Transdermal Drug Delivery Advantages Versus Limitations Biology Essay

Published: Last Edited:

This essay has been submitted by a student. This is not an example of the work written by our professional essay writers.

The pharmaceutical industry has evolved with respect to healthcare to patients according to the needs of the respective generations. Up to a certain extent, it has fulfilled the ever-rising demands but predominantly the pace of the research and the implementations have not been up to the mark.

Probably the reason why certain high profile diseases like cancer, HIV, hormonal imbalances, neurological disorders, cognitive failures, etc, constantly require innovations at various levels.

Now, one of the major aspects in the drug to disorder relationship is the pharmacokinetics; which is a direct correlation of the dose to its pharmacological effect on the intended organ of the body. Therefore, the focus of this particular project has been on the Drug Delivery Dynamics.

The project concerned here, revolves mainly around the determination of the concentrations of acetylsalicylic acid (ASPIRIN) upon its intercalation with a clay material.

The elaboration on clays has been explained in the subsequent portions; however, the main focus here is behind the application of the intercalation technique on aspirin.

Brief introduction to Aspirin:

Aspirin (along with other Non-Steroidal Antiinflammatory Drugs (NSAIDs)) is basically an acetylsalicylic acid by molecular structure, is one of the most important medicines in the world for more than a century now. In fact, it is the most sold medicine ever in the history of healthcare. And therefore, any level of research on any aspect of aspirin therapy is going to create a very significant impact on the healthcare industry and healthcare services in general.

The ability of these agents to subside mild to moderate pain as well as inflammation has made it a household product. On the other hand, aspirin, which comes under the traditional NSAIDs does have its side effects, which mainly include GASTROINTESTINAL IRRITATION to the allergic patients.

As a first line of solutions to this problem, NSAIDs with lesser side effects were devised after the isoforms of cyclooxygenases (COX) (COX-1 and COX-2) were discovered. The COX-2 inhibitors were found to be equally efficient in therapeutic activity and yet showed lesser side effects.

However, the COX-2 inhibitors have recently been associated with even more severe side effects than gastrointestinal irritation, and that is their tendency to increase cardiovascular events.

Therefore, the approach of this particular project of focusing on the traditional aspirin therapy seems logical mainly for two reasons:

Aspirin possesses a wide range therapeutic effects that range from anti-inflammatory effect to the antiplatelet effect.

The fact that aspirin has undergone a significantly detailed levels of clinical trials makes it both practical and progressive.

Now, the main reason behind the gastrointestinal irritation is because the conventional drug delivery systems, those are, the oral dosage form, etc, fail to provide the maximum tolerable dose to the human body due to technical and manufacturing related restraints.

Therefore, a widely evolving concept of controlled release drug delivery has been adopted while considering the various aspects involved in the same.

One of the ways of delivering a medicine via controlled release, is by devising a TRANSDERMAL drug delivery system as explained below:


There are three different routes of delivery across human skin:

The sweat ducts

Via the hair follicles (collectively called as shunt or appendageal route)

Stratum corneum (most direct route).

However, the stratum corneum (the top layer of skin) itself acts as a barrier for many of the drugs and therefore, there has to be a mechanism in place which can allow drug permeation adequately efficiently.


One of the predominantly used techniques in place for bypassing the stratum corneum is by use of coated microneedles which are especially useful in enhancing the passage of macromolecules which are otherwise difficult to pass through the skin. In this system, the microneedles are coated (probably from within) by the drug to be administered. The efficiency of delivery primarily depends on the geometry of the microneedles; hence, their size and shape are engineered according to the drug, its dosage quantity, etc, so as to improve skin permeability. The microneedles used are most often biocompatible which are coated with silicon or metal. The purpose behind using biocompatible needles is that they are safe and easier to manufacture at an industrial scale.

Microprocessor controlled:-

The concept of iontophoresis (Electromotive Drug Administration) is considered as one of the more advanced techniques for transdermal drug delivery. The word iontophoresis means transfer of the drug ions through electric current. However, the flow of these ions has to be precisely controlled so as to serve the very purpose of controlled drug delivery by transdermal route. Therefore, it is a non-invasive process by means of using an electromotive force generated through a small electrical charge applied to an electrophoretic chamber.

However, this method is quite different from the transdermal patches which are essentially injections into the skin. This method, as mentioned above uses electrical field as the driving force for the transportation of the electrically charged medicines/other substances (if any).

Ultrasound technique:-

It is one of the most unique techniques in a way that it is very unconventional, because it uses sound waves to enhance the permeability of the skin to medicines. The process is known as Sonophoresis.

The following table represents the two sides of the Transdermal Drug Delivery systems in general:-

Table 1. Transdermal drug delivery: advantages versus limitations

Advantages Limitations

No gastrointestinal degradation Low skin permeability

No first-pass metabolism by the liver Restricted to potent drugs (low dose

achieves the therapeutic effect)

Steady delivery Cannot deliver large (>500 Da)


Better compliance Significant lag time Skin irritation and/or sensitization

Methods developed for the profiling of Transdermal Drug Delivery:-

The paddle method:

A dissolution vessel is equipped with a convex screen patch holder at its bottom. Therefore the amount of medicine being released can be measured. One of the widely profiled medicines by this method has been Nitroglycerine. The method is important for this medicine because Nitroglycerine is one of those substances which are highly metabolized by the liver if taken through the conventional oral route. The method is highly reproducible and hence it is widely used for many transdermal medicines despite being a relatively new method.

There is a comparatively more traditional patch-holder mechanism called the Sandwich patch-holder mechanism. However, it is more complex and less reliable. Hence, the paddle method is regarded as its more feasible counterpart.

Fast screening strategy for characterizing peptide delivery by transdermal iontophoresis:

Capillary zone electrophoresis (CPZ), as the name suggests, is an effective technique that mimics the low throughput in vitro skin that used to optimize the transdermal iontophoresis driven transdermal peptide delivery. Since it is an iontophoresis technique, the characterization has to depend upon the pH. Therefore, extraction of pertinent molecular characteristics was controlled by modulating the pH. Along with the pH, the optimization of the experimental conditions and the use of the in silico filters have been the high points of this technique in general.

The above mentioned methods are only a couple of the more significant ones, however, the purpose behind the acknowledgement here is that these methods can be important in directing the drug delivery research.

The Drug Delivery related research is widely focused on nanotechnology and hence, we need to elaborate on nanoparticles and microparticles.


