicable regional rules.
| Dosage form | Typical API load | Critical process parameter | Primary compliance anchor | Terminal presentation |
|---|---|---|---|---|
| Tablets and capsules | 55–70% w/w | Granulate loss-on-drying 1.5–2.0%; compression 12–20 kN | USP <711>, USP <905>, FDA 21 CFR 210/211 | Scored tablets 100–300 mg; hard gelatin capsules size 1–3 |
| Injectable solution | 100 mg/mL cimetidine base | pH 5.0–6.0; dissolved oxygen <0.5 mg/L; F0 ≥12 | USP <71>, USP <85>, EU GMP Annex 1:2022 | Type I glass vials 10–50 mL |
| Oral suspension | 20–50 mg/mL | Viscosity 300–600 mPa·s at 25°C; D90≤80 µm | Ph. Eur. 2.2.10, USP <905> | Bottles 100–250 mL; prefilled oral syringes |
| Feed premix / granule | 1.0–5.0% w/w | Moisture <4.0%; blend RSD ≤3.0% | EC 183/2005, ISO 22000:2018, FAMI-QS 5.1 | Sachets 25–50 g; jars 1–5 kg; transfer packs 20 kg |
| Powder for oral reconstitution | 10–20% w/w | Reconstituted pH 5.0–5.5; fill relative humidity ≤30% | USP <795>, USP <905> | Unit-dose sachets; multi-dose bottles with measuring scoop |
Medicated feed premix production for non-food equine patients and zoo animal hospital use applies cimetidine base in dry powder or granule form at 1.0–5.0% w/w (10–50 mg/g), diluted 1:10 to 1:50 before top-dressing on feed. The process is run in a 500 L ribbon blender at 10–15 rpm for 15–20 min, with fill volume not exceeding 70%; blend uniformity is sampled at 10 points and accepted when relative standard deviation is ≤3.0%. The premix is sieved through 300–710 µm and filled into foil-lined HDPE jars or sachets at ≤30% RH; moisture is controlled below 4.0% by Karl Fischer under USP <921> to prevent caking. Colloidal silicon dioxide 0.5% w/w is added as a flow aid. Granules are produced by wet granulation with purified water or 5% povidone K30 solution, then fluid-bed dried to loss-on-drying 2.0–3.0%. Terminal finished product types are 25 g and 50 g sachets for feed top-dress, 1 kg and 5 kg HDPE jars for hospital stock, and 20 kg transfer packs for non-sterile compounding. Compliance is under EU Regulation EC 183/2005 on feed hygiene, ISO 22000:2018 for feed safety management, and FAMI-QS Version 5.1 for specialty feed ingredients; regional animal drug compounding rules govern drug claims. Published data for long-term stability of cimetidine in molasses-based or oil-carrier premixes is limited, and such carriers are not recommended unless stability at 30°C/65% RH for the intended shelf life is generated. This scenario is restricted to non-food equine and non-food zoo/exotic species because cimetidine residue depletion in edible tissues has not been established for food-producing animals in many jurisdictions.
For veterinary powder-for-reconstitution lines, cimetidine base is formulated at 10–20% w/w with sodium citrate anhydrous 15–25% w/w, citric acid monohydrate 5–10% w/w, sucrose or maltodextrin 60–70% w/w, and masking flavor 0.2–0.5% w/w. The citric acid–sodium citrate pair controls the reconstituted pH within 5.0–5.5; if buffering capacity is insufficient and pH drifts below 4.5, cimetidine base solubility increases and recrystallization can occur after storage at 2–8°C. Blending is performed in a 150 L V-blender at 25 rpm for 20 min after geometric dilution of active and buffer salts; the powder is filled into foil-lined unit-dose sachets under 20–25°C and ≤30% RH. Reconstitution with purified water to 50 mL or 100 mL produces 20 mg/mL or 40 mg/mL cimetidine. Release tests include loss-on-drying below 2.0%, content uniformity under USP <905>, reconstituted pH, and sedimentation stability. Because the product is non-sterile compounded, USP <795> defines the quality framework; ICH Q1A(R2) guides stability protocols, and VICH GL18(R) applies to residual solvents. Terminal finished product types are unit-dose powder sachets for oral suspension, multi-dose bottles with measuring scoop, and oral paste kits reconstituted by the veterinarian at point of use. Operational failure occurs when cimetidine and alkaline buffer are mixed in the dry state without geometric dilution; localized caking prevents complete reconstitution. Buffer salts are therefore pre-blended with filler for 10 min before active addition. Published data for beyond-use dating of reconstituted cimetidine oral suspension beyond 14 days at controlled room temperature is limited, so longer storage must be supported by stability studies.
