INTRODUCTION:

The word “polymer” refers to “many parts”. A polymer is a large molecules made up of repeating units.^[1,2] It is used as solubilizers, stabilizers, emulsifiers, preservatives, flavouring agent, colouring agent, sweetening agent and mechanical supports for sustained release of drugs.^[3,4] Polymers are “macromolecules” which refer to any large molecules. So polymers are considered to be a subset of macromolecules. A “monomer” is a small molecule that combines with other molecules of the same or different types to form a polymer. Since drawing a complete structure of a most of polymer is almost impossible, so the structure of a polymer is exhibit by showing the repeating units (the monomer residue) and an “n” number that shows how many monomers are participating in the reaction.

From a thermodynamically perspective, polymers cannot exist in the gaseous form because of their high molecular weight, they exist only as liquid or high solid materials. From the structural prospective, monomers are generally classified as olefinic (double bond) and functional (containing reactive functional groups) for which different polymerization methods are utilized. If two, three, four, or five monomers are attached to each other, the polymer product is known as dimer, trimer, tetramer, pentamer respectively. An oligomer contains from 30 to 100 monomeric units, if contain more than 200 monomers are simply called polymer.^{[1, 2]}Polymers used in various applications in biomedical fields such as drug delivering systems developing scaffolds (proteins are crucial regulators) in tissue engineering, implantation of medical devices, artificial organ, ophthalmology, prosthesis(a device used to implant artificial body part such as heart, limb, breast etc.) dentistry, bone repairing and many other medical fields. Polymers have been used as a main tool to control the drug release rate from the formulations.^[5,6] The polymer plays an important role for a pharmacist or pharmaceutical scientist who deals with drug products on a routine basis.^[1] The polymers are also used as binders in tablets and flow controlling agents in liquids, suspensions and emulsions. It can be used as film coatings to mask the unpleasant taste of a drug, to increase drug stability and modify drug release characteristics.

Polymers serve as:

· It prolongs drug availability if medicines are formulated as hydrogels or microparticles.

· It favourably changes bio distribution, if formulated into dense nanoparticles.

· It enables hydrophobic drug administration if formulated as micelles.

· It transports a drug to its accessible site of action if formulated as gene medicines.

· It makes drugs available in response to stimuli.^[5]

Things are changing, however, scientists and engineers in both academia and industry are paying increasing attention to surface and colloid chemistry and recognizing its importance, e.g., for the design and controlled use of advanced drug delivery formulations.^[7] Polymers sciences have led to the development of several novel drug delivery systems. Biodegradable polymers are used mainly for medical goods such as surgical sutures, tissue in growth materials or for controlled release devices, plasma substituent etc. A proper consideration of surface and bulk properties can aid in the designing of polymers for various drug delivery applications. These newer technology developments include drug modifications by chemical means carrier based drug delivery and drug entrapment in polymeric matrices or within pumps that are placed in desired compartments.^{[5, 6]}

HISTORY:

Polymers are commonly referred to as “plastics” since people are more familiar with plastic products. The first semi synthetic polymer was guncotton (cellulose nitrate) by Christian F. Schonbein in 1845.^[1] It is a term used since 1866 by Berthelot who, in an article published in the Bulletin of the Chemical Society of France, noted that styrolene (styrene), heated at 200°C during a few hours, and transforms itself into a resinous polymer. It was the first recognized synthetic polymer. After few years Frank Davis and Abraham Abuchowski were able to foresee the potential of conjugating poly ethylene glycol (PEG) to proteins causing the birth of technique called PEGlyation. PEGlyation consist in the covalent bond of polyethylene glycol polymer chains to another molecule usually a drug with therapeutic effects. An important stage had been reached with the industrial production of the first synthetic polymers (bakelite, synthetic rubbers). In 1994, the first synthetic polymer drug conjugate designed to treat cancer was clinically tested. It consists of an HPMA (N-2-hydroxy propyl methacrylamide) copolymer conjugate of doxorubicin. Targeted release of anticancer agents can also be made using block co-polymer micelles which have the ability to entrap the drug or to covalently link to it.^[5,8] Other synthetic polymers were invented including:

1) Polyethylene (1933)

2) Poly vinyl chloride (1933)

3) Polystyrene (1933)

4) Polyamide (1935)

5) Teflon (1938)

6) Synthetic rubber (1942)^[1]

In 2000s, two polymer-protein conjugates, PEG-interferon-alpha ( an antiviral drug intended to treat chronic hepatitis C and hepatitis B ) and PEG-GCSF (PEG granulocyte colony- stimulating factor ) were placed in the market and five year later the first therapeutic nanoparticles (albumin-entrapped paclitaxel) was approved as a treatment for metastatic breast cancer.^{[5, 8]}

