| HS Code | 753371 |
| Product Name | Linagliptin Pharma Grade API |
| Chemical Name | 8-[(3R)-3-aminopiperidin-1-yl]-7-(but-2-yn-1-yl)-3-methyl-1-[(4-methylquinazolin-2-yl)methyl]-3,7-dihydro-1H-purine-2,6-dione |
| Cas Number | 668270-12-0 |
| Molecular Formula | C25H28N8O2 |
| Molecular Weight | 472.54 g/mol |
| Api Grade | Pharma Grade API |
| Physical Form | White to yellowish crystalline powder |
| Solubility | Slightly soluble in water; soluble in DMSO and methanol |
| Purity | ≥98.0% (HPLC) |
| Storage Conditions | Store in tightly closed container in a cool, dry place; protected from light and moisture |
| Shelf Life | 24 months when stored under recommended conditions |
| Applications | Used as an active pharmaceutical ingredient in tablets, capsules, granules, and oral/injectable formulations |
| Therapeutic Category | Dipeptidyl peptidase-4 (DPP-4) inhibitor; antihyperglycemic agent |
| Mechanism Of Action | Inhibits DPP-4 enzyme, increasing active incretin levels and regulating blood glucose |
| Route Of Administration | Oral and injectable compatibility |
| Regulatory Status | Pharmaceutical grade; suitable for formulation development |
As an accredited Linagliptin 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 | Pharma-grade Linagliptin API packaged in sealed double polyethylene-lined drums, 25 kg net each, for oral and injectable formulations. |
| Container Loading (20′ FCL) | 20′ FCL loading: Linagliptin API in sealed drums/pallets, weight optimized, safe, dry, ventilated container. |
| Shipping | Linagliptin Pharma Grade API is shipped in sealed, moisture-proof containers to maintain purity and stability. Temperature-controlled logistics prevent degradation, ensuring suitability for oral and injectable dosage forms. All shipments comply with international pharmaceutical regulations, with tamper-evident packaging and full documentation for safe, traceable delivery worldwide. |
| Storage | Store Linagliptin Pharma Grade API in a tightly sealed, original container under controlled room temperature (20–25°C). Protect from light, moisture, and excessive heat. Keep in a cool, dry, well-ventilated area away from incompatible substances. Ensure container remains closed when not in use to preserve stability, potency, and quality for oral and injectable formulations. |
| Shelf Life | Shelf life: 24 months from date of manufacture when stored as directed in original container. |
Linagliptin single-entity tablets are manufactured to deliver 5 mg of the DPP-4 inhibitor per dosage unit, which places the API in the low-dose classification where blend uniformity rather than chemical potency becomes the principal release risk. The labelled tablet core for the reference product includes mannitol, pregelatinized starch, maize starch, copovidone, and magnesium stearate, with a film coat containing hypromellose, titanium dioxide, talc, macrogol, and pigment grade iron oxides. Based on typical core masses between 200 mg and 300 mg, the nominal API load is 1.7% w/w to 2.5% w/w. In production-scale equipment, the failure mode observed with this type of formulation is not dissolution slowdown but fines migration during blender discharge and feed-frame aeration on a rotary tablet press. A pre-blend of linagliptin with 5–10% of the total mannitol charge is therefore run through a comill or screen to break agglomerates before the main mixing step. The final blend is prepared in an IBC bin blender at fill volumes between 60% and 80%; if fill volume drops below 50%, the powder bed may fluidize at tumble speeds above 12 rpm, causing particle size stratification. Compression is performed on a rotary tablet press with a force feeder, where die fill uniformity is maintained by press speed limits typically below 60 rpm for low-dose blends unless forced feeder agitator speed is independently validated. Tablet hardness is maintained in a development range corresponding to tensile strength above 1.5 MPa, and friability testing follows USP <1216> or Ph. Eur. 2.9.7. Film coating is applied in a perforated pan under controlled spray rate and bed temperature to limit core moisture ingress, with coating endpoint confirmed by weight gain and visual uniformity. Release testing includes content uniformity under USP <905> and Ph. Eur. 2.9.40, dissolution under USP <711> or Ph. Eur. 2.9.3, and in-process blend uniformity under 21 CFR 211.110. The finished dosage form is an oral immediate-release film-coated tablet.
