Predictive potential of acido-basic properties, solubility and food on bioequivalence study outcome : analysis of 128 studies

Krajcar, Dejan (author), Jereb, Rebeka (author), Legen, Igor (author), Opara, Jerneja (author), Grabnar, Iztok (author)

Background and Objectives Risk assessment related to bioequivalence study outcome is critical for effective planning from the early stage of drug product development. The objective of this research was to evaluate the associations between solubility and acido-basic parameters of an active pharmaceutical ingredient (API), study conditions and bioequivalence outcome. Methods We retrospectively analyzed 128 bioequivalence studies of immediate-release products with 26 different APIs. Bioequivalence study conditions and acido-basic/solubility characteristics of APIs were collected and their predictive potential on the study outcome was assessed using a set of univariate statistical analyses. Results There was no difference in bioequivalence rate between fasting and fed conditions. The highest proportion of non-bioequivalent studies was for weak acids (10/19 cases, 53%) and neutral APIs (23/95 cases, 24%). Lower non-bioequivalence occurrence was observed for weak bases (1/15 cases, 7%) and amphoteric APIs (0/16 cases, 0%). The median dose numbers at pH 1.2 and pH 3 were higher and the most basic acid dissociation constant (pKa) was lower in the non-bioequivalent group of studies. Additionally, APIs with low calculated effective permeability (cPeff) or low calculated lipophilicity (clogP) had lower non-bioequivalence occurrence. Results of the subgroup analysis of studies under fasting conditions were similar as for the whole dataset. Conclusion Our results indicate that acido-basic properties of API should be considered in bioequivalence risk assessment and reveal which physico-chemical parameters are most relevant for the development of bioequivalence risk assessment tools for immediate-release products.

• Language: English
• Keywords: bioequivalence studies, active pharmaceutical ingredients, acido-basic characteristics, immediate-release products, solubility
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy
• Publication status: Published
• Publication version: Version of Record
• Year: 2023
• Number of pages: Str. 211-220
• Numbering: Vol. 23, iss. 3
• PID: 20.500.12556/RUL-152194
• UDC: 544.351.3:615
• ISSN on article: 1179-6901
• DOI: 10.1007/s40268-023-00426-6
• COBISS.SI-ID: 155412483
• Publication date in RUL: 10.11.2023

Record is a part of a journal

• Title: Drugs in R&D
• Shortened title: Drugs R&D
• Publisher: Springer Nature, Adis
• ISSN: 1179-6901
• COBISS.SI-ID: 520363801

Licences

• License: CC BY-NC 4.0, Creative Commons Attribution-NonCommercial 4.0 International
• Link: http://creativecommons.org/licenses/by-nc/4.0/
• Description: A creative commons license that bans commercial use, but the users don’t have to license their derivative works on the same terms.

Secondary language

• Language: Slovenian
• Keywords: bioekvivalenčne študije, aktivne sestavine učinkovin, acido-bazične lastnosti, sproščanje učinkovin, topnost

Projects

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