Characterizing the Physicochemical Properties of Two Weakly Basic Drugs and the Precipitates Obtained from Biorelevant Media.

Miao Zhang,Qin Hu,Bin Wu,Shudong Zhang,Xijing Chen,Lin Wang,Dongyang Liu

doi:10.3390/pharmaceutics14020330

Abstract

Generally, some weakly basic insoluble drugs will undergo precipitate and redissolution after emptying from the stomach to the small intestinal, resulting in the limited ability to predict the absorption characteristics of compounds in advance. Absorption is determined by the solubility and permeability of compounds, which are related to physicochemical properties, while knowledge about the absorption of redissolved precipitate is poorly documented. Considering that biorelevant media have been widely used to simulate gastrointestinal fluids, sufficient precipitates can be obtained in biorelevant media in vitro. Herein, the purpose of this manuscript is to evaluate the physicochemical properties of precipitates obtained from biorelevant media and active pharmaceutical ingredients (API), and then to explore the potential absorption difference between API and precipitates. Precipitates can be formed by the interaction between compounds and intestinal fluid contents, leading to changes in the crystal structure, melting point, and melting process. However, the newly formed crystals have some advantageous properties compared with the API, such as the improved dissolved rate and the increased intrinsic dissolution rate. Additionally, the permeability of some precipitates obtained from biorelevant media was different from API. Meanwhile, the permeability of rivaroxaban and Drug-A was decreased by 1.92-fold and 3.53-fold, respectively, when the experiments were performed in a biorelevant medium instead of a traditional medium. Therefore, the absorption of precipitate may differ from that of API, and the permeability assay in traditional medium may be overestimated. Based on the research results, it is crucial to understand the physicochemical properties of precipitates and API, which can be used as the departure point to improve the prediction performance of absorption.

Highlights

Physicochemical properties are the key points affecting the absorption of compounds in vivo
The reabsorption of precipitates is an important part of the absorption of some insoluble, weakly basic oral drugs
Evaluating the physicochemical properties of precipitates collected from biorelevant media is fundamental for a full understanding of compound absorption

Summary

Introduction

The oral absorption of some insoluble drugs is susceptible to gastrointestinal (GI) conditions, e.g., the pH in the GI tract, the bile micelle concentration under both fasted and fed states, and so on, which can impact the solubility and permeability of drugs, increasing the difficulty of accurately estimating the absorption characteristic of compounds [3,4,5,6]. Oral absorption is a complex process in the GI tract, especially concerning salts and weakly basic insoluble drugs. The weakly basic insoluble compounds show good solubility in the acidic gastric environment through ionization, but the advantage dissipates when the less soluble unionized compounds are formed in the near-neutral intestinal microenvironment. The precipitate can be redissolved again and cross the intestinal barrier after the full absorption of the dissolved unionized compound [9]

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Discussion

Conclusion