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The aim of the study carried out is to determine and find out how mesoporous silica technology is useful in drug delivery system. Different batches of hollow mesoporous silica are compared in terms of how much drug is absorbed and their amount of drug released is also evaluated. Relation between the drug absorption and release with the surface area of silica and pore size is also discussed.
Silicon dioxide is one of the most profuse chemical compounds on earth. It makes up about 60 percent of the weight of the earth's crust either as an autonomous compound or in amalgamation with metallic oxides that form silicates. Silicates are inorganic compounds whose negative part is he-Sio3 (grouping of atoms). An example is magnesium silicate, mgSio3. Silicon is a non-metal element denoted by the atomic symbol, Si. Atomic number of silicon is 14 and the average atomic weight of its isotopes is 28.0855. It makes twenty-seven percent of the earth's crust, is the second most abundant element; oxygen is the first at forty-seven and aluminum is third at thirteen percent. Although silicon can come together with sixty-four other stable chemical compounds and many additional unstable elements; oxygen is its most frequent partner. Now on it is believed that thousands of compounds which comprise both elements make up nearly ninety-seven percent of earth's crust1. Silicon (Si, element 14) is a non metallic chemical composite found in group four, the carbon family, on the periodic table. Swedish chemist Jons Jacob Berzelius2 first isolated and described the element in 1824. Silicon has an atomic weight of 28.086, melting point of 2,570o F and a boiling point of 4,270o F. There are only three stable isotopes of silicon are known to exist: silicon-28, silicon-29 and silicon -30. Silicon dioxide is produced when silicon reacts with oxygen or it is exposed to open air. A very thin called native-oxide (approximately 1 nm or less) is formed on the surface when it reacts with oxygen in open air under ambient stipulation. By altering the temperature and environment conditions a well controlled layer of silicon dioxide can be produced on the surface of the silicon. In nature silicon dioxide is found with paired with another substance. By combining with oxygen it usually forms quartz and sand which are normally used in production of the glass, pottery, china and other ceramics. Silicon dioxide has covalent bonding and forms a network structure which allows it to react with many other chemical substances. Scientists create pure silicon by heating it to remove the oxygen from the element. Pure silicon is appeared in dark gray colour and has a similar crystalline structure like diamond. The crystalline silica is very popular due to its remarkable insulating and semiconducting properties. A pure silicon crystal contains millions of atoms accompanied by loosely attached electrons that break free upon the introduction of energy, such as light or heat. In the modern world silicon is not only the backbone of the electronic industries; modified silica is playing a very important role in the drug delivery system. A chain of alternating silicon and oxygen atoms, are chemically inert and stable in the presence of heat. Silicone gels have long been used implants in the human body system2. Silicon dioxide occurs as a colourless, odourless, tasteless white or colourless crystals or powder. The most common form of silica is amorphous, crystalline or vitreous. In crystalline form of silicon dioxide, all of the atoms of the silica are arranged in orderly patterns and this form is more stable than the amorphous forms. This form of silica is actively used in the research institutions to carry out the chemical interaction with other chemical substance.
Figure 1: Silica covalent bonding with oxygen.
Although the chemical formulate of the carbon dioxide Co2 and the silicon dioxide Sio2 is almost same; their appearance at room temperature is not same, carbon dioxide is gas at room temperature but silicon dioxide is solid. Carbon dioxide is capable of forming pp-pp bond with oxygen atoms because of its small size (77pm). Due to this reason carbon dioxide is linear and also non- polar. On the other hand, silicon dioxide cannot form pp-pp bond with oxygen atom due to its large size (117 pm). However silicon dioxide has a unique three dimensional network structures in which each silicon atom is bonded to four oxygen atoms, which are normally remains in tetrahedrally arranged. Each one oxygen atom is being communal by two silicon atoms. Since Si-O bonds linger very strong (368 KJ mol-1), therefore, silica is chemically inert and has a very strong melting point. Pure silica is colourless but silica found in sand is normally brownish or yellowish due to presence of impurities of ferric oxide. Crystalline silica was not produced until 18543. In amorphous silicon dioxide the atoms of the silicon and oxygen are arranged in randomly, without giving any clear-cut pattern. This form of silica is less stable than the crystalline silica due to its high energy state. The reaction patterns of the amorphous silica with other chemical components are not clear and stable. In some cases they intend to transform in more stable crystalline form.
