| HS Code | 432224 |
| Productname | Vonoprazan Fumarate Pharma Grade API for Tablet / Capsule / Granule / Injection, Oral & Injectable |
| Casnumber | 1260141-17-2 |
| Chemicalname | 1-[5-(2-Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine fumarate |
| Molecularformula | C21H20FN3O6S (C17H16FN3O2S·C4H4O4) |
| Molecularweight | 461.47 g/mol |
| Appearance | White to off-white crystalline powder |
| Pharmacologicalclass | Potassium-competitive acid blocker (P-CAB) |
| Dosageformsuitability | Tablet, capsule, granule (oral) and injection (parenteral) |
| Primaryindication | Treatment of acid-related gastrointestinal disorders including reflux esophagitis, gastric ulcer, duodenal ulcer, and Helicobacter pylori eradication |
| Grade | Pharmaceutical grade API |
| Assay | 98.0% - 102.0% on anhydrous basis by HPLC |
| Relatedsubstances | Single impurity NMT 0.15%; total impurities NMT 1.0% by HPLC |
| Residualsolvents | Complies with ICH Q3C requirements |
| Solubility | Slightly soluble in water; soluble in methanol; sparingly soluble in ethanol; practically insoluble in hexane |
| Storageconditions | Store in a cool, dry, well-ventilated place in a tightly closed container, protected from light |
| Packaging | Double polyethylene-lined sealed aluminum foil bag in HDPE drum |
As an accredited Vonoprazan Fumarate 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 | Vonoprazan Fumarate API is supplied in sealed double polythene bags with silica gel, inside an aluminium pouch and fibre drum, 25 kg net. |
| Container Loading (20′ FCL) | One 20′ FCL container holds palletized, sealed drums of Vonoprazan Fumarate API, safely secured for pharmaceutical tablet, capsule, granule, and injectable use. |
| Shipping | Shipments of Vonoprazan Fumarate Pharma Grade API are handled in sealed, humidity-protected containers to preserve purity and stability. Temperature-controlled logistics ensure safe transit for oral and injectable formulations. Proper documentation accompanies all deliveries, with strict handling protocols for pharmaceutical manufacturing use only. |
| Storage | Store Vonoprazan Fumarate Pharma Grade API in a tightly closed, light-resistant container in a cool, dry, well-ventilated area. Protect from moisture, excessive heat, and direct sunlight. Maintain stable humidity and temperature conditions, and keep away from incompatible materials. Ensure proper labelling and segregation until use in oral or injectable formulation manufacturing. |
| Shelf Life | Shelf life: 24 months from manufacture date when stored in original unopened container at 20-25°C, protected from moisture and light. |
In low-dose immediate-release tablet production, the controlling unit operation is blend uniformity rather than dissolution rate. Vonoprazan fumarate is dosed at 10 mg or 20 mg per tablet; a core mass of 180 mg places the API at 5.6% w/w and 11.1% w/w respectively. The API is charged through a 0.25 mm conical screen mill with round impeller at 2,000 rpm, then subject to a two-stage geometric pre-blend with lactose monohydrate D50 of 110 μm before addition of microcrystalline cellulose and crospovidone. Main blending is operated at 25 rpm for 20 min in a 600 L bin blender. Stratified sampling at 10 positions is performed under 21 CFR 211.110(b); blend RSD is controlled below 4.0% before compression. The tablet press uses 8.0 kN precompression and 14 kN main compression force, with hardness maintained at 70–90 N. Friability is measured by USP <1216> at 100 rotations and is maintained at not more than 0.8%. Dissolution testing is performed according to USP <711> Apparatus 2 at 50 rpm in 900 mL of pH 6.8 phosphate buffer; the development target is not less than 80% released at 30 min. Direct compression is acceptable only when API lot D90 is below 50 μm and loss on drying is below 1.0% by USP <921>; otherwise wet granulation with povidone K30 at 4.0% w/w is substituted to prevent segregation and top-spray failure. The finished tablets are film-coated with an immediate-release polyvinyl alcohol-based system and packed in aluminum/aluminum blister when export destinations exceed climate zone IV.
