Development Of An Activated Carbon

Published Date: 02 Nov 2017

Contents

4. Experimentation..............................................................................................................................13

4.1 Differential Scanning Calorimetry (DSC)........................................................................................14

4.2 Fourier Transform Infrared Spectroscopy (FTIR)..................................................................15

4.2. Scanning Electron Microscopy (SEM)...................................................................................16

Table of Figures

ABBREVATIONS

DSC: Differential scanning calorimetry

FTIR: Fourier Transform Infrared Sprectorscopy

FOMC: Fibrous ordered mesoporous carbon

GIT: Gastro intestinal tract.

PEG: Polyethylene glycol.

UMCS: Uniform mesoporous carbon spheres

SUMMARY

Paracetamol is one of the most commonly used analgesic and antipyretic drug. The only problem associated with this drug is its poor aqueous solubility and low permeability, which further leads to the poor absorption of drug and hence low bioavailability. Many researchers have worked on this issue and many formulations of paracetamol have already been marketed which use various ‘soluble-drug carriers’ to enhance the solubility of drug. PEG 6000, PEG 4000, Mannitol, Tween 20 etc are few of those millions carriers used in paracetamol formulations; they markedly enhanced the permeability of drug; however these soluble carriers possess various clinical disadvantage and use of these carriers could lead to certain major disorders like – nephrotoxicity. The main aim of this project is to develop a novel drug delivery system to enhance the solubility of paracetamol using activated carbon (porous carbon) as a drug-carrier with minimal side effects. Utilization of organic porous materials in formulations of poorly water-soluble drugs to enhance their dissolution and bioavailability is a rapidly growing area in the field of pharmaceutics. Activated carbon is a promising novel candidate to improve the dissolution rate of poorly soluble drug such as, paracetamol. This is because activated carbon possess a high surface area, large pore volume and uniform pore diameter and the loading of drug generally takes place by physio-sorption and pore filling. The loaded drug remains in a non-crystalline and disordered state. The use of activated carbon as a carrier does not only improve the dissolution rate of drug but it also affects the absorption tendency of the loaded drug. These porous materials can be architected in various ways and external surface of these particles can be modified to be muco-adhesive, the bioavailability can be effectively increased even though these nanoparticles themselves would not enter into the systemic circulation from GIT. In this study, various types of porous carbon systems and their detailed study have been discussed. The use of UMCS (Uniform mesoporous carbon spheres) and FOMC (Fibrous ordered mesoporous carbon) as a drug carrier to enhance the solubility of poorly soluble drug has been studied. The procedures and methods discussed hereby to enhance the solubility of poorly soluble drugs may further be employed to improve the solubility and permeation of the model drug paracetamol. The functionalization and characterization of drug adsorbed in activated carbon will be done by using various analytical techniques-Differential scanning calorimetry, Fourier transform infrared spectroscopy, Scanning electron microscopy. These techniques will be used to assess the solubility of paracetamol. The obtained data will be compared with the standard solubility curve for paractemol in aqueous solution so as to determine the efficiency of the solublizing carrier used.

BACKGROUND

INTRODUCTION

In drug development, delivery of drug to the systemic circulation is the key concern so as to assess the pharmacological activity of the drug. Drug can be an organic or an inorganic compound, therefore its physicochemical properties are to be assessed so as to formulate a dosage form. There are various physicochemical properties of the drugs in a solution that needs to be assessed, which includes – thermodynamics, chemical potential, ionisation of drugs and diffusion of drugs. These factors are responsible to determine the solubility of the drug(Attwood, 2006). In this research project, the study will be carried out to determine the improvement of solubility of Paracetamol (acetaminophen), which is a poorly soluble drug.

General Context

Paracetamol (PCT) was firstly discovered by Von Mering in 1893. It is one of the most widely used analgesic-antipyretic drug and is available in various pharmaceutical forms and varied doses. Currently, in clinical practice, the drug paracetamol is a safe and reliable drug as it is a highly effective drug with minimal side-effects. However, over dosage of drug may lead to ‘hepatic fulminant necroses’, nephrotoxocity and teratogenic effects (Abdullahu et al., 2012).