Nanoparticles are essentially the particles that are below 100nm in size. The wide range of applications pertaining to nanoparticles from biomedical, optical to electronic fields has in turn helped immensely in devising novel techniques as far as drug delivery is concerned.

The stability of nanoparticles is not desirable as compared to that of a bulk material they are a part of; however, this instability is irrelevant at a nano-scale.

The instability of the nanoparticles may be attributed to 'quantum confinement in semiconductor particles', metal particles that display 'surface Plasmon resonance' and as the name would suggest, the magnetic materials imply 'superparamagnetism'. 'Superparamagnetism' is a concept in which materials such as iron, form permanent magnets. The most relevant aspect about the properties just mentioned, is that they are all size-dependent while maintaining their intrinsic nature.

The properties of the particles vary on two variables; firstly, when the size itself approaches the nano scale and secondly, when the nanoparticles assemble more towards the surface of the material.

However, for bulk materials larger than one micrometre, the percentage of atoms towards the surface is significantly negligible.

The properties of the nanoparticles and the intrinsic nature of the bulk material are interrelated. Although, the bulk material has a predominant influence on the overall behaviour of the nanoparticles, nanoparticles have their own variables that contribute to the variations in their stability with respect to the bulk materials.

To demonstrate the above theory, an example quotes that a copper rod, when bent, brings about the nanoparticles to cluster at about 50 nm scale.

On the other hand, the particles sized less than 50 nm do not comply with the bulk material in terms of the malleability.

Therefore, it is very important to judge whether the variations in properties are desirable or not.

Nanoparticles structures can be roughly classified as per following:

Quantum dot




It is important to note that most of the nanoparticles share the following properties, which make them useful for the concerned applications:



Ease of synthesis


The area of interest here has to be Nanomedicine which relates to the use of nanoparticles for drug delivery. The research is ongoing for the extrapolation of the technique for the purpose of molecular nanotechnology (MNT) and nanovaccinology.

As far as biomedical research pertaining to nanoparticles is concerned, the classification should well be application based as follows:

Semi-hydrogel networks of poly(acrylamide) and carbohydrates: antibacterial application

Inorganic nanoparticles for Biotechnology

Platinum-palladium alloy nanoparticles for electrochemical applications

Gold nanoparticles

Nanoparticles for Dental Materials

Noble metal nanoparticles/carbon nanotubes nanohybrids

Plasmonic nanoparticles for biomedical applications

Preparation of semisolid drug carriers for topical application based on solid lipid nanoparticles

Lanthanide-doped upconversion nanoparticles for biomedical applications

Applications of nanoparticles by a high gravity method

Synthesis of nanoparticles by microorganisms and their application in enhancing microbiological reaction rates

Forthcoming applications of gold nanoparticles in drug and gene delivery systems


Semi-hydrogel networks of poly(acrylamide) and carbohydrates:

The nanoparticles have been used here for the preparation of semi interpenetrating hydrogel networks (SIHNs) which require a poly(acrylamide) cross-linked base. The polymerization is carried out in a redox-solution by incorporating N,N'-methylenebisacrylamide (MBA), while there is a further incorporation of carbohydrates, namely gum acacia (GA), carboxymethylcelluose (CMC) and starch (SR).

The outcome of the above incorporations leads to the formation of highly stable silver nanoparticles with the hydrogel networks as the nanoreactors. Since there is a redox reaction involved, an in situ reduction of silver nitrate (AgNO3) with the interference of sodium borohydrate (NaBH4) which is a reducing agent.

Antibacterial activity:

The antibacterial activity of the silver nanoparticles has been attributed to the use of the atomic scale functional materials. However, the silver nanoparticles contribute by increasing the number of resistant strains of bacteria to the most potent antibiotics. The key element in the antibacterial activity of the silver nanoparticles is the size, which should ideally be between 1-10nm.

Inorganic nanoparticles for Biotechnology:

The usefulness of the nanoparticles hinges mainly upon two factors:

Large surface area to volume ratio. This in addition to the efficient chemical functionalisation, enables the bonding of the multifunctional cargo payload (for example, a fluorescent moiety, targeting molecules, etc.)

The fact that the nanoparticles offer a larger surface area, means that they can have an access across more tissues that were otherwise not possible to be accessed.

Magnetic nanoparticles:

As the name suggests, the magnetic nanoparticles have a magnetic core as an integral component namely magnetite or maghemite. Cobalt and nickel have also been used; but due to their toxic and susceptible to oxygen, the usage is restricted.

The iron oxide magnetic nanoparticles (mNPs) are adopted bearing an idea that the human body is efficient enough in processing excess of iron.

The basic role of targeted drug delivery is fulfilled as the cationic mNPs are able to efficiently enter the cells and remain localised in the endosomes for a sustained period of time.

The transfer of iron across various cellular and tissue levels is the most crucially advantageous aspect of the mNPs; because, the iron that is a component of the endosomes and lysosomes (which is a part of the post-cellular uptake) is converted into elemental iron through metabolism and into oxygen by hydrolytic enzymes, where the iron joins the normal body stores.

Thus, the homeostasis of iron can be regulated by the use of iron oxide nanoparticles, essentially by processing any excess iron present.

The superparamagnetic iron oxide (SPIO) nanoparticles are the components influenced by an external magnetic field; as a contrast, removing the external field eliminates the paramagnetism.

The purpose behind the application of an external magnetic field is that it allows lesser concentration of the particles to produce an equivalent signal feedback.

Magnetic Resonance Imaging:

The use of magnetic nanoparticles in Magnetic Resonance Imaging (MRI) has been one of the highpoints of diagnostics. The nanoparticles being able to enter into cells belonging to the most dense cluster, gives them an ability to present an image that shows distinct contrasts between different types of cells and eventually tissues (the tendency is also attributed to 'large magnetic moment'). Apart from offering a more distinguishable image quality, they offer slower clearance from the target site.


The term in itself suggests a change with respect to temperature. As it is well known, in the case of cancer, the tumour cells are more susceptible to necrosis under the influence of temperature as compared to that with normal cells. Hence, some sort of a medium through which the heat can be transferred across the tumour cells had to be devised. Therefore, a nanoscale heater concept in which the nanoparticles function as the components that reach out at the concerned cells, has been one of the most significant innovations in cancer therapy.

