Abstract

<div>Development of novel energetic molecules is a challenging endeavor. Successful discovery and synthesis of a novel viable energetic molecule is an even more challenging endeavor. To qualify for scale-up in production, the molecule must undergo extensive characterization at the small scale and meet criteria for sensitivity, stability, toxicity, lifetime, etc. A failure to qualify for further scale-up can result in significant wasted investment. Cocrystallization of energetic materials is a potentially attractive route to development of new energetic materials because existing molecules can be used to create new materials that have tailored properties different from either coformer. A cocrystal is a combination of two crystalline monomolecular materials that yields a material with a unique crystal structure. While cocrystallization reduces the front-end investment ordinarily required for discovery of new energetic molecules, discovery of energetic cocrystals is not trivial. A number of energetic cocrystals have been reported that display attractive properties such as high density and improved thermal stability. However, the effect of cocrystal formation on larger scale properties, particuarly detonation properties, is not well-understood. Knowledge of these properties is important for understanding the potential improvements gained from pursuing discovery of cocrystals. \\\\</div><div>A challenge with obtaining detonation properties is that most techniques typically require anywhere from hundreds of grams to several kilograms of material. For example, rate stick experiments typically have an L/D (length to diameter) ratio between 12 and 20. Even for ideal explosives, diameters used are typically at least two centimers in diameter. Such experimental configurations are poorly suited for materials in the early stages of development. \\\\</div><div>In this work, comparative detonation velocity measurements were performed for select hexanitrohexaazaisowurtzitane (CL-20) cocrystals that have been reported in the past five years along with corresponding formulations or physical mixtures of the components. The detonation velocity measurements were performed using microwave interferometry, a well-established detonation velocity diagnostic. Using precision-machined hardware and appropriate matching of booster charge to sample charge, it was shown with statistical analysis that well-resolved measurements of detonation velocity could be obtained with shot-to-shot variation in the range of 130 m/s. The detonation velocity for cyclotetramethylene tetranitramine (HMX) was obtained using this experimental technique to validate the method and estimated variation. It was demonstrated that detonation tests with good repeatability could be performed for the nearly ideal explosives considered. \\\\</div><div>The experimental technique described above was performed first for a cocrystal of 1-methyl-3,5-dinitro-1,2,4-triazole (MDNT) and CL-20. Comparative measurements were performed for the cocrystal and physical mixture at a loading density of 1.4 $\gcc$. We chose a fixed loading density in order to isolate isolate effects other than loading density. The cocrystal was observed to detonate about 500 m/s faster than the physical mixture. In comparison, thermochemical equilibrium predictions showed that the cocrystal would detonate about 230 m/s faster than the physical mixture at this density. The enthalpy of formation for this cocrystal was double that of the physical mixture and this difference resulted in the predicted difference. Similar measurements were performed for the cocrystal of cyclotetramethylene tetranitramine (HMX) and CL-20 and CL-20/hydrogen peroxide (HP) solvate at the same loading density. The HMX/CL-20 cocrystal was observed to detonate about 300 m/s faster than the physical mixture. The CL-20/HP solvate was observed to detonate about 300 m/s faster than CL-20. \\\\</div><div>Using the Kamlet scaling laws, it was determined that the differences in detonation velocity observed are attributable to differences in enthalpy of formation. That is, the energy state is different between the configurations. The enthalpy of formation for MDNT/CL-20 was measurably larger than its physical mixture. The CL-20/HP solvate was also measurable larger than that of CL-20. This result has implications for intermolecular bond and configurational energies formed in cocrystals that affects their energy content.</div><div>Fully explaining the precise reason for this, and perhaps exploiting this in future cocrystals and multimolecular systems is a challenge for modelers, theoreticians, and synthesis chemists.</div>

No / Mechanistic understanding of competitive destabilization of carbamazepine:nicotinamide and carbamazepine:saccharin cocrystals under solvent free conditions has been investigated. The crystal phase transformations were monitored using hot stage microscopy, variable-temperature powder X-ray diffraction, and sublimation experiments. The destabilization of the two cocrystals occurs via two distinct mechanisms: vapor and eutectic phase formations. Vapor pressure measurements and thermodynamic calculations using fusion and sublimation enthalpies were in good agreement with experimental findings. The mechanistic understanding is important to maintain the stability of cocrystals during solvent free green manufacturing. / EPSRC (EP/J003360/1, EP/ L027011/1). MHD. Bashir would like to thank CARA for providing doctoral degree scholarship.

