Dual level statistical investigation of equilibrium solubility in simulated fasted and fed intestinal fluid

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Abstract

The oral route is the preferred option for drug administration but contains the inherent issue of drug absorption from the gastro-intestinal tract (GIT) in order to elicit systemic activity. A pre-requisite for absorption is drug dissolution, which is dependent upon drug solubility in the variable milieu of GIT fluid, with poorly soluble drugs presenting a formulation and biopharmaceutical challenge. Multiple factors within GIT fluid influence solubility ranging from pH to the concentration and ratio of amphiphilic substances such as phospholipid, bile salt, monoglyceride and cholesterol and to aid in vitro investigation simulated intestinal fluids (SIF) covering the fasted and fed state have been developed. SIF media is complex and statistical design of experiment (DoE) investigations have revealed the range of solubility values possible within each state due to physiological variability along with the media factors and factor interactions which influence solubility. However, these studies require large numbers of experiments (>60) and are not feasible or sensible within a drug development setting. In the current study a smaller dual level, reduced experimental number (20) DoE providing three arms covering the fasted and fed states along with a combined analysis has been investigated. The results indicate that this small scale investigation is feasible and provides solubility ranges that encompass published data in human and simulated fasted and fed fluids. The measured fasted and fed solubility ranges are in agreement with published large scale DoE results in around half of the cases, with the differences due to changes in media composition between studies. Indicating that drug specific behaviours are being determined and that careful media factor and concentration level selection is required in order to determine a physiologically relevant solubility range. The study also correctly identifies the major single factor or factors which influence solubility but it is evident that lower significance factors (for example bile salt) are not picked up due to the lower sample number employed. A similar issue is present with factor interactions with only a limited number available for study and generally not determined to have a significant solubility impact due to the lower statistical power of the study. The study indicates that a reduced experimental number DoE is feasible, will provide solubility range results with identification of major solubility factors however statistical limitations restrict the analysis. The approach therefore represents a useful initial screening tool that can guide further in depth analysis of a drug’s behavior in gastrointestinal fluids.
LanguageEnglish
Pages4170-4180
Number of pages11
JournalMolecular Pharmaceutics
Volume14
Issue number12
Early online date26 Oct 2017
DOIs
Publication statusPublished - 4 Dec 2017

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Solubility
Pharmaceutical Preparations
Bile Acids and Salts
Monoglycerides
Intestinal Absorption
Phospholipids
Research Design
Cholesterol

Keywords

  • soluble drugs
  • solubility
  • drug administration
  • drug absorption
  • gastro-intestinal tract (GIT)
  • gastrointestinal fluids

Cite this

@article{0024de5c4a934b159b0ed121b6f37bc2,
title = "Dual level statistical investigation of equilibrium solubility in simulated fasted and fed intestinal fluid",
abstract = "The oral route is the preferred option for drug administration but contains the inherent issue of drug absorption from the gastro-intestinal tract (GIT) in order to elicit systemic activity. A pre-requisite for absorption is drug dissolution, which is dependent upon drug solubility in the variable milieu of GIT fluid, with poorly soluble drugs presenting a formulation and biopharmaceutical challenge. Multiple factors within GIT fluid influence solubility ranging from pH to the concentration and ratio of amphiphilic substances such as phospholipid, bile salt, monoglyceride and cholesterol and to aid in vitro investigation simulated intestinal fluids (SIF) covering the fasted and fed state have been developed. SIF media is complex and statistical design of experiment (DoE) investigations have revealed the range of solubility values possible within each state due to physiological variability along with the media factors and factor interactions which influence solubility. However, these studies require large numbers of experiments (>60) and are not feasible or sensible within a drug development setting. In the current study a smaller dual level, reduced experimental number (20) DoE providing three arms covering the fasted and fed states along with a combined analysis has been investigated. The results indicate that this small scale investigation is feasible and provides solubility ranges that encompass published data in human and simulated fasted and fed fluids. The measured fasted and fed solubility ranges are in agreement with published large scale DoE results in around half of the cases, with the differences due to changes in media composition between studies. Indicating that drug specific behaviours are being determined and that careful media factor and concentration level selection is required in order to determine a physiologically relevant solubility range. The study also correctly identifies the major single factor or factors which influence solubility but it is evident that lower significance factors (for example bile salt) are not picked up due to the lower sample number employed. A similar issue is present with factor interactions with only a limited number available for study and generally not determined to have a significant solubility impact due to the lower statistical power of the study. The study indicates that a reduced experimental number DoE is feasible, will provide solubility range results with identification of major solubility factors however statistical limitations restrict the analysis. The approach therefore represents a useful initial screening tool that can guide further in depth analysis of a drug’s behavior in gastrointestinal fluids.",
keywords = "soluble drugs, solubility, drug administration, drug absorption, gastro-intestinal tract (GIT), gastrointestinal fluids",
author = "Ainousah, {Bayan E} and Jeremy Perrier and Claire Dunn and Ibrahim Khadra and Wilson, {Clive G.} and Halbert, {Gavin W}",
year = "2017",
month = "12",
day = "4",
doi = "10.1021/acs.molpharmaceut.7b00869",
language = "English",
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pages = "4170--4180",
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publisher = "American Chemical Society",
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TY - JOUR

T1 - Dual level statistical investigation of equilibrium solubility in simulated fasted and fed intestinal fluid

AU - Ainousah, Bayan E

AU - Perrier, Jeremy

AU - Dunn, Claire

AU - Khadra, Ibrahim

AU - Wilson, Clive G.

