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TOF-SIMS can provide quantitative information on the composition of structurally similar impurities and their locations on the surface of crystals grown in impure solutions.

Partially dissolved crystals of curcumin grow faster and exhibit an accelerated growth rate hysteresis.

Crystallization experiments performed with highly supercooled solutions produced highly pure (>99 wt %) and highly crystalline mesocrystals of curcumin from impure solutions (∼22% of two structurally similar impurities) in one step. These mesocrystals exhibited a crystallographic hierarchy and were composed of perfectly or imperfectly aligned nanometer-thick crystallites. X-ray diffraction and spectroscopic analysis confirmed that the spherulites are a new solid form of curcumin. A theoretical hypothesis based on particle aggregation, double nucleation, and repeated secondary nucleation is proposed to explain the spherulite formation mechanism. The experimental results provide, for the first time, evidence for an organic molecule to naturally form spherulites without the presence of any stabilizing agents. Control experiments performed with highly supercooled pure solutions produced spherulites, confirming that the formation of spherulites is attributed to the high degree of supercooling and not due to the presence of impurities. Likewise, control experiments performed with a lower degree of supercooling produced impure crystals of curcumin via classical molecular addition mechanisms. Collectively, these experimental observations provide, for the first time, evidence for particle-mediated crystallization as an alternate and efficient method to purify organic compounds.

Two sulfa drugs, sulfamethazine and sulfamerazine, have been used as model compounds in the evaluation of microwave assisted slurry conversion crystallization for manufacturing of co-crystals. It is shown that the formation of the co-crystals is much faster using microwaves than simple conductive/convective heating to the same temperature. The favourable effect of using microwaves goes beyond the simple heating effect, likely due to an influence of the microwaves on solution structuring. It is also shown that the process of microwave assisted slurry conversion crystallization for efficient manufacturing of co-crystals can be scaled up from 0.2 to at least 20 g with the same outcome. In the work, three new co-crystals, sulfamethazine–nicotinamide, sulfamerazine–anthranilic acid and sulfamerazine–salicylamide have been found. Their crystal structures were solved successfully using single crystal X-ray diffraction (SC-XRD). A further thorough characterization has been carried out by powder X-ray diffraction (PXRD), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC) and Raman and FT-IR spectroscopy. It is shown that these co-crystals increase the equilibrium concentration of the drug compared to that of the respective pure solid forms. By Hirshfeld analysis and interaction energy calculations, the difference in stability, reactivity and rate of formation of co-crystals for sulfamethazine and sulfamerazine can be explained.

The combination of a small sonicated crystallizer operated as a seed generator with a large normal batch cooling crystallizer for growth of the seeds has been investigated. Altering the sonication power and time allows the number of seeds generated to be controlled. By control of the conditions in the large crystallizer, a narrow size distribution of crystals of a controlled size can be obtained. Piracetam was used as the model compound, and various process analytical technologies were used in examining the process. Commercial software was used for determination of the growth kinetics, and it is shown that the model predictions very well match the product size of the experiments.

peer-reviewed This work investigated the technical feasibility of preparing, stabilizing and isolating poorly water-soluble drug nanoparticles via a small-scale antisolvent precipitation process operating in semi-continuous mode. Specifically, a novel semi-continuous process was demonstrated for the carrier particle mediated production, stabilization and isolation of valsartan nanoparticles into a solid form using montmorillonite clay particles as the carrier. The semi continuous process operated robustly for the full duration of the experiment (~16 min) and steady-state conditions were reached after ~5 min. Nanoparticles of valsartan (51 ± 1 nm) were successfully prepared, stabilized and isolated with the help of montmorillonite (MMT) or protamine functionalized montmorillonite (PA-MMT) into the dried form by this semi-continuous route. The dissolution profile of the isolated valsartan nanocomposite solids was similar to that of valsartan nanocomposite solids produced via the corresponding laboratory scale batch mode process, indicating that the product quality (principally the nanoscale particle size and solid-state form) is retained during the semi-continuous processing of the nanoparticles. Furthermore, tablets produced via direct compression of the isolated valsartan nanocomposite solids displayed a dissolution profile comparable with that of the powdered nanocomposite material. PXRD, DSC, SSNMR and dissolution studies indicate that the valsartan nanoparticles produced via this semi-continuous process were amorphous and exhibited shelf-life stability equivalent to > 10 months.

Crystallization experiments performed with highly supercooled solutions produced highly pure (> 99 wt%) and highly crystalline mesocrystals of curcumin from impure solution (~22% of two structurally similar impurities) in one step. These mesocrystals exhibited a crystallographic hierarchy and were composed of perfectly or imperfectly aligned nanometer thick crystallites. X-ray diffraction and spectroscopic analysis confirmed that the spherulites are a new solid form of curcumin. A theoretical hypothesis based on particle aggregation, double nucleation and a repeated secondary nucleation is proposed to explain the spherulite formation mechanism. The experimental results provide for the first time evidence for an organic molecule to naturally form spherulites without the presence of any stabilizing agent. Control experiments performed with highly supercooled pure solutions produced spherulites confirming the formation of spherulites is attributed to the high degree of supercooling and not due to the presence of impurities. Likewise control experiments performed with a lower degree of supercooling produced impure crystals of curcumin via the classical molecular addition mechanisms. These experimental observations all together provide first time evidence for particle mediated crystallization as an alternate and efficient method to purify organic compounds.

