| HS Code | 429804 |
| Product Name | Digitoxin Veterinary Grade API |
| Chemical Name | Digitoxin |
| Cas Number | 71-63-6 |
| Molecular Formula | C41H64O13 |
| Molecular Weight | 764.94 g/mol |
| Appearance | White to off-white crystalline powder |
| Odor | Odorless |
| Solubility | Practically insoluble in water; soluble in ethanol; freely soluble in chloroform |
| Melting Point | 256-257°C (with decomposition) |
| Assay | 98.0% - 101.0% on dried basis |
| Storage Conditions | Protect from light and moisture; store in tightly closed containers at controlled room temperature |
| Shelf Life | 24 months |
| Suitable Dosage Forms | Tablets, Injections, Capsules, Powders, Granules, Premix, Solutions |
As an accredited Digitoxin 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 | Digitoxin Veterinary Grade API is packaged in sealed, light-resistant containers, quantity 1 kg, for manufacturing tablets, injections, capsules, powders, granules, premix, and solutions. |
| Container Loading (20′ FCL) | 20′ FCL loaded with palletized, sealed drums of Digitoxin veterinary API, safely secured and ventilated for temperature-controlled transport. |
| Shipping | Digitoxin is shipped under strict hazardous material protocols per international regulations. Packaged in sealed, light-resistant containers to ensure API stability and safety. Requires proper ventilation, temperature monitoring, and full documentation, including SDS and toxic-substance declarations. Handling procedures account for its potency across tablets, injections, capsules, powders, granules, premix, and solutions. |
| Storage | Store Digitoxin Veterinary Grade API in a tightly sealed, light-resistant container in a cool, dry, well-ventilated area. Protect from moisture, direct sunlight, and excessive heat. Maintain controlled room temperature, ideally 15–30°C, away from incompatible materials and foodstuffs. Ensure container integrity after each use to preserve potency and stability. |
| Shelf Life | Shelf Life: 24 months from manufacture date when stored properly in sealed containers, protected from light, moisture, and heat. |
A high-potency cardiac glycoside such as digitoxin creates immediate blend-uniformity constraints when formulated as a veterinary tablet. The crystalline API is typically milled to a volume mean diameter below 20 µm and pre-dispersed against a directly compressible filler such as spray-dried lactose monohydrate or dibasic calcium phosphate dihydrate. Tablet strengths of 0.05 mg, 0.1 mg, and 0.2 mg are produced by wet granulation or by a double-trituration direct-compression route; the API is first screened through a 250 µm stainless-steel sieve and blended in a 1:10 API-to-filler ratio before transfer to a 600 L bin blender. Blend uniformity samples are drawn from 10 positions after 15 minutes at 12 rpm, and the content uniformity of finished tablets is assessed with USP <905> or Ph. Eur. 2.9.6; the acceptance value is held at ≤ 15.0 because of the narrow therapeutic index. Dissolution testing uses USP <711> Apparatus 2 at 50 rpm in 900 mL of 0.1 M hydrochloric acid containing 0.2% w/v sodium lauryl sulfate; the 60-minute Q value is not less than 75% for immediate-release tablets. Granulation endpoint is controlled by moisture analysis at 2.0–2.5% w/w, tablet hardness is maintained between 40 N and 70 N, and disintegration is confirmed in 37°C water within 15 minutes. The finished tablets are packaged in amber HDPE bottles with induction-sealed closures and a desiccant canister; child-resistant closures are used for companion-animal dispensing.
Digitoxin is practically insoluble in water, so a 0.2 mg/mL injection is prepared in a vehicle containing 30% v/v ethanol, 30% v/v propylene glycol, 10% v/v glycerol, and water for injection. The API is dissolved first in ethanol at 20–25°C with high-shear mixing until optically clear; the concentrate is then diluted with the remaining vehicle and adjusted to pH 6.5 ± 0.3 with a citrate buffer. The solution is passed through a 0.45 µm PVDF pre-filter and subsequently through a 0.22 µm PVDF sterilising filter; terminal steam sterilisation at 121°C for 15 minutes is generally avoided because the butenolide lactone ring undergoes base-catalysed hydrolysis and the digitoxose residues undergo acid-catalysed cleavage under elevated temperature. Aseptic filtration is therefore the preferred sterilisation route, and the filtered product is filled under nitrogen into 50 mL amber Type I glass vials with siliconised chlorobutyl stoppers. Sterility is tested according to USP <71> or Ph. Eur. 2.6.1; bacterial endotoxin limits are set according to USP <85> or Ph. Eur. 2.6.14; particulate matter is controlled by USP <788> light obscuration. Published forced degradation data for digitoxin in this specific cosolvent vehicle are limited, but the formulation pH is kept below 7.0 to protect the lactone ring and above 5.5 to avoid sugar cleavage. Visual inspection for precipitation is performed after storage at 2–8°C for 72 hours because propylene glycol-water mixtures may separate at low temperature; any batch showing crystalline deposits is rejected. The terminal product is a single-dose or multi-dose parenteral solution for intravenous or intramuscular administration in non-food equine and small-animal patients.
