1. etc) pharmaceutical agents 1. The synthetic polymers

1. Introduction11.

1. The drug polymers Functional polymers used in medicine and has seen considerable growth during the past two decades. Polymers as biomaterials have different applications such as artificial organs, components of medical devices, tissue engineering and dentistry. Polymers useful as therapeutic agents, that exhibit pharmacological properties, before that can be utilized as carriers for selective and sustained delivery vehicles for small molecule or macromolecular (eg.

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proteins, genetic materials, etc) pharmaceutical agents 1. The synthetic polymers with biological materials can also be positive and desirable. Increasing attention has been rewarded to development of systems to deliver drugs for long time period at controlled rates 2.

Some investigators have paying attention on the preparation of bioactive polymeric materials, with bounding the drug to a polymer through covalent linking, e.g. chloromphenicol was formerly attached to a methacrylic by an acetal function and then copolymerized with 2-hydroxyl methacrylate 3.Restriction of a drug to polymer may prolong the activity of the drug.

The goal of various polymeric drug systems was to achieve a delivery profile that would yield a high blood level of the drug over a long period of time, by traditional tablets or injections, the drug stage in the blood follows the profile shown in Figure (1-1) in which the drug stage rises after each administration of the drug and then decreases until the next administration.Controlled drug delivery systems are designed for long period administration, the drug stage in the blood follows the profile shown in Figure (1-2) remaining constant, between the desired maximum and minimum, for an extended period of time 4.32639047625TimeMaximum desired stageMinimum effective stageDrug levelDose00TimeMaximum desired stageMinimum effective stageDrug levelDose Ineffective stage Figure (1-1): Drug level in blood with traditional drug dosing 564515-61595TimeMaximum desired stageMinimum effective stageDrug levelDose00TimeMaximum desired stageMinimum effective stageDrug levelDose Ineffective stage Figure (1-2): Drug level in blood with controlled delivery dosing There has been a growing literature pertaining to the use of functional polymers as delivery agents for therapeutics against a variety of disease states. They contain delivery of drugs at a sustained rate, targeted delivery of drugs at specific sites (to minimize toxicity and enhance selectivity for certain antitumor agents), as well as macromolecular pro-drugs with polymers acting as carrier molecules 5. More recently, polymers have been used as non viral vectors for the delivery of genetic materials for gene therapy 6.There have been important advancements in the area of polymeric drug delivery system (including commercial products).

The key spot with traditional drug administration is that blood level of the agent should remain between a maximum value, which may represent a toxic level, and a minimum value, below which the drug is no longer effective 7. 1.2. Drug carriers The main reason for the development of these “polymeric-drug carriers” is to obtain desirable properties such as sustained therapy, slow drug release, prolonged activity, as well as decreased drug metabolism and excretion.

A model for pharmacologically active polymer-drug carriers had been developed by Ringsdorf 8, Figure (1-3).Figure (1-3): Ringsdorf’s model of polymer drug carrierIn this schematic representation four different groups were attached to a bio stable or biodegradable polymer backbone. One group is the drug, the second is a spacing group, the third is a transport system, and the fourth is a group to solubilize the entire biopolymer system. The drug is the agent that elicits the physiological response in the living system; it can be attached permanently by a stable bond between the drug and the polymer, or it can be temporarily attached and removed by hydrolysis or by an enzymatic process.

The transport systems for these soluble polymer-drug carriers can be made specific for certain tissue cells. Solubilizing groups, such as carboxylates, quaternary amines and sulfonates, are added to increase the hydrophilicity of the complete polymer system in aqueous media, while large alkyl groups adjust the solubility in lipid regions. Another important feature necessary in a polymer-drug carrier is to move the drug away from the polymer backbone of other group so that there is a minimal structural interference with the pharmacological action of the drug 9, 10. A model of drug polymer was synthesized using 1,6-hexane diisocyanate (HDI), polycaprolactone diol (PCL), and afluoroquinolone antibiotic, Ciprofloxacin 11 as in the scheme (1-1).

Scheme (1-1): Model of drug polymer carrier A major approach is to increase the therapeutic efficiency of bioactive agents, while decreasing their toxicity. It involved their chemical attachment to synthetic or naturally occurring macromolecular. Thus, various agents have been bound via degradable linkages to many different polymeric systems 12.The original rationale between this approaches was that systems could be designed that they would undergo hydrolysis or enzyme-catalyzed cleavages when placed in the body, so as to release the agent at a predetermined rate 13.

