Study On Azelnidipine/Maleic Acid Co-Amorphous

The molecular formula for azelnidipine who is a diphenylpiperazine Ca²⁺ antagonist is C₃₃H₃₄N₄O₆ and its molecular weight is 582.65. Azelnidipine is a polymorph drug that has ? and ? polymorphs with several different physicochemical properties. For example, form ? has slightly higher solubility, so it is generally used in dosage form. However, form ? is a metastable phase and easily transforms to form ? at suitable conditions.In order to improve the solubility of azelnidipine, we intend to introduce maleic acid to azelnidipine through grinding method to get ?-azelnidipine/maleic acid co-amorphous and ?-azelnidipine/maleic acid co-amorphous supramolecular system. Because of the difference of starting components and preparation methods, the physicochemical properties of ?-azelnidipine/maleic acid co-amorphous and ?-azelnidipine/maleic acid co-amorphous are different, which affect the stability, bioavailability, and efficacy of the drug.Objective: To improve the physicochemical characteristics such as the solubility of azelnidipine, azelnidipine?crystalline ?-form and ?-form? were used as a model drug and maleic acid was used as a former molecule to screen azelnidipine/maleic acid co-amorphous. In order to explore the molecular interactions in co-amorphous and compare the difference of ?-azelnidipine/maleic acid co-amorphous and ?-azelnidipine/maleic acid co-amorphous, the solid state characterizations were performed. In order to guide the rational design of drug formulations, the physicochemical properties of ?-azelnidipine/maleic acid co-amorphous and ?-azelnidipine/maleic acid co-amorphous, such as equilibrium solubility, dissolution rate and hygroscopicity were measured. In order to provide reference and basis to the drug storage, stability analysis of ?-azelnidipine/maleic acid co-amorphous were performed. Furthermore, simulated calculations were performed on ?-azelnidipine/maleic acid co-amorphous supramolecular system to optimize molecular interactions.Methods:1 Neat grinding method?NG? and solvent assisted grinding method?SG? were used to prepare azelnidipine/maleic acid co-amorphous at molar ratio of 1:1, 1:2 and 2:1. Identifications and research of ?-azelnidipine/maleic acid co-amorphous and ?-azelnidipine/maleic acid co-amorphous were performed using powder X-ray diffraction?PXRD?, differential scanning calorimetry?DSC? scanning electric microscope?SEM?, infrared spectroscopy?IR?, solid-state nuclear magnetic resonance?ss NMR?, terahertz spectroscopy?THz?.2 The equilibrium solubility of ?-azelnidipine, ?-azelnidipine and azelnidipine/maleic acid co-amorphous in 0.01 and 0.1 mol/L HCl solution, acetate buffer?p H 4.5?, phosphate buffers?p H 6.8? and water were determined by shake-flask test method. Moreover, 0.1 mol/L HCl solution was used as dissolution medium to obtain the dissolution rate of ?-azelnidipine, ?-azelnidipine and azelnidipine/maleic acid co-amorphous by paddle method. The hygroscopicity of ?-azelnidipine, ?-azelnidipine and azelnidipine/maleic acid co-amorphous were determined at 25±1? and 75%±1% RH depending on the hygroscopicity determination method recorded in pharmacopeia. Furthermore, the stability analysis of ?-azelnidipine/maleic acid co-amorphous were performed at 4?/0%RH and 25?/0%RH for 42 days.3 The crystallography of ?-azelnidipine was analyzed by Bruker SMART-APEX CCD diffractometer and the SHELX program; ?-azelnidipine/maleic acid co-amorphous were fully optimized at the DFT B3LYP/6-31 G level using the GAUSSIAN-03 program package, then reasonable configurations were simulated and optimization molecular interactions were calculated.Results: 1 The Tgs were found to be 76.5?, 86.2?, 61.4? and 67.2? for ?