| HS Code | 230630 |
| Chemical Name | 3,6-Diamino-10-methylacridinium chloride (as component of acriflavine mixture) |
| Cas Number | 8048-52-0 |
| Molecular Formula | Mixture primarily containing C14H14ClN3 and C13H11N3 |
| Molecular Weight | Approximately 250.7 g/mol for the acriflavine component; mixture without a single exact value |
| Appearance | Reddish-brown to dark orange crystalline powder |
| Solubility | Freely soluble in water; sparingly soluble in ethanol; practically insoluble in ether |
| Identification | Positive response by UV-visible spectrophotometry and thin-layer chromatography |
| Assay | 98.0% to 102.0% on an anhydrous basis |
| Ph | 2.0 to 5.0 for a 1% aqueous solution |
| Storage | Store in a tightly closed container in a cool, dry place protected from strong light |
As an accredited Acriflavine 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 | Acriflavine Veterinary Grade API is supplied in 25 kg sealed drums, suitable for tablets, injections, capsules, powders, granules, premix, and solutions. |
| Container Loading (20′ FCL) | 20′ FCL container: palletized drums/cartons of Acriflavine Veterinary Grade API, safely secured, sealed, and transported in compliance with regulations. |
| Shipping | Acriflavine Veterinary Grade API ships in sealed, light-resistant containers with proper hazmat labeling. Standard delivery is 5–10 business days via courier; cold chain not required. Ensure compliance with local veterinary drug import regulations. Handle with care: use PPE and avoid exposure to moisture, heat, or direct sunlight. |
| Storage | Store Acriflavine Veterinary Grade API in a cool, dry, well-ventilated area, protected from light and moisture. Keep containers tightly closed when not in use. Avoid exposure to excessive heat or incompatible substances. Ensure area is clean, secure, and clearly labeled, following local regulations for pharmaceutical intermediates. |
| Shelf Life | Shelf life: 24 months from manufacture date when stored unopened in original container, in a cool, dry, dark place. |
In tablet manufacturing for ornamental fish and pond treatment, acriflavine hydrochloride is incorporated at low mass fractions into direct-compression blends because the API is intensely coloured and requires segregated handling to prevent cross-contamination. The API is first passed through a 0.5 mm conical sieve and pre-blended with lactose monohydrate in a 600 L bin blender at 12 rpm for 10 min; magnesium stearate is added at 0.25% w/w and blended for an additional 3 min to limit over-lubrication. Blend uniformity testing follows USP <905> with an acceptance value of ≤15.0, and bulk density is held between 0.55 g/cm³ and 0.75 g/cm³ to prevent stratification during transfer. Compression is performed on a rotary tablet press equipped with 10.0 mm round flat-faced bevel-edge tooling, 50 kN pre-compression, 80 kN main compression, and a speed of 30–60 rpm; tablet hardness is controlled at 40–80 N because values above 80 N produce extended disintegration in pond water and values below 40 N increase friability-related weight loss. Field observations on rotary presses with extended dwell times show that acriflavine can form a visible film on chrome-plated punch faces when API moisture exceeds 2.0% w/w, causing weight variability outside ±3.0%; pre-drying at 40 °C for 4 h in a fluid-bed dryer or forced-air cabinet reduces this batch rejection. Friability is tested according to USP <1216> and maintained below 0.8%. Disintegration time in purified water at 25 °C must not exceed 15 min when tested according to USP <701> without discs, because acriflavine tablets are typically administered by direct dissolution rather than oral ingestion. Film coating with a non-ionic PVA-based system containing 0.5–1.0% w/w titanium dioxide reduces photodegradation and masks the yellow-green dye migration into operator contact surfaces. Finished tablets are packaged in amber HDPE bottles with 1 g silica gel desiccant and induction-sealed liners; published data for specific tablet immersion concentrations in this configuration is limited and must be established by local veterinary authorization. Manufacturing is conducted under 21 CFR 210 and 21 CFR 211 or applicable regional GMP, and any food-producing species use requires residue depletion justification before instruction.