Now a days, polymers have been used to develop devices for controlling oral drug delivery as well as for replacing failing natural organs. Targeted delivery to the gastrointestinal tract (e.g. in the colon) was made possible by using polymers that protect drugs during their passages through the difficult environment of the stomach. Transdermal patches use polymers as backings, adhesives, or drug carriers in matrix or membrane products. Controlled delivery of proteins and peptides has been made possible using biodegradable polymers.^[1] All the above achievements and researchers were the core element that led to the development of polymers based on pharmaceuticals. The optimization of these clinical tests in terms of dosage and frequency is still being evaluated today for a large variety of products.^[5,
8]

Figure 1: The polymer therapeutics ^[5]

STRUCTURE OF POLYMERS:

Polymers are composed of basic structure called “mer” units. Polymers are a class of “hydrocarbon” substances which containing only the chemical element carbon and hydrogen (C and H bond) in combination, e.g. polypropylene, polystyrene, polyethylene, polyglycol etc. The difference between the individual hydrocarbon gases, liquid and solid (waxes and polymer) lies simply molecular structure.^[9,10] Polymer structure is also based on two term “configuration” and “conformation”. The term configuration and conformation is used to describe the geometric structures (Cis or Trans) isomer of a polymer. Configuration refers to the order that is determined by chemical bonds. Polymer conformation of a single chain in a solvent may vary considerably between systems. The three conformational extremes are the random coil, the stiff rod, and the hard sphere. The size and shape of polymer molecules depend on a number of factors, such as intermolecular and intermolecular interactions. It also includes Vander Waals, electrostatic, hydrophobic, hydration, and other interactions factors. For ideal such systems, the average conformation(shape) may characterized by the radius of gyration(Rg), which describes the size of the polymer coil, depends on the number (N) and length( L) of freely jointed segments(e.g. monomeric units) making up the chain. Under ideal condition, Rg scales with N as Rg~N1/2. This should be compared to Rg sphere~N1/3. And Rg rod~N1, i.e. the size of the coil increases faster with the molecular weight than for hard sphere molecules such as globular protein but more slowly than for stiff rods (like nucleic acids or other highly charged poly electrolytes).^[7]

Different chemical structures of polymer

Figure 2: Chemical structure of some biodegradable polymers ^[7]

Figure 3: Structure of polymer (a) shows linear chain (b) branched chain (c) cross-linked chain (d) random network polymer ^[11]

CLASSIFICATION OF POLYMERS

Polymers can be classified based on the following categories as shown in table.1:

Table.1 Classification of Polymers^[3]

Based on source (occurence)
Natural	Chitosan, alginate, gelatine, albumin, collagen, dextran,cellulose etc.
Semi synthetic	Hydroxyl propyl cellulose (HPC), methyl cellulose (MC).
Synthetic	Polyesters, polyamides, polyethylene, polylactic acid, polyglycolic acid.
Based on polymerization method
Addition polymer	(Alkane polymers) Polyethylene, polypropylene, polyvinylchloride (PVC)
Condensation polymer	Polyester, polyurethane.
Chain and step growth	Polyethylene, polystyrene, polyacrylates
Based on chemical structure
Activated c-c polymer, inorganic polymers, natural polymers
Based on bio-stability
Biodegradable	Polylactic acid, polyglycolic acid, polycaprolactone.
Non bio degradable	Polydimetylsiloxane, polyether urethane
Based on interaction with water
Hydrophobic polymer	Ethyl cellulose, Polydimethylsiloxane
Hydrophilic polymer	Cellulosic: methylcellulose (MC), hydroxyl propyl cellulose (HPC), Noncellulosic: sodium alginate, xanthum gum, carrageenan, ceratonia, chitosan, pectin
Hydrogel material	Cross-linked polyvinyl alcohol, polyacrylamide

DESCRIPTION OF SOME POLYMER

GUAR GUM:

Guar gum is a hydrophilic polymer. It is also known as galactosol, Guar flour, it is a galatomannan. It is primarily the ground endosperm of guar beans (Cyamopsistetragonoloba) a plant of the leguminosae family. In solid-dosage forms it is used as a binder and disintegrant, oral and topical products as suspending, thickening, and stabilizing, and also as a controlled- release carrier.

ETHYL CELLULOSE:

Chemically, ethyl cellulose is known as cellulose ethyl ether. It is represented by the formula C12H23O6 (C12H22O5) nC12H23O5; wherein can vary provide a wide variety of molecular weights. It is a non toxic, stable, compressible, inert, hydrophobic polymer. It can also be used as coating agent, flavouring agent, tablet binder, tablet filler, viscosity increasing agent and in sustained release products, including film coated tablets, microspheres, microcapsules and matrix tablets for both soluble and poorly soluble drugs.

GELATIN:

It is also known as Cryogen. Gelatin is used as a biodegradable matrix material in an implantable delivery system. Gelatin can be used as coating agent, film forming agent, gelling agent, suspending agent, tablet binder, viscosity- increasing agent. Gelatin is used for the microencapsulation of drugs, where the active drug is sealed inside a micro sized capsule.

