| HS Code | 694731 |
| Productname | Doxycycline Veterinary Grade API |
| Chemicalname | (4S,4aR,5S,5aR,6R,12aS)-4-(dimethylamino)-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide |
| Casnumber | 564-25-0 |
| Molecularformula | C22H24N2O8 |
| Molecularweight | 444.43 g/mol |
| Appearance | Yellow to pale yellow crystalline powder |
| Solubility | Soluble in water (particularly as hyclate salt); slightly soluble in ethanol; freely soluble in aqueous acid and alkaline solutions; practically insoluble in chloroform and ether |
| Meltingpoint | Approximately 270°C with decomposition |
| Ph | pH of 1% aqueous solution is generally between 2.0 and 5.0 depending on salt form |
| Shelflife | 24 to 36 months in original sealed container under recommended storage conditions |
| Storagecondition | Keep in tightly closed container, protected from light and moisture, store at controlled room temperature 15–30°C |
| Compatibledosageforms | Tablets, Injections, Capsules, Powders, Granules, Premix, Solutions |
As an accredited Doxycycline 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 | Doxycycline Veterinary Grade API supplied in 25 kg sealed drums with moisture-proof inner lining, clearly labeled for pharmaceutical manufacturing use. |
| Container Loading (20′ FCL) | Doxycycline veterinary grade API is containerized in a 20-foot FCL as sealed drums on pallets, safely secured for transport. |
| Shipping | Ship Doxycycline Veterinary Grade API in sealed, moisture-proof, light-resistant containers with proper hazard labeling. Use temperature-controlled, ventilated transport, avoiding direct sunlight and humidity. Ensure compliance with veterinary pharmaceutical regulations, include documentation, and secure palletized freight to prevent damage or contamination during transit. |
| Storage | Store Doxycycline Veterinary Grade API in a tightly sealed, light-resistant container in a cool, dry, well-ventilated area. Protect from moisture and direct sunlight. Avoid exposure to temperatures above 30°C. Keep away from incompatible substances. Follow manufacturer-specific labeling and local regulatory requirements to maintain potency, stability, and safety throughout shelf life. |
| Shelf Life | Shelf life is typically 2 years when stored airtight, protected from light, in a cool, dry place. |
Among the dose forms used in commercial swine production, doxycycline hyclate is most frequently incorporated as a 10% w/w premix for Type B and Type C medicated feed intended to manage respiratory disease complexes in grower and finishing pigs. Under EU Regulation (EU) 2019/4, non-target feed carryover from a production line after a medicated batch is limited to 1% of the active substance in the previous batch; therefore, flushing with ground corn and validation of the first 50 kg after flush become batch-release prerequisites. A batch record using 2.0–3.0 kg of 10% w/w doxycycline premix per 1,000 kg finished feed delivers 200–300 mg doxycycline base per kg feed, which corresponds to a target dose of 10 mg/kg bodyweight per day at a 5% bodyweight dry-matter feed intake. Mixing is conducted in a horizontal ribbon mixer at 60–70% fill volume for 10–15 min to achieve a coefficient of variation below 5%; the doxycycline premix is added after the ground-corn fraction and before trace mineral premix to reduce residence time in contact with zinc, iron, and copper, which form low-solubility chelates at the β-diketone site of the naphthacene nucleus. Conditioning at 75–80°C for 15–20 s with steam quality above 85% dry fraction, followed by die pelletization at 70–75°C, preserves assay because doxycycline hyclate shows accelerated epimerization when retained above 80°C for more than 30 s; direct steam injection without post-conditioning cooling is not recommended. Finished matrices include 20 kg Type B intermediate premix, 25 kg pelletized Type C complete feed, and 1 kg top-dress sachets.