| Dosage form | Test or control | Standard / method | Typical acceptance cutoff |
|---|---|---|---|
| Oral tablet | Blend uniformity | 21 CFR 211.110(b), USP <905> | RSD ≤ 4.0% at 10 sampling points |
| Dissolution | USP <711> Apparatus 2 | Q ≥ 80% at 30 min in 900 mL pH 6.8 buffer at 50 rpm | |
| Friability | USP <1216> | NMT 0.8% after 100 rotations | |
| Oral granule | Loss on drying | USP <921> | 1.5–2.5% |
| Content uniformity | Ph.Eur. 2.9.40 / USP <905> | Acceptance value ≤ 15 for 10 units | |
| Injectable | Particulate matter | USP <788> | ≤ 6,000 particles ≥ 10 μm, ≤ 600 particles ≥ 25 μm per container |
| Bacterial endotoxins | USP <85> | Dose-derived limit from product specification | |
| Residual water | USP <921> | NMT 1.0% for lyo cake | |
| API release | Assay | HPLC versus reference standard | 98.5–101.0% on dried basis |
| Total impurities | HPLC area normalisation | NMT 1.0%; single unknown impurity NMT 0.2% |
Commercial H. pylori regimens pair vonoprazan fumarate 20 mg with amoxicillin hydrate 750 mg and clarithromycin 200 mg or metronidazole 250 mg, each given twice daily for 7 days. A single monolithic tablet is generally not manufactured because the total active mass approaches 1,000 mg per dose and the three actives require different granulation behavior. Amoxicillin hydrate is granulated with povidone K30 at 3.5% w/w using low-shear wet granulation and dried to a moisture limit of 2.0%. Clarithromycin is bitter and is either film-coated with an immediate-release polyvinyl alcohol-based system or microencapsulated with ethylcellulose to reduce release of the active in the oral cavity. Vonoprazan fumarate is layered onto microcrystalline cellulose spheres of 250–355 μm in a Wurster bottom-spray coater using a hydroxypropyl cellulose binder solution at 4.0% solids. The three components are then filled as separate heat-sealed pockets in a unit-dose blister or as separate sachets to minimize chemical interaction and allow dose flexibility. Dissolution testing follows USP <711> with a pH gradient from pH 1.2 to pH 6.8 over 2 h, because the combination includes both acid-stable and weak-base actives. Environmental controls during encapsulation are set at not more than 50% relative humidity. No enteric coat is required for the vonoprazan fumarate component because the P-CAB molecule does not degrade in gastric acid, which differentiates the formulation from omeprazole or rabeprazole enteric preparations. Residual solvent control for the ethylcellulose coating step is verified under ICH Q3C(R8), and time limits for holding wet granulations are assigned under 21 CFR 211.111.
Fine granule and orally disintegrating presentations for elderly and dysphagia patients are manufactured by fluid-bed wet granulation rather than high-pressure compression. The API is dispersed in an aqueous binder solution containing mannitol and low-substituted hydroxypropyl cellulose at 5.0% solids, sprayed onto mannitol granules in a fluid-bed granulator with inlet air at 50°C, product temperature 35–40°C, and exhaust humidity below 35% RH. The dried granule is sieved through 0.85 mm and retained above 0.15 mm to support both oral administration and nasogastric tube delivery. The final sachet contains 10 mg or 20 mg vonoprazan fumarate per unit. Loss on drying is controlled to 1.5–2.5% by USP <921>; the granular bed must have an angle of repose not more than 35° and a bulk density between 0.45 g/cm³ and 0.60 g/cm³. Content uniformity is assessed with Ph.Eur. 2.9.40 or USP <905> on 10 individual sachets. Dissolution uses USP <711> Apparatus 2 at 50 rpm in 900 mL pH 6.8 buffer, with not less than 80% release at 15 min for the granule form. The primary packaging is a four-side-sealed aluminum sachet with desiccant when the product is shipped to zone IVb.
Injectable development is aseptic terminal filtration rather than terminal moist-heat sterilization when screening lots show total impurity increase above 0.2% at 121°C for 15 min. Published formulation-specific solubility data for injectable vonoprazan fumarate are limited; therefore, a pH-solubility profile from pH 3.0 to pH 7.0 is generated before buffer selection. A representative lyophilization cycle for a low-mass fumarate salt proceeds from freezing at -45°C, primary drying at shelf -20°C and chamber pressure 100 mTorr, then secondary drying at 25°C for 6 h, with cycle end determined by moisture content not more than 1.0% by USP <921>. The reconstituted solution is prepared with 0.9% sodium chloride injection to a final pH of 6.5–7.5. Filling is conducted in an ISO 14644-1:2015 Class 5 area under EU GMP Annex 1. Sterile filtration uses a 0.22 μm PVDF filter with bubble-point integrity testing before and after filling; bacterial retention validation is performed according to ASTM F838-20. Particulate matter is controlled according to USP <788> limits for small-volume injections, and bacterial endotoxins are tested by USP <85> using a dose-derived limit. The vial closure system is a Type I borosilicate glass vial with an elastomeric bromobutyl closure, and residual water in the lyo cake is monitored at each scale-up interval.
