Development of a discriminative biphasic in vitro dissolution test and correlation with in vivo pharmacokinetic studies for differently formulated racecadotril granules

Deng, Jia; Staufenbiel, Sven; Hao, Shilei; Wang, Bochu; Dashevskiy, Andriy; Bodmeier, Roland

doi:10.1016/j.jconrel.2017.04.034

Cited by 21 publications

(26 citation statements)

References 40 publications

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“…Nanocomposite samples having drug amounts equivalent to saturation solubility, or lower than saturation solubility of BCS Class II drugs in the dissolution medium have been used preferentially because such non-sink conditions have been shown to better discriminate between various nanocomposite formulations [ 59 , 169 , 224 , 225 ]. Water, aqueous surfactant solutions, buffer solutions, or other simulated biological fluids can be chosen as dissolution media.…”

Section: Preparation Characterization and Formulation Of Drug-lamentioning

confidence: 99%

Bioavailability Enhancement of Poorly Water-Soluble Drugs via Nanocomposites: Formulation–Processing Aspects and Challenges

et al. 2018

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Drug nanoparticles embedded in a dispersant matrix as a secondary phase, i.e., drug-laden nanocomposites, offer a versatile delivery platform for enhancing the dissolution rate and bioavailability of poorly water-soluble drugs. Drug nanoparticles are prepared by top-down, bottom-up, or combinative approaches in the form of nanosuspensions, which are subsequently dried to prepare drug-laden nanocomposites. In this comprehensive review paper, the term “nanocomposites” is used in a broad context to cover drug nanoparticle-laden intermediate products in the form of powders, cakes, and extrudates, which can be incorporated into final oral solid dosages via standard pharmaceutical unit operations, as well as drug nanoparticle-laden strip films. The objective of this paper is to review studies from 2012–2017 in the field of drug-laden nanocomposites. After a brief overview of the various approaches used for preparing drug nanoparticles, the review covers drying processes and dispersant formulations used for the production of drug-laden nanocomposites, as well as various characterization methods including quiescent and agitated redispersion tests. Traditional dispersants such as soluble polymers, surfactants, other water-soluble dispersants, and water-insoluble dispersants, as well as novel dispersants such as wet-milled superdisintegrants, are covered. They exhibit various functionalities such as drug nanoparticle stabilization, mitigation of aggregation, formation of nanocomposite matrix–film, wettability enhancement, and matrix erosion/disintegration. Major challenges such as nanoparticle aggregation and poor redispersibility that cause inferior dissolution performance of the drug-laden nanocomposites are highlighted. Literature data are analyzed in terms of usage frequency of various drying processes and dispersant classes. We provide some engineering considerations in comparing drying processes, which could account for some of the diverging trends in academia vs. industrial practice. Overall, this review provides rationale and guidance for drying process selection and robust nanocomposite formulation development, with insights into the roles of various classes of dispersants.

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Section: Preparation Characterization and Formulation Of Drug-lamentioning

confidence: 99%

Bioavailability Enhancement of Poorly Water-Soluble Drugs via Nanocomposites: Formulation–Processing Aspects and Challenges

et al. 2018

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“…A rapid in vitro dissolution rate cannot be translated to the in vivo dissolution rate of ibuprofen. An in vivo study, in which the gastrointestinal (GI) drug dissolution and systemic absorption of ibuprofen was evaluated, demonstrated that the drug could still be found in the GI tract fluids even after 7 h of aspiration, pointing out that BCS II drugs may undergo a slower dissolution in the GI tract due to their low water solubility [5,6,15]. This slow dissolution rate was linked to the very low buffer capacity of luminal fluids.…”

Section: Discussionmentioning

confidence: 99%

“…The discriminatory power of biphasic dissolution is well acknowledged in the literature. Deng et al (2017) observed a high discriminatory power in the organic phase for minor formulation changes using racecadotril as a BCS II model drug [15]. Three granule formulations of the lipophilic drug were prepared with equivalent compositions but using different manufacturing processes.…”

