| HS Code | 306291 |
| Chemical Name | 2-(diphenylmethoxy)-N,N-dimethylethanamine; 8-chloro-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydropurine (1:1) |
| Cas Number | 523-87-5 |
| Molecular Formula | C24H28ClN5O3 |
| Molecular Weight | 469.97 g/mol |
| Appearance | White or almost white crystalline powder |
| Solubility | Sparingly soluble in water; freely soluble in ethanol and chloroform; practically insoluble in ether |
| Melting Point | 102-107°C |
| Pka | Approximately 8.77 (diphenhydramine component) |
| Assay | 98.0% to 102.0% on dried basis |
| Mechanism Of Action | H1 histamine receptor antagonist with central anticholinergic activity; suppresses vestibular stimulation and the vomiting center |
| Therapeutic Indications | Prevention and treatment of motion sickness, nausea, and vomiting in dogs, cats, and other veterinary species |
| Storage Conditions | Store in well-closed containers protected from light and moisture at controlled room temperature 20-25°C |
| Shelf Life | 36 months when stored under recommended conditions |
| Available Dosage Forms | Tablets / Injections / Capsules / Powders / Granules / Premix / Solutions |
| Grade | Veterinary grade API |
As an accredited Dimenhydrinate(Dramamine) 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 | Dimenhydrinate veterinary grade API is packaged in 25 kg net fiber drums with double polyethylene liners, moisture-proof and light-protected. |
| Container Loading (20′ FCL) | 20′ FCL container loading of Dimenhydrinate veterinary API in sealed drums, palletized, secured, ventilated, labeled per regulations. |
| Shipping | Shipping in heat-sealed, moisture-resistant, tamper-evident packaging suitable for tablets, injections, capsules, powders, granules, premix, and solutions. Labeled clearly for veterinary use only. Temperature-controlled freight available upon request. Includes Certificate of Analysis, SDS, and traceable documentation. Delivered with proper customs-compliant labelling to ensure safe, stable worldwide transport. |
| Storage | Store in a well-closed, light-resistant container at controlled room temperature (20–25°C), in a cool, dry, well-ventilated area. Protect from moisture and direct sunlight. Keep away from incompatible substances and food. Ensure container remains tightly sealed when not in use, with appropriate labeling for veterinary use only. |
| Shelf Life | Shelf life is typically three years when stored in tightly sealed, light-resistant containers under cool, dry conditions. |
Because dimenhydrinate is not listed in Table 1 of Commission Regulation (EU) No 37/2010, use in food-producing species is excluded from these application scenarios; any such use would require an MRL under Regulation (EC) No 470/2009 or a positive cascade opinion under Directive 2001/82/EC. The downstream applications described below are confined to companion animal and non-food veterinary preparations. All percentage figures are mass-based unless explicitly identified as w/v or v/v.
Compliance anchors include USP <905> uniformity of dosage units, Ph. Eur. 2.9.40 uniformity of dosage units, USP <701> disintegration in water at 37 °C, USP <1216> tablet friability, and VICH GL18 residual solvent control for any Class 2 solvent carried from dimenhydrinate synthesis. A 50 mg active label in a 150 mg core yields a 33.3% w/w addition ratio; a 25 mg active label in a 140 mg core yields a 17.9% w/w addition ratio. Direct compression is normally restricted to formulations in which the active fraction is ≤20% w/w; at higher loading, the powder is wet granulated in a top-spray fluid bed using a 5.0% w/w polyvinylpyrrolidone K30 binder in purified water, with inlet air at 55–65 °C and drying to a loss on drying of ≤2.0% w/w before compression. The dried granulation is passed through an 850 µm conical mill, lubricated with 0.5% w/w magnesium stearate and 1.0% w/w sodium stearyl fumarate, and compressed on a rotary tablet press with 10 mm round scored punches at 30–60 rpm. Tablets are film-coated with a hypromellose-based aqueous coat applied to 3.0–4.0% weight gain to prevent bitter API release in the buccal cavity and reduce drooling in feline patients. Terminal finished product forms are scored tablets in 25 mg and 50 mg strengths, palatable coated chewable tablets, and unit-dose aluminium/aluminium blister strips. Published production-scale data on uncoated dimenhydrinate tablet friability above 33% loading are limited; friability testing under USP <1216> should therefore be performed across the full cam speed range before a design space is authorised.
