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.

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