The process is based on the fact that the external electromagnetic field provided to the nanoparticles is converted to heat.

One of the practical implementations of the concept of hyperthermia is the study of the effect of temperature on the uptake of doxorubicin (an anticancer medicine) by human breast cancer cells.

On the basis of a similar principle of the ability of the magnetic nanoparticles being able to reach out at different strata of the cellular organization, mNPs have applications in magnetic drug targeting, magnetic transfection, etc.

Gold Nanoparticles:

Gold nanoparticles (AuNPs), also known as colloidal gold, have been very extensively in use for a century. The most advantageous aspect of these particles could be the varying colours with respect to their varying size; for example, particles below 100nm are red and the larger ones are mostly yellow in colour.

The gold nanoparticles work on the principle of absorbing the scattering light which leads to excitation of the electrons resulting into oscillations. These oscillations are also known as surface Plasmon. This collectively helps in enhancing the biological imaging.

On similar principles as the mNPs work, gold nanoparticles too have been used as Cell Delivery Vehicles and Biosensors.

Quantum Dots:

They probably differ from the gold nanoparticles by their crystalline structures. They comprise of Cd, Zn, Se, Te, In, O, As, as some of the elements.

Their applications vary from Single Cell Imaging, In Vitro Imaging and Targeted Therapies as similar as that in the magnetic nanoparticles.

Carbon nanotubes:

They are essentially hollow and porous nanoparticles known as nanotubes, nanoshells and hollow spheres; so that they can be loaded with cargo, and it is observed that it enhances the signal and sensitivity.

The most advantageous properties of the carbon nanotubes are the easier translocation across the cell membrance and relatively low toxicity. The carbon nanotubes can be either single-walled or multi-walled.

Their applications involve relatively high profile implications as compared to some of the other forms of nanoparticles:

Neuronal Tissue Engineering


Figure 2: a substrate patterned with carbon nanotubes is cultured with Neuronal networks (A). Aligned neurites as a result of the patterned growth over a period of 14 days (B).

Imaging and Cancer Treatment.

Imaging and Cancer Treatment

Platinum-palladium alloy nanoparticles for electrochemical applications:

The applicability of the nanoparticles in terms of detecting various other compounds is tested by preparing platinum-palladium alloy nanoparticles/large mesoporous carbon (LMC) nanocomposites (PtxPdy/LMC), where the subscripts X and Y represent the different rations of Pt and Pd.

The introduction of the various proportions of PtxPdy alloy nanoparticles upon the surface of an LMC matrix enable the interaction of the two and brings about peroxide reduction and nitrite oxidation; which otherwise is not possible with depositing Pt on LMC matrix surface. The entire set of Pt1Pd1/LMC nanoparticles modified glassy carbon electrode implies an excellent electrolytic capability, and therefore it has been deemed to be practically useful to detect other compounds.

Gold nanoparticles:

Gold nanoparticles, as discussed before, are significant enough to be categorized separately; one of the reasons being their environment oriented applications in greener production methods, pollution control and water purification.

Gold nanoparticles are in nature more stable compared to other forms of nanoparticles and may be hence they provide applicability in forming appropriate conditions to make a number of catalysts that includes:

Catalysis of CO oxidation

Catalysis of hydrogenation of unsaturated substrates

Electrochemical Redox catalysis of CO and CH3OH oxidation and O2 reduction

Catalysis by functional thiolate-stabilized gold nanoparticles, etc.

Mercury control and sensing: the advantage of controlling and sensing mercury could well be elaborated if required. For example, mercury is generally toxic in nature and thus responsible for a number of adversities such as Alzheimer's disease and autism. To add to the advantage, gold nanoparticles have been found to act as catalysts for the oxidation of mercury.

Oxidation of CO to CO2.

In technology: applications such as in coating glasses so as to change their overall properties and multicolour optical coding for biological assays

To enhance electroluminescence and quantum efficiency in organic light emitting diodes.

Signal amplification.

Detection of trace amounts of the analytes to the extent of a few ppm.

Making of advanced dyes and pigments.

Nanoparticles for Dental materials:

As apparent, the use of nanoparticles in dental materials is for the purpose of improving their optical properties. The use of nanoparticles significantly reduces the stress on mechanical strength and the wear resistance is not sacrificed either.

Clinical experience with dental materials:

The use of the nanofill composite Filtek is at the cetre point of the nanoparticles driven restorations. Therefore, it was observed that the use of nanoparticles offers following advantages:

Long-term universal application to restore dentition

Providing excellent anaesthetics, mechanical function and wear resistance

Longevity of the treatment as high as a period of 3 years was observed, with a peculiar property of self-polishing of the treated surface.

Noble metal nanoparticles/carbon nanotubes nanohybrids:

The focus is shifted slightly on the use of novel forms of nanoparticles with the overall applicability not being too different from that elaborated earlier.

Some of the applications like:

Hybridization of cinnamaldehyde in heterogenous catalysis

Suzuki coupling, selective hydrogenation, CO oxidation, NH3 synthesis and hydrodehalogenation are some of the other examples of heterogenous catalysis.

Figure 3: scheme of carbon nanoparticles for Heck coupling reaction

Similarly, the novel nanoparticles can be used in:

Fuel cells and electrocatalysis


Plasmonic nanoparticles for biomedical applications:

Nanoparticles is one of the emerging technologies in which the research is focused on the fabrication and optical characterization of noble metal nanoparticles varying in aspects like size, shape, structure and tunable Plasmon resonances over VIS-NIR spectral band.

Preparation of semisolid drug carriers for topical application based on solid lipid nanoparticles:

The topical drug delivery is one of the most prevalent and profitable area of pharmaceutical industry, because of the sheer scope in terms of treatment of minor ailments/cosmetic substitutions with irreplaceable remedies.

Therefore, aqueous dispersions of solid lipid nanoparticles (SLN) are a mode of focus here. The manufacturing of a topical semisolid preparation is a complicated process as it involves the incorporation of the solid-liquid-semisolid phases with use of heavy and time-consuming machinery.

However, the use of the nanoparticles potentially reduces the number of steps to ONE which is especially important because it provides more stability to the end product while offering commercial benefits. The equipment used for the production includes a high-pressure homogenizer.