Aqueous injectable acriflavine is compounded at final concentrations of 0.1% w/v to 1.0% w/v in pH 3.0–4.5 citrate or acetate buffer because the free base precipitates above pH 6.0 and photodegradation accelerates under alkaline conditions; published degradation data for this specific configuration is limited, so aseptic processing with a 0.22 µm PVDF sterilizing filter is preferred over terminal autoclaving when colour change exceeds 5.0% on a 450 nm spectrophotometric check. The solution is blanketed with nitrogen in a 316L stainless steel vessel and protected from light during compounding to reduce oxidative cleavage of the acridine ring. Tonicity is adjusted with dextrose or mannitol to 285–310 mOsm/kg, and the fill volume tolerance follows USP <1>. Container-closure is amber Type I borosilicate glass according to USP <660>, sealed with butyl rubber stoppers; silicone tubing and EPDM gaskets are used because acriflavine adsorbs to unplasticized PVC transfer lines and can produce low assay recovery during low-batch filling. Endotoxin control follows USP <85> with a limit calculated as K/M; sterility testing follows USP <71>; particulate matter in containers with nominal volume above 100 mL is controlled under USP <788> with ≤6000 particles/container at ≥10 µm and ≤600 particles/container at ≥25 µm. The historical use of acriflavine injection in non-food equine or canine protozoal conditions requires residue depletion data when local authorities permit food-producing species, and terminal products are restricted to veterinarian dispensing in jurisdictions with a valid veterinary marketing authorization.
| Control point | Method/Standard | Limit |
|---|---|---|
| Sterility | USP <71> | No growth |
| Bacterial endotoxins | USP <85> | Calculated K/M per dose |
| Particulate matter | USP <788> | ≤6000 particles at ≥10 µm; ≤600 particles at ≥25 µm |
| pH | USP <791> | 3.0–4.5 |
| Assay | HPLC with acriflavine reference standard | 95.0–105.0% label claim |
During capsule filling operations at production scale, acriflavine hydrochloride is rarely wet-granulated because the API has a narrow moisture tolerance before encapsulation and prolonged contact with free water can produce mottled surfaces and dissolution inconsistency. The API is pre-blended with lactose monohydrate at a 1:10 ratio in a 100 L tumble blender for 8 min, sieved through a 0.8 mm screen, and then diluted to final capsule weight in a 300 L double-cone blender at 25 rpm for 20 min; magnesium stearate is added at 0.25% w/w and blended for 2 min to avoid hydrophobic over-lubrication. The finished powder is filled into size 3 or size 4 hard gelatin capsules on an intermittent-motion capsule filler operating at 150,000 capsules/h with ±2.5% average fill weight control. Sorted capsules are tested for disintegration according to USP <701> and must release in ≤15 min in water at 37 °C; dissolution testing, where required by the registration dossier, follows USP <711> Apparatus II at 50 rpm in 900 mL purified water, but published pharmacopoeial dissolution monographs for this specific API in hard capsules are limited, so the acceptance criterion must be justified by the applicant. Capsules are packaged in amber PVC/PVDC/aluminium blisters to limit light exposure and to prevent dye transfer to adjacent contact surfaces. Batch-to-batch variability in loose powder density between 0.50 g/cm³ and 0.70 g/cm³ has been observed when API particle morphology shifts from mill grade to micronized grade; therefore, fill weight is adjusted by tapped density determination under USP <616> before each run.
