| HS Code | 585632 |
| Product Name | Repaglinide Pharma Grade API |
| Api Substance | Repaglinide |
| Grade Type | Pharma Grade |
| Applicable Forms | Tablet, Capsule, Granule, Injection |
| Administration Route | Oral and Injectable |
| Chemical Formula | C27H36N2O4 |
| Molecular Weight | 452.59 g/mol |
| Cas Number | 135062-02-1 |
| Solubility Profile | Practically insoluble in water; soluble in acetonitrile, methanol, and dichloromethane |
| Therapeutic Category | Meglitinide class antidiabetic agent |
As an accredited Repaglinide 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 double-lined HDPE drums with sealed inner bags, labelled for oral and injectable pharmaceutical grade use. |
| Container Loading (20′ FCL) | One 20′ FCL loaded with sealed, palletized drums of Repaglinide Pharma Grade API, safely secured for oral and injectable pharmaceutical use. |
| Shipping | This pharmaceutical-grade Repaglinide API is shipped in sealed, inert containers to preserve purity and stability. Transport complies with international safety regulations, with temperature-controlled options available. Handling requires protective equipment and secure packaging to prevent contamination. Deliveries include documentation for customs, research, or manufacturing use only, not for direct patient consumption. |
| Storage | Store in a tightly closed container in a cool, dry place, protected from light, moisture, and heat. Maintain storage temperature between 15–30°C, away from incompatible substances and ignition sources. Ensure adequate ventilation in storage areas, keep container sealed when not in use, and follow pharmacopeial guidelines for pharmaceutical API handling. |
| Shelf Life | Shelf life: 24 months from manufacture when stored in original container, below 25°C, protected from light and moisture. |
Direct compression of repaglinide into monolithic tablet cores is controlled less by label dose and more by blend uniformity risk across 0.5 mg, 1 mg, and 2 mg strengths. The active pharmaceutical ingredient is present at approximately 0.25% to 2.0% w/w of final core mass, assuming a core weight of 90–130 mg. A first-stage geometric dilution with meglumine and poloxamer 188 is passed through a 600 µm sieve before addition to microcrystalline cellulose, anhydrous dibasic calcium phosphate, maize starch, and polacrilin potassium. Final blending in a tumble blender at 15–25 rpm for 20–40 min is used because prolonged blending can demix the low-dose active from larger calcium phosphate particles. Compression on a rotary tablet press with B-tooling operates at 8–15 kN, target hardness 5–8 kp, friability ≤1.0% per USP 1216, disintegration ≤15 min per USP 701, and dissolution under USP 711. Multi-source tablet specifications commonly set Q ≥75% at 30–45 min in 900 mL of surfactant-containing or pH 6.8 phosphate buffer using a paddle apparatus at 50 rpm. Overlubrication with magnesium stearate above 1.5% w/w is avoided because the resultant hydrophobic layer retards aqueous penetration into the polacrilin potassium-disintegrated matrix. Release controls include USP 905 for uniformity of dosage units, ICH Q3A impurity reporting at 0.10%, ICH Q3B for degradation products, ICH Q3C for residual solvents, ICH Q3D for elemental impurities, ICH Q1A stability at 25°C/60% RH long term and 40°C/75% RH accelerated, and 21 CFR 210/211. Terminal finished products are uncoated or film-coated immediate-release tablets in 0.5 mg, 1 mg, and 2 mg strengths, supplied in PVC/aluminium blisters or HDPE bottles with desiccant.
Where direct compression of the 0.5 mg strength fails blend uniformity acceptance under USP 905, production shifts to an aqueous wet granulation route. Repaglinide is suspended or pre-dissolved with meglumine and poloxamer 188 in purified water and granulated with povidone as binder. The wet mass is dried in a fluid-bed dryer at 45–55°C inlet air, milled through a 0.8 mm screen, and lubricated in a low-shear blender. This route improves drug distribution across the granule fraction but increases residual moisture sensitivity and batch processing time. The process decision is governed by blend uniformity data from three sampling ports, not by fixed formula preference. When wet granulation is used, the finished core must still meet the same friability, disintegration, and dissolution endpoints as the direct compression version; the terminal tablet does not change, but the granule morphology and internal porosity are measurably different.