Parenteral dimenhydrinate is manufactured as a 50 mg/mL solution, equivalent to 5.0% w/v active addition, for intravenous, intramuscular, or subcutaneous use in companion animal emergency practice when oral administration is not feasible. Compliance authority is anchored in USP <1> Injections, USP <85> Bacterial Endotoxins, USP <788> Particulate Matter in Injections, Ph. Eur. 2.6.14 bacterial endotoxins, and Ph. Eur. 5.1.1 sterility criteria. Because dimenhydrinate has only slight aqueous solubility, production uses a cosolvent system of propylene glycol 40–50% v/v and benzyl alcohol 1.5–2.0% v/v in water for injection; the exact cosolvent ratio must be justified against published solubility data in the regulatory dossier and should not be extrapolated between different dimenhydrinate grades without revalidation. The compounding vessel is charged with water for injection at 35–40 °C, propylene glycol is added under propeller agitation at 150–250 rpm, and the API is dissolved until clear; pH is then adjusted into the range 5.5–6.5 with 0.1 N hydrochloric acid or sodium hydroxide. Dissolved oxygen removal is a critical control point: the bulk solution is sparged with filter-sterilized nitrogen until headspace oxygen is below 2.0% v/v, because residual oxygen accelerates oxidative degradation of the diphenhydramine tertiary amine during terminal sterilisation. The solution is passed through a 0.22 µm PVDF sterilizing filter and filled into amber type I glass ampoules or vials; multi-dose vials incorporate 1.5% w/v benzyl alcohol as preservative. Finished forms are 1 mL and 2 mL single-dose ampoules, 10 mL multi-dose vials, and pre-filled syringes where silicone barrel compatibility has been validated. If terminal moist heat sterilisation is not used, aseptic processing under applicable GMP microbiological controls is required; visible precipitation during low-temperature storage indicates cosolvent ratio failure and must be evaluated under ICH Q1A(R2) stability protocols.
Oral suspension compounding for cats weighing 2–4 kg addresses the dispensing of 10 mg/mL or 20 mg/mL dimenhydrinate liquids where tablet splitting is imprecise and vomiting prevents retention of solid dosage forms. A 10 mg/mL suspension is equivalent to 1.0% w/v active addition; a 20 mg/mL formulation corresponds to 2.0% w/v. Compliance markers include USP <795> for nonsterile pharmaceutical compounding, USP <51> antimicrobial effectiveness testing for preserved aqueous vehicles, and Ph. Eur. 5.1.3 efficacy of antimicrobial preservation. The vehicle is first prepared by dispersing 0.2–0.5% w/w xanthan gum and 0.5–1.0% w/w microcrystalline cellulose/sodium carboxymethylcellulose in purified water under high-shear mixing at 1,500–3,000 rpm for 30 min; sodium benzoate 0.1% w/w or potassium sorbate 0.15% w/w is added as preservative, with pH adjusted to 5.0–6.5 to maintain preservative efficacy. Dimenhydrinate is then incorporated via a separate pre-slurry of propylene glycol 5.0–10.0% w/v to avoid lump formation; the batch is brought to final volume and homogenised at 2,500 rpm for 10 min. Finished products are amber polyethylene terephthalate bottles with child-resistant closures in 30–100 mL fills, and graduated oral syringes with 0.1 mL markings. Beyond-use dating is assigned from stability-indicating HPLC data rather than default 14-day water-based assumptions because dimenhydrinate hydrolysis accelerates above 30 °C and under strongly acidic conditions. A viscosity specification of 300–800 mPa·s at 25 °C is typically targeted to keep the suspension pourable through a 5 mL oral syringe while slowing sedimentation; published data for this specific dimenhydrinate concentration range is limited, so the label must state the shaking requirement and any in-use temperature boundary.
