[Thesis] Solubility enhancement of poorly water soluble active compounds by supercritical fluids

ChemEng. Marta Fraile Arranz defends her doctoral thesis “Solubility enhancement of poorly water soluble active compounds by supercritical fluids” on Friday 15th November 2013 at Valladolid University “Aula Triste, Palacio de Santa Cruz”

 

Enhancement of solubility, dissolution rate and bioavailability of active compound is a very challenging task with a great relevance in active compound development and formulation for pharmaceutical, cosmetic and food industries.

Among all newly discovered chemical entities about 40% drug are lipophilic. These poorly water soluble drugs having slow drug absorption leads to inadequate and variable bioavailability and gastrointestinal mucosal toxicity. For these reasons is necessary a good formulation in order to increase the solubility, availability at the site of action, maintaining the stability of active compound.

Various techniques are used for the enhancement of the solubility of poorly soluble drugs which include physical and chemical modifications of drug and other methods like crystal engineering, particle reduction, salt formation, addition of agent, solid dispersion, use of surfactant, complexation, and so forth. Selection of solubility improving method is greatly dependent on the physical and chemical nature of the molecules being developed, site of absorption, and required dosage form characteristics. These technologies present several disadvantages such as the production of coarse particles with broad particle size distribution, the degradation of the product due to mechanical or thermal stresses, or the contamination of the particles with organic solvents or other toxic substances.

Composite particle generation and micronization by SCF processes looks as a very promising solution to enhance the dissolution of poorly-soluble compounds, as they allow to improve the performance of these processes in terms of reduction of particle size, control of morphology and particle size distribution, without degradation or contamination of the product.

There are several techniques involving supercritical fluids that can be adapted to produce polymer particles loaded with a homogeneous distribution of particles of an active substance. Supercritical extraction of emulsions process (SFEE), particles from gas saturated solutions (PGSS) process and Supercritical antisolvent process (SAS) represent some of the most usual alternatives to overcome the drawbacks of the conventional processes. The aim of this PhD Thesis is the improvement of the solubility of diverse compounds by different processing techniques with supercritical fluids. Biodegradable polymers have been used in the formulations: starches modified with the group n-octenyl succinic (OSA), Etlylene oxide-propylene oxide block copolymers Pluronic ® F127 and L64, Gelucire 43-01 and glyceryl monostearate (GMS), and ibuprofen and quercetin have been considered as model active compounds with a low solubility in water.

The first processing technology developed was the Supercritical Fluid Extraction of Emulsions (SFEE). In chapter I was aimed at evaluating this new method, for the production of drug-loaded polymer spheres in a well-controlled manner, as an alternative, attractive and scalable process used in manufacturing of microparticles for pharmaceutical applications.

First of all a study of emulsion formation was done evaluating the surface tension and interfacial tension of water-ethyl acetate systems with pluronic ® L64 and F127 and water-dichloromethane with HI-CAP modified OSA (Octenyl Succinic Anhydride-starch). Secondly the efficiency of solvent elimination in the SFEE process was study in order to reach levels not harmful for the human health and was compared with the traditional evaporation. Finally a preliminary studies of Ibuprofen precipitation as model drug was performed for the production of composite with application in sustained-release drug delivery formulation.

Based on the results in the chapter I, an equipment and method was development in the chapter II, under the title of Device and Method for the production of drug micelles nanocarriers by supercritical extraction. This invention provides a method for the encapsulation of a solute in micelles at the aqueous phase, characterized by the following : (a) dissolving the solute in an organic phase, and at least an encapsulating and surfactant material into the aqueous phase and/or the organic phase; (b) forming an emulsion with the aqueous phase as continuous phase and the organic phase as discontinuous phase, where the organic phase includes an organic solvent immiscible or partially miscible in water, defining itself as an organic solvent in which solubility in water is lower than 15% in mass; (c) extracting the organic solvent from the emulsion with a supercritical fluid; and (d) removing the supercritical fluid by decompression, resulting in a micellar solution in which the solute is dissolved and stabilized in water inside of the micelles formed for the encapsulant material. In addition, the object of the invention is the system to carry out the mentioned method.

The second SCF processing technology used was SAS in chapter III, in order to develop the formulation of quercetin by encapsulation in a surfactant polymer capable of forming micelles in aqueous media that can contribute to improve the dissolution of quercetin in water, and thus facilitate the assimilation of this compound by the organism. In this chapter, quercetin was encapsulated in Pluronic® F127 poloxamers by Supercritical Antisolvent (SAS) technique.

The structure and morphology of the product were characterized by SEM, DSC, XRD and FT-IR techniques. Results indicate that by SAS processing a significant reduction of particle size was achieved. With appropriate polymer: active compound ratios, quercetin was homogeneously dispersed in an amorphous polymer matrix, and segregated crystalline particles of quercetin were not observed. These structural and morphological variations enabled an improved dissolution behavior of quercetin in simulated gastric and intestinal fluid.

In chapter IV a PGSS process was used in order to develop a formulation of S-(+)-ibuprofen as a model water-insoluble drug in different carrier materials (poloxamers, gelucire and glyceryl monostearate, GMS). Porous, spherical particles of 50 – 200 m were obtained with encapsulation efficiencies up to 90%. Differential scanning calorimetry assays revealed modifications on the structure of the material, with formation of a solid solution in experiments with poloxamer carriers, and formation of solid dispersions with a possible reduction of the crystallinity of the carrier in experiments with GMS. Drug release tests in simulated gastric and intestinal fluids were performed. Formulations with poloxamer carrier materials provided an increased solubility of ibuprofen in the gastrointestinal fluids, with a very fast release and dissolution of this compound, while gelucire and GMS carriers did not improve the solubility of ibuprofen, but provided a slower, controlled release of the drug. PGSS-processed samples presented a superior performance over physical mixtures in terms of the solubility increase and the control of the release rate. These results show the wide possibilities and flexibility of the PGSS technique for the development of hybrid

formulations of water-insoluble active compounds with hydrophilic or hydrophobic carrier materials, achieving either an increased, accelerated dissolution, or a slower, controlled delivery, depending on the choice of carrier materials.

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