In repaglinide/metformin hydrochloride fixed-dose combinations, repaglinide is segregated into a separate layer rather than blended directly into the high-dose metformin granulation. The repaglinide addition ratio is approximately 0.05% to 0.5% w/w relative to total tablet mass, corresponding to registration strengths of 1 mg/500 mg, 2 mg/500 mg, 1 mg/1000 mg, and 2 mg/1000 mg. Metformin HCl is granulated with purified water or an aqueous binder to a loss-on-drying endpoint of ≤2.0% w/w, then blended with disintegrant and glidant. The repaglinide layer is manufactured as a low-dose premix with meglumine and poloxamer 188 to maintain intimate contact between the active and its solubilizing carriers. Bilayer compression is performed with first-layer tack at 8–12 kN and second-layer main compression at 18–28 kN; in-process controls monitor interlayer hardness and visual separation after storage. The dominant failure mode at the interface is moisture migration from metformin granules into the repaglinide layer after aqueous film coating, which can alter the low-dose layer dissolution signature. Metformin granules are therefore conditioned to a water activity below 0.4 before compression, and coating pan exhaust temperature is kept below 55°C. Dissolution testing requires separate quantification of the high-dose and low-dose actives. Repaglinide release is usually measured with paddle at 50 rpm in 900 mL pH 6.8 phosphate buffer containing 0.1–0.5% surfactant, while metformin release uses 0.1 N HCl or pH 6.8 buffer according to registered methods. Compliance includes USP 711, Ph. Eur. 2.9.3, USP 905, ICH Q3B for degradation products, ICH Q3D, and 21 CFR 314.94 for fixed-dose combination applications. Terminal products are film-coated bilayer or compress-coated tablets supplied in cold-form aluminium/aluminium blisters to limit moisture ingress.
Clinical trial blinding of repaglinide tablets relies on capsule over-encapsulation rather than direct powder filling. This segment is not a primary commercial capsule market for repaglinide; it arises when a licensed tablet must be masked for comparator arms without altering the release profile. The addition ratio is fixed by the original tablet strength: 0.5 mg, 1 mg, or 2 mg repaglinide per capsule. A backfill of lactose monohydrate or microcrystalline cellulose is used to achieve a final capsule fill weight of 150–220 mg in size 3 or 4 hard gelatin or hypromellose shells. Production operations include sorting and weight-checking of source tablets to exclude broken cores, dust removal, filling with a semi-automatic capsule machine, and 100% weight sorting on a checkweigher. Direct encapsulation of repaglinide active powder is avoided because low-dose segregation risk increases and the original dissolution profile would be lost. The filled capsules are stored in light-resistant, child-resistant containers with desiccant. Compliance is governed by 21 CFR 312 for investigational product handling, EU GMP Annex 13 for clinical trial materials, USP 905 for uniformity, USP 701 for disintegration, and ICH Q1A for stability over the intended clinical duration. Terminal finished products are blinded capsule units containing a repaglinide tablet or matching placebo for single-center and multi-center clinical supplies.
Because intact-tablet swallowing can be unreliable for geriatric or dysphagic patients, repaglinide may be prepared as an oral powder or granule in single-dose sachets. Published regulatory approvals for this exact presentation are limited in major markets; use is often linked to hospital pharmacy compounding or unlicensed preparation. The API addition ratio is typically 0.05% to 0.4% w/w when a 0.5 mg or 1 mg dose is delivered in a 500–1000 mg fill of lactose monohydrate, pregelatinized maize starch, and mannitol. Granulation is performed in a high-shear mixer with povidone K30 binder solution, dried in a fluid-bed dryer at 45–55°C inlet air, milled through a 1.0 mm screen, and blended with sodium starch glycolate and colloidal silicon dioxide. Because the active fraction is low, blend uniformity must be verified before filling. Fill weight variation is held at ±5% of target, and the cumulative 90% undersize particle diameter is kept below 500 µm by laser diffraction. Sachet filling is performed on auger or volumetric fillers with inert gas flushing to reduce moisture pickup. Compliance for compounded use includes USP 795 for non-sterile compounding, USP 1174 for powder flow, USP 905 for uniformity, ICH Q3B for degradation products, and ICH Q3D for elemental impurities. Terminal products are single-dose stick packs or sachets labeled for reconstitution into water or sprinkling onto soft food; reconstituted material must be used immediately and is not suitable for prolonged aqueous storage because of repaglinide solubility limitations.