network structure of amorphous silicon dioxide
Figure 2: The continuous random network structure of silicon dioxide. Here each silicon atom has 4 bonds and each oxygen atom has two bonds. (Gold sphere-Si atom, Red sphere- Oxygen atom)
The structure of the amorphous silica can be best described as continuous random network: each atom of the amorphous solid has the same number of covalent bonds as in their crystalline form. In general the amorphous nature of the silica is characterized by the covalent bonds of the atoms. In the diagram (fig-2) the bonding between the atoms are showed4. Vitreous silicon dioxide is the glassy appearance of the compound which may be transparent, translucent or opaque. One form of the silicon dioxide can be converted to another form by changing the temperature and pressure.
An especially interesting form of silicon dioxide is silica gel, which is a powder form of amorphous silica that is highly adsorbent. An adsorbent material is capable of removing other materials, such as water, ammonia, alcohol or other gases, out of the air. Silica gel can absorb 30 to 50 percent of moisture of its own weight from the surrounding atmosphere. Even after adsorbing such percentage of moisture it still feels like dry5.
1.3 Key Particulars:
Other's given name of silicon dioxide: silica, quartz, sand, amorphous silica gel and others.
Common formula: Sio2.
Elements: Silicon, Oxygen
Compound category: Non-metallic oxide; also known as inorganic material.
State: Solid at room temperature. Glass transition takes place upon changing the temperature.
Molecular weight: 60.08 g/mol
Melting point: usually above 1700 c
Boiling point: 2950o c6
Solubility: Solubility depends on crystalline state; generally it is soluble in many acids and alkalis but not dissolved in water. Different phases of silicon dioxide exhibits different solubility patterns. By far the most common crystalline form is quartz. This form of silica can be classified into following classes: (1) Anhydrous crystalline SiO2, (2) Hydrated crystalline Sio2. H2o, (3) Anhydrous amorphous silica, (4) Anhydrous and hydrous amorphous silica and (5) Massive dense amorphous silica glass. Particle size of the silica plays a very important role in solubility. Some impurities such as aluminium in minute amounts not only reduce the solubility of the silica but also modify the surfaces of the silica. Organic compounds also play a vital role in the solubility. They might accelerate the solubility or retard the solubility of the silica material. In some experiments finely divided silica materials dissolves more rapidly. The main fields of using soluble silica materials are given below: Cleaners and detergents that are made by controlling alkalinity are generally made from soluble silicates, adhesive, binder and deflocculated application of the soluble silica is also well known, for the production of precipitated silicas, sodium silica is used7.
Particle size of silica plays a very significant role in the dissolution pattern. It is presume that the rate of dissolution of colloidal silica particles would be proportional to the specific surface area. Thus the importance of surface area of the particles of silica becomes very important to achieve batter dissolution pattern. Some cases it is showed that uniform particle size also make batter dissolution character. Factors that influence the rate of dissolution per unit of surface area include the following: Degree of porosity of the internal molecules or internal hydration in the form of uncondensed silicon groups, Quantity of impurities in the final bulk volume, Particle size, since the solubility of the silica particles increases with decreasing size. It is preferred that the particle size with less than 5 nm give batter dissolution patterns, In the non-uniform particles; smaller ones dissolve more rapidly, In some experiments it was found that silica particles of different batches if used at once, showed poor dissolution profile8.
Mechanism of Interparticle Bonding in Silica: The mechanism of interparticle bonding is not fully understood. In general when particles in a molecule collide it is assumed that adhesion can occur but in case of silica particles there is no reason to believe that the acquaintance is due to the Si-O-Si bonds. One of the reasons for thinking is that the factors which promote polymerization of the silica molecules also play a role in the conversion of Sol of colloidal silica particles to gel. Mostly the particles are link together into chains forming a network like structure. Sometime it was argued that silica particles are made up of fibrous structure. However all the arguments are true at certain conditions and temperature9.
