Permeability assessment of poorly water‐soluble compounds under solubilizing conditions: The reciprocal permeability approach

• Published in: Journal of pharmaceutical sciences 2006-10, Vol.95 (10), p.2170-2185
• Main Authors: Katneni, Kasiram, Charman, Susan A., Porter, Christopher J.H.
• Format: Article
• Language: English
• Subjects: Animals; Antipyrine - chemistry; Antipyrine - metabolism; Biological and medical sciences; Cinnarizine - chemistry; Cinnarizine - metabolism; Diazepam - chemistry; Diazepam - metabolism; General pharmacology; Glycerol - analogs & derivatives; Glycerol - chemistry; In Vitro Techniques; Intestinal Absorption; Intestinal Mucosa - drug effects; Intestinal Mucosa - metabolism; Jejunum - metabolism; Male; Medical sciences; micellar association constant; Micelles; Naproxen - chemistry; Naproxen - metabolism; Permeability; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Polysorbates - chemistry; Polysorbates - pharmacology; poorly water-soluble drug; Propranolol - chemistry; Propranolol - metabolism; Rats; Rats, Sprague-Dawley; Solubility; solubilization; surfactant; Water - chemistry
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1002/jps.20687

The objective of this study was to develop a general method to assess the intestinal permeability of poorly water‐soluble drugs where low‐aqueous drug solubility requires conduct of experiments under solubilizing experimental conditions. The permeability (Papp) of diazepam (DIA) was assessed across excised rat jejunum in the absence (Pappcontrol) and presence (Pappuncorr) of polysorbate‐80 (PS‐80). The micellar association constant (Ka) of DIA, estimated via equilibrium solubility studies, was used to correct Pappuncorr data and obtain an estimate of the true permeability coefficient (Pappcorr). An alternate approach was also developed (the reciprocal permeability approach) to allow direct estimation of Pappcorr without the need for independent estimation of Ka. The approach was further examined experimentally using a range of model drugs. DIA Pappcorr values obtained using the Ka from equilibrium solubility studies deviated from Pappcontrol values, especially at PS‐80 concentrations above 0.1% w/v. In contrast, data obtained using the reciprocal permeability method were consistent with Pappcontrol across the PS‐80 concentration range. Similar trends were observed with propranolol (PRO), antipyrine (ANT), naproxen (NAP), and cinnarizine (CIN). The reciprocal permeability approach therefore provides a simple and accurate method by which the permeability of poorly water‐soluble compounds may be estimated under solubilizing conditions.