Yes / The main objective of this research is to investigate solid-state destabilization mechanism and kinetics of the model cocrystal caffeine : malonic acid (CA:MO) in presence of oxalic acid (OX) as a structural competitor. Competitive destabilization of CA:MO and subsequent formation of CA:OX takes place at temperatures significantly below its melting point. Destabilization mechanism was found to be mediated by sublimation of both CA:MO and OX. During CA:MO destabilization, free CA could not be detected and direct transformation to CA:OX cocrystal was observed. The destabilization kinetics follow Prout-Tompkins nucleation and crystal growth model with activation energy of 133.91 kJ/mol and subsequent CA:OX growth kinetic follow Ginstling – Brounshtien diffusion model with activation energy of kJ/mol.

The aim of this study is to investigate the effects of coformers and polymers on the phase transformation and release profiles of cocrystals. Pharmaceutical cocrystals of Carbamazepine (CBZ) (namely 1:1 carbamazepine-nicotinamide (CBZ-NIC), 1:1 carbamazepine-saccharin (CBZ-SAC) and 1:1 carbamazepine-cinnamic acid (CBZ-CIN) cocrystals, were synthesized. A Quality by Design (QbD) approach was used to construct the formulation. Dissolution and solubility were studied using UV imaging and High Performance Liquid Chromatography (HPLC). The polymorphic transitions of cocrystals and crystalline properties were examined using Differential Scanning Calorimetry (DSC), X-Ray Powder Diffraction (XRPD), Raman spectroscopy (Raman) and Scanning Electron Microscopy (SEM). JMP 11 software was used to design the formulation. It has been found that Hydroxupropyl methylcellulose (HPMC) cannot inhibit the transformation of CBZ-NIC cocrystals to Carbamazepine Dihydrate (CBZ DH) in solution or in the gel layer of the matrix, as opposed to its ability to inhibit CBZ Form III (CBZ III) phase transition to CBZ DH. The selection of different coformers of SAC and CIN can affect the stability of CBZ in solution, resulting in significant differences in the apparent solubility of CBZ. The dissolution advantage of the CBZ-SAC cocrystal can only be shown for 20 minutes during dissolution because of the conversion to its dihydrate form (CBZ DH). In contrast, the improved CBZ dissolution rate of the CBZ-CIN cocrystal can be realised in both solution and formulation because of its stability. The polymer of Hypromellose Acetate Succinate (HPMCAS) seemed to best augment the extent of CBZ-SAC and CBZ-CIN cocrystal supersaturation in solution. At 2 mg/ml of HPMCAS concentration, the apparent CBZ solubility of CBZ-SAC and CBZ-CIN cocrystals can increase the solubility of CBZ III in pH 6.8 phosphate buffer solutions (PBS) by 3.0 and 2.7 times respectively. All pre-dissolved polymers in pH 6.8 PBS can increase the dissolution rates of CBZ cocrystals. In the presence of a 2 mg/ml HPMCAS in pH 6.8 PBS, the cocrystals of CBZ-NIC and CBZ-CIN can dissolve by about 80% within five minutes in comparison with 10% of CBZ III in the same dissolution period. Finally, CBZ-NIC cocrystal formulation was designed using the QbD principle. The potential risk factors were determined by fish-bone risk assessment in the initial design, after which Box-Behnken design was used to optimize and evaluate the main interaction effects on formulation quality. The results indicate that in the Design Space (DS), CBZ sustained release tablets meeting the required Quality Target Product Profile (QTPP) were produced. The tablets’ dissolution performance could also be predicted using the established mathematical model.

No / OBJECTIVES: Cocrystallization of sulfadimidine (SDM) with suitable coformers, such as 4-aminosalicylic acid (4-ASA), combined with changes in the crystal habit can favourably alter its physicochemical properties. The aim of this work was to engineer SDM : 4-ASA cocrystals with different habits to investigate the effect on dissolution, and the derived powder properties of flow and compaction. METHODS: Cocrystals were prepared in a 1 : 1 molar ratio by solvent evaporation using ethanol (habit I) or acetone (habit II), solvent evaporation followed by grinding (habit III) and spray drying (habit IV). KEY FINDINGS: Powder X-ray diffraction showed Bragg peak position was the same in all the solid products. The peak intensity varied, indicating different preferred crystal orientation confirmed by SEM micrographs: large prismatic crystals (habit I), large plate-like crystals (habit II), small cube-like crystals (habit III) and microspheres (habit IV). The habit III exhibited the fasted dissolution rate; however, it underwent a polymorphic transition during dissolution. Habits I and IV exhibited the highest Carr's compressibility index, indicating poor flowability. However, habits II and III demonstrated improved flow. Spray drying resulted in cocrystals with improved compaction properties. CONCLUSIONS: Even for cocrystals with poor pharmaceutical characteristics, a habit can be engineered to alter the dissolution, flowability and compaction behaviour.

