Avaliação da cristalização do metronidazol por acompanhamento com técnicas de análise em tempo real

Abstract

The crystallization process is a unitary operation widely used industrially, because in a single step, high purity crystals and possible possible by-products can be obtained. However, for the crystals to present the final selected characteristics, as there are crystals and uniform dimensions, or control of the crystallization process becomes an object of continuous study. Some control parameters are: agitation speed, cooling rate, seeding - addition of monocrystal for induction of crystallization, addition of anti-solvent, etc. shows that there is difficulty in compacting and inspecting tablets, or in problems of disintegration and dissolution of these, affecting the bioavailability of the drug; thus, the control of the crystallization step is a key step in the process. Supersaturated solutions were prepared in ethanol and water at 42 ° C, cooled at rates of 0.2, 0.4 and 0.6 ° C.min-1 to a final temperature of 5 ° C, obtaining data for comparison of the starting temperature crystallization, average crystal size and crystalline habit. The sample size was assessed by a focused focus - FBRM (Focused Beam Reflectance measurement); there is a lens by an inline microscope video - PVM (Particle Vision and Measurement) and by scanning crystal electron microscopy after vacuum filtration and drying for 24 h in an oven at 60°C. Finally, the temperature of the beginning of crystallization was evaluated by the backscatter index (RBI) and image analysis, by changing the signal of the red, green and blue components (RGB), which, by using a camera as a sensor, low cost analysis and easy access. The influence of the camera's positioning in the system was also studied, one being internal (online) and the other external (online) to the reactor. With the use of PVM, it is possible to evaluate online the different crystal habits influenced by the rates and solvents, being confirmed by the SEM images. In the ethanol system, there was only one formation of the crystalline habit of hexagonal prism for three rates, however, of crystallization in water, of 0.2°C/min from crystals with prismatic crystal habit with an average size close to 100 μm; for rates of 0.4°C and 0.6°C/min, average size varying between 80 and 90 μm, but the first forms a mixture of prismatic crystals with acicular and the second acicular crystals. The online and inline camera systems captured the beginning of crystallization at the same time, showing that the technique is not influenced by the position of the sensor, however, the external position showed less capacity to capture the RGB signal. All the real-time analysis techniques used detected the onset of crystallization at statistically equal times for the same cooling rate. Based on these data, the most suitable condition for making metronidazole tablets is crystallization from aqueous solutions at a rate of 0.2°C/min.