Crystal Structure of Diisopropylammonium Hydrogen Maleate

: Use of salts and co-crystals of active pharmaceutical ingredients (APIs) as a method for tuning their delivery and activity is an area of growing interest. Modifying API properties such as solubility by finding new salts that employ similar hydrogen-bonding have been successful. In an effort to further study the hydrogen-bonding patterns of the maleate ion with other diisopropylammonium we report here the synthesis and diisopropylammonium maleate. The salt was isolated from reaction between diisopropylamine and maleic acid in methanol. The results of elementary analyzes (CHN) showed the presence of the nitrogen atom of diisopropylamine, carbon atoms and hydrogen. The IR spectrum of diisopropylammonium hydrogen maleate, showed the presence of two intense bands due to the vibrations of symmetricand anti-symmetric valence of the carboxylate group and a wide absorption due to the NH 2 groups of the cation. Those which has been confirmed by crystallography. The asymmetric unit contains one diisopropylammonium cation, iPr 2 NH 2+ and one hydrogen maleate anion. In the structure, anions which present an inner O-H…O hydrogen bond are linked to cations through N-H…O hydrogen bonds leading to infinite chains. Chains are connected to their neighbours through weak C-H…O hydrogen bonds affording a layer. The study of the interactions of diisopropylammonium hydrogen menaleate, by the presence of hydrogen bonds leading to supramolecular architectures has shown the possibility of its use in Active Pharmaceutical Ingrédients (API).


Introduction
Various ammonium salts of maleic acid have been synthesized and structurally characterized [1][2][3][4][5][6]. Use of salts and co-crystals of active pharmaceutical ingredients (APIs) as a method for tuning their delivery and activity is an area of growing interest [6]. Modifying API properties such as solubility by finding new salts that employ similar hydrogen bonding have been successful. Maleate derivatives remain among the agents most used in the design of active pharmaceutical ingredients (APIs) because of its power to give APIs a high solubility. Recently, Timolol maleate has been developed and validated as being safe and effective APIs in the treatment of ocular glaucoma [7,8]. Enalapril maleate has been successfully designated and evaluated according to the United States Pharmacopoeia (USP) for the treatment of hypertensive diseases [9]. For example, in the conext of improving the solubility of this drug, three saccharinate, maleate and oxalate salts of Ethionamide (ETH) have been synthesized [1]. Mechanochemical protocols, confirmed by powder X-ray diffraction, sheew a more complete solid state characteriszation for Ethionamide (ETH) maleate [1]. Whenever possible, Active Pharmaceutical Ingredients (APIs) having properties of increasing solubility by the presence of its hydrogen bonds like maleate should be selected for the formation of the optimal salt. In an effort to further study of the hydrogen bonding patterns of the maleate ion with another ammonium counter cation nous avons synthétisé le diisopropylammonium hydrogen maleate. Diisopropylammonium comes from diisoprylamine which was used recently with dichloroacetate as being alleviates liver fibrosis through inhibiting activation and proliferation of hepatic stellate cells [10], we investigated the interactions between diisopropylamine and maleic acid which yielded single crystals of diisopropylammonium hydrogen maleate, {[iPrNH 2 ] + .[HCO 2 CH=CHCO 2 ] -} whose crystallographic characterization is reported herein.

General
Chemicals were purchased from Sigma-Aldrich (Germany) and were used without any further purification. Elemental analyses were performed at the Institut de Chimie Moléculaire, Université de Bourgogne Franche-Comté, Dijon, France. The infrared spectra were recorded on a Bruker Vector 22 spectrometer equipped with a Specac Golden Gate™ ATR device. A crystal of dimensions 0.60 × 0.32 × 0.16 mm was used in the data collection. The structure has been resolved and refined using the SAINT V8.37A programs (Bruker AXS Inc., 2015), XT VERSION 2014/5 [11,12].

Synthesis
All the chemicals were purchased from Aldrich Company (Germany) and used without any further purification. Maleic acid, HCO 2 CH=CHCO 2 H (5.00g, 43mmol) was partially neutralized with diisopropylamine, iPr 2 NH (4.38g, 43mmol) in methanol (50 mL). The clear obtained mixture was stirred 2h at room temperature (300 K). Crystals of the title salt suitable for an X-ray diffraction analysis was obtained after a month of a slow solvent evaporation at room temperature (300 K).  The table 2 shown the Infrared data of diisopropylammonium hydrogen maleate. Compound diisopropylammonium hydrogen maleate was investigated by FT-IR spectroscopy. In the past, several works with FT-IR diisopropylammonium cations, carboylates anions and multiples other vibration bands investigation have been reported [13]. The infrared spectrum enables to diagnose N-H stretching and bending vibrations at 3385 cm −1 , 3251 cm −1 and 11619 cm −1 , CO antisymmetric and symmetric vibrations at 1548 cm −1 , 1576 cm −1 and 1318 cm −1 . The band around 1619 cm -1 is due to the anti-symmetrical vibration of the NH 2 group. This shows the presence of a maleate anion and a diisopropylammonium cation, confirmed by data from the asymmetric unit of the molecule shown in the following (figure 1).
In the structure, the acid anions H 2 OC-CH = CH-CO 2 are linked together by cations via hydrogen bonds OH ·· O, NH ·· O giving rise to zigzag chains parallel to [010] (Figure 2) in which cations and anions alternate.

Conclusion
The structure of diisopropylammonium hydrogen maleate studied is an infinite chain deriving from hydrogen bonds of N-H… O and C-H… O type leading to a supramolecular structure. The study of these interactions has shown the possibility of using these salts in active pharmaceutical ingredients (APIs).