Two different synthetic routes have been employed in the preparation of polymers that contain drug pendent substituent. At first the active agent is converted to a polymerizable derivative that is subsequently polymerized to afford the macromolecular combination. Second bioactive agents have also been chemically bound to performed synthetic or naturally occurring polymers by allowing them, or one of their derivatives, to react with polymers functional groups.An alternative to the direct drug-polymer linkage is the incorporation of a spacer group between the drug and polymer chain, which in general is oxyalkyl segments.

The use of suitable spacer arms can increase the mobility of drug on the polymer chain and enhance the sensitivity of conjugates to undergo chemical or enzymatic hydrolysis 13,14.Drug delivery systems were used to improve the therapeutic efficiency and safety of drugs by delivering them at a rate dictated by the needs of the body over the period of treatment, and to the site of action, which may reduce size and number of doses, side-effects, and biological inactivation and/or elimination 15.Both nondegradable and biodegradable polymers were used as drug carriers basically in two different forms; namely, injectable systems and implants. Injectable polymeric drug delivery systems are usually prepared in the forms of nano- or microcapsules or spheres, or soluble polymer formulations.

Membranes (i.e. hollow fibers, sheets, tubings, or microcapsules) single or multifilament fibers, and woven or non-woven, or knitted fabrics or moulded objects with a variety of shapes (e.g., disks, needles, buttons, hemispheres, etc.) are used as implantable drug carrier systems.

Many different injectable drug delivery systems have been proposed which may be injected into the cardiovascular blood system (the intravascular system) or into tissue (the extra vascular system) 16.An ideal polymeric carrier system for use in intravascular systems is expected to be 17: (1) blood-compatible (does not cause undesirable events e.g., thrombus or emboli formation, complement activation);(2) Circulate in the blood stream without causing embolization at capillaries.(3) Escape from excretion in the kidneys. (4) Release the drug, preferentially at the target area and a desired rate.

(5) Degrade in vivo during or after drug release. Although polymers are used extensively as drug delivery agents, intrinsically bioactive polymers (polymers as active pharmaceutical ingredients) are a relatively development 18. Partly because of their high molecular weight, polymers would appear to offer several advantages over low molecular weight agents as potential therapeutic agents.

The benefits may include lower toxicity, greater specificity of action, and enhanced activity due to multiple interactions (polyvalency). Nevertheless, the concept of polymeric drugs has been a subject of considerable skepticism, with medicinal chemists long considering synthetic polymers uninteresting as a class of potential pharmacophores. Some of the underlying concerns include the issue of polydispersity in molecular weight, and compositional heterogeneity (copolymers in particular) that could complicate process development. The high molecular weight characteristics of polymers, these potentially limiting pharmacological characteristics of polymers can in fact be exploited to design and develop therapeutic agents for disease conditions where low molecular weight drugs have either failed or produced inadequate therapeutic profiles 19, 20. Delivery of drugs by means of controlled release technology began in the 1970 and has continued to expand so rapidly that there are now-numerous products both on the market and in development.

Polymers have played a major role in the development of controlled release systems. Especially, much research on the application of biocompatible and biodegradable polymers as polymeric drug carriers has been carried out 21, polymeric colloidal drug carriers have been paid much attention to various non-parenteral system such as oral, pulmonary, nasal or ophthalmic delivery, as well as to parenteral systems. Such applications require the development of new technologies to prepare nano-sized biodegradable polymeric particles for providing a new function to drug delivery systems 22-27. Microspheres with DL-lactide/glycolide copolymer (PLGA) and poly(lactic acid) (PLA) have been already developed to extend the therapeutic effect of peptide drug 28-30. However, their sizes were too large to direct the drug to target tissues across the mucosal membrane or via systemic circulation. Block or graft copolymers can form micelles in selective solvents.

This solvent is a good solvent for one component of the block or graft copolymer and a precipitant for the other component. In this type of solvent, amphiphilic copolymers will aggregate to form micelles, i.e. particles with an insoluble swollen core surrounded and stabilized by a sheath of soluble chains 31-37. For the preparation of micelles in water, PEG is often used as the hydrophilic block in block copolymer.

