Using Thermal Ink-Jet Printing Technology to Produce Pharmaceutical Cocrystals

Cocrystals are solids that are crystalline materials composed of two or more molecules in the same crystal lattice. Cocrystals are used to improve the performance of APIs that have non-ideal physiochemical properties by cocrystallizing the API with a second compound that modulates the API to provide a way to improve a drug's bioavailability, stability, and processability. Cocrystals, however, are different from traditional pharmaceutical solid-state forms. Unlike polymorphs, which generally contain only the API within the crystal lattice, cocrystals are composed of an API with a neutral guest compound conformer in the crystal lattice (1). Unlike a salt form where the components in the crystal lattice are in an ionized state, the molecules in the cocrystal are in a neutral state and interact by means of nonionic interaction, thereby providing a way to produce solid-state forms even for APIs that lack ionizable functional groups needed for salt formation (1).

Researchers at the University College London (UCL) and the University of Bradford in the United Kingdom recently reported on the use of thermal ink-jet (TIJ) printing as a way to prepare pharmaceutical cocrystals. The researchers identified cocrystals in all cases where the coformers could be dissolved in water and/or water/ethanol solutions (2). The researchers prepared a metastable form of the anti-epileptic drug carbamazepine by first depositing small droplets of template solution followed by droplets of the drug solution, which led to rapid evaporation and crystallization (3). Although applied successfully, TIJ technology to make cocrystals presents certain challenges, such as controlling solution, stage temperature, or stoichmetry (3). Also, the approach is limited to using water or mixtures of ethanol and water as the solvents because other organic solvents may react with the plastic cartridges of the printer (3).

The research was led by Simon Gaisford, reader in pharmaceutics at the UCL School of Pharmacy, whose research is focused on using TIJ technology to produce pharmaceutical forms. Instead of using ink in a print cartridge, the ink is removed and replaced with a drug solution. A TIJ system consists of a reservoir of liquid to be jetted mounted above a printhead. The printhead, usually produced with photolithography, consists of a number of small chambers, filled with liquid from the reservoir, each in contact with a resistive element. Pulsing a current through the element results in a rapid rise in temperature, causing vapourization of some of the liquid, nucleation and then expansion of a vapor bubble. As the bubble expands, some liquid is ejected from the chamber, forming a droplet. The fine control of liquid deposition can be used for pharmaceutical applications (4).

Other applications of TIJ technology from Gaisford's research have included making personalized-dose oral films of salbutamol sulfate by replacing the paper in the printer with a sheet of polymer film that allowed the drug to be jetted onto the surface (4). A printer cartridge was modified so that aqueous drug solutions replaced the ink (5). The film strips were then cut. Varying the concentration of drug solution, area printed or number of print passes allowed the dose to be controlled (4, 5). The print solution viscosity and surface tension were used to determine the performance of the printer. A calibration curve for salbutamol sulfate was prepared, which showed that drug deposition onto an acetate film varied linearly with concentration. The printer was then used to deposit salbutamol sulfate onto an oral film made of potato starch. The researchers found that when doses were deposited in a single pass under the print head, the measured dose was in good agreement with the theoretical dose. With multiple passes, the measured dose was always significantly less than the theoretical dose (5). The researchers surmised that the losses result from the printed layer eroding by shearing forces during paper handling.

References

1. FDA, Draft Guidance for Industry: Regulatory Classification of Pharmaceutical Co-Crystals (Rockville, MD, 2011).

2. S. Gaisford et al., Cryst. Eng. Comm. 15 (6), 1031-1035 (2013).

3. R. Cooper, Chemistry World, "Printing Crystalline Drugs," online, 8 Feb. 2013, http://www.rsc.org/chemistryworld/2013/02/co-crystal-drugs-inkjet-printer, accessed 15 Apr. 2013.

4. UCL, "Profile (S. Gaisford): Research Summary," http://iris.ucl.ac.uk/iris/browse/profile?upi=SGAIS88, accessed Apr. 15 2013.

5. S. Gaisford et al., Pharm Res. 28 (10), 2386-92 (2011).