Elsevier

Analytica Chimica Acta

Volume 744, 26 September 2012, Pages 8-22
Analytica Chimica Acta

Review
An overview of the analytical characterization of nanostructured drug delivery systems: Towards green and sustainable pharmaceuticals: A review

https://doi.org/10.1016/j.aca.2012.07.010Get rights and content

Abstract

The analytical characterization of drug delivery systems prepared by means of green manufacturing technologies using CO2 as a processing fluid is here reviewed. The assessment of the performance of nanopharmaceuticals designed for controlled drug release may result in a complex analytical issue and multidisciplinary studies focused on the evaluation of physicochemical, morphological and textural properties of the products may be required. The determination of the drug content as well as the detection of impurities and solvent residues are often carried out by chromatography. Assays on solid state samples relying on X-ray, vibrational and nuclear magnetic resonance spectroscopies are of great interests to study the composition and structure of pharmaceutical forms. The morphology and size of particles are commonly checked by microscopy and complementary chemical information can be extracted in combination with spectroscopic accessories. Regarding the thermal behavior, calorimetric and thermogravimetric techniques are applied to assess the thermal transitions and stability of the samples. The evaluation of drug release profiles from the nanopharmaceuticals can be based on various experimental set-ups depending on the administration route to be considered. Kinetic curves showing the evolution of the drug concentration as a function of time in various physiological conditions (e.g., gastric, plasmatic or topical) are recorded commonly by UV–vis spectroscopy and/or chromatography. Representative examples are commented in detail to illustrate the characterization strategies.

Highlights

► Analytical evaluation of nanostructured drug delivery systems prepared by scCO2. ► Physicochemical characterization by chromatography and spectroscopy. ► Particle characterization by microscopy and thermal analysis. ► Release assessment by batch, continuous and diffusion devices.

Introduction

Global market predictions show that by 2015 nanoproducts will reach a 10% of the total industrial output of materials, representing about $2.5 trillion business and more than 1 million workers involved in R&D, production and related activities [1]. However, further than figures themselves, more impressing seems to be the rapid evolution of nano-based applications and their expansion to new technological areas. The incorporation of nanoproducts as raw materials of automotive, electronics and chemical industries has opened up new commercial and industrial and research opportunities. Nanoelectronics and nanoenergy have currently the highest visibility in the technological scene, but the greatest short-term business opportunities lie on the sector of materials for medicine, mainly due to the great advances on nanopharmaceuticals [2].

One of the newest and more attractive approaches for manufacturing nanopharmaceuticals relies on green technologies. Nowadays, although most of the current pharmaceuticals are obtained using (non green) conventional methodologies, the relevance of the green counterparts is increasing dramatically. Green pharmaceutical industry aims at designing products and processes that eliminate (or reduce significantly) the use and generation of hazardous substances and prevent environmental and health impacts at the source. Hence, both environmentally and economically sustainable products are encouraged and promoted [3]. In particular, as the ratio of waste-to-useful product is very unfavorable in the pharmaceutical sector, greener innovations that are ‘benign by design’ are welcome.

The emergence of nanotechnology has had a significant impact on sustained drug release [4], [5]. Drug delivery systems (dds) offer several advantages compared with conventional dosage forms [6]. These systems act as a reservoir of therapeutic agents, with specific time-release profiles of the drugs, thus leading to controlled pharmacokinetics and bioavailability [7]. The control becomes complete when the system is designed for drug targeting to specific sites, with an accurate control on the biodistribution, thus resulting in controlled drug delivery (cdd). Current technologies for dds are mainly based on micron- or submicron matrices of homopolymers or blends in which the drug is encapsulated, dispersed, adsorbed or chemically bonded [8]. However, nowadays, the relevance of inorganic materials such as silica, TiO2 or magnetic particles, either alone or combined with polymers in the so-called hybrid matrices, is increasing dramatically [9], [10], [11]. The corresponding dds or cdd systems may overcome problems dealing with drug concentrations below therapeutic levels, rapid metabolization, drug level fluctuation in plasma, side effects, etc.