Because drinking-water medication exposes the active to chlorinated water for up to 24 h in nipple or bell drinker systems, water-soluble doxycycline powder in broiler and turkey operations is formulated with acidic carriers to maintain solubility and reduce 4-epi-doxycycline formation. Residue compliance is governed by Commission Regulation (EU) No 37/2010 Table 1; for poultry, residue depletion must be verified in liver and kidney, where elimination is slower than in muscle, and withdrawal periods are fixed by the national marketing authorization rather than by API specification alone. A 10% w/w powder is added to drinking water at 1.0 g/L to produce 100 mg/L doxycycline base; because the hyclate salt has a base equivalence factor of 0.866, 115.4 mg of doxycycline hyclate supplies 100 mg of base. Dry blending is performed at 20–25°C and relative humidity below 40% in a V-blender for 20–30 min, using anhydrous citric acid at 2–5% w/w and lactose monohydrate q.s.; the powder is sealed in foil-lined sachets because light exposure converts the trans-dienone chromophore to photoisomers. Dissolution specification requires 90% of labeled active dissolved in 500 mL water at 15°C within 10 min without precipitation. Water pH above 6.5 accelerates 4-epi-doxycycline formation, free chlorine above 2 mg/L oxidizes the naphthacene ring, and water hardness above 250 mg/L CaCO3 reduces dissolution by localized alkalinity. Terminal products include 100 g, 500 g, and 1 kg foil sachets for stock solutions up to 1,000 L.
| Scenario | Primary standard or regulation | Analytical or process control | Boundary condition |
|---|---|---|---|
| Swine premix | EU Regulation (EU) 2019/4 | Ribbon mixer CV below 5% | Conditioning above 80°C for more than 30 s increases epimer |
| Poultry water-soluble powder | Commission Regulation (EU) No 37/2010 | Water pH 4.0–5.5 | Free chlorine above 2 mg/L causes oxidative degradation |
| Companion animal tablets | FDA 21 CFR 210/211; USP <905> | Tablet hardness 60–90 N | Dicalcium phosphate filler excluded |
| Injectable solution | USP <71>; USP <85> | pH 5.0–6.5 | Terminal autoclaving not recommended |
| Granules | EU Regulation (EU) 2019/4 | Granule fraction 0.5–1.0 mm | Dust below 0.250 mm must not exceed 5% |
Direct compression of doxycycline hyclate for canine and feline tablets illustrates a conflict between dose uniformity and API flow because the needle-like crystal habit of the hyclate salt produces poor die fill at high machine speeds. Finished dosage forms for companion animals are regulated as new animal drugs in the United States under 21 CFR 514, and manufacturing must follow 21 CFR 210 and 21 CFR 211; batch release includes USP <905> uniformity of dosage units and USP <711> dissolution using Apparatus 2 at 75 rpm in 900 mL water at 37°C, with limits set by the current USP Doxycycline Hyclate Tablets monograph. To achieve 100 mg doxycycline base per tablet, 115.4 mg doxycycline hyclate is required; a 50 mg base tablet requires 57.7 mg hyclate. Wet granulation with pregelatinized starch and microcrystalline cellulose is preferred over direct compression because it reduces segregation and dusting; granulation fluid is purified water or 5% w/w povidone K30, and the dried granule moisture is brought below 1.5% before lubrication with 0.5% magnesium stearate and 1.0% croscarmellose sodium. Compression on a 16-station rotary press at 12–18 kN produces tablet hardness of 60–90 N and disintegration below 15 min. Terminal products are 50 mg and 100 mg tablets in PVC/PVdC-aluminium blisters and 100 mg capsules in HDPE bottles with desiccant. Dicalcium phosphate dihydrate must not be used as a filler because the divalent calcium ion forms stable chelates with the β-diketone moiety, reducing dissolution and oral bioavailability; ferric oxide colorants and calcium sulfate fillers are similarly excluded.
Published data for this specific configuration is limited; however, where parenteral doxycycline products are authorized for cattle and small ruminants in national registrations, the formulation and manufacturing sequence must address the same impurity and precipitation failure modes documented for tetracycline-class injectables. Sterility testing follows USP <71>, bacterial endotoxins are controlled under USP <85>, and particulate matter is evaluated by USP <788>; for EU markets, Annex 1 of EudraLex Volume 4 governs aseptic processing. A 20% w/v solution labeled as 200 mg doxycycline base per mL requires 231 mg doxycycline hyclate per mL, based on the base equivalence factor of 0.866. Propylene glycol or glycerin formal is used as co-solvent, and the aqueous phase is chilled to 5–10°C during pH adjustment to 5.0–6.5 with monoethanolamine; nitrogen sparging through a 0.22 µm point-of-use filter reduces oxidative degradation in the holding tank. The solution is passed through a 0.22 µm PVDF or PES membrane under laminar flow; terminal autoclaving is not recommended because doxycycline hyclate epimerizes rapidly above 80°C and develops visible darkening. The filled product is packaged in 50 mL or 100 mL amber borosilicate vials with bromobutyl stoppers to limit light transmission below 400 nm. Avoid dilution with lactated Ringer's or other calcium-containing infusion fluids because calcium-doxycycline chelation produces particulate precipitation; if intravenous administration is authorized, the compatibility of the final admixture must be confirmed by visual inspection and pH measurement over 12 h.