Lanthanide-doped upconversion nanoparticles for biomedical applications:

Similar to the applications pointed out earlier, these nanoparticles deliver following contributions:


Cancer therapy


Fluorescence imaging

MRI and drug delivery

However, the mention of this type of nanoparticles comes with certain advantages:

Enhanced tissue penetration depths via near-infrared excitation

Photocleaching, photoblinking, photochemical degradation can be avoided

DNA/RNA remain intact without getting photo-damaged at lower excitation light energy

Lower cytotoxicity

Higher detection sensitivity

Applications of nanoparticles by a high gravity method:

Process that involve a role of the nanomaterials, namely, synthesis, polymerization, special chemicals production, reactive absorption, etc are subjected to micromixing which is essentially a mass transfer.

The device used was the Rotation Packed Bed (RPB, or "HIGEE" device) and a unique and intense micromixing was achieved. This was a trigger point for the use of RPB as a fabricator of nanoparticles.

The high gravity method has been designed for the synthesisof nanoparticles such as inorganic and organic with the implementation of gas-liquid, liquid-liquid and gas-liquid-solid multiphase reactions.

Example: inorganic nanoparticles like nanosized CaCO3, TiO2, SiO2, ZnO, Al2O3, ZnS, BaTiO3, etc.

Synthesis of nanoparticles by microorganisms and their application in enhancing microbiological reaction rates:

This particular process works as a complementary procedure, in which, the nanoparticles are first synthesized with the help of micro-organisms such as bacteria, fungi, actinomycetes and yeast and then their effect on the microbial processes is taken into consideration.

The nanoparticles are most widely used for the purposes of reductants and/or catalysts in the field of chemistry because mainly of the two highpoints:

Highly specific surface areas


Although the number of studies conducted on the effect of nanoparticles on the reaction rates is limited, there are some examples which point out the significance of the technique. For example, the formation of the nanosized palladium particles formed on the cell wall or inside the periplasmic region of a bacterium named Shewanella aneidensis brought about a reduction of the dehalogenate polychlorinated biphenyl (PCB).

Forthcoming applications of gold nanoparticles in drug and gene delivery systems:

This particular section expands the applicability of the nanoparticles from drug delivery to gene delivery. The importance of reemphasizing the importance of the gold nanoparticles is because they can be modified to optimum parameters to be suitable for a more intricate level of biomedical delivery system.

As mentioned in a previous section, features such as surface Plasmon resonance, controlled interaction with the thiol groups and most importantly, the non-toxic nature contribute towards devising appropriate dynamics for the gold particles to be efficient.

The nanoparticles intervened drugs present certain improvements in their overall properties which include:

Improvement in solubility

Optimal biodistribution

In vivo stability

Pharmacokinetics enhancement

Similarly, the gold nanoparticles can also be used to carry nucleic acids; hence, the purpose of gene therapy can be focused on. The details into how the entire process is carried out, is irrelevant in this context.


Microparticles essentially differ from nanoparticles in terms of the particle size, however, the difference reflects on to their overall applications when compared to that of the nanoparticles. But the most prevalent attributes between the two classes do not change beyond a certain level.

The size range of the microparticles is between 0.1 to 100 micrometres.

The most commonly found microparticles are sourced from ceramics, glass, polymers and metals.

More natural forms of microparticles include pollen, sand, dust, flour and powdered sugar.

Similar to the principle on which the nanoparticles have been proven to be advantageous, microparticles also have a large surface-to-volume ratio at the macroscale. However, this level of dynamics can be challenging to handle at the industrial level, for example, metal microparticles can be explosive in air.


Application of sulphur microparticles for solid-phase extraction of polycyclic aromatic hydrocarbons from sea water and wastewater samples

Boc-L-tryptophan imprinted polymeric microparticles for bioanalytical applications

Characterization and application to entrapment into biodegradable microspheres

Composite polymer-Fe3O4 microparticles for biomedical applications, produced by Supercritical Assisted Atomization

Design and characterization of bi-soft segmented polyurethane microparticles for biomedical application

Microparticles with GOx for biosensor applications

Preparation and characterization of starch-poly-Ô‘-caprolactone microparticles incorporating bioactive agents for drug delivery and tissue engineering applications

Production and characterization of chitosan microparticles

Tissue engineering applications

Topical applications related to acyclovir-loaded microparticles


Application of sulphur microparticles for solid-phase extraction of polycyclic aromatic hydrocarbons from sea water and wastewater samples:

As compared to the nanoparticles, the microparticles possess a larger size and hence a lesser size to surface ration. Therefore, microparticles can be practically useful as adsorbents.

In this case, the sulphur microparticles function as efficient adsorbents and bring about solid-phase extraction (SPE) and as a consequence determine the trace amounts of 10 polycyclic aromatic hydrocarbons (PAHs). The magnitude of this application is enormous when it is considered that the extraction is carried out from the sea water and wastewater using various separation techniques that mainly include the HPLC (High Profile Liquid Chromatography) coupled with UV detector (ultraviolet detector).

Cell/Tissue Engineering Applications:

In this case, an engineered breed of alginate-based microparticles is produced in order to be applicable for their use in turn as cell/tissue engineering media.

The alginate-based microparticles are formed of an extracellular matrix and neonatal porcine Sertoli cells (SCs). This technique is unique in a way that the source of the matrix was a powder form of isolated and purified urinary bladder matrix (UBM).

The use of the UBM implied that it did not alter the core morphological integrity and the overall dimensional characteristics of the microparticles.

The crux of the above procedure is their applicability in the cell/tissue engineering process. The alginate microparticles were used for the SC encapsulation as an immunoprotective barrier for transplant purposes; on the other hand, the co-entrapped UBM functioned to promote the cell viability and function.

As mentioned before, this technique is very novel in its own way, because it works in a complementary way by increasing the functional life-span of the entrapped cells for cell/tissue engineering applications.

Deign and characteristics of bi-soft segmented polyurethane microparticles:

The modifications at various levels are concentrated towards developing biomedical applications. In this case, the Bi-soft segmented poly(ester urethane urea) microparticles have been prepared and then have been characterized.

Although the biomedical applications offered don't vary radically, it is worth noting the method of preparation of the microparticles so as to correlate with the properties of the same if required.

Two parallel formulations were prepared:

Using poly(propylene oxide)-based tri-isocyanated terminated pre-polymer (TI).

Soft segmented added for the purpose of incorporating poly(Ô‘-caprolactone)diol (PCL).

