Polymers, types, synthesis, applications

Pharmaceutical technology chapter 3

1. POLYMERS

2. INTRODUCTION The word “polymer” means “many parts.” A polymer is a large molecule made up of many small repeating units. In the early days of polymer synthesis, little was known about the chemical structures of polymers. Herman Staudinger, who received the Nobel Prize in Chemistry in 1953, coined the term “macromolecule” in 1922 and used it in reference to polymers. The difference between the two is that polymers are made of repeating units, whereas the term macromolecule refers to any large molecule, not necessarily those made of repeating units. So, polymers are considered to be a subset of macromolecules

3. The word “Polymer” is derived from two Greek words, ‘Poly’ that means many (numerous)  and ‘ Mer ’ which means units. In basic terms, a polymer is a long-chain molecule that is composed of a large number of  repeating units  of identical structure. These identical structures, we understand as a unit made up of two or more molecules, join together to form a long chain Simply stated, a polymer is a long-chain molecule that is composed of a large number of  repeating units  of identical structure.

4. 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 polymer is almost impossible, the structure of a polymer is displayed by showing the repeating unit (the monomer residue) and an “ n ” number that shows how many monomers are participating in the reaction. From the structural perspective, monomers are generally classified as olefinic (containing double bond) and functional (containing reactive functional groups) for which different polymerization methods are utilized.

5. If two, three, four, or five monomers are attached to each other, the product is known as a dimer, trimer, tetramer, or pentamer , respectively. An oligomer contains from 30 to 100 monomeric units. Products containing more than 200 monomers are simply called a polymer. From a thermodynamic perspective, polymers cannot exist in the gaseous state because of their high molecular weight. They exist only as liquids or high solid materials

6. CLASSIFICATION OF POLYMERS Since Polymers are numerous in number with different behaviours and can be naturally found or synthetically created, they can be classified in various ways. The following below are some basic ways in which we classify polymers: Classification based on source Classification based on structure Classification based on polymerisation Classification based on molecular force

7. Classification Based on Source The first classification of polymers is based on their source of origin Natural polymers The easiest way to classify polymers is their source of origin. Natural polymers are polymers which occur in nature and are existing in natural sources like plants and animals. Some common examples are Proteins (which are found in humans and animals alike), Cellulose and Starch (which are found in plants) or Rubber (which we harvest from the latex of a tropical plant). Synthetic polymers Synthetic polymers are polymers, which humans can artificially create/synthesize in a lab. These are commercially produced by industries for human necessities. Some commonly produced polymers which we use day to day are Polyethylene (a mass-produced plastic which we use in packaging) Semi-Synthetic polymers Semi-Synthetic polymers are polymers obtained by making modification in natural polymers artificially in a lab. These polymers formed by chemical reaction (in a controlled environment) and are of commercial importance. Example: Vulcanized Rubber (Sulphur is used in cross bonding the polymer chains found in natural rubber) and Cellulose derivatives such as cellulose acetate (rayon) and cellulose nitrate etc.

8. Classification Based on Structure of Polymers Classification of polymers based on their structure can be of three types: Linear polymers: These polymers are similar in structure to a long straight chain, which identical links connected to each other. The monomers in these are linked together to form a long chain. These polymers have high melting points and are of higher density. A common example of this is PVC (Poly-vinyl chloride). This polymer is largely used for making electric cables and pipes.

9. Branch chain polymers: The structure of these polymers is like branches originating at random points from a single linear chain. Monomers join together to form a long straight chain with some branched chains of different lengths. As a result of these branches, the polymers are not closely packed together. They are of low density having low melting points. Low-density polyethene (LDPE) used in  plastic bags and general purpose containers is a common example

10. Cross-linked or Network polymers: In this type of polymers,  monomers are linked together to form a three-dimensional network. The monomers contain strong covalent bonds as they are composed of bi-functional and tri-functional in nature. These polymers are brittle and hard. Examples :- Bakelite (used in electrical insulators), Melamine etc.

11. Based on Mode of Polymerisation Polymerization is the process by which monomer molecules are reacted together in a chemical reaction to form a polymer chain (or three-dimensional networks). Based on the type of polymerization, polymers can be classified as: Addition polymers: These type of polymers are formed by the repeated addition of monomer molecules. The polymer is formed by polymerization of monomers with double or triple bonds (unsaturated compounds). Note, in this process, there is no elimination of small molecules like water or alcohol etc (no by-product of the process). Addition polymers always have their empirical formulas same as their monomers. Example: ethene n(CH2=CH2)  to polyethene -(CH2-CH2)n-. Condensation polymers: These polymers are formed by the combination of monomers, with the elimination of small molecules like water, alcohol etc. The monomers in these types of condensation reactions are bi-functional or tri-functional in nature. A common example is the polymerization of Hexamethylenediamine and adipic acid. to give Nylon – 66, where molecules of water are eliminated in the process.