| Downstream segment | API addition ratio window | Representative production equipment | Terminal product type |
|---|---|---|---|
| Immediate-release tablet | 0.25–2.0% w/w of core mass | B-tooling rotary press, tumble blender | 0.5 mg, 1 mg, 2 mg tablets |
| Bilayer FDC with metformin HCl | 0.05–0.5% w/w of total tablet mass | Bilayer rotary press, high-shear granulator | 1/500 mg, 2/500 mg, 1/1000 mg, 2/1000 mg film-coated tablets |
| Clinical trial over-encapsulation | 0.5–2 mg repaglinide per capsule | Semi-automatic capsule filler, checkweigher | Size 3 or 4 blinded capsules containing intact tablets |
| Oral powder/sachet | 0.05–0.4% w/w of fill weight | High-shear mixer, fluid-bed dryer, auger filler | Unit-dose sachets 500–1000 mg |
| Parenteral investigational | 0.1–1.0 mg/mL | Sterile filtration line, lyophilizer | Investigational IV solution or lyophilized powder |
Published data for intravenous repaglinide in regulatory submissions are limited; the API is not approved as a commercial injectable product. In a parenteral development setting, repaglinide is dissolved in a co-solvent or cyclodextrin system because its aqueous solubility is low at physiological pH. The formulation addition ratio for a research-grade intravenous solution is generally 0.1 mg/mL to 1.0 mg/mL, achieved with 10–30% v/v polyethylene glycol 400 or 10–20% w/v hydroxypropyl-β-cyclodextrin, often co-solubilized with 0.1–1.0% poloxamer 188 or polysorbate 80. Preparation is carried out in a nitrogen-purged vessel with light protection, followed by pH adjustment to 7.0–7.4 and filtration through a 0.22 µm sterilizing-grade filter in a Grade A/B cleanroom. Lyophilization may be used to improve solid-state stability when the solution is held between dosing sessions; the lyophilized cake is reconstituted with water for injection to the same concentration. Residual solvent levels are controlled according to ICH Q3C, sterility assurance under EU GMP Annex 1 and 21 CFR 210/211, and stability under ICH Q1A with accelerated storage at 5°C ± 3°C for liquid formulations. Terminal product types are investigational intravenous solutions and lyophilized powders for reconstitution used in absolute bioavailability, toxicokinetic, or in vitro dissolution mechanism studies; these items are not marketed therapeutic injections.
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Repaglinide Pharma Grade API for Tablet / Capsule / Granule / Injection, Oral & Injectable is a meglitinide-type prandial insulin secretagogue supplied as a white to off-white crystalline powder. No manufacturer-specific model number is assigned under pharmacopoeial nomenclature; the substance is identified by its compendial name and CAS registration. The chemical identity is (S)-2-ethoxy-4-[2-[[3-methyl-1-[2-(piperidin-1-yl)phenyl]butyl]amino]-2-oxoethyl]benzoic acid, with molecular formula C27H36N2O4, relative molecular mass 452.6 g/mol, and CAS number 135062-02-1. The molecule contains a carboxylic acid function and a piperidinyl amide side chain; it is not a sulfonylurea. The compendial description classifies repaglinide as practically insoluble in water, which makes particle-size distribution, wetting, and dissolution rate critical manufacturing variables for oral solid dosage forms. The API is released against current Ph. Eur. and USP monograph tests for identification by infrared absorption spectrophotometry and HPLC retention time, specific optical rotation using Ph. Eur. 2.2.7 / USP <781>, related substances by HPLC using the compendial liquid chromatography system under Ph. Eur. 2.2.29 / USP <621>, water content by Karl Fischer titration using Ph. Eur. 2.5.32 / USP <921>, residue on ignition, and assay on the anhydrous basis. The product is intended for tablet, direct capsule filling, granule manufacture, and investigational injectable development. Granule material may serve as an intermediate for compression or as a finished single-dose granule presentation after sachet filling. Analytical release data are generated under cGMP laboratory controls consistent with 21 CFR 211 and, where applicable, ISO/IEC 17025 laboratory quality systems. The primary labeled therapeutic use is meal-related reduction of postprandial glucose excursions in adults with type 2 diabetes mellitus; this document describes pharmaceutical processing boundaries rather than therapeutic recommendations.
Low-dose meglitinide formulations require tight control of particle size because blend uniformity is the first processing barrier on a manufacturing line. Laser diffraction testing according to Ph. Eur. 2.9.31 / USP <429> is used to control d10, d50, and d90 after micronization. The exact numerical limits are product-specific and are not fixed in the compendial repaglinide monograph; they are established in the drug product quality target product profile and justified by dissolution data. In practice, micronized repaglinide API is cohesive and can form agglomerates during storage or after silo transfer. On a 10-station rotary tablet press with a gravity feed frame, powder with a Carr index above 20% or a Hausner ratio above 1.25 frequently produces weight variation in excess of 5% relative standard deviation when turret speed exceeds 30 rpm. Direct compression is therefore generally limited to formulations that have been pre-blended with a free-flowing soluble or insoluble diluent and optionally passed through a co-mill or sieve with a mesh aperture in the 600–1000 µm range. Capsule filling on an automatic dosator or tamping-pin capsule machine is also sensitive to plug retention and fill-weight control; low bulk density and high cohesion cause dose-weight drift during run cycles. Content uniformity of the finished tablet or capsule is assessed by USP <905> / Ph. Eur. 2.9.40, with an acceptance value not greater than 15.0 for single-dose content uniformity. Dissolution is evaluated by USP <711> / Ph. Eur. 2.9.3 using a product-specific medium that may include a surfactant to discriminate differences in particle size and polymorphic state. The low aqueous solubility of repaglinide is the main reason the particle-size distribution is considered a critical material attribute rather than a routine quality variable.