The method of analysis used to study the polymeric structure was infrared spectroscopy. The analysis determined the degree of phase separation between the two formulations, in which it was found that the TDI-microparticles show a higher extent of phase separation, and TI-microparticles on the other hand show higher rate of hydrolytic degradation, and therefore, consequently lower toxic effect against the macrophages.

These new formulations can be categorized as the non-biodegradable biomedical systems.

Powder technology: Supercritical Assisted Atomization:

The applications remain generalized to biomedical applications here as well. However, the efficiency improvement is what has been the aim in devising the novel methods of preparation of microparticles and their relevant advantages over their counterparts.

In this case, the Supercritical Assisted Atomization (SAA) is used as an efficient supercritical fluid (SCF) micronization technique.

The most distinct feature of this technique is that it adopts the production of the composite microparticles, which literally mean a composition of more than one component. Therefore, multiple components can be processed.

SAA can be used in the formation of magnetite nanoparticles, derived from the suspensions of nanoparticles in polymer-solvent solutions.

Dextran and chetosan; both glucose derivatives, dextran is a branched glucan (polysaccharide formed by the chain of glucose) and chitosan can be termed as a linear polysaccharide composed of random glucosamine (deacylated unit) and N-acetyl-D-glucosamine (acetylated); have been used as dispersing matrix.

The biocompatibility can be gained by encapsulating the polymer coating, also the particles are physically more stable because they are protected by a steric barrier so as to prevent agglomeration and also avoid opsonisation.

The efficiency of the dispersion was analysed by using

Surface Electron Microscopy (SEM)

Energy Dispersion X-ray (EDX)

ThermoGravimetric Analysis)

Now these techniques actually are able to determine the overall morphology, particle size distribution, nanostructure and the concentration of the loaded nanoparticles/microparticles in the polymeric matrix.

Targeted transfollicular delivery of artocarpin extract with the help of an organism Artocarpus incises by the use of microparticles:

A heartwood named Artocarpus incises is the source of Artocarpus (Ar), which is a plant bearing edible fruits, is pharmacologically important that reduces the 5 alpha inhibitory effect. The biggest problem for the potential therapy by Ar was the lack of appropriate drug delivery mechanism.

Therefore, the employment of alginate/chitosan (ACS) microparticles for targeted transfollicular delivery with a suitable particle size between 2 and 6 micrometres was an area of research. Ionotropic gelation technique, which is a coacervation-phase separation technique that involves:

Formation of 3 immiscible chemical phases

Deposition of coating

Rigidization of coating

This brief explanation focuses back on the drug delivery related applicability of the microparticles, which can be explored further in case of a requirement.

Bioanalytical applications: Boc-L-tryptophan imprinted polymeric microparticles:

There is a concept named molecularly imprinted polymers, which is essentially, as the name suggests, employs molecular imprinting technique that is useful in forming cavities in a polymer matrix with affinity to a desired template molecule in microparticles.

Now these microparticles with efficient separation that is chromatographic characteristics were synthesized with the use of the suspension polymerization process in one single preparation step. There are a lot of potential variables during the processing that affect the end product, those are, porogen concentration, polymerization temperature, functional monomer types and their concentrations and the cross-linker used. Now these variables mainly affect the particle size distribution and the particle morphology.

The fact that this technique uses templates in some way, it implies that its applications can be targeted to the bioanalytical separation of peptides and proteins which are the components of a chain formation as far as amino acids in general are concerned, and hence they are the building units of a chain forming larger biomolecules.

Biosensor Applications: polypyrrole/polyacrylamide microparticles:

The sulfonate dopant anion, which is a doping agent which is essentially a trace impurity element that alters the electrical and optical properties when inserted into a substance.

This dopant anion is used in the synthesis of polypyrrole. To make a controlled release drug form, polypyrrole was incorporated into the water phase of the water in oil (W/O) concentrated emulsion. This combined with the varying amounts of the acrylamide monomer and the crosslinker bisacrylamide.

Now the water-dispersed portion is capable of forming the microparticles that size with an average value of 4.5 micrometres, as mentioned above, polypyrrole is entrapped.

Now the conductivity varies against the proportions of polypyrrole vs polyacrylamide in the water phase. The aim is to maintain it within the range of semiconductor materials' conductivity.

GOx (glucose oxide) was the next focus, it was immobilized in the microparticles so as to maintain its stability and efficacy by incorporating the enzyme into the water phase (same phase as mentioned above) and then the next major step was the polymerisation.

The entire incorporated phase was used as a biological component of an amperometric glucose sensor that is sensitive to glucose under the aerobic and anaerobic conditions.

Now, apart from all the revolving techniques used, the above protocol emphasizes more on the importance of the immobilization technique and the relevant possible applicability of the semi-conducting microparticles.

Characterization and entrapment into biodegradable microspheres:

Gelatin microparticles are the main components to be entrapped into the biodegradable microspheres in this case.

Microspheres are essentially spherical microparticles with details that are not totally relevant in the context.

Now the gelatin microparticles were prepared by carrying out something known as co-lypophilization with the poly(ethylene glycol) (PEG), which works as a protein micronization adjuvant.

Lyophilisation is a process in which the substance is subject to dehydration so as to preserve it.

The intricate details of the entire process can be studied as per the requirements; however, all that is important to note is that this technique is useful in studying as well as developing various drug delivery systems.

The following diagram illustrates in brief, how the formation of gelatin microparticles is carried out:

Figure 4: Formation of Gelatin microparticles.

Courtesy: Takahiro Morita, et al.

Topical application of acyclovir-loaded microparticles:

Acyclovir is basically a guanosine analogue antiviral drug.

Therefore, the drug designing in this context revolves around acyclovir; and hence the aim was set to be the increase in the level of acyclovir (ACV) in the basal epidermis, which is the target site for the virus causing the Herpes simplex infections.

Now, by using the microparticles as carriers, a co-solubilisation of the ACV with Poly(D,L-lactic-co-glycolic acid) was done with the use of a solvent evaporation technique.

Now, to determine the concentration of the ACV into the skin was determined by slicing out the porcine skin and the layer of the skin tested was the basal epidermis.

As an arbitrary conclusion, it was found that the drug retention was significantly increased by the use of microparticles when the transdermal drug delivery was taken into consideration.

Use of chitosan microparticles containing papain:

On similar lines to ACV as discussed above, the chiotosan microparticles were tested for their capability as the controlled drug delivery carriers by using crosslinking agents and papain.

