Effect of Side Groups on the Properties of Cationic Polyaspartamides

View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Repository of the Academy's Library Effect of side groups on the properties of cationic polyaspartamides Csaba Németha, Dóra Szabóa, Benjámin Gyarmatia, Alexander Gerasimovb, Mikhail Varfolomeevb, Timur Abdullinc, Krisztina Lászlóa, András Szilágyia* aDepartment of Physical Chemistry and Materials Science, Budapest University of Technology and Economics, Műegyetem rkp. 3., H-1111 Budapest, Hungary bDepartment of Physical Chemistry, Kazan (Volga Region) Federal University, 420008 Kazan, Russia cInstitute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, 18 Kremlyovskaya St., 420008 Kazan, Russia Corresponding author, e-mail: [email protected] GRAPHICAL ABSTRACT 1 HIGHLIGHTS Polyaspartamides with dialkylaminoalkyl and alkyl side groups were synthesized. The polymers have glass transition temperatures around 25 °C and are thermally stable. A correlation was established between the Tg and the polymer composition. Dissolution kinetics of the polymers was determined by fluorescent labeling. ABSTRACT Polyaspartamides with dialkylaminoalkyl and short chain alkyl side groups were synthesized and characterized in order to prepare polymer films. Their structure was confirmed by nuclear magnetic resonance (1H NMR) and Fourier transform infrared (FTIR) spectroscopy and their thermal decomposition temperature (Td) was determined by thermogravimetric analysis. The composition of the polymers was adjusted to obtain polyaspartamides with glass transition temperatures (Tg) at around room temperature and the relationship between the structure and the properties was examined. The dissolution profile of polymer films made of polyaspartamides was measured with the help of fluorescent marking to show that dissolution rate of the films depends on the pH and can be controlled by the composition of the polymers. KEYWORDS biopolymers, cationic polyaspartamide, thermal analysis, fluorescent marking, taste masking 2 1. INTRODUCTION A large amount of drug molecules have unpleasant taste which makes their oral administration uncomfortable [1,2]. The taste masking of pharmaceuticals used in the GI tract can be achieved with entero-soluble coatings, which have poor or moderate solubility in the mouth, but they are highly soluble at the pH of the stomach [2,3]. Polymers with tertiary amine side groups are used as starting materials for the coatings, because these side groups provide low solubility at neutral and slightly alkaline pH (pHsaliva ~7, [4]), but very high solubility in acidic media (pHstomach ~1.2). Furthermore, the tertiary amine side groups act as internal plasticizers resulting in Tg values below the room temperature which provides large deformability for the film coatings prepared from these polymers [5,6]. The most commonly used polymers in entero-soluble film coatings for taste masking are derivatives of poly(acrylic acid) and poly(methacrylic acid) with dialkylaminoalkyl side groups (cationic polyacrylates), e.g. dimethylaminoethyl(meth)acrylate (Eudragit® E, Eudragit® E PO) [6–8] and diethyaminoethyl(meth)acrylate (Kollicoat® Smartseal 30 D) [2,9]. Solubility, rate of dissolution, decomposition- and glass transition temperature can be controlled by the copolymerization of properly chosen (meth)acrylic esters [5,10]. However, acrylate copolymers have several disadvantages, such as moderate adjustment of their physico-chemical properties, and relatively complex synthesis of the monomers and/or the polymers often requiring toxic additives [10,11]. Additionally, polyacrylates are not biodegradable in general [10]. These drawbacks can be overcome by the application of polyaspartamides which can be synthesized with large structural variety under mild reaction conditions because their precursor polymer, polysuccinimide (PSI) exhibits high reactivity towards primary amines [12–15]. Moreover, due to their protein like structure, these polymers are expected to be biocompatible [16] and biodegradable [17]. 3 A limited number of publications deal with the synthesis and characterization of cationic polyaspartamides. Polymers [18,19] and gels [15,20] displaying temperature or pH sensitivity or sol-gel transition [16] were prepared using (di)alkylaminoalkyl – e.g. isopropylaminoethyl or dimethylaminopropyl – ligands as side groups. However, no attempts have been made to determine the effect of side groups on the thermal properties and dissolution rate of these polymers. Moreover, according to the best of our knowledge, polymer films have not been prepared from polyaspartamides up to now. Accordingly, our aim was to synthesize polyaspartamides with tertiary amine side groups to adjust their glass transition temperature (Tg) to around room temperature. PSI was modified with various dialkylaminoalkyl- and alkylamines and the chemical structure of the polymers was confirmed by nuclear magnetic resonance (1H NMR) and Fourier transform infrared (FTIR) spectroscopy. Thermogravimetric measurements were carried out to determine the thermal stability of the polymers. Furthermore, we analyzed the relationship between the Tg and the chemical structure of the polyaspartamides. Polymer films were prepared by solvent evaporation and the dissolution rate of the various polyaspartamides at pH = 1.2 and pH = 6.8 was characterized by fluorescent tracking. 