12. Classification Based on Molecular Forces Intramolecular forces   are the  forces  that hold atoms together within a  molecule . In Polymers, strong covalent bonds join atoms to each other in individual polymer molecules.  Intermolecular forces  (between the molecules) attract polymer molecules towards each other. Properties exhibited by solid materials like polymers depend largely on the strength of the forces between these molecules. Using this, Polymers can be classified into 4 types Elastomers: Elastomers are rubber-like solid polymers that are elastic in nature. Elastic polymers mean that the polymer can be easily stretched by applying a little force. The most common example of this can be seen in rubber bands (or hair bands). Applying a little stress elongates the band. The weakest intermolecular forces, hence allowing the polymer to be stretched, hold the polymer chains. But by removing that stress also results in the rubber band taking up its original form. This happens as we introduce crosslinks between the polymer chains, which help it in retracting to its original position, and taking its original form.

13. Thermoplastics: Thermoplastic polymers are long-chain polymers in which inter-molecules forces (Van der Waal’s forces) hold the polymer chains together. These polymers when heated are softened (thick fluid like) and hardened when they are allowed to cool down, forming a hard mass. They do not contain any cross bond and can easily be shaped by heating and using moulds. A common example is Polystyrene or PVC (which is used in making pipes). Thermosetting: Thermosetting plastics are polymers which are semi-fluid in nature with low molecular masses. When heated, they start cross-linking between polymer chains, hence becoming hard and infusible. They form a three-dimensional structure on the application of heat. This reaction is irreversible in nature. The most common example of a thermosetting polymer is that of Bakelite, which is used in making electrical insulation. Fibres: In the classification of polymers, these are a class of polymers, which are a thread like in nature, and can easily be woven. They have strong inter-molecules forces between the chains giving them less elasticity and high tensile strength. The intermolecular forces may be hydrogen bonds or dipole-dipole interaction. Fibres have sharp and high melting points. A common example is that of Nylon-66, which is used in carpets and apparels

14. POLYMER SYNTHESIS To make polymers, monomers have to interact with each other. The structure of the monomer molecule will tell us how we should polymerize it. A monomer may be unsaturated; in other words it may contain a double bond of σ (sigma) and π (pi) between a pair of electrons. The π bond generally requires low energy to break; therefore, polymerization starts at this site by the addition of a free radical on the monomer. On the other hand, if a monomer does not contain a double bond but possesses functional groups such as hydroxyl, carboxyl, or amines, they can interact via condensation.

15. Addition Polymerization Free-radical polymerization is also known as chain or addition polymerization. As the name implies, a radical generating ingredient induces an initiator triggering polymerization. The process of addition polymerization is consisted of following steps Initiation The initiator is an unstable molecule that is cleaved into two radical-carrying species under the action of heat, light, chemical, or high-energy irradiation. Each initiating radical has the ability to attack the double bond of a monomer. In this way, the radical is transferred to the monomer and a monomer radical is produced. This step in polymerization is called initiation . Propagation The monomer radical is also able to attack another monomer and then another monomer, and so on and so forth. This step is called propagation by which a macroradical is formed

16. Termination Macroradicals prepared in this way can undergo another reaction with another macroradical or with another inert compound (e.g., an impurity in the reaction) which terminates the macroradical . Figure shows the free-radical polymerization of styrene, a monomer, to polystyrene. Monomers such as acrylic acid, acrylamide, acrylic salts (such as sodium acrylate), and acrylic esters (methyl acrylate) contain double bonds and they can be polymerized via addition reactions

17. Condensation Polymerization In condensation polymerization, also called step polymerization, two or more monomers carrying different reactive functional groups interact with each other as shown in Figure . For example, a monomer containing a reactive hydrogen from the amine residue can react with another monomer containing a reactive hydroxyl group (a residue of carboxyl group) to generate a new functional group (amide) and water as a side product

