(2S)-1-[N-(3-Hydroxytricyclo[3.3.1.1~3,7~]Dec-1-Yl)Glycyl]Pyrrolidine-2-Carbonitrile
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HS Code |
740868 |
| Chemical Name | (2S)-1-[N-(3-Hydroxytricyclo[3.3.1.13,7]Dec-1-Yl)Glycyl]Pyrrolidine-2-Carbonitrile |
As an accredited (2S)-1-[N-(3-Hydroxytricyclo[3.3.1.1~3,7~]Dec-1-Yl)Glycyl]Pyrrolidine-2-Carbonitrile factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 10 - gram vial packaging for (2S)-1-[N-(3 - Hydroxytricyclo[3.3.1.1³,⁷]Dec - 1 - Yl)Glycyl]Pyrrolidine - 2 - Carbonitrile |
| Shipping | The chemical (2S)-1-[N-(3 -Hydroxytricyclo[3.3.1.1³,⁷]Dec - 1 - Yl)Glycyl]Pyrrolidine - 2 - Carbonitrile will be shipped in secure, specialized containers, compliant with chemical transport regulations, ensuring safe and proper handling during transit. |
| Storage | Store (2S)-1-[N-(3-Hydroxytricyclo[3.3.1.1³,⁷]dec-1-yl)Glycyl]Pyrrolidine - 2 - Carbonitrile in a cool, dry place, away from heat sources and direct sunlight. Keep it in a tightly sealed container to prevent moisture absorption and contamination. Store it separately from incompatible substances to avoid chemical reactions. |
In the production of single-entity vildagliptin tablets by direct compression, the active pharmaceutical ingredient, (2S)-1-[N-(3-hydroxytricyclo[3.3.1.1~3,7~]dec-1-yl)glycyl]pyrrolidine-2-carbonitrile (vildagliptin), is incorporated at a nominal content of 50 mg per core, which typically represents 20–33 wt% of the uncoated tablet mass, depending on the selected intragranular filler-to-diluent ratio. Compliance with the pharmacopoeial monograph for Vildagliptin Tablets—specifically USP 43-NF 38 and the corresponding Ph. Eur. monograph 10.5—mandates dissolution testing using Apparatus 2 (paddle) at 50 rpm in 900 mL of pH 6.8 phosphate buffer, with a Q value of not less than 80% at 30 min. The downstream manufacturing process employs dry blending of vildagliptin with microcrystalline cellulose (Avicel PH-102), lactose monohydrate (Pharmatose 200M), sodium starch glycolate (Typ A, 2–4 wt%), and colloidal silicon dioxide (0.5–1.0 wt%) in a bin blender operating at 10–15 rpm for 300–500 revolutions, followed by lubrication with magnesium stearate (0.75–1.25 wt%) for an additional 60–90 revolutions to avoid over-lubrication and consequent tensile strength reduction of the compact. Tableting is performed on a rotary press (e.g., Korsch XL 400 or Fette 3200i) equipped with 8–10 mm round, flat-faced beveled-edge tooling at a target compression force of 10–20 kN, yielding cores with a hardness range of 50–100 N and friability below 0.5% as per USP <1216>. Process validation batches routinely monitor weight variation (USP <905>) to comply with an RSD limit of ≤2.0% for individual tablet weights, an acceptance criterion that becomes challenging when tablet press speeds exceed 150,000 tablets per hour because of die-filling inconsistencies inherent to low-density, high-fines blends. The terminal dosage form is an immediate-release, non-scored, film-coated tablet intended for twice-daily oral administration, and the entire manufacturing sequence is conducted under cGMP conditions audited against ICH Q7 and the relevant sections of 21 CFR Part 211.How does wet granulation influence vildagliptin content uniformity in high-dose metformin tablets?When formulating fixed-dose combinations containing 1000 mg metformin hydrochloride and 50 mg vildagliptin, the mass ratio of the two actives approaches 1:20, making blend homogeneity the single most consequential processing parameter. In the Eucreas-type formulation manufactured via fluid-bed wet granulation, vildagliptin constitutes approximately 4.2 wt% of the final core mass (roughly 1150–1200 mg), while metformin HCl accounts for 85–88 wt%, density-bridging excipients such as microcrystalline cellulose and povidone K30 filling the remainder. Regulatory filings for this combination product reference USP <905> Uniformity of Dosage Units with an