Methanol-water manipulated polymorphic nucleation of L-Ornithine-L-Aspartate

Screening for a suitable polymorph is crucial in pharmaceutical engineering. Here we reported the polymorphic nucleation of L-Ornithine-L-Aspartate (LOLA) in a methanol–water binary solvent. A new metastable form named monohydrate was discovered, which was found affected the nucleation of LOLA anhydrate. The antisolvent crystallization experiments showed that when the molar fraction of methanol was less than 0.387 or more than 0.448, the anhydrate LOLA nucleated, while it was between 0.390–0.416, the monohydrate appeared. Specifically, the isolated water molecules were the key parameter for polymorphic nucleation of LOLA. When methanol was less or more, it was insufficient to break the water hydrogen bonding network or enough to form methanol–water network, both could cause less isolated water, thus the anhydrate nucleated. On the contrary, when the methanol content was 0.390–0.416, methanol molecules could occupy some spatial sites in the water network resulting in more isolated water, thus the monohydrate appeared.