Rapid determination of drug solubilization versus supersaturation in natural and digested lipids

Gautschi, Nicolas; Bergström, Christel A. S.; Kuentz, Martin

doi:10.1016/j.ijpharm.2016.09.015

Cited by 28 publications

(25 citation statements)

References 51 publications

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“…reported that the accuracy of solubility predictions in lipids slightly increased, when T m and Δ S f were both considered. More recently, Gautschi et al . similarly found that T m alone could not reliably predict drug solubility in C‐8 and C‐10 triglycerides (TGs).…”

Section: Lipophilicity and Hydrophobicity Regarding Different Formulamentioning

confidence: 99%

“…In formulation design, it is critical for the excipient selection to know if the compound of interest needs to form polar and/or non‐polar interactions with a given excipient. Such interactions of a drug molecule and an excipient can be visualised in molecular dynamics simulations to improve the understanding of where a drug molecule resides in a LBF and in the complex mixture after aqueous dispersion/digestion . As an example, these studies can be used to explain why high solubility in LBFs may not entail high solubility after dispersion or digestion in the intestinal media.…”

Section: Lipophilicity and Hydrophobicity Regarding Different Formulamentioning

confidence: 99%

See 1 more Smart Citation

Lipophilicity and hydrophobicity considerations in bio-enabling oral formulations approaches – a PEARRL review

Ditzinger

Price

Ilie

et al. 2019

Journal of Pharmacy and Pharmacology

Self Cite

104

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Current literature suggests that selection of formulation approaches in pharmaceutics is still highly dependent on the availability of technological expertise in a company or research group. Encouraging is that, recent advancements point to more structured and scientifically based development approaches. More research is still needed to better link physicochemical drug properties to pharmaceutical formulation design.

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Section: Lipophilicity and Hydrophobicity Regarding Different Formulamentioning

confidence: 99%

Section: Lipophilicity and Hydrophobicity Regarding Different Formulamentioning

confidence: 99%

Lipophilicity and hydrophobicity considerations in bio-enabling oral formulations approaches – a PEARRL review

Ditzinger

Price

Ilie

et al. 2019

Journal of Pharmacy and Pharmacology

Self Cite

104

View full text Add to dashboard Cite

show abstract

“…Recent studies have identified the absence of an absorption compartment in the current in vitro lipolysis setup as a major reason for the poor prediction of the in vivo performance of LBFs ( 3 , 6 , 7 ). Therefore, the present study evaluated the compatibility between Caco-2 monolayers—the gold standard for intestinal absorption in vitro studies ( 11 )—and components present during digestion studies.…”

Section: Discussionmentioning

confidence: 99%

“…During in vitro lipolysis experiments, the drug is not transported away from the solution as would be the case if it was absorbed. This artifact drives higher supersaturation levels leading to precipitation in vitro that would not occur in vivo ( 7 ).…”

Section: Introductionmentioning

confidence: 99%

Caco-2 Cell Conditions Enabling Studies of Drug Absorption from Digestible Lipid-Based Formulations

Keemink

Bergström

2018

Pharm Res

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PurposeTo identify conditions allowing the use of cell-based models for studies of drug absorption during in vitro lipolysis of lipid-based formulations (LBFs).MethodsCaco-2 was selected as the cell-based model system. Monolayer integrity was evaluated by measuring mannitol permeability after incubating Caco-2 cells in the presence of components available during lipolysis. Pure excipients and formulations representing the lipid formulation classification system (LFCS) were evaluated before and after digestion. Porcine mucin was evaluated for its capacity to protect the cell monolayer.ResultsMost undigested formulations were compatible with the cells (II-LC, IIIB-LC, and IV) although some needed mucin to protect against damaging effects (II-MC, IIIB-MC, I-LC, and IIIA-LC). The pancreatic extract commonly used in digestion studies was incompatible with the cells but the Caco-2 monolayers could withstand immobilized recombinant lipase. Upon digestion, long chain formulations caused more damage to Caco-2 cells than their undigested counterparts whereas medium chain formulations showed better tolerability after digestion.ConclusionsMost LBFs and components thereof (undigested and digested) are compatible with Caco-2 cells. Pancreatic enzyme is not tolerated by the cells but immobilized lipase can be used in combination with the cell monolayer. Mucin is beneficial for critical formulations and digestion products.Electronic supplementary materialThe online version of this article (10.1007/s11095-017-2327-8) contains supplementary material, which is available to authorized users.

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“…Much advancement has been made in the prediction of drug solubility in aqueous systems 1 and solvent mixtures, 2 and there are also approaches to estimate solubility in lipid-based excipients. [3][4][5] However, all computational approaches have their limitations and especially difficult are solubility predictions in complex mixtures and in presence of impurities. Thinking of lipid-based excipients, they are mostly themselves mixtures of major components together with some minor components that are often not even chemically specified.…”

Section: Introductionmentioning

confidence: 99%

A Relative Permittivity Approach for Fast Drug Solubility Screening of Solvents and Excipients in Lipid-Based Delivery

Niederquell

Dujovny²,

Probst³

et al. 2019

Journal of Pharmaceutical Sciences

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Drug solubility screening in solvents and lipids is central for the development of lipid-based formulations (LBFs), and any guidance to reduce the experimental workload would be highly desirable. Solubility parameters are interesting as they can be predicted in silico for a drug but they are hardly predictable for complex lipids. This paper uses a new approach to convert an in silico drug solubility parameter to an estimated relative permittivity, ε r. Diverse solvents and lipid-based excipients were then experimentally tested for ε r and solubility using fenofibrate as model. The typical excipients and solvents used in LBFs showed an ε r range of about 2-24, and good solubility of fenofibrate was indeed evidenced in vicinity of its estimated relative permittivity 13.2 ± 2.7. Mixtures of promising excipients were studied subsequently, and the obtained ε r was predictable based on the known values of the individual components. The novel permittivity approach has demonstrated its usefulness, it has much potential in early development for ranking of suitable excipients, and it gives an initial orientation to design formulations. Future research may clarify further opportunities and limits of the novel approach for LBFs.

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Rapid determination of drug solubilization versus supersaturation in natural and digested lipids

Cited by 28 publications

References 51 publications

Lipophilicity and hydrophobicity considerations in bio-enabling oral formulations approaches – a PEARRL review

Lipophilicity and hydrophobicity considerations in bio-enabling oral formulations approaches – a PEARRL review

Caco-2 Cell Conditions Enabling Studies of Drug Absorption from Digestible Lipid-Based Formulations

A Relative Permittivity Approach for Fast Drug Solubility Screening of Solvents and Excipients in Lipid-Based Delivery

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