Physicochemical properties of paracetamol:

The drug exist in white, crystalline power form and molecular formula of paracetamol is C8H9NO2 (Monographs). The chemical name of paracetamol is N-(4-Hydroxyphenyl)acetamide and the IUPAC name of the drug is 4′-Hydroxyacetanilide (Monographs). The density of drug is found to be 1.293 g/cm3 at 21°C (Lide, 1997) and the relative molecular mass is 151.17 (Monographs). Paracetamol is insoluble in water and very soluble in ethanol and the melting point of drug is 170oC (Lide, 1997). It was reported by Yalkowsky and Dannenfelser that water solubility of paracetamol is 1.4E+004mg/L at 25oC(Yalkowsky and Dannenfelser, 1992). The octanol/water partition coefficient (log P) value for paracetamol is 0.31 (Hansch et al., 1995).

Figure : Structural formula of Paracetamol(Monographs).

Common problem associated with paracetamol

According to Bio pharmaceutics classification system (BCS), paracetamol falls under class III drugs having low permeability and the standard dose of paracatemaol is 100-500 mg (Sweetman, 2005). The major problem associated with the drug is its poor water solubility. The drug is insoluble in water and very soluble in ethanol. Therefore, it is not properly absorbed in the body and is unable to reach the systemic circulation. Thus bioavailability of the drug remains low and effective therapeutic effects is not produced (Sweetman, 2005).

Previous Scientific Literatures

Multi factorial studies have already been done in order to increase the aqueous solubility of drugs. An example of such method includes the use of drug carries as co-solvents. Drug carriers are used to improve the delivery and the effectiveness of drugs(Papisov, 2004). They have following applications:

to increase the duration of action of drug(Papisov, 2004).

to reduce the metabolism of drug(Papisov, 2004).

to reduce the toxicity of drug(Papisov, 2004).

The next section will discuss the various formulations which have already been introduced in the market with improved paracetamol solubility by using different carriers.

Effects of Different Carriers (Mannitol,Tween 20 and PEG 6000) on the Solubility of Paracetamol)

In a previous study, Mannitol, PEG 6000 and Tween 20 were used as carriers along with paracetamol in order to improve the drug solubility. A standard curve of paracetamol was plotted by dissolving 100 mg of the drug in 100mL methanol. Various dissolutions were prepared and these dilutions were further analyzed for absorbance at 257nm by using a UV-Visible spectrophotometer. A calibration curve was obtained(Majid et al., 2009).

Figure : Standard curve of paracetamol (Majid et al., 2009)

Phase Solubility Studies of Various Drug Carriers on Paracetamol

In the phase solubility studies of paracetamol, different carriers were used and it can be incurred from the graph plotted below that PEG 6000 was found to be the most effective in improving the drug solubility. Furthermore, the other two carriers, i.e - mannitol and tween 20 were also found to improve the drug solubility but were less effective when compared with PEGylated paracetamol (Majid et al., 2009).

Figure : Influence of carrier on solubility of paracetamol(Majid et al., 2009)

Disadvantages of carriers used in above research

Disadvantages associated with PEG 6000:

Immunological reaction due to PEG polymers: Administration of PEG can cause blood clotting or cell adhesion which causes embolism following intravenous administration. They can also cause hypersensitivity reactions which can further lead to anaphylactic shock(Knop et al., 2010).

Non biodegradable nature of PEG molecules: The oxidative degradation of PEG is reduced with increasing molar mass and therefore higher molecular mass PEG are sustained in the body(Knop et al., 2010).

Degradation under stress: Under stress due to oxygen, water and energy such as radiation, heat and mechanical forces can cause degradation of PEGylated polymers thus compromising therapeutic activity of drug (Knop et al., 2010).

Disadvantages of mannitol

If mannitol is administered in high doses it is freely filtered by the glomerulus and it fails to undergo tubular re absorption. Thus, it acts as a diuretic and cause the removal of sodium ions and electrolyte free water which may cause hypernaterimia and may also lead to volume depletion (Cancer et al., 1965).

Disadvantages of tween 20

Tweens are known for causing oxidative damage in proteins, mainly in their tryptophan and methionine moieties.

How will the problem be addressed?

Since much research have been done and many soluble carriers have previously been used in order to enhance the solubility of paracetamol. Activated carbon is a novel excipient which can be used as a drug carrier to effectively enhance the solubility of paracetamol.

What is Activated Carbon?

