Title: Effect of polymer/surfactant mixture over the aqueous solubility of Ketoprofen and its derivatives.
Chapter No #1 Introduction
Drugs and their classification:
Drugs are defined as substance that interaction with body physiology on absorption into living organism’s body. A Drug in pharmacology is entitled, “a chemical constituent used for the treatment of disease or improve bodily mental well-being”. Drugs are used to treated chronic diseases on large scale. Oral, rectal, parenteral, tropical, respiratory, nasal, eye and ear ways are used to administer drugs. Carriers are required for dissolution to deliver in every procedures. Low soluble drug causes many problems in in vivo absorption.
Bioavailability of drugs is controlled by the dissolution and its presence as solutions form at target site. That’s why, low bioavailability is observed in absorption in body solutions of low soluble drugs after administration. Low soluble drugs have limited dissolution rate. For systematic absorption, drug’s biological absorption in fluid in required. The rate of systematics absorption of drugs in biological fluids is controlled by dissolution and delivery rate of low soluble drugs. In low waster soluble drugs, almost 40% of various different chemical constituents are present. Therefore, improvement in dissolution rate and solubility of poor water soluble drugs is main topic of interest in research.
On the basis of water solubility and diffusion in biological membranes, US food and drug administration (FDA) has classified drugs in four categories. They categories are: class I (highly soluble, highly permeable), class II (poorly soluble, highly permeable), class III (highly soluble, poorly permeable), and class IV (poorly soluble, poorly permeable). Problems like, large dose, slow action, and low or changing bioavailability is observed in low water soluble drugs. Alternation of crystal habit, emulsifying action, solid dispersion, surfactant as solubilizing agent, salt formation, pH change, co-crystallization, use of binary solvents, micronization and nanao-sization.
The solubility rate of drugs depended upon particle size, as lower the particle size higher the surface: volume ratio. The solubility of drugs increases as the surface area increases due to reason of higher interaction with the solvent. High surface area of the drug particles increases the dissolution of drugs they as solubility action is done on surface. Drugs are functions in action when administered within veins instead of oral way because of low oral absorption. Griseofulvin, nitrofurantoin, and many steroids’ oral dissolution is increased by reducing the particle size to increase surface area of the particle. Particle’s permeability is increased in small sized particles. The relation between the saturation solubility of drug and its particle size is described by Ostwald-Freundlich equation.
???????= 2 ??2.303 ????———-1
Where CS is the saturation solubility, C? is the solubility of the solid particles with large sizes, ? is the interfacial tension, V is the molar volume, R is the gas constant, T is the absolute temperature, ? is the solid density, and r is the radius. It is evident that the saturation solubility (CS) of particular drugs will increase by reducing the particle size (r).
In nanosization method, drug particle size is reduced to size ; 1µm to form nano-particles. Physical, chemical and biological characteristics of drugs is improved the drug release rate which is benefit of using nano-technology. The driving force behind the conversion of particle to nano-particle is to control the size of the particle, surface properties, and drug dissolution rate, drug release rate and dose amount.
Ketoprofen is class II drug example. It is white crystalline and completely insoluble in water. It is a non-steroid anti-inflammatory drugs (NSAIDs) which is painkilling and febrifuge function. The purpose of this research to increase its solubility, dissolution rate by employing anti-solvent procedure.
Amidon and et al classified the bases of solubilities of drugs employing biopharmaceutical classification system after understanding significance of solubility of drugs and listed in Table I. Large number of compounds with quick treatment properties have been discovered recently but mostly compounds have low solubility in water and fall into class II or IV.
Table 1.1 Classification of Drugs on the Basis of Solubility and Bio-availability by Amidon and et al.
Class Solvability Penetrability Illustration
I Extensive Extensive Drugs having higher rate of immersion than that of excretion.
II Low Extensive These drugs show poor systematic availability by their salvation rate.
III Extensive Low Although they show poor immersion rate but their salvation rate is much higher.
IV Low Low These drugs have poor systematic availability. They are poorly absorbed over the intestinal mucosa and a high variability is expected.
1.2 The Non-steroidal Anti-inflammatory Drugs (NSAIDs)
The drugs which are not narcotic have good painkilling properties and do not increase body temperature. These drugs are called non-steroid anti-inflammatory drugs and abbreviated as NSAIDs due to strong anti-inflammatory effect. Side effects of NSAIDs are gastric irritation and dose method is simple in comparison with other drugs. As NSAIDs is crucial in gastric ulcer patients. Therefore, research is done to get rid of its side effect and lessen its severity.