2. EXPERIMENTAL 2.1 Materials 3-(dimethylamino)-1-propylamine (DMP, 99%), 2-dimethylaminoethylamine (DME, 98%), 2-diethylaminoethylamine (DEE, 99%), phosphoric acid (99%), L-tryptophan methyl ester hydrochloride (T), triethyl citrate (TEC, ≥98%), D2O (99.9 atom% D, contains 0.05 wt% 3-(trimethylsilyl)propionic-2,2,3,3-d4 acid, sodium salt (TMS)) and d6-DMSO (99.96 atom% D, contains 0.03 vol% tetramethylsilane) were bought from Sigma-Aldrich. L-aspartic acid (99%), 3-(diethylamino)-1-propylamine (DEP, ≥98%), n-propylamine (P, 99%), dibutylamine (DBA, 99%), potassium chloride (99.5%), and dimethyl sulfoxide (DMSO, 4 ≥99.9%) were purchased from Merck. Hydrochloric acid (HCl, 35%) and ethyl acetate (EtAc, 99.89%) were obtained from LachNer. N,N-Dimethylformamide (99.9%), 2-propanol (99.9%), n-hexylamine (H, 99%) and sodium hydroxide (NaOH, a.r.) were bought from Reanal. All of the reagents and solvents were used without further purification. Ultrapure water was used for all reactions and the preparation of aqueous solutions (Millipore Milli-Q Gradient, ρ > 18.2 m). Gastric fluid was simulated with an HCl solution (pH = 1.2), while saliva by PBS buffer (pH = 6.8). The ionic strength of the solutions was adjusted to 0.15 M by the addition of KCl. The pH of the buffer solutions was checked with a pH/ion analyzer (Radelkis OP 271/1). 2.2 Synthesis and preparation 2.2.1 Synthesis of polysuccinimide Polysuccinimide (PSI) was synthesized by the thermal polycondensation of L-aspartic acid in a solvent free reaction. 20.00 g (0.15 mol) of L-aspartic acid and 20.00 g (0.2 mol) of crystalline phosphoric acid were mixed in a rotary flask and the mixture was heated to 200 °C under vacuum using a rotary evaporator. The pressure was maintained at 10 mbar during the reaction. A slightly brown product was formed after 5 h. PSI was purified by precipitation in 1 DMF–H2O (1:3) and dried in vacuum at 25 °C for 24 h. H NMR (300 MHz, d6–DMSO): 5.27 (1H, CO-CH-CH2-CO); 3.21 and 2.70 (2H, CO-CH-CH2-CO). The viscosity average molecular weight of polysuccinimide ( Mv, PSI ) was determined by viscometry. PSI was dissolved in 0.1 M LiCl/DMF solution, and samples with polymer concentration between 0.004 and 0.02 g mL-1 were prepared for the measurement. The experiment was carried out using a rolling ball viscometer (Anton Paar Lovis 2000) at a tilting angle of 45°. Diameters of the capillary and the ball used were 1.6 and 1.5 mm, respectively. 5 M v, PSI was calculated from the intrinsic viscosity data using the Kuhn–Mark–Houwink equation: KM v, PSI (1) -1 where K = 1.32×10 and = 0.76 for PSI were taken from the literature [21]. M v, PSI was determined to be 29 kDa. Poly(aspartic acid) (PASP) was synthesized by the hydrolysis of PSI. 1 g (0.01 mol) of 3 PSI was added to 200 cm 0.1 M NaOH(aq) and the mixture was stirred for 5 h. The final solution was dialyzed against ultrapure water and lyophilized. A slightly yellow product was obtained. 1 H NMR (300 MHz, D2O): 4.55 (1H, NH-CH-CO-CH2), 2.66 (2H, CO-CH-CH2-CO). 2.2.2 Synthesis of cationic polyaspartamides PSI was functionalized with dialkylaminoalkyl and alkyl side groups by the nucleophilic addition of various dialkylaminoalkyl- and alkylamines onto the imide groups of the polymer chain (Scheme 1). A typical procedure was as follows (e.g. PSI modified with 90 mol% 3-(dimethylamino)-1-propylamine and 10 mol% propylamine; abbreviated as DMP90P10): 3.00 g of PSI (30.93 mmol of succinimide repeating units) was dissolved in 26 g of DMSO and then 2.844 g of 3-(diethylamino)-1-propylamine (27.83 mmol) was added dropwise to the solution. The mixture was stirred at room temperature for 24 h. Afterwards, 0.238 g of n-propylamine (4.02 mmol, in excess) was added to the solution and the mixture was stirred at room temperature for another 24 h. The polymer was precipitated by adding 400 ml of ethyl acetate, the precipitate was filtered and washed four times with 50 ml of ethyl acetate then dried under vacuum at 25 °C for 24 h. A slightly yellow powder was obtained with an average yield of 75%. The polymers were stored at room temperature. 1 DMP90P10: H NMR (500 MHz, d6-DMSO, δ) [ppm]: 4.55 (1H, NH-CH-CO-CH2), 3.06 (2H, NH-CH2-CH2-CH2-N(CH3)2; 2H, NH-CH2-CH2-CH3), 2.64 (2H, CO-CH-CH2-CO), 2.18 (2H, 6 NH-CH2-CH2-CH2-N(CH3)2), 2.10 (6H, NH-CH2-CH2-CH2-N(CH3)2), 1.53 (2H, NH-CH2- CH2-CH2-N(CH3)), 1.43 (2H, NH-CH2-CH2-CH3), 0.82 (3H, NH-CH2-CH2-CH3); -1 FTIR (KBr) [cm ]: 3317 (νNH Amide), 1653 (ν, Amide I), 1538 ( Amide II), 2944 (νasCH3, 1 νasCH2).

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