Supercritical adsorption coupled with the high adsorption capacity of silica aerogel allows the preparation of a new kind of delivery systems of poor water soluble drugs. In order to overcome drawbacks of conventional techniques where the use of liquid solvents can cause the fracture of aerogel porous structure, in this work a new adsorption process of drugs from a supercritical mixture is proposed. Adsorption takes place from a fluid solution of the drug in supercritical CO2 and ethanol as cosolvent. A fixed bed adsorption plant has been developed to allow fast mixing of fluid phase and effective contact in the adsorption column. The use of ethanol as cosolvent allows to overcome the limitation of supercritical adsorption due to low solubility of many drugs in supercritical CO2. Adsorption isotherms were measured for one-model substance, nimesulide, at 40°C, and breakthrough curve was experimentally obtained. The drug loading of the drug into silica aerogel was up to 9 wt%. The drug composite was characterized using scanning electron microscopy, and release kinetics of the adsorbed drug were also evaluated by in vitro dissolution tests. The dissolution of nimesulide from loaded aerogel is much faster than dissolution of crystalline nimesulide. Around 80% of nimesulide dissolves from the aerogel within 6 minutes, whereas dissolving 80% of the crystalline drug takes about 90 min.
The poor water solubility of some drugs limited their bioavailability. A fast dissolving system can be defined as a dosage form for oral administration, which, when placed in mouth, rapidly dispersed or dissolved increasing compliance and efficacy of the therapy. Fast dissolving and fast dispersing drug delivery system may offer a solution to these problems. A possible approach for ensuring maximum bioavailability is the increase of drug dissolution rate and/or solubility. To improve the dissolution rate of drugs, different techniques have been developed [
Low viscosity and high diffusivity of SC-CO2 allow a rapid equilibration and micropore penetration of the fluid phase within the matrix. SCFs also have zero surface tension that not only facilitates the rapid permeation and diffusion into porous substrates, but also avoids the pore collapse of SA that occurs using organic liquids, due to capillary stresses caused by the liquid-vapour menisci within pores.
Until now, SC adsorption within SA has been studied using simple batch vessels in which SA and active molecules are loaded and equilibrated until equilibrium is reached [
In this work, the adsorption of a model drug on SA was studied using a new experimental apparatus properly designed for this purpose. The best way to deal with SC-fluid mixture is to use a continuous process in which the fluid phase is continuously pumped in an adsorption column containing the SA matrix. Because, a fundamental stage of the process is the formation of the ternary mixture SC-CO2/organic solvent/active compound, a mixing stage has been provided that allows a fast and effective solubilization of the components.
The new experimental plant has been tested with nimesulide as active compound and ethanol as solvent. Nimesulide has been chosen for comparison purposes because in a previous study [
Hydrophilic silica aerogel (SA) in form of monolithic blocks was purchased from Merketech Int. (USA). The nominal density is 0.1 g/cm3 the surface area is 800 m2/g, and the mean pore size is about 20 nm. Deposition experiments were performed using cubic blocks of 1 cm obtained by cutting SA monoliths with a knife. Nimesulide (purity 98%) was purchased from Sigma-Aldrich Italy. CO2 research grade 4.8 was purchased from SON (Italy). All products were used as received.
Samples of the loaded SA were observed by Field Emission Scanning Electron Microscopy (FE-SEM) (LEO 420, USA) operating at 5 kV. Crushed fragments of the sample were dispersed on a carbon tab previously stuck to an aluminium stub and coated with gold palladium (layer thickness 250 Å) using a sputter coater (mod. 108A; Agar Scientific, UK). Several FE-SEM images from different parts of the sample were taken for each run to verify the powder uniformity.
Drug dissolution profiles were obtained with a United States Pharmacopeial Convention (USP) apparatus 2, consisting of Varian 7025 paddle dissolution tester (Varian, Agilent Technologies Italia s.p.a, Italy). All studies were run according to the USP 25 paddle method: 150 rpm, 900 mL of dissolution medium,
The laboratory plant is described in Figure
Continuous plant for the adsorption of drugs from supercritical carbon dioxide solutions. P-1, P-2: pumps; C: cooling bath;
The mixer is a stainless steel autoclave (NWA GmbH, Germany) having an internal volume of 100 mL, closed on the bottom and on the top with two finger tight clamps. The top cap holds three 1/8 inch ports. Mixing is provided by an impeller mounted on the top cap and driven by a variable velocity electric motor. The autoclave is heated by thin band heaters (H) (Watlow, USA mod.
The adsorption column is a 316 SS cylindrical vessel with an internal volume of 50 cm3. It is packed with a silica aerogel bed. The pressure inside the column is maintained by a micrometric valve MV2 heated by electric heaters to avoid clocking during CO2 expansion. From the exit of the column the gaseous flow of CO2 and solvent is sent to a gravimetric gas/liquid separator, that is a Pyrex element properly designed for the separation of the solvent from the gas stream. At the inlet port of the separator an impact surface is provided to improve separation. The liquid is collected at the bottom of the cylinder where a probe connected to an UV spectrophotometer allows the continuous measurement of the liquid composition. The separator has been designed to condense ethanol. At the exit of the separator a rotameter (FE) is used to measure CO2 flow rate.
The design of the separator has been based on the method proposed by Treybal [
Supercritical adsorption has been carried out in a continuous mode until saturation of the SA bed is reached. SC-CO2 and a liquid solution (ethanol + nimesulide) after mixing are continuously delivered to the high pressure adsorption column.
