| HS Code | 308570 |
| Product Name | Pentoxyverine Citrate Pharma Grade API |
| Chemical Name | 2-(2-Diethylaminoethoxy)ethyl 1-phenylcyclopentanecarboxylate dihydrogen citrate |
| Synonym | Carbetapentane Citrate |
| Cas Number | 23142-01-0 |
| Molecular Formula | C26H39NO10 |
| Molecular Weight | 525.59 g/mol |
| Appearance | White or almost white crystalline powder |
| Solubility | Freely soluble in water; sparingly soluble in ethanol; practically insoluble in ether |
| Melting Point | 94°C to 96°C |
| Assay Content | 98.0% to 101.0% on dried basis |
| Grade | Pharma Grade |
| Dosage Forms | Tablet, Capsule, Granule, Injection |
| Administration Route | Oral and Injectable |
| Storage Condition | Store in tightly closed container in a cool, dry place, protected from light |
| Shelf Life | 24 months when stored as required |
| Therapeutic Category | Antitussive |
As an accredited Pentoxyverine Citrate Pharma Grade API for Tablet / Capsule / Granule / Injection, Oral & Injectable factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | Packed in 25 kg drums with double polyethylene liners inside, sealed, labeled, and moisture-protected for oral and injectable pharmaceutical use. |
| Container Loading (20′ FCL) | 20′ FCL loading: pharma-grade Pentoxyverine Citrate API packed in sealed drums/cartons, palletized, secured for safe transport. |
| Shipping | Pentoxyverine Citrate Pharma Grade API ships in sealed, moisture-proof drums with COA and tamper-evident packaging. Transport is via temperature-controlled, secure freight to protect purity. Handle per GMP guidelines, avoid heat, humidity and direct sunlight. Shipments comply with international pharmaceutical regulations and require proper documentation for customs clearance. |
| Storage | Store in tightly sealed, light-resistant containers in a cool, dry, well-ventilated area. Maintain temperatures between 15–30°C, away from moisture, heat, and incompatible substances. Keep original packaging intact, protect from strong oxidizers, and avoid exposure to excessive humidity. Suitable for oral and injectable pharmaceutical formulations when stored properly. |
| Shelf Life | Shelf life is typically 24 months when stored in tight containers, protected from light, at controlled room temperature. |
Direct compression of pentoxyverine citrate into 25 mg immediate-release tablets is executed on a 45-station B-tooling rotary tablet press fitted with a force feeder operating at 30–60% paddle speed. The dry blend comprises pentoxyverine citrate 16.7% w/w, mannitol 58.0% w/w, microcrystalline cellulose PH102 20.0% w/w, crospovidone type A 4.0% w/w, colloidal silicon dioxide 0.8% w/w, and magnesium stearate 0.5% w/w for a 150 mg core tablet; when the core weight is adjusted from 120 mg to 220 mg, the API addition ratio ranges from 11.4% w/w to 20.8% w/w. Precompression force is maintained at 3.0–5.5 kN, and main compression force is held between 8.0 kN and 15.0 kN. Tablet hardness is controlled at 50–80 N, and friability is limited to ≤0.8% after 100 revolutions. Content uniformity is assessed by USP <905> and Ph. Eur. 2.9.40, while dissolution is monitored by USP <711> and tablet friability by USP <1216>. Process bottleneck: magnesium stearate blended for more than 20 min at total concentrations above 0.75% w/w reduces interparticulate bonding and causes capping at main compression force approaching 18 kN. Finished product types include uncoated, film-coated, and scored 25 mg tablets packaged in PVC/PVDC/aluminium blisters.
Capsule filling operations with pentoxyverine citrate at a 25 mg unit dose are run on a tamping-pin capsule filler at 60 000–100 000 capsules/h using size 3 hard HPMC capsules. The API addition ratio is 20.8% w/w for a 120 mg fill weight; the powder blend comprises lactose monohydrate 200 mesh 57.0% w/w, pregelatinized starch 20.0% w/w, talc 2.0% w/w, and magnesium stearate 0.2% w/w. APIs sifted through 425 µm mesh are blended in a bin blender for 15–20 min at 10–12 rpm. The capsule machine is set with powder bed height 35–45 mm and tamping pin penetration 3–5 mm; in-process capsule mass is verified every 15 min. Content uniformity is tested by USP <905> and Ph. Eur. 2.9.40; disintegration is controlled by USP <701> and Ph. Eur. 2.9.1. Published data quantifying segregation velocity for this specific pentoxyverine citrate-lactose-pregelatinized starch system are limited; pilot runs with mass verification every 15 min are required to set final machine parameters. Finished product types include printed size 3 hard HPMC capsules containing 25 mg pentoxyverine citrate in HDPE bottles with desiccant.
