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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.

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).