CHITOSAN:

Chitosan is a natural polymer. It has been largely used in many areas ranging from food processing to waste management, medicine and pharmaceutical industries.It is biodegradable, biocompatible and less toxic. Chitosan is widely used in pharmaceutical application as formulations excipients. It has been used as mucoadhesive, oral absorption enhancer and in protein and gene delivery.

ALGINATE:

Alginate is also a natural polymer and is safe, non-immunogenic and inexpensive polymer with high mucoadhesive properties. Excellent immune responses have been obtained by oral administration of alginate micro particles / microspheres ranging in size from about 1 micron to more than about 30 microns. Alginate is also used as thickener, emulsion stabilizer.

COLLAGEN:

Collagen is one of the main components of many tissues in the body, and has been used for controlled drug delivery and tissue engineering application, due to its biocompatibility and ease of gelatin via physical or chemical cross- linking reaction.

ALBUMIN:

It is also known as Alba and chemically it is known as serum albumin. Albumin is a natural polymer. Human serum albumin has a molecular weight of about 6650 and is a single polypeptide chain consisting of 585 amino acids. It can be used as stabilizing agent, therapeutic agent. Albumin is primarily used as anexcipients in parentralpharmaceutical formulations, stabilizing agent. Albumin is also used to prepare microspheres and microcapsules for drug delivery system.

DEXTRAN:

Dextran is also a natural polymer. It can be produced by fermentation of media containing sucrose by Leuconostocmesnteroides. Fractions of dextran are readily soluble in water and other solvent like methyl sulphide, form amide, ethylene glycol and glycerol.

POLYETHYLENE GLYCOL:

It is also known as carbowax. It is chemically known as α- hydro-o- hydroxyl poly (oxy-1, 2-ethanediyl). Polyethylene glycols are family of water- soluble linear polymer formed by the additional reaction ethylene oxide with mono ethylene glycols or di ethylene glycols. Based upon the source polyethylene glycol is a natural polymer. Polyethylene glycol is stable, hydrophilic substance and it is essentially non- irritant to the skin and its films are waxy, hygroscopic. Polyethylene glycol is commonly mixed with hydrophobic polymers to regulate drug release owing to their excellent film-forming properties and solubility in organic solvents. For example, polyethylene glycol 400, polyethylene glycol 300, polyethylene 200 etc.

POLYETHYLENE:

Polyethylene is a synthetic and addition polymer respectively. Polyethylene is also known for chain growth polymerization. It is commonly used as plastic matrix materials. It has been added to modified drug- release pattern. Sustained release tablet based upon and inert compressed plastic matrix.

POLYGLYCOLIC ACID:

Polyglycolic acid is synthetic and biodegradable polymer respectively. It can be prepared starting from glycolic acid by means of poly condensation or ring-opening polymerization. It is the simplest linear, aliphatic polyester and known as tough fibre as a polymer. Solubility of poly glycolic acid is dependent on the type and composition of monomer.

POLYESTER:

Based on the type of polymerization it is a condensation polymer. A vast majority of biodegradable polymers studied belong to the polyester family. Thesepolymers have been used as sutures plates and fixture for fracture fixation devices and scaffolds for cell transplantation.

CARRAGEENAN:

Carrageenan is a hydrophilic polymer. It is also known condors extract. It can be used emulsifying agent, gel base, stabilizing agent, suspending agent, sustained- release agent and viscosity- increasing agent. It is chemically known as carrgeenan, i-carrageenan, k-carrageenan, l-carrageenan. Carrageenan can mask the chalkiness of antacid suspension when used as a suspending agent.

POLYPROPYLENE:

Polypropylene is a synthetic and addition polymer. The use of plastic or polymeric materials packages for tablets has become very popular, especially with unit-dose hospital packages for which aluminium foils is sometimes used. Polypropylene is commonly used polymeric materials to fit different shape and sizes of tablet packages.

HYDROXY ETHYL CELLULOSE:

Hydroxyl Ethyl Cellulose is a semi synthetic and hydrophilic polymer. It is also known as Cellulose Hydroxyl Ethylate. It is used as a thickening agent in ophthalmic and topical formulation, and also used a binder and film-coating agent for tablets. It is present in lubricant preparations for dry eye, contact lens care, and dry mouth.^[3]

COPOLYMER

Further types of polymer structure arise when two or more kinds of “mer” are mixed in a single polymer chain. For example, ethylene and propylene, polystyrene may be copolymerised to give copolymer, which has the properties of somewhat different from the parent homopolymer. The synthesis of macromolecules composed of more than one monomeric repeating unit has been explored as a means of controlling the properties of the resulting material.^{[9, 10]}They show great diversity and adaptability to required application depending on the nature of their repeating units in a given polymer strand but also manipulating their ratio and position in backbone sequence.^[12]These possibilities give rise to a number of copolymer classes given in table.2.