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Cimetidine Veterinary Grade API for Tablets / Injections / Capsules / Powders / Granules / Premix / Solutions is a histamine H2-receptor antagonist supplied as a white to almost white crystalline powder with molecular formula C10H16N6S, molar mass 252.34 g/mol, and CAS registry number 51481-61-9. The base material is assigned model code CIM-VET/API-01; suffix variants CIM-VET/API-01-M and CIM-VET/API-01-G designate micronized and premix-granulated grades. Compendial alignment is referenced to the current Ph. Eur. cimetidine monograph and the USP–NF cimetidine monograph. Release testing is performed under ICH Q7 GMP for active pharmaceutical ingredients. The material is non-sterile and is intended for downstream formulation into oral tablets, hard capsules, powders, granules, feed premixes, and pH-adjusted injectable solutions. Its pharmacodynamic action is competitive, reversible inhibition of histamine at gastric parietal cell H2 receptors, reducing basal and stimulated gastric acid secretion. In veterinary medicine this supports management of gastric and duodenal erosion, acid reflux, gastrinoma-related hypersecretion, and stress ulcer prophylaxis in companion and production species. In most regulatory jurisdictions cimetidine is approved as a human medicinal product and is used in veterinary patients under professional extra-label discretion or national cascade rules; no unified global veterinary label exists.
Unlike acid-labile proton-pump inhibitors such as omeprazole, cimetidine does not require enteric coating for acid protection in oral tablets or granules. The base nevertheless exhibits only slight aqueous solubility; injectable solution preparation requires conversion to the hydrochloride or another acid addition salt and pH reduction to achieve complete dissolution. These two properties—acid stability and pH-dependent solubility—drive the tableting and parenteral processing controls described below.
| Parameter | Release limit | Method / Standard reference |
|---|---|---|
| Appearance | white to almost white crystalline powder | visual examination |
| Identification | IR spectrum consistent with reference; melting point 139–144 °C | Ph. Eur. 2.2.24, Ph. Eur. 2.2.14 |
| Assay | 98.0–102.0% on dried basis | Ph. Eur. 2.2.29 / USP HPLC |
| Loss on drying | ≤0.5% | Ph. Eur. 2.2.32 |
| Residue on ignition | ≤0.1% | Ph. Eur. 2.4.16 |
| Heavy metals | ≤20 ppm | Ph. Eur. 2.4.8 |
| Related substances | total specified impurities ≤1.0%; individual unspecified impurities ≤0.10% | Ph. Eur. 2.2.29 / USP HPLC |
| Residual solvents | conforms to VICH GL18 / ICH Q3C | Ph. Eur. 2.4.24 |
| Particle size | not fixed by monograph; release control by laser diffraction if required for dosage form | Ph. Eur. 2.9.31 / USP <786> |
Packaging for bulk API consists of low-density polyethylene double liners inside a 25 kg fiber drum. The product is stored at controlled room temperature 20–25 °C, with excursions allowed to 15–30 °C. The drum should remain sealed and protected from light because cimetidine can discolor under prolonged light exposure. Under these conditions the manufacturer retest interval is 36 months from release; ongoing stability batches are evaluated for assay, related substances, and moisture. Veterinary grade in this context does not signify lower purity. It identifies a non-sterile release chain intended for veterinary dosage-form manufacture and feed-mixing operations, with packaging sizes adapted to compounding rather than human pharmacy distribution. The same chemical identity, assay, related-substance, and residual-solvent controls apply as for human pharmacopoeial cimetidine.