Granule dosage forms of doxycycline hyclate are selected when feed mills require a free-flowing, dust-free top-dressing for individual piglet or calf medication and when inclusion precision in a final mix is below 0.5% by weight. Granules intended for food-producing species in the EU are covered by Regulation (EU) 2019/4 if administered as medicated feed; in the United States, extralabel use restrictions under 21 CFR 530 apply when no approved doxycycline granule product exists for the target species. A 5% w/w granule formulation is applied at 1 g per 5 kg bodyweight to deliver 10 mg/kg doxycycline base; the equivalent hyclate input per gram of granules is 57.7 mg when the 0.866 base equivalence factor is applied. Granulation is carried out by fluidized-bed top-spray granulation using a 5% w/w povidone binder on a lactose and pregelatinized starch substrate; the dried granules are sieved to 0.5–1.0 mm, and the dust fraction below 0.250 mm must not exceed 5% to limit cross-contamination and operator exposure. If a protective ethylcellulose coating is applied, dissolution must be confirmed at pH 1.2 and pH 4.5 because the coating delays release in gastric or abomasal fluid. Terminal products include 500 g and 1 kg HDPE jars with induction seals and 250 g foil-lined sachets for farm dispensing.
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Doxycycline veterinary-grade API is supplied predominantly as doxycycline hyclate (CAS 24390-14-5, molecular formula C22H24N2O8·HCl·0.5C2H6O·0.5H2O, molecular weight 512.94 g/mol) and doxycycline monohydrate (CAS 17086-28-1, molecular weight 462.45 g/mol). The hyclate salt is the high-solubility grade for injectable and aqueous oral preparations; the monohydrate is the low-hygroscopicity grade for dry tablet, capsule, powder, granule, and premix applications. The powder is a yellow to orange-yellow crystalline solid supplied in double polyethylene-lined fibre drums with desiccant and is intended for further pharmaceutical processing under Good Manufacturing Practice conditions. Release testing follows the USP-NF Doxycycline Hyclate monograph and the Ph. Eur. Doxycycline Hyclate monograph for identity by infrared absorption, HPLC assay, related substances, water content by Karl Fischer, specific rotation, elemental impurities, and microbial enumeration. Representative assay limits are 95.0–102.0% on the dried, solvent-free basis; total related substances are controlled at ≤2.0%, and the ethanol associated with the hemiethanolate crystal form is verified against the manufacturer’s validated specification. Residual solvents other than the solvated ethanol are controlled under ICH Q3C and VICH GL18. Storage is recommended below 25°C and below 40% RH, with protection from light because the tetracycline chromophore undergoes photodegradation.
Batch-to-batch particle-size variability in doxycycline hyclate exerts direct effects on dry blend flow and segregation. Sieve analysis per USP <786> and laser diffraction per ISO 9276-2:2014 are used to set vendor specifications. A D90 above 425 µm can cause failed content uniformity in low-dose tablets; a D10 below 10 µm increases cohesive flow behavior and dusting during granulation. Carrier blends for premixes require matched bulk density; bulk density differences above 20% between API and carrier are mitigated by geometric dilution or granulation. Flow properties are characterized by Carr index and Hausner ratio according to ASTM D6393-21; values above 1.35 Hausner ratio indicate poor flow and require glidant addition. Colloidal silicon dioxide can improve flow, but excess silica may adsorb doxycycline and slow dissolution in tablet matrices.