Inflammation is described as swelling and pain in the living tissue in response to any injury or infection. Several diseases like rheumatism, hepatitis all types, traumas injury, TB, cancer, etc. causes inflammation. Steroidal and non-steroidal drugs are prescribed commonly for inflammation and rheumatism. As described earlier, non-steroid anti-inflammatory drugs is easy is use and more active as compared to steroid drugs.
Ketoprofen is a propionic acid derivative having formula 2-(3-benzolphenyl) propionic acid. It is effective non-steroid anti-inflammatory drug (NSAID). It is used for effective inhibition of cyclooxygenase-2 and sulphonailides and it is used to cure severe and progressive inflammatory disorders like rheumatoid arthritis, osteoarthritis, ankylosing spondylitis and menstrual abdominal cramps due to its anti-inflammatory and painkilling effects, that’s why it function as painkiller drug.
Structure of ketoprofenThe low water suability and drug release in aqueous environment creates hurdles in developing oral or tropical drugs. Ketoprofen belings to Class II of the biopharmaceutical classification system (BCS). It is somewhat water insoluble drug. This low water solubility of ketoprofen leads to low bioavailability. Ketoprofen is an odorless, white or pale white crystalline powder form, melting point of ketoprofen is between 93-96°C. . It is practically soluble in organic solvents such as acetone, ethanol, and methylene chloride and in strong alkalis having pH greater than 8 (4, 8, 12, 13, and 19). Its pH dependent solubility nature leads to very low solubility in aqueous and acidic environment. Therefore, it is concluded that low solubility of drugs in aqueous condition is responsible for its low bioavailability which create problem during drug formulation.
Low solubility of drug is increased by employing several procedures. Most famous and successful procedure is solid dispersions in water-soluble carriers. Drug dissolution and saturation solubility in the gastrointestinal fluid is made better by integrating solid dispersion in a water-soluble matrix of very low soluble drugs. Ketoprofen is also formulated by employing solid dispersion method and for this purpose different carriers have been tested.
Mechanism of action of Ketoprofen:
Ketoprofen is a non-steroid anti-inflammatory drug which is painkiller and febrifuge in action. Ketoprofen like other NSAIDs causes inhibition of cyclooxygenasell pathway of the arachidonic acid metabolism. Arachidonic is the most abundant and possibly the most essential of the precursors of the eicosanoids. Enzyme activates the phospholipid A2 which catalyze the free release of arachidonic acid from the membrane phospholipids. Arachidonic acid is then converted into different structure of prostogladins. Ketoprofen is one of the most effective inhibitors of cyclooxygenasell at concentrations well within the range of therapeutic plasma concentrations (EC50 2 µg/L). In remote guinea pig lung preparations perfused with arachidonic acid, ketoprofen is six to twelve times more effective and potent that naproxen and indomethacin in inhibition of protogladin synthesis. Ibuprofen, phenylbutazone, and aspirin are reportedly 800-1500 times less strong than ketoprofen. Ketoprofen cause antipyretic effect by a resetting hypothalamic thermoregulatory center and cause anti-inflammatory and painkilling effects by inhibition of protogladin synthesis.
Uses and Administrations:
Ketoprofen is used to treat musculoskeletal and joint deceases such as ankylosing spondylitis, osteoarthritis, and rheumatoid arthritis, and in peri-articular deceases such as bursitis and tendinitis. It is also used to relieve post-operative pain, agonizing and inflammatory disorders such as acute gout or soft tissue deceases and to reduce fever. It is also used to cure acute painful shoulder syndrome and infantile rheumatoid arthritis. . It is medically equivalent to aspirin, indomethacin and ibuprofen in rheumatoid arthritis and to aspirin in osteoarthritis. Ketoprofen can also be used in the following circumstances.
• Prophylaxis and cure of migraine headaches.
• Painkilling action for surgical and painful situation in sports injuries, orthopedic manipulation and dental extraction.
• The painkilling, anti-inflammatory and febrifuge effect in infectious diseases.
• Uterine relaxation in post-partum, non-nursing women and the controlling of dysmenorrheal using intrauterine device (IUD) which are part of gynecological situation.• Ketoprofen (propionic acid derivatives) is substitute drug for other non-steroids anti-inflammatory drugs (NSAIDs) in inhibition of cyclooxygenase. As explained by pharmacological studies, ketoprofen can be administered via oral, intramuscular, rectal, or intravenous routes and it remains active for four to six hours long. Since 1980, ketoprofen has been used as anti-inflammatory drug but febrifuge is new in children and there are small knowledge about this problem. The research has explained that ketoprofen has painkilling action in kids just like in post-surgical patients and it has anti-inflammatory action in juvenile rheumatoid arthritis.
