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

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.

Polyglutamic Acid-Gated Mesoporous Silica Nanoparticles for Enzyme-Controlled Drug Delivery

“…Moreover some drugs show poor solubility, stability or are rapidly eliminated. [6][7][8] In this context nanomedicine attempts to offer a broad variety of tools aimed to improve conventional therapeutic and diagnostic strategies, being a landmark purpose the development of more effective and safer treatments, reducing toxicity of drugs to non-target organs. [9][10][11][12][13] In this scenario a large variety of drug nanocarriers with different size, structure and surface features, such as liposomes, [14][15][16] polymeric nanoparticles [17][18][19] or inorganic nanoparticles has been developed over the last few decades.…”

Current Status of Supersaturable Self-Emulsifying Drug Delivery Systems

“…There are several paper including the solid-state characterization techniques used to evaluate drug precipitates during in vitro digestion. Differential scanning calorimetry, powder X-ray diffraction, polarized light microscopy, scanning electron microscopy, and Fourier-transform infrared spectroscopy can be used for solid-state characterization in conjunction with in vitro digestion tests [18,74,75]. From a different perspective, potential polymorphic transitions during precipitation may further complicate supersaturation behavior and warrant solid-state analysis [76,77].…”

Lipid-associated oral delivery: Mechanisms and analysis of oral absorption enhancement

“…The increased drug concentration in the aqueous lumen serves as a driving force for drug absorption, often resulting in enhanced bioavailability. Recent studies have shown that fast depletion of the lipid (triglyceride) phase relative to drug release from formulation can result in precipitation [25], potentially making re-solubilization the rate-limiting step in overall absorption. A mechanistic representation of these concurrent processes that may affect overall drug absorption are shown in Figure 1.…”

“…Dissolution can also be important to consider for LBF if precipitation occurs, followed by solid re-dissolution (Figure 1). Some drugs precipitate from LBFs in an amorphous rather than crystalline form typical of solid drug formulations [25]. While the type of solid form (i.e.…”

“…The intrinsic complexity of nucleation and particle growth make precipitation a complicated process to model [195]. Precipitated drug can form either an amorphous solid structure or a crystalline structure (as in typical solid dosage forms) [25]. Depending on the type of solid structure present, different precipitation kinetics may occur.…”