Polymers in Pharmacy: Applications, Properties, and Delivery

Polymers and Its Applicatins In Introduction Pharmacy Synthetic and natural-based polymers have found their way into the pharmaceutical and biomedical industries and their applications are growing at a fast pace. Understanding the role of polymers as ingredients in drug products is import...

Polymers and Its Applicatins In Introduction Pharmacy Synthetic and natural-based polymers have found their way into the pharmaceutical and biomedical industries and their applications are growing at a fast pace. Understanding the role of polymers as ingredients in drug products is important for a pharmacist or pharmaceutical scientist who deals with drug products on a routine basis. Having a basic understanding of polymers will give you the opportunity to not only familiarize yourself with the function of drug products but also possibly develop new formulations or better delivery.systems The first semisynthetic polymer ever made was guncotton (cellulose nitrate) by Christian F. Schönbein in 1845. The manufacturing process for this polymer was changed over the years due to its poor solubility, processability, and explosivity resulting in a variety of polymers such as Parkesine, celluloid (plasticized cellulose nitrate), cellulose acetate (cellulose treated with acetic acid), and hydrolyzed cellulose acetate soluble in acetone. In 1872, Bakelite, a strong and durable synthetic polymer based on phenol and formaldehyde, was invented. Polycondensation-based polymeric products such as Bakelite and those based Other synthetic polymers were invented later including polyethylene (1933), poly (vinyl chloride) (1933), polystyrene (1933), polyamide (1935), Teflon (1938), and synthetic rubbers (1942). Polyethylene was used to make radar equipment for airplanes. The British air force used polyethylene to insulate electrical parts of the radars in their airplanes. Synthetic rubber, which could be made in approximately 1 hr as compared to 7 years for natural rubbers, was used to make tires and other military supplies. Teflon was used in atomic bombs to separate the hot isotopes of uranium. Nylon was used to make parachutes, replacing silk, which had to.be imported from Japan In recent years, polymers have been used to develop devices for controlling drug delivery or for replacing failing natural organs. In oral delivery, polymers are used as coatings, binders, taste maskers, protective agents, drug carriers, and release controlling agents. Targeted delivery to the lower part of the gastrointestinal tract (e.g., in the colon) was made possible by using polymers that protect drugs during their passage through the harsh 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. In many drug products you may find at least one polymer that enhances product performance. The key difference between early polymers and pharmaceutical polymers is biocompatibility. Polymers in General 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 just those made of repeating units. So, polymers are considered to be a subset of macromolecules + Pharmaceutical Polymers In pharmaceutical solid oral dosage forms, the Eudragit polymers are used for sustained release, drug protection, and taste-masking applications. These polymers are made of acrylic esters (methyl methacrylate, ethyl acrylate). Their solubility, swellability, and pH dependent properties have been modified by incorporating anionic and cationic monomers such as methacrylic acid and dimethylaminoethyl acrylate. From a commercial standpoint, polymer properties can be simply changed by mixing or blending one or two polymer systems. Polymer blends are simply made by physical blending of two different polymers in molten or in solution state. The blend is either solidified at lower temperature if prepared by melting or recovered at higher temperature if prepared in solution. Some thermoplastic polymers are not resistant to sudden stresses. Once impacted, the craze (microcrack) and macrocracks will grow very quickly within their structure and the polymer will simply and suddenly break apart. These polymers have rigid structures with high Tg values. Adding a low Tg polymer (in other words, a flexible polymer) such as rubber particles improves the impact resistance of these polymers by preventing.the cracks from growing Interpenetrating Polymer Networks Interpenetrating polymer networks (IPNs) are also composed of two or more polymer systems but they are not a simple physical blend. Semi-IPNs or semi-interpenetrating polymer networks are prepared by dissolving a polymer into a solution of another monomer. An initiator as well as a cross-linker is added into the solution and the monomer is polymerized and cross-linked in the presence of the dissolved polymer. The result will be a structure in which one cross-linked polymer interpenetrates into a non–cross-linked polymer system. With fully interpenetrated structures, two different monomers and their corresponding cross-linkers are polymerized and cross-linked simultaneously. This results in a doubly cross-linked polymer system that interpenetrates into one another. Alternatively, conducting the cross-linking reaction on a semi- interpenetrated product can form a full-IPN structure. The non–cross-linked phase of the semi-IPN product will be further cross-linked with a chemical cross-linker or via physical complexation. IPN Polymer Structure Elastic superporous hydrogels have been developed for oral gastric retention of the drugs with a narrow absorption window. These hydrogels are prepared using a two-step process. First, a semi-IPN structure is prepared by polymerizing and cross-linking a synthetic monomer (such as acrylamide) in the presence of a water-soluble polymer (e.g., alginate). Although the cross-linked acrylamide polymer is not soluble in water, the alginate component is. In the second step, the prepared semi-IPN is further treated with cations (such  Molecular Weight and Polymer Properties Mechanical properties of a given polymer generally increase with an increase in molecular weight. Polymer melts and polymer solutions are handled with more difficulty as their molecular weight increases. This is due to a phenomenon called entanglement, which affects the flow of the polymer chains. As molecular weight increases, polymer chains are more likely entangled into each other at certain molecular weights. This results in poor polymer flow either in solid state (as a melt) or in solution state (as a solution). For many applications, there is a working range of molecular weights that a given polymer in solid or solution state can successfully be processed.. Topology and Isomerism The topology of a polymer describes whether the polymer structure is linear, branched, or cross-linked. Topology can affect