Acriflavine soluble powder for immersion bath preparation is milled to balance rapid cold-water dispersion against excessive airborne dust. The API is pin-milled at 3000 rpm and screened through a 150 µm mesh, yielding a particle size distribution with D90 ≤250 µm; material above 250 µm has been observed to settle in 100 L mixing tanks before complete dissolution, producing local high-concentration zones that can stain equipment and reduce dose accuracy. Dissolution is checked in purified water at 20 °C at a concentration of 1.0 g/L; complete visual dissolution is typically achieved within 5 min when the powder is added under high-shear agitation, while static addition extends wetting time and produces floating aggregates. The powder is filled into laminated foil sachets under nitrogen or dry air below 40% RH, because acriflavine picks up surface moisture above 60% RH and forms clumps that fail to pass USP <786> sieve limits. Sachet fill weight is controlled to ±2.0% on a volumetric filler with gravimetric checkweighing. Microbial quality follows USP <61> and USP <62>, with total aerobic microbial count ≤10¹ CFU/g, total combined yeasts and moulds ≤10² CFU/g, and absence of Salmonella spp. in a 10 g composite sample. Terminal products are labelled for ornamental fish or non-food aquaculture species only; use in food-producing fish requires residue depletion and environmental exposure assessment under VICH GL48 or the applicable regional guidance.
When direct-compression granules are required for medicated bath products or intermediate dilution into oral solutions, acriflavine hydrochloride is densified by wet granulation with a low-viscosity binder system. The dry blend is loaded into a high-shear granulator with an impeller speed of 300 rpm and chopper speed of 1500 rpm; a 2.0% w/w povidone K30 aqueous binder is added at 5–7% of dry powder mass, and wet massing continues for 3–5 min until the granule endpoint shows a hand-squeeze compact and no visible dry fines. Drying is carried out in a fluid-bed dryer with inlet air at 50 °C, product temperature 35–40 °C, and dew point 5 °C; the target loss on drying is ≤2.0% w/w as determined by USP <731>. Dried granules are milled through a 0.8 mm screen and classified between 200 µm and 800 µm; granules below 200 µm are regarded as fines and are limited to ≤15% w/w of the final granule mass to avoid segregation during sachet filling. Bulk flow is characterized by Carr index ≤15 and Hausner ratio ≤1.18 according to USP <616>. Finished granules are filled into amber polyethylene terephthalate jars with screw caps lined with induction-sealed aluminium foil. Batch rejection occurs when the moisture content after drying exceeds 2.5% w/w because the material adheres to hopper walls during filling and product weight variability exceeds ±3.0%.
Acriflavine premix intermediates are manufactured as 0.1% w/w to 1.0% w/w active mixtures on a lactose monohydrate or calcium carbonate carrier, intended for subsequent dilution by feed mills or compounding pharmacies rather than direct administration. Dust containment at the API charging point is critical because acriflavine is a heterocyclic dye with high visibility and can generate cross-contamination complaints at levels below 0.05% w/w; a single-point extraction booth with 0.5 m/s face velocity and HEPA back-up is used during manual addition. The premix is produced in a 500 kg ribbon blender at 20 rpm for 15 min, using a stepwise dilution sequence: a 1:10 API-tricalcium phosphate pre-blend is screened through a 0.5 mm sieve, then mixed with 50% of the carrier for 5 min, then the remaining carrier is added and blended for 10 min. Blend uniformity is tested on 10 stratified sampling points and must show relative standard deviation ≤5.0%; samples are assayed by HPLC with a 95.0–105.0% label-claim acceptance band. Premix terminal packaging uses 25 kg fibre drums with two LDPE liners and desiccant when ambient RH exceeds 60%. Use of such premixes in food-producing species is restricted by regional residue control programmes; absence of authorized maximum residue limits means that veterinary prescription and diagnostic confirmation are required before extralabel application.
