The impact of surface area per volume (SA/V) ratio on drug transport from supersaturated solutions of ketoconazole

Higashino, Haruki; Develin, Corey; Higashino, Chie; Lim, Tyler; Miezeiewski, Blair; Strab, Robert; Patel, Rachana; Bhoopathy, Siddhartha; Hidalgo, Ismael J.

doi:10.1016/j.ejpb.2023.05.016

Cited by 5 publications

(2 citation statements)

References 30 publications

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“…One possible reason for this would be that PPB has been used in the in vitro systems in most cases. However, other factors such as the coexistence of bile micelles and mucus components, − agitation strength, and permeation clearance may also affect the precipitation of drugs in vivo . − These factors should be considered when investigating in vivo predictability. Jede et al reported that in vivo supersaturation in rats was better predicted by BCB than by PPB …”

Section: Discussionmentioning

confidence: 99%

Drug Crystal Precipitation in Biorelevant Bicarbonate Buffer: A Well-Controlled Comparative Study with Phosphate Buffer

Yamamoto,

Sugano

2024

Mol. Pharmaceutics

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The purpose of the present study was to clarify whether the precipitation profile of a drug in bicarbonate buffer (BCB) may differ from that in phosphate buffer (PPB) by a well-controlled comparative study. The precipitation profiles of structurally diverse poorly soluble drugs in BCB and PPB were evaluated by a pH-shift precipitation test or a solvent-shift precipitation test (seven weak acid drugs (pK a : 4.2 to 7.5), six weak base drugs (pK a : 4.8 to 8.4), one unionizable drug, and one zwitterionic drug). To focus on crystal precipitation processes, each ionizable drug was first completely dissolved in an HCl (pH 3.0) or NaOH (pH 11.0) aqueous solution (450 mL, 50 rpm, 37 °C). A 10-fold concentrated buffer solution (50 mL) was then added to shift the pH value to 6.5 to initiate precipitation (final volume: 500 mL, buffer capacity (β): 4.4 mM/ΔpH (BCB: 10 mM or PPB: 8 mM), ionic strength (I): 0.14 M (adjusted by NaCl)). The pH, β, and I values were set to be relevant to the physiology of the small intestine. For an unionizable drug, a solvent-shift method was used (1/100 dilution). To maintain the pH value of BCB, a floating lid was used to avoid the loss of CO 2 . The floating lid was applied also to PPB to precisely align the experimental conditions between BCB and PPB. The solid form of the precipitants was identified by powder X-ray diffraction and differential scanning microscopy. The precipitation of weak acids (pK a ≤ 5.1) and weak bases (pK a ≥ 7.3) was found to be slower in BCB than in PPB. In contrast, the precipitation profiles in BCB and PPB were similar for less ionizable or nonionizable drugs at pH 6.5. The final pH values of the bulk phase were pH 6.5 ± 0.1 after the precipitation tests in all cases. All precipitates were in their respective free forms. The precipitation of ionizable weak acids and bases was slower in BCB than in PPB. The surface pH of precipitating particles may have differed between BCB and PPB due to the slow hydration process of CO 2 specific to BCB. Since BCB is a physiological buffer in the small intestine, it should be considered as an option for precipitation studies of ionizable weak acids and bases.

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Section: Discussionmentioning

confidence: 99%

Drug Crystal Precipitation in Biorelevant Bicarbonate Buffer: A Well-Controlled Comparative Study with Phosphate Buffer

Yamamoto,

Sugano

2024

Mol. Pharmaceutics

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“…[1][2][3][4] The IDAS2 has a much smaller absorptive surface area (SA) per volume ratio (SA/V) than other in vitro systems. [1][2][3][4][5][6][7][8][9][10][11] Thus, there is a concern that the permeated amount may not increase with increasing the drug dose due to the saturation of cell monolayer permeation. If the IDAS2 is insensitive to the applied dose, all test formulations will be erroneously deemed BE due to the lack of the ability to detect the difference in the permeated amount.…”

Section: Introductionmentioning

confidence: 99%

Qualification of <i>In Vitro</i> Dissolution Absorption System 2 (IDAS2) with Caco-2 and MDCK Cell Monolayers: Dose Sensitivity Study Using BCS Class I and III Drugs

Higashino,

Develin,

Higashino

et al. 2024

Biological & Pharmaceutical Bulletin

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The effects of degree and duration of supersaturation on in vivo absorption profiles for highly permeable drugs, dipyridamole and ketoconazole

Higashino

Minami

Takagi

et al. 2023

European Journal of Pharmaceutics and Biopharmaceutics

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The impact of surface area per volume (SA/V) ratio on drug transport from supersaturated solutions of ketoconazole

Cited by 5 publications

References 30 publications

Drug Crystal Precipitation in Biorelevant Bicarbonate Buffer: A Well-Controlled Comparative Study with Phosphate Buffer

Drug Crystal Precipitation in Biorelevant Bicarbonate Buffer: A Well-Controlled Comparative Study with Phosphate Buffer

Qualification of <i>In Vitro</i> Dissolution Absorption System 2 (IDAS2) with Caco-2 and MDCK Cell Monolayers: Dose Sensitivity Study Using BCS Class I and III Drugs

The effects of degree and duration of supersaturation on in vivo absorption profiles for highly permeable drugs, dipyridamole and ketoconazole

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