acceptance value (AV) of ≤15.0, a test that frequently determines batch release because metformin’s poor flow and high dose inherently amplify segregation during post-granulation handling. The recognized manufacturing solution—disclosed in multiple originator process patents and adopted in ANDA submissions—dissolves the entire vildagliptin charge in an aqueous binder solution containing 3–5 wt% povidone K30 before spraying it at a rate of 80–150 g/min onto a fluidized bed of metformin HCl, microcrystalline cellulose, and crospovidone in a Glatt GPCG 60 or equivalent top-spray granulator, with an inlet air temperature maintained at 55–70 °C and product temperature not exceeding 38 °C to avoid thermal conversion of vildagliptin to its diketopiperazine cyclic impurity (specified at NMT 0.2% per ICH Q3B). Granulation endpoint is determined by loss-on-drying (LOD 1.5–2.5%) rather than by impeller power draw, because moisture content directly influences tabletability of the subsequently milled granules; terminal drying to a target residual moisture of 0.8–1.2% in a fluid-bed dryer at 60 °C inlet temperature is required to prevent sticking during high-speed compression. Milled granules are passed through a 1.0 mm screen, blended with extragranular crospovidone and magnesium stearate, and compressed on a high-speed rotary press at 40–60 rpm using 19 × 9 mm capsule-shaped tooling, with compression forces typically in the 15–25 kN range to achieve tablet breaking strengths of 150–250 N. Failure to dissolve vildagliptin in the granulation fluid results in measurable segregation during hopper discharge, with content uniformity AV values routinely exceeding 20 and necessitating an additional pre-blending step with a micronized carrier—a process modification that introduces additional cleaning validation requirements under 21 CFR 211.67. The finished dosage form is an immediate-release, film-coated tablet for oral administration, designed to deliver bioequivalent systemic exposure to the reference listed drug under fasted conditions as per the FDA guidance for metformin hydrochloride/vildagliptin tablets.During scale-up of direct compression batches beyond 100 kg, segregation of low-dose vildagliptin from the major diluent fraction becomes a statistically detectable source of out-of-specification content uniformity results, particularly when the active ingredient exhibits a median particle size (Dv50) above 80–100 µm and the lactose-based blend is transferred from the bin blender to the tablet press hopper via gravity-fed split valves. Although the formulation still contains vildagliptin at 50 mg per tablet—representing 25 wt% in a 200 mg tablet core—the seemingly robust percentage obscures the fact that vildagliptin crystals are acicular and prone to densification-induced stratification under vibration. Process engineers on commercial lines measure blend uniformity at multiple sampling points (top, middle, bottom of the tote) following internal protocols harmonized with FDA Guidance for Industry “ANDAs: Blend Uniformity Analysis,” with acceptance criteria set at 90.0–110.0% of label claim and RSD ≤5.0%. When the RSD approaches 4.5%, a risk of individual tablets falling outside USP <905> Stage 1 limits increases above the 2-sigma threshold, triggering corrective actions such as shortening transfer distances, installing hopper vibratory feeders with amplitude control, or replacing the free-fall blend transfer with a vacuum dense-phase conveying system operated at a conveying velocity below the minimum pickup velocity for the fines fraction. The manufacturing equipment qualification references ASTM D6128-16 for hopper mass-flow design; a hopper wall angle of 70° from horizontal and a bin outlet diameter of ≥250 mm are empirically determined minimums to maintain mass-flow discharge of the vildagliptin-magnesium stearate post-lubrication blend. Failure to implement these measures has been observed to increase reject rates at