For pediatric dry syrup or single-dose sachet delivery, wet granulation binds pentoxyverine citrate particles to the diluent surface, reducing segregation and improving content uniformity. A 1.0 g sachet containing 30 mg pentoxyverine citrate has an API addition ratio of 3.0% w/w; the dry blend comprises sucrose or mannitol 93.0% w/w, povidone K30 3.0% w/w, citric acid 0.5% w/w, sodium citrate 0.3% w/w, and colloidal silicon dioxide 0.2% w/w. Wet massing is performed in a high-shear granulator at impeller speed 250–400 rpm and chopper speed 1500–2500 rpm for 3–6 min, with purified water added at 5–8% w/w. The wet granules are dried in a fluid bed at inlet air 55–70 °C to loss-on-drying 1.5–2.5%. The target granule fraction is 150–500 µm, and fines below 75 µm are limited to ≤15% w/w. Content uniformity for single-dose sachets is tested per USP <905> and Ph. Eur. 2.9.5; microbial quality is controlled by USP <61> and USP <62>. Residual moisture above 2.5% induces caking in sachets and increases microbial growth risk in Zone IVb packaging; overdrying below 1.0% increases fine granule friability and fill weight drift on vertical form-fill-seal equipment. Finished product types include stick-pack granules for reconstitution to 25 mg/5 mL oral suspension, and 100 mL bottle dry syrup with a dosing spoon.
Terminal moist-heat sterilization of a 10 mg/mL pentoxyverine citrate solution in Type I borosilicate glass ampoules requires endotoxin control below 0.5 EU/mg and sub-visible particulate limits per USP <788> and Ph. Eur. 2.9.19. The bulk solution addition ratio is 1.0% w/v; sodium chloride is present at 0.9% w/v, and citric acid monohydrate/sodium citrate buffer holds pH at 5.0–5.7. The compounding sequence consists of dissolution in Water for Injection at 20–30 °C, addition of 0.1% w/v activated charcoal for 15 min, adsorption filtration, pre-filtration through 0.45 µm PES, sterile filtration through 0.22 µm PES, filling under Grade A laminar flow, and autoclaving at 121 °C for 15 min, corresponding to F0 ≥ 8.0 min. Sterility is tested per USP <71>; bacterial endotoxins per USP <85>; elemental impurities per ICH Q3D. The terminal autoclave cycle may increase hydrolytic degradation of the citrate ester; the pH upper limit of 5.7 is specified to limit hydrolysis and visible discoloration. Process incompatibility: avoid elastomeric closures with zinc-accelerated vulcanization systems during stability, because leachable zinc ions form citrate complexes and can raise sub-visible particle counts after 6 months at 40 °C/75% RH. Finished product types include 1 mL ampoules containing 10 mg pentoxyverine citrate and 2 mL ampoules containing 20 mg for parenteral antitussive use in hospital settings.
Pentoxyverine citrate oral solution at 25 mg/5 mL is manufactured at an API addition ratio of 0.5% w/v. The aqueous vehicle comprises sorbitol 70% non-crystallizing 20% w/v, glycerin 10% w/v, methylparaben 0.18% w/v, propylparaben 0.02% w/v, citric acid monohydrate 0.1% w/v, sodium citrate dihydrate 0.2% w/v, and purified water q.s. to 100%. The API is dissolved under low-shear propeller agitation at 200–300 rpm and 20–25 °C; the bulk solution is filtered through 10 µm polypropylene depth media and filled into 100 mL amber polyethylene terephthalate bottles. Antimicrobial effectiveness is tested per USP <51>; microbial enumeration and specified organisms are controlled by USP <61> and USP <62>. Process bottleneck: methylparaben partitions into non-ionic surfactants; polysorbate 20 concentration above 0.5% w/v reduces free preservative concentration and can cause failure of USP <51>. Finished product types include 100 mL syrup bottles and 15 mL oral drops with a calibrated dropper.
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Pentoxyverine Citrate Pharma Grade API is the citrate salt of 2-[2-(diethylamino)ethoxy]ethyl 1-phenylcyclopentanecarboxylate, supplied as a white or almost white crystalline powder with CAS registry number 23142-01-0, molecular formula C20H31NO3·C6H8O7, and relative molecular mass 525.59 g/mol. The product model designation “Pentoxyverine Citrate Pharma Grade API for Tablet / Capsule / Granule / Injection, Oral & Injectable” refers to monograph-grade material intended for finished pharmaceutical dosage forms; it is distinct from technical-grade, research-grade, or unqualified pentoxyverine citrate. The compound is a non-opioid centrally acting antitussive. Selection of the citrate salt rather than the free base converts the lipophilic active moiety into a crystalline powder with reproducible aqueous dissolution behavior, enabling direct compression, wet granulation, capsule filling, oral liquid compounding, and injectable manufacturing under pharmaceutical quality systems.