Palatability-masked granules are prepared for cats and small dogs that reject tablets but accept sprinkle-administration on canned food. A 25 mg active per 1,000 mg total granule fill corresponds to a 2.5% w/w addition ratio; lower-dose feline products may use 1.0–2.5% w/w with larger fill weights to maintain dose uniformity. Compliance anchors include USP <905> for unit-dose sachet uniformity, USP <701> for disintegration of coated granules, and VICH GL2 stability testing in the selected moisture barrier. The limiting factor below 500 µm is segregation potential during final sachet filling, because dimenhydrinate crystals and lactose monohydrate have different particle densities and static charge. In production, API, lactose monohydrate with a D50 of 100–150 µm, and povidone K30 are dry blended in a 200 L bin blender for 15 min at 15 rpm, then wet granulated in a high-shear granulator with an ethanol:water 80:20 v/v binder at 2.0–5.0% w/w addition. The wet mass is milled through an 850 µm screen, dried in a fluid bed at 45–50 °C to LOD ≤2.0% w/w, and screened with 125/250/500/850 µm sieves. Palatability masking may use a 2.5–5.0% w/w ethylcellulose coat applied by Wurster bottom spray; coating efficiency below 90% at particle sizes below 500 µm indicates static losses to filter bags and poor fluidization. Finished products are unit-dose sachets of 0.5 g, 1.0 g, and 2.0 g foil-lined laminates, and jars with a 1.0 g calibrated scoop. The terminal granule blend should meet a specification of D50 300–700 µm, with no more than 15% below 250 µm, to avoid dose variation and segregation during filling.
Veterinary compounding pharmacies processing dimenhydrinate bulk powder into capsules and oral powders operate under a different quality model than licensed manufacturing; the primary constraint is that the powder blend must be triturated to a uniform active concentration without inducing particle size shift or static adhesion. For a 25 mg dimenhydrinate capsule filled to a total powder weight of 100 mg, the addition ratio is 25.0% w/w; a 50 mg capsule at 150 mg fill weight corresponds to 33.3% w/w. USP <795> governs nonsterile compounding, and in the US the specific inspection regime may follow state board of pharmacy rules rather than 21 CFR 211 unless the pharmacy participates in an outsourcing facility framework; export buyers should confirm the exact regulatory class before sourcing. In powder processing, the API is passed through a 250 µm stainless steel sieve, mixed with lactose monohydrate by geometric dilution in a stainless steel mortar or low-shear blender, then filled into hydroxypropyl methylcellulose capsules of size 3 or 4 with a manual capsule machine producing 100–500 capsules per batch. Weight sorting is performed at ±5.0% of target weight, and capsules falling outside this range are rejected; API content variance should be checked by stability-indicating HPLC quantification at 254 nm, not by weight alone, because dimenhydrinate and lactose can segregate by particle size during capsule filling even when gross weight remains within range. Finished types are oral capsules in 12.5 mg, 25 mg, and 50 mg strengths, and oral powders for reconstitution into suspension at the point of use, labelled with beyond-use dates derived from chemical stability data rather than extrapolation from other antihistamines.
