Sialic acid (SA) is a sugar with a net negative charge; it is often present on terminating branches of N-glycans, O-glycans, and glucosphingolipids (gangliosides), and occasionally capping side chains of GPI anchors. Sialic acid modification of cell surface molecules plays a role in many biological phenomena such as protein structure stability, regulation of cell adhesion, and signal transduction. Sialic acid deficiency disorders such as GNE Myopathy, which is also known as Hereditary Inclusion Body Myopathy (HIBM), Distal Myopathy with Rimmed Vacuoles (DMRV) or Nonaka Myopathy are clinical diseases resulting from a reduction in sialic acid production.
Because the production of sialic acid is the key reason the mutation causes the disease, replacing a metabolite after the genetic block in the pathway could, in theory, alleviate symptoms of a sialic acid deficiency. Jay et al., Gene Reg. and Sys. Biology 3: 181-190 (2009). In practice, however, administering one or more compounds in the sialic acid biosynthetic pathway in vivo is a significant challenge. These compounds have extraordinarily rapid clearance rates and are excreted in the urine before they can be metabolized. Thus, release formulations of sialic acid, or a pharmaceutically acceptable salt, solvate, or ester thereof, has been developed and described in WO 2012/009474 and WO 2013/109906, the contents of which are hereby incorporated by reference.
Another aspect which is important in drug development is that active substances should have stable possible crystalline morphology for pharmaceutical quality medicinal formulations. Those skilled in the pharmaceutical arts understand that crystallization of an active pharmaceutical ingredient offers the best method for controlling important physiochemical qualities, such as stability, solubility, bioavailability, particle size, bulk density, flow properties, polymorphic content, and other properties. Thus, there is a need for crystalline forms of sialic acid and processes to produce such forms. These crystalline forms should be suitable for pharmaceutical use.