Direct compression of cimetidine base is constrained by particle-size distribution, polymorph composition, and moisture sensitivity at the tablet press. The USP powder flow chapter USP <1174> provides the appropriate framework: Hausner ratio values between 1.19 and 1.35 are generally acceptable for rotary press feed, while values above 1.40 indicate cohesive flow that usually requires wet granulation. Production-scale rotary presses with turret speeds of 20–60 rpm and compression forces of 5–15 kN are used for cimetidine tablets, but ejection force must be monitored continuously because batch-to-batch polymorph variation can produce punch sticking and capping. If the active particle-size distribution contains an excessive fraction above 250 µm by laser diffraction, tablet weight variability may exceed the USP <905> uniformity requirement before the compendial disintegration limit is reached. For uncoated immediate-release tablets, disintegration in 0.1 N HCl at 37 °C is tested according to USP <701>; the compendial limit for uncoated tablets is typically 15 min unless the specification is justified differently.
Wet granulation becomes necessary when the direct-compression mixture displays high fines or acicular crystal habit. High-shear granulators are operated with chopper speeds in the range of 800–1200 rpm, binder solution addition rates controlled by mass-flow meters, and final granule moisture in the range of 1.5–2.5% before fluid-bed drying. Drying is terminated when loss on drying is below 1.5%, because residual moisture above this level can promote punch filming and slow disintegration. Magnesium stearate is held at or below 1.0 wt% because the hydrophobic lubricant can depress dissolution of the slightly soluble base. Disintegration testing and dissolution testing according to USP <711> are used to confirm that the selected granulation route does not create an overcompacted matrix. Cimetidine polymorphs can convert during wet granulation, so X-ray powder diffraction and differential scanning calorimetry are used as orthogonal identity tools. Where tablet sticking persists, processing is moved to controlled humidity below 50% RH and forced feeders are used; dryer exhaust temperature should not exceed the melting onset of the polymorph mixture to avoid form conversion.
For oral tablets and hard capsules, cimetidine base is usually formulated in unit strengths of 100 mg or 300 mg for companion animal dosing, although the exact strength is a finished product approval decision. Veterinary references list published oral doses for dogs of 5–10 mg/kg every 8–12 h; published data for equine and ruminant dosing variability is limited, and prescribers verify the dose against the approved veterinary product or regional cascade. Because cimetidine is a competitive H2-receptor antagonist, breakthrough acid secretion can occur if a dose is missed or delayed. The shorter duration of action relative to proton-pump inhibitors such as omeprazole means that multiple daily dosing is common in acute veterinary gastroprotection protocols.
Hard capsules are used when the API is dry-filled with direct-compression diluents or milled granules. Powder formulations for oral suspension are usually compounded at the point of care or manufactured as sachets. For oral suspensions, the base is micronized to d90 30–60 µm and suspended with a wetting agent; particle-size reduction below this range can create electrostatic clouding and caking in the suspension, while larger particles create sedimentation and poor dose uniformity. The non-enteric acid stability of cimetidine allows powder and granule formulations to be mixed with food or administered by nasogastric tube without the acid-protection constraint associated with omeprazole granules.
Because cimetidine is eliminated primarily by renal excretion, accumulation occurs in dehydrated animals or those with reduced glomerular filtration rate. Veterinary treatment protocols reduce the frequency or total daily dose when serum creatinine is elevated. The API itself does not carry a species-specific withdrawal period; withdrawal periods are assigned to the formulated veterinary medicinal product based on residue depletion studies in food-producing species.