Solubility is described as property of solid, liquids and gases and it is defined as when solute which is present in smaller quantity in dissolved in solvent of solid, liquid and gaseous phase which is present in larger quantity to form homogeneous solution of solute in particular solvent. The factors that controls solubility are solvent, temperature and pressure. The saturation concentration is measure of degree of solubility of solute in particular solvent and it says that concentration of solution is not increased by dissolving more solute. The solvent is commonly pure liquid or may be binary solvent. Solid solution are used but solutions in gases are rare.
The value of solubility is estimated from more soluble (fully miscible) i.e. Ethanol in water to partially soluble i.e. Silver chloride in water. The compounds wit much less solubility are termed as insoluble.
The Biopharmaceutics Classification System (BCS) is a method for the estimation of the absorption of drugs in intestinal region is provided by U.S. Food and Drug administration (FDA). The factors of solubility and intestinal diffusion prediction is constraints by this method.
The highest dose strength of the instant release of drug in intestine is the basis of solubility. When the highest dose strength is soluble in 250mL or less aqueous solution with pH range of acidic to neutral i.e. 1-7.5 then that drug is described to have maximum solubility. The estimated volume 250mL is evaluated from characteristic bioequivalence study procedures which suggest administration of drug in people in fasting period with one glass of water.
A contrast to the intravenous inoculation is the basis of the intestinal permeability classification. All those factors are extremely crucial since 85% solid drugs are administered orally.
All drugs have been divided into four classes:
Class I—high soluble and high permeable,
Class II—low soluble and high permeable,
Class III—low soluble and high permeable
Class IV—low soluble and low permeable.
Surfactants are described as compounds which reduce the surface tension (or interfacial tension) between layers of two liquids or layers of between liquid and solid. Surfactants may function as detergents, wetting agents, emulsifiers, frothing agents, and dispersants. The term “surfactant: is chiefly used for the surface active agents.
Composition and Structure of Surfactants:
Surfactants are organic compounds having amphiphilic nature which have two portions a tails and a head. A tail is made by hydrophobic group and head is made by hydrophobic group. That’s why surfactant is both water-soluble and oil-soluble. Surfactant will distribute in water and adsorb on the surface between air and water or on the surface between oil and water when water is mixed with oil. The water-insoluble hydrophobic group adjust them into air or in oil phase while separating form water phase and water-soluble hydrophilic head group arrange itself in water. Classification of surfactants:
The surfactant are classified on the basis of their uses, physical properties and chemical structure. But the nature of the hydrophilic group is used to classify usually and surfactant are classified into four type bases on this classification. It is described as:
They have negative charge on the head group for example, RCOO-Na+ and RC6H4SO3-NA+. They are used for making raw material and for dying in textile industries.
They have positive charge on the head group for example RN+H3Cl- and RN+(CH3)3Cl-. They are used in preparation of fungicides, germicides, softening and leveling agents, agrochemicals and pharmaceuticals.
They have both positive and negative charges on their structure, for example RN+H2CH2COO- and RN+(CH3)2CH2CH2SO-3.
They have zero charge on their structure but they possess large polar groups which are responsible for their surface activity, for example, RCOOCH2CHOHCH2OH and RC6H4 (OC2H4)xOH. They are used in the removal of gases and oil from the metal surface and also from fabrics, oil recovery, ore extraction and degreasing agents.
The hydrophobic and electrostatic interactions are responsible for surfactant assemblies. The concentration of surfactant solution is the factor which determine the type of assemblies. Lamellar phase’s higher surfactant concentration is required for the formation of ordered assemblies such as cubic, hexagonal. Low surfactant concentration is responsible for disordered assemblies.
Figure: Shape of surfactants of micelles
Critical Micelle Concentration (cmc) and Micelles
The concentration of surfactants at or above which the surfactants molecules aggregates in the form of spherical assemblies which are called micelles, is termed critical micelle concentration (cmc). If the concentration of the surfactants is lesser than its cmc then surfactants are exist as single molecules, called monomers.
