Solid-State Dehydration Mechanism of Diclofenac Sodium Salt Hydrates

Hidehiro Uekusa,Akiko Sekine,Takashi Miyamoto,Hironaga Oyama,Ilma Nugrahani

doi:10.3390/cryst11040412

Abstract

Salt formation is a useful technique for improving the solubility of active pharmaceutical ingredients (APIs). For instance, a nonsteroidal anti-inflammatory drug, diclofenac (DIC), is used in a sodium salt form, and it has been reported to form several hydrate forms. However, the crystal structure of the anhydrous form of diclofenac sodium (DIC-Na) and the structural relationship among the anhydrate and hydrated forms have not yet been revealed. In this study, DIC-Na anhydrate was analyzed using single-crystal X-ray diffraction (XRD). To determine the solid-state dehydration/hydration mechanism of DIC-Na hydrates based on both the present and previously reported crystal structures (4.75-hydrate and 3.5-hydrate), additional experiments including simultaneous powder XRD and differential scanning calorimetry, thermogravimetry, dynamic vapor sorption measurements, and a comparison of the crystal structures were performed. The dehydration of the 4.75-hydrate form was found to occur in two steps. During the first step, only water molecules that were not coordinated to Na+ ions were lost, which led to the formation of the 3.5-hydrate while retaining alternating layered structures. The subsequent dehydration step into the anhydrous phase accompanied a substantial structural reconstruction. This study elucidated the complete landscape of the dehydration/hydration transformation of DIC-Na for the first time through a crystal structure investigation. These findings contribute to understanding the mechanism underlying these dehydration/hydration phenomena and the physicochemical properties of pharmaceutical crystals.

Highlights

In drug development, improving the poor water solubility of many active pharmaceutical ingredients (APIs) is an attractive area of research
Sodium salt formation is a well-known technique for increasing the solubility of poorly soluble acidic APIs in drug development, and sodium ions account for approximately 60%
Sodium API salts often form hydrate crystals in which the water coordination geometry around Na+ is more flexible than the structure of the transition metal ion hydrate owing to the s-block atomic nature of Na [12]

Summary

Introduction

In drug development, improving the poor water solubility of many active pharmaceutical ingredients (APIs) is an attractive area of research. In addition to the formulation of low-crystallinity solids such as solid dispersions [1,2] and cyclodextrin inclusion compounds [3], other methods can increase solubility through the formation of a stable multi-component crystalline state such as salt formation [4], co-crystallization [5], and salt co-crystallization [6,7,8], in which the crystal structure differs from the mother API crystal, providing an opportunity to change the solubility. Sodium API salts often form hydrate crystals in which the water coordination geometry around Na+ is more flexible than the structure of the transition metal ion hydrate owing to the s-block atomic nature of Na [12]. This “pseudo-coordination bond” property of Na+ –O(water) interactions contributes the specific hydration–dehydration behaviors of sodium API salts [13,14,15,16,17,18,19]

Methods

Discussion

Conclusion