phases and this topic is crucial during pharmaceutical development [1,2]. To date, just one paper dealing with tobramycin solid state characterization is available ...
SOLID STATE CHARACTERIZATION OF TOBRAMYCIN F. Martinelli1, D. Frascio1, A. G. Balducci2, P. Colombo1, F. Buttini2, R. Bettini2 1
Department of Pharmacy, University of Parma, Viale Usberti 27/A, Parma, Italy Interdepartmental Center, Biopharmanet-TEC, University of Parma, Viale delle Scienze 27/A, 43124 Parma, Italy
2
Purpose: Tobramycin is an aminoglycoside broad-spectrum antibiotic, effective against Gram negative bacteria, especially pseudomonal infections. It is delivered by intramuscular injections, intravenous infusions, as ophthalmic ointment or drops or by inhalation. When solid dosage forms are considered, the solid state characteristic of the active ingredient, i.e. polymorphism, represent an issue that should be addressed. Powders may have different polymorphic phases and this topic is crucial during pharmaceutical development [1,2]. To date, just one paper dealing with tobramycin solid state characterization is available in the literature [3]. The aim of this work was to investigate the solid state properties of different tobramycin raw materials and a spray-dried powder.
Methods: The spray-dried powder was produced with a B-290 Mini Spray-Dryer (Büchi Laboratoriums-Technik, Swiss) starting from an aqueous solution. Tobramycin was supplied by TEVA Pharmaceutical (Powder A) and by Biovet (Powder B); a jetmilled tobramycin was obtained by Chiesi (Powder C). They were characterized in terms of morphology by Scanning Electron Microscopy, thermal analysis by Differential Scanning Calorimetry and Thermogravimetric Analysis. DSC and TGA traces were recorded at temperature ranging from 25 to 250 °C at scanning rate of 10 °C/min under a N2 flux. Tobramycin crystallinity was investigated with X-Ray Powder Diffractometry. XRPD patterns were collected at scanning rate of 1.5 °/min over a 2θ range of 2-35 °. Dynamic Vapour Sorption was employed to monitor the water uptake as function of the relative humidity (0-95%) at constant temperature of 22 °C.
Results: XRPD patterns showed that Powder A and C were crystalline. In contrast, the SD powder and Powder B were amorphous. The DSC profiles highlighted some differences among raw materials. Powder A showed two main endothermic peaks and one exothermic event between them. This behaviour was interpreted as a melting of the starting phase follow by a recrystallization and subsequent fusion of a second crystal phase. Interestingly, Powder C presented only the endotherm corresponding to the fusion of the high melting phase. Overall, DSC patterns were different respect to those reported in literature [3]. TGA pointed out a water content of 6.0%, 5.0%, 5.6% for Powder A, C and B, respectively. Spraydried tobramycin showed the highest water content (9.8%). Isothermal DVS measurements on spray-dried powder afforded a recrystallization between 50-70% RH giving rise to a crystal phase with DSC and XRPD traces similar to those mentioned in [3]. This phase proved to be a monohydrate.
Conclusions: The analysis on raw materials pointed out the existence of two solid phases of tobramycin. A monohydrate, already described in literature, can be obtained upon isothermal crystallization between 50% and 70% RH. The relative thermodynamic stability of the studied solid phases need to be further investigated.
References: [1] ICH Q6A. 1999. Specifications: test procedures and acceptance criteria for new drug substances and new drug products: chemical substances. International Conference on Harmonisation. [2] ICH Q8. 2009. Pharmaceutical development. International Conference on Harmonisation. [3] A. K. Dash and R. Suryanarayanan. Solid-state properties of tobramycin. Pharmaceutical research, Vol. 8, No 9 (1991).