Activated carbon also known as porous carbon is charcoal that has been treated with oxygen in order to open up a large number of tiny pores between the carbon atoms. It usually offers a very high degree of micro porosity and adsorptive capacity(Incorporated, 2006).

For adsorption to occur the internal surface area should be approachable for the fluid or vapour. Having highly developed internal surface is not the only requirement, it is necessary to have a well developed network of pores of varied diameters. The various pore sizes available in the activated carbon are categorized as follows(Incorporated, 2006):

Micropores: Less than 40 Angstroms

Mesopores : Between 40 - 5,000 Angstroms

Macropores : Larger than 5,000 Angstroms

Mechanism of adsorption by activated carbon

The process by which the activated carbon works is forces is known as ‘Adsorption’. Adsorption may be defined as the process where the fluid molecules are taken up by a liquid or solid and are distributed through that liquid or solid medium(Incorporated, 2006). In the physical adsorption process, molecules are held by the surface of carbon by weak molecular forces known as VanDer Walls Forces, which may result due to intermolecular attractions of the molecules. Hence, no chemical changes occur between carbon surface and the adsorbate. However, in Chemisorption, molecules of adsorbate chemically react with the surface of carbon and form strong chemical bonds Physisorption is the most common method employed by the activated carbon(Incorporated, 2006).

http://www.unifycarbon.com/images/activited-carbon.jpg

Figure Mechanism of action of activated carbon(carbon, 2013)

Activated carbon has great adsorption ability for phenols. The two most common forms in which activated carbon is being used is, powder form and granular form. In case of liquid-phase adsorption the adsorption capacity of activated carbon depends upon the following factors(DÄ…browski et al., 2005):

Physical nature of adsorbent, for example - pore structure, pore size and functional groups.

The nature of adsorbate, for example - pKa, polarity, molecular weight and size.

In a recent study a detailed investigation was done on how does the carbon surface chemical composition affects the adsorption of phenols. It was observed that two factors which strongly influence the adsorption properties of carbon are: surface modification of carbon and the temperature(DÄ…browski et al., 2005). A study was done in order to measure the paracetamol adsorption and desorption isotherm on both modified and non modified carbon and it was observed that adsorption of paracetamol increases with rise in temperature.

The main steps involved in adsorption of solute by porous carbon are:

Movement of a solute through the liquid film to the exterior of granule(DÄ…browski et al., 2005).

Dispersion of solute inside the pores of an adsorbent(DÄ…browski et al., 2005).

Adsorption of solute on the interior surfaces consisting of pores and capillary spaces of adsorbent (DÄ…browski et al., 2005).

Activated carbon (porous carbon) as a novel adsorbent

Activated carbon is widely used in pharmaceutical area to enhance the solubility of poor soluble drugs. The mesoporous carbon based materials have a pore size ranging between 40 - 5,000 Angstroms. An advantage of using mesoporous materials in drug delievery is their large surface area and large pore volume(Xu et al.). These porous materials effectively enhance the adsorption from gastrointestinal tract to systemic circulation These properties allows the carbon to accommodate large amount of drug, protect the drug from degradation and enhance its controlled and rapid drug release(Xu et al.).

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Figure : The graph depicts the rate of drug release from poorly soluble drug in pure form and the drug loaded in mesoporous system (Xu et al.).

The major problems associated with clinical application of these molecules are, their safety aspect. However, majority of these products are excreted safely from the body and a extensive toxicity screening of few frequently used products has also been conducted(Xu et al.). The other challenging factor associated with mesoporous products is their large scale production at reasonable cost. However, if these materials could be employed in industrial process as a carrier product for poor soluble drugs, to enhance their bioavailability, this might lead to a great advancement in the pharmaceutical industry(Xu et al.).

Intended Procedure

A solution of poorly soluble drug (paracetamol) is prepared by mixing with ethanol.

In the next step activated (porous) carbon is added to the above solution. Due to the presence of pores on the surface of carbon and large surface area the drug will be adsorbed on the surface of activated carbon.

The activated carbon will then be separated from the solution by using general separation/filtration techniques.

The powdered activated carbon is collected which contains inside it’s pores

The amount of drug is measured.

Physicochemical characterization of the drug is done and the studies are done to investigate the enhancement in solubility of drug.