Because the phase behavior of the ternary system CO2/EtOH/Nime is not available, our analysis starts from the binary system CO2/EtOH. The miscibility curve of the binary system CO2/EtOH is shown in Liparoti et al. [
At this condition of temperature and pressure the effect of the weight ratio CO2/EtOH
Adsorption data of nimesulide on silica aerogel at different values of the CO2/EtOH weight ratio (
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|
|
Loading, % | Time | Eff, % |
---|---|---|---|---|---|
7.2 | 0.88 | 0.000047 | 0.48 | 94 | 92.6 |
3.4 | 0.78 | 0.000856 | 1.0 | 75 | 93.3 |
1.5 | 0.61 | 0.0015 | 2.8 | 50 | 96.1 |
0.9 | 0.48 | 0.00197 | 5.4 | 60 | 92.3 |
0.6 | 0.38 | 0.00245 | 8.9 | 37 | 94.8 |
The variation of nimesulide loading on SA with respect to the concentration of nimesulide in the fluid solution is reported in Figure
Adsorption isotherm for nimesulide on silica aerogel at 40°C/10 MPa.
As expected, the loading of nimesulide on SA increases with increasing concentration of nimesulide in the fluid phase. The maximum loading obtained is 8.85 wt%, corresponding to 227.7 mg of nimesulide adsorbed in the bed. Brunauer et al. [
These data must be compared with the loading of nimesulide on SA reported by Caputo et al. [
From Table
The most important criterion in the design of fixed-bed adsorption systems is the prediction of column breakthrough curve which determines the operating life of the bed and regeneration time. When the fluid phase starts flowing in to the bed, the top of the adsorbent in contact with the gas stream quickly adsorbs the solute during first contact. The gas stream leaving the bed is practically free from the solute. As the volume of fluid getting from the bed increases, an adsorption zone of mass transfer gets defined. In this zone, adsorption is complete and it moves downwards through the bed in relation to time until the breakthrough occurs. When this zone reaches the end of the bed, the solute cannot be adsorbed any longer. This moment is called “breakpoint”. The plot obtained after this point gives the concentration history and is called breakthrough curve. When the mass transfer zone leaves the bed, the bed is completely saturated, adsorption does not occur, and the outlet stream has the same concentration as one enters.
The breakthrough curve for the adsorption of nimesulide on SA at 40°C and 10 MPa is shown in Figure
Breakthrough curve for adsorption of nimesulide on silica aerogel bed from a stream of CO2 and ethanol at 40°C, flow rate = 6.89 mL/min,
The starting point of the curve is shifted of 15 min. This time corresponds to the dead time of the process due to residence time of the fluid phase in the mixer. After 35 min the concentration of nimesulide in the effluent stream starts to increase significantly (0.114 mg/mL). This point, corresponding to 10% of inlet concentration, can be assumed as breakpoint. Indeed, after this time the concentration increased sharply and reached a value of 50% of the inlet concentration after only 3 minutes. 38 min represents the apparent half-time of the bed. Taking into account the dead time of the plant, the real half-time is 23 minutes.
In the transition regime all the solute fed to the column is used to saturate the bed. So the mass balance can be written as
The mass balance is thus
The efficiency of the adsorption is one of the main parameters of the process. It is an expression of the quantity of drug adsorbed with respect to the drug fed to the column:
Silica aerogel samples were analyzed by FE-SEM to observe the morphology of the material before and after loading. FE-SEM images taken at the same magnification (60 K magnification) for samples obtained at 1, 5.4, and 8.9 wt% are reported in Figure
FE-SEM photographs of (a) not treated SA and SA samples loaded with different amount of nimesulide: (b) 1.0 wt%, (c) 5.4 wt%, (d) 8.9 wt%.
FE-SEM images reveal that all samples have the same morphology and no nimesulide crystals were formed on the SA surface also at the higher loading. The presence of nimesulide within SA matrix is clearly revealed by Energy Dispersive X-ray spectroscopy (EDX) spectrum. In Figure
EDX spectrum of nimesulide/silica aerogel.
We studied also the dissolution rate of the drug in vitro. Solution of phosphate buffer at pH = 7.4 was chosen as dissolution medium following the recommendation of US Pharmacopeia. The dissolution profile of the drug from the powdered loaded aerogel was compared with that of the pure crystalline drug. Release kinetics are shown in Figure
Release kinetics of nimesulide in buffer phosphate at
In this study, it was demonstrated that the supercritical fluid adsorption is an effective way to incorporate low water soluble drugs into a microporous silica aerogel.
The use of a fixed bed adsorption column fed with a supercritical CO2 solution with ethanol cosolvent allows to obtain a pure drug delivery system at high drug content. Indeed, it was possible to prepare SA samples containing up to 9 wt% of nimesulide. Moreover, the process is highly efficient in terms of quantity of drug adsorbed with respect to the drug fed to the column (>94%). With respect to conventional techniques that use liquid as eluent, SC-CO2 offer the advantage to preserve the 3D porous structure of the aerogel. Indeed, low viscosity and high diffusivity of SC-CO2 (or SC-mixtures) coupled with zero surface tension allow the rapid permeation and diffusion into aerogel micropores but also avoid the pore collapse of SA that occurs using organic liquids, due to capillary stresses caused by the liquid-vapour menisci within pores.
The SA/nimesulide composite has an enhanced dissolution rate that can be explained by both the increase in the specific surface area of the adsorbed drug and its noncrystalline structure in the formulation.
One limitation of the proposed process is related to the high cost associated with high-pressure plant when compared to wet processes at atmospheric pressure. However, results encourage the development of industrial application of the proposed process.