Although the actual synthesis of an API is crucial, it is not the exclusive consideration in API development. In addition
to producing an API with high purity, yield and stereoselectivity, an API must be able to remain stable during storage and
distribution and have the desired drug mechanism once administered to a patient. Solid-state chemistry is an important part
of drug development, and public research is advancing the field.
Researchers at the Institute of Chemical and Engineering Sciences (ICES) at Singapore's Agency for Science, Technology, and
Research (A*STAR) recently reported on a novel method for producing cocrystals. The researchers discovered that adding water
droplets can help form cocrystals of caffeine. Caffeine is unstable to humidity and cocrystal formation is possible with biocompatible
compounds such as 4-hydroxybenzoic acid (4HBA). Previous research showed that computer models could predict cocrystals of
caffeine and 4HBA in the ratio of 1:1, which would be the form with the most stable structure. To date, researchers had only
been able to produce 2:1 and 1:2 co-crystals, according to information from A*STAR (1).
The ICES researchers successfully formed 1:1 cocrystals of caffeine and 4HBA in the form of a monohydrate. By grinding together
a 1:1 mixture of the two components with two drops of water, a crystal structure was formed in which each pair of crystallization
partners is partly held together by a water molecule. The key to the water's ability to produce the 1:1 cocrystal is its capacity
to both donate and accept hydrogen bonds, the intermolecular force that holds cocrystals components together. In the case
of the caffeine-4HBA cocrystal hydrate, unused hydrogen-bond acceptors and donors are satisfied by forming hydrogen bonds
with the water molecule. Without water, the number of hydrogen-bond donors and acceptors is unbalanced, resulting in the preferential
formation of the 2:1 and 1:2 crystals instead, according to the A-STAR information. The researchers have also applied the
process to other APIs. They generated a 1:1 cocrystal hydrate of 4HBA with piracetam, a cognitive-enhancing drug. The results
suggest that forming hydrates offers an alternative way to generate cocrystals with particular ratios of constituents, expanding
the options for forming pharmaceutical materials.
The Synthesis & Solid State Pharmaceutical Center (SSPC) at the University of Limerick in Ireland was recently one of seven
research centers that received part of an EUR 300 million ($391 million) investment through the Science Foundation Ireland's
(SFI) Research Centers Program. SFI is the national research foundation in Ireland, and the funding represents funding from
both SFI and private funding from industry. SSPC is a collaboration between 17 companies and academic institutions. These
groups have expertise in process modelling and design, scale-up, computational fluid dynamics, in situ solution and solid-phase
monitoring, crystallography and powder characterisation. The center's goal is to rationally design solid-state pharmaceutical
materials in the required physical and chemical forms for advanced formulation and drug-delivery systems.
1. S. Aitipamula et al., Cryst. Eng. Comm. 14 (7), 2381–2385 (2012).