| Attribute | Test method | Representative limit |
|---|---|---|
| Sterility | USP <71> / Ph. Eur. 2.6.1 | No growth |
| Bacterial endotoxins | USP <85> / Ph. Eur. 2.6.14 | ≤ 5.0 EU/kg/h per maximum single dose |
| Particulate matter | USP <788> | ≤ 6000 particles ≥10 µm and ≤ 600 particles ≥25 µm per container |
| Content uniformity | Ph. Eur. 2.9.6 | Acceptance value ≤ 15.0 |
Fixed-dose digitoxin tablets are frequently unsuitable for cats and dogs weighing less than 5 kg because tablet splitting introduces dose errors that exceed the safe window for a narrow-therapeutic-index cardenolide. Capsule compounding from veterinary-grade API allows dose increments of 0.005 mg to 0.02 mg. The API is triturated with lactose monohydrate in a porcelain mortar using a 1:10 geometric dilution sequence; after each dilution, the material is passed through a 180 µm stainless-steel sieve to reduce agglomeration. A 100 g batch of 0.01 mg capsules requires a two-stage pre-blend: 0.1 g digitoxin plus 0.9 g lactose for the first dilution, followed by 1.0 g of that pre-blend combined with 99.0 g lactose. The final blend is filled into size 4 hard gelatin capsules using a manual capsule machine with a fill weight of 100 mg ± 5 mg. Content uniformity of the compounded capsules is verified by high-performance liquid chromatography against a compendial digitoxin reference standard; the acceptance criterion is ±10% of label claim or as specified in USP <795> for nonsterile preparations. Because digitoxin is light-sensitive and hygroscopic, capsules are stored in amber vials with silica gel, and the beyond-use date is limited to 90 days under refrigeration unless stability data support longer storage. The terminal product is a patient-specific oral capsule intended for once-daily administration under veterinary supervision.
In non-food equine practice, digitoxin oral powder is prepared as a water-dispersible trituration for nasogastric tube administration. The API is blended with anhydrous glucose or lactose monohydrate at 1:100 or 1:1,000 ratios in a low-shear tumble blender for 20 minutes; the powder is then passed through a 355 µm sieve and filled into single-use foil-laminate sachets under nitrogen. Moisture content is controlled below 1.5% w/w by Karl Fischer titration because higher residual moisture accelerates hydrolysis of the terminal lactone ring. Each sachet is reconstituted in 50 mL of warm water immediately before administration, and the suspension is drawn into a nasogastric tube within 10 minutes to minimise sedimentation. The sachets are overwrapped in aluminium pouches with desiccant and stored at 15–25°C. This powder is not intended for food-producing animals; no withdrawal period is assigned because the cardenolide is contraindicated in species entering the human food chain. The terminal product is a polypropylene syringe of homogeneous suspension prepared at the point of administration from a single-dose sachet.
When the API is embedded in a non-segregating granule for sachets, the process is built around fluid-bed granulation rather than dry mixing. A 0.025 mg/g granule is prepared by dissolving digitoxin in ethanol and spraying the solution onto a moving powder bed of microcrystalline cellulose and lactose in a bottom-spray fluid-bed granulator. The spraying solution contains povidone K30 at 4.0% w/w of the dry charge; inlet air temperature is controlled at 50°C, product temperature at 30–35°C, and spray rate at 15 g/min for a 5 kg batch. Granules are dried to a loss on drying of ≤ 2.0% and passed through a 1.25 mm conical mill. The finished granule has a Hausner ratio below 1.25 and a median particle size of 350–500 µm, a range that minimises segregation during filling into stick-pack sachets. Dose uniformity is evaluated using Ph. Eur. 2.9.6; each 500 mg sachet delivers a nominal 0.0125 mg digitoxin. Sachets are formed from polyester/aluminium/low-density polyethylene laminate with moisture vapour transmission below 0.01 g/m²/day; the laminate protects the hygroscopic granule during storage at 15–25°C. The terminal product is a single-dose oral granule that can be sprinkled on a small amount of food for dogs or cats under veterinary supervision.