In the linagliptin/metformin fixed-dose combination, the approved strength ratios are 2.5 mg linagliptin with 500 mg, 850 mg, or 1000 mg metformin hydrochloride per tablet. The linagliptin component therefore represents less than 0.5% w/w of total core mass in the 1000 mg metformin strength and still below 1% w/w in the 500 mg strength once granulation excipients are included. Metformin HCl is freely water-soluble and exhibits poor compactibility; a common production route is aqueous or non-aqueous high-shear wet granulation of metformin with povidone or hydroxypropyl cellulose, followed by fluid-bed drying to a loss-on-drying endpoint below 2.0% and dry milling through a conical mill to a granule D50 between 150 µm and 300 µm. Linagliptin is then added in the extragranular phase as a trituration with filler, because intragranular addition exposes the micronized API to granulation moisture and subsequent drying heat, potentially altering particle size distribution and dissolution. The dominant process conflict is density-driven segregation: metformin granules have a high bulk density while micronized linagliptin remains low-density and electrostatically active. Final blending time must therefore be bounded by blend uniformity studies; over-blending beyond the validated interval can re-segregate API fines into the upper blender zone, producing content uniformity outliers under USP <905>. Lubrication with magnesium stearate at 0.5–1.0% w/w is time-limited because metformin granule surfaces are abrasive and over-lubrication reduces tablet hardness and slows dissolution. Compression uses oval or oblong tooling with precompression to remove air from the high-mass tablet; film coating is applied to reduce surface damage and control moisture uptake during storage. Dissolution testing under USP <711> is run with media justified against active ingredient solubility and the release mechanism of the metformin component. Degradation products are controlled under ICH Q3B, residual solvents under USP <467> or Ph. Eur. 2.4.24, and manufacturing records are governed by 21 CFR 211.110. The terminal product is an oral fixed-dose combination film-coated tablet.
Hard capsule filling of linagliptin at the 5 mg strength shifts the manufacturing bottleneck from compression physics to powder flow and fill weight reproducibility under low fill weight conditions. For a size 3 capsule with a fill mass between 150 mg and 250 mg, the linagliptin load is 2.0% w/w to 3.3% w/w; if a smaller size 4 capsule is used, the drug load rises toward 5.0% w/w but the fill mass window becomes narrower. The process route may use either a direct powder blend or a roller-compacted granule, with the choice governed by the Carr index and flow function coefficient of the selected filler. Encapsulation is carried out on an automatic capsule filling machine with dosator or tamping-pin dosing; fill weight is monitored by checkweigher at intervals defined by the validation protocol, and metal detection is performed before final packaging. Shell material selection introduces a stability boundary: gelatin shells are processed under controlled humidity, typically 35–65% RH, whereas HPMC shells are selected when the blend or granule has a low-moisture transfer demand. At relative humidity above 60%, pre-drying of the API/excipient blend may be required to prevent plug formation in the dosing station. Quality release includes mass variation under Ph. Eur. 2.9.5, content uniformity under USP <905>, dissolution under USP <711>, and residual solvent control under ICH Q3C if a granulation solvent is used. The terminal product is an oral immediate-release hard capsule.
When dry granulation is selected for linagliptin at the 5 mg strength, the unit formula commonly includes binder at 2–5% w/w, disintegrant at 3–8% w/w, lubricant at 0.5–1.5% w/w, and filler to 100% w/w, with the API load retained near 1–5% w/w depending on the sachet or dosage-unit fill mass. The purpose of this route is to produce a granule intermediate for later encapsulation or compression without exposing linagliptin to moisture or solvent. Roller compaction is performed on a roller compactor with roll pressure, roll gap, and rotor speed set to achieve ribbon solid fraction between 0.6 and 0.8; ribbons outside this range either generate excessive fines that re-segregate the low-dose API or produce hard granules that resist disintegration. The milled granule is screened to a target particle size range, often 20–30 mesh, and then blended with extragranular disintegrant and lubricant in a bin blender; total final blend time is limited because lubricant over-distribution reduces tablet tensile strength and capsule dissolution. At ambient relative humidity above 50%, powder sticking on the roller surfaces may require dehumidification of the processing suite. No finished product monograph for linagliptin oral granules exists in USP–NF or Ph. Eur., so release is based on in-house specifications aligned with ICH Q6A, 21 CFR 211.110, and where applicable Ph. Eur. 2.9.5 or USP <905> after conversion into the final dosage unit. The terminal product is either an oral single-dose granule sachet, an oral capsule, or a compressed tablet depending on the downstream filing route.