Papain is (a cysteine protease enzyme) sorption; along with chitosan was crosslinked with sodium tripolyphosphate (TPP) 10% (w/v) solution or glutaraldehyde (GLU) 0.75% (w/w).

The characterization of the microparticles was carried out with the help of the FTIR (Fourier transformed infrared spectroscopy) for detecting chemical modifications, the morphology was tested by using the SEM (scanning electron microscopy) and DSC (Differential scanning calorimetry).

The papain and TPP were found to lower the stability of the chitosan matrix, and probably as a result, the drug delivery was possible through the matrix.

Therefore, it was concluded that this technique was potentially useful for the controlled drug delivery of papain with potential biomedical applications.



The clay minerals are a class of layered silicates that are present in abundance as the fine-grained fraction of soils and sediments. The layered structures give them a nomenclature as PHYLLOSILICATES.

The clays share advantages as well as disadvantages for being majorly crystalline in nature.

The particle size of the clay minerals is most frequently below 2 micrometres. Being crystalline in nature, they possess an equivalent spherical diameter (e.s.d.).

Therefore, clays can be correlated to the properties of the microparticles in general, yet there needs to be a detailed analysis in deciding in which aspects do they have similar attributes as those of the microparticles in general.

The reason behind the analysis is required is because, not all clay minerals are below 2 micrometres and not all possess a crystalline structure.

It is necessary to clarify the difference between the term 'clay mineral' and 'clay'. 'clay' pertains to naturally occurring material of fine-grained texture that has the tendency to become plastic when subject to a liquid and consequently has the tendency to harden when dried or fired.

On the other hand, the 'clay minerals' are essentially hydrated phyllosilicates and minerals impart plasticity to clay and then undergo hardening upon drying.

'Clay minerals' can be synthetic unlike the clays which are strictly natural.

The fine-grained nature of clay minerals demands various methods of analysis that include:

X-ray diffractometry

Chemical and thermal analyses together with electron microscopy

Organic intercalation

Now for more detailed and elaborate analyses, the above mentioned techniques have to be complemented with the following techniques:

Fourier transform infrared (FTIR)

Mossbauer, numclear magnetic resonance (NMR)

X-ray absorption

X-ray photoelectron spectroscopies

However, these techniques can prove to be insufficient when there are certain 'impurities' present that essentially change the basic structural dynamics of clay minerals. These impurities include carbonates, quartz and iron/aluminium hydr(oxides). These impurities are either very discrete in nature or they are surface adsorbed. Therefore, techniques such as X-ray diffractometry (XRD) are not sufficient.


The phyllosilicates are formed by multilayered components which comprise an alumina-silicate layer comprising a silica tetrahedral sheet and alumina octahedral sheet.

These components are joined together in varying proportions and these proportions actually decide the class of the clay mineral.

The tetrahedron component places the Si4+ cation at the central region of the sheet which is coordinated to four oxygens.

The octahedron has Al3+ at the centre or a Mg2+ at the centre and either of the two coordinated to six hydroxyls.

The structures are geometrically specific, as in, the tetrahedral sheet is formed when the individual tetrahedral are interlinked at three corners each.

This alignment makes the oxygen arrange in a coplanar manner, which forms an overall visually hexagonal structure and a ditriangular structure in reality, while the apical (denoting an apex) oxygens point in the same direction.

On the other hand, the octahedral in the octahedral sheet are linked through sharing edges. When Al3+ acts as a cation, the electrical neutrality is maintained by aligning only two of every three octahedral sites being occupied. The resultant structure as found for example in mineral gibbsite is known as dioctahedral.

On parallel parameters, the Mg2+ induces all three octahedral positions to close in together in order to form bonds which results in the formation of 'trioctahedral'.

The following diagram should give a pictorial presentation of the structures:

C:\Users\parag\Documents\THESIS\CLAY STRUCTURE\figure 1.1_files\1-s2.0-B9780444533548000013-f01-01-9780444533548.jpg


Figure 4: "Bottom: (A) a silica tetrahedron in which the central silicon is coordinated to four oxygens (B) a tetrahedral sheet formed by linking silica tetrahedral through corner-sharing. Top (A): an alumina octahedron in which the central aluminium ion is coordinated to six hydroxyls; (B) an aluminium octahedral sheet formed by linking octahedral through edge-sharing" the bigger circles represent Oxygens and the smaller ones represent Silicons. COURTESY: Grim et al, 1968.

The tetrahedral (T) sheet and the octahedral (O) sheet when condensed together, form a 1:1 (T-O) layer structure.

C:\Users\parag\Documents\THESIS\CLAY STRUCTURE\figure 1.2_files\1-s2.0-B9780444533548000013-f01-02-9780444533548.jpg

Figure 5: "schematic representation of a silica tetrahedral sheet condensing with an alumina octahedral sheet to form a 1:1-type layer structure. The mode of condensation between the two sheets is indicated by the solid rectangles" COURTESY: B.K.G Theng.

In this case further, the projection of the tips of the tetrahedral sheet occurs into a hydroxyl plane of the octahedral sheet, which replaces two-thirds of the hydroxyl ions as what happens in kaolinite.

Figure 6: "the structure of kaolinite, viewed along the a-axis , showing the superposition of adjacent 1:1-type layers within a particle. The outer hydroxyls are denoted by A and B (both situated along the upper surface). The inner-surface hydroxyls by C and the inner hydroxyl by D (both situated along the lower surface). The basal or d(001) spacing of approx 7 Armstrong units is equal to the layer thickness. The unit cell dimension is indicated by the broken rectangle. CREDITS: modified after Dixon, et al, 1989.

As a consequence, the two surfaces (layers) consist of different components; the basal plane of the layer comprises of oxygens which are attached from the tetrahedral sheets, on the other hand the other is made up of hydroxyl which is attached from the octahedral sheet.

The phyllosilicates are classified into two main classes:



The planar ones are further subdivided into Smectites, which are one of the seven subclasses of the planar 2:1-type phyllosilicates.

One of the important members of the smectite group that feature in the clay-polymer interaction are the dioctahedral beidellite and trioctahedral hectorite. The composition of an ideal beidellite structure can be written as: M+x-nH2O (Al2)(Si4-xAlx)O10(OH)2, which by an observation indicates that the negative layer charge is sourced from partial substitution of Al3+ for Si4+ in the tetrahedral sheet.

The substance to be focused for the purpose of this project is the MONTMORILLONITE.