A 1% w/w digitoxin premix is manufactured as an intermediate under ICH Q7 GMP conditions, not as a finished dosage form. The API is co-milled with microcrystalline cellulose through a 0.5 mm screen using a cone mill at 2000 rpm; the milled material is then geometrically diluted with lactose in a 500 L planetary mixer for 20 minutes. Bulk density is controlled at 0.55 ± 0.05 g/mL and tapped density at 0.65 ± 0.05 g/mL; these measurements are recorded for each lot to detect particle-size drift. Potency of the premix is assayed by liquid chromatography with photodiode array detection at 220 nm; the specification is 90.0–110.0% of label claim. Residual ethanol and isopropanol are tested according to USP <467> or Ph. Eur. 2.4.24; the API is dissolved in ethanol during granulation, so solvent control is critical. The premix is filled into double polyethylene liners inside fibre drums with desiccant pouches and held at 15–25°C. Pharmacies use this premix to prepare patient-specific capsules and oral solutions; a veterinary pharmaceutical manufacturer may use the same premix as a tableting feed after re-testing potency. This premix is not a medicated feed premix and is not intended for direct administration to food-producing species. The terminal product depends on the downstream operation: a compounded capsule, an oral solution, or a compressed tablet.
A 0.05 mg/mL digitoxin oral solution for dogs and cats is compounded or manufactured from the API or from the 1% w/w premix. The vehicle consists of 70% v/v sorbitol solution, 10% v/v propylene glycol, 0.1% w/v methylparaben, and 0.02% w/v propylparaben, adjusted to pH 6.5 with citrate buffer. The API is first dissolved in propylene glycol at 20–25°C; the aqueous portion is then added slowly under continuous stirring to avoid local precipitation. The bulk solution is passed through a 10 µm polypropylene filter to remove undissolved particulate; sterile filtration is unnecessary for an oral preparation but the filter housing is sanitised before use. Chemical stability is pH-dependent: the lactone ring remains stable in the range pH 5.5–7.0, while rapid hydrolysis occurs above pH 8.0 and below pH 3.0. The finished solution is filled into 30 mL amber PET bottles fitted with a calibrated dropper marked in 0.1 mL increments; each 0.1 mL delivers 0.005 mg digitoxin. Precipitation may occur if the product is stored below 2°C, so storage is controlled at 15–25°C and freezing is prohibited. The terminal product is an oral solution for once-daily administration in small-animal cardiology; the beyond-use date after opening is 60 days unless preservative challenge testing supports a longer period.
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Digitoxin Veterinary Grade API (CAS 71-63-6; C41H64O13; relative molecular mass 764.94) is released as a white to almost white crystalline powder for downstream processing into tablets, capsules, powders, granules, premixes, and non-aqueous or co-solvent-containing oral and injectable liquids. The material is controlled against current pharmacopoeial monographs and the issuing site’s certificate of analysis includes identity by infrared absorption spectrophotometry and specific optical rotation, chromatographic purity for related cardiac glycosides, assay, residual solvents, and elemental impurities. Because veterinary dose units frequently fall below 0.25 mg, the API is routinely milled and pre-blended under controlled relative humidity to maintain content uniformity without introducing amorphous content that would accelerate chemical degradation.
The API is practically insoluble in water, soluble in chloroform, and only slightly soluble in ethanol; this solubility profile dictates the use of dry mixing procedures for solids and non-aqueous or co-solvent systems for liquids. Crystalline digitoxin is stable at room temperature when protected from light and moisture, but acid or alkaline hydrolytic conditions produce digitoxigenin and sugars, increasing the need for pH-neutral granulation and storage in closed containers at 15–25 °C.
| Control parameter | Method / standard | Function in release |
|---|---|---|
| Identification | Ph. Eur. 2.2.24; specific optical rotation | Confirms chemical identity and stereochemical configuration |
| Related cardiac glycosides | Liquid chromatography; Ph. Eur. 2.2.29 | Limits cardioactive impurities, especially digitaloid steroids |
| Assay | Liquid chromatography or spectrophotometric reference method | Reports active content against the label claim |
| Residual solvents | Headspace gas chromatography; ICH Q3C | Ensures solvent residues are controlled |
| Elemental impurities | ICH Q3D with inductively coupled plasma mass spectrometry | Confirms catalyst- and process-derived metal control |
| Particle size | Laser diffraction; Ph. Eur. 2.9.31 | Supports blend uniformity and segregation control |
For low-dose oral solids, reducing digitoxin particle size before geometric dilution is preferred when the delivered powder D90 exceeds the blend uniformity threshold for the selected filler system. Direct milling of digitoxin without a carrier can generate fines that adhere to stainless steel and acrylic transfer surfaces; this is observed on rotary tablet presses and capsule machines as intermittent weight drift. Geometric dilution in 1:1, 1:2, and 1:4 steps using lactose monohydrate or dibasic calcium phosphate dihydrate reduces content uniformity relative standard deviation below 3.0% in validated processes, whereas single-step addition frequently produces superpotent and subpotent zones during hopper discharge. Sieve calibration with 250 µm and 500 µm screens may be used to break soft agglomerates; force-feeder speed should be lowered when the milled pre-blend contains more than 10% fines.