Aggregation of Silica Particles: The word 'aggregation' for all the ways in which the colloidal particles are link together forming a network like structure. Aggregation includes the following: Gelling-particles are linked together in branched chains. The particle forms a network like structure and retains the liquid by capillary action, Coagulation- where the particles come together into relatively close packed clusters. In this case the silica is more concentrated. Flocculation- here the particles are linked together by bridges of the flocculating agent. These differences of silica particle aggregation are noted only in the dilute preparations, Coacervation- the last type of silica particle aggregation, in which the silica particles are surrounded by an adsorbed layer of materials which makes the particles less hydrophilic10.
1.4 Development of Silica Particles less than 10 nm in size:
In the early years of industrial production of silica molecules the particle size of the silica were made larger than 8 nm so that it could be concentrated to at least 30% Sio2 for economical shipment. Such particle size is extremely stable at high temperature. Then it was realized that smaller particle size of the silica are necessary for some uses e.g. drug delivery and sols at lower silica concentrations were made. But problem arises for particles smaller than 5 nm like spontaneous growth of particles upon storage at different conditions and temperature. This problem of the small particle size of the silica also changes the physical properties of the lead sample. To solve the problems scientists used many different and validated methods. In some experiments using of stabilizer like ammonia minimizes the particle growth11. The primary particles of colloidal silica are usually non-porous if forms or growth in alkaline solution and in particular if formed at elevated temperature. Silica sols can be made with discrete particles having pores. They are formed ordinary at normal temperature in water by the uniform aggregation of much smaller particles, less than 5 nm in size. Scientists also made porous silica particles larger than 100 nm in diameter which was highly porous. By altering the temperature and conditions during the chemical reaction, the porosity of the inner and outer regions of the particles could be tainted and the size could be made from the range from 100 to 500 nm. Spherical particles of very uniform diameter can also be made. In some cases micro porosity of the silica particles were also characterized with low angle X-ray diffraction. An exceptional experiment by Ogino and Kuronuma in addition introduces spindle shaped silica particles. It was the first time that the discrete silica particles of colloidal size have been synthesized with a shape rather than spherical. It was due to the addition of hydrogen ion exchange resin slowly to a dilute solution of sodium silicate at 40o c until the pH go down at 3, then adding ammonia to increase the pH to 8-9 and heating 1 hour at 80o c12. Measurement of porosity of silica particles is only possible with aggregates that are mechanically strong enough not to be affected by the method of test. In some cases, during characterizing pore of silica particles the network structure of the silica collapse. The following structural variables characterize pores: Specific surface area (m2 g-1)-this include the total surface of the silica particles. But this theory is not applicable for extremely small aggregates that are submicron in size, Explicit pore volume (VP, ml g-1)-is the total volume of the pores per gram of solid, Average pore diameter, Pore size distribution in terms of a allocation purpose, Degree to which entrance to larger pores are constrained by the smaller pores. These constraints are consequent from one or more types of experimental data. The most common techniques used to characterize pores of silica particles are: Gas or vapour adsorption isotherms, Low angle X-ray scattering, Electron microscopy etc13.
1.5 Concept of Modified Surfaces:
After the preparation of silica particles, the surface area of the silica particles can also be modified by the attachment of different atoms or groups to modify physical behaviour as well chemical characters. Sometime the whole silica sphere is covered with chemical layers to attain required characteristics. Modified surfaces are made according to the desire behaviour required from the preparation at specified condition and temperature. Now a day's modified silica surface are extensively used in the pharmaceutical industry for the preparation of sustain release dosage form and cancer treatment. Apart from the health sector modified silica particles also have a momentous role in the glass and plastic industries.
A very effective summary of silica surface was described by Hockey in 1965. The concept of attaching organic groups to the surface of the silica came through him. He successfully modified silica surfaces with different organic compounds.
