Comparison of the relative stability of pharmaceutical cocrystals consisting of paracetamol and dicarboxylic acids

Objective: The aim of this study is to evaluate the relative stability of pharmaceutical cocrystals consisting of paracetamol (APAP) and oxalic acid (OXA) or maleic acid (MLA).

Significance: These observations of cocrystal stability under various conditions are useful coformer criteria when cocrystals are selected as the active pharmaceutical ingredient in drug development.

Method: The relative stability was determined from the preferentially formed cocrystals under various conditions.

Result: Cocrystal of APAP–OXA was more stable than that of APAP–MLA in a ternary cogrinding system and possessed thermodynamical stability. On the other hand, when grinding with moisture or maintaining at high temperatures and relative humidity conditions, APAP–MLA was more stable, and OXA converted to OXA dihydrate. In the slurry method, APAP–OXA was more stable in aprotic solvents because the APAP–OXA with low-solubility product precipitated.

Conclusions: The relative stability order was affected by preparing conditions of presence of moisture. This order might attribute to the small difference of crystal structure in the extension of the hydrogen bond network.     

不同组分比的HMX/DMI共晶炸药结构与性质的理论研究

利用分子动力学,研究了分子摩尔比对HMX/DMI共晶炸药几个重要晶面成键能的影响,对于不同分子的摩尔比的力学性质也进行了估算,借助M06-2x/6-311+G(2df,2p)方法对HMX/DMI复合物的溶剂效应也进行了研究。计算结果表明,(020)和(100)取代基模型具有最高的成键能和稳定性,1∶1和2∶1的化合物最稳定且具有最高的力学性能。分子间相互作用能和N–NO_2键离解能的变化对HMX/DMI共晶炸药的稳定性有较大影响。制备稳定的HMX/DMI共晶炸药应选用较低介电常数作溶剂。     

Preparation and Performance of a HNIW/TNT Cocrystal Explosive

A novel cocrystal explosive composed of 2,4,6,8,10,12‐hexanitrohexaazaiso‐wurtzitane (HNIW) and 2,4,6‐trinitrotoluene (TNT) in a 1 : 1 molar ratio was effectively prepared by solvent/nonsolvent cocrystallization adopting dextrin as modified additive. The structure, thermal behavior, sensitivity, and detonation properties of HNIW/TNT cocrystal were studied. The morphology and structure of the cocrystal were characterized by scanning electron microscopy (SEM) and single crystal X‐ray diffraction (SXRD). SEM images showed that the cocrystal has a prism type morphology with an average size of 270 μm. SXRD revealed that the cocrystal crystallizes in the orthorhombic system, space group Pbca, and is formed by hydrogen bonding interactions. The properties of the cocrystal including sensitivity, thermal decomposition, and detonation performances were discussed in detail. Sensitivity studies showed that the cocrystal exhibits low impact and friction sensitivity, and largely reduces the mechanical sensitivity of HNIW. DSC and TG tests indicated that the heterogeneous exothermic decomposition of the cocrystal occurs in the temperature range from 170 °C to 265 °C with peak maxima at 220 °C and 250 °C and significantly increases the melting point of TNT by 54 °C. The cocrystal has excellent detonation properties with a detonation velocity of 8426 m s⁻¹ and a calculated detonation pressure of 32.3 MPa at a charge density of 1.76 g cm⁻³, respectively. Moreover, the results suggested that the HNIW/TNT cocrystal not only has unique performance itself, but also effectively alters the properties of TNT and HNIW. Therefore, the cocrystal formed by HNIW and TNT could provide a new and effective method to modify the properties of certain compounds to yield enhanced explosives for further application.     

Molecular dynamic simulations on TKX-50/RDX cocrystal

Dihydroxylammonium 5,5′-bistetrazole-1,1′-diolate (TKX-50) is a newly synthesized energetic material with excellent comprehensive properties. Cyclotrimethylenetrinitramine (RDX) is currently one of the most widely used energetic materials in the world. TKX-50 and RDX supercell models and TKX-50/RDX cocrystal model were constructed based on their crystal cell parameters and the formation mechanism of cocrystal, respectively, then they were simulated by molecular dynamics (MD) simulations. The maximum trigger bond (NNO₂) length(L_max), binding energy (E_bind), radial distribution function (RDF), cohesive energy density(CED) and mechanical properties were simulated at different temperatures based on the simulated equilibrium structures of the models. The simulated results indicate that hydrogen bond and van der Waals force interactions exist in the cocrystal system and the hydrogen bonds are mainly derived from the hydrogen atom of TKX-50 with the oxygen or nitrogen atom of RDX. Moreover, TKX-50/RDX cocrystal structure significantly reduces the sensitivity and improves the thermodynamic stability of RDX, and it also shows better mechanical properties than pure TKX-50 and RDX, indicating that it will vastly expand the application scope of the single compound explosives.     

Influence of eutectic mixture as a multi-component system in the improvement of physicomechanical and pharmacokinetic properties of diacerein

A multi-component system of diacerein (DIA) with 2, 4 – dihydroxybenzoic acid (DHA) as coformer at various molar compositions was formulated to simultaneously improve solubility, compressibility and bioavailability of DIA by applying acetone assistant grinding technique. Various evaluation parameters pertaining to measure physicomechanical properties were conducted. Thermal analysis revealed a ‘V’-shaped binary phase diagram along with single melting event as a possibility of eutectic formation between drug and coformer. It was further confirmed PXRD and FT-IR. Equidimensional shape with platy nature of eutectic material was observed in SEM images imparting its better flow and compressibility. Solubility and dissolution study showed 2 and 1.8 folds enhancement respectively compared to pure DIA and control batch. Pharmacokinetic study proved 2.1 times higher bioavailability in case of prepared eutectic compared to DIA along with its stable nature. Hence, the multi-component system can become a potential way for the improvement of material characteristics.     