Section: Discussionmentioning

confidence: 99%

“…It is composed of a two-phase system in which the simultaneous evaluation of drug dissolution and partitioning into an organic phase is studied, and it can be used as a non-compendial exploratory dissolution method. This approach was first described in the early 60s and its use has gained much attention in recent years [3,5,[10][11][12][13][14][15][16][17][18].…”

Section: Introductionmentioning

confidence: 99%

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Biphasic Dissolution as an Exploratory Method during Early Drug Product Development

et al. 2020

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Dissolution testing is a major tool used to assess a drug product’s performance and as a quality control test for solid oral dosage forms. However, compendial equipment and methods may lack discriminatory power and the ability to simulate aspects of in vivo dissolution. Using low buffer capacity media combined with an absorptive phase (biphasic dissolution) increases the physiologic relevance of in vitro testing. The purpose of this study was to use non-compendial and compendial dissolution test conditions to evaluate the in vitro performance of different formulations. The United States Pharmacopeia (USP)-recommended dissolution method greatly lacked discriminatory power, whereas low buffer capacity media discriminated between manufacturing methods. The use of an absorptive phase in the biphasic dissolution test assisted in controlling the medium pH due to the drug removal from the aqueous medium. Hence, the applied non-compendial methods were more discriminative to drug formulation differences and manufacturing methods than conventional dissolution conditions. In this study, it was demonstrated how biphasic dissolution and a low buffer capacity can be used to assess in vitro drug product performance differences. This can be a valuable approach during the early stages of drug product development for investigating in vitro drug release with improved physiological relevance.

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“…[11][12][13] To the best our knowledge, validated chiral methods are not available for RAC, despite the growing interest in analytical characterization of the drug. [14][15][16][17] Because of the different pharmacological effects of RAC enantiomers and possibilities of future chiral switches, development of a sensitive, precise, and reliable enantioselective method is required.…”

Section: Introductionmentioning

confidence: 99%

Enantioseparation of racecadotril using polysaccharide‐type chiral stationary phases in polar organic mode

et al. 2017

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Enantioseparation of the antidiarrheal drug, racecadotril, was investigated by liquid chromatography using polysaccharide-type chiral stationary phases in polar organic mode. The enantiodiscrimininating properties of 4 different chiral columns (Chiralpak AD, Chiralcel OD, Chiralpak AS, Chiralcel OJ) with 5 different solvents (methanol, ethanol, 1-propanol, 2-propanol, and acetonitrile) at 5 different temperatures (5-40°C) were investigated. Apart from Chiralpak AS column the other 3 columns showed significant enantioseparation capabilities.Among the tested mobile phases, alcohol type solvents were superior over acetonitrile, and significant differences in enantioselective performance of the selector were observed depending on the type of alcohol employed. Van't Hoff analysis was used for calculation of thermodynamic parameters which revealed that enantioseparation is mainly enthalpy controlled; however, enthropic control was also observed. Enantiopure standard was used to determine the enantiomer elution order, revealing chiral selector-and mobile-phase dependent reversal of enantiomer elution order. Using the optimized method (Chiralcel OJ stationary phase, thermostated at 10°C, 100% methanol, flow rate: 0.6 mL/min) baseline separation of racecadotril enantiomers (resolution = 3.00 ± 0.02) was achieved, with the R-enantiomer eluting first. The method was validated according to the ICH guidelines, and its application was tested on capsule and granules containing the racemic mixture of the drug.

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Development of a discriminative biphasic in vitro dissolution test and correlation with in vivo pharmacokinetic studies for differently formulated racecadotril granules

Cited by 21 publications

References 40 publications

Bioavailability Enhancement of Poorly Water-Soluble Drugs via Nanocomposites: Formulation–Processing Aspects and Challenges

Bioavailability Enhancement of Poorly Water-Soluble Drugs via Nanocomposites: Formulation–Processing Aspects and Challenges

Biphasic Dissolution as an Exploratory Method during Early Drug Product Development

Enantioseparation of racecadotril using polysaccharide‐type chiral stationary phases in polar organic mode

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