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Paracetamol is one of the most widely used analgesic and antipyretic drug. The only problem associated with this phenolic drug is its poor aqueous solubility, which further leads to the poor absorption of drug and hence low bioavailability. Since much research have already been done and many formulations of paracetamol have already been marketed which use various 'soluble-drug carrier' to enhance the solubility of drug. PEG 6000, PEG 4000, Mannitol, Tween 20 etc are few of those millions carriers used in paracetamol formulations, however there are various disadvantages associated with these drug carriers. 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 minial 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 posses a high surface area, large pore volume and uniform pore diameter and the loading of drug generally takes place by physisorption 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 mucoadhesive, 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 in detail. The use of UMCS and FOMC as a drug carrier to enhance the solubility of poorly soluble drug Lovastatin has been studied. The procedures discuseed hereby will further be employed in order to improve the solubility and permeation of the model drug paracetamol. Safety issues are always a concern, but in the cases, like in oral delivery, where the carrier material is degraded and excreted from body in a safe manner this concern is not expected to become a major obstacle.
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.
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, it's over dosage may lead to 'hepatic fulminant necroses', nephrotoxocity and teratogenic effect. (Abdullahu et al., 2012)
PARACETAMOL: PHARMACEUTICAL ASSESSMENT
PHYSICOCHEMICAL DATA OF PARACETAMOL
Molecular Formula: C8H9NO2
Physical Form: A white, crystalline powder
Chemical Name: N-(4-Hydroxyphenyl)acetamide
IUPAC Name: 4â€²-Hydroxyacetanilide
Density: 1.293 g/cm3 at 21Â°C
Molecular mass: 151.17(Monographs)
Molecular Structure of Paracetamol(Agency, 2010)
PHYSICOCHEMICAL PROPERTIES OF PARACETAMOL
pKa of paracetamol is 9.38
Stability of the Drug to Temperature, Light, and Moisture
Paracetamol is table to temperature, light, and moisture.
pH Range of Paracetamol over which Drug is Stable in Solution
The drug is stable at a pH between 5.5-6.5. So it is slightly acidic in nature.
pH of Commercially Available Liquid Products
Paracetamol oral solution (ie, elixir, adult liquid) has a pH of 3.8 to 6.1 and the oral suspension (ie, infants' drops, children's suspension) has a pH of 5.4 to 6.9.
1.4E+004 mg/L (at 25 Â°C) (Yalkowsky and Dannenfelser, 1992)
Octanol/water partition coefficient (log P):
The log P of paracetamol is 0.31
Common problem associated with Paracetamol
The major problems associated with paracetamol is its poor water solubility. The drug is insoluble in water and very soluble in ethanol. Therefore, it will not be properly absorbed in the body and will not reach the systemic circulation. Thus bioavailability of the paracetamol remains low and the effective therapeutic effects will not be produced by the drug. (Lide, 1997).
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 carriersÂ are used to improve the delivery and the effectiveness of drugs. They have following applications:
to increase the duration of action of drug
to reduce the metabolism of drug
to reduce the toxicity of drug.
In this section, we 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 100mg 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 has found to be 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 adhesion of cells together which causes embolism on intravenous administration. They can also cause hypersensitivity reactions which can further lead to anaphylactic shock.
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.
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 higher doses it is freely filtered by the glomerulus and it fails to undergo tubular reabsorption. 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)
Disorders like - Metabolic acidosis, Volume expansion, Hyponatremia, Hyperkalemia may occur. (Manninen et al., 1987)
DISADVANTAGES OF TWEEN 20
Tweens are known for causing oxidative damage in proteins, mainly in their tryptophan and methionine moieties.
RECENT SCIENTIFIC LITERATURE
Various solubility studies of paracetamol (with and without using activated carbon as an adsorbent) are discussed below:
A STUDY TO EVALUATE THE INCREASE IN SOLUBILITY OF PARACETAMOL BY
SOLID DISPERSION TECHNIQUE BY THE USE OF DIFFERENT POLYMERS
In the current clinical study the drug is dispered with different polymers to enhance it's 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. Solid dispersions were prepared by physical mixing and kneading method at the 1:1, 1:2 and 2:1 drug to polymer ratio.