Fixed-dose triple combination tablets containing linagliptin 5 mg, empagliflozin 10 mg or 25 mg, and metformin hydrochloride extended-release 1000 mg present a formulation problem in which two low-dose APIs must remain uniformly distributed while the release-controlling polymer matrix of the metformin component is protected from compression damage. The linagliptin drug load is below 0.5% w/w, and the empagliflozin load is below 2% w/w in an extended-release core that may exceed 1000 mg before film coating; both low-dose actives therefore require separate pre-blends before addition to the main granulation. The metformin extended-release component is produced by wet granulation with a release-controlling matrix former, followed by drying and milling to granules with controlled particle size. Compression is performed on a rotary tablet press at lower press speed and with precompression to avoid crushing the extended-release polymer network; tablet hardness is balanced against the dissolution mechanism of the metformin component. Dissolution testing must cover all three actives and is typically performed with USP <711> using multimedia or pH-shift protocols with HPLC quantification to avoid interference among linagliptin, empagliflozin, and metformin. Content uniformity follows USP <905> and Ph. Eur. 2.9.40. Degradation product limits are set under ICH Q3B, and in-process monitoring follows 21 CFR 211.110. The terminal product is an oral fixed-dose triple combination extended-release film-coated tablet.
No commercial linagliptin injection is listed in the FDA Orange Book or EMA Article 57 database as of the current reporting period, and no USP–NF or Ph. Eur. monograph for linagliptin injection has been established. Published data for this specific configuration is limited; therefore a validated formulation addition ratio cannot be assigned from compendial or regulatory sources. A calculation template for an exploratory 0.1% w/v solution, equivalent to 1 mg/mL, yields a 1:1000 API-to-vehicle ratio, but this is not a release specification and must not be read as an approved formula. If a parenteral route is pursued in an investigational setting, the formulation approach must first resolve the pH-dependent aqueous solubility of linagliptin and its tendency to adsorb to sterilizing-grade membrane filters. Aseptic processing would be required under EU GMP Annex 1 (2022) with Grade A/ISO 5 filling zones, supported by environmental monitoring under ISO 14644-1 and filtration process controls under 21 CFR 211.113. The finished dosage form would be either a solution for injection or a lyophilized cake for reconstitution, with release testing including USP <71> sterility, USP <85> bacterial endotoxins, USP <788> particulate matter, and stability under ICH Q1A. Process boundaries include defined hold times before filtration, filter material compatibility, and residual moisture limits if lyophilized. This scenario defines the regulatory boundary for an injectable presentation; it does not assert that an injectable linagliptin product is commercially available.
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Linagliptin Pharma Grade API for Tablet / Capsule / Granule / Injection, Oral & Injectable is a white to slightly yellowish crystalline powder belonging to the dipeptidyl peptidase-4 inhibitor class. The molecular formula is C25H28N8O2, the CAS number is 668270-12-0, and the relative molecular mass is 472.54 g/mol. In commercial oral monotherapy, linagliptin is used at 5 mg once daily; the low unit dose makes particle size distribution, bulk density, polymorph identity, and blend uniformity more critical than in higher-dose direct compression formulations. The API is manufactured under ICH Q7 GMP conditions and is commonly released against a specification that includes HPLC assay in the range 98.0–102.0% on the anhydrous and solvent-free basis, total related substances not exceeding 0.5%, any unspecified individual impurity not exceeding 0.10%, residual solvents per USP <467>, water content by Karl Fischer ≤0.5%, sulfated ash ≤0.1%, and elemental impurities per ICH Q3D using USP <232>/<233>. Linagliptin has limited aqueous solubility, moderate lipophilicity, and oral bioavailability of approximately 30%; protein binding is high and non-linear at therapeutic concentrations. Because only about 5% of an oral dose is eliminated unchanged by the kidney, the product is distinguished from several DPP-4 inhibitors by the absence of mandatory renal dose adjustment. A micronized grade with Dv90 controlled to ≤20 µm is generally requested for direct compression, while a non-micronized grade may be acceptable for wet granulation if the granulation process provides sufficient redistribution of the active substance.