18. PHARMACEUTICAL POLYMERS Rosin Rosin is a solid form of resin obtained from pines and some other plants, a film‐forming biopolymer and its derivatives have been extensively evaluated pharmaceutically as filmcoating and microencapsulating materials to achieve sustained drug release. They are also used in cosmetics, chewing gums, and dental varnishes. Rosin has been used to prepared spherical microcapsules by a method based on phase separation or by solvent evaporation. Rosin combination with polyvinyl pyrrolidone and dibutyl phthalate (30 % w/w) produces smooth film with improved elongation and tensile strength. Chitin and Chitosan Chitin a naturally abundant muco polysaccharide and consist of 2‐acetamido‐2‐ deoxy ‐b‐D‐glucose. Chitin can be degraded by chitinase . Chitosan is a linear polysaccharide composed of randomly distributed β‐(1‐4)‐linked D‐glucosamine ( deacetylated unit) and N‐ acetylD glucosamine (acetylated unit). The most important property of chitosan with regards to drug delivery is its positive charge under acidic conditions. This positive charge comes from protonation of its free amino groups. Lack of a positive charge means chitosan is insoluble in neutral and basic environments Zein Zein an alcohol‐soluble protein contained in the endosperm tissue of Zeamais , occurs as a by‐product of corn processing. Zein has been employed as an edible coating for foods and pharmaceuticals for decades. Zein is an inexpensive and most effective substitute for the fast disintegrating synthetic and semi synthetic film coatings currently used for the formulation of substrates that allow extrusion coating

19. Collagen Collagen is the most widely found protein in mammals and is the major provider of strength to tissue. It not only has been explored for use in various types of surgery, cosmetics and drug delivery, but in bioprosthetic implants and tissue engineering of multiple organs. Starches It is the principal form of carbohydrate reserve in green plants and especially present in seeds and underground organs. Starch occurs in the form of granules (starch grains), the shape and size of which are characteristic of the species, as is also the ratio of the content of the principal constituents, amylose and amylopectin. A number of starches are recognized for pharmaceutical use. These include maize ( Zea mays), rice ( Oryza sativa), wheat ( Triticum aestivum ), and potato ( olanum tuberosum ). Polycaprolactone Polycaprolactone (PCL) is biodegradable polyester with a low melting point of around 60°C and a glass transition temperature of about −60°C. PCL is prepared by ring opening polymerization of ε‐ caprolactone using a catalyst such as stannous octanoate . The most common use of polycaprolactone is in the manufacture of speciality polyurethanes. Polycaprolactones impart good water, oil, solvent and chlorine resistance to the polyurethane produced.

20. CLASSIFICATION OF BIOMEDICAL PHARMACEUTICAL POLYMERS Polymers have played important roles in the preparation of biomedical pharmaceutical products. Their applications range widely from material packaging to fabrication of the most sophisticated drug delivery devices. Of the many materials used in the pharmaceutical formulations, polymers play the most important roles. Polymers in pharmaceutical applications are classified into three general categories according to their common uses: Polymers in conventional dosage forms Polymers in controlled release dosage forms Polymers for drug packaging From the solubility point of view, pharmaceutical polymers can be classified into two categories: Water-soluble polymers Water-insoluble polymers (oil soluble or organic soluble)

21. Polymers in Conventional Dosage Forms Despite the well-known advantages of controlled release dosage forms, conventional dosage forms are still more widely used, probably because they cost less to manufacture. More than three-quarters of all drug formulations are made for oral administration. Oral dosage forms such as tablets, capsules, and liquids are still most popular. Polymers Used in Modified Release Dosage Forms One of the most important applications of polymers in modern pharmaceutics is the development of new, advanced drug delivery systems, commonly known as controlled release drug delivery systems. Controlled release formulations attempt to alter drug absorption and subsequent drug concentration in blood by modifying the drug release rate from the device. Polymer use in controlled release dosage is reduced fluctuations in the plasma drug concentration, less side effects, and increased patient compliance. Controlled release products consist of the active agent and the polymer matrix or membranes that regulate its release.

22. Advances in controlled release technology in recent years have been possible as a result of advances in polymer science that allow the fabrication of polymers with tailor made specifications, charge density, such as molecular size, specific functional groups, hydrophobicity, biocompatibility, and degradability. Controlled release dosage forms refresh old drugs by reducing pharmaceutical shortcomings and improving biopharmaceutical properties of the drugs. Polymers used in controlled release dosage forms are an alternative to the development of new drugs, which is extremely costly. The controlled release dosage forms are also important in the delivery of newly developed protein drugs. Currently, most protein drugs are administered by injection. Although protein drugs have delicate bioactivity, its success in treating chronic illness largely depends on the development of new delivery systems for the routine administration other than injection.