Dimenhydrinate premix blends are prepared as concentrated intermediates for manufacturers producing companion animal tablets, capsules, or granules from bulk API. A typical premix addition ratio is 5.0–20.0% w/w active, with a final let-down ratio of 1:5 to 1:20 into the terminal powder blend. Compliance for this intermediate is anchored in VICH GL1 validation of analytical procedures, VICH GL2 stability testing, and the manufacturing authorisation requirements of Regulation (EU) 2019/6. Because dimenhydrinate is a 1:1 salt of diphenhydramine and 8-chlorotheophylline, a premix is not adequately controlled by a single weight assay or total nitrogen assay; HPLC with dual-wavelength detection at 254 nm and 220 nm is used to quantify both components and detect any stoichiometric drift after wet granulation or humid storage. The premix is prepared in a V-blender fitted with an intensifier bar, charged with API, microcrystalline cellulose, and pregelatinised starch; after 20 min blending at 25 rpm, the molar ratio of diphenhydramine to 8-chlorotheophylline is expected to remain within 0.98:1.00 and 1.02:1.00. Moisture ingress above 60% RH is the defined boundary; open storage of premix in non-barrier packaging for 14 days at 30 °C and 75% RH has been associated with caking and non-representative sampling, though published data for this specific dimenhydrinate premix configuration is limited. The premix is discharged through a 500 µm sieve and packed in double-lined polyethylene bags inside fibre drums with desiccant. Terminal use is as an intermediate for oral tablets, capsules, or granules in companion animal products; this premix is not suitable for food-producing animal feed premixes due the absence of a Commission Regulation (EU) No 37/2010 Table 1 entry.
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Introduced as a crystalline 8-chlorotheophylline salt of diphenhydramine, Dimenhydrinate (CAS 523-87-5) veterinary-grade active pharmaceutical ingredient is released under the grade identifiers DMH-VET-API-M for micronized material with D90 ≤ 20 µm and DMH-VET-API-C for coarse material with D90 ≤ 150 µm. The molecular formula C17H21NO·C7H7ClN4O2 corresponds to a molecular weight of 469.98 g/mol; each mole contains 54.3% w/w diphenhydramine base and 45.7% w/w 8-chlorotheophylline. The powder is white to off-white, crystalline, and melts between 102°C and 107°C. Solubility is slight in water, with increased solubility in ethanol and propylene glycol, a factor that directly governs the choice of injection vehicles and granulation solvents. Release specifications are aligned with the USP Dimenhydrinate monograph and the corresponding European Pharmacopoeia text; routine certificates include assay 98.0%–102.0% on dried basis, loss on drying ≤0.5%, residue on ignition ≤0.1%, and aerobic microbial count ≤100 CFU/g for non-sterile processing. Packaging employs double polyethylene liners inside an HDPE drum with desiccant; the label records lot number, retest date, CAS number, and BSE/TSE statement.
Two particle-size grades are produced from the same final crystallisation lot by separate mechanical sizing steps. Milling is performed on a cone mill with a 0.5 mm screen under nitrogen sweep to prevent electrostatic charging; residual dust is captured by a closed vacuum transfer system. The milled powder is then passed through a 250 µm sieve to remove agglomerates and packed under controlled humidity below 40%. The coarse grade is used for premix and granule applications because it reduces dusting and improves flow; the micronized grade is used for tablets, capsules, and suspensions where dissolution rate is critical.
Diphenhydramine hydrochloride (291.82 g/mol) is freely soluble in water and yields one mole of active base per mole of salt; dimenhydrinate requires twice the molecular mass for the same diphenhydramine load and delivers 54 mg diphenhydramine base per 100 mg dose. The 8-chlorotheophylline counterion reduces aqueous solubility and may promote a slower dissolution front in compressed tablets, which is not a defect but a formulation variable. Dimenhydrinate acts primarily as an H1-receptor antagonist with antimuscarinic activity; its antiemetic effect in dogs and cats is associated with vestibular nuclei and chemoreceptor trigger-zone suppression. This mechanism differs from maropitant citrate, a neurokinin-1 receptor antagonist, and from ondansetron hydrochloride, a 5-HT3 receptor antagonist. The three agents do not share the same adverse-effect profile: dimenhydrinate commonly produces sedation and dry mucous membranes at therapeutic doses, maropitant does not rely on H1 blockade, and ondansetron lacks the anticholinergic component. For compounding pharmacists and veterinary manufacturers, the choice of dimenhydrinate over diphenhydramine hydrochloride may be driven by the desired salt form, dissolution profile, or regulatory master file availability; published data for this specific configuration is limited.