-azelnidipine/maleic acid 1:1?NG?, 1:1?SG?, 1:2?NG? and 1:2?SG?, respectively. The Tgs were found to be 67.2?, 92.3?, 67.2?, 71.9? and 93.9? for ?-azelnidipine/maleic acid 1:1?NG?, 1:1?SG?, 1:2?NG?, 1:2?SG? and 2:1?NG?, respectively. SEM morphology characterization revealed that crystalline sample of pure ?-azelnidipine and ?-azelnidipine were slice-shape which was the nature of crystalline state. However, the images of ?-azelnidipine/maleic acid co-amorphous and ?-azelnidipine/maleic acid co-amorphous combinations showed sphere-shape particles without special shape which revealed the essence of amorphous. The weak hydrogen bond interaction of ?-azelnidipine/maleic acid co-amorphous was characterized by IR, ss NMR and simulation calculation. The results showed that ?-azelnidipine and maleic acid molecules were connected by hydrogen bonds of N–H···O, C–H···O and O–H···O. Based on the three hydrogen bonds, two heterogeneous dimers and one trimer were simulated. The interaction energies??E? of the dimer-1 and dimer-2 were-29.17 and-18.70 k J/mol, and the interaction energy??E? for the trimer was-48.89 k J/mol. PXRD characterization revealed that ?-azelnidipine/maleic acid co-amorphous at 4?/0%RH and 25?/0%RH during the store period still had typical halo patterns;2 The equilibrium solubility of intact ?-AZE, ?-AZE/MAL 1:1?NG?, 1:1?SG?, 1:2?NG? and 1:2?SG? in 0.1 mol/L HCl solution were 222.46±2.8, 248.47±2.4, 174.19±1.4, 347.80±2.8 and 139.22±1.7 ?g/m L, respectively. The equilibrium solubility of intact ?-AZE, ?-AZE/MAL 1:1?NG?, 1:1?SG?, 1:2?NG? and 1:2?SG? in 0.1 mol/L HCl solution were 268.40±3.2, 456.77±4.6, 207.64±1.8, 694.62±5.9, 632.99±4.8 and 331.77±2.6 ?g/m L, respectively. The t₅₀ values of intact ?-azelnidipine and ?-azelnidipine in 0.1 mol/L HCl solution were 803.3 min and 292.7 min, respectively. However, the t₅₀ values of ?-azelnidipine/maleic acid 1:2?SG? and ?-azelnidipine/maleic acid 1:1?SG? co-amorphous were 64.2min and 126.7min, respectively. The result of statistics analysis showed significant differences?P<0.05? in t₅₀ value of ?-azelnidipine/maleic acid 1:2?SG? and ?-azelnidipine/maleic acid 1:1?SG?compared with respective intact azelnidipine.Conclusions:1 The formation of co-amorphous were demonstrated by the typical halo patterns of XRD, the single glass transition temperature?Tg? in DSC curve and the sphere-shape particles in SEM photos. Moreover, the Tg values of ?-azelnidipine/maleic acid co-amorphous were higher then ?-azelnidipine/maleic acid co-amorphous, indicating that the former was more stabilization. The IR spectra suggested that the hydrogen bonding was produced between C=O in maleic acid and the N–H group in azelnidipine, and the difference of various co-amorphous were confirmation by different peak position of ss NMR and THz spectroscopy. PXRD characterization revealed that ?-azelnidipine/maleic acid co-amorphous were stabilized at 4?/0%RH and 25?/0%RH.2 The significant differences occurred on equilibrium solubility and dissolution rate of ?-azelnidipine/maleic acid co-amorphous and ?-azelnidipine/maleic acid co-amorphous. It indicated that ?-azelnidipine/maleic acid 1:2?SG? co-amorphous and ?- azelnidipine/maleic acid 1:1?SG? co-amorphous could potentially improve the dissolution rate and had the feasibility of enhancing in vivo absorption of azelnidipine.3 The interaction energy??E? for the trimer was stabilized at about 1 k J/mol than the sum of the interaction energies of dimer-1 and dimer-2, and it indicated that the trimer was the optimum combination form in the ?-azelnidipine/maleic acid supramole system. The long-range order in the ?-azelnidipine crystalline structure was broken, and a short-range and local order in the co-amorphous combinations was built. From this perspective, a short-range order and flexibility are the nature of co-amorphous configurations.