Jacek Zeglinski

Investigating the role of solvent-solute interaction in crystal nucleation of salicylic acid from organic solvents.

In previous work, it has been shown that the crystal nucleation of salicylic acid (SA) in different solvents becomes increasingly more difficult in the order: chloroform, ethyl acetate acetonitrile, acetone, methanol, and acetic acid. In the present work, vibration spectroscopy, calorimetric measurements, and density functional theory (DFT) calculations are used to reveal the underlying molecular mechanisms. Raman and infrared spectra suggest that SA exists predominately as dimers in chloroform, but in the other five solvents there is no clear evidence of dimerization. In all solvents, the shift in the SA carbonyl peak reflecting the strength in the solvent-solute interaction is quite well correlated to the nucleation ranking. This shift is corroborated by DFT calculated energies of binding one solvent molecule to the carboxyl group of SA. An even better correlation of the influence of the solvent on the nucleation is provided by DFT calculated energy of binding the complete first solvation shell to the SA molecule. These solvation shell binding energies are corroborated by the enthalpy of solvent-solute interaction as estimated from experimentally determined enthalpy of solution and calculated enthalpy of cavity formation using the scaled particle theory. The different methods reveal a consistent picture and suggest that the stronger the solvent binds to the SA molecule in solution, the slower the nucleation becomes.

Unravelling the specific site preference in doping of calcium hydroxyapatite with strontium from ab initio investigations and Rietveld analyses

Strontium can be substituted into the calcium sublattice of hydroxyapatite without a solubility limit. However, recent ab initio simulations carried out at 0 K report endothermic nature of this process. There is also striking discrepancy between experimentally observed preference of Sr doping at Ca-II sites and the first principles calculations, which indicate that a Ca-I site is preferred energetically for the Sr substitution. In this paper we combine insights from Density Functional Theory simulations and regular configurational entropy calculations to determine the site preference of Sr doping in the range of 0-100 at% at finite temperatures. In addition, samples of Sr-HA are synthesized and refinement of the relevant structural information provides benchmark information on the experimental unit cell parameters of Sr-HA. We find that the contribution of the entropy of mixing can efficiently overcome the endothermic excess energy at a temperature typical of the calcining step in the synthesis route of hydroxyapatite (700-950 °C). We observe that the most preferential substitution pattern is mixed substitution of Sr regardless of the concentration. For a wet chemical method, carried out at a moderate temperature (90 °C), the mixed doping is still slightly favourable at higher Sr-concentrations, except the range at 20% Sr, where Site II substitution is not restricted energetically and equally possible as the mixed doping. We observe a close correspondence between our theoretical results and available experimental data. Hence it should be possible to apply this theory to other divalent dopants in HA, such as Zn(2+), Mg(2+), Pb(2+), Cu(2+), Ba(2+), Cd(2+) etc.

Biocidal effect and durability of nano-TiO2 coated textiles to combat hospital acquired infections

While antimicrobial textiles have received considerable interest and attention from both the scientific community and general consumers, there have been very few studies investigating the durability of such antimicrobial activities. In this study, we describe the modification of the surface of textiles that were modified with commercially available titanium dioxide (TiO2) powder (P25 Aeroxide®, Degussa™) using a sonochemical technique. The antibacterial activity of TiO2 can improve textile quality and effectively reduce the rate of infections acquired in hospitals. Medical garments produced from such fabrics may improve the patients recovery and revolutionize the textile market. This modification imparts biocidal properties to these textiles, which were then optimized to acquire properties of the textile. Samples were washed for 30 cycles at three different temperatures (40 °C, 60 °C and 90 °C) to test the durability of the bonding of the nanoparticles to textiles and the effectiveness was examined with respect to their antimicrobial activity against hospital pathogens: Escherichia coli, MRSA and Candida albicans. Samples surfaces were examined by a Scanning Electron Microscope equipped with Energy Dispersive X-ray Spectroscopy (SEM/EDS) for surface imaging. Atomic Absorption Spectrometry (AAS) was used as a technique to quantify the Ti present on the fabric. The best durability of TiO2 on textiles was best retained after washing at 40 °C. From an environmental point of view, the release of nanomaterial from textiles was acceptable against currently available benchmarks. We have investigated the adhesion of nanoparticles (NPs) to the textile surface. Medical garments, bed linens and upholstery produced from such fabrics may improve hospital hygiene against antibiotic resistant superbugs and help reduce hospital acquired infections.

Influence of solvent on crystal nucleation of risperidone

Over 2100 induction time experiments were carried out for the medium-sized, antipsychotic drug molecule, risperidone in seven different organic solvents. To reach the same induction time the required driving force increases in the order: cumene, toluene, acetone, ethyl acetate, methanol, propanol, and butanol, which reasonably well correlates to the interfacial energies as determined within classical nucleation theory. FTIR spectroscopy has been used to investigate any shifts in the spectra and to estimate the interaction of solute and solvent at the corresponding site. The solution condition has also been investigated by Density Functional Theory (DFT) calculations over (1 : 1) solvent-solute binding interactions at 8 different sites on the risperidone molecule. The DFT computational results agree with the spectroscopic data suggesting that these methods do capture the binding strength of solvent molecules to the risperidone molecule. The difficulty of nucleation correlates reasonably to the DFT computations and the spectroscopic measurements. The results of the different measurements suggest that the stronger the solvent binds to the risperidone molecule in solution, the slower the nucleation becomes.