| Property | Doxycycline Hyclate | Doxycycline Monohydrate |
|---|---|---|
| CAS registry number | 24390-14-5 | 17086-28-1 |
| Molecular weight | 512.94 g/mol | 462.45 g/mol |
| Pharmacopoeial solubility description | Freely soluble in water; soluble in methanol | Slightly soluble in water; sparingly soluble in alcohol |
| Hygroscopicity | Hygroscopic; requires desiccated storage | Less hygroscopic; preferred for low-moisture dry blends |
| pH of 1% aqueous dispersion | 2.0–3.0 | 5.0–6.5 |
| Primary formulation use | Injectable solutions, oral solutions, water-soluble powders | Tablets, capsules, granules, premixes, pellets |
| Typical particulate control | D90 ≤ 425 µm | D90 ≤ 425 µm |
| Typical loss on drying | ≤2.0% | ≤1.5% |
Doxycycline hyclate aqueous chemistry is dominated by amphoteric ionisation and pH-dependent stability. The molecule exhibits pKa values near 3.5, 7.4, and 9.3; at pH above 7.5, solubility decreases and epimerization to 4-epi-doxycycline accelerates. Injectable solutions are therefore compounded in the acidic to weakly acidic range; a final pH of 5.0–6.5 is often specified to balance solubility, tissue tolerance, and impurity formation. During dissolution of the hyclate salt, the unbuffered solution can fall to pH 2.0–3.0 before pH adjustment; therefore addition of sodium hydroxide or trometamol buffer must be carried out with continuous mixing and pH monitoring. Production-scale vessels constructed from 316L stainless steel with electropolished surfaces are used to reduce metal-ion catalysts; dissolution in glass-lined tanks is also acceptable. Oxygen exposure is limited by nitrogen overlay, and dissolved oxygen is typically kept below 1 mg/L during compounding and filling. Terminal steam sterilisation is not generally used because aqueous doxycycline is thermally labile above 60°C; published data for specific veterinary injection formulations exceeding 200 mg/mL is limited, and forced degradation studies are required to establish terminal sterilisation limits.
Filter compatibility is validated by recovering doxycycline after passage through 0.22 µm PVDF or PES membranes; adsorption should be below 2% of the target concentration. Nylon membranes are avoided because of reported adsorptive losses with tetracycline derivatives in aqueous media. The filling line should use amber USP Type I glass vials or opaque polymer containers, and stoppers should be pre-treated to reduce leachable metal ions. Sterilising filtration followed by aseptic filling is the standard manufacturing route for heat-labile injectable preparations. Container closure studies should include headspace oxygen, stopper compatibility, and photostability testing under ICH Q1B or VICH GL3.
Dry oral forms are produced by direct compression, dry granulation, or wet granulation. The hygroscopic nature of doxycycline hyclate introduces sticking and picking on tablet presses if loss on drying exceeds 2.0% or if RH exceeds 60% in compression suites. Particle size is controlled to D50 100–150 µm and D90 ≤ 425 µm to maintain blend uniformity in low-dose tablets. Fluid-bed granulation with aqueous binder should not exceed product temperature 42°C; inlet air temperature in the range 50–55°C is representative. The monohydrate salt is preferred when microcrystalline cellulose, starch, or crospovidone contribute moisture to the blend. For capsules, slugging or roller compaction can avoid aqueous exposure; final blend moisture is controlled at ≤1.5% for hyclate and ≤1.5% for monohydrate. Tablet dissolution testing follows USP <711>; immediate-release veterinary tablets typically specify not less than 75% release at 45 min in 0.1 N HCl, but the exact acceptance criterion must be established from the approved regulatory file.
Feed premixes and granules expose doxycycline to moisture, heat, and transition-metal ions in carriers such as limestone, corncob, or wheat middlings. Degradation follows epimerization and oxidative discolouration; drying above 60°C increases related substances and shifts the product from yellow to brown. Stainless steel 316L or glass-lined granulators are preferred to avoid copper and iron ion contact; published data for trace metal acceleration in doxycycline premixes is limited, but the tetracycline class is known to chelate divalent and trivalent cations, which reduces antibiotic activity. Representative fluid-bed drying uses inlet air 50–55°C and product temperature below 42°C; final moisture is controlled at ≤2.0%. The dried premix is filled into aluminium-lined bags with oxygen absorbers and stored below 25°C. Light protection is required because the tetracycline chromophore absorbs UV and visible radiation; photostability testing according to ICH Q1B or VICH GL3 is recommended because published data for photodegradation kinetics in specific premix matrices is limited. Stability studies under 25°C/60% RH and 40°C/75% RH are used to assign a retest period; feed matrix interactions at doxycycline levels between 100 g/tonne and 500 g/tonne should be generated during formulation development.
