Purpose To identify the in vitro dissolution parameters able to predict the in vivo performance of nifedipine after oral administration of immediate release (IR) soft gelatine capsules taken in the fasted state and in the presence of orange juice and ethanol (47% v/v). Methods Dissolution experiments in Fasted State Simulated Gastric Fluid (FaSSGF) were performed using USP1, USP2 (Dissolution tester DT826 LH, Automatic Sampling Station, Syringe Pump SP840, Fraction Collector FRL800, Erweka), USP3 (Bio-Dis Reciprocating Cylinder Apparatus and 750 Heater, Agilent Technologies) and USP4 (DFZ 720, Piston pump type HKP 720, Heater DH 1520i, Erweka). Variables tested for USP1 and USP2 experiments: volume of media (500-900 mL), pH (1.6-3.4), speed (50-100 rpm) and ethanol (0-47% v/v). Variables tested for USP3 experiments: volume of media (100-200 mL), pH (1.6-3.4), dipping rate (5-15 dpm), and ethanol (0-47% v/v). Variables tested for USP4 experiments: flow rate (4-8 mL/min), pH (1.6-3.4), and mode of operation (open and close). pH and ethanol content were chosen to mimic the in vivo study performed by (Qureshi, S. et al., 1992 Pharm. Res. 9, 683-686). Two Adalat 10 mg IR capsules were used for each experiment (n = 3). One mL sample was withdrawn at 5, 10, 15, 20, 25, 30, 40, 60, 90, and 120 min for USP1 and 2 experiments. Sampling times for USP3 experiments were 3, 6, 9, 12, 15, and 18 minutes, while sampling times for USP4 experiments were: 15, 30, 45, 60, 75, 90, 105 and 120 min. Nifedipine quantification was performed with HPLC-UV (USP1 and USP2 samples: Waters 2695; USP3 and USP4 samples: Agilent 1100) using a C18 column (250 X 4.6, 5μm) and MeOH/H2O 60/40 v/v as mobile phase. Injection volume was 50 µL, flow rate 1 mL/min, run time 15 min, detection at 238 nm and column temperature 22°C. All the experiments and sample preparation and analysis were performed in darkness to prevent nifedipine’s photodegradation. In vivo absorption profiles were obtained after deconvolution of published oral data (Qureshi, S. et al., 1992 Pharm. Res. 9, 683-686) using the Loo-Riegelman two compartment model. The PK constants used for the deconvolution were calculated based on published in vivo intravenous data (Kleinbloesem, C.H. et al. 1984 Clin. Pharmacol. Ther. 35, 6, 742-749) via the feathering method and using the PKPlus module of Gastroplus. In vitro-in vivo correlations (IVIVC) were obtained using the in vitro dissolution and the in vivo absorption data. When necessary, data points were calculated using the linear interpolation method of in vitro data and time scaling was applied. Results The dissolution profile of nifedipine IR capsules under different dissolution conditions showed to be affected by the chosen parameters, as well as the type of apparatus. In particular, precipitation of nifedipine was observed in the absence of ethanol, with total amount dissolved after 120 minutes of 66% (USP1 and USP2 apparatus). In the case of the experiments performed in FaSSGF, nonlinear IVIVC could be obtained for USP1, USP2 and USP3 apparatus, as the in vitro dissolution was faster than the in vivo absorption. On the contrary, a linear IVIVC was obtained with the data from the USP4 apparatus. In particular, a linear level A IVIVC was obtained for the open system mode data at 4 and 8 mL/min at pH 1.6 (0.95 < R2 < 0.98), while a nonlinear correlation was obtained for the data from the other experimental setups with this apparatus. In the case of the experiments with 47% v/v of ethanol performed on the USP1 apparatus, it was possible to obtain linear (0.91 < R2 < 0.99), and nonlinear level A IVIVC from the dissolution data under the different conditions tested. For the dissolution data obtained from the USP2 apparatus all five experiments in ethanol produced nonlinear level A IVIVC, and after time scaling linear level A IVIVC were obtained in two cases (0.98 < R2 < 0.99). Linear correlations (0.97 < R2 < 0.99) after time scaling were obtained from the data from the USP3 experiments with ethanol. Conclusion This study reveals that choosing the appropriate in vitro dissolution conditions and hydrodynamics is critical in order to achieve a good correlation with in vivo data. In particular, USP1 showed to give good prediction for dissolution conditions in the presence of ethanol, while USP4 was able to predict the dissolution without ethanol. In all cases good linear and nonlinear IVIVC were obtained with the four apparatus used, depending on the set up conditions. In some cases, use of time scaling was required to obtain a linear IVIVC.
|Publication status||Published - 2015|
|Event||AAPS Annual Meeting, 2015 - Orlando, USA United States|
Duration: 25 Oct 2015 → 29 Oct 2015
|Conference||AAPS Annual Meeting, 2015|
|Country||USA United States|
|Period||25/10/15 → 29/10/15|