C:\Users\parag\Documents\THESIS\CLAY STRUCTURE\MONTMORILLONITE_files\1-s2.0-B9780444533548000013-f01-09-9780444533548.jpg

Figure 7: "The 'Hofmann' layer structure of montmorillonite, showing isomorphous substitution in the octahedral and tetrahedral sheets, and the presence of exchangeable cations and water molecules in the interlayer space. The basal ord(001) spacing varies according to the nature of the interlayer cation and the ambient relative humidity. Under the conditions of complete dehydration and layer collapse, the basal spacing is ∼ 0.95 nm". COURTESY: B.K.G. Theng.

The montmorillonite comprises of a hectorite which is relatively more negatively charged because a more positive Mg2+ is replaced by Li+, which is less positive, in the octahedral sheet.


Structure-property relationships:

The concept of clays into industrial use has been a very old practice. Clays have been used to fabricate jars, bowls or amphoras.

The most crucial reasons behind the success of clays into particulate use is because of their ability to absorb ample quantity of liquid, water to be more direct, and then exfoliate. Therefore, the flexibility in the overall structure so as to adapt to the changing dynamics makes them malleable. So, the effect of temperature when heated again, reverses their structure to its original self.

This particular property is very difficult to achieve at a low overall cost with such high efficiency.

This property is particularly true for the montmorillonite clay which shows above average adsorption and absorption properties.

These dynamics are essentially important for the purpose of intercalation within the clay sheets and for the interaction between the clay and other substance(s), for example: Acetylsalicylic acid.

The recent development in research has led to the polymer-clay nanocomposites that offer enhanced mechanical , electrical, heat resistant or coating properties.

C:\Users\parag\Documents\THESIS\CLAY STRUCTURE\clay cis trans_files\1-s2.0-S0166128005007797-gr2.jpg

Figure 7: cis and trans sites in dioctahedral clays. (a) Schematic representation of an octahedral sheet showing the different sites; (b) cis site; (c) trans site. COURTESY: P. Boulet, et al.

On the flipside, the swelling tendency can show a large extent of instability when it comes to the field of petroleum activities the hydration of clays may lead to borehole instabilities.


The main aim behind conducting this analysis is to determine the interlayer gallery height of the clays before the pillaring and after. The data thus obtained might help in determining the intercalation profile of the Ca2+-montmorillonite and Bentonite with respect to various therapeutic or otherwise substances.

As discussed before, the smectite clays sandwich a central aluminium-containing layer [1-3] between alluminosilicates having a layered structure with two silicate sheets.

There is essentially an interaction between the aluminium cations and the oxygen anions which forms an octahedral arrangement; the simple repetition of these interactions in two separate layers and the subsequent inter-bonding forms the octahedral structured layer.

Now, the area of analysis as far as the NMR technique is concerned, is the electrostatic forces between the two layers which are vulnerable enough to be penetrated by the polar species between them.

However, the pillaring between the layers involves a dedicated process, and it is based on the swelling mechanism that is brought about by certain techniques.

The most important logically correct step towards keeping the two layers apart is to alter the anion to cation interaction. And this can be done by replacing the exchangeable cations, for example Na+, Ca+, from the regions between the two layers and simply holding them apart with the organic and inorganic complexes.

Now, as the initial hurdle is dealt with, the pore size between the two layers can be varied accordingly by varying the size, charge and shape of the entering ions.

This allows the penetration of large molecules and hence a permanent interlayer pore system is established.

The importance of this process is briefly mentioned as follows:

The clays play the role as catalysts and catalyst supports, and thus this pillaring mechanism can contribute towards clays as catalysts in cracking heavy residual materials, etc. For example: crude oil.


The materials and methods can be divided into three sections:

Determination of the solubility of Aspirin in Isopropanol and the calibration curve for Aspirin in Isopropanol

Determination of the efficiency of Intercalation between Aspirin (acetylsalicylic acid) and the montmorillonite clay.

Determination of efficiency of intercalation on time-dependent intervals.

The reason behind forming two separate sections for essentially one single experiment, is because the overall analysis was a stepwise process.


Determination of the solubility of Aspirin in Isopropanol and the calibration curve for Aspirin in Isopropanol:


The solubility of Aspirin was determined by using the most basic instruments:

Powdered, crystalline form of acetylsalicylic acid (Aspirin) at room temperature.

Liquid form of Isopropanol (Propan-2-ol) stored in an amber coloured bottle at room temperature.

'Sartorius' weighing machine for aspirin.

One 250ml beaker.

One 100ml volumetric flask.

Calibration curve determination for Aspirin:

A set of 10ml, 20ml, 25ml, 100ml & 250ml volumetric flasks.

A set of 250ml beakers.

'Sartorius' weighing machine for aspirin.

The 'Sigma-Aldrich' UV spectrometry equipment; a UV cuvette, a connected personal computer with a UV spectrometry scanning software installed.

Determination of the efficiency of Intercalation between Aspirin (acetylsalicylic acid) and the montmorillonite clay:

Crystalline form of aspirin at room temperature, powdered form of dry Na+ montmorillonite clay at room temperature.

'Serturius' weighing machine for weighing aspirin as well as the clay.

Sonication machine for mixing the clay into Isopropanol.

A set of 250ml, 100ml & 50ml beakers; a set of 10ml, 20ml, 50ml, 100ml & 250ml volumetric flasks.

A set of 20ml transparent plastic containers for keeping the aspirin-clay mixture.

A sideway shaker for keeping the above mixture for shaking at a particular magnitude and for a predetermined time.

The 'Sigma-Aldrich' UV spectrometry equipment; a UV cuvette, a connected personal computer with a UV spectrometry scanning software installed.

Determination of efficiency of intercalation on time-dependent intervals:

Crystalline form of aspirin at room temperature, powdered form of dry Na+ montmorillonite clay at room temperature.

'Serturius' weighing machine for weighing aspirin as well as the clay.

Sonication machine for mixing the clay into Isopropanol.

A set of 250ml, 100ml & 50ml beakers; a set of 10ml, 20ml, 50ml, 100ml & 250ml volumetric flasks.

A set of 20ml transparent plastic containers for keeping the aspirin-clay mixture.

A sideway shaker for keeping the above mixture for shaking at a particular magnitude and for a predetermined time.

The 'Sanyo' manual/automated centrifugation machine capable of 3000 RPM speed for a period of at least 10 minutes.