| Step | Shelf temperature | Chamber pressure | Critical control |
|---|---|---|---|
| Freezing | -45°C | Atmospheric | Hold time sufficient for complete solidification, vial bottom thermocouples stable |
| Primary drying | -20°C | 100 mTorr | Product temperature below collapse temperature, condenser -60°C or colder |
| Secondary drying | 25°C | 50 mTorr | Residual water NMT 1.0% by USP <921> |
For ulcer prophylaxis co-administered with low-dose aspirin or non-steroidal anti-inflammatory drugs, vonoprazan fumarate granules are placed in a separate capsule compartment or co-pack from the gastro-irritant API because aspirin is often enteric-coated while the P-CAB is not. Aspirin pellets are layered onto sugar spheres and coated with Eudragit L 30 D-55 at 12% dry polymer weight gain to delay release until pH 5.5 or above. Vonoprazan fumarate is blended with mannitol, microcrystalline cellulose, and crospovidone at 20 mg per unit and compressed as an immediate-release portion. Bilayer tableting is avoided when aspirin requires moisture protection; in such cases a multi-compartment capsule or a co-blister with desiccant is used. Dissolution of the aspirin component is tested by USP <711> with 0.1 N hydrochloric acid for 2 h followed by pH 6.8 phosphate buffer; the enteric coat must release not less than 80% of aspirin within 45 min after buffer shift. The vonoprazan fumarate component is assayed by HPLC against an external standard, with total degradation products not more than 1.0% under ICH Q1A(R2) conditions. The combination is intended for patients who require continued acid suppression during NSAID therapy; it is not a first-line gastric protection strategy. Stability studies are conducted under 21 CFR 211.166(a) with finished product stored at 30°C/65% RH for real-time data and 40°C/75% RH for accelerated data.
Accelerated stability data at 40°C/75% RH for 6 months according to ICH Q1A(R2) are used to justify a PVDC-based blister with 60 g/m² film gauge or an aluminum/aluminum cold-form blister when the tablet contains crospovidone as a disintegrant. Crospovidone wicks moisture and can increase tablet hardness drift if the water activity of the core exceeds 0.35 after compression. Coating is performed in a perforated pan with inlet air at 60–70°C and product temperature 38–42°C; a PVA-based film coat is applied to a weight gain of 3.0–4.0%. Tablets are then packed in HDPE bottles with a 1 g silica gel canister when the market requires 180-count bulk packaging. Moisture vapor transmission rate of the blister is tested by ASTM F1249-20; the limit for the complete pack is set at not more than 0.25 mg/day per cavity. This packaging combination reduces water uptake below 2.0% over 24-month real-time storage at 30°C/65% RH zone IV conditions. For injectable vials, the chosen closure system is validated for moisture and oxygen ingress at 25°C/60% RH over the assigned shelf life; bromobutyl closure residual moisture is controlled below 0.8% before stoppering.
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Vonoprazan fumarate pharma-grade active pharmaceutical ingredient is supplied as a crystalline fumarate salt for oral solid dosage forms—tablet, capsule, and granule—and, when additional microbial and particulate controls are imposed, for injectable product development. The molecular identity is 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine monofumarate. The fumarate salt carries CAS 1260141-27-2; the free base carries CAS 881681-00-1. The molecular formula is C17H16FN3O2S·C4H4O4, and the formula weight is 461.46 g/mol. The material is a white to off-white crystalline powder. The API is a weak base with pKa 9.06, which is higher than the pKa range of benzimidazole proton-pump inhibitors and supports accumulation in the acidic compartment of gastric parietal cells. The product is supplied as an oral-grade micronised model and an injectable-grade model; the injectable grade is differentiated by bacterial endotoxin, bioburden, and insoluble particulate release limits. The fumarate salt is not acid-labile, so enteric coating is not required for oral solid dosage forms. Specifications are structured around ICH Q3A, ICH Q3C, and ICH Q3D impurity and elemental impurity frameworks, with additional pharmacopoeial controls for the intended route of administration.
The oral-grade and injectable-grade models share the same chemical identity and solid-state control strategy but diverge in microbiological and particulate specifications. For direct compression and capsule filling, particle size distribution is the primary physical attribute governing content uniformity. For injectable development, bacterial endotoxin control is critical because sterilising-grade filtration does not remove endotoxin. The following sections define the specification boundaries, processing constraints, and comparative performance characteristics relevant to formulation into tablet, capsule, granule, and injection presentations.
