The topography of simulated intestinal equilibrium solubility

Research output: Contribution to journalArticle

Abstract

Oral administration of a solid dosage form requires drug dissolution in the gastrointestinal tract before absorption. Solubility is a key factor controlling dissolution, and it is recognized that, within the intestinal tract, this is influenced by the luminal fluid pH, amphiphile content, and composition. Various simulated intestinal fluid recipes have been introduced to mimic this behavior and studied using a range of different experimental techniques. In this article, we have measured equilibrium solubility utilizing a novel four component mixture design (4CMD) with biorelevant amphiphiles (bile salt, phospholipid, oleate, and monoglyceride) within a matrix of three pH values (5, 6, and 7) and total amphiphile concentrations (11.7, 30.6, and 77.5 mM) to provide a topographical and statistical overview. Three poorly soluble drugs representing acidic (indomethacin), basic (carvedilol), and neutral (fenofibrate) categories have been studied. The macroscopic solubility behavior agrees with literature and exhibits an overall increasing solubility from low pH and total amphiphile concentration to high pH and total amphiphile concentration. Within the matrix, all three drugs display different topographies, which can be related to the statistical effect levels of the individual amphiphiles or amphiphile interactions on solubility. The study also identifies previously unreported three and four way factor interactions notably between bile salt, phospholipid, pH, and total amphiphile concentration. In addition, the results also reveal that solubility variability is linked to the number of amphiphiles and the respective ratios in the measurement fluid, with the minimum variation present in systems containing all four amphiphiles. The individual 4CMD experiments within the matrix can be linked to provide a possible intestinal solubility window for each drug that could be applied in PBPK modeling systems. Overall the approach provides a novel overview of intestinal solubility topography along with greater detail on the impact of the various factors studied; however, each matrix requires 351 individual solubility measurements. Further studies will be required to refine the experimental protocol in order the maximize information garnered while minimizing the number of measurements required.

LanguageEnglish
Pages1890-1905
Number of pages16
JournalMolecular Pharmaceutics
Volume16
Issue number5
Early online date8 Mar 2019
DOIs
Publication statusPublished - 6 May 2019

Fingerprint

Solubility
Bile Acids and Salts
Phospholipids
Pharmaceutical Preparations
Monoglycerides
Fenofibrate
Dosage Forms
Oleic Acid
Indomethacin
Oral Administration
Gastrointestinal Tract

Keywords

  • oral drugs
  • drug dissolution
  • absorption

Cite this

@article{44583fbf11f54aa781f51c1747663baa,
title = "The topography of simulated intestinal equilibrium solubility",
abstract = "Oral administration of a solid dosage form requires drug dissolution in the gastrointestinal tract before absorption. Solubility is a key factor controlling dissolution, and it is recognized that, within the intestinal tract, this is influenced by the luminal fluid pH, amphiphile content, and composition. Various simulated intestinal fluid recipes have been introduced to mimic this behavior and studied using a range of different experimental techniques. In this article, we have measured equilibrium solubility utilizing a novel four component mixture design (4CMD) with biorelevant amphiphiles (bile salt, phospholipid, oleate, and monoglyceride) within a matrix of three pH values (5, 6, and 7) and total amphiphile concentrations (11.7, 30.6, and 77.5 mM) to provide a topographical and statistical overview. Three poorly soluble drugs representing acidic (indomethacin), basic (carvedilol), and neutral (fenofibrate) categories have been studied. The macroscopic solubility behavior agrees with literature and exhibits an overall increasing solubility from low pH and total amphiphile concentration to high pH and total amphiphile concentration. Within the matrix, all three drugs display different topographies, which can be related to the statistical effect levels of the individual amphiphiles or amphiphile interactions on solubility. The study also identifies previously unreported three and four way factor interactions notably between bile salt, phospholipid, pH, and total amphiphile concentration. In addition, the results also reveal that solubility variability is linked to the number of amphiphiles and the respective ratios in the measurement fluid, with the minimum variation present in systems containing all four amphiphiles. The individual 4CMD experiments within the matrix can be linked to provide a possible intestinal solubility window for each drug that could be applied in PBPK modeling systems. Overall the approach provides a novel overview of intestinal solubility topography along with greater detail on the impact of the various factors studied; however, each matrix requires 351 individual solubility measurements. Further studies will be required to refine the experimental protocol in order the maximize information garnered while minimizing the number of measurements required.",
keywords = "oral drugs, drug dissolution, absorption",
author = "Claire Dunn and Jeremy Perrier and Ibrahim Khadra and Wilson, {Clive G.} and Halbert, {Gavin W.}",
year = "2019",
month = "5",
day = "6",
doi = "10.1021/acs.molpharmaceut.8b01238",
language = "English",
volume = "16",
pages = "1890--1905",
journal = "Molecular Pharmaceutics",
issn = "1543-8384",
publisher = "American Chemical Society",
number = "5",

}

TY - JOUR

T1 - The topography of simulated intestinal equilibrium solubility

AU - Dunn, Claire

AU - Perrier, Jeremy

AU - Khadra, Ibrahim

AU - Wilson, Clive G.

