Mathematical Models to Explore Potential Effects of Supersaturation and Precipitation on Oral Bioavailability of Poorly Soluble Drugs

Kleppe, Mary S.; Forney-Stevens, Kelly M.; Haskell, Roy; Bogner, Robin H.

doi:10.1208/s12248-015-9748-2

Cited by 8 publications

(5 citation statements)

References 48 publications

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“…These characteristics of the de-supersaturation profiles have been typically observed in unseeded isothermal crystallization. 10,25 Since C init was lower than C s,III in each experiment, and polymorphic form III is the most stable anhydrous form at 25 C, 22 the decrease in concentration is attributable to the precipitation of CBZ DH .…”

Section: Thermodynamic Solubilities Of Cbz III and Cbz Dhmentioning

confidence: 91%

Population Balance Model for Simulation of the Supersaturation–Precipitation Behavior of Drugs in Supersaturable Solid Forms

Ozaki

2019

Journal of Pharmaceutical Sciences

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We developed a simulation method to describe in vitro drug concentration-time profiles under supersaturated conditions. In a nonsink dissolution test of carbamazepine polymorphic form III (CBZ), a model supersaturable solid, the concentration of carbamazepine reached a supersaturated state against its dihydrate form (CBZ). After a certain period, de-supersaturation due to the precipitation of CBZ was observed. In the simulation of this typical dissolution-precipitation profile, the precipitation process of CBZ was simulated by a population balance model in which the rates of primary/secondary nucleation and growth of CBZ were considered. Six rate constants in the precipitation model were determined from de-supersaturation profiles in unseeded isothermal crystallization experiments of CBZ. The dissolution process of CBZ was modeled on the basis of its dissolution profile under a sink condition. The simulated concentration versus time curves satisfactorily reproduced the characteristics of dissolution, supersaturation, and precipitation behavior of the model drug. The presented method will enable rational design of formulations and accurate prediction of the oral absorbability of drugs in supersaturable solid forms.

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Section: Thermodynamic Solubilities Of Cbz III and Cbz Dhmentioning

confidence: 91%

Population Balance Model for Simulation of the Supersaturation–Precipitation Behavior of Drugs in Supersaturable Solid Forms

Ozaki

2019

Journal of Pharmaceutical Sciences

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“…in the GI tract. Various methods have been proposed to address these issues, including both in vitro assays [ 22 , 23 ] and mathematical predictions [ 24 , 25 , 26 ]. Consequently, the precipitation process has been considered in the dissolution models integrated within PBBM software [ 27 , 28 , 29 , 30 ].…”

Section: Interpretation Of Oral Drug Dissolution Permeation and Absor...mentioning

confidence: 99%

Model-Informed Drug Development: In Silico Assessment of Drug Bioperformance following Oral and Percutaneous Administration

Djuris,

Cvijic,

Djekic

2024

Pharmaceuticals

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The pharmaceutical industry has faced significant changes in recent years, primarily influenced by regulatory standards, market competition, and the need to accelerate drug development. Model-informed drug development (MIDD) leverages quantitative computational models to facilitate decision-making processes. This approach sheds light on the complex interplay between the influence of a drug’s performance and the resulting clinical outcomes. This comprehensive review aims to explain the mechanisms that control the dissolution and/or release of drugs and their subsequent permeation through biological membranes. Furthermore, the importance of simulating these processes through a variety of in silico models is emphasized. Advanced compartmental absorption models provide an analytical framework to understand the kinetics of transit, dissolution, and absorption associated with orally administered drugs. In contrast, for topical and transdermal drug delivery systems, the prediction of drug permeation is predominantly based on quantitative structure–permeation relationships and molecular dynamics simulations. This review describes a variety of modeling strategies, ranging from mechanistic to empirical equations, and highlights the growing importance of state-of-the-art tools such as artificial intelligence, as well as advanced imaging and spectroscopic techniques.

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“…However, the dissolution, supersaturation, and precipitation of enabled solids are more complex and the assessment tools are still evolving [40]. Consequently, judicious application of orthogonal dissolution screens and careful analysis and modeling of data can provide reasonably predictive results [41,42].…”

Section: Time (Hr) Total Plasma Concmentioning

confidence: 99%

Commentary: Why Pharmaceutical Scientists in Early Drug Discovery Are Critical for Influencing the Design and Selection of Optimal Drug Candidates

2017

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Abstract. This commentary reflects the collective view of pharmaceutical scientists from four different organizations with extensive experience in the field of drug discovery support. Herein, engaging discussion is presented on the current and future approaches for the selection of the most optimal and developable drug candidates. Over the past two decades, developability assessment programs have been implemented with the intention of improving physicochemical and metabolic properties. However, the complexity of both new drug targets and non-traditional drug candidates provides continuing challenges for developing formulations for optimal drug delivery. The need for more enabled technologies to deliver drug candidates has necessitated an even more active role for pharmaceutical scientists to influence many key molecular parameters during compound optimization and selection. This enhanced role begins at the early in vitro screening stages, where key learnings regarding the interplay of molecular structure and pharmaceutical property relationships can be derived. Performance of the drug candidates in formulations intended to support key in vivo studies provides important information on chemotype-formulation compatibility relationships. Structure modifications to support the selection of the solid form are also important to consider, and predictive in silico models are being rapidly developed in this area. Ultimately, the role of pharmaceutical scientists in drug discovery now extends beyond rapid solubility screening, early form assessment, and data delivery. This multidisciplinary role has evolved to include the practice of proactively taking part in the molecular design to better align solid form and formulation requirements to enhance developability potential.

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Mathematical Models to Explore Potential Effects of Supersaturation and Precipitation on Oral Bioavailability of Poorly Soluble Drugs

Cited by 8 publications

References 48 publications

Population Balance Model for Simulation of the Supersaturation–Precipitation Behavior of Drugs in Supersaturable Solid Forms

Population Balance Model for Simulation of the Supersaturation–Precipitation Behavior of Drugs in Supersaturable Solid Forms

Model-Informed Drug Development: In Silico Assessment of Drug Bioperformance following Oral and Percutaneous Administration

Commentary: Why Pharmaceutical Scientists in Early Drug Discovery Are Critical for Influencing the Design and Selection of Optimal Drug Candidates

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