Solvent and additive interactions as determinants in the nucleation pathway: general discussion

Sarah Price opened a general discussion of the paper by Sven Schroeder: I have been generating the thermodynamically plausible crystal structures of organic molecules for many years, and back in 2004 we did a crystal structure prediction (CSP) study on imidazole1 and found that it was relatively straightforward. Following your paper, we have reclassified the low energy structures according to the tilt within the hydrogen-bonded chain and the relative direction of the chains. Although the observed structure was the global minimum, two other structures with a displacement of otherwise identical layers are very close in energy. Do you think that if imidazole had crystallised in one of these alternative structures it would be distinguishable by NEXAFS? This would be a very sensitive test of whether NEXAFS combined with CSP could be used in characterising crystal structures.

Analysis of the structure and morphology of fenoxycarb crystals

In this paper, we have explored the relationship between surface structure and crystal growth and morphology of fenoxycarb (FC). Experimental vs. predicted morphologies/face indices of fenoxycarb crystals are presented. Atomic-scale surface structures of the crystalline particles, derived from experimentally indexed single crystals, are also modelled. Single crystals of fenoxycarb exhibit a platelet-like morphology which closely matches predicted morphologies. The solvent choice does not significantly influence either morphology or crystal habit. The crystal morphology is dominated by the {001} faces, featuring weakly interacting aliphatic or aromatic groups at their surfaces. Two distinct modes of interaction of a FC molecule in the crystal can be observed, which appear to be principal factors governing the microscopic shape of the crystal: the relatively strong collateral and the much weaker perpendicular bonding. Both forcefield-based and quantum-chemical calculations predict that the aromatic and aliphatic terminated {001} faces have comparably high stability as a consequence of weak intermolecular bonding. Thus we predict that the most developed {001} surfaces of fenoxycarb crystals should be terminated randomly, favouring neither aliphatic nor aromatic termination.

Investigation of polymorphic transitions of piracetam induced during wet granulation

Graphical abstract Figure. No Caption available. Abstract Piracetam was investigated as a model API which is known to exhibit a number of different polymorphic forms. It is freely soluble in water so the possibility exists for polymorphic transformations to occur during wet granulation. Analysis of the polymorphic form present during lab‐scale wet granulation, using water as a granulation liquid, was studied with powder X‐ray diffraction and Raman spectroscopy as off‐line and inline analysis tools respectively. Different excipients with a range of hydrophilicities, aqueous solubilities and molecular weights were investigated to examine their influence on these solution‐mediated polymorphic transitions and experimental results were rationalised using molecular modelling. Our results indicated that as an increasing amount of water was added to the as‐received piracetam FIII, a greater amount of the API dissolved which recrystallised upon drying to the metastable FII(6.403) via a monohydrate intermediary. Molecular level analysis revealed that the observed preferential transformation of monohydrate to FII is linked with a greater structural similarity between the monohydrate and FII polymorph in comparison to FIII. The application of Raman spectroscopy as a process analytical technology (PAT) tool to monitor the granulation process for the production of the monohydrate intermediate as a precursor to the undesirable metastable form was demonstrated.

Crystal nucleation of tolbutamide in solution: relationship to solvent, solute conformation, and solution structure

The influence of the solvent in nucleation of tolbutamide, a medium-sized, flexible and polymorphic organic molecule, has been explored by measuring nucleation induction times, estimating solvent-solute interaction enthalpies using molecular modelling and calorimetric data, probing interactions and clustering with spectroscopy, and modelling solvent-dependence of molecular conformation in solution. The nucleation driving force required to reach the same induction time is strongly solvent-dependent, increasing in the order: acetonitrile<ethyl acetate<n-propanol<toluene. The combined DFT and MD modelling results show that in acetonitrile, ethyl acetate and n-propanol the nucleation difficulty is a function of the strength of solvent-solute interaction, with emphasis on the interaction with specific H-bonding polar sites of importance in the crystal structure. A clear exception from this rule is the most difficult nucleation in toluene despite the weakest solvent-solute interactions. However molecular dynamics modelling predicts that tolbutamide assumes an intramolecularly H-bonded conformation in toluene, substantially different from and more stable than the conformation in the crystal structure, and thus presenting an additional barrier to nucleation. This explains why nucleation in toluene is the most difficult and why the relatively higher propensity for aggregation of tolbutamide molecules in toluene solution, as observed with FTIR spectroscopy, does not translate into easier nucleation. Thus, our combined experimental and molecular modelling study suggests that the solvent can influence on the nucleation not only via differences in the desolvation but also through the influence on molecular conformation.

Prediction of melting point of the co-crystals: ANN models

Using Artificial Neural Networks (ANNs),1 a model has been developed for prediction of the melting point (Tm)2 of unsynthesized co-crystals (CCs). The model uses four input parameters for the pure Active Pharmaceutical Ingredient (APIs) and four for the pure coformer. In addition, as input parameters the model uses the 1:1 gas phase binding energy in the anticipated main synthon of the cocrystal as calculated by a force field method and ΔpKa value of the respective cocrystals2 (mostly extracted from the literature). The model is trained using known cocrystal melting temperatures giving an average relative deviation of 1.98%, and can then predict the melting point of a validation set to a relative deviation of 3.37%. In total, 61 CCs (two-component molecular cocrystals3) Tm were used to construct the model, and the Tm values were extracted from the literature for four APIs, namely, i.e. caffeine (CAF), theophylline (THP), nicotinamide (NA) and isonicotinamide (INA). The number of CCs included were: 14–CAF, 9–THP, 29–INA and 9–NA. The advantage of our model is that, it could be possible to set the melting point of the new solid form of the respective drug molecules within the target range by a selection of an ideal coformer for cocrystal formation. Hence, it will reduce the cost, manpower and time in the pharmaceutical industry. [1] Svetlana. I. et. al. (2012), Pharmaceutics. 4, 531-550. [2] Gamidi, R. K. et al. (2017), Cryst. Growth Des. 17, 175–182. [3] Duggirala, N. K. et al. (2016), Chem. Commun. 52, 640–655.