AU - Halbert, Gavin W.

PY - 2019/5/6

Y1 - 2019/5/6

N2 - Oral administration of a solid dosage form requires drug dissolution in the gastrointestinal tract before absorption. Solubility is a key factor controlling dissolution, and it is recognized that, within the intestinal tract, this is influenced by the luminal fluid pH, amphiphile content, and composition. Various simulated intestinal fluid recipes have been introduced to mimic this behavior and studied using a range of different experimental techniques. In this article, we have measured equilibrium solubility utilizing a novel four component mixture design (4CMD) with biorelevant amphiphiles (bile salt, phospholipid, oleate, and monoglyceride) within a matrix of three pH values (5, 6, and 7) and total amphiphile concentrations (11.7, 30.6, and 77.5 mM) to provide a topographical and statistical overview. Three poorly soluble drugs representing acidic (indomethacin), basic (carvedilol), and neutral (fenofibrate) categories have been studied. The macroscopic solubility behavior agrees with literature and exhibits an overall increasing solubility from low pH and total amphiphile concentration to high pH and total amphiphile concentration. Within the matrix, all three drugs display different topographies, which can be related to the statistical effect levels of the individual amphiphiles or amphiphile interactions on solubility. The study also identifies previously unreported three and four way factor interactions notably between bile salt, phospholipid, pH, and total amphiphile concentration. In addition, the results also reveal that solubility variability is linked to the number of amphiphiles and the respective ratios in the measurement fluid, with the minimum variation present in systems containing all four amphiphiles. The individual 4CMD experiments within the matrix can be linked to provide a possible intestinal solubility window for each drug that could be applied in PBPK modeling systems. Overall the approach provides a novel overview of intestinal solubility topography along with greater detail on the impact of the various factors studied; however, each matrix requires 351 individual solubility measurements. Further studies will be required to refine the experimental protocol in order the maximize information garnered while minimizing the number of measurements required.

AB - Oral administration of a solid dosage form requires drug dissolution in the gastrointestinal tract before absorption. Solubility is a key factor controlling dissolution, and it is recognized that, within the intestinal tract, this is influenced by the luminal fluid pH, amphiphile content, and composition. Various simulated intestinal fluid recipes have been introduced to mimic this behavior and studied using a range of different experimental techniques. In this article, we have measured equilibrium solubility utilizing a novel four component mixture design (4CMD) with biorelevant amphiphiles (bile salt, phospholipid, oleate, and monoglyceride) within a matrix of three pH values (5, 6, and 7) and total amphiphile concentrations (11.7, 30.6, and 77.5 mM) to provide a topographical and statistical overview. Three poorly soluble drugs representing acidic (indomethacin), basic (carvedilol), and neutral (fenofibrate) categories have been studied. The macroscopic solubility behavior agrees with literature and exhibits an overall increasing solubility from low pH and total amphiphile concentration to high pH and total amphiphile concentration. Within the matrix, all three drugs display different topographies, which can be related to the statistical effect levels of the individual amphiphiles or amphiphile interactions on solubility. The study also identifies previously unreported three and four way factor interactions notably between bile salt, phospholipid, pH, and total amphiphile concentration. In addition, the results also reveal that solubility variability is linked to the number of amphiphiles and the respective ratios in the measurement fluid, with the minimum variation present in systems containing all four amphiphiles. The individual 4CMD experiments within the matrix can be linked to provide a possible intestinal solubility window for each drug that could be applied in PBPK modeling systems. Overall the approach provides a novel overview of intestinal solubility topography along with greater detail on the impact of the various factors studied; however, each matrix requires 351 individual solubility measurements. Further studies will be required to refine the experimental protocol in order the maximize information garnered while minimizing the number of measurements required.

KW - oral drugs

KW - drug dissolution

KW - absorption

UR - https://pubs.acs.org/journal/mpohbp

U2 - 10.1021/acs.molpharmaceut.8b01238

DO - 10.1021/acs.molpharmaceut.8b01238

M3 - Article

VL - 16

SP - 1890

EP - 1905

JO - Molecular Pharmaceutics

T2 - Molecular Pharmaceutics

JF - Molecular Pharmaceutics

SN - 1543-8384

IS - 5

ER -