Impact of Simulated Intestinal Fluids on Dissolution, Solution Chemistry, and Membrane Transport of Amorphous Multidrug Formulations

The solution behavior and membrane transport of multidrug formulations were herein investigated in a biorelevant medium simulating fasted conditions. Amorphous multidrug formulations were prepared by the solvent evaporation method. Combinations of atazanavir (ATV) and ritonavir (RTV) and felodipine (FDN) and indapamide (IPM) were prepared and stabilized by a polymer for studying their dissolution (under non-sink conditions) and membrane transport in fasted state simulated intestinal fluid (FaSSIF).

The micellar solubilization by FaSSIF enhanced the amorphous solubility of the drugs to different extents. Similar to buffer, the maximum achievable concentration of drugs in combination was reduced in FaSSIF, but the extent of reduction was affected by the degree of FaSSIF solubilization. Dissolution studies of ATV and IPM revealed that the amorphous solubility of these two drugs was not affected by FaSSIF solubilization. In contrast, RTV was significantly affected by FaSSIF solubilization with a 30% reduction in the maximum achievable concentration upon combination to ATV, compared to 50% reduction in buffer.

This positive deviation by FaSSIF solubilization was not reflected in the mass transport–time profiles. Interestingly, FDN concentrations remain constant until the amount of IPM added was over 1000 μg/mL. No decrease in the membrane transport of FDN was observed for a 1:1 M ratio of FDN-IPM combination. This study demonstrates the importance of studying amorphous multidrug formulations under physiologically relevant conditions to obtain insights into the performance of these formulations after oral administration.

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Materials: RTV and ATV sulfate were purchased from Attix Pharmaceuticals (Toronto, Canada) and Chemtronica (Stockholm, Sweden). IPM was obtained from Recipharm (Milan, Italy). FDN was a gift from AstraZeneca (Mölndal, Sweden). Hydroxypropyl methylcellulose acetate succinate (HPMCAS: Shin-Etsu AQOAT, Type AS-MF) polymer was a gift from Shin-Etsu Chemical Co. (Tokyo, Japan). Polyvinylpyrrolidone (PVP: Kollidon, Type 17-PF) polymer was a gift from BASF Ltd. (Stockholm, Sweden). The chemical structures of the model drugs and polymers are presented in Figure 1. Acetonitrile, methanol, and dichloromethane were acquired from CARLO ERBA Reagents S.A.S. (Barcelona, Spain) or Sigma-Aldrich (Stockholm, Sweden). Sodium hydroxide pellets, sodium chloride, and sodium dihydrogen phosphate dihydrate were purchased from CARLO ERBA Reagents S.A.S. (Barcelona, Spain), Sigma-Aldrich (Stockholm, Sweden), and Merck (Darmstadt, Germany), respectively. FaSSIF-V1 powder was procured from biorelevant.com (Croydon, UK). Spectra/Por 1 regenerated cellulose membrane with a molecular weight cutoff value of 6–8 kD was purchased from VWR (Stockholm, Sweden). Milli-Q water was used for all aqueous solutions. All drugs were received and used as received except for ATV. The amorphous base form of ATV was prepared as described earlier; (12) briefly, the drug was dissolved in methanol, then the solution was titrated with 0.1 M sodium hydroxide until the amorphous base precipitated. The crystalline form was then obtained by adding a water/methanol (1:1 v/v) mixture to the amorphous powder while stirring for 96 h at room temperature. Molecular properties of the model drugs were calculated with the software ADMET predictor (SimulationPlus, CA) using molecules as the structure data file.

Article information: Mira El Sayed, Amjad Alhalaweh, and Christel A. S. Bergström. Molecular Pharmaceutics Article ASAP. DOI: 10.1021/acs.molpharmaceut.1c00480