ABSTRACT
High concentration formulations have become an important pre-requisite in the development of biological drugs, particularly in the case of subcutaneous administration where limited injection volume negatively affects the administered dose. In this study, we propose to develop high concentration formulations of biologics using a reversible protein-polyelectrolyte complex (RPC) approach. First, the versatility of RPC was assessed using different complexing agents and formats of therapeutic proteins, to define the optimal conditions for complexation and dissociation of the complex. The stability of the protein was investigated before and after complexation, as well as upon a 4-week storage period at various temperatures. Subsequently, two approaches were selected to develop high concentration RPC formulations: first, using up-concentrated RPC suspensions in aqueous buffers, and second, by generating spray-dried RPC and further resuspension in non-aqueous solvents. Results showed that the RPC concept is applicable to a wide range of therapeutic protein formats and the complexation-dissociation process did not affect the stability of the proteins. High concentration formulations up to 200 mg/mL could be achieved by up-concentrating RPC suspensions in aqueous buffers and RPC suspensions in non-aqueous solvents were concentrated up to 250 mg/mL. Although optimization is needed, our data suggests that RPC may be a promising avenue to achieve high concentration formulations of biologics for subcutaneous administration.
Subject(s)
Biological Products , Drug Compounding , Proteins , Excipients , SolventsABSTRACT
For the first time, the highly sensitive 1-(nitratomethyl)-5H-tetrazole (1-NAMT) was synthesized, representing the shortest possible 1-(nitratoalkyl)-5H-tetrazole with a combined nitrogen and oxygen content of 81.4%. Compared to its related ethyl derivative, 1-(nitratoethyl)-5H-tetrazole, it exhibits improved oxygen balance, resulting in higher detonation parameters. 1-NAMT was thoroughly analyzed by single-crystal diffraction experiments accompanied by elemental analysis, IR spectroscopy, and multinuclear (1H, 13C, and 14N) NMR measurements. The thermal behavior of 1-NAMT was analyzed by differential thermal analysis supported by thermogravimetric analysis. Furthermore, energetic coordination compounds (ECCs) of Cu with different inorganic (e.g., nitrate, chlorate, and perchlorate) and nitroaromatic anions (e.g., picrate and styphnate) were synthesized and thoroughly analyzed. It is shown that the formation of ECCs with nitroaromatic anions (Tdec â¼ 180 °C) is a suitable strategy to improve the rather low thermal stability of 1-NAMT (125 °C).
ABSTRACT
The almost ancient and very sensitive silver fulminate (SF), which was involved in the establishment of fundamental chemical concepts, was desensitized for the first time with different nitrogen-rich triazoles and tetrazoles, yielding SF complexes [Agx(CNO)x(N-Ligand)y] (x = 1-4; y = 1-3). These were accurately characterized (X-ray diffraction, scanning electron microscopy, IR, elemental analysis, differential thermal analysis, and thermogravimetric analysis) and investigated concerning their energetic character. The highly energetic coordination compounds suddenly show, in contrast to SF, sensitivities in a manageable range and are therefore safer to handle. In particular, compounds [Ag4(CNO)4(BTRI)] [3; BTRI = 4,4'-bis(1,2,4-triazole)] and [Ag4(CNO)4(2,2-dtp)] [8; 2,2-dtp = 1,3-di(tetrazol-1-yl)propane] show values in the range of desired lead styphnate alternatives with similar energetic performances. The crystal structure experiments reveal silver cluster formation in all complexes with distinct argentophilic interactions close to 2.77 Å. Furthermore, it was possible to synthesize 8 in a one-pot reaction, avoiding the isolation of highly sensitive SF.
ABSTRACT
N,N-Substituted ditetrazolylalkanes are widely used molecules in the field of coordination chemistry and are known with different alkyl chain lengths. The missing fragment within this row is presented by the elementary methylene-bridged ditetrazoles. The three different isomers (di(tetrazol-1-yl)methane (1,1-dtm, 1), (tetrazol-1-yl)(tetrazol-2-yl)methane (1,2-dtm, 2), and di(tetrazol-2-yl)methane (2,2-dtm, 3)) were synthesized in a convenient one-step reaction. All of them were successfully incorporated as neutral ligands in 15 new energetic coordination compounds (ECC) based on Cu2+ and Ag+ as well as different anions (nitrate, picrate (PA), styphnate (TNR), trinitrophloroglucinate (TNPG), and perchlorate) revealing an extraordinary coordination behavior of the ligands compared to other 5H-ditetrazolylalkanes. All compounds were extensively characterized using single-crystal X-ray diffraction experiments, infrared spectroscopy (IR), elemental analysis (EA), and differential thermal analysis (DTA). Furthermore, the sensitivities were determined using standard techniques, and Hirshfeld surface calculations of the ligands were applied to explain their significant divergences to external stimuli. The ECC possess very good exothermic decomposition temperatures up to 242 °C. The ignition of all colored complexes was tested in laser experiments, and two copper(II) perchlorate compounds showed promising results in classic initiation capability tests using pentaerythritol tetranitrate (PETN).
