| HS Code | 680526 |
| Product Name | Bromhexine Veterinary Grade API |
| Chemical Name | 2,4-Dibromo-6-{[cyclohexyl(methyl)amino]methyl}aniline hydrochloride |
| Cas Number | 611-75-6 |
| Molecular Formula | C14H20Br2N2·HCl |
| Molecular Weight | 412.60 g/mol |
| Appearance | White or almost white crystalline powder |
| Solubility | Slightly soluble in water; soluble in alcohol; freely soluble in chloroform |
| Melting Range | 239–244 °C |
| Assay | 99.0%–101.0% on dried basis |
| Suitable Dosage Forms | Tablets, Injections, Capsules, Powders, Granules, Premix, Solutions |
| Storage Conditions | Store in airtight containers, protected from light and moisture, at controlled room temperature |
| Therapeutic Category | Mucolytic / expectorant for veterinary respiratory use |
As an accredited Bromhexine 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 | Bromhexine veterinary grade API is supplied in 25 kg sealed drums with inner polyethylene bags, suitable for tablets, injections, capsules, powders, granules, premix, and solutions. |
| Container Loading (20′ FCL) | A 20′ FCL container shipment of Bromhexine Veterinary Grade API, available as powders, granules, premix, tablets, capsules, injections, or solutions, safely packed. |
| Shipping | Bromhexine Veterinary Grade API ships in sealed, inert containers to prevent contamination and moisture ingress. Label per international hazmat and pharmaceutical regulations. Store away from incompatible substances. Use temperature-controlled transport where required. Ensure documentation matches customs requirements for veterinary pharmaceutical raw materials. Protect from direct sunlight during transit. |
| Storage | Store in a cool, dry, well-ventilated area between 15–25°C, protected from light and moisture. Keep the original, tightly closed container away from incompatible substances and foodstuffs. Avoid freezing and excessive heat. Ensure handling area is clean, and prevent dust accumulation or direct exposure to avoid degradation, maintaining potency and purity of the veterinary-grade API. |
| Shelf Life | Shelf life is typically 24 months from manufacture when stored sealed, protected from light, in a cool, dry place. |
Bromhexine hydrochloride veterinary API is incorporated into concentrated swine premixes when feed-directed respiratory therapy must be delivered through dry rations rather than water medication. In a typical 10 kg batch of 1.0% w/w concentrated premix, the API is first passed through a conical sieve fitted with a 75 µm screen to remove agglomerates generated during warehousing. The sieved fraction is combined with anhydrous lactose monohydrate and a hydrophobic silica flow aid in a ribbon mixer operated at 60–80% gross volume fill; lower fill reduces shear transfer, while higher fill reduces bed turnover and increases dead zones. Mixing is terminated after 8–12 min when stratified sampling through a powder thief achieves a coefficient of variation not exceeding 5.0% RSD for bromhexine HCl by high-performance liquid chromatography with ultraviolet detection. Batch-to-batch variance on production-scale lines most often arises when the micronised fraction is added directly to the full carrier mass, producing API-rich fines that migrate to the mixer discharge during pneumatic conveying. Compliance for this application falls under Regulation (EU) 2019/6 for veterinary medicinal products and VICH GL18(R2) for residual solvent control in the API and finished premix; sampling protocols align with ISO 6497:2002. In-use inclusion is typically 0.5–1.0 kg concentrated premix per tonne complete feed, yielding 5–10 mg/kg bromhexine HCl in final feed. Finished product types include 5 kg and 10 kg heat-sealed foil-laminated premixes intended for on-farm top dressing or feed-mill incorporation.
Stock solution stability in poultry drinking water delivery is governed primarily by the ionisation state of bromhexine HCl and the carbonate hardness of the water source. The API is dissolved at 2.0% w/v in an acidified co-solvent vehicle composed of propylene glycol and purified water; final pH is maintained below 4.2 to prevent precipitation of the poorly soluble free base when the stock is diluted into hard bore water. A representative in-use concentration is 0.5 L stock per 1000 L drinking water, giving 10 mg/L bromhexine HCl. Production-scale mixing uses a vacuum-emulsifying homogeniser with a rotor-tip speed of 18–22 m/s until the API is dissolved, followed by filtration through a 10 µm polypropylene cartridge to remove low-solubility agglomerates. Chlorine at municipal drinking-water levels oxidises bromhexine; inline medication systems should bypass ultraviolet and ozone treatment and use fresh stock within 24 h after dilution. Filling into 1 L and 5 L high-density polyethylene containers with light-protective outer cartons is conducted under nitrogen blanketing to minimise headspace oxygen. Compliance includes Ph. Eur. 2.9.40 for uniformity of dosage units in single-dose sachets, VICH GL11 for stability testing, and Regulation (EU) 2019/6 for marketing authorisation. Finished forms include oral solutions, water-soluble concentrates, and in-line dosing pump packs.
