Biorelevant intrinsic dissolution profiling in early drug development: Fundamental, methodological, and industrial aspects

Bergström, Christel A. S.; Box, Karl; Holm, René; Matthews, W. Stephen; McAllister, Mark; Müllertz, Anette; Schäfer, Kerstin; Teleki, Alexandra

doi:10.1016/j.ejpb.2019.03.011

Cited by 22 publications

(17 citation statements)

References 128 publications

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“…Dissolution experiments were carried out in a small-scale dissolution apparatus using in situ fiber optic probes to measure the amount of drug dissolved over time by UV absorbance (μDiss Profiler, Pion Inc., Billerica, MA, USA) [ 3 ]. Drug dissolution was carried out from suspensions (S) or discs (D) depending on the solubility of the compound in the biorelevant media studied ( Table 3 ).…”

Section: Methodsmentioning

confidence: 99%

“…In fact, the drug discovery and development pipeline of the pharmaceutical industry is estimated to comprise at least 50–60% of BCS class II compounds [ 2 ]. Formulation strategies aimed at improving dissolution of these compounds are often guided by measurements of their intrinsic dissolution rates (IDR, μg/min/cm 2 ), i.e., the surface specific dissolution rate of the compound [ 3 ]. IDR is an intrinsic property of the compound that can indicate selection of a certain solid state form (e.g., salt, co-crystal, or polymorph) [ 4 ], enabling formulation strategy (e.g., solid dispersion or cyclodextrin inclusion) [ 5 , 6 ], or optimize particle size to ensure complete dissolution of a certain drug dose during intestinal transit [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

“…The main approaches and equipment available are (i) miniaturized dissolution vessels, flow-through cells, or microtiter plate-based methods with off-line determination of API concentration changes [ 8 ], (ii) imaging-based methods [ 9 ], and (iii) small-scale (sometimes) automated dissolution instruments with in situ API concentration determination by UV fiber optic probes [ 10 , 11 , 12 , 13 ]. The interested reader is referred to a recent review for a comprehensive description of all methods relevant for IDR determinations [ 3 ]. Here, we will focus on the third method, the UV fiber optic probes.…”

Section: Introductionmentioning

confidence: 99%

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Intrinsic Dissolution Rate Profiling of Poorly Water-Soluble Compounds in Biorelevant Dissolution Media

2020

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The intrinsic dissolution rate (IDR) of active pharmaceutical ingredients (API) is a key property that aids in early drug development, especially selecting formulation strategies to improve dissolution and thereby drug absorption in the intestine. Here, we developed a robust method for rapid, medium throughput screening of IDR and established the largest IDR dataset in open literature to date that can be used for pharmaceutical computational modeling. Eighteen compounds with diverse physicochemical properties were studied in both fasted and fed state simulated intestinal fluids. Dissolution profiles were measured in small-scale experimental assays using compound suspensions or discs. IDR measurements were not solely linked to API solubility in either dissolution media. Multivariate data analysis revealed that IDR strongly depends on compound partitioning into bile salt and phospholipid micelles in the simulated intestinal fluids, a process that in turn is governed by API lipophilicity, hydrophobicity, and ionization.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Intrinsic Dissolution Rate Profiling of Poorly Water-Soluble Compounds in Biorelevant Dissolution Media

2020

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“…The small quantities of the QSIs restricted the development of controlled suspensions through ball milling or ultrasonication. 33 , 34 For such formulations, typically larger volumes need to be prepared than the ones prepared herein, and much material is lost during processing.…”

Section: Discussionmentioning

confidence: 99%

Model-Informed Drug Discovery and Development in Pulmonary Delivery: Biopharmaceutical Pharmacometric Modeling for Formulation Evaluation of Pulmonary Suspensions

Sou

Soukarieh²,

Williams³

et al. 2020

ACS Omega

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For respiratory conditions, targeted drug delivery to the lungs could produce higher local concentrations with reduced risk of adverse events compared to systemic administration. Despite the increasing interest in pulmonary delivery, the pharmacokinetics (PK) of drugs following pulmonary administration remains to be elucidated. In this context, the application of modeling and simulation methodologies to characterize PK properties of compounds following pulmonary administration remains a scarcity. Pseudomonas aeruginosa (PA) lung infections are resistant to many of the current antibiotic therapies. Targeted treatments for pulmonary delivery could be particularly beneficial for these local conditions. In this study, we report the application of biopharmaceutical pharmacometrics (BPMX) for the analysis of PK data from three investigational antimicrobial agents following pulmonary administration of a suspension formulation. The observed drug concentration–time profiles in lungs and plasma of the compound series were combined for simultaneous analysis and modeling. The developed model describes the PK data, taking into account formulation properties, and provides a mechanism to predict dissolved drug concentrations in the lungs available for activity. The model was then used to evaluate formulation effects and the impact of variability on total and dissolved drug concentrations in lungs and plasma. The predictions suggest that these therapies for lung delivery should ideally be delivered in a sustained release formulation with high solubility for maximum local exposure in lungs for efficacy, with rapid systemic clearance in plasma for reduced risk of unwanted systemic adverse effects. This work shows the potential benefits of BPMX and the role it can play to support drug discovery and development in pulmonary delivery.

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“…In the case of ASD formulation, predictive in vitro and in silico biopharmaceutics characterization can help to secure the in vivo success by considering the excipients' solubilization factors, supersaturation generation, and maintenance potential, precipitation inhibitory capacity in the GI environment, and contribution to accelerating or decelerating the drug permeation rate (66). It is common practice to perform in vitro dissolution of ASD formulations under non-sink conditions, meaning that the total drug amount in a given medium volume is several times higher than the solubility of the crystalline counter-part (67). The exact in vitro/ex vivo simulation of in vivo situations is challenging since disintegration, drug solubilization, ASD surface plasticization, and supersaturation are connected events.…”

Section: Biopharmaceutics Assessmentmentioning

confidence: 99%

Developing HME-Based Drug Products Using Emerging Science: a Fast-Track Roadmap from Concept to Clinical Batch

et al. 2020

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This paper presents a rational workflow for developing enabling formulations, such as amorphous solid dispersions, via hot-melt extrusion in less than a year. First, our approach to an integrated product and process development framework is described, including state-ofthe-art theoretical concepts, modeling, and experimental characterization described in the literature and developed by us. Next, lab-scale extruder setups are designed (processing conditions and screw design) based on a rational, model-based framework that takes into account the thermal load required, the mixing capabilities, and the thermo-mechanical degradation. The predicted optimal process setup can be validated quickly in the pilot plant. Lastly, a transfer of the process to any GMP-certified manufacturing site can be performed in silico for any extruder based on our validated computational framework. In summary, the proposed workflow massively reduces the risk in product and process development and shortens the drug-to-market time for enabling formulations.

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Biorelevant intrinsic dissolution profiling in early drug development: Fundamental, methodological, and industrial aspects

Cited by 22 publications

References 128 publications

Intrinsic Dissolution Rate Profiling of Poorly Water-Soluble Compounds in Biorelevant Dissolution Media

Intrinsic Dissolution Rate Profiling of Poorly Water-Soluble Compounds in Biorelevant Dissolution Media

Model-Informed Drug Discovery and Development in Pulmonary Delivery: Biopharmaceutical Pharmacometric Modeling for Formulation Evaluation of Pulmonary Suspensions

Developing HME-Based Drug Products Using Emerging Science: a Fast-Track Roadmap from Concept to Clinical Batch

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