Recent scientific studies on activated (porous) carbon

Various solubility studies of paracetamol (with and without using activated carbon as an adsorbent) are discussed below:

A study to assess the increase in solubility of paracetamol by solid dispersion technique using different polymers concentration

In the current clinical study the drug was dispersed with different polymers to enhance its solubility. The aim of researchers to carry out this study was to prepare, characterize and compare the solid dispersions of paracetamol with PEG 4000 and polyvinyl pyrrolidone (PVP) so as to increase the dissolution rate of the drug (PRAMOD KUMAR SHARMA, 2011). Solid dispersions were prepared by physical mixing and kneading method at the 1:1, 1:2 and 2:1 drug to polymer ratio (PRAMOD KUMAR SHARMA, 2011).

Multiple dissolution studies were carried out and it was found that the rate of drug release for solid dispersion was much higher as compared to the pure drug taken alone. However, on the basis of drug release pattern, the kneading method was found to have more drug release when compared with physical mix method. In the end, it was concluded that using PEG 4000 as a carrier in the paracetamol formulation would give the faster dissolution rate among all the selected formulations (PRAMOD KUMAR SHARMA, 2011).

However as it has already been discussed there are various disadvantages related to PEG polymer.

In vitro study to determine the role of different solvents on adsorption of paracetamol on activated carbon

A recent study was carried out to enhance the adsorption of paracetamol on activated carbon by adding different solvents in water (Terzyk and Rychlicki, 2000). A solution of paracetamol and activated carbon along with water was prepared. Three different chemicals, sulphuric acid, nitric acid and gaseous ammonia were added separately to the previously prepared solution. The adsorption and desorption of paracetamol on modified and non-modified carbons showed that with an increase in temperature and addition of sulphuric acid, the adsorption of paracetamol was found to be increased. However, there was no change in adsorption properties of activated carbon when ammonia was added and an opposite effect was observed with addition of nitric acid (Terzyk and Rychlicki, 2000).

A study of uniform mesoporous carbon spheres (UMCS) and fibrous ordered mesoporous carbon (FOMC) on poorly water soluble drugs

A study was carried out on two forms of porous carbon (activated carbon). The aim of the study was to investigate the use of porous carbon as carrier for poorly soluble drugs and to check its cytotoxicity (Zhao et al., 2012).

In this research, uniform mesoporous carbon spheres (UMCS) with 3-D pore system and fibrous ordered mesoporous carbon (FOMC) with 2-D structure were employed as carriers for poorly soluble drug Lovastatin. In the next step, the rate of drug release and degree of drug loading of UMCS and FOMC were then compared and the effects of different pore architecture and pore size on drug uptake and release were investigated. In addition, cytotoxicity studies of UMCS and FOMC were also carried out (Zhao et al., 2012).

The result showed that UMCS had a higher drug loading ( 36.26% drug weight/total weight) when compared with FOMC(Zhao et al., 2012). Moreover, the dissolution rate of poorly aqueous soluble drug lovastatin with UCMS increased dramatically when compared with pure crystalline form of drug. However, both UMCS and FOMC were observed to have a weak extremely cytotoxicity (10–800 lg/ml) (Zhao et al., 2012).

In vitro release profile

The drug release profile for the pure crystalline drug and drug loaded samples was studied. LOV belongs to the class of drug which exhibit very poor solubility in water and GIT tract, and found have a very slow release rate and low bioavailability(Zhao et al., 2012).

For crystalline form of drug : The cumulative dissolution of pure crystalline drug was only about 30% after 90 minutes, representing poor absorption and low bioavailability (approx 20-40%) (Zhao et al., 2012).

For drug loaded FOMC: In case of drug loaded samples of LOV-FOMC, a much better and faster dissolution rate was observed as compare to that of pure form. The cumulative dissolution of drug in buffer (ph 6.8) was more than 55% at the sampling time of 10 minutes(Zhao et al., 2012). The increase in dissolution rate may be due to the following reasons:

The transformation of drug from crystalline to non crystalline state, leading to reduced binding energy, thus increased solubility(Zhao et al., 2012).

Relatively high dispersion of drug molecules in to the pore channels of the carrier carbon(Zhao et al., 2012).

The particle size of the drug is significantly reduced in drug-loaded sample, hence there is an increase in surface area and increase in contact between drug and dissolution medium(Zhao et al., 2012).