| Stock solution parameter | Operating boundary | Observed process effect |
|---|---|---|
| Post-dilution pH | ≤ 4.2 | Free base precipitation in hard water |
| Carbonate hardness | < 200 mg/L CaCO₃ | Haze and cartridge filter pressure rise |
| Free chlorine residual | < 0.2 mg/L | Oxidative degradation of bromhexine HCl |
| Stock solution hold time | ≤ 24 h | Assay drift and visible particulate formation |
Terminal steam sterilisation of a 3 mg/mL bromhexine HCl bovine injection imposes a narrow pH window because the molecule undergoes hydrolytic degradation in alkaline aqueous conditions, while strongly acidic vehicles can accelerate elastomeric closure leaching. The solution is prepared in Water for Injections at pH 3.8–4.2 using citric acid/sodium citrate, sparged with pharmaceutical-grade nitrogen, and filled into Type I amber glass vials under an inert headspace. The filled vials are autoclaved at 121°C for 15 min with a load probe in the coldest vial location; overkill lethality is confirmed by a minimum F0 ≥ 15 min. Production bottlenecks on multi-use injectable lines typically involve silicone tubing adsorption of bromhexine HCl from the recirculated bulk solution, leading to low assay results in early filling; stainless-steel or fluoroelastomer transfer lines reduce this loss. Published data for concentrations above 5 mg/mL in purely aqueous vehicles without a co-solvent is limited. Compliance is governed by Ph. Eur. 2.6.1 sterility, Ph. Eur. 2.9.19 particulate contamination, and compendial assay by Ph. Eur. 2.2.29 liquid chromatography. The finished veterinary product types are 50 mL and 100 mL injection vials for intramuscular or subcutaneous administration in cattle and calves.
In equine oral granule production, the bitter taste of bromhexine HCl and its sensitivity to moisture require a wet granulation route that places the API inside a carbohydrate matrix rather than as an external powder coat. A 1.0% w/w bromhexine HCl granule formulation is produced by pre-blending the API with lactose monohydrate, maize starch, and microcrystalline cellulose in a planetary mixer for 5 min, then adding an aqueous binder solution of povidone K30 at 3.0% w/w solids. The wet mass is passed through a 1.2 mm extruder screen and dried in a fluid bed dryer with inlet air at 60°C and product temperature not exceeding 40°C; final loss on drying is controlled to ≤ 2.5% per Ph. Eur. 2.2.32. The dried granules are screened through an 850 µm sieve and filled into 25 g and 50 g sachets. Granule dissolution criticality appears when top-dressing onto dry feed: release of bromhexine HCl from the povidone matrix is slowed if the granule is over-dried below 1.5% moisture, because the binder becomes less soluble in saliva and gut fluid. Compliance comprises Ph. Eur. 2.9.1 disintegration, Ph. Eur. 2.9.3 dissolution, and VICH GL18(R2) for residual solvents; microbial quality follows Ph. Eur. 2.6.13 for non-sterile products. The finished dosage forms are oral granules and sprinkle capsules for horses, with carton labelling that specifies forage-only administration.