The silica surface of the silica particles limits their dispersion in organic liquids to lower alcohols, amides and ketons. There are various ways of attaching organic groups to the surface of the silica particles. They include the followings: Through organic ions, Through Si-O-C linkages and silicic esters, Silicon carbon bonds as organosilicon groups14.
The chemistry of silica surfaces is very interesting. But the nature of silica surface is not totally discovered. However the silica surfaces are classified in the following classes:
Hydroxylated surface-the surface structure terminates in silicon groups. This type is readily wettable by water and water soluble organic molecules, Siloxane surface-consist mainly of oxygen atoms and each oxygen atoms are bonded to adjacent silicon atoms. Sometimes a low fraction of isolated or paired Si- OH groups is also present, Organic surface- these types of silica surfaces are formed by chemical or physical attachment of organic molecules or radicals15.
1.6 Mesoporous Silica:
Mesoporous materials are those that contain pores and diameter range between 2-50 nm. Porous materials can be classify according to their size, micro porous materials pore diameter less than 2nm and macro porous materials pore diameter more than 50nm and mesoporous materials diameter between 2 and 50 nm. Researches in 1990 were first synthesized mesoporous silica nanoparticles in Japan and named Mobil Crystalline of Materials (MCM-41). After six year University of California in Santa Barbara researchers announced that silica nanoparticles with much larger 4.6 to 30 nanometre pore. The material was named Santa Barbara Amorphous type material (SBA-15). Now a day their application is most common in medicine, biofuels, and imaging. This mesoporous materials include silica (silicon dioxide, also known as silica originate from the Latin ward silex, is an oxide of silicon with a chemical formula of SiO2) and alumina. The mesoporous silica is form silica and it is synthesized as nano compound. The most common mesoporous silica nanoparticles are MCM-41, SBA-15, MSU-, KSW-and FSM. SAB-15 inhibits cellular respiration at 25-500 microg/mL. MCM-41 had no effect on respiration rate but both nanoparticles inhibited respiration of isolated mitochondria and sub mitochondrial particles16, 17. Using surfactants as the structural directing agent's mesoporous silica can be synthesize with remarkable progress. This mesoporous silica can use as a template for the synthesis of other new mesoporous material like carbon and metals. Apart from using surfactant other methods are also used to prepare mesoporous silica. Mesoporous silica nanoparticles can also be synthesized by reacting between reacting tetraethyl orthosilicate with template of micellar rod. Then collect nano-sized spheres or rods that fill with regular pores. Solvent with proper pH can be use for remove template18. Mobile oil corporation researchers in the early 1900's synthesize mesoporous silicate by using surfactant as template. The lyotropic liquid crystalline phase of surfactants can be use as templates for synthesis of mesoporous nanostructure materials. Mesoporous material can be obtained as fine powders biphasic nature in reaction medium. Low concentration surfactant can be use to process fibers and supported thin films. But in 1995 monophasic lytropic liquid crystalline phase use as templates for synthesis of silica and metallosilicates from sol-gel precursors like TMOS(tetramethyl orthosilicate). Surfactant concentration more than 30wt% in water is use to achieve direct template19.
1.7 Silica Nano-technology in Drug Delivery:
Chemotherapy which is used for cancer as cytotoxic drug, have adverse side effects and have limited effectiveness. But now many studies showed that these problems could be attributed to the lack of target specificity of the current state-of-the-art antitumor drugs. To overcome this problem a widely pursuit strategy is to design a target specific drug delivery system that reach the targeted cells and tissue at effective dose of drug. Hinges have ability to construct a biocompatible carrier that allows loading drug molecule without premature release of the cargo. Several perquisites need to be incorporated into such a material in order to serve as an efficient drug delivery system: Drug molecule should be high loading or encapsulation capacity, the carrier material should be biocompatible, no leaking of drug molecules (zero premature release), cell type or tissue specificity and site directing ability.
To achieve an effective local concentration, control release of drug molecules with proper rate of release required. It seems to be impossible to find a material that could have high affinity for absorbing certain drug molecules, several biodegradable materials like polymeric nanoparticles dendrimers and liposome can be use as "smart" drug delivery systems. In aqueous solution they control release of pharmaceutical drugs up to the structural degradation of the carrier triggered by various chemical factors like pH, under physiological conditions.