Release of the API is controlled by a set of identity, purity, solid-state, and particulate attributes. The solid-state form is confirmed by X-ray powder diffraction against a qualified reference diffractogram. Because the fumarate salt can exist as more than one crystalline form, the XRPD pattern is used as a batch-to-batch consistency indicator. Differential scanning calorimetry and thermogravimetric analysis support form identification and solvate exclusion. Particle size distribution is measured by laser diffraction according to USP <429> or ISO 13320. For direct compression of low-dose tablet and capsule blends, d90 is typically controlled at or below 100 µm to reduce segregation risk under USP <905> uniformity of dosage units. The table below provides a representative specification framework; product-specific acceptance criteria should be taken from the active substance master file or a current pharmacopoeial monograph where adopted.
| Quality attribute | Reference method or standard | Representative acceptance criterion |
|---|---|---|
| Appearance | Visual inspection | White to off-white crystalline powder |
| Identification | IR, HPLC retention time | Positive against reference standard |
| Assay | Stability-indicating HPLC | 98.0–102.0% on anhydrous, solvent-free basis |
| Related substances | Stability-indicating HPLC | Total impurities ≤ 1.0%; unspecified individual ≤ 0.10% |
| Water content | Karl Fischer titration, Ph. Eur. 2.5.12 or USP <921> | ≤ 0.5% for oral-grade; injectable-grade limit tightened according to stability data |
| Residual solvents | ICH Q3C | Class 1 solvents absent; Class 2 below permitted daily exposure limits |
| Elemental impurities | ICH Q3D | Permitted daily exposure limits according to route of administration |
| Particle size | Laser diffraction, USP <429> | d90 ≤ 100 µm for direct-compression grade; certificate of analysis confirms distribution |
| Polymorph | XRPD | Match qualified reference diffractogram |
| Bacterial endotoxin | Ph. Eur. 2.6.14 or USP <85> | Limit derived from maximum total daily dose for injectable grade |
On production-scale twin-shell blenders at 10–50 kg, segregation of low-dose active from excipients is a recognised failure mode when d90 exceeds 100 µm and bulk density differences remain uncorrected. For capsule filling, powder flow is assessed by angle of repose and Carr index. If flowability is insufficient, dry granulation or roller compaction is introduced before encapsulation. The fumarate salt is soluble enough in acidic media to permit dissolution testing in pH 1.2, 4.5, and 6.8 media, but published data for a universal dissolution specification for this API is limited; method selection is made from product-specific development data.
Micronised material may show elevated surface energy and agglomeration. Jet-milled active can exhibit poor flow even when the particle size specification is met. For this reason bulk density, tapped density, and specific surface area are monitored alongside laser diffraction. If a direct-compression blend fails flow testing, the preferred corrective action is dry granulation rather than increased lubricant concentration, because excessive lubricant can retard dissolution. Roller compaction at moderate pressure may be used to densify the blend without converting the fumarate salt to an amorphous fraction; XRPD after compaction is used to confirm that the compact contains the intended crystalline form.
Vonoprazan fumarate inhibits gastric H+,K+-ATPase by reversible, K+-competitive binding to the enzyme. It does not require activation by parietal cell acid and does not form a covalent disulfide adduct. This mechanism differs from benzimidazole proton-pump inhibitors such as omeprazole and esomeprazole, which are acid-labile prodrugs requiring acid-catalysed rearrangement to a sulfenamide and covalent binding to cysteine residues. Because vonoprazan has pKa 9.06, it becomes protonated and concentrated in the acidic secretory canaliculus; the ionised form has a long residence time at the target. The result is rapid suppression of intragastric acidity after the first dose, with effect onset reported within hours, whereas conventional proton-pump inhibitors require repeated dosing over 3–5 days to approach maximal effect.
The metabolic route also reduces genotype-dependent variability. Vonoprazan is cleared principally by CYP3A4/5, with minor contributions from CYP2B6, CYP2C19, and CYP2D6. Benzimidazole proton-pump inhibitors are extensively cleared by CYP2C19, which is polymorphic. The comparative table below summarises the technical differences relevant to formulation and clinical use.