AU - Halbert, Gavin W

PY - 2017/12/4

Y1 - 2017/12/4

N2 - The oral route is the preferred option for drug administration but contains the inherent issue of drug absorption from the gastro-intestinal tract (GIT) in order to elicit systemic activity. A pre-requisite for absorption is drug dissolution, which is dependent upon drug solubility in the variable milieu of GIT fluid, with poorly soluble drugs presenting a formulation and biopharmaceutical challenge. Multiple factors within GIT fluid influence solubility ranging from pH to the concentration and ratio of amphiphilic substances such as phospholipid, bile salt, monoglyceride and cholesterol and to aid in vitro investigation simulated intestinal fluids (SIF) covering the fasted and fed state have been developed. SIF media is complex and statistical design of experiment (DoE) investigations have revealed the range of solubility values possible within each state due to physiological variability along with the media factors and factor interactions which influence solubility. However, these studies require large numbers of experiments (>60) and are not feasible or sensible within a drug development setting. In the current study a smaller dual level, reduced experimental number (20) DoE providing three arms covering the fasted and fed states along with a combined analysis has been investigated. The results indicate that this small scale investigation is feasible and provides solubility ranges that encompass published data in human and simulated fasted and fed fluids. The measured fasted and fed solubility ranges are in agreement with published large scale DoE results in around half of the cases, with the differences due to changes in media composition between studies. Indicating that drug specific behaviours are being determined and that careful media factor and concentration level selection is required in order to determine a physiologically relevant solubility range. The study also correctly identifies the major single factor or factors which influence solubility but it is evident that lower significance factors (for example bile salt) are not picked up due to the lower sample number employed. A similar issue is present with factor interactions with only a limited number available for study and generally not determined to have a significant solubility impact due to the lower statistical power of the study. The study indicates that a reduced experimental number DoE is feasible, will provide solubility range results with identification of major solubility factors however statistical limitations restrict the analysis. The approach therefore represents a useful initial screening tool that can guide further in depth analysis of a drug’s behavior in gastrointestinal fluids.

AB - The oral route is the preferred option for drug administration but contains the inherent issue of drug absorption from the gastro-intestinal tract (GIT) in order to elicit systemic activity. A pre-requisite for absorption is drug dissolution, which is dependent upon drug solubility in the variable milieu of GIT fluid, with poorly soluble drugs presenting a formulation and biopharmaceutical challenge. Multiple factors within GIT fluid influence solubility ranging from pH to the concentration and ratio of amphiphilic substances such as phospholipid, bile salt, monoglyceride and cholesterol and to aid in vitro investigation simulated intestinal fluids (SIF) covering the fasted and fed state have been developed. SIF media is complex and statistical design of experiment (DoE) investigations have revealed the range of solubility values possible within each state due to physiological variability along with the media factors and factor interactions which influence solubility. However, these studies require large numbers of experiments (>60) and are not feasible or sensible within a drug development setting. In the current study a smaller dual level, reduced experimental number (20) DoE providing three arms covering the fasted and fed states along with a combined analysis has been investigated. The results indicate that this small scale investigation is feasible and provides solubility ranges that encompass published data in human and simulated fasted and fed fluids. The measured fasted and fed solubility ranges are in agreement with published large scale DoE results in around half of the cases, with the differences due to changes in media composition between studies. Indicating that drug specific behaviours are being determined and that careful media factor and concentration level selection is required in order to determine a physiologically relevant solubility range. The study also correctly identifies the major single factor or factors which influence solubility but it is evident that lower significance factors (for example bile salt) are not picked up due to the lower sample number employed. A similar issue is present with factor interactions with only a limited number available for study and generally not determined to have a significant solubility impact due to the lower statistical power of the study. The study indicates that a reduced experimental number DoE is feasible, will provide solubility range results with identification of major solubility factors however statistical limitations restrict the analysis. The approach therefore represents a useful initial screening tool that can guide further in depth analysis of a drug’s behavior in gastrointestinal fluids.

KW - soluble drugs

KW - solubility

KW - drug administration

KW - drug absorption

KW - gastro-intestinal tract (GIT)

KW - gastrointestinal fluids

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

U2 - 10.1021/acs.molpharmaceut.7b00869

DO - 10.1021/acs.molpharmaceut.7b00869

M3 - Article

VL - 14

SP - 4170

EP - 4180

JO - Molecular Pharmaceutics

T2 - Molecular Pharmaceutics

JF - Molecular Pharmaceutics

SN - 1543-8384

IS - 12

ER -