Topical aqueous or aqueous-alcoholic solutions of acriflavine are compounded at 0.1% w/v to 1.0% w/v in veterinary wound and skin antisepsis products where the pH is maintained at 2.5–4.5 to keep the acridine base in the ionized chloride species and to reduce precipitation on open wound surfaces. Glycerol or propylene glycol is included at 5.0–10.0% v/v as a co-solvent and humectant, and the finished solution is clarified through a 0.45 µm polypropylene depth filter to remove particulate matter without the dye-staining losses observed on nylon membranes. Light protection is required because aqueous acriflavine solutions exposed to direct UV for 8 h can show visible colour fading and a loss of assay relative to the initial reading; amber PET containers with 0.5 mm wall thickness reduce light transmission below 400 nm by more than 90% when measured spectrophotometrically. Metal container closure systems are avoided because ferric ions complex with the acridine nitrogen and produce dark precipitates; polypropylene caps with EPE liners are used. In-use stability for open bottles is controlled by the manufacturer through a 28-day simulated use study at 25 °C and 60% RH, with assay and pH measured at 0, 7, 14, 21, and 28 days. The product is not terminally sterilized unless specifically labelled as sterile; non-sterile topical solutions are tested for microbial enumeration under USP <61> and specified microorganisms under USP <62>. Published data for specific wound-contact residue and absorption profiles is limited; therefore, applications on large open wounds in food-producing animals require withdrawal period justification.
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Acriflavine Veterinary Grade API for Tablets / Injections / Capsules / Powders / Granules / Premix / Solutions is an orange-red to reddish-brown crystalline powder supplied as the hydrochloride salt of a methylated acridine derivative. The material is composed of the quaternized 3,6-diamino-10-methylacridinium cation and a defined proportion of the non-methylated analogue 3,6-diaminoacridine, commonly known as proflavine. The veterinary-grade designation indicates that the API is manufactured under current good manufacturing practice for veterinary medicinal products and released against a certificate of analysis covering identity, assay, related substances, residual solvents, heavy metals, and physical properties. The hydrochloride form is freely soluble in water at approximately 1 g in 3 mL, sparingly soluble in ethanol, and practically insoluble in ether; these solubility characteristics support aqueous granulation, parenteral dilution, and immersion-solution manufacture. Product codes are manufacturer-specific and are not model numbers; procurement should reference the generic name, pharmacopoeial grade, and the required particle size distribution when dry processing is intended.
| Parameter | Specification | Test method |
|---|---|---|
| Appearance | Orange-red to reddish-brown crystalline powder | Visual inspection |
| Identification | Positive by UV or infrared absorption | Ph. Eur. 2.2.25 / Ph. Eur. 2.2.24 |
| Assay (HPLC) | 97.0–102.0% on dried basis | Ph. Eur. 2.2.29 |
| Loss on drying | ≤8.0% | Ph. Eur. 2.2.32 |
| Sulfated ash | ≤0.1% | Ph. Eur. 2.4.14 |
| pH of 1% solution | 3.0–5.0 | Ph. Eur. 2.2.3 |
| Related substances | Total impurities ≤2.0% | Ph. Eur. 2.2.29 |
| Heavy metals | ≤20 ppm | Ph. Eur. 2.4.8 |
Direct compression of acriflavine hydrochloride is uncommon because the untreated API exhibits poor flow and marked cohesiveness. For tablet manufacture, the API is usually pre-sieved through a 710 µm stainless steel screen, milled through a cone mill fitted with a 0.5 mm round screen at 800–1200 rpm, and dry-blended with microcrystalline cellulose and croscarmellose sodium. During pilot-scale blending in a 300 L tumble blender at 15 rpm, batch-to-batch variation in bulk density between 0.35 g/cm³ and 0.55 g/cm³ has been observed; this variation requires adjustment of die fill depth to maintain a target tablet weight of 150 mg with a hardness of 70–100 N. Blending for 20–30 minutes after geometric dilution is sufficient when the API particle size D90 is ≤100 µm; longer mixing can increase electrostatic charge and adhesion to blender walls. Tablet cores are then compressed on a rotary tablet press fitted with 8 mm round concave punches. The tablet formulation typically includes 0.5% magnesium stearate as lubricant and 1.0% colloidal silicon dioxide as glidant. Finished tablets are tested for content uniformity according to Ph. Eur. 2.9.40, with acceptance value AV ≤15. Disintegration is tested per Ph. Eur. 2.9.1 in water at 37°C; a threshold of ≤15 minutes is applied because the acridine salt remains readily soluble. Dry blending with strongly alkaline materials or oxidizing agents is avoided because the cationic acridine core is susceptible to decomposition and discoloration. Lactose-based direct compression is not recommended if the API is hygroscopic; pre-drying at 50°C for 4 hours is recommended when relative humidity exceeds 60%.
