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The Precipitation Behavior of Poorly Water-Soluble Drugs with an Emphasis on the Digestion of Lipid Based Formulations

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ABSTRACT

An increasing number of newly discovered drugs are poorly water-soluble and the use of natural and synthetic lipids to improve the oral bioavailability of these drugs by utilizing the digestion pathway in-vivo has proved an effective formulation strategy. The mechanisms responsible for lipid digestion and drug solubilisation during gastrointestinal transit have been explored in detail, but the implications of drug precipitation beyond the potential adverse effect on bioavailability have received attention only in recent years. Specifically, these implications are that different solid forms of drug on precipitation may affect the total amount of drug absorbed in-vivo through their different physico-chemical properties, and the possibility that the dynamic environment of the small intestine may afford re-dissolution of precipitated drug if present in a high-energy form. This review describes the events that lead to drug precipitation during the dispersion and digestion of lipid based formulations, common methods used to inhibit precipitation, as well as conventional and newly emerging characterization techniques for studying the solid state form of the precipitated drug. Moreover, selected case studies are discussed where drug precipitation has ensued from the digestion of lipid based formulations, as well as the apparent link between drug ionisability and altered solid forms on precipitation, culminating in a discussion about the importance of the solid form on precipitation with relevance to the total drug absorbed.

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Abbreviations

LBDDS:

Lipid based drug delivery systems

BCS:

Biopharmaceutics classification system

LFCS:

Lipid formulation classification system

SRM :

Maximum supersaturation ratio

XRD:

X-ray diffraction

CPLM:

Crossed polarized light microscopy

DSC:

Differential scanning calorimetry

FTIR:

Fourier transform infrared spectroscopy

USP:

United States pharmacopeia

PPI:

Polymeric precipitation inhibitor

PVP:

Polyvinylpyrrolidone

HPMC:

Hydroxypropylmethyl cellulose

MC:

Medium chain

LC:

Long chain

SNEDDS:

Self nano-emulsifying drug delivery system

SMEDDS:

Self micro-emulsifying drug delivery system

SAXS:

Small-angle x-ray scattering

NMR:

Nuclear magnetic resonance

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ACKNOWLEDGMENTS AND DISCLOSURES

This manuscript was supported by the Australian Research Council through the Discovery Projects scheme (DP120104032). B.J.B. holds an ARC Future Fellowship.

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Authors and Affiliations

  1. Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, 3052, Australia

    Jamal Khan & Ben Boyd

  2. Department of Pharmacy, Pharmaceutical Design and Drug Delivery, University of Copenhagen, Studiestræde 6, København K, Denmark

    Thomas Rades

  3. ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), 381 Royal Parade, Parkville, VIC, 3052, Australia

    Ben Boyd

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Khan, J., Rades, T. & Boyd, B. The Precipitation Behavior of Poorly Water-Soluble Drugs with an Emphasis on the Digestion of Lipid Based Formulations. Pharm Res 33, 548–562 (2016). https://doi.org/10.1007/s11095-015-1829-5

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