Quasi-equilibrium analysis of the ion-pair mediated membrane transport of low-permeability drugs

Miller, Jonathan M.; Dahan, Arik; Gupta, Divender; Varghese, Sheeba; Amidon, Gordon L.

doi:10.1016/j.jconrel.2009.02.018

Cited by 56 publications

(50 citation statements)

References 27 publications

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“…The formation of an ion pair in aqueous solution and its partition into an immiscible organic solvent (like octanol) are described by quasi-equilibrium analysis as reported by Miller et al (2009). In this study amifostine was selected as Basic compound, where [B] represent concentration of basic drug in aqueous phase.…”

Section: Ion Pair Mediated Octanol-buffer Partitioning (Ph 65)mentioning

confidence: 99%

See 1 more Smart Citation

Enhancement and in vitro evaluation of amifostine permeation through artificial membrane (PAMPA) via ion pairing approach and mechanistic selection of its optimal counter ion

Samiei

Shafaati

Zarghi

et al. 2014

European Journal of Pharmaceutical Sciences

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Section: Ion Pair Mediated Octanol-buffer Partitioning (Ph 65)mentioning

confidence: 99%

“…(2). The distinct and thermodynamically stable formed species [AB] aq partition between the aqueous and organic phases (Miller, 2009;Miller et al, 2009Miller et al, , 2010.…”

Section: Ion Pair Mediated Octanol-buffer Partitioning (Ph 65)mentioning

confidence: 99%

Enhancement and in vitro evaluation of amifostine permeation through artificial membrane (PAMPA) via ion pairing approach and mechanistic selection of its optimal counter ion

Samiei

Shafaati

Zarghi

et al. 2014

European Journal of Pharmaceutical Sciences

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“…Experimental octanol-buffer partition coefficients, Log D, for pseudoephedrine and metoprolol at pH 6.5, 7.0, and 7.5 were determined using the traditional shake-flask method (18,19). Briefly, solutions of pseudoephedrine or metoprolol were prepared in octanol-saturated phosphate buffers with pH values of 6.5, 7.0, and 7.5.…”

Section: Determination Of Octanol-buffer Partition Coefficientsmentioning

confidence: 99%

“…The simultaneous determination of pseudoephedrine, metoprolol and phenol red was achieved using a Waters (Milford, MA) Acquity UPLC BEH C 18 …”

Section: Ultra-performance Liquid Chromatographymentioning

confidence: 99%

Regional-Dependent Intestinal Permeability and BCS Classification: Elucidation of pH-Related Complexity in Rats Using Pseudoephedrine

Fairstein

Swissa

Dahan

2013

AAPS J

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Abstract. Based on its lower Log P value relative to metoprolol, a marker for the low/high-permeability (P eff ) class boundary, pseudoephedrine was provisionally classified as BCS low-permeability compound. On the other hand, following oral administration, pseudoephedrine fraction dose absorbed (F abs ) and systemic bioavailability approaches 100%. This represents a challenge to the generally recognized P eff -F abs correlation. The purpose of this study was to elucidate the underlying mechanisms behind the confusion in pseudoephedrine's BCS classification. Pseudoephedrine's BCS solubility class was determined, and its physicochemical properties and intestinal permeability were thoroughly investigated, both in vitro and in vivo in rats, considering the complexity of the whole of the small intestine. Pseudoephedrine was found to be unequivocally a high-solubility compound. All of the permeability studies revealed similar phenomenon; at any given intestinal segment/pH, the permeability of metoprolol was higher than that of pseudoephedrine, however, as the intestinal region becomes progressively distal, and the pH gradually increases, pseudoephedrine's permeability rises above that of metoprolol in the former segment. This unique permeability pattern likely explains pseudoephedrine's complete absorption. In conclusion, pseudoephedrine is a BCS Class I compound; no discrepancy between P eff and F abs is involved in its absorption. Rather, it reflects the complexity behind P eff when considering the whole of the intestine. We propose to allow high-permeability classification to drugs with P eff that matches/exceeds the low/high class benchmark anywhere throughout the intestinal tract and not restricted necessarily to the jejunum.

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“…Permeability studies through artificial membrane were carried out using the hexadecane-based parallel artificial membrane permeability assay (PAMPA), as described previously (9,19,20). Various levels of supersaturated nifedipine solutions (0.5 to 20 times equilibrium solubility) were prepared from the ASDs with pH6.5 10 mM MES buffer.…”

Section: Parallel Artificial Membrane Permeability Assaymentioning

confidence: 99%

The Twofold Advantage of the Amorphous Form as an Oral Drug Delivery Practice for Lipophilic Compounds: Increased Apparent Solubility and Drug Flux Through the Intestinal Membrane

Dahan

Beig

Ioffe-Dahan

et al. 2012

AAPS J

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Abstract. The purposes of this study were to assess the efficiency of different nifedipine amorphous solid dispersions (ASDs) in achieving and maintaining supersaturation and to investigate the solubilitypermeability interplay when increasing the apparent solubility via ASD formulations. Spray-dried ASDs of nifedipine in three different hydrophilic polymers, hydroxypropyl methylcellulose acetate succinate (HPMC-AS), copovidone, and polyvinylpyrrolidone (PVP), were prepared and characterized by powder X-ray diffraction and differential scanning calorimetry. The ability of these formulations to achieve and maintain supersaturation over 24 h was assessed. Then, nifedipine's apparent intestinal permeability was investigated as a function of increasing supersaturation in the parallel artificial membrane permeability assay model and in the single-pass rat intestinal perfusion model. The efficiency of the different ASDs to achieve and maintain supersaturation of nifedipine was found to be highly polymer dependent; while a dispersion in HPMC-AS enabled supersaturation 20× that of the crystalline aqueous solubility, a dispersion in copovidone enabled 10×, and PVP allowed supersaturation of only 5× that of the crystalline solubility. Nifedipine flux across the intestine from supersaturated solutions was increased, and the apparent intestinal permeability was constant, irrespective of the degree of supersaturation or the polymer being used. In conclusion, while with other solubility-enabling approaches (e.g., surfactants, cyclodextrins, cosolvents), it is not enough to increase the apparent solubility, but to strike the optimal solubility-permeability balance, which limits the chances for successful drug delivery, the amorphous form emerges as a more advantageous strategy, in which higher apparent solubility (i.e., supersaturation) will be readily translated into higher drug flux and overall absorption.

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Quasi-equilibrium analysis of the ion-pair mediated membrane transport of low-permeability drugs

Cited by 56 publications

References 27 publications

Enhancement and in vitro evaluation of amifostine permeation through artificial membrane (PAMPA) via ion pairing approach and mechanistic selection of its optimal counter ion

Enhancement and in vitro evaluation of amifostine permeation through artificial membrane (PAMPA) via ion pairing approach and mechanistic selection of its optimal counter ion

Regional-Dependent Intestinal Permeability and BCS Classification: Elucidation of pH-Related Complexity in Rats Using Pseudoephedrine

The Twofold Advantage of the Amorphous Form as an Oral Drug Delivery Practice for Lipophilic Compounds: Increased Apparent Solubility and Drug Flux Through the Intestinal Membrane

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