Cerrai et al. 38 prepared triblock copolymers of PEG–caprolactone Because diblock copolymers form micelles are easier than the triblock copolymers , Cerrai et al. have also proved the improved efficiencies of non-catalysed diblock copolymeric nanospheres composed of MePEG and poly(-caprolactone) 38.

However, MePEG/poly(-caprolactone) nanosphere possesses the disadvantage that the -caprolactone block is highly hydrophobic by virtue of its long pentamethylene sequence, and may further aggregate by strong hydrophobic interaction of polymer–polymer and polymer–hydrophobic drug. Poly(-caprolactone) is also crystallisable due to the stereo regular. Poly(-caprolactone) chains have been sought for biodegradable and biocompatible nano-spheres with controlled hydrophilic/hydrophobic balance 39,40. In the synthesis of most biodegradable polymers, many researchers used catalysts to activate the reaction 41, 42. For the application of biomedical polymers in contact with body, a small amount of the catalysts remained was of concern because they could cause a lot of problems in the physicological environments.Poly(lactic acid) (PLA) is known to be biodegradable and meets the requirement for this purpose 43,44.

However, the rapid uptake of PLA nanosphere by cells of the mononuclear phagocytes system is a major obstacle when long enough blood circulation time is required. To achieve a long blood circulation half-life, a poly(ethylene glycol) (PEG) was chosen as the hydrophilic segment. It is known to impart protein and cellular stealth properties to surfaces and interfaces, and has a nontoxic nature 45. Furthermore, the biodegradability of PLA could be enhanced by copolymerization of PEG and DL-lactide.The molecular weight of PEG is important, PEG with low molecular weight (i.e.

less than 3.0×103 g/mole) is known to be cytotoxic in the body 46. Therefore, MePEG with a molecular weight of 5.0×103 used which is different from the previous study of Tanodekaew et al.39. On the prepared diblock copolymer using -lactide and EO monomers and the remaining EO monomer has a potential harm for human beings because of its toxicity.

This is a continuing study 39,40 on biodegradable nano-spheres prepared using block copolymer synthesized without catalysts 47.A variety of functional polymers have been used to conjugate therapeutic proteins, with the selection of polymers requiring stringent criteria. The polymers need to be nonantigenic, biocompatible, and intrinsically non denaturing to the ward the therapeutic protein.

A number of reactive polymers including copolymers of maleic anhydride with divinylether and styrene, poly (vinyl alcohol), poly(vinylpyrrolidinone), and poly(ethylene glycol)(PEG) have been utilized for this purpose 48. Veronese et al. have suggested novel drug-containing polymeric devices with; (1) degradation times appropriate for pulmonary drug delivery (thereby reducing polymer build-up in the lung upon repeat administration); (2) improved surface chemistries to optimize aerodynamic performance (thereby increasing delivery efficiency); and (3) properties that reduce particle clearance rates in the deep lung (thereby increasing drug delivery duration). A countless number of drugs could potentially benefit from controlled delivery via the lung, including many hormones, cytokines, asthma medications, insulin, vaccines, genes and more 49.

1.3. The pro-drug concept Albert 50 was the first one to suggest, the concept of pro-drug approach for increasing the efficiency of drug.

He described pro-drugs as pharmacologically inactive chemical derivatives that could be used to alter the physicochemical properties of drugs, in a temporary manner, to increase their usefulness or to decrease associated toxicity. Thus pro-drug can be defined as a drug derivative that undergoes biotransformation enzymatically or non enzymatically, inside the body before exhibiting its therapeutic effect. Ideally, the pro-drug is converted to the original drug as soon as the derivative reaches the site of action, followed by the rapid elimination of the released derivatizing group without causing side effects in the process (Figure 1.4)51. Figure (1-4): Enzymatic or chemical transformation of inactive prodrug (PD)to active drug(D) at the site of action. Methacrylic derivatives have also been proposed as a carrier monomer for salicylic acid 52.

Antibacterial agents bound to polymeric carrier have been investigated by teams, as early as 1968 Ushakov and Panarin 53 demonstrated that derivatives of penicillin bound to a copolymer of vinyl alcohol and vinyl amine (2%) units, shows an activity which is 30-40 times longer lasting than that of the free penicillin.There is a series of further examples of the in vitro activity of polymeric antibacterial, since such preparations are also applied as protection of polymeric materials against bacterial attack or as pesticides like a poly(methacryloyloxy phenoarsine) 54. Mori 55 synthesized two acrylamides containing proline and hydroxyproline moieties, the acrylamides were polymerized by reversible addition fragmentation chain transfer polymerization to yield well defined amino acid based polymer with thermo-responsive properties. 1.4.