The 'Sigma-Aldrich' UV spectrometry equipment; a UV cuvette, a connected personal computer with a UV spectrometry scanning software installed.


The methods too can be divided according to the three sets of experiments that were carried out. Hence, the sequence shall remain the same as mentioned in the 'methods' section.

Determination of the solubility of Aspirin in Isopropanol and the calibration curve for Aspirin in Isopropanol:

The solubility of aspirin in isopropanol was determined by setting up a range for both aspirin and isopropanol in terms of their respective concentrations.

The method had to be designed in such a way, that the amount of isopropanol used can be at practical levels when considered an industrial scale of production.

Therefore, the total volume of the aspirin in isopropanol solution was set at 100ml.

The process was carried out at room temperature in normal daylight as it was found that aspirin is stable and not photosensitive.

The protocol for the experiment:

Weighed various amounts of aspirin on the 'Sertorius' weighing machine in an appropriate location, that is, at a location where there is no probability of heavy wind as it may affect the accuracy of the highly sensitive machine.

Decanted approximately 125ml of Isopropanol in a 250ml glass beaker. Keep ready a 100ml volumetric flask at the same time.

Poured the weighed aspirin (even though varying amounts of aspirin are weighed, take individually weighed aspirin at a time) into the volumetric flask, made sure that the aspirin particles/crystals do not stick to the top edges of the volumetric flask.

Gradually added the decanted 125ml isopropanol into the volumetric flask, with an initial addition of approximately 50ml.

Shook the mixture of aspirin in isopropanol vigorously. Observed if the solution is clear or if there are still aspirin particles floating inside. A period of 10-15 minute shaking was considered standard.

If the amount of isopropanol added was insufficient to dissolve the aspirin, more of isopropanol was added until the solution is clear and colourless (it should be colourless by default given the property of aspirin).

The clear solution was then made up to 100ml volume by adding appropriately required amount of isopropanol.

The above process was initialized by weighing 1g of aspirin first; the process was repeated by adding gradually increasing amounts of aspirin, for example: 2g, 3g, 4g, 5g, 5.5g, 6g & finally 7g of aspirin to 100ml of isopropanol.

The highest concentration of aspirin wherein the end solution was absolutely clear was noted and considered as the solubility value for aspirin in isopropanol.

Calibration curve determination for aspirin in isopropanol:

The protocol for this set of experimentation is an extension to the solubility test of aspirin in isopropanol.

While obtaining a calibration curve or any experiment related to UV spectrometric analysis, there is a frequent need to dilute the stock solution with more of the solvent used for the stock solution. Therefore, it is necessary to determine a volume that is within practical range, otherwise, it becomes impractical to reproduce the method on an industrial scale.

However, in the case of aspirin, this task is quite a challenge as the UV spectrometry equipment is highly responsive to the aspirin content.

The other factor to be considered, is the possibility that the solvent itself can sometimes be UV-ACTIVE, and that will definitely affect the overall absorption calculated by the UV machine.

The positive part is, isopropanol is not UV active.

Considering the advantage, the procedure is as follows:

Weighed a predetermined amount of aspirin and dissolved in approx 70ml of isopropanol in a volumetric flask.

Shook the solution vigorously until it is perfectly clear; note that it is always a transparent solution.

Made up the total volume to 100ml with isopropanol.

Now this solution was subjected to UV analysis, but the concentration of aspirin was so high, that the optical density obtained was far beyond the measurable range.

Hence, the stock solution was diluted to such an extent, that the optical densities obtained are below 1.0 units; preferably between 0.4 and 0.8 units.

Based on the readings, a calibration curve was drawn on a Microsoft excel sheet.

Determination of the efficiency of Intercalation between Aspirin (acetylsalicylic acid) and the montmorillonite clay:

Weighed a pre-defined amount of aspirin (exact weight mentioned in the results section); same applies to the amount of Na+ montmorillonite.

Dissolved aspirin in the isopropanol and made up the total volume to 100ml in a volumetric flask.

On a parallel basis, added montmorillonite to 70ml of isopropanol. Subjected the emulsion to sonication so as to impart the equal dispersion of the montmorillonite particles. Then made up the volume to a total of 100ml.

The aim was to determine the change in optical density with respect to the change in concentration of aspirin pertaining to the clay. Therefore, the aspirin concentration had to be varied. In such a way that:

The volume of aspirin in isopropanol and the volume of clay in isopropanol are equal at 10ml each; so that the total volume of the mixture becomes 20ml.

So the concentration of aspirin is varied within the 10ml portion of the aspirin in isopropanol solution.

Now, the above step is carried out with the assumption that clay material does not show any optical density when subjected to UV spectrometry.

The next step was to mix the two 10ml portions together with respect to their varying concentrations of aspirin and keep them for shaking at a magnitude of 125 units. The shaking was continued for a period of 20 to 24 hours. There were five solutions prepared.

After the duration was over, each solution was first filtered with a syringe filter until the filtrate is clear.

Now, the UV spectrometry machine was set up so as to be compatible with this analysis. The parameters adjusted in order to obtain a baseline were:

The optical density frequency was set to 'medium'

The absorbance range (optical density range) was set between 200 and 500 instead of the by default 200-800.

The baseline correction option was set to zero baseline level.

Then the 'set baseline' button was pressed, but before that, blank isopropanol solution was put into the black-box in a cuvette.

The next step in setting up the baseline was to block the beam by an opaque cardboard and run the machine by pressing the 'start button' on the computer monitor. Thus, the baseline was set to zero level.

The undiluted filtrate, when subjected to UV spectrometry, produced way out of the range readings. Therefore, it had to be diluted in such a way, that the optical density obtained was below 1.0 units, ideally below 0.8 units considering the values obtained for the calibration curve.

The serial dilutions were carried out in such a way that their respective optical densities were proportionate to the calibration curve for aspirin.

Determination of efficiency of intercalation on time-dependent intervals.

As elaborated before, the aspirin and the montmorillonite clay were weighed and their respective solutions in isopropanol were prepared and mixed together.

The distinct point of difference in the protocol, was the time intervals in which the readings were obtained.

Another crucial alteration in the process was the use of centrifugation machine ('Sanyo') for carrying out phase separation.

The parameters set were:

3000 RPM

Duration= 10 minutes

Temperature: room temperature

Time taken to accelerate to 3000 RPM= 1 minute 15