Dissolution-permeation approach for biopharmaceutical evaluation: a feasibility study using naproxen

Abstract

Objectives: Dissolution and/or release profile alone are insufficient to predict the in vivo absorption of poorly soluble drugs. Thus, permeation test becomes a critical component for biopharmaceutical assessment. Currently, none of the dissolution-permeation systems include the compendial dissolution, or provide large acceptor volumes, or are compatible with ex vivo membranes. Addressing the limitations of the existing dissolution-permeation testing systems, we propose the integration of the Ussing (permeability) chamber to the dissolution apparatus.

Methods: The assembled dissolution-permeation system evaluated the effect of 5% and 10% soy L-α-phosphatidylcholine in dodecane (LiDo) and permeable membrane material on apparent permeability coefficients of naproxen, a BCS II class drug.

Results: Naproxen release from the tablets reached approximately 100% within 30 min. Naproxen P_app across a 0.45 µm PVDF membrane was 0.91 ± 0.35 × 10^-8 cm/s for 5% LiDo, and 0.75 ± 0.23 × 10^-8 cm/s for 10% LiDo. The 0.20 μm PC membrane with 5% LiDo showed a P_app of 1.99 ± 0.57 × 10^-8 cm/s.

Conclusion: The proposed compendial dissolution-permeation system with an Ussing chamber allowed for the simultaneous determination of dissolution and permeability of naproxen. All P_app values obtained were approximately 100-fold lower than those reported in the literature. The results may have been influenced by the differences in sink conditions and permeable membrane composition. The use of a PC membrane resulted in higher permeability, compared to the PVDF membrane. Adequately improved, this methodology could be transferred for the ex vivo membrane dissolution-permeability testing.

Introduction

According to the Biopharmaceutical Classification System (BCS) and its modification, the Developability Classification System (DCS), orally administered drugs are classified into four classes based on their permeability across the gastrointestinal (GIT) membranes and dose solubility in relevant GIT fluid volumes [1]. The modern paradigm in pharmaceutical science pipelines clearly shows the shift from drugs with no solubility issues in aqueous media (BCS classes I/III) to the predominance of poorly soluble drugs (BCS classes II/IV) [2]. For the latter, the dissolution and/or release profile data alone are insufficient to predict in vivo drug behaviour, making permeation testing a critical component of biopharmaceutical assessment [3]. Permeability across the GIT membranes, which determines the absorption and influences the bioavailability, is crucial for assessing the intrinsic properties of drug substances and for formulation screening. Currently, dissolution-permeation testing is mostly applied to poorly soluble drugs. Few systems are commercially available, each with advantages and limitations, which have been addressed comprehensively in the recent review article regarding dissolution-permeation systems [3].

To the best of our knowledge, the volume of the acceptor compartment of the commercially available dissolution-permeation systems, which includes compendial dissolution/release testing does not exceed 50 mL. None of the commercially available dissolution-permeation systems allows simultaneous compatibility with ex vivo membranes. Addressing the limitations of the existing dissolution-permeation testing systems, we propose the integration of the Ussing (permeability) chamber to the compendial dissolution apparatus. Dissolution testing procedures and volumes are highly standardised, and they allow the use of larger acceptor compartment volumes, which is crucial for poorly soluble compounds, whereas the Ussing chamber is compatible with ex vivo tissue and artificial membranes. Compared to the equipment, such as MicroFLUX and MacroFLUX, the proposed system could be compatible with an excised intestinal tissue. Compared to the parallel artificial membrane permeability assay (PAMPA), and equipment, such as MicroFLUX and MacroFLUX, the proposed system provides larger and adjustable acceptor compartment [3]. The innovative compendial dissolution-permeation method, when applied in biopharmaceutical research of oral dosage forms, targets multiple current global pharmaceutical drug development problems such as, the improvement of the bioavailability of oral formulations, the reduction of financial investments in clinical studies, the increase in success rate and reduction in risks of clinical studies, the improvement in therapeutical outcomes of drug treatment, the reduction of the drug doses required to achieve therapeutical effects, the reduction of non-absorbed drug amount and its impact on the environment.

Primarily, this study aimed to assemble a dissolution-permeation system setup based on the compendial dissolution (USP2) apparatus and the commercially available Ussing chamber. A secondary aim was to utilise the assembled setup and evaluate the effect of 5% and 10% soy L-α-phosphatidylcholine in dodecane (LiDo) and permeable membrane material on the apparent permeability coefficients (Papp) of naproxen. Naproxen is a passively transported drug, and although it exhibits limited solubility in acidic biological fluids, it exhibits high solubility in close to neutral pH solutions [4], with no issues regarding permeability across intestinal membranes. Lastly, the observed naproxen permeability was compared with literature data.

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Chemicals and reagents

Naproxen of Ph. Eur. purity standard (Sigma Aldrich, USA), and commercially available coated tablets Nalgesin (KRKA, Slovenia) containing 550 mg naproxen sodium, equivalent to 500 mg naproxen were used. KH2PO4 and NaOH were obtained from Sigma Aldrich, USA. Soy L-α-phosphatidylcholine (95%) was obtained from Avanti Polar Lipids, USA. Anhydrous dodecane (>99%) was obtained from Sigma Aldrich, USA. Ultra-purified water was obtained with a StakPure system (StakPure, Germany). 0.45 µm Hydrophobic PVDF (Durapore) membrane filters (thickness of 125 µm) were obtained from Merck Millipore (Millipore, Ireland). 0.2 µm polycarbonate membrane filters (PC, thickness of 10 µm) were obtained from GVS (USA).

Sitovs A, Gurkina K, Petersone L and Mohylyuk V (2026) Dissolution-permeation approach for biopharmaceutical evaluation: a feasibility study using naproxen. J. Pharm. Pharm. Sci. 29:16570. doi: 10.3389/jpps.2026.16570

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