Wet granulation can be used to overcome poor flow and segregation, but water contact introduces the risk of partial API dissolution, polymorphic conversion, or recrystallization as a different crystalline habit. Repaglinide contains a carboxylic acid group; its aqueous solubility is pH-dependent, and the use of an alkaline binder solution can ionize and solubilize a fraction of the API. During drying, the dissolved fraction may redeposit on excipient surfaces or form bridges that change granule porosity, tablet hardness, and dissolution. In a high-shear granulator with working capacity from 600 L to 1200 L, impeller speed and chopper speed are commonly maintained in the 200–400 rpm and 1500–3000 rpm ranges, respectively, but the specific energy input must be tied to torque endpoint rather than fixed speed alone. Granule moisture is monitored by loss-on-drying or near-infrared reflectance and is usually kept in the 1–4% range for low-dose tablet granulations; however, the repaglinide-specific thermal and moisture window must be confirmed by differential scanning calorimetry, thermogravimetric analysis, and forced degradation studies under ICH Q1A. Drying in a fluid-bed dryer with inlet air temperature between 50 °C and 70 °C is typical for heat-sensitive prandial secretagogues, but published data for repaglinide-specific thermal degradation thresholds is limited. If wet granulation is not viable, dry granulation by roller compaction may be used. Ribbon density and granulate fines below 150 µm are controlled because excessive fines can re-introduce segregation and weight variation. The granules are then compressed or filled into capsules after lubrication with magnesium stearate; lubricant concentration below 1.0% w/w is common to avoid excessive mixing and subsequent dissolution slowing.
Injectable development with repaglinide is constrained by the absence of approved parenteral formulations in major ICH regions. The free acid is poorly soluble in aqueous media at physiological pH, so a simple isotonic solution is not feasible for clinical parenteral administration. Feasible formulation approaches may include pH adjustment with a buffering species, cosolvent systems, cyclodextrin complexation, or conversion to a more soluble salt or prodrug. Published data for this specific injectable configuration is limited, and the developer is responsible for generating solution-state stability data under ICH Q1A and photostability data under ICH Q1B. If a parenteral formulation is contemplated, endotoxin control becomes mandatory; the compendial repaglinide monograph does not automatically impose a parenteral endotoxin limit, and the limit must be derived from the maximum daily injectable dose using USP <85> / Ph. Eur. 2.6.14. Sterile filtration of a low-solubility formulation must account for filter membrane compatibility, adsorption losses, and precipitation risk. Elemental impurity limits also change from oral to parenteral route because the permitted daily exposure values in ICH Q3D may be lower for injectable products due to different bioavailability assumptions. The finished injectable product would also be subject to particulate matter testing according to USP <788> or USP <787> for subvisible particles. These route-dependent requirements are not merely analytical; they influence the decision to use a lyophilized or solution presentation and the selection of primary packaging.
Residual solvent control follows ICH Q3C and is verified by headspace gas chromatography according to USP <467> and Ph. Eur. 5.4. Class 1 solvents such as benzene are controlled at the strict concentration limits of the guideline, while Class 2 solvents are summed according to the ICH Q3C option selected in the dossier. Class 3 solvents with a 50 mg/day permitted daily exposure may be controlled by a loss-on-drying method or by routine gas chromatography if the manufacturing process is changed. Elemental impurity risk assessment is performed according to ICH Q3D and the monographs USP <232>/<233> and Ph. Eur. 2.4.20. The oral and injectable routes have different permitted daily exposure values; cadmium, lead, arsenic, and mercury limits for an injectable repaglinide formulation are generally lower than those for oral tablets on a per-day basis. The control architecture for oral solid dose manufacture should identify potential elemental residues from catalysts or process vessels, while the injectable route must also consider container closure leachables and the aqueous processing environment. Analysis is performed by inductively coupled plasma–mass spectrometry after closed-vessel acid digestion. The following table summarizes route-dependent attributes that differ between oral and injectable development.