Sometime matrix-entrapped drug molecule can leak out the biodegradable carrier when system introduced into water. This premature release problem not only limits the usage of these biodegradable drug delivery system materials for effective disease treatment, but also presents a major challenge for the site-selective delivery of protein and nucleotide-based drugs via oral administration. If the carriers have not enough protection pharmaceutical enzymes, DNA, RNA would decompose in highly acidic environment in stomach. Many structurally stable drugs have been investigated for drug delivery, silica materials with defined structures and surface properties are known to be biocompatible and silica use in inorganic nanoparticles. For example, silica coated semiconductor quantum dots, such as cadmium sulfide and selenide, have been demonstrated to possess high stability, chemical versatility, and biocompatibility that are crucial for many biomedical application. For osteogenic properties silica employed in the formulation of artificial implants. For controlled release applications, it has been shown that silica is able to store and gradually release therapeutically relevant drugs like antibiotics. Silica also uses to enhance the biocompatibility of several drug delivery systems, such as magnetic nanoparticles, biopolymers, and micelles20.
For example; MCM-41 mesoporous silica synthesis use as control release delivery system that is stimuli-responsive and chemically inert to the matrix entrapped compounds. This system consists of 2-(propyldisulfanyl) ethylamine functionalized mesoporous silica nano-sphere with particle size of 200.0 nm and an average pore diameter of 2.3 nm. MCM-41 type mesoporous silica synthesizes and characterized by using surface-derivatized cadmium sulfide (CdS) nano-crystals. This MSN system biocompatibility and delivery efficiency with neuroglial cells (astrocytes) in vitro was demonstrated. Compare to other delivery system the molecules of interest were encapsulated inside the porous framework of the MSN not by adsorption or sol-gel types of entrapment but by capping the openings of the mesoporous channels with size-defined CdS nanoparticles to physically block the drugs/neurotransmitters of certain sizes from leaching out. MSN system plays an important role in developing new generations of site-selective, controlled-release delivery nano-devices21.
MSNs and the CdS disulfide linkages are chemically liable in nature and can be cleaved with various disulfide-reducing agents, like dithiothreitol (DTT) and mercaptoethanol (ME). By introducing various amounts of release triggers the release of the CdS nanoparticles caps from the drug/neurotransmitter-loaded MSNs can be regulated22.
1.8 Recent Advancement:
In drug delivery systems new applications of mesoporous silica have been explored for the batter control of drug storage and release due to their high surface area, well defined pore structures and tenable pore surface23. Most of the times amorphous mesoporous silica materials have been focused as a drug carrier since it is non-toxic, highly bio-compatible, adjustable pore diameter, low cost and the wall of the pores containing free silicon group with abundant Si-OH bonds which can take part in the reactions with appropriate drug functional groups23, 24. These materials acquire modifiable and uniformed pore sizes in the range of 1.5 to 10 nm25. The potential applications of mesoporous silica in catalysis, separation, sensing and optical active materials make them very attractive and batter choice for drug carrier in the last decade. Recent there has been increased interest in hollow mesoporous silica materials for utilization as drug carrier in the field of controlled drug release, to meet the need for prolonged and batter formulation of drug administration. Many research scientists have investigated the drug storage and releasing properties of mesoporous silica materials. The obtained results have indicated that the appropriate pore size and pore volume of hollow mesoporous silica spheres make them batter and ensured supports for the hosting and moreover releasing a large variety of drug molecules having specific therapeutic activity in the required area of the biological system. Investigations was also been done for the conventional silica materials which also lead some good results of storage and releasing drug molecules. However the drug carrier property of conventional silica materials was not been relatively high. They also showed some irregular bulk morphology which makes difficult for the scientist to design required drug delivery system. That's why researchers worked to design a system which will recover these disadvantages. One effective strategy is synthesizing hollow mesoporous silica spheres with penetrating pore channels. Some of the research groups found that hollow mesoporous silica spheres are ideal carrier for drug storage and release24. Research on hollow mesoporous silica