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Figure : The first two pictures represents the effect of pore size and pore channel structure on drug uptake. The graph represents the release rate of drug - UMCS, FOMC and Raw crystallized drug. The drug release rate from UMCS was found to be highest (Zhao et al., 2012).

For drug loaded UMCS: They exhibit even faster dissolution rate when compared with previous two samples. The cumulative dissolution was found to be 70-90% at sampling time of 15 minutes(Zhao et al., 2012). Also UMCS has a 3-D pore system and length of pore channel is very short compared to FOMC, this is the main reason why UMCS possess faster release rate (Zhao et al., 2012).

In the nutshell, the larger the mesopore, the faster is the dissolution rate. The reason behind this may be that large pores can effectively provides less resistance for the drug to pass through the channels(Zhao et al., 2012). This study on poor soluble drug Lovastatin suggested the of mesoporous carbon for the delivery of poorly soluble drugs(Zhao et al., 2012).The similar technique may also be applied to enhance the solubility of paracetamol.

Intended design and method of investigation

In order to solve the problem of low aqueous solubility of paracetamol, activated (porous) carbon can be used as a solubilising carrier. A method has been designed which will be used in the experimental technique.

The experiment will be carried out in following three steps(Xu et al.):

Formation of drug and carrier complex.

Physicochemical characterization by using DSC (Differential Scanning Calorimetry), FTIR

(Fourier transform infra red spectroscopy) and microscopy (SEM or TEM).

Investigation of drug release kinetics by studying drug release profile.

Drug and carrier complex formation

The concentration of poorly soluble drug (paracetamol) is low, the mesoporous carriers (activated carbon) is loaded by using following three methods(Xu et al.):

Organic solvent immersion method (Xu et al.).

Incipient wetness impregnation (Xu et al.).

Melt method (Xu et al.).

The drug loading procedure remains same for all the three methods(Xu et al.):

Immersion of mesoporous material into concentrated drug solution and filling of pores by capillary action.

In second step the drug is diffused into the mesopores and adsorption of drug takes place on to the walls of the pores.

In the final step, the drug loaded mesoporous material is recovered from the solution.

Organic solvent immersion method is the most commonly used method for drug loading. In another method, i.e Incipent wetness impregnation, a high loading degree is obtained by using a highly concentrated drug solution (the drug concentration is nearly close to its solubility). The volume of the drug solution equals to the pore volume of mesoporous carriers, which is one of the main differences compared to the immersion method. The second method is generally used in the cases when only small amount of drug is available, as in such case it is easy to determine the amount of loaded drug in advance. However, a major disadvantage associated with these systems is the difficulty to keep a control on uniformity of drug distribution (Xu et al.).

Loading degree: Loading method directly affects the loading degree obtained, thus affects the packaging of molecules into the pores and distribution of molecules into the carrier as well, which may further affect the release kinetics of drug. Loading degree exceeding 60 wt% is difficult to attain. The various factors which affect the loading degree are, pore size, surface chemistry, pore volume and surface area and the type of solvent used (Xu et al.).

Physicochemical characterization:

Characterization of non-loaded mesoporous carriers

The two most common characteristics of mesoporous carrier are the chemical composition of its surface and structure of its pore network. Spectroscopic method such as Fourier Transformation Spectroscopy (FTIR) is widely used for the characterization of chemical groups on the surface of these porous materials. The structure of the pore is generally characterized by using various types of microscopy techniques, i.e – Transmission electron microscopy (TEM) or SEM.(Xu et al.)

Characterization of loaded mesoporous carriers

Characterization of loaded carrier generally focuses on the interaction between drug and carrier, the amount and physical characters of loaded drug. FTIR is the most common technique used to study drug-carrier interactions and thermogravimetry is the most common technique used to measure the drug loading degree(Xu et al.). Another technique like, High performance liquid chromatography (HPLC) is most commonly used to study the drug concentration assay(Xu et al.).

It is very necessary to note the state of the drug in mesoporous drug carrier. The release of the drug from the pores may get blocked if a drug is present on the outer surface of carrier molecule and could drastically alter the release rate of loaded drug. Drug material located outside the pores can be distinguished from the drug material present inside the pores by the size of the crystallites. The crystalline size is limited by the pore walls inside the pores, whereas such restraints do not exist outside the pores and crystallites may grow significantly larger(Xu et al.). The most widely used technique to determine the physical state of drug is Differential scanning calorimeter (DSC)(Xu et al.).

