Determination of co-crystal phase purity by mid infrared spectroscopy and multiple curve resolution.

Multivariate Curve Resolution (MCR) was used to determine the phase purity of pharmaceutical co-crystals from mid infrared spectra. An in-silico coformer screening was used to choose one of ten potential coformers. This analysis used quantum chemistry simulation to predict which coformers are thermodynamically inclined to form cocrystals with the model drug, hydrochlorothiazide. The coformer chosen was nicotinamide. An experimental solvent screening by ultrasound assisted slurry co-crystallization was performed to evaluate the capacity of the method to determine phase purity. Afterwards, slurry and slow evaporation co-crystallizations were performed at 10, 25, and 40 °C using 7 solvent systems, and two levels of agitation for the evaporation co-crystallization (on and off). Mid infrared spectroscopy (MIRS) analysis of the products of these co-crystallizations was used to develop an MCR model to determine co-crystal phase purity. The MCR results were compared with a reference co-crystal. Experimental design (DoE) was used to investigate the effect of solvents, temperature, and agitation on the purity of co-crystals produced by slurry and evaporation co-crystallization. DoE revealed that evaporation co-crystallization with agitating at 65 rpm formed co-crystals with greater phase purity. The optimal temperature varied with the solvent used.

Surface-Activated Fibre-Like SBA-15 as Drug Carriers for Bone Diseases.

Here, we report an inorganic hexagonally ordered mesoporous fibre-like carrier made of silica as an effective drug delivery system with mineralisation potential. Fibre-like SBA-15 has been modified by employing a simple surface activation (rehydroxylation) procedure. The surface-rehydroxylated fibre-like SBA-15 (SBA-15-R) was used to investigate the possible mechanism of hydroxyapatite (HA) nucleation and deposition onto silica's surface after immersion in simulated body fluid (SBF). Amorphous calcium phosphate, Ca-deficient HA and bone-like HA deposits were observed on SBA-15-R surface consecutively after 7, 14 and 21 days of immersion in SBF. Accordingly, our low-angle XRD, STEM and N2 adsorption/desorption results indicated that deposited ions were mostly located at the silica's surface and could modify the size of the mesopores. The SBA-15-R was studied in vitro as the potential bioactive drug delivery system using doxorubicin (DOX) as a model water-soluble and anticancer drug. The adsorbed DOX molecules were mostly located at the pore walls and pore openings, likely together with the silanol groups. The DOX release was diffusion-controlled and relatively slower in SBF (pH = 7.4) than in phosphate-buffered solution (pH = 5.0), most probably due to both the stronger electrostatic interactions occurring between the DOX and the SBA-15-R and the simultaneous deposition of calcium and phosphates ions from SBF.

Solute clustering in undersaturated solutions - systematic dependence on time, temperature and concentration.

Molecular clustering and solvent-solute interactions in isopropanol solutions of fenoxycarb have been thoroughly and systematically investigated by dynamic light scattering, small-angle X-ray scattering, and nanoparticle tracking, supported by infrared spectroscopy and molecular dynamics simulations. The existence of molecular aggregates, clusters, ranging in size up to almost a micrometre is clearly recorded at undersaturated as well as supersaturated conditions by all three analysis techniques. The results systematically reveal that the cluster size increases with solute concentration and time at stagnant conditions. For most concentrations the time scale of cluster growth is of the order of days. In undersaturated solutions the size appears to eventually reach a maximum value, higher the higher the concentration. Below a certain concentration threshold clusters are significantly smaller. Clusters are found to be smaller in solutions pre-heated at a higher temperature, which offers a possible explanation for the so-called "history of solution" effect. The cluster distribution is influenced by filtration through membranes with a pore size of 0.1 µm, offering an alternative explanation for the "foreign particle-catalysed nucleation" effect. At moderate concentrations larger clusters appear to be sheared into smaller ones, but the original size distribution is rapidly re-established. At higher concentrations, although still well below solubility, the cluster size as well as solute concentration are strongly affected, suggesting that larger clusters contain at least a core of more organized molecules not able to pass through the filter.

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

Investigation of polymorphic transitions of piracetam induced during wet granulation.

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.

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.

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.

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.

Bioactive silica-based drug delivery systems containing doxorubicin hydrochloride: in vitro studies.

This study reports the applicability of sol-gel derived silica and silica-polydimethylsiloxane (silica-PDMS) composites as a potential bioactive implantable drug delivery system for doxorubicin hydrochloride (DOX). These composites also contain calcium chloride (CaCl(2)) and triethylphosphate as precursors of Ca(2+) and (PO(4))(3-) ions. These composites were immersed for 20 days in a simulated body fluid (SBF) at 37°C to study the release rate of the DOX, dissolution of the silica and the formation of hydroxyapatite on the composites' surface. The results show that the release rate of the DOX can be effectively tailored by either the addition of a polydimethylsiloxane (PDMS), or by varying the amount of CaCl(2), where the elution rate of DOX increases with increasing amount of the CaCl(2) precursor. Importantly, irrespective of the amount of CaCl(2), no burst release of DOX has been observed in any of the silica-PDMS system investigated. On the other hand, a slow release of DOX has been observed with a trend that followed a zero (0)-order kinetics for a total of 20 days of elusion. The dissolution of silica in SBF was ca. two-times faster than that of silica-PDMS, with the former reaching an average saturation level of 80 µg/mL whilst the latter reached 46 µg/mL within 20 days. Both the silica and the silica-PDMS composites show bioactivity i.e. they absorb calcium phosphate from SBF. Within 10 days, a ten-fold increase in the concentration of calcium phosphate deposit has been observed on the silica-PDMS relative to the silica. The constant rates of DOX release observed for the silica-PDMS composites indicate that the calcium phosphate deposit do not obstruct controlled release of the drug.

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.

Silica xerogel-hydrogen peroxide composites: their morphology, stability, and antimicrobial activity.

Hydrogen peroxide was incorporated into silica xerogel matrix over the concentration range from 3.8 to 68.0 wt% via the sol-gel route. The obtained composites were characterized by scanning electron microscopy (SEM) and differential scanning calorimetry (DSC). The release rates of H(2)O(2) from the composites into the aqueous phase were examined. In most cases, a 90% release was attained after ca. 10 min, and it was only slightly dependent on H(2)O(2) concentration and particle size. The antimicrobial activity of the composite containing 3.59% H(2)O(2) was evaluated against Escherichia coli and Micrococcus luteus. A comparative assay was carried out for aqueous solution of H(2)O(2) of the same concentration. The results demonstrated a potent microbicidal efficacy of the composite. Furthermore, diffusion range of the hydrogen peroxide from the solid composite into an agar medium matched that of the H(2)O(2) in aqueous solution. The stability tests with the xerogels containing 3.8, 26.4, and 68.0% of H(2)O(2) showed that after 63 days respective losses of the H(2)O(2) at 3 degrees C were 8.8, 9.7, and 6.2%. Both the DSC results and the stability tests have shown that the molecular water present in the pores stabilizes the composite, probably through improving the binding of the H(2)O(2) molecules onto the silica surface.