Novel technologies and process intensification in the production of micro-systems with pharmacological/nutraceutical activity

2011 - 2012Purpose of the PhD thesis was to develop a novel microencapsulation process, designing and building a single-pot semi-continuous bench scale apparatus. The novel process is based on the coupling of two emerging techniques, involving ultrasound and microwave, used in atomization and heating operations, respectively. The process has been designed to respond to the needs for process intensification, i.e. improvement of process efficiency and cutting down of energy consumption. With this aim, a review of the main processes used for microencapsulation was first performed: conventional processes showed a number of drawbacks, such as high energy consumption, batch configuration, use of solvents and long times of production. On the basis of the state of the art, the idea of an intensified apparatus for particles production, exploiting alternative resources, such as ultrasound and microwave, was formulated. The apparatus was composed of three main sections: feeding, atomization, separation/stabilization. The feeding and atomization sections were built connecting a double channel ultrasonic atomizer to a system for feeding solutions in a purposely designed separation/stabilization section, thus realizing a semi-continuous apparatus. Separation section consisted of a wet-collector, i.e. a sort of hydrocyclone, which allowed a uniform distribution of the hardening solution and the consequent contact with the atomized drops, a filtering device, and a microwave oven. The wet-collector was placed into the microwave oven to obtain an “on-line” drying. Recirculation of the hardening solution, to renew contact surface between droplets and cross-linker, was guaranteed by a system of centrifugal pumps. In this configuration, when atomization occurred, drops were harvested in the wet-collector. After atomization, the obtained suspension was collected in the cross-linker tank, then the filtering device was inserted in the lower part of the wet-collector, so that hardening solution was recovered and particles settled on the filter, when the suspension was brought again to the wet-collector and after its complete emptying. An eventual following washing step can be done in a similar way to the previous hardening step. Finally, particles were stabilized by microwave drying, and then recovered. The steps for building the microencapsulation apparatus were accurately shown. Then, criteria used for components selection, in order to obtain the best performances from the plant, were highlighted. After building the plant, the process parameters were defined. First, the research for the best combination of feeding parameters, such as type of materials, composition, concentration and feed rate, that assure the encapsulation of the core material in the shell, was carried out. Then, the parameters of the ultrasonic atomizer (atomization section), essentially power, were tuned. Finally, for stabilization/separation section, fundamental was the relevant stabilization step, where microwave power was set to avoid too high temperatures that could degrade molecules... [edited by Author]XI n.s

Single-Pot Semicontinuous Bench Scale Apparatus To Produce Microparticles

This work presents both the design of a novel process to produce microparticles with a shell−core structure and a bench scale apparatus purposely realized. The developed process was designed to respond to mandatory needs of process intensification. It involved the coupling of two emergent technologies: atomization assisted by ultrasonic energy and microwave heating. The former was used to atomize polymeric solutions; the latter was applied to stabilize the produced droplets by drying. Both operations were performed in the same vessel with the aim to have a single-pot process chamber and were carried out by a semicontinuous procedure. Basic design criteria and advantages of the ultrasonic−microwave coupled operations in the realized apparatus are presented and discussed. Results of testing and of operating runs to produce shell−core microparticles are also reported, emphasizing the main features of the produced particles

Intensifying the microencapsulation process: Ultrasonic atomization as an innovative approach

In this review, new approaches to the microencapsulation processes, widely used in the manufacturing of pharmaceutical products, are discussed focusing the attention on the emerging ultrasonic atomization technique. Fundamentals and novel aspects are presented, and advantages of ultrasonic atomization in terms of intensification and low energy requests are emphasized

In vitro dissolution of pH sensitive microparticles for colon-specific drug delivery

Objective: The objective of this work is to prepare oral dosage systems based on enteric materials in order to verify their possible use as Colon-Specific Drug Delivery Systems (CSDDSs). Methodology: In particular, three different copolymers of methyl-methacrylate (MMA) - acrylic acid (AA) are synthesized with increasing percentage of MMA (from 70% to 73%) and they are used to produce microparticles by the double-emulsion solvent evaporation method. The microparticles, loaded using theophylline as model drug, are then tested for drug release under varying pH to reproduce what happens in the human GI tract. Results: All the investigated systems have shown an effective pH sensitiveness: they show a good gastro-resistance, releasing the model drug only at higher pH, small intestine or colon, depending on the kind of used copolymer. Conclusion: The results confirm the usefulness of both the materials and the methods proposed in this study for colon-specific delivery applications

Synthesis and characterization of P(MMA-AA) copolymers for targeted oral drug delivery

