Toward the establishment of standardized in vitro tests for lipid-based formulations, part 3: understanding supersaturation versus precipitation potential during the in vitro digestion of type I, II, IIIA, IIIB and IV lipid-based formulations

Hywel D Williams; Philip Sassene; Karen Kleberg; Marilyn Calderone; Annabel Igonin; Eduardo Jule; Jan Vertommen; Ross Blundell; Hassan Benameur; Anette Müllertz; Colin W Pouton; Christopher J H Porter; LFCS Consortium

doi:10.1007/s11095-013-1038-z

Toward the establishment of standardized in vitro tests for lipid-based formulations, part 3: understanding supersaturation versus precipitation potential during the in vitro digestion of type I, II, IIIA, IIIB and IV lipid-based formulations

Hywel D Williams, Philip Sassene, Karen Kleberg, Marilyn Calderone, Annabel Igonin, Eduardo Jule, Jan Vertommen, Ross Blundell, Hassan Benameur, Anette Müllertz, Colin W Pouton, Christopher J H Porter, LFCS Consortium

76 Citations (Scopus)

Abstract

PURPOSE: Recent studies have shown that digestion of lipid-based formulations (LBFs) can stimulate both supersaturation and precipitation. The current study has evaluated the drug, formulation and dose-dependence of the supersaturation - precipitation balance for a range of LBFs.

METHODS: Type I, II, IIIA/B LBFs containing medium-chain (MC) or long-chain (LC) lipids, and lipid-free Type IV LBF incorporating different doses of fenofibrate or tolfenamic acid were digested in vitro in a simulated intestinal medium. The degree of supersaturation was assessed through comparison of drug concentrations in aqueous digestion phases (APDIGEST) during LBF digestion and the equilibrium drug solubility in the same phases.

RESULTS: Increasing fenofibrate or tolfenamic acid drug loads (i.e., dose) had negligible effects on LC LBF performance during digestion, but promoted drug crystallization (confirmed by XRPD) from MC and Type IV LBF. Drug crystallization was only evident in instances when the calculated maximum supersaturation ratio (SR(M)) was >3. This threshold SR(M) value was remarkably consistent across all LBF and was also consistent with previous studies with danazol.

CONCLUSIONS: The maximum supersaturation ratio (SR(M)) provides an indication of the supersaturation 'pressure' exerted by formulation digestion and is strongly predictive of the likelihood of drug precipitation in vitro. This may also prove effective in discriminating the in vivo performance of LBFs.

Original language	English
Journal	Pharmaceutical Research
Volume	30
Issue number	12
Pages (from-to)	3059-76
Number of pages	18
ISSN	0724-8741
DOIs	https://doi.org/10.1007/s11095-013-1038-z
Publication status	Published - Dec 2013

Keywords

Chemical Precipitation
Crystallization
Digestion
Fenofibrate
Humans
Hypolipidemic Agents
Intestines
Lipid Metabolism
Lipids
Pharmaceutical Vehicles
Solubility
ortho-Aminobenzoates

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Williams, H. D., Sassene, P., Kleberg, K., Calderone, M., Igonin, A., Jule, E., Vertommen, J., Blundell, R., Benameur, H., Müllertz, A., Pouton, C. W., Porter, C. J. H., & LFCS Consortium (2013). Toward the establishment of standardized in vitro tests for lipid-based formulations, part 3: understanding supersaturation versus precipitation potential during the in vitro digestion of type I, II, IIIA, IIIB and IV lipid-based formulations. Pharmaceutical Research, 30(12), 3059-76. https://doi.org/10.1007/s11095-013-1038-z

Toward the establishment of standardized in vitro tests for lipid-based formulations, part 3: understanding supersaturation versus precipitation potential during the in vitro digestion of type I, II, IIIA, IIIB and IV lipid-based formulations. / Williams, Hywel D; Sassene, Philip; Kleberg, Karen et al.
In: Pharmaceutical Research, Vol. 30, No. 12, 12.2013, p. 3059-76.

Research output: Contribution to journal › Journal article › Research › peer-review

Williams, HD, Sassene, P, Kleberg, K, Calderone, M, Igonin, A, Jule, E, Vertommen, J, Blundell, R, Benameur, H, Müllertz, A, Pouton, CW, Porter, CJH & LFCS Consortium 2013, 'Toward the establishment of standardized in vitro tests for lipid-based formulations, part 3: understanding supersaturation versus precipitation potential during the in vitro digestion of type I, II, IIIA, IIIB and IV lipid-based formulations', Pharmaceutical Research, vol. 30, no. 12, pp. 3059-76. https://doi.org/10.1007/s11095-013-1038-z

Williams HD, Sassene P, Kleberg K, Calderone M, Igonin A, Jule E et al. Toward the establishment of standardized in vitro tests for lipid-based formulations, part 3: understanding supersaturation versus precipitation potential during the in vitro digestion of type I, II, IIIA, IIIB and IV lipid-based formulations. Pharmaceutical Research. 2013 Dec;30(12):3059-76. doi: 10.1007/s11095-013-1038-z

Williams, Hywel D ; Sassene, Philip ; Kleberg, Karen et al. / Toward the establishment of standardized in vitro tests for lipid-based formulations, part 3 : understanding supersaturation versus precipitation potential during the in vitro digestion of type I, II, IIIA, IIIB and IV lipid-based formulations. In: Pharmaceutical Research. 2013 ; Vol. 30, No. 12. pp. 3059-76.