Investigation Of Drug Release Profile

After the characterization of drug loaded mesoporous carriers has been done, the next step is to study the drug release profile. In general, enhancement of rate of dissolution in GIT is the first and foremost target for the delivery of poor soluble drug by porous materials. The drug is loaded inside the mesoporous material by the methods explained above. As compared to the crystalline form of drug, amorphous phase of drug inside the mesopores helps to reduce the lattice energy and improve the wettability and thus enhance the dissolution rate of the drug and thus increases the bioavailability(Xu et al.).

Following are the four steps that place after immersion of drug loaded microsphere into the living media(Xu et al.):

Absorption of liquid/aqueous media into the porous system by the capillary action.

Dissolution of loaded drug into the release medium inside the pores.

Diffusion of drug molecules outside the pores depending upon the concentration gradients

Transportation of drug molecules in the release medium

While investigating the drug release profile, it should ke kept in mind that there are various various factors that affects the rate of drug release from porous carriers, they are:

Pore size plays a major role in rate of drug release and the rate of drug is released by diffusion mechanism(Xu et al.).

Surface chemistry of porous material plays an important role in determining the rate of drug release(Xu et al.).

Pore structure of porous carrier also plays an important role in drug release. A 3D mesoporous architecture could provide more efficient mass transfer which facilitate drug release without causing blockage of pores.(Xu et al.)

EXPERIMENTATION

LIST OF ANALYTICAL TECHNIQUES TO BE USED:

DSC (Differential Scanning Calorimetry)

FTIR (Fourier Transform Infrared Spectroscopy)

Scanning Electron Microscopy

Differential Scanning Calorimerty:

Principle: Differential scanning calorimetry is based on the principle that heat flow through the compound depends on phase changes or a chemical reaction taking place during the heat flow through the sample which is measured by comparing it with reference standard. The difference between the reference and the standard is converted to heat flow using calibration data as well as data obtained from metals of known enthalpy of fusion(Sorrell, 2011).

Instrumentation: DSC cell consist of DSC sensor which is placed below the two crucibles. One crucible is used to keep the sample while the other is used for the reference standard. DSC sensor is made up of multiple thermocouples for high sensitivity. The crucibles are kept in a close system so as to maintain the atmosphere and inert gas is used to wipe out the oxidation process(Sorrell, 2011).

Paracetamol and activated carbon with 99.9% purity will be used as a reference standard.

Figure : Schematic diagram of DSC(Sorrell, 2011)

Application of DSC:

DSC is employed to observe the size of the crystallites and crystalline phases in the loaded materials. Hereby, the major application of DSC is that it can effectively be used to differentiate between the drug present inside the pores from that present on to the external surface, as the drug which is present inside the pores does not contribute to the normal (bulk) melting endotherm(Xu et al.). If the drug is crystallized inside the pores, this causes a depressed melting endotherm due to the small crystallite size. An advantage of DSC in this context is that it is more sensitive for detection of crystalline material with small crystallite size. (Xu et al.)

Fourier Transform Infrared Spectroscopy (FTIR):

Principe: FTIR is based on the principle of measurement of molecular vibration taking place in a compound. When a compound absorbs electromagnetic radiation with wavelength in the IR region it causes vibration in bonds of a molecule. The frequency of vibration depends on the mass of atoms in a molecule, strength of the bond and dipole-dipole interactions between the atoms.(Sorrell, 2011)

Instrumentation:

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Figure : Schematic diagram of inner components of FTIR(Sorrell, 2011)

Application:

It will be used to identify the new bond formation occurring when the paracetamol is adsorbed on the surface of activated carbon(Sorrell, 2011). FTIR is the most common technique used to study drug-carrier interactions.

Scanning Electron Microscopy:

The structure of the pore is generally characterized by using this technique. This technique enables the investigation of carbon with a resolution down to the nanometer scale(Sorrell, 2011). The beam of electron is being generated by electron cathode and the electromagnetic lense of column and it is finally moved on to the surface of the sample to be analysed. A raster is described by the path of beam which is then correlated to the raster of grey level on the screen(Sorrell, 2011).

The sample is generally imaged at a range of magnifications from x40 up to x1200(Sorrell, 2011).