Low-dose tablets for companion animals become a content-uniformity exercise when bromhexine HCl is present at 0.8% w/w of total core mass, such as a 2 mg active dose in a 250 mg tablet. The API is first dry-mixed with pre-screened microcrystalline cellulose and croscarmellose sodium in a bin blender with a fill ratio of 70%; then a small fraction of compression mix is passed through a 1.0 mm conical mill to break bromhexine HCl agglomerates. Magnesium stearate is added at 0.75% w/w and blended for 3 min to avoid lubricant over-mixing and tablet friability reversal. Compression is run on a rotary tablet press with 8 mm round tooling at a main compression force of 7–10 kN; hardness is maintained at 40–60 N to achieve disintegration below 15 min in 0.1 M HCl at 37°C. For capsules, the same granulation can be filled on a dosator or tamping-pin capsule machine with a target fill weight variation of ± 3.0%. Incompatibility data indicate that bromhexine HCl in intimate contact with strong alkalizers or certain effervescent systems can generate free-base liberation and should be excluded from chewable tablets without an acidified barrier coating. Compliance is anchored to Ph. Eur. 2.9.40 for content uniformity, Ph. Eur. 2.9.3 for dissolution, and USP <711> where US market requirements apply. Finished product types include 2 mg, 4 mg, and 8 mg tablets for dogs and cats, as well as hard gelatin capsules.
Multi-species feed mill premix manufacture is the most contamination-sensitive downstream operation for bromhexine HCl because the same mixer, pneumatic conveyor, and bucket elevator may also handle non-medicated rations. A 2.0% w/w bromhexine HCl intermediate premix is produced by stepwise geometric dilution: the API is first combined with calcium carbonate in a 1:1 mass ratio, then with ground oat hulls to 10% w/w, and finally with the remaining carrier in a double-ribbon mixer at 65–75% fill for 10–15 min. In final feed, inclusion rates range from 0.25 kg per tonne for pigs to 0.5 kg per tonne for calves, depending on the bromhexine HCl concentration and licensed species. Carryover risk concentrates in bucket elevator cups, rotary feeder vanes, and dust-collector socks; a production-scale line should flush with 10 kg of untreated carrier after each medicated batch and assay the flush for bromhexine HCl by HPLC before releasing the next non-medicated batch. The analytical limit of quantification is typically 0.5 mg/kg feed, and sequencing medicated batches after non-medicated batches rather than before reduces contamination risk. Compliance for this application is driven by Regulation (EU) 2019/6, ISO 6497:2002 sampling, and feed safety systems meeting GMP+ FSA or FAMI-QS codes; residue control is evaluated under VICH GL18(R2). Finished terminal products include 20 kg multi-wall paper bags with inner polyethylene liners and 500 kg bulk bags for integrated feed mills.
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Bromhexine Veterinary Grade API for Tablets / Injections / Capsules / Powders / Granules / Premix / Solutions is the hydrochloride salt of 2-amino-3,5-dibromo-N-cyclohexyl-N-methylbenzylamine. The chemical entity is identified by CAS 611-75-6, molecular formula C14H20Br2N2·HCl, and relative molecular mass 412.60 g/mol. The veterinary-grade designation refers to the supporting documentation, impurity qualification, and manufacturing controls rather than to a separate chemical species. The material is released as a white to almost-white crystalline powder and is intended as a starting material for licensed veterinary medicinal products. The product model, where designated, corresponds to the particle-size grade and intended dosage form—standard, milled, or micronized—rather than to a proprietary trade name.
The solubility profile is pH-dependent: dissolution in neutral water is limited, while acidified aqueous systems increase solubility through protonation of the tertiary amine. This behaviour defines the formulation strategy across all seven dosage forms. Bulk containers are supplied with a certificate of analysis covering appearance, identification, related substances, residual solvents, loss on drying, sulfated ash, assay, and particle-size distribution. Materials intended for injectable manufacture are additionally controlled for bacterial endotoxins and, where required, microbial enumeration. Because bromhexine hydrochloride contains two bromine substituents, process and storage conditions that accelerate dehalogenation or photolytic discoloration are controlled during downstream manufacturing. The API is not authorized as a direct medication for end users and does not carry a target-species withdrawal period; withdrawal periods are assigned to the finished veterinary medicinal product based on residue depletion studies in food-producing species.
Release testing follows the current Ph. Eur. monograph for bromhexine hydrochloride. Residual solvents are assessed under VICH GL18 and ICH Q3C, and impurity qualification is conducted in accordance with VICH GL10. Identification is confirmed by infrared absorption spectrophotometry against a reference standard and by a positive chloride reaction. Related substances are measured by liquid chromatography; a representative release specification declares individual unspecified impurities not more than 0.10% and total impurities not more than 0.30%, with the pharmacopoeial monograph taking precedence. Assay on the dried basis against a reference standard is commonly controlled at 98.5% to 101.0%. Loss on drying is determined by Ph. Eur. 2.2.32, with limit not more than 0.5%. Sulfated ash is determined by Ph. Eur. 2.4.14. These parameters are selected not only for chemical purity but because residual moisture above 0.5% can alter granulation endpoint and reduce chemical stability in moisture-sensitive packages.