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abstract = "PURPOSE: Recent studies have shown that digestion of lipid-based formulations (LBFs) can stimulate both supersaturation and precipitation. The current study has evaluated the drug, formulation and dose-dependence of the supersaturation - precipitation balance for a range of LBFs.METHODS: Type I, II, IIIA/B LBFs containing medium-chain (MC) or long-chain (LC) lipids, and lipid-free Type IV LBF incorporating different doses of fenofibrate or tolfenamic acid were digested in vitro in a simulated intestinal medium. The degree of supersaturation was assessed through comparison of drug concentrations in aqueous digestion phases (APDIGEST) during LBF digestion and the equilibrium drug solubility in the same phases.RESULTS: Increasing fenofibrate or tolfenamic acid drug loads (i.e., dose) had negligible effects on LC LBF performance during digestion, but promoted drug crystallization (confirmed by XRPD) from MC and Type IV LBF. Drug crystallization was only evident in instances when the calculated maximum supersaturation ratio (SR(M)) was >3. This threshold SR(M) value was remarkably consistent across all LBF and was also consistent with previous studies with danazol.CONCLUSIONS: The maximum supersaturation ratio (SR(M)) provides an indication of the supersaturation 'pressure' exerted by formulation digestion and is strongly predictive of the likelihood of drug precipitation in vitro. This may also prove effective in discriminating the in vivo performance of LBFs.",

keywords = "Chemical Precipitation, Crystallization, Digestion, Fenofibrate, Humans, Hypolipidemic Agents, Intestines, Lipid Metabolism, Lipids, Pharmaceutical Vehicles, Solubility, ortho-Aminobenzoates",

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year = "2013",

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doi = "10.1007/s11095-013-1038-z",

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T1 - Toward the establishment of standardized in vitro tests for lipid-based formulations, part 3

T2 - understanding supersaturation versus precipitation potential during the in vitro digestion of type I, II, IIIA, IIIB and IV lipid-based formulations

AU - Williams, Hywel D

AU - Sassene, Philip

AU - Kleberg, Karen

AU - Calderone, Marilyn

AU - Igonin, Annabel

AU - Jule, Eduardo

AU - Vertommen, Jan

AU - Blundell, Ross

AU - Benameur, Hassan

AU - Müllertz, Anette

AU - Pouton, Colin W

AU - Porter, Christopher J H

AU - LFCS Consortium

PY - 2013/12

Y1 - 2013/12

N2 - PURPOSE: Recent studies have shown that digestion of lipid-based formulations (LBFs) can stimulate both supersaturation and precipitation. The current study has evaluated the drug, formulation and dose-dependence of the supersaturation - precipitation balance for a range of LBFs.METHODS: Type I, II, IIIA/B LBFs containing medium-chain (MC) or long-chain (LC) lipids, and lipid-free Type IV LBF incorporating different doses of fenofibrate or tolfenamic acid were digested in vitro in a simulated intestinal medium. The degree of supersaturation was assessed through comparison of drug concentrations in aqueous digestion phases (APDIGEST) during LBF digestion and the equilibrium drug solubility in the same phases.RESULTS: Increasing fenofibrate or tolfenamic acid drug loads (i.e., dose) had negligible effects on LC LBF performance during digestion, but promoted drug crystallization (confirmed by XRPD) from MC and Type IV LBF. Drug crystallization was only evident in instances when the calculated maximum supersaturation ratio (SR(M)) was >3. This threshold SR(M) value was remarkably consistent across all LBF and was also consistent with previous studies with danazol.CONCLUSIONS: The maximum supersaturation ratio (SR(M)) provides an indication of the supersaturation 'pressure' exerted by formulation digestion and is strongly predictive of the likelihood of drug precipitation in vitro. This may also prove effective in discriminating the in vivo performance of LBFs.

AB - PURPOSE: Recent studies have shown that digestion of lipid-based formulations (LBFs) can stimulate both supersaturation and precipitation. The current study has evaluated the drug, formulation and dose-dependence of the supersaturation - precipitation balance for a range of LBFs.METHODS: Type I, II, IIIA/B LBFs containing medium-chain (MC) or long-chain (LC) lipids, and lipid-free Type IV LBF incorporating different doses of fenofibrate or tolfenamic acid were digested in vitro in a simulated intestinal medium. The degree of supersaturation was assessed through comparison of drug concentrations in aqueous digestion phases (APDIGEST) during LBF digestion and the equilibrium drug solubility in the same phases.RESULTS: Increasing fenofibrate or tolfenamic acid drug loads (i.e., dose) had negligible effects on LC LBF performance during digestion, but promoted drug crystallization (confirmed by XRPD) from MC and Type IV LBF. Drug crystallization was only evident in instances when the calculated maximum supersaturation ratio (SR(M)) was >3. This threshold SR(M) value was remarkably consistent across all LBF and was also consistent with previous studies with danazol.CONCLUSIONS: The maximum supersaturation ratio (SR(M)) provides an indication of the supersaturation 'pressure' exerted by formulation digestion and is strongly predictive of the likelihood of drug precipitation in vitro. This may also prove effective in discriminating the in vivo performance of LBFs.

KW - Chemical Precipitation

KW - Crystallization

KW - Digestion

KW - Fenofibrate

KW - Humans

KW - Hypolipidemic Agents

KW - Intestines

KW - Lipid Metabolism

KW - Lipids

KW - Pharmaceutical Vehicles

KW - Solubility

KW - ortho-Aminobenzoates

U2 - 10.1007/s11095-013-1038-z

DO - 10.1007/s11095-013-1038-z

M3 - Journal article

C2 - 23661145

SN - 0724-8741

VL - 30

SP - 3059

EP - 3076

JO - Pharmaceutical Research

JF - Pharmaceutical Research

IS - 12

ER -