Polymerization synthesis

Polymerization is a process of reacting monomer molecules together in a chemical reaction to form linear chains or a three dimensional network of polymer chains. There are many forms of polymerization and different system exists to categorize them like addition polymerization and condensation polymerization.

Polymerization methods:

The former polymerization methods includes the bulk and solution polymerization where the later include any dispersed system such as suspension, emulsion and there reverse phase counterparts. The methods are categorized as:

Homogeneous polymerization:

Bulk polymerization occurs when no other materials except the monomer and the initiator are used. When an olefinic water- soluble monomer is polymerized in bulk, of water – swell able polymer is prepared. If the monomer is water soluble, a linear water soluble polymertheoretically prepared. With oil-soluble monomer, the polymer will be linear and soluble in oil. This is due to excessive exothermic heat resulting in hydrogen abstractions from the polymer backbone, which promotes cross-linking reaction at the defective site. The cross-linked polymer obtained without using any chemical cross-linker is called popcorn polymer and the reaction is called “popcorn polymerization”. Cross povidone a super-disintegrant in solid dose formulation, is a cross-linked polymer of vinyl pyrrolidone which is produced by popcorn polymerization.

Dispersion polymerization:

In dispersion polymerization, two incompatible phases of water and oil are dispersing into each other. This polymerization occurs in suspension, emulsion, inverse suspension, and inverse emulsion. One phase is known as minor (dispersed) phase and the other as the major (continuous) phase. To conduct polymerization in a dispersed system, the monomer (in the dispersed phase) is dispersed into the continuous phase using a surface- active agent. The active material (monomer) can be water soluble or oil soluble. The surfactant is chosen on the basis of the nature of the continuous phase. Therefore, if the continuous phase is water, the surfactant should have more hydrophilic groups. On the other hand, if the continuous phase is oil, a more hydrophobic (lipophilic) surfactant would be selected. Generally, two basic factors control the nature of the dispersion system. These are surfactant concentration and the surface tension of the system (nature of the dispersed phase).

POLYMER PARTICLES:

Most dispersed systems are thermodynamically unstable, and therefore they flocculate and eventually they cause macroscopic phase separation. Such behaviour has major influence on the performance of colloidal dispersions, and hence also for their application in drug delivery applications. In order to understand the stability of such colloidal systems, it is essential to have basic knowledge regarding the forces between the particles. Depending on the system, these forces may contain numerous contributions. Almost invariably, a Vander Waals interaction is present in colloidal systems, generally contributing to an attractive interparticle interaction. This illustrated in figure.6 the larger the difference in refractive index between the particles and the ambient solution, the more attractive the Vander Waals interaction.

This means, e.g., that the Vander Waals interaction between dense polymer particles is more attractive than that between solvent-swollen gel particles. For most disperse polymer particle systems, the Vander Waals attraction is balanced by electrostatic interactions.

TABLE 3: Cross-linker is added if a swell able polymer is desired. Polymer is soluble in organic solvents, but the latex itself is water dispersible.

	Bulk	Solution	Suspension	Inverse suspension	emulsion	Inverse emulsion	Pseudo latex
monomer	WS or OS	WS or OS	OS	WS	OS	WS	-
Initiator	WS or OS	WS or OS	Generally OS	Generally WS	Generally OS	Generally WS	-
Cross-linker	WS or OS	WS or OS	Generally OS	Generally WS	Generally OS	Generally WS	-
Water	-	If WS monomer is used	CP	DP	CP	DP	CP
Organic solvent	-	If OS monomer is used	DP	CP	DP	CP	DP
surfactant	-	-	WS; Surf <CMC; high HLB	OS; Surf <CMC; low HLB	WS; Surf >CMC; high HLB	OS; Surf >CMC; low HLB	WS
polymer	-	-	-	-	-	-	OSt

WS = water-soluble; OS = organic-soluble; DP = dispersed phase; CP = continuous phase; CMC = critical micelle concentration; HLB = hydrophilic lipophilic balance; Surf = surfactant concentration^[1]

Figure 6: Effect of refractive index difference between polymer particles/ surfaces and the solvent on the Vander Waals attraction. The larger the Haymaker constant, the more attractive the interaction. In the calculations, the refractive index of the solvent was taken to be 1.34 (i.e., that of water), and the refractive index of the particles/surfaces is varied.

In the case of simpler colloidal systems with only one type of particles, the similar charge of the particles generates a repulsive electrostatic interaction between the particles, which increases with the charge density. The range of the interaction decreases with increasing salt concentration.

