Evidence of Crystal Nuclei Breeding in Laboratory Scale Seeded Batch Isothermal Crystallization Experiments

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 (S₀ = 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.