Overcoming drug impurity challenges in amorphous solid dispersion with rational development of biorelevant dissolution-permeation method

Huzjak, Tilen (author), Jakasanovski, Ognen (author), Berginc, Katja (author), Puž, Vid (author), Zajc-Kreft, Katarina (author), Jeraj, Žiga (author), Janković, Biljana (author)

Hot-melt extrusion is often used to prepare amorphous solid dispersion to overcome low drug solubility and enhance bio-performance of the formulation. Due to the uniqueness of each drug - polymer combination and its physico-chemical properties, setting the appropriate HME barrel temperature, feed rate and screw speed ensures drug amorphization, absence of residual crystallinity, absence of water, and a suitable drug release profile. In this research, samples with BCS II/IV model drug and PVP/VA polymer were prepared to evaluate the impact of HME process parameters, incoming drug form (anhydrous vs. hydrate), and drug supplier (i.e., impurity profile), on biorelevant drug release. This study provides a relationship between observed in vitro supersaturation and precipitation behavior of amorphous solid dispersion formulation with in vivo results, on patients, by using the acceptor profile of side-by-side dissolution-permeation apparatus. An in vitro dissolution method, in small volumes, in an apparatus with paddles and dissolution-permeation side-by-side method was developed on the MicroFlux™ apparatus to assess if the differences observed in vitro bears relevance to the bioequivalence outcome in vivo. The former was used to guide the generic drug product development due to high discriminatory strength, while the latter was biorelevant, due to the inclusion of the second compartment assuring absorptive environment to capture the impact of supersaturation and subsequent precipitation on bioavailability. Bio-relevancy of the in vitro method was confirmed with the in vivo dog study and clinical study on patients, and an in vitro - in vivo correlation was established. For the investigated BCS II/IV drug, this research highlights the importance of considering supersaturation and formation of colloidal species during amorphous solid dispersion release testing to assure product quality, safety and efficacy.

• Language: English
• Keywords: biorelevant dissolution-permeation, hot-melt extrusion, In vitro – in vivo correlation, liquid-liquid phase separation, solid dispersion, supersaturation
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy
• Publication status: Published
• Publication version: Version of Record
• Year: 2024
• Number of pages: 12 str.
• Numbering: Vol. 192, art. 106655
• PID: 20.500.12556/RUL-155631
• UDC: 544.351.3:615.45
• ISSN on article: 0928-0987
• DOI: 10.1016/j.ejps.2023.106655
• COBISS.SI-ID: 188116227
• Publication date in RUL: 09.04.2024

Record is a part of a journal

• Title: European Journal of Pharmaceutical Sciences
• Shortened title: Eur. j. pharm. sci.
• Publisher: Elsevier
• ISSN: 0928-0987
• COBISS.SI-ID: 17553413

Licences

• License: CC BY-ND 4.0, Creative Commons Attribution-NoDerivatives 4.0 International
• Link: http://creativecommons.org/licenses/by-nd/4.0/
• Description: Under the NoDerivatives Creative Commons license one can take a work released under this license and re-distribute it, but it cannot be shared with others in adapted form, and credit must be provided to the author.

Secondary language

• Language: Slovenian
• Keywords: farmacevtske oblike, topnost, biorelevantno raztapljanje-prepustnost, ekstrudiranje z vročim taljenjem, in vitro – in vivo korelacija, ločevanje tekoče-tekoče faze, trdna disperzija, prenasičenost

Projects

• Funder: Other - Other funder or multiple funders
• Project number: MA-16430-2020

• Funder: ARRS - Slovenian Research Agency
• Project number: P1-0189
• Name: Farmacevtska tehnologija: od dostavnih sistemov učinkovin do terapijskih izidov zdravil pri otrocih in starostnikih