In this work, different strategies of ultrasonication (continuous, single pulse, and multiple pulse) are compared for control of the product crystal size distribution of three model API compounds: piracetam, paracetamol, and ibuprofen. Experiments have been performed on 0.5 and 3 L scales continuously recorded by FTIR and FBRM. Irrespective of the sonication operating mode, sonication in general produced smaller sized crystals with a more narrow size distribution in comparison to those for a normal cooling crystallization process. A multiple-pulse sonication mode, in particular, was capable of delivering more narrow size distributions. Sonication power per unit mass of solution does not appear to be a relevant scaling-up parameter.

peer-reviewed The development of solid dosage forms and manufacturing processes are governed by complex physical properties of the powder and the type of pharmaceutical unit operation the manufacturing processes employs. Suitable powder flow properties and compactability are crucial bulk level properties for tablet manufacturing by direct compression. It is also generally agreed that small scale powder flow measurements can be useful to predict large scale production failure. In this study, predictive multilinear regression models were effectively developed from critical material properties to estimate static powder flow parameters from particle size distribution data for a single component and for binary systems. A multilinear regression model, which was successfully developed for ibuprofen, also efficiently predicted the powder flow properties for a range of batches of two other active pharmaceutical ingredients processed by the same manufacturing route. The particle size distribution also affected the compactability of ibuprofen, and the scope of this work will be extended to the development of predictive multivariate models for compactability, in a similar manner to the approach successfully applied to flow properties.

Characterization of the guest–host interactions and the heterogeneity of porous materials is essential across the physical and biological sciences, for example for gas sorption and separation, pollutant removal from wastewater, biological systems (protein–ligand binding) and molecular recognition materials such as molecularly imprinted polymers. Information about the guest–host interactions can be obtained from calorimetric experiments. Alternatively, more detailed information can be obtained by properly analysing the experimentally acquired adsorption equilibrium data. Adsorption equilibrium is usually interpreted using theoretical adsorption isotherms that correlate with the equilibrium concentration of the adsorbate in the solid phase and in the bulk fluid at a constant temperature. Such theoretical isotherms or expressions can accurately predict the adsorbent efficiency (at equilibrium) as a function of process variables such as the initial adsorbate concentration, adsorbent mass, reactor volume and temperature. Detailed analysis of the adsorption isotherms permits the calculation of the number density of the adsorbent sites, their binding energy for the guest molecules and information about the distribution of adsorption site binding energies. These analyses are discussed in this review. A critical evaluation of the analytical and numerical methods that can characterize the heterogeneity and guest–host interactions involved in terms of discrete or continuous binding site affinity distribution was performed. Critical discussion of the limitations and the advantages of these models is provided. An overview of the experimental techniques that rely on calorimetric and chromatographic principles to experimentally measure the binding energy and characteristic properties of adsorbent surfaces is also included. Finally, the potential use of site energy distribution functions and their potential to provide new information about the binding energy of adsorbents for a specific guest molecule application is discussed. We thank the EU for the Intra European Marie Curie Research Fellowship (PIEF-GA-2013-623227).

The present work investigates the application of different sonochemical reactor designs for the preparation of stable nanoemulsions considering the emulsion of coconut oil in water as the model system. The effect of different operating parameters as well as chemical compositions on the stability and droplet size of emulsion has also been investigated. Different processing capacities over the range of 50mL–2 L have been used with different power ratings for the sonochemical reactors. Two emulsifying agents viz. Tween 80 and Span 80 were used to prepare stable emulsions and the effect of emulsifying agent volume fraction on the emulsion droplet size has been illustrated. Zeta sizer has been used to measure the droplet size and distribution of internal phase of emulsion. Intensity mean diameter has been used to compare the droplet size distribution of the nanoemulsion formed using different sonochemical reactors. Power dissipated per unit volume of emulsion has been considered as the unified criteria for understanding the dependency of the prepared emulsions on the type of sonochemical reactor designs.

The present work reports the use of venturi-based hydrodynamic cavitation reactor for the preparation of stable submicron emulsions. Different types of cavitating devices such as circular venturi and slit venturi have been used in this study. Effect of different operating parameters such as inlet pressure and number of passes of the emulsion through the cavitating zone on the droplet size and the stability of emulsion has been investigated. Emulsion of coconut oil in water has been chosen as the model system. Two types of emulsifying agents, namely, Tween 80 and Span 80, were used for the preparation of the emulsions, and the effect of emulsifying agent volume fraction on the emulsion droplet size has been illustrated. Zetasizer has been used to measure the droplet size and distribution of internal phase of emulsion. It has been established that the inlet pressure affects the droplet size of emulsion favorably due to the enhanced cavitational intensity with increasing inlet pressures. Among the two types ...

This work investigates the application of ultrasound for improving the antisolvent crystallization of benzoic acid. The main objective of applying ultrasound is to enhance the crystal productivity ...

The present work deals with measurements of the droplet size distribution in an ultrasonic atomizer using photographic analysis with an objective of understanding the effect of different equipment parameters such as the operating frequency, power dissipation and the operating parameters such as the flow rate and liquid properties on the droplet size distribution. Mechanistic details about the atomization phenomena have also been established using photographic analysis based on the capture of the growth of the instability and sudden ejection of droplets with high velocity. Velocity of these droplets has been measured by capturing the motion of droplets as streaks. It has been observed that the droplet size decreases with an increase in the frequency of atomizer. Droplet size distribution was found to change from the narrow to wider range with an increase in the intensity of ultrasound. The drop size was found to decrease with an increase in the fluid viscosity. The current work has clearly highlighted the approach for the selection of operating parameters for achieving a desired droplet size distribution using ultrasonic atomization and has also established the controlling mechanisms for the formation of droplet. An empirical correlation for the prediction of the droplet size has been developed based on the liquid and equipment operating properties.