Release analysis is conducted by reversed-phase HPLC with a C18 column and UV detection, with assay calculated on the dried basis. Representative release criteria include assay 99.0–101.0 % on the dried basis, loss on drying ≤0.5 %, sulfated ash ≤0.1 %, unspecified impurity ≤0.2 %, and total impurities ≤0.5 %. These values are aligned with the current Ph. Eur. monograph for pentoxyverine citrate and with ICH Q3A(R2) reporting, identification, and qualification thresholds. Identification requires infrared absorption spectrophotometry against a certified reference standard and a positive citrate reaction. Residual solvents are controlled under ICH Q3C; elemental impurities are assessed under ICH Q3D for oral and injectable routes. The table below summarizes the release-control matrix used during batch certification.
| Parameter | Representative specification | Analytical reference |
|---|---|---|
| Description | White or almost white crystalline powder | Ph. Eur. monograph |
| Identification | Infrared spectrum corresponds to reference; citrate reaction positive | Ph. Eur. monograph |
| Assay, dried basis | 99.0–101.0 % | Ph. Eur. monograph HPLC |
| Related substances | Unspecified impurity ≤0.2 %; total impurities ≤0.5 % | ICH Q3A(R2) |
| Loss on drying | ≤0.5 % | Ph. Eur. 2.2.32 |
| Sulfated ash | ≤0.1 % | Ph. Eur. 2.4.14 |
| Residual solvents | Per synthesis route; Class 2 and Class 3 solvents controlled | ICH Q3C |
| Elemental impurities | Oral and injectable PDE limits applied | ICH Q3D |
| Particle size | D90 ≤250 µm for direct compression; finer grade for suspension | ISO 13320 |
Because the citrate salt is a distinct chemical entity, monograph identity and purity requirements differ from those applied to pentoxyverine base or other salts. The free base is not interchangeable with the citrate salt in manufacturing without recalculation of the active moiety. The base-equivalent conversion factor is 0.635 when the label claim is expressed as pentoxyverine; no correction is applied when the claim is expressed as pentoxyverine citrate.
Particle size distribution is measured by laser diffraction under ISO 13320 with dry dispersion pressure 2.0–3.0 bar and obscuration 0.5–5 %. For tablet and capsule processes, a D10 ≥20 µm, D50 80–150 µm, and D90 ≤250 µm reduce segregation during transfer and improve content uniformity. Excess fines below 10 µm increase adhesion to stainless steel and triboelectric charging; the resulting weight variation is controlled by adding colloidal silicon dioxide at 0.1–0.5 wt% and shortening pneumatic transfer lines.
For solid oral dosage forms, the citrate salt is blended with microcrystalline cellulose, lactose monohydrate, crospovidone, and magnesium stearate. Powder flow is characterized by the Hausner ratio and compressibility index per USP <1174>; blend release is accepted when the Hausner ratio is ≤1.25 and the Carr index is ≤25 %. Compression is performed on a rotary tablet press at 8–25 kN; ejection force is monitored below 1 000 N to reduce picking and sticking. Tablet friability is tested under Ph. Eur. 2.9.7 or USP <1216> with a limit of ≤1.0 % for uncoated cores. Content uniformity follows USP <905> or Ph. Eur. 2.9.40 with acceptance value AV ≤15.0 for single-dose preparations.
High-shear wet granulation of pentoxyverine citrate is used when direct compression produces segregation or poor flow. Process control centers on impeller speed 300–500 min⁻¹, wet massing time 2–5 min, and granule loss on drying 1.5–2.5 %. Overgranulation to particle sizes above 1 000 µm reduces tablet hardness and prolongs disintegration; undergranulation below 75 µm increases dusting and die fill variability. Dried granules are milled through a screen with aperture 0.8–1.2 mm and lubricated with magnesium stearate at 0.25–0.75 wt%. Dissolution testing for immediate-release tablets is conducted using USP <711> Apparatus 2 at 50 rpm in 900 mL of pH 6.8 phosphate buffer or 0.1 M hydrochloric acid; a Q value of ≥75 % at 45 min is often used during development, but the final specification must be validated under ICH Q2(R1).
Capsule filling is performed with a dosator or tamping-pin machine. Target capsule mass is set to control fill weight variation at ≤5 %; powder bed height and pin compression are adjusted during encapsulation runs to maintain plug integrity. Empty capsule shells conditioned at 40–50 % RH reduce brittle fracture. Capsules containing pentoxyverine citrate are typically tested by disintegration under Ph. Eur. 2.9.1 or USP <701>, with complete disintegration within 15 min for immediate-release formulations.
