Biphasic Dissolution as an Exploratory Method during Early Drug Product Development

Silva, Daniela Amaral; Al-Gousous, Jozef; Davies, Neal M.; Chacra, Nadia Bou; Webster, Gregory K.; Lipka, Elke; Amidon, Gordon L.; Löbenberg, Raimar

doi:10.3390/pharmaceutics12050420

Cited by 11 publications

(13 citation statements)

References 44 publications

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“…The partitioning of LTG from the buffer into octanol from the reference and test was rapid between 15 min and 2 h due to rapid drug release from dosage forms, whereas the slow partitioning after 2 h was related to the equilibrium of two phases rather than drug release, which is consistent with the previous findings in other studies [52,54]. The partitioning of the drug from the buffer medium into the organic solvent is considered to be an important parameter for optimizing biphasic tests, reflecting the absorption [55,56].…”

Section: Discussionsupporting

confidence: 91%

“…In the biphasic dissolution test, the octanol phase reflected the intestinal absorption of LTG. It has also been widely used in other biphasic dissolution studies in the literature since octanol can mimic biological membranes [50][51][52][53]. LTG has a suitable solubility in octanol (4.14 mg/mL) and a high affinity to octanol, making this drug a good candidate for the biphasic dissolution test.…”

Section: Discussionmentioning

confidence: 99%

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In Vivo Relevance of a Biphasic In Vitro Dissolution Test for the Immediate Release Tablet Formulations of Lamotrigine

Incecayir,

Demir

2023

Pharmaceutics

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Biphasic in vitro dissolution testing is an attractive approach to reflect on the interplay between drug dissolution and absorption for predicting the bioperformance of drug products. The purpose of this study was to investigate the in vivo relevance of a biphasic dissolution test for the immediate release (IR) formulations of a Biopharmaceutics Classification System (BCS) Class II drug, lamotrigine (LTG). The biphasic dissolution test was performed using USP apparatus II with the dual paddle modification. A level A in vitro-in vivo correlation (IVIVC) was constructed between the in vitro partition into the octanol and absorption data of the reference product. A good relation between in vitro data and absorption was obtained (r2 = 0.881). The one-compartment open model was introduced to predict the human plasma profiles of the test product. The generic product was found to be bioequivalent to the original product in terms of 80–125% bioequivalence (BE) criteria (85.9–107% for the area under the plasma concentration curve (AUC) and 82.7–97.6% for the peak plasma concentration (Cmax) with a 90% confidence interval (CI)). Overall, it was revealed that the biphasic dissolution test offers a promising ability to estimate the in vivo performance of IR formulations of LTG, providing considerable time and cost savings in the development of generic drug products.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

In Vivo Relevance of a Biphasic In Vitro Dissolution Test for the Immediate Release Tablet Formulations of Lamotrigine

Incecayir,

Demir

2023

Pharmaceutics

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“…Another method, to allow better predictions of the IVIVS, is to use in vitro data from biphasic dissolution. In this case, a two-phase system is utilized where the simultaneous dissolution and partition into an organic phase is concomitantly assessed [56].…”

Section: Discussionmentioning

confidence: 99%

An In Vitro–In Vivo Simulation Approach for the Prediction of Bioequivalence

Vlachou

Karalis

2021

Materials

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The aim of this study was to develop a new in vitro–in vivo simulation (IVIVS) approach in order to predict the outcome of a bioequivalence study. The predictability of the IVIVS procedure was evaluated through its application in the development process of a new generic product of amlodipine/irbesartan/hydrochlorothiazide. The developed IVIVS methodology is composed of three parts: (a) mathematical description of in vitro dissolution profiles, (b) mathematical description of in vivo kinetics, and (c) development of joint in vitro–in vivo simulations. The entire programming was done in MATLAB® and all created scripts were validated through other software. The IVIVS approach can be implemented for any number of subjects, clinical design, variability and can be repeated for thousands of times using Monte Carlo techniques. The probability of success of each scenario is recorded and finally, an overall assessment is made in order to select the most suitable batch. Alternatively, if the IVIVS shows reduced probability of BE success, the R&D department is advised to reformulate the product. In this study, the IVIVS approach predicted successfully the BE outcome of the three drugs. During the development of generics, the IVIVS approach can save time and expenses.

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“…A 0.45 μm syringe filter was used to withdraw a five ml samples at a predetermined time intervals and a fresh dissolution media was replaced. Drug concentrations were analyzed using UV-spectrophotometer (Shimadzu , Japan) (16) . Table 1.…”

Section: In-vitro Dissolution Tests Monophasic Dissolution Test Under...mentioning

confidence: 99%

Assessment of two-phase dissolution system as a guide in drug formulation: The furosemide case

Hussein,

Sahib

2024

IJPS

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The performance and the quality control of a drug may be evaluated using different approaches. Dissolution test is a corner stone in these processes. However, many issues appeared when using monophasic dissolution system like keeping the sink condition and/or described the in-vivo performance for Class II and IV drugs. Therefore, this study was to evaluate the biphasic dissolution system as discriminatory tool to differentiate between manufacture process and different excipient use for Class IV drug. Furosemide was prepared by two different methods: direct compression and wet granulation. Different excipients (acid and base) were used for each method. Furthermore, two commercially available products (Lasix® and generic product FA) were used for comparison with the prepared formulation. All formulations were evaluated for physical properties like hardness, friability and disintegration. Monophasic and biphasic dissolution tests were carried out for all formulas. All physical properties of the prepared tablets were within acceptable values. The dissolution rates of all three types of formulas (brand, generic, and prepared formulation) were identical under monophasic conditions. The similarity factor was more than 50 and difference factor less than 15. On the other hand, the biphasic dissolution profiles (aqueous phase, organic phase and overall dissolution media) showed significant differences between all prepared formulations and the brand product. Moreover, the two phase system still had the ability to show the similarity between brand and generic product. Furthermore, the direct compression method showed lower release than wet granulation method. Similarly, the acid excipients showed higher release than the basic one. As a conclusion, the biphasic dissolution system showed an excellent discriminatory power. Moreover, this approach was superior over conventional dissolution system regarding identifying variations in production processes and excipients content.

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Biphasic Dissolution as an Exploratory Method during Early Drug Product Development

Cited by 11 publications

References 44 publications

In Vivo Relevance of a Biphasic In Vitro Dissolution Test for the Immediate Release Tablet Formulations of Lamotrigine

In Vivo Relevance of a Biphasic In Vitro Dissolution Test for the Immediate Release Tablet Formulations of Lamotrigine

An In Vitro–In Vivo Simulation Approach for the Prediction of Bioequivalence

Assessment of two-phase dissolution system as a guide in drug formulation: The furosemide case

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