Method for studying polymer particle system

In general, For disperse system the most important parameter is used to determine whether or not the system is stable under the condition of interest primary information of interest concerns the particle size and particle distribution and possibly also the particle shape and shape distribution. Such methods are therefore generally the most important ones for investigation of disperse particle system. There are many different methods for this a few commonly employed techniques and principle will briefly outline:

Dynamic light scattering method:

Dynamic light scattering or photon correlation spectroscopy (PCS) and it is widely used method which is particularly useful for determining the size of small disperse particles ( ≤ 500 nm). It is based on the temporal development of light scattering form particle dispersion. Due to diffusion of the particles, the interference between light scattered from individual particles results in intensity fluctuations. For polydisperse particle dispersions size distributions may in principle are obtained by fitting of different mathematical models to the autocorrelation function. This, in turn, may be translated into a particle radius (Rh) through given formula:

Rh = kT/6πηD

Where, K, T, η and D refers to Boltzmann constant, T is temperature, η is viscosity.

Light diffraction method:

It is another commonly used optical technique for particle size analysis is light diffraction which is a potent analysis technique for particle larger than about 0.1µm as with dynamic scattering it requires working with dilute particles samples. The technique is based on measuring the light scattering as a function of the scattering angle, and then applying appropriate optical theories in order to extract the particle size and size distribution particularly for heterogeneous particles. E.g. (liposome or porous polymer particles).In principle, the method is absolute and does not require calibration, but it is also rather sensitive to input data, e.g., relation to the optical properties of the dispersed particles.

Figure 7: Schematic illustration of the principle of Coulter counting. A small opening between the electrodes I constitute the sensory zone through which suspended particles pass. In the sensing zone, each particle displaces its own volume of electrolyte. This volume is measured as a voltage pulse. From the volume the particle size is determined.

Coulter counters method:

Coulter counting is based on the charge in resistance resulting from low- conducting particles passing over a thin gap over which a current is flowing. Particles size analysis since coulter counting is based on “counting” all particles passing the gap, and since the size of these is monitored. Particle size analysis is largely limited to large particle (≥ 1 µm). This generates voltage pulses when particles pass over the gap, the size of which is proportional to the particles volume.

Microscopy method:

The information about the size of particles can be obtained by this method, and also about their shape, and distribution in size and shape, it is used direct visualization by microscopic techniques. Many such techniques are available e.g. Electron micros copies, fluorescence microscopy, light microscopy, different scanning probe microscopes, which of these techniques are best suited for analysis of a particular system largely depends on the system and in particular the particles size. Since particles size analysis by microscopy is based on probing the structure of a small number of particles, statistics is generally a problem with pol- disperses particle system.

Electro-kinetic method:

When a charge particle is placed in an electric field it will migrate towards the electrode of opposite charges. The speed of this migration, the so- called electro- phoretic mobility may be used to characterize the charge of the particles. More precisely, the information obtained from such measurement is the magnitude of the electrostatic potential at the plane of shear, which is usually referred to as the zeta potential. Alternatively, charge information may be obtained from applying in electric field over an electrolyte solution in contact with a microscopic surface and following the induced electro-osmotic flow or by applying a pressure and following the streaming the potential generated to flow irrespective a how the electro-kinetic information is obtained. Electrophoresis in particular relies on using dilute systems of non-settling particles (i.e., not significantly affected by gravity), the movement of which in the electric field is largely determined by electrophoresis. For such systems, on the other hand, valuable information can be obtained regarding particle coatings, the nature of charged groups on the particle surface, etc.

Figure 8: (a) Schematic illustration of electro-phoretic mobility. (b) Effect of pH on the charging of amine- functionalized quartz, and of coating the quartz with uncharged PEO (polyethylene oxide) of different molecular weight. Note that the surface modification with high molecular weight PEO in particular results in the charges of the amine functional on the charging of amine-functionalized quartz, and of coating the quartz with uncharged PEO of different molecular.

Acoustic method:

Acoustic method is another non-optical method which is used for particle analysis. The basic method is the electro-phoretic mobility of charged particles in an electric- field. By applying an alternating electric field, charged particles can be made to oscillate in space. These oscillation in turn couple to the movement of the ambient solution and generate an ultrasonic signal which can be analyzed in order to obtain information about both the zeta potential and particle size.At least a 10% difference in density is required to obtain reliable data. Due to the technique being based on an acoustic response, another limitation is that the investigation of highly compressible systems, such as emulsions, liposome, or dispersed gas bubbles, is precluded.

