Advancing in-vitro drug precipitation testing: new process monitoring tools and a kinetic nucleation and growth model

Arnold, Yvonne Elisabeth; Imanidis, Georgios; Kuentz, Martin

doi:10.1111/j.2042-7158.2010.01228.x

Cited by 39 publications

(30 citation statements)

References 20 publications

(51 reference statements)

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“…Several in vitro assays have been developed to simulate the precipitation of weakly basic drugs during gastrointestinal passage . These are valuable approaches for estimating a drug precipitation profile at intestinal pH in the presence of bile salts and phospholipids.…”

Section: Discussionmentioning

confidence: 99%

“…However, as the in vivo evaluation of intraluminal content is inherently difficult, drug precipitation has generally been studied using in vitro assays. One‐ or two‐compartment experimental setups were developed and simulated gastrointestinal media were usually employed to simulate the transfer from the stomach into the small intestine . These assays simulate dispersive conditions without digestive enzymes and can provide valuable information about the intrinsic pH‐induced precipitation behavior of weakly basic compounds (in the presence of bile salts and phospholipids).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Toward an Improved Understanding of the Precipitation Behavior of Weakly Basic Drugs from Oral Lipid-Based Formulations

Stillhart

Dürr

Kuentz

2014

Journal of Pharmaceutical Sciences

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Toward an Improved Understanding of the Precipitation Behavior of Weakly Basic Drugs from Oral Lipid-Based Formulations

Stillhart

Dürr

Kuentz

2014

Journal of Pharmaceutical Sciences

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“…Mechanistically, precipitation is characterized by a nucleation phase, where dissolved molecules spontaneously aggregate, and a particle growth phase, where dissolved molecules aggregate into existing precipitated (aggregated) particles. 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].…”

Section: Value Of Mathematical Modeling and Existing Modeling Apprmentioning

confidence: 99%

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

Rezhdo

Speciner

Carrier

2016

Journal of Controlled Release

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The majority of newly discovered oral drugs are poorly water soluble, and co-administration with lipids has proven effective in significantly enhancing bioavailability of some compounds with low aqueous solubility. Yet, lipid-based delivery technologies have not been widely employed in commercial oral products. Lipids can impact drug transport and fate in the gastrointestinal (GI) tract through multiple mechanisms including enhancement of solubility and dissolution kinetics, enhancement of permeation through the intestinal mucosa, and triggering drug precipitation upon lipid emulsion depletion (e.g., by digestion). The effect of lipids on drug absorption is currently not quantitatively predictable, in part due to the multiple complex dynamic processes that can be impacted by lipids. Quantitative mechanistic analysis of the processes significant to lipid system function and overall impact on drug absorption can aid understanding of drug-lipid interactions in the GI tract and exploitation of such interactions to achieve optimal lipid-based drug delivery. In this review, we discuss the impact of co-delivered lipids and lipid digestion on drug dissolution, partitioning, and absorption in the context of the experimental tools and associated kinetic expressions used to study and model these processes. The potential benefit of a systems-based consideration of the concurrent multiple dynamic processes occurring upon co-dosing lipids and drugs to predict the impact of lipids on drug absorption and enable rational design of lipid-based delivery systems is presented.

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“…However, for a biopharmaceutical test, drug concentrations are considerably lower and biorelevant media may provide an additional analytical complexity. A Raman fibre optic dip probe has been used in a biopharmaceutical transfer test [102]. The drug dipyridamole was studied as it was transferred from a simulated gastric into simulated intestinal medium.…”

Section: Real‐time Analysis Of Small‐scale Drug Dissolution and Precimentioning

confidence: 99%

“…Monitoring of drug particles can be a valuable source of information, especially in the drug precipitation process. Dynamic image analysis was recently applied to a drug transfer test [102]. A flow‐through cell was equipped with a Xenon flash light that was synchronized with a CCD camera.…”

Section: Real‐time Analysis Of Small‐scale Drug Dissolution and Precimentioning

confidence: 99%

Analytical technologies for real-time drug dissolution and precipitation testing on a small scale

Kuentz

2014

Journal of Pharmacy and Pharmacology

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Objectives This review focuses on real-time analytics of drug dissolution and precipitation testing on a comparatively small scale. Key findings Miniaturisation of test equipment is an important trend in pharmaceutics, and several small-scale experiments have been reported for drug dissolution and precipitation testing. Such tests typically employ analytics in realtime. Fibre optic ultraviolet (UV) analytics has become a well-established method in this field. Novel imaging techniques are emerging that use visible or UV light; also promising is Fourier transform infrared imaging based on attenuated total reflection. More information than just a rate constant is obtained from these methods. The early phase of a dissolution process can be assessed and drug precipitation may eventually be observed. Some real-time techniques are particularly well suited to studying drug precipitation during formulation dispersion; for example, turbidity, focused beam reflectance measurement and Raman spectroscopy. Summary Small-scale dissolution tests equipped with real-time analytics have become important to screen drug candidates as well as to study prototype formulations in early development. Future approaches are likely to combine different analytical techniques including imaging. Miniaturisation started with mini-vessels or small vials and future assays of dissolution research will probably more often reach the level of parallel well plates and microfluidic channels.

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Advancing in-vitro drug precipitation testing: new process monitoring tools and a kinetic nucleation and growth model

Abstract: The analytical methods and the kinetic model provided new insights into biorelevant drug precipitation and could in the future support formulation development.

Cited by 39 publications

References 20 publications

Toward an Improved Understanding of the Precipitation Behavior of Weakly Basic Drugs from Oral Lipid-Based Formulations

Toward an Improved Understanding of the Precipitation Behavior of Weakly Basic Drugs from Oral Lipid-Based Formulations

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

Analytical technologies for real-time drug dissolution and precipitation testing on a small scale

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