Biomedical polymers To choose a polymer for use in biomedical application, the scientist or clinician must specify which physical properties are required. Design parameters are based on a thorough understanding of the physiological functions and conditions under which the device must operate. Defining these parameters will permit a critical review of other investigations 56. For a polymer to be used in biomedical device, it must have the appropriate mechanical properties, can be consulted to identify potential commercial materials that have a minimum of the required physical properties 57.

The polymer must be available in reproducibly pure form. Under proprietary rights, manufacturers may alter the formulation of their product at any time without notifying users and market the new formulation under the same trade name. Therefore, constant monitoring is essential 58.

Blais synthesis provides an alternative to commercial sources. This can allow direct control of the conditions of polymerization and the presence of additives or contaminants. However, even here the burden of characterization and documentation of the production of a reproducible polymer falls on the investigator 56 .

A reliable and reproducible source of polymer must be assured before a material is selected for a device. Quality control in biomedical manufacturing is more critical than in other fields, especially for materials that will have direct contact with body tissue and fluids. Biomedical polymers should not be adversely affected by the normal physiological environment. No biodegradation that could compromise function over the short or long term should occur, and no process should release toxic products to the environment. No changes should take place in the bulk polymer that would alter its mechanical properties; for example, crystallization, embrittlement, or plasticizing may result from oxidation, absorption of biological compounds (eg, proteins, lipids), deposition of inorganic material or in growth of tissue, resulting in impaired function.

Surface morphology should be stable; this is particularly important in inter facially sensitive applications, as in blood. The physiological temperature, ie, 37 0C, may accelerate these effects over what is seen at room temperature 57 .Adverse biological responses to an implanted biomedical polymer include excessive foreign-body response, thrombogenicity, and immunogenic, anti-leukotactic (predisposition toward infection), and mutagenic or carcinogenic responses 58.

Many biomedical applications require polymer systems with unique properties, such as diffusion properties in membranes for dialysis, drug-delivery applications, oxygenators, and contact-lens applications, and biodegradation properties for long-term implants and biodegradable applications, including sutures and some drug-delivery system. The Artificial Kidney Program of the National Institute of Arthritic. Metabolic and Digestive Diseases (NIAMDD) has suggested test methods membranes and dialyzer evaluation 57. The design and preparation of novel bioerodible hydrogels Figure (1-5) developed by free radical polymerization of acrylamide and acrylic acid and some formulations with bis-acrylamide, in the presence of a corn starch/ethylene-co-vinyl alcohol copolymer blend (SEVA-C), is reported for drug delivery 59.

Elvira et al. HYPERLINK “http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6TX2-4TFW96M-1&_user=7381840&_coverDate=11%2F30%2F2008&_alid=1435519084&_rdoc=28&_fmt=high&_orig=search&_cdi=5578&_sort=r&_docanchor=&view=c&_ct=50995&_acct=C000010758&_version=1&_urlVersion=0&_userid=7381840&md5=9a381585709f291f6a424d00f09d632b” l “bib137#bib137” 60 performed swelling studies as a function of pH in different buffer solutions to determine the water-transport mechanism that governs the swelling behavior. They performed degradation studies of the hydrogels in simulated physiological solutions for times up to 90 days, determining the respective weight-loss, and analyzing the solution residue by 1H NMR. They characterized mechanical properties of the xerogels by tensile and compressive tests, as well as by dynamic-mechanical analysis (DMA).

Figure ( 1-5): Chemical reactions of the prepared hydrogel formulationsThe polymer must be fabricated into the desired from without being degraded or adversely affected in a way that could influence biological performance. The polymer and its surface must not be chemically altered,(eg. oxidized), contaminated (eg. By dust, air bubbles, residual solvents, machining oils, mold-release agents, buffing compounds, etc), or physically altered (eg.

Crystallinity, bulk or surface morphology, or the creation of fabrication-induced stresses) in any adverse manner. For reproducible biological performance, the fabrication technique must allow for process control to obtain reproducible polymer morphology and properties. Biomedical polymers (including additives and degradation products) should not exhibit toxic or irritant qualities, or elicit adverse physiological responses locally or systemically.

