Experimental investigations of the batch seeded crystallization of paracetamol in 2-propanol were carried out at 200, 300, and 375 rpm agitation rates, using a large seed size (355–500 μm) and a low level of initial supersaturation (S 0 = 1.2) in a laboratory scale reactor. Such experiments are normally conducted for the indirect measurement of crystal growth, contingent on the assumption of negligible nucleation, agglomeration, and breakage. In the present work a copious increase in crystals nuclei was noted shortly following seed addition. The formation of substantial numbers of new nuclei was substantiated through focused beam reflectance measurement, laser diffraction, and scanning electron microscopy. Secondary nucleation was proposed as the origin of the new crystals, and a secondary nucleation threshold was determined, with relative supersaturation between 1.09 and 1.11. Below this limit, crystal growth only was apparent. A study was undertaken to investigate the origin of secondary nucleation. Crystal nuclei breeding, as a mechanism of secondary nucleation, has being theorized for many years; however, it is only very recently that definitive molecular dynamics simulations have provided mechanistic insight as to its action. The mechanically driven attrition and breakage mechanism of secondary nucleation remains prominent in the literature. Stirred vessel experiments were conducted using paracetamol seed crystals suspended in a nonsolvent indicated. Despite 3 h of continuous agitation, no significant change in particle number or size was detected. Only after a threshold of 4 h were significant crystal fatigue and fragmentation evident. Shadowgraphy investigations of crystal jet wall impingement revealed the squeeze film as a key protective element in preventing crystal attrition and breakage. A low temperature (283.15 K) crystallization was conducted which indicated a significant temperature dependency, entirely inconsistent with the attrition and breakage mechanism of secondary nucleation. It was shown through the use of smaller seed crystals (125–250 μm), a high agitation rate, and elevated solution temperature that the rate of secondary nucleation could be enhanced thereby creating the potential for confounding rapid secondary nucleation with growth. The current work elucidates the potential impact of cluster breeding in laboratory scale crystallizations and furthermore provides additional experimental support for the crystal breeding mechanism of secondary nucleation.

Two prominent theories surround the origin of secondary nuclei in batch crystallization experiments. Traditionally, the generation of secondary nuclei has been attributed to attrition breeding, resulting from collisions between crystals, impeller, and vessel geometry. Mechanistically, it is assumed that the collision of crystals leads to the generation of fine particles and nucleation sites. More recently, an alternative mechanism has received considerable attention, namely, cluster breeding secondary nucleation whereby the source of fine particles is attributed to clusters in solution. In the present work, a detailed experimental investigation of particle wall collisions of active pharmaceutical ingredient crystals is conducted. A pressurized test rig was developed whereby crystals in suspension were fired through a nozzle perpendicular to a stainless steel target. Using shadowgraphy, direct imaging particle-plane collisions are captured for crystals between 100−400 μm as they approach a target surface with initial velocities of up to 10 m/s. Crystals approaching a target surface are seen to be cushioned by a squeeze film boundary layer, greatly reducing their impact velocities. Furthermore, below a critical freestream particle Reynolds number, complete particle arrest was observed, preventing contact with the target surface entirely. This work provides further evidence to suggest that indeed secondary nucleation cannot be accounted for through particle−impeller breakage events. The alternative crystal breeding ideology is therefore further supported.

This paper describes a new nonintrusive method for the determination of high-temperature solubility data. Accurate high-temperature solubility data is vital to many industrial manufacturing processes such as cooling crystallization with direct implications for yield, throughput, and solvent usage. However, the provision of such data is notably absent from published literature for many active pharmaceutical ingredients. Pressurized-synthetic methodology is presented as a new technique for determining high-temperature solubility data. Paracetamol (acetaminophen) is used as a reference active pharmaceutical ingredient to validate the methodology. Solubility data determined using the pressurized-synthetic approach is reported for several pure solvents across a significantly extended temperature range. In the case of methanol, solubility data is obtained up to 354.15 K, above the atmospheric boiling point of the solvent, 337.65 K, and far in excess of the temperature range for which data exists in the literature, 268.15–303.15 K. The data obtained using the pressurized-synthetic method is validated against an extended gravimetric data set at temperatures up to the atmospheric boiling point for each solvent. Sensitivity studies were conducted to determine the influence of factors such as temperature gradient on the ultimate solubility determination. A temperature-based standard deviation of 0.1 K was established for paracetamol in 2-propanol at 303.15 K, comparing favorably with the temperature-based equivalent standard deviation of 0.2 K for the gravimetric approach. Binary interaction parameters for the pressurized-synthetic solubility data are derived and estimated for four different activity coefficient models, namely Margules, Van-Laar, Wilson, and non-random two-liquid (NRTL), along with the empirical solubility equation of Apelblat. For each solvent, the quality of fit of each of the activity coefficient models is analyzed. The NRTL model was found to best fit the experimental data for methanol, ethanol, 2-propanol, and acetone with mean square errors of 5.73 × 10–5, 3.00 × 10–4, 1.70 × 10–4, and 7.35 × 10–5, respectively. The pressurized-synthetic approach provides a nonintrusive, validated, and readily automated approach for the provision of valuable high-temperature solubility data that can be readily extended to binary and ternary systems.

The solubility of (S)-3-(aminomethyl)-5-methylhexanoic acid in both 2-propanol and water and methanol and water mixtures, as well as in pure solvents, is reported across the temperature range of 283.15−338.15 K, as determined gravimetrically under atmospheric conditions. The experimental data is correlated using the empirical Apelblat and (CNIBS)/Redlich− Kister equations to describe the influence of temperature and solvent composition on solubility, respectively. A maximum solubility is observed between x 2 /(x 2 + x 3 ) = 0.15 and x 2 /(x 2 + x 3 ) = 0.25 for 2-propanol and water mixtures and between x 2 /(x 2 + x 3 ) = 0.35 and x 2 /(x 2 + x 3 ) = 0.5 for methanol and water mixtures. The solubility data is then used to estimate the binary activity coefficient using the Wilson and NRTL activity coefficient models, as well as the coefficients of the Jouyban−Acree empirical solubility model, as a function of temperature and composition. The goodness of fit is determined using the mean square error as a metric in which the Jouyban−Acree model provides the best fit to the solubility data. The modified Apelblat equation is also used to calculate enthalpies of solution under standard conditions.

Concurrent helminth infections have been suggested to be associated with protection against cerebral malaria in humans, a condition characterised by systemic inflammation. Here we show that a concurrent chronic gastro-intestinal nematode infection does not alter the course of murine cerebral malaria. Mice infected with Heligmosomoides polygyrus, and co-infected with Plasmodium berghei ANKA 14 days later, developed malaria parasitemia, weight loss and anemia, at the same rate as mice without nematode infection. Both groups developed cerebral malaria around the same time point. The data suggest that a chronic helminth infection does not affect the development of cerebral malaria in a murine model.