Various 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)
IN VITRO STUDY TO DETERMINE THE INFLUENCE OF ACTIVATED CARBON SURFACE CHEMICAL COMPOSITION ON ADSORPTION OF PARACETAMOL ON VARYING THE TEMPERATURE WHILE KEEPING THE pH NEUTRAL
A recent study was carried out to enhance the adsorption of paracetamol on activated carbon by adding different solvents in water. A solution of paracetamol and activated carbon along with water was prepared. Three different chemicals which were added separately to the previously prepared solution - Sulphuric acid, nitric acid and gaseous ammonia. The adsorption and desorption of paracetamol on modified and non-modified carbons showed the following results:
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)
IN VITRO STUDY TO STUDY THE INFLUENCE OF ACTIVATED CARBON SURFACE CHEMICAL COMPOSITION ON THE ADSORPTION OF PARACETAMOL (ACETAMINOPHEN)
Another research was done by(Terzyk and Rychlicki, 2000) to study the effect of paracetamol adsorption from water and paracetamol solution by using two different types of activated carbon systems as adsorbents, i.e - modified carbon (using concentrated nitric acid, sulphuric acid, gaseous ammonia and which is modified via ionic exchange process with Cu2) and non- modified de-ashed commercial carbon D43:1. The characterization of the carbon was then done by using FTIR and XPS techniques.
Pharmacokinetic study of paracatemol adsorption by both carbons was carried out at three different temperatures i.e, 300,310 and 320 K. It was observed that the up to the relative adsorption value of 0.5 the paracetamol adsorption kinetics was defined by the hydrophilicity of carbon surface. However, the rate of this process increases with subsequent increase in values of the enthalpy of carbon immersion in water.
Following were the conclusions made by the above research done:
On direct comparison of the rate of adsorption of all the five carbons at three different temperatures and in the area up to 0.5 relative adsorption represented that rate of absorption increases in the following order (at 310K),
D43:1-NH3BD43:1-pureBD43:1- H2SO4BD43:1-HNO3B and D43:1-O_Cu2_
However, the rate of adsorption was found to be same for first two as well as last two carbons. When measured at 320K the rate of paracetamol adsorption on the carbon modified with ammonia was found to be lowest.
It was concluded by both the adsorption and adsorption kinetics studies of paracetamol from water solution at the neutral pH is that among all the applied procedures of D43:1 carbon surface modification, the surface modification with sulphuric acid seems to be most benifical and promising way to enhance the adsorption of paracetamol.(Terzyk, 2001)
However as it has already been discussed there are various disadvantages related to PEG polymer. In order to enhace the solubility and thus bioavailability of paracetmol formulation with minial side effects 'activated carbon' is one of the novel carrier which can solve the purpose.
RECENT STUDY OF UNIFORM MESOPOROUS CARBON SPHERES AND FIBROUS ORDERED MESOPOROUS CARBON ON POORLY WATER SOLUBLE DRUGS
A study was carried out on two forms of porous carbon (i.e- activated carbon). The aim of the study was to investigate the use of porous carbon as carrier for poorly soluble drugs and to check it's cytotoxicity.
In this study, Uniform mesoporous carbon spheres(UMCS) with 3-D pore system and fibrous ordered mesoporous carbon (FOMC) with 2-D structure were studies as carriers for poorly soluble drug Lovastatin.
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 study of UMCS and FOMC was also done.
The results clearly indicated that UMCS had a higher drug loading ( 36.26% drug weight/total weight) when compared with FOMC. 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 cytotoxicity (10-800 lg/ml).(Zhao et al., 2012)
In vitro release profiles:
The drug release profile for the pure crystalline drug and drug loaded samples is studies. LOV belongs to the class of drug, which exhibit very poor solubility in water and GIT tract, and thus was found to have a very slow release rate and an extremely low bioavailability.
According to the cumulative dissolution of pure crystalline drug was only about 30% after 90 minutes, which represents poor absorption and low bioavailability (approx 20-40%).
In case of drug loaded samples LOV-FOMC, a much better and faster dissolution rate was observed as compare to that of pure form.
In this case, the cumulative dissolution of drug in buffer (ph 6.8) was more than 55% at the the sampling time of 10 minutes. The increase in dissolution rate may be due to the following reasons:
The transformation of drug from crystalline state to non crystalline state, which results into reduced binding energy, thus increased solubility.
Relatively high dispersion of drug molecules in to the pore channels of the carrier carbon.
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
LOV-UMCS exhibit even faster dissolution rate when compared with LOV-FOMC . The cumulative dissolution was found to be 70-90% at sampling time of 15 minutes.
Also UMCS has a 3-D pore system and length of pore channel is very short when compared with FOMC. This is the main reason why UMCS possess faster release rate when compared with FOMC.