McBain stated that there are two types of micelles formed which depend upon the aggregation number. One type of surfactants with aggregation number <10 have concentration below cmc of the surfactants and other type has aggregation number >10, have concentration above cmc of the surfactant. The micelles with below cmc can possess their charge but the micelles with above cmc have little or no charge which results in the solution having mixed micelles such as having both highly charged and partially charged lamellar micelles. Hartley proposed a spherical model, which explain that the surfactants behave like a strong electrolyte up to the cmc and are completely dissociated. . The aggregation of surfactants starts when their concentration reaches to cmc, at first the small spherical micelles are formed which grow quickly over a narrow range of concentration. According to Hartley that the hydrophilic part of the surfactant stay at the surface of the micelles whereas their hydrophobic chain forms interior of the micelles. He stated that only one type of micelles is formed for a given range of concentration of the surfactants.
Use of Surfactants to increase Solubility of Drugs:
The surfactants finds its application in the improvement of the solubility of low soluble drugs which is proved successful in pharmaceutical as well as in chemistry. When series of binary solvents and surfactants are used, the solubility of NSAIDs is improved up to 25 times. Large amount of micelles on the surface is responsible for dissolutions. Generally, large quantity of surfactant is needed for dissolution of drugs.
A polymer is a huge molecule or macromolecule which consist of numerous repeated subunits. The word “polymer” is derived from two words, Greek poly-, “many” + -mer, “parts”. Both synthetic and natural polymers play important and ubiquitous part in daily life due to their various properties.
Types of Polymers:
There are two categories of polymers, which are described as:
The example of natural polymers is shellac, amber, wool, silk and natural rubber which are being used for eras. . A range of other natural polymers occur, such as cellulose, which is the central component of wood and paper.
The example of synthetic polymers is synthetic rubber, phenol, formaldehyde, resins, Bakelite, neoprene, nylon, polyvinylchloride (PVC Corvinyl), polystyrene, polyethylene, polypropylene, polyacrylonitrile, PVB, silicone and etc.
Polymerization is the procedure of combining many small molecules recognized as monomers into a covalently bonded chain or network. During the polymerization procedure, some chemical groups may be lost from each monomer.
Laboratory synthetic methods are classified into two types:
Step growth polymerization
Chain growth polymerization
In step growth polymerization method, chains of monomers are combined with one another directly i.e., polyester and in chain growth polymerization method, monomers are added to chain one by one in specific time i.e. polyethylene. But new methods like plasma polymerization are neither in step growth polymerization nor chain growth polymerization. Synthetic polymerization reactions may be occur with or without a catalyst.
Use of Polymer in Drug Solubility:
Polymers are used as solid dispersions in a carrier of drugs in which drugs is exist as amorphous or crystalline form in a carrier or drugs can be solubilized molecularly in the polymers to offer stability to the drugs. Both methods increases solubility of the drugs because of no lattice energy to overcome to dissolve drug. When carrier is dissolve, drug is delivered to target site in dissolved form.
Prodrugs are described as bio reversible derivations of drugs molecules which go through enzymatic or chemical conversion in vivo so that it can deliver the active parent drugs in GIT which has effective pharmacological effect. Physiochemical, biopharmaceutical, or pharmacokinetic properties of pharmacologically active drugs are improved by using prodrugs. 5-7% worldwide prescribed drugs are prodrugs. Prodrugs was discovered in early days of drugs which made its importance huge.
Huge chemical and pharmacological research is done on NSAIDs prodrugs. In order to protect the gastrointestinal tract (GIT) from local irritation, such prodrugs of non-selective COX inhibitors are beings developed which has protected acidic group. By contrast, purpose of conversion of COX-2 inhibitors to prodrugs is to obtain derivatives which have high water solubility for parenteral use or high bioavailability in oral use. Despite huge research to develop, prepare and estimate useful NSAIDs, only few drugs have clinical use and some of it have no balanced drug design.
Aims and objectives
The aim is to synthesize and dissolve ketonprofen and its ester derivatives in surfactants or polymers. Almost one third of the newly discovered drugs have low solubility, hence, low bioavailability. With respect to time, amount of such drugs are increasing. Different methods involving application of drug delivery carriers like surfactants, liposome, noisome, polymers, micro-emulsion, nano-particles etc, are used to increase water solubility of such drugs. Optimum concentration of the drug at target site is required to achieve maximum effieciency and to avoid side effects. Previoisly explained drug delivery method are used to deliver drugs at target site which increases aqueous solubility with minimum side effects. Surfactants are used to increase solubility of poor water solubility of ketoprofen and its derivatives.
To synthesize derivatives of ketoprofen.
Purification and physical categorization of the compounds including FTIR and UV spectroscopy.
To determine their solubility in surfactants and polymer solutions