| Control attribute | Oral solid dose basis | Injectable development basis | Test methodology / equipment |
|---|---|---|---|
| Residual solvents | ICH Q3C limits; USP <467> / Ph. Eur. 5.4 | Same ICH Q3C limits plus any solvents introduced in lyophilization or cosolvent formulation | Headspace gas chromatography |
| Elemental impurities | Oral daily intake PDEs per ICH Q3D; USP <232>/<233> | Parenteral daily intake PDEs per ICH Q3D; sometimes lower by bioavailability-related factor | ICP-MS after closed-vessel digestion |
| Bacterial endotoxins | Not a routine oral monograph parameter | Required for parenteral finished product; dose-based limit from USP <85> / Ph. Eur. 2.6.14 | Kinetic chromogenic limulus amebocyte lysate |
| Particulate matter | Controlled by visual inspection and tablet friability | Controlled by USP <788> / Ph. Eur. 2.9.19 for finished injection | Light obscuration and microscopic particle count |
| Particle size distribution | Controlled for blend uniformity and dissolution; d10/d50/d90 product-specific | Controlled for dispersibility or complete dissolution before sterile filtration | Laser diffraction Ph. Eur. 2.9.31 / USP <429> |
| Water content | Controlled to prevent powder flow defects and hydrolysis; KF limit product-specific | Controlled at lower residual moisture if lyophilized cake is manufactured | Karl Fischer Ph. Eur. 2.5.32 / USP <921> |
Repaglinide differs structurally from sulfonylureas because it lacks an arylsulfonylurea pharmacophore. The molecule binds the SUR1 subunit of the pancreatic beta-cell ATP-sensitive potassium channel and promotes insulin secretion, but the binding site and kinetic behavior differ from sulfonylurea drugs. The clinical label uses a meal-related dosing schedule, whereas selected sulfonylureas have longer duration and different administration requirements. Differences from nateglinide are also material at the chemical level. Nateglinide is a D-phenylalanine derivative with molecular formula C19H27NO3 and relative molecular mass 317.43 g/mol, while repaglinide is a carbamoylmethyl benzoic acid derivative with relative molecular mass 452.6 g/mol. Both are meglitinide-type short-acting secretagogues, but their metabolic pathways differ; repaglinide is metabolized mainly by CYP2C8 and CYP3A4, while nateglinide is metabolized primarily by CYP2C9 and CYP3A4. Glibenclamide, a representative sulfonylurea, has molecular formula C23H28ClN3O5S and relative molecular mass 494.0 g/mol. These differences influence drug-interaction boundaries and product specifications rather than tablet press conditions. From a manufacturing perspective, the most important distinction is the low unit dose of repaglinide tablets, commonly 0.5 mg, 1 mg, or 2 mg. Such low doses require high-precision blending, strict content uniformity control, and avoidance of spray-dried or wet-granulated excipient carryover that can create blend assay bias.
| Attribute | Repaglinide | Nateglinide | Glibenclamide |
|---|---|---|---|
| Structural class | Carbamoylmethyl benzoic acid derivative | D-phenylalanine derivative | Sulfonylurea |
| Molecular formula | C27H36N2O4 | C19H27NO3 | C23H28ClN3O5S |
| Relative molecular mass | 452.6 g/mol | 317.43 g/mol | 494.0 g/mol |
| Sulfonylurea moiety | Absent | Absent | Present |
| Primary metabolic pathway | CYP2C8 and CYP3A4 | CYP2C9 and CYP3A4 | CYP2C9 |
| Secretion profile | Short-acting prandial secretagogue | Short-acting prandial secretagogue | Longer-acting sulfonylurea |
| Approximate terminal half-life | 1 h | 1.5 h | 10 h |
Storage of repaglinide pharma grade API in sealed double polyethylene bags inside a fiber drum with desiccant is consistent with maintaining water content below product-specific limits when stored at or below 25 °C and below 60% relative humidity. Pre-drying should be considered if the powder is exposed to relative humidity above 60% before direct compression or capsule filling; however, the drying temperature and residual moisture target must be verified against the supplier’s stability data and forced degradation profile. The substance should not be combined with strong oxidizing agents unless compatibility has been established, because organic API oxidation can generate unspecified impurities that exceed pharmacopoeial related-substance limits. For injectable development, single-use containers and reduced headspace are preferred because repetitive opening of an API container may raise water activity and microbial bioburden. The material is not intended for direct patient administration as a bulk API; it must be formulated and released as a finished drug product according to the applicable marketing authorization requirements in the target region.