Wet granulation is limited by the poor aqueous solubility of digitoxin; high binder concentrations can induce local agglomeration of API fines, while low concentrations may not consolidate the powder bed. The granulation endpoint is controlled by impeller power consumption and post-granulation moisture below 2.0%. Drying in a fluid-bed dryer at inlet air temperature below 60 °C avoids thermal degradation, though long drying times may improve granule friability and tablet hardness uniformity. Compression force settings on rotary tablet presses are adjusted to maintain tablet hardness within the range qualified for the final product; for a small-animal tablet containing a microgram-level active content, hardness is usually set by placebo matrix properties rather than API deformation characteristics.
If direct compression is used, the pre-blend is typically discharged through a 1 mm screen and mixed in a bin blender at 60–70% of nominal bin volume. Overfilling the blender reduces the free-flowing headspace and produces slow mixing, while underfilling can create dead zones. Blending time is established by sampling at 10, 20, and 30 minutes and measuring active content by high-performance liquid chromatography. Content uniformity of the finished tablets follows Ph. Eur. 2.9.40 or USP 905; low-dose products with microgram-level labelled claim are tested with the full pharmacopoeial sampling plan because they are particularly sensitive to agglomeration in the feed frame.
Capsule filling on dosator or tamping-pin equipment depends on the pre-blend’s bulk density and flow character. Bulk density is monitored by Ph. Eur. 2.9.34 or USP 616; deviations above 10% from the qualified range can shift fill weight and content uniformity at high filling speeds. The Hausner ratio and Carr index from tapped density testing are used to assess flow; a Hausner ratio above 1.25 indicates poor flow and may require addition of a glidant such as colloidal silicon dioxide at 0.2–0.5% w/w. Over-lubrication with magnesium stearate above 1.0% w/w can coat the API and reduce dissolution because digitoxin is hydrophobic. Dissolution testing with USP apparatus 1 or 2 in acid or surfactant media should be part of development screening to detect slow release from over-blended or hydrophobic matrices. Because digitoxin is highly potent, dust extraction during encapsulation is designed to contain airborne fines, and the capsule shell may require dedusting before printing. Empty gelatin shells stored above 60% relative humidity may soften and cause sticking on the filling machine, while excessively dry shells can crack.
Digitoxin injectables are not aqueous isotonic solutions because the API is practically insoluble in water. Formulation development typically employs ethanol, propylene glycol, or polyethylene glycol as the primary solvent, with water for injection added only in proportions that do not reduce solubility below the target concentration at 5 °C, the temperature condition used for low-temperature storage screening. Forced-degradation studies under ICH Q1B and Q1A are used to identify hydrolysis, oxidation, and photolysis products; published data for this specific configuration is limited, necessitating batch-specific stability profiling. Terminal autoclaving may be unsuitable if the solvent matrix accelerates hydrolytic degradation; sterile filtration through 0.22 µm membrane filters is therefore employed where the formulation is filterable. Filter compatibility must be evaluated because digitoxin can adsorb onto hydrophobic polyvinylidene fluoride or polytetrafluoroethylene surfaces, leading to potency loss during clarification.
The injection vehicle should be protected from light and stored in amber glass or sealed plastic containers with low moisture vapour transmission. Headspace oxygen should be limited by nitrogen flushing because oxidative degradation of the unsaturated lactone ring can occur in dilute solution. pH adjustment is constrained; acidic and alkaline extremes accelerate digitoxin hydrolysis, so a weakly neutral target is used where solubility permits. If the manufacturing line performs pre-filtration nitrogen overlay, dissolved oxygen in the bulk solution is monitored before filling, and the fill volume is selected with an overage based on stability data. For lipophilic APIs in non-aqueous vehicles, extractables from rubber closures are monitored because non-aqueous solvents can extract vulcanisation residues and alter closure integrity.