Oral solutions and water-soluble powders use the hyclate salt because of its high aqueous solubility. Aqueous concentrates are usually buffered to pH 5.0–6.0 with citrate or phosphate; if pH rises above 7.0, precipitation and epimerization occur. Non-aqueous vehicles such as propylene glycol or glycerol formal reduce water activity and improve photostability, but solvent choice is constrained by animal species tolerability and withdrawal-period requirements. Dissolved oxygen is reduced by nitrogen sparging; amber glass or opaque HDPE containers are used to limit light transmission. Polyvinyl chloride dosing bags are avoided because doxycycline can sorb to plastic or interact with plasticisers; published data for veterinary oral dosing syringes is limited. In medicated drinking water, water hardness above 200 ppm calcium carbonate can reduce soluble doxycycline by chelation. Multi-dose drinking water concentrates require preservative effectiveness testing according to Ph. Eur. 5.1.3 or USP <51> if a preservative is present; otherwise, single-dose packaging or short in-use stability is required.
Switching from doxycycline hyclate to doxycycline monohydrate is evaluated when tablet formulations contain moisture-liberating excipients or when coating requires extended thermal exposure. Monohydrate has lower aqueous solubility and slower dissolution in 0.1 N HCl, but better solid-state stability under 40°C/75% RH open storage in some comparative supplier data. The salt form also changes the pH of the granulating fluid; hyclate solutions are acidic, while monohydrate aqueous slurries are near neutral, requiring different binder compatibility. Direct compression blends using monohydrate often require particle size D90 below 300 µm for content uniformity in tablets containing 50 mg to 200 mg active. Dry granulation by roller compaction is preferred over wet granulation when water content exceeds 5% of blend mass; aqueous granulation can induce phase transformation and impurity formation. If wet granulation is unavoidable, the granulating fluid should be nonaqueous or low-water isopropanol, and drying should not exceed product temperature 42°C.
Compared with oxytetracycline and chlortetracycline, doxycycline has higher lipid solubility and greater apparent volume of distribution in cattle and pigs; published pharmacokinetic parameters vary by formulation and route. Doxycycline has a lower tendency to chelate calcium than earlier tetracyclines, but the interaction with feed minerals remains clinically relevant. In premix manufacturing, doxycycline hyclate requires stricter moisture control than oxytetracycline dihydrate because of its hygroscopicity; the monohydrate form is more comparable in handling behavior. The API is also distinguished by a longer elimination half-life in many species and lower phototoxicity compared with chlortetracycline, although published comparative phototoxicity data for veterinary species is limited.
Premix homogeneity is critical because the target inclusion rate in final feed can be as low as 100 g/tonne; coefficient of variation for tracer or active analysis should be within 5% relative standard deviation across at least 10 sampling points according to feed industry guidance. Ribbon mixers with working capacity 60–80% and mixing times 5–10 min are representative; actual mixing time must be validated with the specific carrier. Carryover into subsequent batches is managed by sequencing, flush material, or dedicated equipment; published data for doxycycline carryover in specific feed mill equipment is limited. For granules and powders, the API is often pre-blended with carrier to form a concentrated premix at 100 g/kg or 200 g/kg before dilution; geometric mixing steps avoid segregation. Particle size and density differences between doxycycline and carrier require periodic content uniformity testing, and electrostatic charge can be controlled by maintaining RH above 30% in the packaging suite.
| Quality attribute | Compendial or guidance reference | Representative control |
|---|---|---|
| Identity | USP-NF Doxycycline Hyclate monograph, IR absorption | Positive match to reference standard |
| Assay | USP-NF Doxycycline Hyclate HPLC | 95.0–102.0% dried basis |
| Related substances | Ph. Eur. Doxycycline Hyclate monograph, HPLC | Total impurities ≤2.0% |
| Water content | USP <921> Karl Fischer | ≤2.0% for hyclate; ≤1.5% for monohydrate |
| Residual solvents | ICH Q3C, VICH GL18 | Class 3 solvents within limits; ethanol as solvate monitored |
| Microbial limits | Ph. Eur. 2.6.12, 2.6.13 | TAMC ≤10³ CFU/g, TYMC ≤10² CFU/g, E. coli absent |
| Storage | Manufacturer stability data under 25°C/60% RH, 40°C/75% RH | Below 25°C, RH ≤40%, light-protected |