Feed premix and granule production is a geometric dilution operation. Cimetidine base is first pre-blended with a compatible carrier such as lactose monohydrate or calcium carbonate, then passed through a 500 µm safety screen before addition to a horizontal ribbon mixer or double-cone tumble mixer. The carrier particle size is selected so that its bulk density and particle-size distribution overlap the active fraction; otherwise the active segregates at the top or bottom of the premix during transport and auger distribution. Premix homogeneity is evaluated by sampling at 10 to 20 points across the mixer and finished bag; a coefficient of variation of ≤5.0% is commonly applied as a batch-release limit, but the final acceptance criterion is dossier-specific. For medicated feed dilution at 1:100 or 1:1000, the premix must remain free-flowing and non-caking. Residual moisture is maintained below 5.0% to limit microbial growth and physical instability. The granulated premix variant is produced by low-shear wet granulation or fluid-bed spray granulation; the granule fraction is controlled by sieve analysis to minimize segregation during bag filling. Mixing time in a horizontal ribbon mixer is typically 10–15 min after geometric dilution, with mixing speed in the range of 25–50 rpm; overshearing can generate fines and electrostatic charge that increase segregation during discharge.
Injectable solution processing of cimetidine base is a distinct operation. The base has a pKa of approximately 6.8 and is described as slightly soluble in water; at 25 °C the intrinsic solubility is broadly within 1–10 mg/mL. To reach injectable concentrations above this range, the base is dissolved with hydrochloric acid or another pharmaceutically acceptable acid to form a solution with final pH in the acidic range, commonly 4.0–6.0 for cimetidine injection formulations. Acid addition is performed slowly with continuous cooling to keep the solution below 25 °C. The API itself is non-sterile; sterility is a finished product property achieved by terminal moist-heat sterilization at 121 °C for 15 min where formulation stability permits, or by aseptic filtration through 0.22 µm membrane filters. Parenteral manufacturers apply USP <85> bacterial endotoxin testing and USP <788> particulate matter testing to the final solution; the endotoxin limit is calculated from the maximum veterinary dose and is not an intrinsic release limit of the base API unless contractually established. The pH adjustment step must be validated for assay retention and related-substance growth after terminal sterilization, because cimetidine can form degradation products in strongly acidic or alkaline conditions.
Cimetidine is a known reversible inhibitor of cytochrome P450 isoforms CYP1A2, CYP2C9, CYP2D6, and CYP3A4; this property is more pronounced than that of famotidine or ranitidine at therapeutic concentrations. In vitro human liver microsome assays have reported isoform-dependent IC50 values from approximately 10 µM to 500 µM depending on substrate and incubation conditions; published data using canine, feline, or equine microsomes is limited. The clinical consequence is that co-administered drugs cleared primarily by these pathways—theophylline, cyclosporine, diazepam, metronidazole, and certain anticonvulsants—may exhibit reduced clearance and increased exposure when cimetidine is added. This is not an API purity defect or a formulation incompatibility; it is an operational boundary requiring a prescriber to review the co-medication list before the first dose. Ranitidine availability has been restricted in some regions because of N-nitrosodimethylamine impurity findings, while cimetidine has not been subject to the same class-wide withdrawal; nitrosamine risk assessment is nevertheless required under current CHMP and VICH guidance.
| Property | Cimetidine base | Famotidine | Omeprazole |
|---|---|---|---|
| Molar mass | 252.34 g/mol | 337.45 g/mol | 345.42 g/mol |
| Mechanism | H2-receptor antagonist | H2-receptor antagonist | proton pump inhibitor |
| Acid stability | stable; no enteric coating required | stable; no enteric coating required | acid-labile; enteric coating or coated pellets required |
| CYP inhibition | CYP1A2, CYP2C9, CYP2D6, CYP3A4 inhibitor | negligible at therapeutic concentrations | CYP2C19 substrate/inhibitor potential; CYP3A4 substrate |
| Dosing frequency implication | multiple daily dosing common | multiple daily dosing common | once-daily acid suppression common |
For a veterinary tablet line using direct compression in a low-humidity suite, cimetidine base is dry-blended with microcrystalline cellulose, croscarmellose sodium, and magnesium stearate at ≤1.0 wt% lubricant. Tablets are compressed to hardness 5–8 kp and tested for disintegration in 0.1 N HCl at 37 °C according to USP <701>. If tablet hardness must be raised above 8 kp to survive handling, a wet-granulation route is substituted because direct-compression matrices become overcompacted and may fail dissolution. The API hopper and feed frame are operated at ≤50% RH to limit punch sticking. This configuration represents the primary tablet manufacturing boundary for the product.