Toxicity can also be affected by the rate of release of the substance and the biological processing and removal of the substance 61. Biomaterial science has advanced significantly, any synthetic polymer system used in an implant should be fully characterized in order to establish structure-response relationships and reproducibility of results. This is not always done, since many investigators are not adequately trained in polymer chemistry 62. 1.5.

Synthetic polymerSynthetic resins or polymers are inherently resistant to biological attack because of their hardness, limited moisture absorption, smooth surface, and lack of susceptibility to enzymatic systems. However, susceptibility to biodegradation varies and is affected by additives, especially plasticizers 61. Poly(vinyl alcohol) is almost completely resistant to fungi and bacteria in dry state. Aqueous solutions are susceptible to microbial degradation 61.

1.6. Antibiotics:Alexander Fleming made one of modern day medicine’s most important discoveries in 1928, when he noticed a strange mold present in some old bacteria cultures that had an area surrounding the mold that was bacteria free. Fleming continued to study his discovery and was able to culture the mold and to extract a liquid that was effective at killing a variety of bacteria 63.

He would go on to call the compound penicillin since the mold was of the genus Penicillium. It would take another decade of research before a team led by Howard Walter Florey would be able to show promising clinical results for using penicillin in treating infections. Finally, in 1942 the new medicine was available for clinical use, with most of the penicillin production occurring in the United States. There are now over 12,000 known antibiotics, 160 of which have been used for human clinical use 63.

Major classes of antibiotics, their mechanisms against bacteria, and their synthetic methods will be briefly reviewed. Antibiotics can be categorized based on their mechanisms for killing or slowing down the growth of bacteria. Six major classes have been indentified and include: ?-lactam, macrolide, quinolones, tetracyclines, aminoglycosides, and glycopeptides. Common uses of antibiotics include the treatment of pneumonia, meningitis, urinary tract infections, bronchitis, intestinal infections, skin infections, and tuberculosis 64.?-Lactam: ?-Lactams kill bacteria by blocking transpeptidase and trans glycosylase enzymes.

These enzymes play a role in providing a strong peptidoglycan layer in the cell wall of bacteria. By blocking these enzymes a build-up of peptidoglycan precursors occurs, which triggers the digestion of existing peptidoglycan by autolytic hydrolases. Without the production of new peptidoglycan cell wall destruction occurs.

?-Lactam antibiotics all contain a four member ?-lactam ring and include penicillins and cephalosporins, which together account for the majority of antibiotic use. Macrolide: Macrolides kill bacteria by blocking one or more of the protein biosynthetic steps on the 50S subunit of the bacterial ribosome. Quinolone: Quinolones kill bacteria by DNA replication and repair inhibition. Tetracyclines: Tetracyclines kill bacteria by blocking one or more of the protein biosynthetic steps on the 30S subunit of the bacterial ribosome. Aminoglycoside: Aminoglycosides kill bacteria by targeting regions of polyanionic 16S rRNA on the 30S ribosome, which inhibit protein synthesis.

Glycopeptide: Glycopeptides kill bacteria by complexing with uncrosslinked peptides, such as acyl-D-alanyl-D-alanine, in the peptidoglycan layer in the cell wall. Production of new peptidoglycan is stopped, leading to a breakdown of the cell wall. A large number of antibiotic-producing strains of streptomycetes have been developed. Other key microorganisms for antibiotic fermentation include: the bacteria, Saccharopolyspora erythraea .the mold, Penicillium chrysogenum 65 and the fungus, Cephalosporium acremonium . The manufacture of some antibiotics, such as cephalosporins, can be accomplished by chemical synthesis.

Some of these processes start with an initial reagent from a fermentation broth and the resulting products are called semi-synthetic antibiotics. Typically, the synthesis consists of several sequential steps, which take place in organic solvents and at low temperature to prevent decomposition. Two examples of synthetic processes are for the manufacture of Cephalexin and thienamycin 66. The enzymatic synthetic routes are considered environmentally friendly alternatives to traditional synthesis, because the use of toxic solvents is eliminated.

The enzyme penicillin G acylase is used often for the synthesis of ?-lactam antibiotics 67. 1.6.1.

Sulfadiazine drug.Sulfadiazine is an antibiotic 68 .Chemistry formulaC10H10N4O2S.