Replacement of diphenhydramine hydrochloride with dimenhydrinate in a chewable tablet formulation requires recalculation of active moiety content. A 25 mg diphenhydramine base claim becomes 46 mg dimenhydrinate per tablet, assuming 54.3% w/w base content. If the formulation is not corrected, underdosing occurs. Mechanistic differences also affect compatibility: dimenhydrinate should not be dry-blended with strongly alkaline excipients because free diphenhydramine can be liberated, producing a low-viscosity liquid phase in humid conditions and blocking tablet tooling. Similarly, acidic wet granulation at pH below 3.0 accelerates hydrolysis of the salt and raises 8-chlorotheophylline-related impurities; a buffered granulation medium at pH 6.0–7.0 is preferred for aqueous processing.
Release testing for veterinary-grade dimenhydrinate follows compendial and internal manufacturing limits. The table below summarizes the routine specification for the micronized grade; the coarse grade differs only in particle size distribution and density parameters.
| Parameter | Method | Limit |
|---|---|---|
| Assay (dried basis) | USP monograph HPLC | 98.0%–102.0% |
| Loss on drying | USP <731> | ≤0.5% |
| Residue on ignition | USP <281> | ≤0.1% |
| Melting range | USP <741> | 102°C–107°C |
| Particle size D90 (micronized) | Laser diffraction | ≤20 µm |
| Bulk density (micronized) | USP <616> | 0.35–0.55 g/mL |
| Tapped density (micronized) | USP <616> | 0.50–0.70 g/mL |
| Specific surface area (micronized) | BET | 1.0–3.0 m²/g |
| Total aerobic microbial count | USP <61> | ≤100 CFU/g |
| Yeast and mould count | USP <61> | ≤50 CFU/g |
| Residual solvents | USP <467> | Option 1 limits |
| Elemental impurities | USP <232>/<233> | ICH Q3D oral/injectable limits |
The micronized D90 ≤ 20 µm grade is specified for low-dose tablets, suspensions, and injectable solution preparation where dissolution rate is a limiting factor; the coarse grade reduces dusting during premix blending and is preferred for feed-additive operations. Because the two grades contain identical chemical identity and compendial assay limits, interchangeability is governed by milling validation and blend uniformity rather than identity testing alone.
Because dissolution of dimenhydrinate tablets is pH-dependent, the salt dissolves more slowly in phosphate buffer pH 6.8 than in 0.1 N hydrochloric acid due to the weakly basic nature of diphenhydramine. USP diphenhydramine dissolution conditions are not automatically applicable to dimenhydrinate veterinary tablets; finished product dossiers should establish a discriminatory method with sink conditions, typically using 900 mL of 0.1 N HCl or pH 4.5 acetate buffer at 50 rpm basket. Published data for this specific configuration is limited.
Dimenhydrinate does not require pre-drying under routine warehouse conditions, but relative humidity above 60% at weigh-out can increase surface moisture and reduce flow of the micronized grade. For tablet strengths at or below 10 mg active per unit, the micronized API is pre-blended with lactose monohydrate or dicalcium phosphate dihydrate in a twin-shell V-blender or bin blender; the intensifier bar is run only during the final 5 minutes of blending to limit shear-induced crystal fracture. A production-scale rotary tablet press with 10 mm round tooling and compression force 12–18 kN typically achieves acceptable hardness when the formulation contains ≥70% direct-compression diluent. If flow is inadequate, roller compaction is preferred over aqueous wet granulation because it avoids hydrolysis of the salt and removes the drying step; granules from a roller compactor with 2.0 mm screen yield a compactible granule without organic solvent. Segregation risk increases when the API D90 exceeds 150 µm and drug loading is below 5%; in these cases, a slugging or roller compaction step is specified before compression. Final blend and tablet content uniformity are evaluated per USP <905>; dissolution testing per USP <711> should be part of the finished product dossier.
