Biorelevant dissolution testing of a weak base: Interlaboratory reproducibility and investigation of parameters controlling in vitro precipitation

Berben, Philippe; Ashworth, L. J.; Bevernage, Jan; Bruel, Jean-Luc; Butler, James; Dressman, Jennifer B.; Schäfer, Kerstin; Hutchins, Paul; Klumpp, Lukas; Mann, James; Nicolai, Janine; Ojala, K.; Patel, Sanjaykumar R.; Powell, Sarah; Rosenblatt, Karin M.; Tomaszewska, Irena; Williams, James; Augustijns, Patrick

doi:10.1016/j.ejpb.2019.04.017

Cited by 35 publications

(13 citation statements)

References 19 publications

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“…By careful selection of in-vitro experimental conditions such as the type (i.e., pH, ionic strength, surfactants) and volume of dissolution media, agitation speed, temperature and sampling procedures, the extent of supersaturation and formation of crystalline seeds can be captured [ 90 , 91 ]. Dissolution can be performed in one-, two- or multi-compartment experimental design (to simulate partitioning in the GI and systemic circulation) or in a custom-made technical design, such as TNO intestinal model 1 (TIM-1) or USP II apparatus coupled with peristaltic pumps to simulate flow of different intestinal fluids to the site of drug release and absorption [ 92 ]. The complexity of an in-vitro dissolution system therefore depends on the extent of detailed simulation of in-vivo gut physiology that is desired to be reproduced with the in-vitro set-up.…”

Section: Product Development Strategymentioning

confidence: 99%

Amorphous Solid Dispersions (ASDs): The Influence of Material Properties, Manufacturing Processes and Analytical Technologies in Drug Product Development

Iyer¹,

Jovanovska

Berginc

et al. 2021

Pharmaceutics

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Poorly water-soluble drugs pose a significant challenge to developability due to poor oral absorption leading to poor bioavailability. Several approaches exist that improve the oral absorption of such compounds by enhancing the aqueous solubility and/or dissolution rate of the drug. These include chemical modifications such as salts, co-crystals or prodrugs and physical modifications such as complexation, nanocrystals or conversion to amorphous form. Among these formulation strategies, the conversion to amorphous form has been successfully deployed across the pharmaceutical industry, accounting for approximately 30% of the marketed products that require solubility enhancement and making it the most frequently used technology from 2000 to 2020. This article discusses the underlying scientific theory and influence of the active compound, the material properties and manufacturing processes on the selection and design of amorphous solid dispersion (ASD) products as marketed products. Recent advances in the analytical tools to characterize ASDs stability and ability to be processed into suitable, patient-centric dosage forms are also described. The unmet need and regulatory path for the development of novel ASD polymers is finally discussed, including a description of the experimental data that can be used to establish if a new polymer offers sufficient differentiation from the established polymers to warrant advancement.

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Section: Product Development Strategymentioning

confidence: 99%

Amorphous Solid Dispersions (ASDs): The Influence of Material Properties, Manufacturing Processes and Analytical Technologies in Drug Product Development

Iyer¹,

Jovanovska

Berginc

et al. 2021

Pharmaceutics

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“…1). A "pH-dilution" method such as that performed by Gao and coworkers (40) or multicompartment methods could be employed when testing bases in a sequential dissolution transfer test, for example, from pH 2.0 to 6.5 medium (40)(41)(42)(43)(44)(45)(46)(47)(48)(49)(50)(51)(52)(53). Since neutral drugs do not ionize over the intestinal pH range, they can be tested in any single pH medium.…”

Section: Recommendationsmentioning

confidence: 99%

“…In addition, the concentration of dissolved drug is affected by absorption into the intestinal membrane or transit down the GI tract. While closed container in vitro dissolution devices cannot mimic this situation, using a pH-stat or multicompartmental devices that incorporate both transit and secretion move closer to capturing the dynamic situation in vivo (40)(41)(42)(43)(44)(45)(46)(47)(48)(49)(50)(51)(52)(53).…”

Section: Recommendationsmentioning

confidence: 99%

Selection of In Vivo Predictive Dissolution Media Using Drug Substance and Physiological Properties

