The bulk crystallization of alpha-lactose monohydrate from aqueous solution

The bulk crystallization of a-lactose monohydrate from aqueous solution by primary nucleation has been studied under controlled conditions of supersat uration, temperature, and pH. The induction times to nucleation were extrem ely long compared with those generally observed for other materials, even a t the high supersaturations used in the experiment. As a result, it was nec essary to stir the supersaturated solution vigorously to induce nucleation in a reasonable but still lengthy working time. Even then, nucleation only occurred to a limited extent, following which growth ceased for 8-10 h befo re resuming. After this period, growth recommenced but again slowed to a lo w rate after another 8 h. At this stage, the yield of product was low and i n most cases the particles had achieved sizes close to the maximum noted. T he yields increased with further crystallization time (22-72 h total from t he recommencement of growth) to give, under high initial supersaturation co nditions, amounts of product close to the theoretical value, For the most p art, however, the particle size did not increase with this later increase i n yield, showing only significant changes after the extremely long total cr ystallization times. It is proposed that these extreme properties result fr om the formation in solution by mutarotation of the anomer alpha -lactose, which inhibits nucleation as well as its previously observed influence on g rowth. (C) 2001 Wiley-Liss, Inc. and the American Pharmaceutical Associatio n J Pharm Sci 90:823-832, 2001.