The application of nanotechnology to healthcare had led to the development of a variety of novel nanoproducts for cdd that are changing the foundations of disease diagnosis, monitoring and treatments [12], [13], [14]. The in vivo fate of the active agent can be modulated from the properties of the matrix, in this case, through the nanocarrier concept [15], [16]. It has been shown that nanocarriers can penetrate through small capillaries, across numerous physiological barriers and can be taken up by cells, thus inducing efficient drug accumulation at the target site. Nanocarriers can be designed for different administration routes such as intravenous, intramuscular, subcutaneous, oral, nasal, ocular, etc.

Nanometric or colloidal carriers consists of small simple or composite particles with a diameter often in the range 10–400 nm (see Fig. 1). Nanocarriers are compatible with a wide range of drugs, including those unstable in the biological environment. The structure of dds effectively protects the active agent against hydrolysis or enzymatic degradation. As shown in Table 1, a broad variety of pharmaceuticals relying on nanoparticles has been reported for both drug delivery and diagnosis tasks [17]. Apart from the most common oral and intravenous administration routes, these products open up new opportunities in other directions such as topical and transdermal delivery owing to their ability to penetrate through human tissues, implantable release systems for tissue engineering applications and ophthalmic delivery in which the drug release can be externally controlled by stimuli-responsive nanocomponents [18], [19], [20], [21]. Other issues such as cancer diagnosis and therapy have been revolutionized by exploiting magnetic nanoparticles. Furthermore, in vivo imaging could be facilitated enormously by using quantum dots [22], [23], [24], [25].

The continuous advances in the field of nanopharmaceuticals are bringing an increasing interest in potential harmful concerns of these products. As a result, a new discipline referred to as nanotoxicology has recently emerged [26]. The effects of nanomaterials on biological systems are related to some scale-dependent properties such as optical interactions, capillary forces, magnetism, surface energy and reactivity. Indeed, nanostructured surfaces are extremely reactive in front of catalytic and oxidative processes and, thus, they can result in a source of unwanted phenomena. It has been found that nanoparticles display a different toxicity profile compared with larger particles [27]. In the past years, nanotoxicity research was focused on cell culture systems. Some recent discussions on absorption, distribution, metabolism and excretion (ADME) behavior and toxicity of drug nanoparticles in the organism can be found elsewhere [28], [29].

Although the principal topic of this paper is the analytical characterization of dds, a brief introduction to the manufacturing procedures is given in the following section, with specially emphasis to those technologies based on supercritical fluids.

Nanotechnology is now compatible with large-scale production of different tailored entities, ranging from nanoparticles to carbon nanotubes [30], [31]. Currently, the feasibility of upscaling the fabrication of complex nanostructured products, such as those required in drug delivery is a major challenge to be proved.

The principal conventional (i.e., not green) methodologies to be used for dds manufacturing are briefly discussed as follows. The Würster fluid-bed process is recognized as the best technology for polymeric film coating to prepare dds nanocapsules as those described in Table 1 [6], [32], [33]. The procedure relies on a nozzle at the bottom of a fluidized bed of solid particles. The nozzle sprays atomized droplets of coating solution concurrently with particle flow. However, this technology can be used to encapsulate efficiently only at the micrometric scale. Following a similar idea, the spray drying method has been developed to prepare nanopharmaceuticals. Highly dispersed powders are produced from an atomized fluid by evaporating the polymer solution under a stream of heated air or nitrogen. The most common techniques for the preparation of dds are, however, the emulsion-solvent methods. The single emulsion approach was used primarily to encapsulate hydrophobic drugs dissolved in an organic solvent containing the polymeric matrix emulsified in a water phase (oil-in-water). Water-soluble drugs can be encapsulated by the double-emulsion water-in-oil-in-water method. The solvent in the emulsion is removed by evaporation, lyophilization or extraction. Coprecipitation, phase separation by addition of an organic antisolvent and complex coacervation are also widely used methods for the manufacturing of nanostructured dds based on organic matrices. Ceramic nanoparticles, mesoporous silica, ferrofluids and quantum dots (see scheme in Table 1) are prepared using the sol–gel and colloidal precipitation approaches.

The aforementioned mass-production methods, including vapor-related physical routes and liquid-related chemical bulk processes, have severe limitations dealing with high cost and reduced purity, respectively [34]. Typical organic solvents (e.g., methanol, toluene, xylene, methyl ethyl ketone or dichloromethane) to be used for manufacturing and purification post-processing have well-known disadvantages like toxicity, flammability and environmental concerns. Furthermore, the manipulation of nanoentities in organic solvents is extremely difficult due to undesired processes such as agglomeration, degradation or contamination that may damage the labile surfaces of nanomaterials.

