Liquid-Assisted Grinding to Prepare a Cocrystal of Adefovir Dipivoxil Thermodynamically Less Stable than Its Neat Phase

Sungyup Jung,Insil Choi,Il Kim

doi:10.3390/cryst5040583

Abstract

Liquid-assisted grinding was employed to generate a cocrystal of adefovir dipivoxil (AD) and glutaric acid (GLU), which had not been successfully obtained through solution crystallization. The cocrystal formation was confirmed with powder X-ray diffraction, and its thermal stability and release behavior were studied through differential scanning calorimetry and dissolution experiments, respectively. The AD/GLU cocrystal was less stable than neat AD phase and the previously reported AD cocrystals with other dicarboxylic acids, such as suberic acid and succinic acid. This suggests that the intermolecular interactions of the AD/GLU cocrystal are probably weaker than the other crystal phases. The release behavior of the AD/GLU was comparable with the cocrystal with suberic acid. The current study verifies the effectiveness of the liquid-assisted grinding for the preparation of the thermodynamically less stable cocrystal phase.

Highlights

Crystallization of active pharmaceutical ingredients (APIs) is the process that determines the physical properties of the API solid phases
We have studied the cocrystallization of adefovir dipivoxil (AD, Figure 1), a prodrug of a broad-spectrum antiviral known as adefovir, mainly through the solution process [16]
Liquid-assisted grinding was utilized to obtain the AD/glutaric acid (GLU) cocrystal that was difficult to isolate in its pure form through solution crystallization

Summary

Introduction

Crystallization of active pharmaceutical ingredients (APIs) is the process that determines the physical properties of the API solid phases. Some of the processes to prepare pharmaceutical cocrystals are solution crystallization, grinding, sublimation, and so on [5,10]. There were cases where the solution method was not successful in yielding cocrystals, such as caffeine/glutaric acid, paracetamol/oxalic acid, and itraconazole/malonic acid, in their pure forms, which could be obtained through liquid-assisted grinding [13,14,15]. Liquid-assisted grinding was utilized to prepare the AD/GLU cocrystals, and their thermal stability and release behavior were compared with those of AD/SUB cocrystals as well as neat AD crystals

Cocrystal Formation

Thermal Stability and Release Behavior

Experimental Section

Conclusions