This paper describes the development of pH-sensitive poly(methyl methacrylate-acrylic acid) copolymers for the enteric coating of pharmaceutical products for oral administration. To obtain the dissolution at the desired pH level, different pH-sensitive polymers are available on the market. Usually, for each desired dissolution pH, an ad hoc polymer is designed. Thus, different dissolution pH values could ask for completely different polymers. Instead, the materials proposed in this work are copolymers of the same two monomers, and the different dissolution pH was obtained by changing the volume fraction of the hydrophobic methyl methacrylate monomer to the hydrophilic acrylic acid monomer. Increasing the volumetric percentage of methyl methacrylate causes the polymer to dissolve at increasing pH, until the dissolution does not take place at all, and it is replaced by a slow swelling phenomenon. The copolymers obtained were characterized by differential scanning calorimetry, in order to evaluate their glass transition temperature, and these latter were related to %MMA. The molecular weights of the pure polymers (PAA, PMMA) were measured by intrinsic viscosity, to further validate the glass transition temperatures observed. The dissolution of the copolymers was carefully tested in buffer solutions for a dense set of pH values. A linear relationship between dissolution pH and volumetric percentage of methyl methacrylate was obtained from these measurements. As a result, for any physiological compartment, the copolymer which dissolves at the pH of interest can be easily synthesized. doi:10.1007/s00289-009-0040-

Analysis and modeling of swelling and erosion behavior for pure HPMC tablet

This work is focused on the transport phenomena which take place during immersion in water of pure hydroxypropylmethylcellulose tablets. The water uptake, the swelling and the erosion during immersion were investigated in drug-free systems, as a preliminary task before to undertake the study of drug-loaded ones. The tablets, obtained by powder compression, were confined between glass slabs to allow water uptake only by lateral surface and then immersed in distilled water at 37 °C, with simultaneous video-recording. By image analysis the normalized light intensity profiles were obtained and taken as a measure of the water mass fraction. The time evolutions of the total tablet mass, of the water mass and of the erosion radius were measured, too. Thus a novel method to measure polymer and water masses during hydration was pointed out. Then, a model consisting in the transient mass balance, accounting for water diffusion, diffusivity change due to hydration, swelling and erosion, was found able to reproduce all experimental data. Even if the model was already used in literature, the novelty of our approach is to compare model predictions with a complete set of experimental data, confirming that the main phenomena were correctly identified and described

Pharmaceutical Applications of Biocompatible Polymer Blends ontaining Sodium Alginate

Biocompatible polymer blends, such as alginate blends, have a widespread use in pharmaceutical and medical applications due to their specific features, such as biodegradation, adhesiveness, and thermo- and pH sensitivity and that can be obtained from the mixture composition. In this work, the use of alginate blends was tested in a novel production methodology of therapeutic dosage forms based on polymeric chain reticulation phenomena induced by exposure to bivalent ions. Two kinds of sodium alginate were used to obtain gel films (structured films) in blends with Pluronic F127®. The blends were considered for applications in gel paving of drug-eluting stents. Sodium alginate was also used in shell–core particle production (structured particles) to obtain shell-barrier reducing drug release in the preparative steps (see wash operations). Both structures, films and particles, were obtained using Cu2+ and Ca2+ ions, respectively. Film/shell barrier properties were tested in dissolution experiments using vitamin B12 as an active molecule model. Experimental work demonstrated that the alginate composition is a crucial point in defining reticulated structures

An Engineering Point of View on the Use of the Hydrogels for Pharmaceutical and Biomedical Applications

In this chapter, the modern uses of hydrogels in pharmaceutical and biomedical applications are revised following an engineering point of view, i.e. focusing the attention on material properties and process conditions. The chapter discusses the applications following the increase in scale‐size. First, the nanoscale systems, i.e. hydrogel nanoparticles (HNPs), are analysed in terms of preparative approaches (polymerization methods and uses of preformed polymers) and with a brief mention of the future trends in the field. Secondly, systems based on hydrogel microparticles (HMPs) are examined following the same scheme (polymerization methods, uses of preformed polymers, a mention of novel and future trends). Thirdly, and last but not the least, the hydrogel‐based drug delivery systems (macroscopic HB‐DDSs) are presented, focusing in particular on tablets made of hydrogels, discussing the characterization methods and on the modelling approaches used to describe their behaviour. Other macroscopic systems are also discussed in brief. Even if the vastness of the field makes its discussion impossible in a single chapter, the presented material can be a good starting point to study the uses of hydrogels in pharmaceutical and biomedical sciences

An engineering approach to biomedical sciences: advanced strategies in drug delivery systems production

Development and optimization of novel production techniques for drug delivery systems are fundamental steps in the “from the bench to the bedside” process which is the base of translational medicine. In particular, in the current scenery where the need for reducing energy consumption, emissions, wastes and risks drives the development of sustainable processes, new pharmaceutical manufacturing does not constitute an exception. In this paper, concepts of process intensification are presented and their transposition in drug delivery systems production is discussed. Moreover, some examples on intensified techniques, for drug microencapsulation and granules drying, are reported

Droplet size prediction in the production of drug delivery microsystems by ultrasonic atomization

Microencapsulation processes of drugs or other functional molecules are of great interest in pharmaceutical production fields. Ultrasonic assisted atomization is a new technique to produce microencapsulated systems by mechanical approach. It seems to offer several advantages (low level of mechanical stress in materials, reduced energy request, reduced apparatuses size) with respect to more conventional techniques. In this paper the groundwork of atomization is briefly introduced and correlations to predict droplet size starting from process parameters and material properties are presented