The new cocrystal of molnupiravir-caprolactam discovered by melt crystallization with improved tableting properties

Molnupiravir (MPV) is an oral antiviral drug widely used for the treatment of coronavirus disease 2019 (COVID-19). However, the commercial form I of MPV has a poor tabletability, greatly restricting its manufacture. To solve this problem, a new cocrystal named MPV-caprolactam (CPL) was discovered by melt crystallization, and its crystal structure was successfully determined by single crystal X-ray diffraction. Meanwhile, the formation mechanism of the MPV-CPL cocrystal was studied via the formation enthalpies, and the negative formation enthalpy (−27.61 J/g at 25 ℃) is responsible for the crystallization of the MPV-CPL cocrystal. Finally, the powder tableting properties of the MPV-CPL cocrystal were investigated, and the MPV-CPL cocrystal has superior tabletability, achieving a tensile strength of 2.06 ± 0.09 MPa at 262.5 MPa compression pressure — a 1.93-fold increase over pure MPV. The MPV-CPL cocrystal also shows good compressibility, compactibility, and plasticity. This work establishes two key advances: (1) melt crystallization is a supplement to solution methods, and it can produce pharmaceutical cocrystals that tend to form solvates in solution, and (2) the improvement in tabletability of MPV-CPL cocrystal overcomes the main barrier in developing MPV tablets, which makes it a promising candidate for developing MPV tablets.