Oral solutions are prepared by dissolving the citrate salt in purified water at 20–25 °C, then adjusting pH to 4.0–6.0 with dilute hydrochloric acid or sodium hydroxide. The citrate counterion provides self-buffering and reduces pH drift during shelf life. The solution is clarified through a 0.45 µm filter and filled into amber glass bottles with child-resistant closures; preservative efficacy is demonstrated under Ph. Eur. 5.1.3 or USP <51>. Because the ester linkage undergoes pH-dependent hydrolysis, accelerated stability studies for oral liquids are conducted at 40 °C/75 % RH under ICH Q1A(R2), with assay loss and related substances monitored at 0, 3, and 6 months.
For injectable presentations, pentoxyverine citrate is dissolved in water for injection and adjusted to pH 4.0–6.0. If terminal sterilization at 121 °C for 15 min produces related substances above the ICH Q3B qualification threshold, aseptic filtration through a 0.22 µm polyethersulfone membrane is used. Pre-filtration bioburden is controlled to ≤10 CFU/100 mL as a process limit before sterilising filtration; this is consistent with Ph. Eur. 5.1.1. Filter integrity is verified by bubble point or diffusion test before and after filtration. The solution is filled under Grade A laminar flow in a Grade B background, with nitrogen overlay to minimize oxidative degradation. Filling pump speed and needle height are controlled to avoid foaming; residual oxygen in headspace is maintained below 2 % v/v. The citrate salt is preferred over the hydrochloride in injectable compounding because it contributes buffering capacity and reduces local pH shift during diluent addition.
Subvisible particle testing for small-volume injectable preparations is conducted by light obscuration under USP <788> or Ph. Eur. 2.9.19. Acceptance limits are ≤6 000 particles per container for particles ≥10 µm and ≤600 particles per container for particles ≥25 µm. Visible particles are assessed under Ph. Eur. 2.9.20. Filter compatibility studies include polyethersulfone, PVDF, and nylon membranes; the selected filter must not adsorb pentoxyverine citrate more than 5 % after 24 h recirculation.
Formulators select pentoxyverine citrate over codeine phosphate when central antitussive efficacy is required without opioid handling and controlled-substance reconciliation. Unlike codeine phosphate, which is an opioid subject to Schedule II or equivalent controls in many jurisdictions and requires controlled storage, pentoxyverine citrate is not listed in the 1961 Single Convention as a narcotic drug. Compared with dextromethorphan hydrobromide, pentoxyverine citrate has an ester-based degradation pathway producing hydrolysis fragments rather than the morphinan N-demethylation impurities seen with dextromethorphan. The citrate counterion also differs from the hydrobromide and phosphate salts in its ability to complex trace metal ions; formulations containing calcium or iron should undergo excipient compatibility screening because citrate can reduce free cation activity in aqueous systems.
| Attribute | Pentoxyverine citrate | Codeine phosphate hemihydrate | Dextromethorphan hydrobromide monohydrate |
|---|---|---|---|
| Relative molecular mass of salt | 525.59 g/mol | 406.37 g/mol | 370.32 g/mol |
| Pharmacological class | Non-opioid centrally acting antitussive | Opioid antitussive | Non-opioid morphinan antitussive |
| International narcotic control | Not listed in the 1961 Single Convention as narcotic | Controlled in many jurisdictions | Not listed in the 1961 Single Convention; national restrictions may apply |
| Key formulation implication | Citrate buffering and chelation; ester hydrolysis is a principal degradation route | Controlled substance handling; phosphate salt may interact with calcium salts | High-solubility hydrobromide salt; CYP2D6-mediated metabolism; bitter taste requires masking |
Dose reconciliation between pentoxyverine citrate and the active moiety uses the base-equivalent factor 0.635. Manufacturing records for products labeled on active moiety must include the salt correction; products labeled on the citrate salt do not use a correction factor. This distinction is critical during technical transfer because unqualified use of the free-base mass can introduce a dose error of approximately 36.5 %.
Regulatory submissions for the pharma grade API should include batch analyses at commercial scale, forced degradation data under hydrolytic, oxidative, thermal, and photolytic conditions, and stability under ICH Q1A(R2) conditions. The material is packaged in double polyethylene bags inside aluminum-lined drums and stored at 15–25 °C protected from light. When ambient relative humidity exceeds 60 %, drying before use may be required. The API should not be combined with strong alkalis or strong oxidizers because these conditions accelerate ester hydrolysis and oxidative degradation. Near-infrared process analytical technology can be used to monitor blend uniformity, but the method must be validated against HPLC and correlated to USP <905> or Ph. Eur. 2.9.40. Published data for specific twin-screw granulation profiles of pentoxyverine citrate are limited; process development should include design-of-experiments trials across the compression and granulation ranges described above.
