A STABILITY-INDICATING RP-HPLC METHOD DEVELOPMENT AND VALIDATED ACROSS FOUR BIORELEVANT MATRICES FOR AZELNIDIPINE–TELMISARTAN

Battula Sammaiah*, Dr. K. Ram Prasad

Azelnidipine (AZL) and telmisartan (TEL) are both BCS Class II antihypertensives of high lipophilicity (logP 4.5 and 7.7), co-formulated as a once-daily fixed-dose combination (FDC) whose oral performance is governed by solubility rather than permeability. Existing chromatographic methods for the pair quantify tablet content in simple buffers; none has asked how the bile-salt micellar environment of the intestinal lumen reshapes either the degradation chemistry or the dissolution behaviour of the two drugs. We developed a single isocratic reversed-phase HPLC method — Inertsil ODS-3 (250 × 4.6 mm, 5 μm), acetonitrile: 0.1% ortho-phosphoric acid (pH 3.0), 60:40 (v/v), 1.0 mL min⁻¹, 30 °C, 240 nm, 10 min — and validated it in four matrices (diluent, FaSSGF, FaSSIF-V2, FeSSIF-V2) per ICH Q2(R1)/Q2(R2). Working concentrations of 17.78 μg mL⁻¹ (AZL) and 44.44 μg mL⁻¹ (TEL) corresponded to complete label-dose release into the 900 mL compendial vessel. Resolution reached 7.92; every validation figure of merit passed in every matrix (r² ≥ 0.9999; recovery 99.11–99.90%; pooled precision %RSD ≤ 0.89%). Forced degradation was run under six ICH stress conditions in diluent and, as the analytical departure of this work, repeated with each drug embedded in FaSSIF-V2 and FeSSIF-V2 micelles. The fed-state medium attenuated AZL degradation by 4.0–5.5 percentage points and TEL degradation by 4.3–7.8 percentage points, the protection scaling with taurocholate concentration — a magnitude far above what freely soluble drugs experience, and consistent with near-complete partitioning of both high-logP molecules into the micelle core. No matrix-specific degradant appeared; the micelle changed rate, not pathway. Biorelevant dissolution exposed a striking release contrast: at 15 min TEL reached 85.5% in FeSSIF-V2 against 23.8% in compendial 0.1 N HCl, an ≈ 62 percentage-point gap, with AZL showing the same fed-state acceleration. Both partners returned f₂ < 50 for fed-versus-fasted comparisons (AZL 34.98; TEL 27.46) — a bilateral in vitro food-effect signal not previously reported for this FDC. Tablet assay recovered 99.96% (AZL) and 99.88% (TEL) of label claim. The method couples full biorelevant-matrix validation with in-medium degradation probing for the first time in this drug pair, and the data argue for FeSSIF-V2 as a discriminating early-development screen for lipophilic antihypertensive combinations.