Oral solutions and liquid feed additives are prepared from the same co-solvent principles but must be tested for precipitation upon dilution in drinking water. Simulated tap-water dilution at 5 °C and 25 °C with nephelometric clarity measurement detects precipitation that is not visible during laboratory reconstitution. If a powdered oral formulation is used, the API is triturated with soluble carriers, filled into aluminium foil sachets, and controlled for residual moisture below 1.0% to prevent caking. Granules for medicated feed premixes are produced by spraying the digitoxin pre-blend onto a carrier such as lactose or wheat middlings in a low-shear mixer; the finished granule dust fraction is maintained below 5% because dusty material segregates in animal feed mixing and can deposit in transfer lines. Premix potency is confirmed by sampling from the mixer using a statistically justified number of points, and the carrier particle size distribution is matched to the final feed matrix to avoid demixing during transport.
Cleaning validation for digitoxin manufacturing equipment is based on pharmacological potency rather than simple visual cleanliness. Acceptable residue limits are calculated from the permitted daily exposure of the next product and the batch size; swab samples are taken from the product contact surfaces of the blender, sieve, tablet press, and filling needle. Because digitoxin is lipophilic, alkaline or solvent-based cleaning agents are more effective than water alone; aqueous rinses may leave a thin residue film on stainless steel surfaces. After cleaning, high-performance liquid chromatography with low-level detection is used to confirm residues below the calculated limit.
Veterinary active substances may be released against Ph. Eur., USP, or VICH-aligned requirements. The digitoxin monograph and ICH Q3C residual solvent limits can differ among jurisdictions; manufacturers exporting to multiple regions should use a raw material specification that includes chromatographic purity for gitoxin, digitoxigenin, and related cardioactive steroid impurities, with acceptance limits aligned to the strictest recognized compendial profile. Elemental impurities are assessed according to ICH Q3D; when the synthetic or extraction route includes metal catalysts or activated carbon purification, a risk-based justification for the final dosage form is maintained. Residual solvents from recrystallisation, typically ethanol or acetone, are monitored by headspace gas chromatography; the reporting threshold should be set at or below the ICH Q3C Option 1 limit for class 3 solvents.
Stability testing for the solid API should include at least long-term and accelerated conditions per VICH GL3 or ICH Q1A; for non-aqueous liquid preparations, photostability studies are necessary because the cardenolide lactone ring can absorb ultraviolet light and form polar degradation products. The analytical method used for assay and related substances should be validated for specificity against digitoxigenin, gitoxin, and matrix components; a relative response factor is established for each impurity when the detector response differs from digitoxin. Solid-state integrity is monitored by X-ray powder diffractometry and differential scanning calorimetry. Micronization to reduce particle size can introduce amorphous surface domains that lower thermal stability; therefore milling conditions are selected so that the crystalline form remains within the qualified pattern. Batch-to-batch variation in residual solvent content may occur depending on recrystallisation and is controlled by drying endpoint and headspace gas chromatography.
Digitoxin differs from digoxin by the absence of the 12-hydroxy substituent present in digoxin. This structural difference reduces aqueous solubility and increases lipophilicity, affecting formulation solvent selection and dissolution testing. Digoxin may be formulated in hydroalcoholic vehicles with a larger aqueous fraction, while digitoxin requires a higher non-aqueous fraction or a more selective solubiliser to maintain solution clarity. Ouabain, a more polar cardioactive glycoside, is not interchangeable because its aqueous solubility and stability profile are different. In solid dosage forms, digitoxin’s lower water solubility reduces sensitivity to wet granulation binder selection compared with more soluble cardenolides, but its high potency requires stricter containment and cleaning validation.
| Property | Digitoxin | Digoxin | Ouabain |
|---|---|---|---|
| Water solubility | Practically insoluble | Practically insoluble to very slightly soluble | Soluble |
| Primary formulation constraint | Low-dose uniformity; non-aqueous solubilisation | Low-dose uniformity; aqueous co-solvent solubility | Aqueous parenteral pH stability |
| Impurity markers | Digitoxigenin, gitoxin, related cardenolides | Digoxigenin, gitoxin, digoxin-related compounds | Strophanthidin derivatives |
Analytical method transfer for digitoxin-containing veterinary products should include specificity against digitoxigenin and gitoxin, forced-degradation peaks, and recovery from the final matrix. Methods originally validated for digoxin may require re-optimization of mobile phase pH or organic modifier to resolve digitoxin-related substances. During scale-up, the method detection limit should be verified against the calculated carryover limit for shared production equipment, and the dissolution or dispersion test should be matched to the actual route of administration rather than assumed from human cardioactive glycoside monographs.