| Parameter | Vonoprazan fumarate | Omeprazole / esomeprazole |
|---|---|---|
| Mechanism | K+-competitive reversible H+,K+-ATPase inhibition | Covalent proton-pump inhibition |
| Acid activation required | No | Yes |
| pKa | 9.06 | Approximately 4.0–5.0 |
| Gastric acid stability | Stable; no enteric coating required | Acid-labile; enteric coating required |
| Onset of maximal acid suppression | Rapid; within hours after first dose | Delayed; 3–5 days |
| Elimination half-life | Approximately 7–8 h | Approximately 0.5–1.5 h |
| Primary metabolic clearance | CYP3A4/5; low CYP2C19 dependence | CYP2C19; high genotype dependence |
The differences in acid stability and target residence time influence formulation strategy. Vonoprazan fumarate can be formulated as an immediate-release tablet or capsule without an enteric polymer, reducing coating complexity and the risk of delayed release caused by pH-sensitive film failure. For granules, the API can be exposed to gastric pH without the degradation that would be expected for a proton-pump inhibitor. Published regulatory review documents support the rapid onset and prolonged half-life, but batch-specific release data are required for formulation design. Compared with histamine H2-receptor antagonists, vonoprazan fumarate acts directly on the terminal acid pump rather than blocking one of several parietal cell activation pathways; therefore acid suppression is not subject to meal-related or tolerance phenomena. This distinction is reflected in formulation requirements: vonoprazan is a low-dose high-potency API requiring tighter blend uniformity than many H2 antagonist tablet products.
For tablet and capsule development, direct compression and dry granulation are preferred unit operations for oral-grade API. The typical oral dose strengths are 10 mg and 20 mg. At these low doses, blend uniformity requires control of active particle size distribution and excipient bulk density. If a wet granulation step is used, the pH of the granulating fluid should be maintained in the acidic to weakly acidic range because deprotonation near pKa 9.06 can alter solubility and powder wetting. The fumarate salt is hygroscopic enough that storage in tightly closed containers is specified; exposure to moisture can increase water content above 0.5% and shift particle cohesion during high-shear mixing. For capsule formulations, the granulate or powder blend is filled after flowability assessment; if angle of repose exceeds 40°, roller compaction or glidant addition is introduced. These processing boundaries are derived from standard pharmaceutical manufacturing practice rather than product-specific failure studies; published data for vonoprazan fumarate in continuous direct compression lines is limited.
Injectable presentations require selection of a vehicle pH based on solubility and chemical stability data for the fumarate salt. Aseptic processing or terminal sterilisation is selected according to solution stability. Sterilising-grade filtration at 0.22 µm does not remove bacterial endotoxin; therefore the injectable-grade API must meet a bacterial endotoxin limit derived from the maximum total daily dose and the USP <85> or Ph. Eur. 2.6.14 method. Insoluble particulate matter is controlled by USP <788> or Ph. Eur. 2.9.19. Subvisible particle counts are measured by light obscuration; visual inspection is not sufficient for release. The injectable-grade model is also monitored for bioburden and specified microorganisms according to Ph. Eur. 5.1.4 or USP <1111>. Published data for vonoprazan fumarate injectable formulations is limited in public compendial literature; therefore each formulation must generate its own terminal sterilisation or aseptic validation data under ICH Q8.
The specification boundaries for oral-grade and injectable-grade vonoprazan fumarate are not identical. Oral-grade material is released with routine microbial limits and water content; injectable-grade material carries additional bacterial endotoxin, bioburden, and insoluble particulate specifications. The change in route also changes the permitted daily exposure for elemental impurities under ICH Q3D, because parenteral bioavailability is higher and the exposure route bypasses first-pass metabolism. Residual solvent limits under ICH Q3C remain applicable to both grades, but Class 2 solvents used in the final crystallisation must be reduced to levels suitable for the highest intended daily dose.
For impurity control, ICH Q3A thresholds apply to both grades. At a maximum daily dose of 20 mg/day, the reporting threshold is 0.05%, the identification threshold is 0.10%, and the qualification threshold is 0.15%. Impurities exceeding the qualification threshold must be toxicologically qualified or reduced to an acceptable level. Because the injectable route can alter impurity exposure, the same thresholds may be supplemented by parenteral safety assessments. The stability-indicating HPLC method must resolve oxidative, acid, base, thermal, and photolytic degradation products generated under ICH Q1A forced degradation conditions. The pyrrole ring and sulfonyl function are oxidation-prone; the API is not blended with strong oxidising agents unless compatibility data support that combination.
Long-term storage is typically evaluated at 25°C/60% RH and accelerated storage at 40°C/75% RH, with retest intervals assigned from the resulting data. Packaging for the API is a tightly closed, light-resistant container. Protection from moisture is required because water uptake above the specification can alter powder flow, compressibility, and solid-state stability. Photostability is assessed according to ICH Q1B; if light exposure produces degradation, amber glass or opaque packaging is specified. The fumarate salt is not combined with strongly alkaline granulating agents because free base generation can alter particle cohesion and dissolution. The final API release is therefore based not on a single test but on the combined profile of identity, assay, related substances, water content, residual solvents, elemental impurities, particle size, and polymorphic form.