Mechanical property design of molecular solids

The current emphasis of crystal engineering, which has evolved over the past three decades through crystal packing analysis and identification of crystal design strategies, has shifted from structure to properties, i.e., design of molecular solids with targeted combination of properties. Amongst the panoply of chemical, physical, and biological properties that these materials exhibit, a comprehensive understanding of the mechanical properties is perhaps the most challenging as it involves connecting molecular level structural features to macroscopic mechanical behavior. However, the adoption of the nanoindentation technique, with which it is possible to measure—both quantitatively and accurately—the mechanical response of even small single crystals, in crystal engineering, has paved the way for substantial progress in the recent past. In this review, we summarize some recent results with an emphasis as to how one can design and control properties of molecular solids such as elastic modulus and hardness. This review closes with an enumeration of the key challenges that lie ahead. Such studies show a big scope for studying mechanical properties of organic crystals as a function of crystal structure, and in turn to understand their structure-property relationship for designing future smart materials. This emerging research field has prospects and a potential to play an important role in the future development of crystal engineering.     

Synthesis,Characterization, Detonation Performance,and DFT Calculation of HMX/PNO Cocrystal Explosive

A novel 1,3,5,7-tetranitro-1,3,5,7-tetrazocane (HMX)/pyridine-N-oxide (PNO) cocrystal at 1:1 molar ratio was synthesized by a solvent evaporation method, and its crystal structure was determined using X-ray diffraction (XRD). It crystallizes in the orthorhombic system with the Pbcn space group and cell parameters a = 12.712(3)Å, b = 9.315(3)Å, c = 12.909(3)Å. In addition, detonation performance of this cocrystal was estimated. The predicted detonation velocity and detonation pressure of this cocrystal are 7.47 km/s and 23.20 GPa, respectively, suggesting that it is less powerful than β-HMX. Finally, density functional theory, involving binding energy, atoms in molecule (AIM) theory, natural bond orbital (NBO) analysis, band structure, and density of states, was adopted to characterize the driving forces for the formation of this cocrystal. The results show that driving forces are dominated by the interactions between O atoms of PNO and methylene groups of HMX. It is expected that this research provides some bases for further HMX cocrystal design and preparation.     

Preparation and Performance of Nano HMX/TNT Cocrystals

Cocrystals of 1,3,5,7‐tetranitro‐1,3,5,7‐tetraazacyclooctane (HMX) and 2,4,6‐trinitrotoluene (TNT) with high energy and low sensitivity were obtained by a spray drying method. Scanning electron microscopy (SEM), X‐ray diffraction (XRD), and Fourier Transform Raman spectroscopy (FT‐Raman) were used to characterize the raw materials and cocrystals. Impact sensitivity and thermal decomposition properties of the cocrystals were tested and analyzed. The results show that microparticles prepared by the spray drying method are spherical in shape and 1–10 μm in size. The particles are aggregates of many tiny cocrystals, ranging from 50 nm to 200 nm. The formation of cocrystals originates from the N O ⋅⋅⋅ H hydrogen bonding between  NO₂ (HMX) and  CH₃ (TNT). Compared with raw HMX, the impact sensitivity of the cocrystals reduces obviously and it is much harder to decompose the cocrystal thermally.     

Naproxen–nicotinamide cocrystals produced by CO2 antisolvent

Cocrystals of naproxen (NPX) and nicotinamide (NCTA) were successfully prepared in acetone using CO₂ as antisolvent in the so-called GAS technique (Gaseous Anti Solvent). Infra-red spectroscopy and powder X-ray analysis evidenced the same hydrogen-bond network and stoichiometry than cocrystals produced by cooling crystallization, i.e. 2 NPX for 1 NCTA, which coincided with literature results as well. The purity of powders in cocrystals was evaluated thanks to chromatography analysis and the homocrystals identification by powder X-rays diffraction. The effect of initial mixture composition (NPX:NCTA ratio) and of CO₂ and acetone mixing conditions (CO₂ introduction rate, stirring speed) was investigated. Results showed that the cocrystal purity was closed to 98 ± 2% whatever the initial ratio in solution of 3:1, 2:1, 1:1 but levelled down to 67% when a 1:2 solution was processed. The mixing conditions did not influence the cocrystal stoichiometry or purity (experiments carried out from a 2:1 mixture) but impacted on precipitation yield and size distribution. In best conditions, 62% of the initial processed amount was collected in the vessel as a powder of sizes below 180 μm made at 98% of NPX₂:NCTA₁ cocrystals.     

Promising CL‐20‐Based Energetic Material by Cocrystallization

A novel cocrystal (NEX‐1) of CL‐20 and MDNT is presented herein. The CL‐20: MDNT cocrystal, obtained in high yield by resonant acoustic mixing, shows new properties versus the discrete components. This is the first example of cocrystallization of CL‐20 where the new material is less sensitive to friction than CL‐20 itself, while demonstrating similar impact and ESD sensitivity. The CL‐20: MDNT cocrystal shows promise in the production of new energetic materials of interest by the cocrystallization of well‐characterized components.