Used together with pyrimethamine , it is the treatment of choice for toxoplasmosis 69.It is a second line treatment for otitis media , prevention of rheumatic fever, chancroid , chlamydia and infections by Haemophilusinfluenzae 68.It is taken by mouth 68.Common side effects include nausea, diarrhea, headache, fever, rash, depression, and pancreatitisI 68.t should not be used in people who have severe liver problems, kidney problems, or porphyria I 69.f used during pregnancy it may increase the risk of kernicterus in the baby 68.

While the company that makes it does not recommend use during breastfeeding , use is believed to be safe if the baby is otherwise healthyI 70.t is in the sulfonamide class of medications68.Sulfadiazine works by inhibiting the enzyme dihydropteroate synthetase. In combination with pyrimethamine (a dihydrofolatereductase inhibitor), sulfadiazine is used to treat active toxoplasmosis .It eliminates bacteria that cause infections by stopping the production of folate inside the bacterial cell, and is commonly used to treat urinary tract infections , and burns.In combination, sulfadiazine and pyrimethamine , can be used to treat toxoplasmosis , a disease caused by Toxoplasma gondii.

1.6.2. Chlorodiazepoxide drug.Chlordiazepoxide, trade name Librium, Chemistry formulaC16H14Cl N3O, is a sedative and hypnotic medication of the benzodiazepine class; it is used to treat anxiety, insomnia and withdrawal symptoms from alcohol and/or drug abuse.