materials has demonstrated that drug storage and release with hollow mesoporous silica is a good technology for controlled drug delivery system. Controlled release technology has become very important and effective in modern medication and pharmaceuticals. Controlled release formulation has many advantages over the conventional form of dosage forms: appropriately maintaining patient's blood level for the required set of time, minimizing deleterious side effects, prolonging effectiveness, making a rapid increase of bioavailability at short intervals, protecting sensitive drug from the enzymatic and acidic degradation in the gastrointestinal tract and most importantly improving patient's compliance. It has been investigated that quite a few factors may convey enormous influence on the drug release profiles from hollow mesoporous silica carriers. One of the most significant aspects is the pore size of the mesoporous silica, or steric hindrance. It is by and large accepted that kinetics of the drug molecules is pronouncedly influenced by the pore size of the mesoporous silica. Some researchers reported that drug delivery rate gradually decreases with the reduction of the pore size. The second key feature is the interaction between the mesoporous silica molecules and the drug to be stored, usually known as host-guest interaction. Here the property of the mesoporous silica spheres and the drug plays a vital role for a stable drug storage system. Munoz et al. originate that drug release from the host can be slow down because of the higher affinity between the drug and the mesoporous silica. The third feature is the aperture geometry of the mesoporous silica. It is establish that smaller pore openings of mesoporous silica with one-dimensional (1D) or three-dimensional (3D) " cage-like" pore structure is of great benefit to slow down the drug release rate26. Different morphologies for mesoporous silica can be achieved by using templating method or by the phase transformation approach. This usually involves the size and shape of the mesoporous silica in the micron scale. It gives the scope for the mesoporous silica to show rich morphological behaviour. The main reasons for showing such performance are: Silicate ions indicate as a counter ions forming soft hexagonal liquid crystalline phase, An affluent arrangement of the surfactant system can be rationalized to form various types of mesoporous structures, By changing the composition of the reaction system or the conditions the morphology of the mesoporous structure also change, The rate of the silica condensation reaction is also controllable at the later stage of the reaction, Self organization and the Siloxane bond formation progression can also independently control. In the end, the pH of the dissolution media could affect the drug delivery profiles as well25. .
Ibuprofen is one of the eminent non-steroidal anti-inflammatory drugs which is frequently using for the treatment of inflammation, analgesic or rheumatism and this drug furthermore contains one carboxylic acid group that makes the strong bonding with many functional groups via acid-base reaction23, 24. This drug has a short biological half-life which makes the drug strongest contestant for the sustained or controlled release drug delivery system. Therefore, preference was given to ibuprofen as a model drug for the sustained/controlled release system26. It also shows good pharmacological activity and the appropriate particle size (1.0 x 0.6 nm) of the drug ensures its straightforward diffusion into or out of the mesoporous channels of as prepared hollow mesoporous silica spheres. Although study with some other drugs like- vancomycin, gentamycin, cisplatin, aspirin, captopril and naproxen was done for batter drug storage and releasing property by other research groups27. Ibuprofen works by reducing hormones which cause inflammation and pain. Ibuprofen can increase heart circulation problems. Long time use of ibuprofen increases the risk of heart attack. Apart from heart problems it also causes some problems like bleeding or perforation in the stomach and intestine. Mostly ibuprofen is available as tablet to take by mouth. It is mostly taken three or four times a day. Other dosage forms are also available like chewable tablet, suspension and drops. Ibuprofen may be taken with food or milk to prevent stomach upset28.
In this research four different batches of mesoporous silica were prepared using non-ionic surfactant and one different batch using ammonia group. However, the batches in addition with adaptation with functional groups were characterized by X-ray diffraction (XRD), High-pressure Liquid Chromatography (HPLC), Gemini-Surface area Analyzer, UV Spectroscopy, Mastersizer-particle size analyzer and Scanning electron microscopy (SEM). All the batches of prepared hollow silica materials were also characterize in terms of how much ibuprofen drug loaded into the samples and their release pattern in vitro.