the tablet press by 3–7% during 8-hour continuous runs, primarily due to under- or over-weight tablets detected by the in-line weight control system. The terminal dosage form remains a direct-compressed, immediate-release tablet, and the post-compression phase proceeds immediately to aqueous film coating to minimize exposure of the hygroscopic sodium starch glycolate in the cores to ambient humidity.Film coating equilibration and moisture ingress thresholds for vildagliptin 50 mg tabletsAqueous film coating of vildagliptin tablet cores with a ready-to-use Opadry II complete coating system (polyvinyl alcohol-based) is performed in a fully perforated side-vented coating pan (e.g., O’Hara LabCoat II or Glatt GC Smart) at a target coating weight gain of 2.5–4.0% relative to the core weight. The application parameters—pan speed 6–12 rpm, inlet air temperature 60–75 °C, exhaust air temperature 40–50 °C, spray rate 15–30 mL/min per gun, atomizing air pressure 1.0–1.5 bar—are qualified during process validation by demonstrating that the tablet bed temperature remains below 44 °C throughout, a threshold derived from differential scanning calorimetry data indicating the onset of vildagliptin’s glass transition event (Tg) in the presence of residual moisture at approximately 48–52 °C. Compliance with compendial weight variation testing (USP <2091>) requires that the coated tablets exhibit a mass RSD of ≤2.5%, a limit that is directly influenced by the uniformity of the spray pattern and the pan loading, which is typically maintained at 60–80% of the nominal fill volume. The addition of the film coat does not alter the immediate-release performance; nonetheless, dissolution profiles of coated tablets are compared to those of uncoated cores using the similarity factor f2, with an acceptance range of 50–100 for profiles sampled at 10, 15, 20, 30, and 45 min in USP Apparatus 2 at 50 rpm in 900 mL pH 6.8 phosphate buffer. One specific processing vulnerability arises when the dew point of the incoming process air exceeds 10 °C, because elevated humidity at the tablet surface during the initial drying phase can generate a localized hydrolysis microenvironment that promotes trace formation of the amide-hydrolysis impurity (3-hydroxytricyclo[3.3.1.13,7]decane-1-acetic acid) above the ICH Q3A identification threshold of 0.10%. To mitigate this, tablet cores are pre-warmed to a bed temperature of 38–42 °C before spraying begins, and the atomization air supply is dehumidified to a relative humidity below 15%. The terminal product is a coated immediate-release tablet for oral administration, and batch release includes additional testing for moisture content (Karl Fischer, limit ≤2.0%) conducted after a 24-hour equilibration period in a 25 °C/60% RH environment to ensure packaging operations do not enclose tablets with transient surface moisture.Stability studies on vildagliptin 50 mg tablets in high-humidity zones (ICH Zone IVb, 30 °C/75% RH) indicate that packaging material selection exerts a first-order effect on the cyclic diketopiperazine impurity level, which can increase from an initial 0.04% to 0.18% over 36 months when a simple PVC/PVDC blister is used, whereas a cold-form aluminium/aluminium (Alu/Alu) blister maintains the same impurity below 0.10% for the entire shelf life. The formulation—vildagliptin at 20–33 wt% of the core, as previously described—relies on the moisture-impermeable foil barrier to prevent water vapor transmission, which is specified at a maximum of 0.001 g/m2/day for the forming foil (OPA/Al/PVC laminate) and 0.0002 g/m2/day for the lidstock, tested in accordance with ASTM F1249-20. The downstream packaging process operates on a continuous-motion blister machine (e.g., Uhlmann B1440) with forming temperatures of 120–140 °C and sealing temperatures of 180–220 °C, monitored to avoid heat transmission to the tablet pockets that could pre-trigger the solid-state cyclization reaction of vildagliptin. Packaging