Chlordiazepoxide has a medium to long half-life but its active metabolite has a very long half-life. The drug has amnesic, anti convulsant, anxiolytic, hypnotic, sedative and skeletal muscle relaxant properties 71. Chlordiazepoxide was discovered in 195972. It was the first benzodiazepine to be synthesized and the discovery of chlordiazepoxide was by pure chance 73. Chlordiazepoxide and other benzodiazepines were initially accepted with widespread public approval but were followed with widespread public disapproval and recommendations for more restrictive medical guidelines for its use 74.Chlordiazepoxide is indicated for the short-term (2–4 weeks) treatment of anxiety that is severe and disabling or subjecting the person to unacceptable distress. It is also indicated as a treatment for the management of acute alcohol withdrawal syndrome 75. It can sometimes be prescribed to ease symptoms of irritable bowel syndrome combined with clidinium bromide as a fixed dose medication, Librax76.Chlordiazepoxide acts on benzodiazepine allosteric sites that are part of the GABA A receptor/ion-channel complex and this results in an increased binding of the inhibitory neurotransmitter GABA to the GABA A receptor thereby producing inhibitory effects on the central nervous system and body similar to the effects of other benzodiazepines 77. Chlordiazepoxide is anticonvulsant 78 . There is preferential storage of chlordiazepoxide in some organs including the heart of the neonate. Absorption by any administered route and the risk of accumulation is significantly increased in the neonate. The withdrawal of chlordiazepoxide during pregnancy and breast feeding is recommended, as chlordiazepoxide rapidly crosses the placenta and also is excreted in breast milk 79 . Chlordiazepoxide also decreases prolactin release in rats80 . Benzodiazepines act via micromolar benzodiazepine binding sites as Ca2+ channel blockers and significantly inhibit depolarization-sensitive Calcium uptake in animal nerve terminal preparations81. Chlordiazepoxide inhibits acetylcholine release in mouse hippocampal synaptosomes in vivo. This has been found by measuring sodium-dependent high affinity choline uptake in vitro after pretreatment of the mice in vivo with chlordiazepoxide. This may play a role in chlordiazepoxide’s anticonvulsant properties 82 .1.6.3. ParacetemolParacetamol consists of a benzene ring core, substituted by one hydroxyl group and the nitrogen atom of an amide group in the para (1,4) pattern 83. The amide group is acetamide (ethanamide). It is an extensively conjugated system, as the lone pair on the hydroxyl oxygen, the benzene pi cloud, the nitrogen lone pair, the p orbital on the carbonyl carbon, and the lone pair on the carbonyl oxygen is all conjugated.The presence of two activating groups also makes the benzene ring highly reactive toward electrophilic aromatic substitution. As the substituents are ortho, para-directing and para with respect to each other, all positions on the ring are more or less equally activated. The conjugation also greatly reduces the basicity of the oxygens and the nitrogen, while making the hydroxyl acidic through delocalisation of charge developed on the phenoxide anion.Paracetemol or acetaminophen is a widely used over-the-counter analgesic (pain reliever) and antipyretic (fever reducer). It is commonly used for the relief of headaches, other minor aches and pains, and is a major ingredient in numerous cold and flu remedies. In combination with opioid analgesics, paracetamol can also be used in the management of more severe pain such as post surgical pain and providing palliative care in advanced cancer patients 84. The onset of analgesia is approximately 11 minutes after oral administration of paracetamol, 85 and its half-life is 1–4 hours.While generally safe for use at recommended doses (1,000 mg per single dose and up to 4,000 mg per day for adults, up to 2,000 mg per day if drinking alcohol), acute overdoses of Paracetemol can cause potentially fatal liver damage and, in rare individuals, a normal dose can do the same; the risk is heightened by alcohol consumption. Paracetemol toxicity is the foremost cause of acute liver failure in the Western world, and accounts for most drug overdoses in the United States, the United Kingdom, Australia and New Zealand 86,88. 1.6.4. Pseudoephedrine drug.Pseudoephedrine is a diastereomer of ephedrine and is readily reduced into methamphetamine or oxidized into methcathinone. is a sympathomimetic drug of the phenethylamine and amphetamine chemical classes Chemistry formulaC10H15NO ,It may be used as a nasal/sinus decongestant , as a stimulant , or as a wakefulness-promoting agent in higher doses89.Pseudoephedrine is a sympathomimetic amine . Its principal mechanism of action relies on its direct action on the adrenergic receptor system 90,91. The vasoconstriction that pseudoephedrine produces is believed to be principally an ?-adrenergic receptor response 92.Pseudoephedrine acts on ?- and ?2-adrenergic receptors, to cause vasoconstriction and relaxation of smooth muscle in the bronchi, respectively 90,91 ?-adrenergic receptors are located on the muscles lining the walls of blood vessels. When these receptors are activated, the muscles contract, causing the blood vessels to constrict (vaso-constriction). The constricted blood vessels now allow less fluid to leave the blood vessels and enter the nose, throat and sinus linings, which results in decreased inflammation of nasal membranes, as well as decreased mucus production. Thus, by constriction of blood vessels, mainly those located in the nasal passages, pseudoephedrine causes a decrease in the symptoms of nasal congestion. Activation of ?2-adrenergic receptors produces relaxation of smooth muscle of the bronchi 90, causing bronchial dilation and in turn decreasing congestion (although not fluid) and difficulty breathing.1.6.5. Theophylline drug. Theophylline, also known as 1, 3-dimethylxanthine, is a methylxant- hine drug. Chemistry formula C7H8N4O2, used in therapy for respiratory diseases such as chronic obstructive pulmonary disease (COPD) and asthma under a variety of brand names. As a member of the xanthine family, it bears structural and pharmacological similarity to theobromine and caffeine, and is readily found in nature, and is present in tea (Camellia sinensis) and cocoa (Theobroma cacao). A small amount of theophylline is one of the products of caffeine metabolic processing in the liver 93. 