Thus, it was concluded, larger the mesopore - the faster the dissolution rate is. The reason behind this may be that large pores can effectively provides less resistance for the drug to pass through the channels.
This study on poor soluble drug Lovastatin suggested the use of mesoporous carbon for the delivery of poorly soluble drugs.
The similar technique may also be applied to enhance the solubility of paracetamol.(Zhao et al., 2012)
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 one of the novel excipient which can be used as a drug carrier and can 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 carbonÂ atoms. It usually offers a very high degree of micro porosity and adsorptive capacity.
For adsorption to occur the internal surface area should be approachable for the fluid or vapour. Thus, having highly developed internal surface is not the only requirement. Also, 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:
Micropores <40 Angstroms
Mesopores 40 - 5,000 Angstroms
Macropores >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. 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.(Incorporated, 2006).
RECENT STUDIES ON ACTIVATED CARBON (POROUS CARBON)
Activated carbon have great adsorption ability for phenols. The two most common forms in which activated carbon is being used is: in powder form and in granular form. However, In case of liquid-phase adsorption the adsorption capacity of activated carbon depends upon the following factors:
Physical nature of adsorbent - It's pore structure, pore size and functional groups.
The nature of adsorbate - 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 paracetamol. It was observed that two factors which strongly influence the adsorption properties of carbon towards the paracetamol drug are : surface modification of carbon and the temperature. 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.
Three main steps involved in adsorption of solute by porous carbon are:
Movement of a solute through the liquid film to the exterior of granule.
Dispersion of solute inside the pores of an adsorbent.
Adsorption of solute on the interior surfaces consisting of pores and capillary spaces of adsorbent.(DÄ…browski et al., 2005)
ACTIVATED CARBON AS A NOVEL ADSORBENT
Activated carbon is widely used in pharmaceutical area to enhance the solubility of poor soluble drugs. One of the benefit of mesoporous materials in drug delievery is due to its large surface area and large pore volume. 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.
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.
Also, 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.
The mesoporous carbon based materials have a pore size ranging between 40 - 5,000 Angstroms. They are usually prepared by a 'hard tem-plate' technique, i.e by adsorption and subsequent carbonization of organic compounds on mold of mesoporous silica. The final product is obtained after washing the silica template with aqeuous hydrofluoric acid or sodium hydroxide (Xu et al.)
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.
INTENDED DEISGN AND METHOD OF INVESITGATION
In order to solve the problem of low aqueous solubility of paracetamol, activated (porous) carbon will be used as a carrier. A method has been designed which will be used in the experimental technique.
The experiment will be carried out in following three steps
Formation of drug and carrier complex.
Physicochemical characterization by using techniques - 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
As we know that the concentration of poorly soluble drug (Paracetamol) is low, the mesoporous carriers (activated carbon) is loaded by using following three methods:
Organic solvent immersion method
Incipient wetness impregnation
The drug loading procedure remains same for all the three methods:
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.)
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 or it can be studied by determining the adsorption isotherms of the model drug. However, Thermogravimetry is the most common technique used to measure the drug loading degree. Another technique like, High performance liquid chromatography (HPLC) is most commonly used to study the drug con-centration assay as it is also able to collect the information related to the possible degradation of the payload molecules.
It is very important to note the state of the drug in mesoporous carrier . The release of the drug from the pores may get blocked if a poorly soluble drug is present on the outer surface of carrier molecule and could alter the release rate of loaded drug. Drug material located outside the pores can be distinguished from the drug inside the pores by the size of the crystallites. In the pores, the crystalline size is restricted by the pore walls whereas outside the pores such restraints do not exist and crystallites tend to grow significantly larger. Differential scan-ning calorimeter (DSC) is the most commonly used technique to determine the physical state of drug. DSC is the most common method employed to detect the size of the crystallites and crystalline phases in the loaded materials. The most common use of DSC is that it can be used to differentiate between the drug present inside the pores from that on the external particles surface, as the drug which is present inside the pores does not contribute to the normal (bulk) melting endotherm. 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.)
INVESTIGATION OF DRUG RELEASE PROFILE
After the characterization of drug loaded mesoporous carriers, 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.
These are the four steps that takes place after immersion of drug loaded microsphere into the living media:
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
However, there are various factors when affects the rate of drug release from porous carriers.
As the rate of drug release is controlled by diffusion mechanism, effect of pore size plays a major role.
Surface chemistry of porous material also plays an important role in determining the rate of drug release.
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.)
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