line qualification follows the principles of USP <671> Containers—Performance Testing, and integrity is verified by dye penetration testing (ASTM D3078-02) on a statistical sample from each forming station. The terminal dosage form shipped to the customer is an Alu/Alu blister-packed immediate-release tablet, and the label claim stability is assigned based on extrapolation of 12-month real-time data from batches manufactured at a minimum of three intermediate-precision scales.Particle size of the active ingredient in the batch-to-batch release specification is controlled because the dissolution rate of direct-compressed vildagliptin tablets is inversely correlated with the volume-weighted mean diameter of the non-micronized crystals. The pharmaceutical manufacturer typically sets a Dv90 acceptance criterion of ≤150 µm (laser diffraction, Malvern Mastersizer, dry dispersion according to USP <429>) and a Dv50 target of 50–80 µm to maintain a surface area that ensures wetting and disintegration without requiring a surfactant in the dissolution medium. When the upstream chemical synthesis of (2S)-1-[N-(3-hydroxytricyclo[3.3.1.1~3,7~]dec-1-yl)glycyl]pyrrolidine-2-carbonitrile yields crystalline material with a Dv90 above 200 µm, a de-lumping or air-jet milling step (e.g., Hosokawa Alpine AFG) is inserted prior to formulation, with milling chamber pressure and classifier rotor speed configured to preserve the crystal habit while achieving the target size distribution. The direct compression formula incorporates the milled API at the same nominal 50 mg per tablet, and compendial compliance remains anchored to the Vildagliptin Tablets monograph dissolution test (Q = 80% at 30 min, USP Apparatus 2, 50 rpm, 900 mL pH 6.8 buffer). Finished product manufactured at the lower end of the particle size specification (Dv50 near 30–40 µm) occasionally exhibits reduced powder flow (Carr index > 30) during die filling, which is compensated by elevating the glidant concentration to 1.0–1.5% colloidal silicon dioxide, a modification registered in the Drug Master File and approved under the FDA’s SUPAC-IR Level 1 change guidance. The terminal dosage form is an immediate-release tablet, and the milling equipment is dedicated and validated for this API to avoid cross-contamination, as required by 21 CFR 211.65. |
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(2S)-1-[N-(3-Hydroxytricyclo[3.3.1.13,7]dec-1-yl)glycyl]pyrrolidine-2-carbonitrile (CAS 274901-16-5, molecular formula C17H25N3O2, relative molecular mass 303.41 g·mol⁻¹) is the international nonproprietary name vildagliptin, a chiral cyanopyrrolidine derivative that functions as a substrate-mimetic, slow-binding inhibitor of dipeptidyl peptidase-4 (DPP-4; EC 3.4.14.5). The molecule integrates a (2S)-pyrrolidine-2-carbonitrile warhead, a glycyl linker, and a 3-hydroxyadamantyl capping group—the trihydroxyadamantane scaffold identical to that of the tricyclic amino acid 3-hydroxytricyclo[3.3.1.13,7]decane-1-carboxylic acid. The solid-state form of pharmaceutical-grade drug substance is the thermodynamically stable anhydrous polymorph (Form A), characterised by X-ray powder diffraction peaks at 2θ angles of 9.5°, 13.8°, and 18.3° (Cu Kα radiation). The nitrile moiety undergoes nucleophilic attack by the active-site serine (Ser630) of DPP-4, forming a reversible covalent imidate adduct with a dissociation half-life exceeding 55 minutes—a kinetic signature that sharply distinguishes vildagliptin from rapidly reversible competitive inhibitors such as sitagliptin phosphate and alogliptin benzoate. Pharmacopoeial specifications (Ph. Eur. monograph 3034, USP 44) stipulate a loss on drying of ≤ 0.5%, residue on ignition ≤ 0.1%, and enantiomeric purity of ≥ 99.0% enantiomeric excess for the (2S)-isomer, with the (2R)-epimer controlled at ≤ 0.50%. Typical commercial lots assay at 99.5% (HPLC, area%, anhydrous basis) and exhibit a single maximum unspecified impurity ≤ 0.15%.