Mudie

Samiei

Marshall

et al. 2020

AAPS J

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The rate and extent of drug dissolution in the gastrointestinal (GI) tract are highly dependent upon drug physicochemical properties and GI fluid properties. Biorelevant dissolution media (BDM), which aim to facilitate in vitro prediction of in vivo dissolution performance, have evolved with our understanding of GI physiology. However, BDM with a variety of properties and compositions are available, making the choice of dissolution medium challenging. In this tutorial, we describe a simple and quantitative methodology for selecting practical, yet physiologically relevant BDM representative of fasted humans for evaluating dissolution of immediate release formulations. Specifically, this methodology describes selection of pH, buffer species, and concentration and evaluates the importance of including bile salts and phospholipids in the BDM based upon drug substance log D, pKa, and intrinsic solubility. The methodology is based upon a mechanistic understanding of how three main factors affect dissolution, including (1) drug ionization at gastrointestinal pH, (2) alteration of surface pH by charged drug species, and (3) drug solubilization in mixed lipidic aggregates comprising bile salts and phospholipids. Assessment of this methodology through testing and comparison with literature reports showed that the recommendations correctly identified when a biorelevant buffer capacity or the addition of bile salts and phospholipids to the medium would appreciably change the drug dissolution profile. This methodology can enable informed decisions about when a time, complexity, and/or cost-saving buffer is expected to lead to physiologically meaningful in vitro dissolution testing, versus when a more complex buffer would be required.

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“…Advanced in vitro tools such as the TIM-1 system (TNO Nutrition and Food Research, Zeist, The Netherlands) can provide a useful indication along with simpler biorelevant dissolution experiments known as pH shift methods. Recent OrBiTo papers described a simple biorelevant pH shift method, for which there are variations used widely in the industry (52,53). Once the extent of precipitation in vivo is assessed, the modeler can incorporate the findings.…”

Section: Dissolution Data For Modellingmentioning

confidence: 99%

The Case for Physiologically Based Biopharmaceutics Modelling (PBBM): What do Dissolution Scientists Need to Know?

Gray¹,

Mann²,

Barker³

et al. 2020

Dissolution Technol.

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The purpose of this article is to inform the dissolution scientist of a powerful emerging tool that provides in vivo linkage to dissolution methods. This tool is physiologically based biopharmaceutics modelling (PBBM). Dissolution scientists are mostly concerned with analytical sections of drug development, so exposure to modeling and other pharmacokinetics and biopharmaceutic concepts may be uncommon. PBBM is an in-silico model that focuses on the interactions between the in vivo physiology and the formulation and drug characteristics. The principles behind PBBM is that all mechanisms related to drug release, dissolution, and diffusion from the site of administration to the site of action can be described in a mechanistic way or semi-empirical way. The integration of in vitro dissolution data in PBBM is described, including examples of software and modeling applications. The expertise needed to use the software and appropriate training is discussed. The key inputs that are expected from the dissolution scientist include an understanding of the aqueous solubility across the physiological pH range, impact of in vivo relevant bile salts and phospholipids on solubilization, and the impact of surface pH on dissolution rate. An example of an advanced in vitro system, TNO intestinal model (TIM-1), will be discussed and its importance in establishing a biorelevant understanding of dissolution behavior. PBBM can evaluate the clinical relevance of a dissolution method and justify specifications and ultimately provide an approval advantage to the sponsor. A well-supported dissolution method that provides clinically relevant drug product specifications (CRDPS) will be viewed with favor by the regulators. Therefore, the partnering of a dissolution scientist and biopharmaceutics scientist to develop PBBM is clearly an important step forward in drug development.

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Biorelevant dissolution testing of a weak base: Interlaboratory reproducibility and investigation of parameters controlling in vitro precipitation

Cited by 35 publications

References 19 publications

Amorphous Solid Dispersions (ASDs): The Influence of Material Properties, Manufacturing Processes and Analytical Technologies in Drug Product Development

Amorphous Solid Dispersions (ASDs): The Influence of Material Properties, Manufacturing Processes and Analytical Technologies in Drug Product Development

Selection of In Vivo Predictive Dissolution Media Using Drug Substance and Physiological Properties

The Case for Physiologically Based Biopharmaceutics Modelling (PBBM): What do Dissolution Scientists Need to Know?

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