| Parameter | Typical veterinary release criterion | Method anchor |
|---|---|---|
| Appearance | White or almost-white crystalline powder | Ph. Eur. general monograph |
| Identification | IR spectrum concordant with reference; chloride reaction positive | Ph. Eur. 2.2.24 |
| Related substances | Individual unspecified impurity ≤ 0.10%; total ≤ 0.30% | Liquid chromatography |
| Assay | 98.5%–101.0% dried basis | Liquid chromatography |
| Loss on drying | ≤ 0.5% | Ph. Eur. 2.2.32 |
| Residual solvents | Complies with VICH GL18 | Headspace GC |
| Sulfated ash | ≤ 0.1% | Ph. Eur. 2.4.14 |
| Particle-size distribution | Defined per grade; D90 ≤ 250 µm standard, ≤ 25 µm micronized | ISO 13320 |
Particle-size distribution is not a pharmacopoeial identity parameter but controls downstream content uniformity and dissolution. Three practical grades are used in veterinary formulation: a standard grade with D90 not exceeding 250 µm, a milled grade with D90 not exceeding 100 µm, and a micronized grade with D90 not exceeding 25 µm. The standard grade is usually selected for wet-granulated tablets and sachet granules. The micronized grade is specified when content uniformity is critical in low-dose direct-blend premixes or when dissolution is the rate-limiting step. Uncontrolled fine fractions can generate dust, segregation, and feeding variability on rotary tablet presses, particularly when the API fraction is below 2% w/w.
Veterinary premixes containing bromhexine hydrochloride at 0.1% to 5.0% w/w in lactose or dextrose carriers require geometric dilution before final blending. The weighed API is preblended 1:10 with carrier in a drum blender or high-shear mixer before transfer to a ribbon blender. Stratified sampling from 10 positions is used for content-uniformity validation; acceptance is based on the relevant veterinary premix monograph or an approved in-house validation. Direct addition of the active ingredient to the full carrier load without preblending can produce relative standard deviations above 5% because of particle-size segregation. In production, re-blending is triggered when top and bottom sampling-port assays differ by more than 3% absolute.
For tablets, wet granulation is preferred when the API fraction is below 15% w/w. Granules are formed in a high-shear granulator with impeller speed 300–800 rpm and chopper speed 1500–3000 rpm, then dried in a fluid-bed dryer with inlet air temperature not exceeding 60 °C. Terminal moisture for compression is set at 1.0% to 2.5%. The dried granules are passed through a 0.8–1.2 mm screen and lubricated with 0.5% to 1.0% magnesium stearate before tableting. Direct compression of unmilled bromhexine hydrochloride is generally impractical because of high brittleness and insufficient flow; roller compaction followed by granulation is a preferred alternative. Capsules are filled on tamping-pin or dosator machines using blends adjusted to a Carr index below 25% and a Hausner ratio below 1.25 to prevent weight variation. In vitro dissolution testing for bromhexine hydrochloride tablets is commonly performed with paddle apparatus at 50 rpm in 900 mL of 0.1 M hydrochloric acid or buffered media specified in the marketing authorization. Addition of polysorbate 80 at 0.1% to 1.0% may be used only when justified by sink conditions and method validation. Published data for specific veterinary tablet dissolution profiles is limited, so the release method is validated product-by-product.
Injectable solutions are prepared in acidified aqueous systems because neutral pH causes precipitation of the poorly water-soluble base. A common manufacturing approach acidifies water for injection with citric acid or dilute hydrochloric acid to pH 3.0 to 4.5, then dissolves bromhexine hydrochloride under agitation. Propylene glycol at 10% to 30% v/v may be included when higher solution concentrations are required. Terminal steam sterilization at 121 °C for 15 minutes is acceptable only after validation demonstrates the related-substance profile remains within specification; otherwise, aseptic filtration through a 0.22 µm sterilizing-grade membrane is used. Precipitation during storage is a known failure mode when the solution contacts alkaline glass or when headspace carbon dioxide raises pH. Type II soda-lime-silica glass can shift the formulation pH and produce visible crystallization; Type I borosilicate glass is therefore preferred for parenteral primary packaging.