Figure 9: Schematic illustration of the basis of acoustic size measurements. When an oscillating field is generated, the movement of the suspended particles and the electrolyte solution is different. From the coupling of this relative movement, information can be obtained about both the particle size and charge^[7]

Polymer particle in drug delivery:

Pharmaceutical polymers are widely used to controlled released for example, extended pulsatile and targeted enhanced stability, and improved bioavailability monolithic delivery devices are system in which a drug is dispersed within a polymer matrix and released by diffusion. Dispersed particles prepared from such polymer are interesting for example, oral delivery of drugs not stable in the stomach for oral vaccination and for formulations where boiadhesion is desirable. The rate of the drug releases from a matrix product dependence on the initial drug concentration and relaxation of the polymer chains, which overall displays a sustained release characteristic. Extended release alprazolam tablet is an example monolithic product, in which extended or sustained delivery is provided by swelling and erosion of the polymer matrix. Alternatively, a drug can be released from a drug core through a porous or non porous membrane. Enteric- coated products are the once that pass the stomach environment safely and release the drug at a higher PH environment of the intestine. These have to be coated with a pH- operative coating such as an anionic polymer. E.g., of enteric- coated products are duloxetine, mesalazine, naproxen, omeprazole, and amino salicylic acid drugs such as lutein and lycopene are stable in membrane dosage forms^[1]

Loading of polymer particles:

Polymer particles for drug delivery can be loaded by drugs in few different ways:

1. Adsorption of the drug at the particle surface.

2. Swelling of the particle in a solvent containing the drug and passive diffusion into the particles.

3. Swelling of the particle in a solvent containing the drug and passive diffusion into the particles.

4. Pressure- enhanced incorporation in performed particles.

5. Incorporation of the drug to its present during polymerization process.

6. Mixing a drug in polymer melt or a polymer solution followed by spray cooling or spraysdrying

Release from polymer particles:

Since polymer particles used in drug delivery are generally designed to be readily biodegradable, it is natural that the drug release rate is addressed mainly by controlling the degradation rate. Often there is a close correlation between the degradation and drug release rate. This is illustrated in Figure 10: for a series of nalbuphine prodrugs and polylactide-polyglycolide copolymers of different composition. However, the drug release from the biodegradable polymer particle affected also by other factors, notably the drug physiochemical properties. For example, similar to the release of drug solubilised in micellar, liquid crystalline, liposome, microemulsion and emulsion system, the drug release from polymer particle depends on the drug hydrophobicity. In fact, the relation between degradation, drug portioning and drug release may be even more complex than this, since the drug may also affect the degradation rate. For example, basic drug may behave as a base catalyst which may enhance the degradation rate and hence the release rate. On the other hand basic drug may also neutralize the polymer terminal carboxyl residue of polyester, thereby reducing the autocatalysis due to the acidic end.

Figure 10: (a) Chemical structure of the nalbuphine prodrugs investigated. (b) Relationship between the release rate and the aqueous solubility of various nalbuphine prodrugs.

Table 4: Mechanism involved in the uptake of particles

Site/ mechanism	Particle size
Villius tips per sorption	5-150µm
Intestinal macrophages- phagocytosis	1µm
Enterocytes- endocytosis	<200nm
Payer’s patches-transparacellular	<10µm

Table 5: Factor affecting the extent of uptake of particles

1.	particle size
2.	particle surface ( e.g., hydrophobility and charge)
3.	Dose of particle administered
4.	Administration vehicles
5.	Use of targeted delivery to M cells
6.	Fed state
7.	Age
8.	Species under investigation
9.	Method used to quantify uptake

PROPERTIES OF POLYMER:

Polymer display different properties like thermal, physical, mechanical, visco-elastic depending on their structure molecular weight, linearity, intra-molecular and inter-molecular interaction. If the structure is linear polymer chain can pack together in regular arrays. For example, polypropylene, chains fit together in way that intermolecular attractions stabilized the chains into regular lattice crystal state with increased temperature the crystal cells (crystallites) start to melt and the whole polymer mass suddenly melts at a certain temperature above the melting temperature polymer molecules are in continuous motion and the molecules can slip past one another.

· Physical properties:

Amorphous and crystalline polymer:

A glass is a solid material exciting in a non-crystalline (i.e., amorphous) state. Amorphous structure is formed due to either rapid cooling of a polymer. Amorphous or glassy polymers do not generally display a sharp melting point; instead they soften over a wide temperature range. Crystalline polymers display better various properties and durability in presence of attacking molecules diffusion and solubility are in to important features that are related to the level of crystallite in a polymer. Another unique property of a crystalline polymer or a polymer contained crystalline domains is anisotropy. A crystal cell displays different properties along longitudinal and transverse direction. This causes polymer to behave like an anisotropic material.

· Thermal transitions properties:

Thermal transition in polymers can occur in different orders. In other words the volume of a polymer can change with a temperature as a first or second order transition. When a crystal melts, the polymer volume is increases significantly as the solid terms to a liquid. The melting temperature (Tm) represents first order thermal transitions in polymer. On the other hand, the volume of an amorphous polymer gradually changes over a wide temperature range are so called glass transition temperature (Tg). Tm and Tgof a given polymer can be detected by differential scanning calorimeter (DSC) as an endothermic peak and a base line shift, respectively. This illustrated in Figure 11.^[15]

Figure 11: Thermal transition in polymers

· Plasticized polymers:

Plasticizer is added to a polymer formulation enhance its flexibility and to help its processing the addition of a plasticizer to a polymer results in a reduction in the glass transition temperature of the mixture. Since plasticizers increase molecular motions, drug molecules can be fuse through the plasticized polymers matrix at a higher rate depending on a plasticizer concentration.

