Design and preparation of a 4: 1 lamivudine-oxalic acid CAB cocrystal for improving the lamivudine purification process

Lamivudine (LMV), a cytosine derivative and a reverse transcriptase inhibitor, faces the challenge of inefficient purification after its chemical synthesis. Currently available methods of purification involve salt formation (salicylate or oxalate) followed by treatment with a toxic base, triethyl amine (TEA), to neutralize the protonated LMV. Any reduction in the use of TEA will make the purification process greener and more economical. In this context, we designed and successfully isolated a new and elusive 4:1 CAB cocrystal between LMV and oxalic acid (OXA) that has the potential to significantly improve the efficiency of the LMV purification process. The new CAB cocrystal of LMV was efficiently produced by carefully controlling the ratio of LMV to OXA in the crystallization medium. Compared to salts currently used for purification, much less TEA is required for the 4:1 CAB cocrystal (LMV/LMVH⁺/OXA ^2- at 2:2:1 mole ratio) because only half of the LMV is protonated that requires TEA treatment.