INSTURMENTATION:

Figure : Schematic diagram of inner components of SEM(Sorrell, 2011)

Research Plan (GANNT Chart)

Tasks Involved

January

February

March

April

May

June

July

August

September

Weeks

1

2

3

4

1

2

3

4

1

2

3

4

1

2

3

4

1

2

3

4

1

2

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4

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4

1

2

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4

Meeting with

supervisor

Send Draft of Progress to Supervisor

A

B

C

D

E

Collection of Literature

I

2

3

Proposal

Introduction

Write-up

Lab Induction

Health and Safety Talk

Complete COSHH and Safety Requirements

Practical work

Formation of Drug and Activated Carbon Complex

Drug + Activated carbon complex prepared

Analysis Process

Analysis Process

In-vitro studies

(Study drug release kinetics)

Content Analysis

Abstract submission and Project

Poster Presentation

Project duration

LEGEND

The entire project duration is from the 2nd week to January to the 2nd week of September. In the third week of January a meeting with supervisor was done in order to discuss the proposal plan. Meeting with supervisor was held again in first week of February. The draft for proposal was sent to the supervisor for review. The research proposal has been submitted in the first week of March. A meeting will be scheduled again with supervisor in the second week of March and literature review will be done again for the introductory part of the project. The introduction write up work should be started by April 3rd week and submitted to supervisor by June second week and a meeting should be held with supervisor for the feedback by third week of June. The lab induction and health & safety talk have to be attended in the 1st and 2nd week of May. The experimental work will be begin on 27th May up to 26th July with regular project meetings with supervisor. The final project report should be submitted by the 1st week of September and a poster presentation should be done in the second week.

ANNOTATED BIBLIOGRAPHY

ABDULLAHU, B., MORINA, N. & ISLAMI, H. 2012. Study of Formulation of Mild Pharmaceutical Forms of Paracetamol in Medical Practice. Mat Soc Med, 24, 148-150.

''This paper describes the study of four pharmaceutical formulations of paracetamol in medical practice. The various excipients used in the four formulations are also studied.''

ATTWOOD, A. T. F. A. D. 2006. Physicochemical Principles of Pharmacy, London, Pharmaceutical Press 2006.

''A section of this book highlights the various physicochemical properties of drugs in solution that needs be assessed, that include thermodynamic properties, chemical potential of drug etc.''

CANCER, G., GIPSTEIN, R. M. & BOYLE, J. D. 1965. Hypernatremia complicating prolonged mannitol diuresis. New England Journal of Medicine, 272, 1116-1117.

'' This journal highlights the various problems and disadvanatges associated with the use of mannitol in clinical applications. The information from the journals was used to describe the disadvantages of using mannitol as soluble carrier for paracetamol''

CARBON, G. A. C. A. P. A. 2013. Unify Carbon [Online]. Available: http://www.unifycarbon.com/activated-carbon.html [Accessed 27 February 2013].

'' The reference is given for the image which has been used to describe the mechanism of adsorption by activated carbon.''

DĄBROWSKI, A., PODKOŚCIELNY, P., HUBICKI, Z. & BARCZAK, M. 2005. Adsorption of phenolic compounds by activated carbon—a critical review. Chemosphere, 58, 1049-1070.

''This journal described the use activated carbon as a medical adsorbent. The reference is used in order to validate the use of activated carbon as an adsorbent for phenolic compounds specially paracetamol and to describe the adsorption by porous carbon.''

HANSCH, C., LEO, A., HOEKMAN, D. & HELLER, S. R. 1995. Exploring QSAR, American Chemical Society Washington, DC.

''This particular reference has been added to validate the log P value of Paracetamol.''

INCORPORATED, C. C. 2006. Activated Carbon and Related Technology [Online]. MD, USA. Available: http://www.cameroncarbon.com/documents/carbon_structure.pdf [Accessed].

''This website is reffered because it support the discussion related to the details of activated carbon, its manufacture, structure, properties and mechanism of action.''

KNOP, K., HOOGENBOOM, R., FISCHER, D. & SCHUBERT, U. S. 2010. Poly (ethylene glycol) in drug delivery: pros and cons as well as potential alternatives. Angewandte Chemie International Edition, 49, 6288-6308.