· Molecular weight properties:

Polymer batch may contain polymer chains with different length (molecular weights) and Hence, different molecular weight distribution. A very narrow molecular distribution is very much desired for a polymer that is intended to be mechanically strong. On the other hand, a polymeric adhesive may have while distribution of molecular sizes. In general, a given polymer cannot be identified as a molecule with a specific molecular weight. Chains or different, the molecular weight of all chains should be considered and must be averaged to have a more realistic figure for molecular weight of a given polymer. However, the most common ways are number (Mn) and (Mw) average calculations. If all polymer chains are similar in size, then the number and weight average value will be equivalent. If chains are in different sizes, then weight average is distinction itself from the number average value. The term polydispersity (PD) indicates how far the weight average can distinct itself from the number average. A polydispersity value closer to 1 means the polymer system is closed to monodispersed and all of the polymer chains are almost similar in size. The farther the value from 1 indicates that the polymer system is polydisperse or chains in different size. As given in formula shows the concept:

· Mechanical properties:

Depending on their structure, molecular weight, and intermolecular forces, polymers resist differently when they are stressed. They can resist against stretching (tensile strength), compression (compressive strength), bending flexural strength, sudden stress (impact strength), and dynamic loading (fatigue). With increasing molecular weight and hence the level of intermolecular forces, polymers displays superior properties under and applied stress. A polymer is loaded and its deformation is monitored to measures its strength. As shown in Figure12^[16]the stress strain behaviour of different material. For elastic material such as Meta and ceramics, the stress and strain (deformation) correlation upto the failure point. Generally, these material shows high stress and very low elongation (deformation, strain), at their breaking point. Polymeric materials such as fibres and highly cross-linked polymers displays elastic behaviour, in other words, a linear stress/ strain correlation upto their breaking point.

Figure 12: Mechanical properties of polymers.

Modulus and stiffness are two terms that can be used interchangeably to demonstrate the strength of a polymer. Tough plastics show these typical behaviour rubbers or Elastomers on the other hand display completely different behaviour. Generally under very small stresses they deform to a large extinct to more than 10 to 15 times their original length.

· Viscoelastic properties:

Polymers are neither pure elastic nor a pure fluid material. They have the ability to store energy (displays elastic behaviour) and to dissipate it (display viscous behaviour). For this reason, most polymers are viscoelastic material). For example, poly (vinyl chloride) has a glass transition temperature of about 100°c.

This means, it behaves like solid at temperature below its Tg (glass transition temperature) and like a fluid at temperatures aboveits. A poly vinyl chloride (PVC) product behaves like a solid or glassy at any temperature (including its service temperature) below its Tg over time, the polymer intermolecular forces will essentially become weaker and hence, the polymer becomes softer. There are generally two methods to evaluate the viscoelsticity in polymer; the creep test and the stress relaxation test.^[1]

BIOADHESION:

Bioadhesion can be defined as a phenomenon of interfacial molecular attractive forces amongst the surfaces of the biological substrate and the natural or synthetic polymer to adhere to the biological surface for extended period of time. Usually means the adhesion/adsorption at mucosal surfaces. Since mucins, the main constituent in mucosa, are negatively charged and contain hydrophobic domains. The use of a mucoadhesive polymer that attach to related tissue or to the surface coating of the tissue for the targeting various absorptive mucosa such as ocular, nasal, pulmonary, buccal, vaginal etc. this system of drug delivery is called mucoadhesive/ bioadhesive drug delivery system. The various mucoadhesive polymers used for the development of buccal delivery systems include cyanoacrylates, polyacrylic acid, sodium carboxymethyl cellulose, hyaluronic acid, chitosan and gellan.^[5,7]

Mechanism of Bioadhesion:

The mucoadhesive must spread over the substrate to initiate close contact and increase surface contact, promoting the diffusion of its chains within the mucus. Attraction and repulsion forces arise and, for a mucoadhesive to be successful, the attraction forces must dominate. The mechanism of mucoadhesion is generally divided into two steps, the contact stage and the consolidation stage. ^[5,
17]

Figure 13: The two steps of the mucoadhesion process.

Polymers in pharmaceutical applications:

Polymers is used for drug protection, taste masking, controlled release of a given drug, targeted delivery, increases drug bioavailability, and so on. Apart from solid dosage forms, polymers have found applications in liquid dosage forms as rheology modifiers. They are used to control the viscosity of aqueous solution or to stabilize suspensions or even for the granulation step in preparation of solid dosage forms. Major application of polymers in current pharmaceutical field is for controlled drug release. This requires that the polymers have unique properties.

Plastics and rubbers:

· Silicones used in pacifiers, therapeutic devices, implants, medical grade adhesive for Transdermal delivery.