No / Spherical crystallization involves crystallization and simultaneous agglomeration of a crystalline particle using an immiscible phase, which has preferential affinity for the crystal surface. Here, we report application of a spherical crystallization technique to the field of co-crystallization. Carbamazepine/saccharin (CBZ/SAC) co-crystals were generated using reverse antisolvent addition and agglomerated using different bridging liquids. Two crystal forms of CBZ/SAC co-crystals were formed, depending on the levels of supersaturation achieved during processing. The selective agglomeration of co-crystal occurred during the agglomeration stage, depending on the relative interaction between bridging liquid and the crystal surfaces. The computational investigation of isosteric heats of adsorption of the bridging liquids at the prominent crystal surfaces proved to be a useful tool in understanding the surface interactions. The spherical crystallization technique shows opportunity to generate co-crystals and its purification through selective agglomeration.

Yes / Polymorphism in active pharmaceutical ingredients (APIs) can be regarded as critical for the potential that crystal form can have on the quality, efficacy and safety of the final drug product. The current contribution aims to characterize thermodynamic interrelationship of a dimorphic co-crystal, FI and FII, involving carbamazepine (CBZ) and saccharin (SAC) molecules. Supramolecular synthesis of CBZ-SAC FI and FII have been performed using thermo-kinetic methods and systematically characterized by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), solubility and slurry measurements. According to Berger and Ramberger’s heat of fusion rule, FI (ΔHfus = 121.1 J/g, mp 172.5 °C) and FII (ΔHfus= 110.3 J/g, mp 164.7 °C) are monotropically related. The solubility and van’t Hoff plot results suggest that FI stable and FII metastable forms. This study reveals that CBZ-SAC co-crystal phases, FI or FII, could be stable to heat induced stresses, however, FII converts to FI during solution mediated transformation. / Authors would like to acknowledge UKIERI (TPR 26), EPSRC (EP/J003360/1, EP/L027011/1) for the support. Open Access funded by Engineering and Physical Sciences Research Council

Yes / Objectives: Cocrystallization of sulfadimidine (SDM) with suitable coformers, such as 4-aminosalicylic acid (4-ASA), combined with changes in the crystal habit can favourably alter its physicochemical properties. The aim of this work was to engineer SDM:4-ASA cocrystals with different habits in order to investigate the effect on dissolution, and the derived powder properties of flow and compaction. Methods: Cocrystals were prepared in a 1:1 molar ratio by solvent evaporation using ethanol (habit I) or acetone (habit II), solvent evaporation followed by grinding (habit III) and spray-drying (habit IV). Key findings: Powder X-ray diffraction showed Bragg peak position was the same in all the solid products. The peak intensity varied, indicating different preferred crystal orientation confirmed by SEM micrographs: large prismatic crystals (habit I), large plate-like crystals (habit II), small cube-like crystals (habit III) and microspheres (habit IV). The habit III exhibited the fasted dissolution rate; however, it underwent a polymorphic transition during dissolution. Habits I and IV exhibited the highest Carr’s compressibility index, indicating poor flowability. However, habits II and III demonstrated improved flow. Spray drying resulted in cocrystals with improved compaction properties. Conclusions: Even for cocrystals with poor pharmaceutical characteristics, a habit can be engineered to alter the dissolution, flowability and compaction behavior. / Science Foundation Ireland. Grant Number: SFI/12/RC/2275

Yes / Apigenin (4′,5,7-trihydroxyflavone, APG) has many potential therapeutic benefits; however, its poor aqueous solubility has limited its clinical applications. In this work, a large scale cocrystal screening has been conducted, aiming to discover potential APG cocrystals for enhancement of its solubility and dissolution rate. In order to reduce the number of the experimental screening tests, three computational prescreening tools, i.e., molecular complementarity (MC), hydrogen bond propensity (HBP), and hydrogen bond energy (HBE), were used to provide an initial selection of 47 coformer candidates, leading to the discovery of seven APG cocrystals. Among them, six APG cocrystal structures have been determined by successful growth of single crystals, i.e., apigenin-carbamazepine hydrate 1:1:1 cocrystal, apigenin-1,2-di(pyridin-4-yl)ethane hydrate 1:1:1 cocrystal, apigenin-valerolactam 1:2 cocrystal, apigenin-(dl) proline 1:2 cocrystal, apigenin-(d) proline/(l) proline 1:1 cocrystal. All of the APG cocrystals showed improved dissolution performances with the potential to be formulated into drug products.