Within the DPP-4 inhibitor class, linagliptin differs from sitagliptin, saxagliptin, vildagliptin, and alogliptin in dose size, elimination route, and terminal half-life. Sitagliptin is administered at 100 mg once daily, saxagliptin at 5 mg once daily, vildagliptin at 50 mg twice daily, and alogliptin at 25 mg once daily. Linagliptin at 5 mg once daily has a terminal half-life greater than 100 h, whereas sitagliptin, saxagliptin, vildagliptin, and alogliptin have terminal half-lives of approximately 12.4 h, 2.5 h, 2.8 h, and 21 h respectively. The low linagliptin dose combined with its primarily biliary excretion creates a formulation challenge: content uniformity must be demonstrated in tablet cores that may weigh from 120 mg to 400 mg, giving an API mass fraction as low as 1.25%. Blend and dosage unit uniformity are therefore evaluated against USP <905> acceptance value AV ≤ 15 for solid oral dosage forms. Compared with sitagliptin, which has a larger dose and higher aqueous solubility, linagliptin cannot be transferred directly onto a common direct compression platform without revalidation of pre-blending and lubrication steps.
| Attribute | Linagliptin | Sitagliptin | Saxagliptin | Vildagliptin | Alogliptin |
|---|---|---|---|---|---|
| Molecular weight (g/mol) | 472.54 | 407.31 | 315.41 | 303.40 | 339.39 |
| Standard oral dose | 5 mg once daily | 100 mg once daily | 5 mg once daily | 50 mg twice daily | 25 mg once daily |
| Approximate terminal half-life | >100 h | 12.4 h | 2.5 h parent | 2.8 h | 21 h |
| Renal elimination of unchanged drug | ≈5% | ≈87% | ≈75% | ≈85% | 60–70% |
| Principal formulation implication | Low-dose content uniformity; biliary clearance dominates | Higher dose; renal adjustment required | Low-dose content uniformity; active metabolite | Twice-daily dosing; renal adjustment | Moderate dose; renal adjustment |
For granule production, linagliptin may be incorporated into a binder dispersion or blended with granulation excipients before high-shear or fluid-bed granulation. In high-shear mixers with impeller speed 200–400 rpm and chopper speed 1,500–3,000 rpm, the endpoint is commonly judged by power consumption and granule growth. Overdrying below 1.5% w/w water content can produce friable granules that segregate during transfer or capsule filling. If a non-micronized API is used, the wet granulation liquid must provide adequate dispersion because linagliptin has limited aqueous solubility; dissolution testing for the finished granule or capsule may require a low-pH medium or a surfactant, but published data for a universal biorelevant medium for this specific configuration is limited. The selected medium must be justified by data rather than by extrapolation from other DPP-4 inhibitors.
Direct compression of linagliptin is feasible only when the micronized API is pre-blended with a low-dose carrier such as mannitol or lactose monohydrate and passed through a 0.5 mm or 1.0 mm screen to break electrostatic agglomerates. If the API fraction is ≤2% w/w and the batch size exceeds 200 kg, segregation risk during bin transfer and tablet press hopper refill increases; this operational boundary often triggers evaluation of wet granulation or roller compaction. Wet granulation with a binder solution of hypromellose or copovidone at 2–8% w/w in water provides coated granules with improved content uniformity. Drying in a fluid-bed drier must be controlled to inlet air temperature 55–65°C and product temperature ≤40°C until loss on drying reaches 1.0–2.0% w/w, unless forced degradation studies support a broader drying window. The crystalline form should be verified by X-ray powder diffraction after drying because published data for linagliptin-specific thermal degradation thresholds at pilot scale is limited. If aqueous granulation is incompatible with stability data, dry granulation by roller compaction may be used, but ribbon density and milling screen parameters must be selected by factorial design for the specific API lot because flow and compressibility vary with particle size and residual solvent state.
For capsule filling, the powder or granule fill weight is determined by capsule size. A size 3 capsule may hold approximately 150–250 mg depending on bulk density; linagliptin capsule formulations therefore typically use the same low-dose blend platform as tablets but may omit extragranular disintegrant if the capsule shell and granule porosity provide adequate disintegration. In high-speed capsule filling, blend samples taken at ≤10 minute intervals are used to detect segregation; fill weight variation for a 5 mg product must comply with USP <905> or Ph.Eur. 2.9.40 for solid dosage units. Granule-filled sachets require a larger particle size to reduce dusting; granules with Dv50 150–300 µm and fines below 45 µm limited to ≤15% w/w are often targeted. If the granule contains non-micronized linagliptin, dissolution testing may require a surfactant in the release medium; the choice is formulation-dependent and must be supported by recovery and discrimination data.