The hydrochloride salt dissolves in water for injection to form a deep orange solution; the saturated aqueous concentration is approximately 330 mg/mL, but the practical injectable strength is usually 0.1%–2.0% w/v. At pH values above 5.0, the free base form of acriflavine can precipitate because the protonated acridine is in equilibrium with the less soluble free amine. Terminal formulations are therefore buffered to pH 3.5–4.5 with dilute hydrochloric acid or citrate buffer. Manufacturing usually proceeds in a jacketed stainless steel vessel at 20–25°C under subdued lighting; the solution is filtered through a 0.45 µm polypropylene or PVDF prefilter and then through a 0.22 µm sterilizing filter. Autoclaving at 121°C for 15 minutes is feasible only if the container closure system is validated for heat and light stability; the acridine ring is photosensitive and aqueous solutions packaged in clear glass show visible fading. For this reason, amber Type I glass vials or opaque polypropylene ampoules are used. Particulate matter is assessed by Ph. Eur. 2.9.19 and endotoxin by Ph. Eur. 2.6.14; the endotoxin limit for a parenteral veterinary product is usually ≤0.5 EU/mg. Saline concentrations above 0.9% should be avoided where formulation development data is absent, because high ionic strength may reduce solubility and increase aggregation. The injectable route is historically associated with trypanosomiasis and piroplasmosis treatment in cattle and horses; current regulatory acceptance varies by jurisdiction, and published data for specific food-producing species is limited.
For capsule filling, the API is rarely filled as a neat powder because of staining intensity, electrostatic attraction to gelatin and HPMC capsule shells, and inconsistent powder flow. A wet-granulated blend is preferred, using 20%–40% active ingredient on a dry basis, lactose monohydrate, microcrystalline cellulose, and pregelatinized starch. Granulation is performed in a high-shear granulator fitted with a chopper at 1500 rpm and an impeller at 200 rpm; purified water or a 5% povidone K30 binder solution is added until a target granule endpoint of 1.0%–2.5% residual moisture is achieved. The wet mass is passed through an 800 µm screen, dried in a fluid bed dryer at 50–60°C inlet air temperature, and regranulated through a 710 µm screen. The final granulate is filled into size 3 hard capsules to a target fill weight determined by assay; content uniformity is evaluated by Ph. Eur. 2.9.40. Powder formulations for oral sachets are prepared by geometric dilution of the milled API with lactose or dextrose to a final active content of 0.1%–1.0%; the sachet powder is dried to ≤1.0% moisture before packaging in foil-lined laminate because the acridine salt darkens when exposed to moisture and light.
Medicated premix production requires a carrier system that controls segregation and dusting. For acriflavine hydrochloride, a stepwise dilution sequence is used with feed-grade corn cob meal, calcium carbonate, or lactose as the carrier; the final premix active concentration is commonly 0.5%–5.0% w/w depending on targeted final feed inclusion. A ribbon mixer with a working volume of 500 kg and a mixing time of 15–20 minutes is typically used after manual pre-blending of the API with 10 kg of carrier. Blend uniformity samples are taken from 10 locations using a sampling thief and assayed by HPLC; acceptance is set at 90%–110% of label claim with an RSD of ≤5%. Because acriflavine is cationic and light-sensitive, premix packaging uses moisture-barrier bags with an outer UV-protective layer. Storage conditions are maintained below 25°C and 60% relative humidity. The premix is intended for in-feed or in-water administration in ornamental and non-food fish species; use in food-producing species may be restricted or prohibited under regional veterinary regulations. Acriflavine premix should not be combined with strong oxidizing agents or copper sulfate in the same mash feed, because redox interactions can reduce potency and generate unidentified degradation products. Published data for acriflavine premix stability in complete feed matrices is limited; therefore, finished medicated feed should be used within 48 hours of preparation unless a site-specific stability study demonstrates longer retention.