For higher strengths, aqueous wet granulation on a 600 L high-shear granulator is feasible only when the binder solution is buffered to pH 6.0–7.0 and the granulation endpoint is controlled by impeller power consumption rather than time alone. The wet mass is dried in a fluid-bed dryer at inlet air temperature 55°C–60°C to moisture content ≤1.8%. Overdrying below 0.5% moisture increases electrostatic adhesion to stainless steel transfer surfaces, while residual moisture above 2.5% promotes sticking in tablet tooling and may increase dimer-related impurities. These processing boundaries are derived from general wet-granulation practice for low-solubility antihistamine salts; published data for dimenhydrinate-specific dimer kinetics is limited.
Injectable solutions of dimenhydrinate are prepared with a non-aqueous solvent system because the API is only slightly soluble in water. A representative vehicle contains 50% v/v propylene glycol and 10% v/v ethanol with water for injection; the target concentration is commonly 50 mg/mL. The pH of the final solution is adjusted to 6.0–7.5 before addition of an antioxidant if required. Terminal moist-heat sterilization at 121°C for 15 minutes is not recommended unless solution pH and oxygen headspace are tightly controlled; aseptic filtration through a 0.22 µm sterilizing-grade membrane is the preferred filling route for ampoules or vials. Precipitation may occur if the solution is diluted with water or normal saline below 25% v/v cosolvent content; therefore, slow reconstitution into the same solvent system or injection port dilution is specified. Pre-filtration bioburden control is maintained with a 0.45 µm prefilter followed by the final 0.22 µm membrane; filter compatibility should be tested because high ethanol content may extract leachables from certain mixed cellulose ester membranes. Stability of opened ampoules should not be estimated from dry API data; published data for this specific configuration is limited.
In oral compounding, solutions are prepared at 1–10 mg/mL using a co-solvent vehicle containing propylene glycol, glycerin, and a buffer; the solution should be protected from light and stored in amber polyethylene terephthalate or glass. Because dimenhydrinate has a bitter taste and a mild local anesthetic effect on the tongue, oral powders for in-feed use are often blended with palatability enhancers. Hard gelatin capsule filling of dimenhydrinate at 50 mg or 100 mg dose typically uses the micronized grade in a powder blend containing 1% colloidal silicon dioxide and 2% magnesium stearate; capsule filling on an intermittent-motion dosator machine may require a minimum bulk density of 0.45 g/mL to maintain weight variation below 3%. The coarse grade is avoided in capsules because larger crystals reduce powder bed packing and increase fill weight variability. In feed premixes, the micronized API is first mixed with corn starch or lactose carrier in a ribbon blender at 15–20 rpm for 15 minutes, then diluted geometrically to a target concentration of 250 mg/kg to 2 g/kg in final feed. The powder should not be hammer-milled in the same step as mineral premixes; re-grinding of the API with trace minerals may increase contact moisture and reduce chemical stability. Field-scale batch records show that pre-blending with a 1:5 API-to-carrier ratio before final dilution improves content uniformity and reduces segregation during pneumatic transport; published data for this specific configuration is limited.
For marketing authorisation submissions, each lot is supplied with a certificate of analysis, safety data sheet, and GMP declaration. The active substance is manufactured under a quality system aligned with ICH Q7; a drug master file or veterinary master file may be referenced in regulatory submissions, and the supply chain should be audited from raw material receipt to final packaging. Dimenhydrinate is manufactured as a non-sterile powder, so finished sterile dosage forms require downstream sterilisation or aseptic filling. Residual solvent and elemental impurity declarations follow USP <467> and USP <232>/<233>, and the product is not of animal origin, which supports BSE/TSE-free certification. Storage below 25°C in a dry area is specified; retest after 36 months from manufacture, not after opening. Avoid contact with strong oxidising agents and strong acids because the salt may decompose to diphenhydramine free base and 8-chlorotheophylline under such conditions.