For a 5 mg linagliptin tablet in a core weight of 120–400 mg, the API mass fraction is 1.25–4.17%. Under these conditions, powder flow and electrostatic charging are primary content uniformity failure modes. Micronization increases specific surface area, typically to 5–15 m²/g, and reduces bulk density; the resulting cohesive powder may adhere to stainless steel and polycarbonate contact surfaces. The flow function coefficient measured by ring shear testing per ASTM D6773 is commonly below 4 for micronized linagliptin, indicating cohesive flow; the formulation therefore requires glidants such as colloidal silicon dioxide at 0.1–0.5% w/w and lubricants such as magnesium stearate at 0.25–1.0% w/w. Over-lubrication can retard dissolution of a poorly water-soluble API; the preferred mixing time for magnesium stearate is 3–5 min after the API has been uniformly incorporated. On production-scale rotary tablet presses, segregation of low-dose APIs has been observed when hopper level falls below 30%; linagliptin batches therefore require automatic hopper level control or start-up, middle, and end stratified sampling. Content uniformity must meet USP <905> acceptance value AV ≤ 15. If the AV exceeds 15, the tiered acceptance criteria may still permit release if individual contents fall within ±15% of label claim, but the root cause must be investigated and corrected before subsequent batches.
Injectable-grade linagliptin differs from oral-grade material in release specification rather than molecular identity. The injectable grade requires bacterial endotoxin testing, particulate matter evaluation, and container closure compatibility data before formulation. Because linagliptin has limited aqueous solubility, a parenteral formulation cannot be prepared by simple dilution to isotonic pH; development may require pH adjustment, a cosolvent system, or complexation with cyclodextrins, depending on target concentration and route. Terminal sterilization by autoclaving at 121°C for 15 min is acceptable only if forced degradation studies demonstrate no significant related substance increase. If terminal sterilization is not supported, aseptic filtration through a 0.22 µm sterilizing-grade filter per ASTM F838-20 and processing under ISO 14644-1 Class 5 conditions are required. Endotoxin limits are calculated from the maximum human dose using USP <85>; for a 5 mg parenteral dose and a 70 kg patient, the intravenous threshold of 5 EU/kg gives a derived API limit of 70 EU/mg, but the final limit depends on route, infusion rate, and dosing interval. Because linagliptin is highly protein-bound, intravenous administration can alter free drug fraction; an injectable form is therefore not automatically bioequivalent to the oral tablet.
| Attribute | Method/Standard | Acceptance criterion |
|---|---|---|
| Appearance | Visual | White to off-white crystalline powder |
| Assay (HPLC) | USP <621> | 98.0–102.0% on anhydrous, solvent-free basis |
| Related substances | HPLC | Total ≤0.5%; unspecified individual ≤0.10% |
| Water content | Karl Fischer USP <921> | ≤0.5% w/w |
| Residue on ignition | USP <281> | ≤0.1% |
| Residual solvents | USP <467> / ICH Q3C | Class 1 and Class 2 within limits; Class 3 ≤5000 ppm or justified |
| Elemental impurities | USP <232>/<233> / ICH Q3D | Class 1, 2A, 2B, and 3 elements within PDE limits |
| Particle size | Laser diffraction USP <429> | Micronized grade: Dv90 ≤20 µm; non-micronized: report value |
| Bulk/tapped density | USP <616> | Report value; target depends on capsule/tablet filling |
| Polymorph identity | XRPD | Positive match to designated reference form |
| Microbial limits | USP <61>/<62> | TAMC ≤100 CFU/g; TYMC ≤10 CFU/g; absence of specified organisms |
| Bacterial endotoxins | USP <85> | If injectable grade: derived limit, e.g., 70 EU/mg for 5 mg IV dose |
When linagliptin is run on a shared manufacturing line after sitagliptin or saxagliptin, cleaning verification must use HPLC rinse or swab methods with residue limits calculated from the permitted daily exposure, the next product’s batch size, and the lowest shared surface area. Visual absence of powder is not sufficient because a 5 mg dose leaves a small visible residue that may exceed the permitted daily exposure. Cleaning validation is required under 21 CFR 211.67 and ICH Q7, and the acceptance limit must be documented before line clearance. The same API grade used for tablets, capsules, or granules must be revalidated for injectable processing because the absence of a specific oral excipient interaction does not predict parenteral compatibility with solvents, buffers, or container closures.