Solution dosage forms for topical and immersion use are prepared from the same API by dissolving the hydrochloride salt in purified water at 0.1%–1.0% w/v. In ornamental fish practice, a bath concentration of 2–5 mg/L of acriflavine is often cited for external protozoal and bacterial conditions; repeated baths are separated by 24–48 hours and water chemistry is monitored for ammonia and nitrite. The solution is mixed in a stainless steel or plastic stock tank; direct addition of the powder to the display tank is avoided because undissolved particles can adhere to gill surfaces. Stock solutions are packaged in opaque HDPE or amber PET containers and stored at 15–25°C. Because acriflavine is photodegradable, diluted working solutions should be used within 24 hours under normal hatchery lighting; no reliable potency is guaranteed beyond that interval. When formulating large volumes, batch dissolution is performed with a bottom-entry stirrer at 250–350 rpm for 15 minutes, and the solution is filtered through a 60 µm basket strainer before distribution. Published data for this specific configuration is limited, so bath protocols are typically derived from clinical case reports and local prescribing practice rather than standardized international monographs.
Acriflavine differs from chlorhexidine gluconate and povidone-iodine in that its antibacterial activity is associated with a planar acridine structure that intercalates into DNA and inhibits nucleic acid synthesis. This mechanism supports activity against gram-positive bacteria, some gram-negative bacteria, fungi, and external protozoa; in contrast, chlorhexidine is primarily membrane-active and lacks the antiprotozoal profile required in fish practice. Compared with malachite green, a triphenylmethane dye, acriflavine is more water-soluble and less persistent in lipid-rich tissues, but it is not a residue-free alternative. The hydrochloride salt, with the quaternized nitrogen atom, is more hydrophilic than neutral proflavine; this increases aqueous solubility and reduces passive diffusion across lipid membranes. This difference is relevant when selecting an API for tablets versus immersion solutions: the hydrochloride form dissolves rapidly but can be less suitable for delayed-release matrices, whereas neutral acriflavine is less soluble and used only in specialized formulations. Regulatory differences also apply. Many jurisdictions prohibit malachite green residues in food fish, while acriflavine remains permissible for ornamental fish and may be restricted in food-producing species. Users must confirm that the intended use is authorized under the applicable veterinary medicinal product regulation, because the mutagenic potential of acriflavine imposes handling and disposal requirements under occupational safety and environmental legislation. The safety data sheet for the hydrochloride salt may include hazard statements such as H302, H315, H318, and H341 where the national classification applies.
Acriflavine hydrochloride should be stored in well-closed amber glass or double-lined polyethylene containers below 25°C at relative humidity ≤60%. The API is hygroscopic; repeated opening of bulk containers in high-humidity regions leads to moisture uptake that accelerates darkening and agglomerate formation. Pre-drying at 45–55°C for 3–4 hours is applied only when loss-on-drying exceeds 8.0% and is performed in a tray dryer with validated temperature uniformity. Ultraviolet exposure is a primary degradation route; therefore, warehouse lighting should use UV-filtered fluorescent fixtures. The API is incompatible with strong oxidizing agents, strong bases, and anionic surfactants; combination with sodium lauryl sulfate in tablet or granule formulations can cause precipitation of the cationic dye and uneven colour distribution. Use of stainless steel 316L equipment is recommended for prolonged contact; uncoated carbon steel shows visible staining but published corrosion data for acriflavine contact is limited. Batch-to-batch variance in crystal habit may affect flow; suppliers should be requested to control particle size distribution to a D90 between 50 µm and 150 µm for dry formulations, while finer material may be acceptable for solution compounding. Shipment under ambient conditions is acceptable for sealed bulk drums, but shipping containers should not exceed 40°C for periods longer than 72 hours; temperature excursion data for this specific API is limited.