'' This section has been discussed to validate the various disadvanatges related to the clinical use of PEG. The disdvanatges of PEG has been discussed because PEG is one of the most commonly used soluble carrier in case of paracetamol formulations.''

LIDE, D. R. 1997. CRC Handbook of Chemistry and Physics, Boca Raton, Florida., CRC Press.

'' This reference has been added to validate the density, water solubility and melting point of paracetamol.''

MAJID, M., MISHRA, R. & KUNVAR MISHRA, B. 2009. Effects of Various Carriers on the Solubility of Paracetamol. Research Journal of Pharmacy and Technology, 2, 419-420.

'' This paper has been discussed as it gives detailed information about the various soluble carrier which have already been used in currently marketed paracetamol formulations. The purpose of discussing this paper is to show the previous research literature of the drug and discuss their disadvanatges and mention how 'activated carbon' as a novel drug carrier can be used to overcome those problems related to the previously used soluble carriers.''

MONOGRAPHS, I. Paracetamol Monograph [Online]. Available: http://monographs.iarc.fr/ENG/Monographs/vol73/mono73-20.pdf [Accessed 25-02-2013 2013].

'' The website is reffered as it gives the 'Monograph of drug Paracetamol' and hence is used to validate the various physicochemical and structural properties of paracetamol.''

PAPISOV, M. I. 2004. Drug-carrier complexes and methods of use thereof. Google Patents.

'' The reference has been given to support the evidence and applications of drug carrier-complex formation.''

PRAMOD KUMAR SHARMA, J. G. M., RISHABHA MALVIYA 2011. EVALUATION OF ENHANCEMENT OF SOLUBILITY OF PARACETAMOL BY SOLID DISPERSION TECHNIQUE USING DIFFERENT POLYMERS CONCENTRATION. Asian Journal of Pharmaceutical and Clinical Research, 4.

'' This paper enlightens the recent literature of the drug. It gives information about the evaluation of how solubility of paracetamol was enhanced by using PEG 6000 polymer as a soluble carrier.''

SORRELL, J. 2011. Characterisation of Silsesquioxane-Poly (Methyl Methacrylate) blends. University of Birmingham.

''The section has been reffered to support the discussion of three analytical techniques discussed in the proposal, i.e - DSC, FTIR and SEM.

SWEETMAN, S. C. 2005. Martindale: the extra pharmacopoeia. Pharmaceutical Press, London, 1371, 1372-1377.

'' This section has been refered in order to support the fact that solubility and low permeation is the common problem associated with the paracetamol and also to validate the BCS category of drug.''

TERZYK, A. P. & RYCHLICKI, G. 2000. The influence of activated carbon surface chemical composition on the adsorption of acetaminophen (paracetamol) in vitro: The temperature dependence of adsorption at the neutral pH. Colloids and Surfaces A: Physicochemical and Engineering Aspects, 163, 135-150.

'' This paper provides a detailed study of recently used techniques of using acitvated carbon as an adsorbent for paracetamol. However, various factors such as how does the chemical composition of activated carbon influence the adsoprtion rate has also been discussed. Characterization of activated carbon has also been done by using various analytical techniques.''

XU, W., RIIKONEN, J. & LEHTO, V.-P. Mesoporous systems for poorly soluble drugs. International Journal of Pharmaceutics.

''This piece of work on mesoporous system for poorly soluble drugs by International Journal of Pharmaceutics have been referred, as it provides a detailed study about the various characteristics, properties and methodology of how porous carbons can be used as an adsorbents. The methods of drug carrier-complex formation and influence of drug loading has also been referred. ''

YALKOWSKY, S. & DANNENFELSER, R. 1992. Aquasol database of aqueous solubility. College of Pharmacy, University of Arizona, Tucson, AZ.

'' The reference is given particularly in order to validate the water/aqueous solubility of paracetamol.''

ZHAO, P., WANG, L., SUN, C., JIANG, T., ZHANG, J., ZHANG, Q., SUN, J., DENG, Y. & WANG, S. 2012. Uniform mesoporous carbon as a carrier for poorly water soluble drug and its cytotoxicity study. European Journal of Pharmaceutics and Biopharmaceutics, 80, 535-543.

'' The paper of European Journal of Pharmaceutics and Biopharmaceutics has been reffered in order to validate the use of mesoporous (porous carbon) as a drug solublizing carrier in recent studies for poorly soluble drug.''