Parenteral solutions of bromhexine hydrochloride must not be mixed with sodium bicarbonate or other alkalizing agents in the same infusion line. Raising the solution pH above 7.0 can generate insoluble bromhexine base. Published compatibility data for specific veterinary infusion admixtures, lipid emulsions, or total parenteral nutrition preparations is limited; compatibility testing under ICH Q1A conditions is required before coadministration claims are accepted. The API should be protected from light during storage and processing because photolytic degradation can produce brown discoloration and trace-brominated impurities.
Granules for in-feed use are produced on a fluid-bed top-spray granulator using povidone or hydroxypropyl methylcellulose binder solutions. Binder spray viscosity is maintained below 500 mPa·s at 25 °C to avoid nozzle blockage. Drying endpoint is confirmed by loss on drying and sieve retention; final granules are blended with 0.1% to 0.5% w/w colloidal silicon dioxide to improve flow into pre-portioning machines. For oral solutions, bromhexine hydrochloride is dissolved in purified water with a preservative system and buffer, and sorbitol or invert syrup may be added as a density-adjusting and taste-masking vehicle. Final solution pH is maintained below 5.5 to reduce precipitation risk and is protected from light. Powders for reconstitution are dry-blended with lactose, sucrose, or sorbitol and packaged in sachets with desiccant when the label claims long-term room-temperature stability. In premix manufacturing, the targeted inclusion in finished feed is defined by the approved veterinary label. Homogeneity is confirmed by assay from multiple sampling points across the blender and from final filled bags. Because the API can adhere to stainless steel surfaces at low moisture, the mixing line is inspected for residue after campaign completion. If the same line processes medicated premixes for other species, a validated cleaning procedure and, where required by regional regulation, flush batches or swab limits are used to control carryover.
Bromhexine hydrochloride differs from ambroxol hydrochloride in formulation-relevant properties. Bromhexine exhibits lower aqueous solubility at neutral pH, which complicates injectable formulation but can be advantageous in taste-masked oral powders because the API remains suspended in saliva rather than dissolving rapidly. Ambroxol hydrochloride is the N-dealkylated metabolite with higher aqueous solubility and is often selected for injectable products that must be diluted with physiological saline. Guaifenesin is an expectorant with a different molecular structure and is not a direct substitute for bromhexine when reduction of sputum viscosity is the therapeutic objective. Acetylcysteine acts by thiol-disulfide exchange and requires alkaline pH, whereas bromhexine does not generate hydrogen sulfide odor and is compatible with acidic premix matrices. These differences control the choice of granulation solvent, preservative, buffer, and packaging material, not only the pharmacological classification.
| Property | Bromhexine hydrochloride | Ambroxol hydrochloride | Guaifenesin |
|---|---|---|---|
| CAS | 611-75-6 | 23828-92-4 | 93-14-1 |
| Mechanistic class | Mucolytic/secretolytic | Mucokinetic/secretolytic | Expectorant |
| Aqueous solubility at neutral pH | Low; requires acidified aqueous system or cosolvent | Higher; simpler injectable formulation | Moderate; oral syrups often use cosolvent |
| Solid-dose processing | Wet granulation or roller compaction preferred; fluid-bed drying below 60 °C | Direct compression possible for selected granulations | Direct compression possible; heat-stable |
| Primary incompatibility | Alkaline buffers, strong oxidizing agents | Strong oxidizing agents, pH above 8 | Strong bases, some amines |
Regulatory submissions for veterinary products containing bromhexine hydrochloride commonly cite residual solvent data under VICH GL18, impurity qualification under VICH GL10, and stability data under VICH GL3. Bulk API retest intervals are assigned from long-term data on at least three production batches. The material should be stored in well-closed, light-resistant containers at controlled room temperature, with long-term conditions of 25 °C ± 2 °C and 60% RH ± 5% RH unless the marketing authorization specifies refrigeration. Containers are resealed immediately after use because moisture uptake can affect assay and granulation performance. The API is incompatible with strong oxidizing agents and should not be exposed to prolonged high-humidity conditions without protective packaging. Cleaning of production equipment after bromhexine hydrochloride processing follows standard alkaline-detergent and purified-water cycles, with swab limits established from toxicological data and analytical recovery studies.