The pyrrolidine-2-carbonitrile pharmacophore positions the electrophilic nitrile carbon within hydrogen-bonding distance of the Ser630 hydroxyl, facilitated by the glycyl spacer and adamantyl P2-pocket occupancy. Inhibition proceeds through a two-step mechanism: rapid formation of a non-covalent enzyme-inhibitor complex (Ki 3 nM) followed by slow nucleophilic addition yielding a tetrahedral imidate adduct. The association rate constant (kon) approximates 1.5 × 10⁴ M⁻¹s⁻¹, while the reverse rate (koff) of 2.1 × 10⁻⁴ s⁻¹ translates to a covalent-complex half-life of 55 min. Consequently, even after plasma concentrations fall below the quantification limit, residual DPP-4 inhibition remains above 80% for more than 12 hours. This behaviour contrasts with sitagliptin, which, despite a comparable Ki, dissociates with a half-life of less than 10 min and requires sustained plasma occupancy to maintain target engagement.
The pivotal C–C bond-forming step in the synthesis of the (2S)-pyrrolidine-2-carbonitrile core employs sodium cyanide in an aqueous medium under nitrogen inertisation. The reaction is run at 0 °C to 5 °C in a glass-lined reactor fitted with a high-torque anchor agitator and a jacket capable of −10 °C brine circulation. The aqueous-phase pH is rigorously held between 10.5 and 11.5 by metered addition of sodium hydroxide solution; below the pKa of hydrogen cyanide (9.2), free HCN gas evolves, rapidly exceeding the OSHA permissible exposure limit of 4.7 ppm (8‑hour TWA). The upper pH boundary is equally critical—exceeding 12.0 accelerates α‑proton abstraction at the pyrrolidine stereocentre and triggers racemisation, directly eroding enantiomeric excess. The exothermic cyanide addition (adiabatic temperature rise ~15 °C) demands jacket set-points of −5 °C and a feed rate limited to 0.5 L/min to hold the internal temperature below 5 °C. Real-time process analytical technology (PAT) is deployed: in-line Raman spectroscopy tracks the nitrile C≡N stretch at 2245 cm⁻¹ and, via a validated chemometric model, quantifies (2R)-epimer content to trigger corrective pH adjustment when the epimer exceeds 0.3% area. Cyanide quenching is performed by oxidation with sodium hypochlorite solution at pH >10, converting residual cyanide to cyanate; the spent aqueous stream passes through a packed-bed catalytic oxidation column to bring total cyanide below 0.1 mg/L, meeting the EU Waste Framework Directive emission limit and monitored by continuous flow injection analysis with amperometric detection per EN ISO 14403-2:2012. The isolated wet cake is reslurried in purified water at 20 °C and washed with acetone to reduce residual cyanide on the solid below 10 ppm before drying.
Vildagliptin is administered as 50 mg tablets taken twice daily, with or without food. The twice-daily regimen sustains near-maximal (> 80%) DPP-4 inhibition over the full 24‑hour interval despite a plasma elimination half-life of 1.5–4.5 hours. The VERIFY study (NCT01528254; n = 2001 early-stage type 2 diabetes patients) demonstrated that a treatment strategy of early combination of vildagliptin 50 mg bid plus metformin reduced the relative risk of initial glycemic failure (HbA1c ≥7.0% on two consecutive visits ≥13 weeks apart) by 49% (hazard ratio 0.51; 95% CI 0.45–0.58) compared with standard metformin monotherapy over a five-year follow-up. The agent is contraindicated in patients with hepatic impairment defined by AST or ALT > 3 × ULN; dose adjustment is not required for mild renal impairment (eGFR ≥50 mL/min/1.73 m²) but is contraindicated in moderate-to-severe impairment owing to a lack of sufficient safety data. Unlike saxagliptin, which undergoes CYP3A4/5-mediated metabolic activation to a hydroxy metabolite with 3‑fold higher potency, vildagliptin’s simplicity eliminates the risk of metabolite-mediated off-target effects, but its nitrile function imposes an incompatibility with excipients bearing primary amine groups, which can engage in Maillard-type imine formation under accelerated storage conditions (40 °C/75% RH).