23. POLYMERIZATION METHODS Reactions may be carried out in homogeneous or heterogeneous systems. The former includes bulk and solution polymerizations, whereas the latter includes any dispersed system such as suspensions, emulsions, and their reverse phase counterparts; in other words, inverse suspensions and inverse emulsions. Homogeneous Polymerization Bulk polymerization occurs when no other materials except the monomer and initiator are used. If the monomer is water-soluble, a linear water-soluble polymer is theoretically prepared. With oil-soluble monomers, the polymer will be linear and soluble in oil. Surprisingly, sometimes when an olefinic (unsaturated hydrocarbons) water-soluble monomer is polymerized in bulk, a water- swellable polymer is prepared. This is due to excessive exothermic heat resulting in hydrogen abstraction from the polymer backbone, which promotes cross-linking reactions at the defective site.

24. The cross-linked polymer obtained without using any chemical cross-linker is called a popcorn polymer and the reaction is called “popcorn polymerization.” Crospovidone , a superdisintegrant in solid dose formulations, is a cross-linked polymer of vinyl pyrrolidone which is produced by popcorn polymerization.

25. Dispersion Polymerization Dispersion polymerization occurs in Suspensions, Emulsions, Inverse suspensions, Inverse emulsions. In dispersion polymerization, two incompatible phases of water and oil are dispersed into each other. One phase is known as the minor (dispersed) phase and the other as the major (continuous) phase. The active material (monomer) can be water-soluble or oil-soluble. 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 surfactant is chosen on the basis of the nature of the continuous phase. Generally, a successful dispersion polymerization requires that the surfactant be soluble in 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)

26. The surfactant concentration determines the size of the polymer particles. The system will be a suspension or inverse suspension with particle sizes around 0.2 to 0.8 mm below the critical micelle concentration. Above the critical micelle concentration, 10 to 100 μ m particles are formed. Nanosize particles can be made if a sufficient amount of surfactant is used. Nanoemulsion or inverse nanoemulsion systems are rarely used in the pharmaceutical industry because of the amount of surfactant required to stabilize the system. Surfactants represent undesirable impurities that affect drug stability and formulation acceptability. Water-insoluble polymers based on acrylic or methacrylic esters are prepared via suspension or emulsion polymerization. Eudragit L30 D is a copolymer of methacrylic acid and ethyl acrylate which is manufactured using an emulsion technique. Eudragit NE30D is also a copolymer of ethyl acrylate and methyl methacrylate which can be manufactured in an emulsion system. On the other hand, water-soluble polymers based on acrylic or methacrylic salts as well as acrylamide can be prepared using inverse suspension or inverse emulsion systems. Emulsion systems that use water as a continuous phase are known as latex.

27. COPOLYMERS AND POLYMER BLENDS If one polymer system cannot address the needs of a particular application, its properties need to be modified. For this reason, polymer systems can be physically blended or chemically reacted. With the former, a two-phase system generally exists, whereas with the latter a monophase system exists. Copolymerization refers to a polymerization reaction in which more than one type of monomer is involved. Generally, copolymerization includes two types of monomers. If one monomer is involved, the process is called polymerization and the product is a homopolymer . For example, polyethylene is a homopolymer since it is made of just one type of monomer

28. Depending on their structure, monomers display different reactivities during the polymerization reaction. If the reactivities of two monomers are similar, there will be no preference for which monomer is added next, so the polymer that is formed is called a random copolymer . When one monomer is preferentially added to another monomer, the monomers are added to each other alternatively and the polymer product is called an alternate copolymer . Sometimes, monomers preferentially add onto themselves and a block copolymer is formed. This happens when one monomer has a very high reactivity toward itself. Once more reactive monomers have participated in the reaction, the macroradical of the first monomer will attack the second monomer with the lower activity, and the second monomer will then grow as a block. Pluronic surfactants (EO-PO-EO terpolymers ) are composed of block units of ethylene oxide and propylene oxides attached to each other.

29. The major difference between graft copolymer and the other copolymer types is the nature of their building blocks. Other copolymer types are made of two or more monomer types, while a monomer and a polymer are generally used to make graft copolymers. For example, the physical chemical properties of carboxymethyl cellulose (CMC) can be changed by grafting various monomers such as acrylic acid, acrylamide, and acrylonitrile onto the cellulose backbone. Although not very common, a terpolymer will be obtained when three monomers participate in the polymerization reaction.