1.6 Maleic anhydrideMaleic anhydride is an organic compound with the formula C2H2(CO)2O. It is the acid anhydride of maleic acid. It is a colorless or white solid with an acrid odor. It is produced industrially on a large scale for applications in coatings and polymers 94. The chemistry of maleic anhydride is very rich, reflecting its ready availability and bi-functional reactivity. It hydrolyzes, producing maleic acid, cis -HOOC–CH=CH–COOH. With alcohols, the half-ester is generated, eg, cis -HOOC–CH=CH–COOCH 3 Maleic anhydride is a classic substrate for Diels-Alder reactions 95. It was used for work in 1928, on the reaction between maleic anhydride and 1,3-butadiene, for which Otto Paul Hermann Diels and Kurt Alder were awarded the Nobel Prize in 1950. It is through this reaction that maleic anhydride converted to many pesticides and pharmaceuticals.Michael reaction:of maleic anhydride with active methylene or methine compounds such as malonate or acetoacetate esters in the presence of sodium acetate catalyst.These intermediates were subsequently used for the generation of the Krebs cycle intermediates aconitic and isocitric acids96.Maleic anhydride dimerizes in a photochemical reaction to form cyclobutanetetracarboxylicdianhydride (CBTA). This compound is used in the production of polyimides and as an alignment film for liquid crystal displays97.Maleic anhydride is used in many applications. Around 50% of world maleic anhydride output is used in the manufacture of unsaturated polyester resins (UPR). Chopped glass fibers are added to UPR to produce fiberglass reinforced plastics that are used in a wide range of applications such as pleasure boats, bathroom fixtures, automobiles, tanks and pipes.Maleic anhydride is hydrogenated to 1,4-butanediol (BDO), used in the production of thermoplastic polyurethanes, elastane/Spandex fibers, polybutylene terephthalate (PBT) resins and many other products.A number of smaller applications for maleic anhydride, The food industry uses maleic anhydride in artificial sweeteners and flavor enhancements. Personal care products consuming maleic anhydride include hair sprays, adhesives and floor polishes. Maleic anhydride is also a precursor to compounds used for water treatment detergents, insecticides and fungicides, pharmaceuticals, and other copolymers 94.1.7. Swelling1.7.1 Unlimited swelling 98It is that process which leads to spontaneous dissolution Figure (1-5). It is similar to complete mixing process of different liquids like water and alcohol. When the polymer is in direct contact with a low molecular weight liquid, the molecular of the latter will try to pass quickly through the polymer phase starting to fill the spaces present among the structure elements “polymeric chain”.The liquids that possess a high to a certain polymer and known as good solvents to penetrate through the chain to give this type of swelling that led finally to polymeric dissolution.-20955114935+ SolventSSSSSSSSSSSSSSSSSSSSSSSSPolymer chainSwelling unlimitedDissolution00+ SolventSSSSSSSSSSSSSSSSSSSSSSSSPolymer chainSwelling unlimitedDissolutionFigure (1-5): Swelling unlimited for some polymers 1.7.2 Limited swellingIt is a process of inter interaction between the polymers and liquids of tiny volume, i.e., the polymeric chains do not separate completely from each other, Figure (1-6). Thus two phases are formed, one separated from the solute in the swelling polymer and the other from the pure solute.-20955137160+ SolventSCross linked polymerSwelling limitedNo DissolutionSSSSSSSS00+ SolventSCross linked polymerSwelling limitedNo DissolutionSSSSSSSS8667751803400056197532321500204470222885004711701771650077597095885002616205334000Figure (1-6): Swelling limited for some polymers1.7.3 Rate and kinetics of swelling 99From the scientific point of view, it is necessary to know the ability of the polymer to swell in different liquids.The degree of swelling is determined by a volumetric or gravimetric method. The second is done by weighting the polymer sample before and after swelling, then the swelling degree (?m) is determined from the following equation: Wheremo = weight of the polymer before swellingmt = weight of the polymer after swelling.We can determine the degree of swelling to the limited swelling polymers only, and cannot be used for the unlimited swelling because of the continuous decreasing of the sample weight due to dissolution. From the figure (1-7) it is obvious that the swelling increase with the time until it reaches the equilibrium state, the point on which on the slope take a horizontal path, a point at which the swelling stops, a point of maximum or equilibrium of swelling. Different polymers take different periods to reach point of equilibrium, this property is very important, thus we observe the maximum swelling for the first sample in Figure (1-7) is greater than the second sample.So if we put both samples in a certain solvent for a long period of time, we will notice that the second sample will swell much greater than the first, but if the degree of swelling is determined after a short period of time, it is possible to notice the opposite, which means that the quantity of swelling in the first is greater than the second. So we should judge the ability of the polymers to swell from the maximum swelling point 108.105727586360TimeDegree of swellingSlow swelling sampleQuick swelling sample00TimeDegree of swellingSlow swelling sampleQuick swelling sample Figure (1-7): Kinetic of swellingAim of the work1 – Preparation of new monomers of the type of maleimide loaded with different drugs by the reaction of the maleic anhydride with 4–amino benzoic acid and then loaded several drugs including (sulfadiazine, Chlorodiazepoxide, Paracetemol, Pseudoephdrine, Theophylline)2 – Polymerization the prepared monomers by free radical polymerization to produce homo and hetero polymers 3 – Identification of prepared monomers and (homo and hetero) polymers by FT-IR, 1HNMR, and CHN techniques.4- Study the solubility, density and viscosity of the prepared monomers and polymers, and measuring the speed of medical release of polymers prepared.6 – Study of the effectiveness of the biological activity of some of the prepared polymers

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