Classical alternatives to the use of organic solvents consist of wet milling, high pressure-homogenization, vapor-condensation or freeze drying [6], [32], [33]. However, these methodologies are not suitable for dealing with thermally labile drugs. As commented in the following section, a different option relies on intrinsic benign solvents, particularly supercritical fluids (scf).

With difference, the most extensively used green technologies in the production of pharmaceutical products rely on scf [35], [36]. Other green processing alternatives such as those based in ionic liquids (IL) have also been investigated. ILs are salts of poorly coordinated ions, liquids below 100 °C or even at room temperature, with a very low vapor pressure. ILs have been assayed for processing nanopharmaceuticals without needing organic solvents. However, although some favorable results have been obtained, important questions regarding purity, toxicity and regulatory approval need to be solved.

The critical point of a fluid is defined by the temperature and pressure coordinates, above which no physical distinction exists between the liquid and the gas phases. The unique properties of scf, which are intermediate between liquids (high density) and gases (low viscosity and null surface tension), can be used to design innovative fabrication processes [37], [38]. Compressed or supercritical CO2 is the most important fluid in the pharmaceutical industry. In the last years, scCO2 has been proposed as an alternative to overcome upscaling problems associated with both organic solvents and nanostructuring. Besides, the straightforward preparation of dry products in confined autoclaves and the intrinsic sterility of CO2 are of particular interest to produce dds. CO2 has other relevant features that facilitates the processing of pharmaceutical products: (i) low critical temperature (31 °C) fully compatible with most of thermally labile materials, (ii) tunability of its solvent power through pressure modulation, (iii) high diffusivity that facilitates mass transfer while reducing processing times, (iv) possibility of implementing of one-stage processes with simultaneous control of the composition and the (nano)structure, (v) working standard conditions (10–25 MPa) that can easily be up scaled since these values are relatively low, and (vi) CO2 is gaseous at ambient conditions so it can be easily removed by depressurization, thus, leading directly to dry products.

The CO2 technology takes advantage of the compressed CO2 such as gas-like viscosity and null surface tension, converting this fluid in an ideal non-damaging solvent for nanostructures [39]. Moreover, a wide variety of amorphous polymer plasticizers swell in the presence of scCO2, becoming viscous liquids without the need of high temperatures [40].

Industrial applications of scCO2 have been principally developed for the extraction of some food components (e.g., decaffeinate coffee, spices) and active agents in nutraceuticals [41]. Nowadays, most of the challenges of introducing the scCO2 technology into pharmaceutical manufacturing have been overcome successfully and several scaled up plants are currently in operation. Besides, very important R&D investments on scCO2 technology are currently dedicated to applications in complex end products such as dds.

Several particle formation techniques using scCO2 have been proposed to prepare both pure and encapsulated drug forms at the micro and nano scale (Fig. 2). Particle generation may be accomplished by spraying processes based on scCO2, such as expansion (e.g. Rapid Expansion of Supercritical Solutions (RESS) and Particles from Gas Saturated Solutions (PGSS)), or dilution of liquids by dense gases (e.g. Gas AntiSolvent (GAS), Supercritical AntiSolvent (SAS), and Aerosol Solvent Extraction System (ASES)) [42].

The fundamental differences among the aforementioned supercritical techniques concern the role of scCO2 in the processes, either as a solvent, an antisolvent or a solute. In the case of the RESS technique, scCO2 is used as a solvent and the process works efficiently for compounds exhibiting significant solubility in the fluid (lipophilic compounds of relatively low molecular weight). The product is dissolved in a compressed fluid and rapidly depressurized through a nozzle resulting in the precipitation of small and monodispersed particles. Scale-up of RESS process is limited by the poor solubilities of many pharmaceuticals active compounds in scCO2. For drugs that are more CO2-phobic, polar co-solvents such as acetone or ethanol are used to increase the solubility.

