Novel Water-Soluble Quaternary Piperazine Derivatives of Chitosan: Synthesis and Characterization Jukka Holappa,* 1 Tapio Nevalainen, 1 Rustam Safin, 1 Pasi Soininen, 2 Tomas Asplund, 3 Tiina Luttikhedde, 3 Ma ´r Ma ´sson, 4 Tomi Ja ¨rvinen 1 1 Department of Pharmaceutical Chemistry, University of Kuopio, P.O. Box 1627, FIN-70211 Kuopio, Finland Fax: þ358-17-162456; E-mail: Jukka.Holappa@uku.fi 2 Department of Chemistry, University of Kuopio, P.O. Box 1627, FIN-70211 Kuopio, Finland 3 Ciba Specialty Chemicals Oy, Water and Paper Treatment, Surface & Coatings R & D, Analytics, Raisionkaari 55, P.O. Box 250, FIN-21201 Raisio, Finland 4 Faculty of Pharmacy, University of Iceland, Hofsvallagata 53, 107 Reykjavik, Iceland Received: October 18, 2005; Revised: December 7, 2005; Accepted: December 8, 2005; DOI: 10.1002/mabi.200500202 Keywords: chitosan; piperazine; quaternary; synthesis; water-soluble polymers Introduction Chitosan has been extensively studied as a non-toxic and biodegradable biopolymer in various applications in diffe- rent fields. The poor solubility properties are considered to be the most significant drawbacks to the processability and use of chitosan. The poor solubility in organic solvents impairs the processability of chitosan materials whereas the poor aqueous solubility limits the use of chitosan in most applications. Therefore, several chitosan derivatives have been synthesized in order to improve the solubility proper- ties of chitosan. [1–3] Quaternary ammonium derivatives of chitosan are inte- resting water-soluble chitosan derivatives, since most of the unique properties of chitosan are attributable to its cationic nature.Quaternarychitosanderivativeshavevariouspotential pharmaceuticalapplications,e.g.,aspermeationenhancers, [4] as gene delivery systems [5] and as antimicrobials, [6] and also some other possible applications, e.g., in papermaking. [7] We have earlier described the preparation of non- quaternary piperazine derivatives of chitosan, but these were only slightly more soluble in water than the parent chitosan. [8] Since quaternary piperazine moieties have been used to enhance the aqueous solubility of small molecules, e.g., in prodrug technology, [9] our aim was to attach qua- ternary piperazine moieties into chitosan. However, quater- nary piperazine derivatives of chitosan cannot be prepared properly by quaternization of non-quaternary piperazine derivatives of chitosan. Alkylation, e.g., with methyl iodide, will result in mixtures of mono and diquaternary monomers in the polymer, i.e., structurally uniform polymer structures cannot be prepared with this synthesis strategy. Further- more, the hydroxyl groups and unsubstituted amino groups of chitosan would also be alkylated with this type of strategy. We report here two separate synthetic procedures for the preparation of chitosan derivatives with a quaternary piperazine moiety. These novel quaternary derivatives were prepared either by coupling a quaternary piperazinium acetic acid into chitosan or by attaching a tertiary 1,4- dimethylpiperazine into N-chloroacetyl-6-O-triphenyl- methylchitosan. The end products were thoroughly Summary: Novel synthesis methods for the preparation of quaternary piperazine derivatives of chitosan were devel- oped. Quaternary ammonium moiety can be selectively insert- ed into either one or both of the piperazine nitrogens, yielding structurally uniform chitosan derivative structures. Water- soluble end products were thoroughly characterized with FT- IR, 1 H NMR, 13 C NMR and 2D 1 H- 13 C HSQC NMR. The molecular weights of the end products were determined by GPC with triple detection. Macromol. Biosci. 2006, 6, 139–144 ß 2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim Communication DOI: 10.1002/mabi.200500202 139