Pharmacodynamic crossover studies have compared vildagliptin 50 mg bid with sitagliptin 100 mg once daily under meal-test conditions. Vildagliptin increased the 24‑hour weighted mean active glucagon-like peptide-1 (GLP-1) area under the curve by approximately 1.4‑fold relative to sitagliptin, a consequence of the prolonged enzyme-inhibitor complex half-life and the resultant accumulation of intact incretins during interprandial periods. In a randomised, cross-over trial enrolling 24 patients with type 2 diabetes, vildagliptin provided a 24% greater reduction in postprandial glucose AUC compared with sitagliptin, while the maximal postprandial GLP-1 concentration (Cmax) was 60–70% higher. Because the binding-site covalent modification is stoichiometric and saturable, no linear dose–response exists beyond maximal DPP-4 occupancy; the 50 mg bid schedule seats at the top of the dose–response plateau.
Crystallisation from an isopropanol/water (85:15 v/v) mixture with controlled cooling from 50 °C to 5 °C over 8 hours guarantees exclusive isolation of the thermodynamically stable Form A polymorph, critical for consistent dissolution performance in tablet formulations. The drug substance specification incorporates tests aligned with ICH Q6A and Q3D guidelines.
| Test | Acceptance Criterion | Typical Value |
|---|---|---|
| Appearance (visual) | White or almost white crystalline powder | White crystalline powder |
| Identification (IR) | Conforms to reference spectrum (Ph. Eur. 2.2.24) | Conforms |
| Assay (HPLC, anhydrous basis) | 98.0%–102.0% | 99.5% |
| Enantiomeric purity (chiral HPLC) | (2S)-isomer ≥ 99.0%; (2R)-epimer ≤ 0.50% | 99.9%; 0.04% |
| Any individual impurity (HPLC) | ≤ 0.10% | 0.05% |
| Total impurities (HPLC) | ≤ 0.5% | 0.15% |
| Residual nitrile (GC) | ≤ 0.05% (w/w) | <0.01% |
| Water (Karl Fischer) | ≤ 0.5% | 0.1% |
| Residue on ignition | ≤ 0.1% | 0.02% |
| Elemental impurities (ICH Q3D) | Class 1: As ≤ 1.5 µg/g, Pb ≤ 0.5 µg/g, Cd ≤ 0.5 µg/g, Hg ≤ 1.5 µg/g | All < limit |
| Polymorphic form (XRPD, USP <941>) | Form A only; no detectable Form B peaks | Form A (2θ 9.5°, 13.8°, 18.3°) |
Comparative pharmacodynamic and clinical evidence differentiates vildagliptin from other widely prescribed DPP-4 inhibitors. The following tabulation contrasts key properties that influence therapeutic selection.
| Parameter | Vildagliptin | Sitagliptin | Saxagliptin |
|---|---|---|---|
| Inhibition mechanism | Slow-binding reversible covalent (imidate adduct) | Competitive reversible | Slow-binding reversible covalent (imidate adduct) |
| DPP-4 Ki | 3 nM | 18 nM | 1.3 nM |
| Enzyme-inhibitor complex t½ | ~55 min | <10 min | ~49 min |
| Standard daily dose | 50 mg bid | 100 mg qd | 5 mg qd |
| Plasma elimination half-life | 1.5–4.5 h | 12.4 h | 2.5 h (parent); 3.1 h (active metabolite) |
| Major metabolic pathway | Hydrolysis of cyano group (inactive) | Not significantly metabolised | CYP3A4/5-mediated hydroxylation (active metabolite) |
| Renal excretion of unchanged drug | 13% | 79% | 24% |
| Food effect | None; may be taken with or without food | None | None |
| Dosing in renal impairment (eGFR 30–50 mL/min) | Contraindicated | 50 mg qd | 2.5 mg qd |
| Evidence of long-term β-cell protection (trial name) | VERIFY (HR 0.51 for glycemic failure vs metformin) | Not demonstrated in dedicated durability studies of similar size | SAVOR-TIMI 53 did not evaluate β-cell durability as primary endpoint |