In a second group of techniques, scCO2 has been used as an antisolvent to prepare dds. Several variations of the antisolvent technique have been described, including the original batch GAS and SAS processes, the semicontinuous PCA, and the ASES mode using a coaxial nozzle. All of them rely on reducing the density and solvating power of the organic solvent in which the drug is dissolved. The wide variety of antisolvent operational conditions provides higher flexibility in product processing by choosing the liquid solvent to dissolve the treated compound (from organics or organomethalics to polymers).

As a third possibility, in PGSS, scCO2 can be used as a solute dissolved in amorphous or semicrystalline high molecular weight materials (e.g., polymers and solid lipids or even some drugs). In PGSS, the pressurized gas diffuses into the product, lowering both its melting point and viscosity. This process produces particles by spraying the mixture via a nozzle. The process has been demonstrated on a large scale, but it is only applicable to produce micrometric particles.

A common feature in all these techniques is that the fluid is expanded through a restriction device or nozzle in a controlled fashion. The geometry of the nozzle influences the morphology of the particles precipitated. In RESS and PGSS processes, the nozzle controls the nucleation and crystal growth by affecting the dynamics of jet expansion and the Joule–Thompson temperature drop. In antisolvent processes such as GAS or SAS, the nozzle affects the particle size by controlling the initial liquid droplet diameter and the rate of solvent extraction by the supercritical fluid.

In addition to particle formation, scCO2 has been used to fabricate porous polymers that can be further impregnated using scCO2 to obtain a dds. After impregnation, the drug is often dispersed at a molecular level inside the polymer. scCO2 impregnation process is also applied to intrinsic porous materials, such as mesoporous silica (Table 1). For instance, aerogel nanoparticles can only be produced and impregnated using scf technology. Coating or encapsulation with a thin layer of polymer using scCO2 processes are powerful alternatives over the conventional chemical coating. Complex pharmaceuticals have also been precipitated in scCO2/water emulsions.

Section snippets

Characterization of drug release systems

Table 2 shows a list of dds nanopharmaceuticals that have been prepared according to green manufacturing strategies described above. The principal analytical techniques that have been applied to their physicochemical, morphological and textural characterization as well as the most relevant features concerning size distribution, drug loading and release are given as well.

The thorough evaluation of dds still represents a considerable analytical challenge [88]. Two key queries need to be answered:

Conclusions

The impact of nanostructured drug delivery systems in the pharmaceutical field is greatly increasing. Among the diverse approaches for manufacturing nanopharmaceuticals, those based on green technologies are gaining marked share rapidly. Pharmaceuticals for sustained or controlled drug delivery based on nanostructured matrices consist of sophisticated products from the point of view of design, preparation, composition and performance. Nanometric carriers play an important role on the features

Concepción Domingo is in charge of the Supercritical Fluids team integrated in the Solid State Chemistry Department of the Materials Science Institute of Barcelona (CSIC, Spain). The main activity research of the team is focused on the synthesis, characterization and design of new micro and nanometric particulate systems and in the preparation of functional porous composites. The team works principally developing supercritical fluid methods as chemical mass-production bottom-up routes. Dr.

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    Concepción Domingo is in charge of the Supercritical Fluids team integrated in the Solid State Chemistry Department of the Materials Science Institute of Barcelona (CSIC, Spain). The main activity research of the team is focused on the synthesis, characterization and design of new micro and nanometric particulate systems and in the preparation of functional porous composites. The team works principally developing supercritical fluid methods as chemical mass-production bottom-up routes. Dr. Domingo has published more than 80 SCI research articles and has lead and participates on a large number of National and European projects involving Research Projects such as SurfaceT or Networks of Excellence like Expertissues. The research team is included in the Line “Biomaterials and materials for drug delivery, therapy, diagnostics and sensing” of the Strategic Plan of the ICMAB (CSIC) 2010–2013.

    Javier Saurina is associate professor of Analytical Chemistry at the University of Barcelona. He obtained his degree in Chemistry in 1988, degree in Pharmacy in 1996, M.Sci. in Chemistry in 1990 and Ph.D. in Chemistry in 1997. His research is focused on the development of methods for clinical, pharmaceutical and food analysis based on capillary electrophoresis, liquid chromatography, flow injection analysis, sensors and biosensors. Another topic of interest deals with the application of chemometrics to both optimization of analytical methods and data analysis in the aforementioned studies. He has published more than 100 papers in scientific journals and has presented numerous communications to international congresses.

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