Toward an Improved Understanding of the Precipitation Behavior of Weakly Basic Drugs from Oral Lipid-Based Formulations

Stillhart, Cordula; Dürr, Désirée; Kuentz, Martin

doi:10.1002/jps.23892

Cited by 54 publications

(63 citation statements)

References 35 publications

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“…It dissolves in the acidic pH of the stomach, as it is presented in its ionized form. However, in basic pH, carvedilol may precipitate in the distal small intestine (6,8,9). Stillhart et al, for example, found that 78.2-91.8% of carvedilol precipitates in a crystalline or amorphous form under digestion condition (9).…”

Section: Introductionmentioning

confidence: 99%

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pH-Dependent Solubility and Dissolution Behavior of Carvedilol—Case Example of a Weakly Basic BCS Class II Drug

et al. 2015

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Abstract. The objective of this study was to investigate the pH-dependent solubility and dissolution of weakly basic Biopharmaceutical Classification Systems (BCS) class II drugs, characterized by low solubility and high permeability, using carvedilol, a weak base with a pK a value of 7.8, as a model drug. A series of solubility and in vitro dissolution studies was carried out using media that simulate the gastric and intestinal fluids and cover the physiological pH range of the GI from 1.2 to 7.8. The effect of ionic strength, buffer capacity, and buffer species of the dissolution media on the solubility and dissolution behavior of carvedilol was also investigated. The study revealed that carvedilol exhibited a typical weak base pH-dependent solubility profile with a high solubility at low pH (545.1-2591.4 μg/mL within the pH range 1.2-5.0) and low solubility at high pH (5.8-51.9 μg/mL within the pH range 6.5-7.8). The dissolution behavior of carvedilol was consistent with the solubility results, where carvedilol release was complete (95.8-98.2% released within 60 min) in media simulating the gastric fluid (pH 1.2-5.0) and relatively low (15.9-86.2% released within 240 min) in media simulating the intestinal fluid (pH 6.5-7.8). It was found that the buffer species of the dissolution media may influence the solubility and consequently the percentage of carvedilol released by forming carvedilol salts of varying solubilities. Carvedilol solubility and dissolution decreased with increasing ionic strength, while lowering the buffer capacity resulted in a decrease in carvedilol solubility and dissolution rate.

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Section: Introductionmentioning

confidence: 99%

“…However, in basic pH, carvedilol may precipitate in the distal small intestine (6,8,9). Stillhart et al, for example, found that 78.2-91.8% of carvedilol precipitates in a crystalline or amorphous form under digestion condition (9). Due to its poor aqueous solubility, carvedilol exhibits very low bioavailability (10,11).…”

Section: Introductionmentioning

confidence: 99%

pH-Dependent Solubility and Dissolution Behavior of Carvedilol—Case Example of a Weakly Basic BCS Class II Drug

et al. 2015

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“…Furthermore, it appears that in the case of the non-ionisable com-603 pound such as fenofibrate, the risk of reduced in vivo absorption due to digestion-induced drug precipitation is low [14,23,31]. 605 However, in the case of weak bases, in particular, there is potential 606 for formulation digestion by intestinal lipases to result in a loss of 607 solubilisation and cause precipitation [32,33]. These effects appear 608 to be drug and formulation specific and currently need to be 609 assessed on a case by case basis [34].…”

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confidence: 98%

Lipidic dispersion to reduce food dependent oral bioavailability of fenofibrate: In vitro, in vivo and in silico assessments

O’Shea

Faisal

Ruane‐O’Hora

et al. 2015

European Journal of Pharmaceutics and Biopharmaceutics

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“…Hence, for standard in vitro testing of LBFs, physiological levels of calcium are desirable as drug distribution is believed to be predictive of in vivo bioavailability. It is not sufficient to assume that only solubilized drug will be available for absorption, when applying in vitro lipolysis models, as recent studies have shown that precipitated drug depending on its solid state might be available for absorption (39)(40)(41). More studies are, however, needed in order to fully elucidate how drug distribution data from in vitro lipolysis are interpreted as recent studies have found discrepancies between drug distribution data and bioavailability (42,43).…”

Section: Discussionmentioning

confidence: 99%

Toward the Establishment of Standardized In Vitro Tests for Lipid-Based Formulations, Part 6: Effects of Varying Pancreatin and Calcium Levels

Sassene

Kleberg

Williams³

et al. 2014

AAPS J

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Abstract. The impact of pancreatin and calcium addition on a wide array of lipid-based formulations (LBFs) during in vitro lipolysis, with regard to digestion rates and distribution of the model drug danazol, was investigated. Pancreatin primarily affected the extent of digestion, leaving drug distribution somewhat unaffected. Calcium only affected the extent of digestion slightly but had a major influence on drug distribution, with more drug precipitating at higher calcium levels. This is likely to be caused by a combination of removal of lipolysis products from solution by the formation of calcium soaps and calcium precipitating with bile acids, events known to reduce the solubilizing capacity of LBFs dispersed in biorelevant media. Further, during the digestion of hydrophilic LBFs, like IIIA-LC, the un-ionizedionized ratio of free fatty acids (FFA) remained unchanged at physiological calcium levels. This makes the titration curves at pH 6.5 representable for digestion. However, caution should be taken when interpreting lipolysis curves of lipophilic LBFs, like I-LC, at pH 6.5, at physiological levels of calcium (1.4 mM); un-ionized-ionized ratio of FFA might change during digestion, rendering the lipolysis curve at pH 6.5 non-representable for the total digestion. The ratio of un-ionized-ionized FFAs can be maintained during digestion by applying non-physiological levels of calcium, resulting in a modified drug distribution with increased drug precipitation. However, as the main objective of the in vitro digestion model is to evaluate drug distribution, which is believed to have an impact on bioavailability in vivo, a physiological level (1.4 mM) of calcium is preferred.

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Toward an Improved Understanding of the Precipitation Behavior of Weakly Basic Drugs from Oral Lipid-Based Formulations

Cited by 54 publications

References 35 publications

pH-Dependent Solubility and Dissolution Behavior of Carvedilol—Case Example of a Weakly Basic BCS Class II Drug

pH-Dependent Solubility and Dissolution Behavior of Carvedilol—Case Example of a Weakly Basic BCS Class II Drug

Lipidic dispersion to reduce food dependent oral bioavailability of fenofibrate: In vitro, in vivo and in silico assessments

Toward the Establishment of Standardized In Vitro Tests for Lipid-Based Formulations, Part 6: Effects of Varying Pancreatin and Calcium Levels

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