· Polycarbonate used in case for biomedical and pharmaceutical products.

· Polychloroprene is used in septum for injection, plungers for syringes, and valve components.

· Polystyrene is used for making petridishes and containers for cell culture.

· Polypropylene is used for making tight packaging, heat shrinkable films, containers.

· Acrylic acid and butyl acrylate copolymer is used in high Tg (glass transition temperature) pressure-sensitive adhesives for Transdermal patches.

· 2-ethylhexyl acrylate and butyl acrylate copolymer is used in low Tg pressure-sensitive for Transdermal patches.

· Polyurethane Transdermal patch backing, blood pump, artificial heart, and vascular grafts, foam in biomedical and industrial products.

· Polyisobutylene pressure sensitive adhesives for Transdermal delivery.

· Polycyanoacrylate biodegradable tissue adhesives in surgery, a drug carrier in nano- and microparticles.

· Poly (vinyl acetate) binder for chewing gum.

· Poly (vinyl chloride) blood bag and tubing.

· Polyethylene Transdermal patch backing for drug in adhesives design, wrap, packaging, containers.

· Poly (methyl methacrylate) hard contact lenses.

· Poly (Hydroxyethyl methacrylate) soft lenses.

Cellulose-based polymers:

· Ethyl cellulose insoluble but dispersible in water, aqueous coating system for sustained release applications.

· Carboxymethyl cellulose super disintegrant, emulsion stabilizer.

· Hydroxyethyl and hydroxypropyl cellulose soluble in water and in alcohol for tablet coating.

· Cellulose acetate phthalate enteric coating.

Water-soluble synthetic polymers:

· Poly (acrylic acid) cosmetics, pharmaceuticals, immobilization of cationic drugs, base carbol polymers.

· Poly (ethylene oxide) coagulant, flocculent, very high molecular-weight up to a few millions, swelling agent.

· Poly (ethylene glycol) molecular weight <10,000; liquid (molecular weight <1000) and wax (molecular weight >1000), plasticizers, base, for suppositories.

· Poly (vinyl alcohol) water-soluble packaging, tablet binder, tablet coating.

Hydrocolloids:

· Alginic acid oral and topical pharmaceutical products; thickening and suspending agent in a variety of pastes, creams, and gels, as well as a stabilizing agent for oil-in-water emulsions; binder and disintegrant.

· Chitosan cosmetics and controlled drug delivery applications, mucoadhesive dosage forms, rapid release dosage forms.

· Carrageenan modified release, viscosifier.

Water-insoluble biodegradable polymers:

· (Lactide-co-glycolide) polymer microparticles-nanoparticles for protein delivery.

Starch-based polymers:

· Starch glidant, diluents in tablets and capsules, a disintegrant in tablets and capsules, a tablet binder.

· Sodium starch glycolate super disintegrant for tablets and capsules in oral delivery ^{[1, 5, 18, 19,20]}

CONCLUSION:

Polymer-based pharmaceutical are starting to be seen as key elements to treat many lethal diseases that affect a great number of individual such as cancer or hepatitis. They are included in dosage forms to fulfil specialized functions for improved drug delivery because many new drugs have unfavourable physicochemical and pharmacokinetic properties. The synthetic polymer can be designed or modified as per requirement of the formulation by altering polymer characteristics, biocompatible, non-toxic, environment friendly and economical.

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Received on 28.04.2016 Modified on 23.05.2016

Research J. Pharm. and Tech 2016; 9(7):982-994.

DOI: 10.5958/0974-360X.2016.00188.8

		Representation of copolymer
Random copolymers	Monomers are distributed randomly, and sometimes unevenly
Alternating copolymers	Monomers are distributed in a regular alternating fashion, with nearly equal molar amounts of each in the chain
Block copolymers	Monomers are segmented or blocked in a long sequence
Graft copolymers	Branched copolymer with a backbone of one type of monomer and one ore more side chains of another monomer

Drug	Polymer	Method
Atenolol	Xanthan gum, Guar gum	Direct compression method ^[21]
Acetyl salicylic acid	Ethyl cellulose, Eudragit Rs 100	Direct compression method ^[22]
Acelofenac	Guar gum, ethyl cellulose, microcrystalline cellulose (pH 102).	Wet granulation method ^[23]
Clarithromycin	Hydroxylpropylmethylcellulose, microcrystalline cellulose, ethyl cellulose.	Direct compression method ^[24]
Dexibuprofen	Hydroxyl propyl methyl cellulose, Xanthan gum	Wet granulation method ^[25]
Diclofenac sodium	Microcrystalline cellulose(MCC), starch, lactose	Wet granulation method ^[26]
Furosemide	Guar gum, pectin, Xanthan gum	Direct compression method ^[27]
Indomethacin	Ethyl cellulose, starch, Hydroxyl Propyl Methyl Cellulose k-100M	Wet granulation method ^[28]