polymer properties in its solid or solution states. With a linear polymer, the polymer chains are not chemically attached to each other, instead weaker intermolecular forces hold the polymer chains together. A linear polymer can show dual behavior. Chains in a linear polymer can freely move, which offers the polymer a low melting temperature. On the other hand, linear chains have a higher chance of approaching each other in their solid state, which increases their crystallinity and melting temperature. The same holds true for branched polymers in which short or long side groups are attached to the backbone of the polymer. Branched polymer chains move with difficulty because of the steric hindrance induced by the side groups but they presumably possess weaker intermolecular forces, which apparently help them move freely. With cross-linked polymers, the chains are chemically linked and will be restricted from moving to a sensible extent depending on the level of cross-linking. Very highly cross-linked polymers are very rigid structures that degrade at high temperatures before their chains start to move. In solution, a branched polymer might display a better solvent permeability compared to its linear counterpart due to its side groups. Gum Arabic is a highly branched polymer with very high solubility in water. If a linear polymer is cross-linked, its solubility will be sacrificed at the expense of swellability. Therefore, a cross-linked polymer can swell in a solvent to an extent that is inversely related to the amount of cross-linker. Isomerism can be classified as structural isomerism (Fig. 20-8a), sequence isomerism (Fig. 20-8b), and stereoisomerism (Fig. 20- 8c). Gutta Percha natural rubber (trans-polyisoprene) and its synthetic counterpart (cis-polyisoprene) are similar in structure but their trans and cis nature results in a medium-crystal and amorphous behavior, respectively. This important feature can be accounted for in terms of the position of a methyl group. The cis andtrans isomers of a same polymer display different Tg and Tm values, for example, polyisoprene (Tg of -70°C versus -50°C; Tm of 39°C versus 80°C), polybutadiene (Tg of - 102°C versus -50°C; Tm of 12°C versus 142°C).1 With sequence isomerism, monomers with pendant groups can attach to each other in head-to-tail, head-to-head, or tail-to-tail conformation. Stereoisomerism applies to polymers with chiral centers, which results in three different configurations—isotactic (pendant groups located on one side), syndiotactic (pendant groups located alternatively on both sides), and atactic (pendant groups located randomly on both sides) configurations..Fig. 20-7. Polymer topology and properties Example 20-4 Stereoisomerism The isotactic and atactic polypropylenes display glass transition temperatures of 100°C and -20°C, respectively. While the isotactic one is used for special packaging purposes, the atactic one is commonly used as a cheap excipient in general adhesive formulations. Polymer Properties Crystalline and Amorphous Polymers Polymers display different thermal, physical, and mechanical properties depending on their structure, molecular weight, linearity, intra- and intermolecular interactions. If the structure is linear, polymer chains can pack together in regular arrays. For example, polypropylene chains fit together in a way that intermolecular attractions stabilize the chains into a regular lattice or crystalline 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. In many cases, the structure of a polymer is so irregular that crystal formation is thermodynamically infeasible. Such polymers form glass instead of crystal domains. A glass is a solid material existing in a noncrystalline (i.e., amorphous) state. Amorphous structure is formed due to either rapid cooling of a polymer melt in which crystallization is prevented by quenching or due to the lack of structural regularity in the polymer structure. Rotation around single bonds of the polymer chains becomes very difficult at low temperatures during rapid cooling; therefore, the polymer molecules forcedly adopt a disordered state and form an amorphous structure. Amorphous or glassy polymers do not generally display a sharp melting point; instead, they soften over a wide temperature range.8 Example of Crystalline and Amorphous Polystyrene and poly (vinyl acetate) are amorphous with melting range of 35°C to 85°C and 70°C to 115°C, respectively. On the other hand, poly (butylene terephthalate) and poly (ethylene terephthalate) are very crystalline with sharp melting range of 220 and 250°C to 260°C, respectively. Polymer strength and stiffness increases with crystallinity as a result of increased intermolecular interactions. With an increase in crystallinity, the optical properties of a polymer are changed from transparent (amorphous) to opaque (semicrystalline). This is due to differences in the refractive indices of the amorphous and crystalline domains, which lead to different levels of light scattering. From a pharmaceutical prospective, good barrier properties are needed when polymers are used as a packaging material or as a coating. Crystallinity increases the barrier properties of the polymer. Small molecules like drugs or solvents usually cannot penetrate or diffuse through crystalline domains. Therefore, crystalline polymers display better barrier properties and durability in the presence of attacking molecules. Diffusion and solubility are two important terms that are related to the level of crystallinity in a polymer. On the other hand, a less crystalline or an amorphous polymer is preferred when the release of a drug or an active material is intended. Crystallinity in a given polymer depends on its topology and isomerism (linear versus branched; isotactic versus atactic), polymer molecular weight, intermolecular forces, pendant groups (bulky versus small groups), rate of cooling, and stretching mode (uniaxial versus biaxial). Another unique property of a crystalline polymer or a polymer-containing crystalline domains is anisotropy. A crystal cell displays different properties along longitudinal and transverse directions. This causes the polymer to.behave like an anisotropic material Entanglement Let us say that there are two laundry machines with the total capacity of each 20 lb and you separate your clothes into two small (shorts) and large (pants) groups, each weighing 20 lb. Once the laundry step is completed, the clothes are to be transferred into a dryer. An important observation to make is that more time will be spent to separate the large clothes from each other, which is not the case with the small clothes. This happens because large clothes have a tendency to tie into each other. Because of this, the washer should be loaded with a smaller number of large articles of clothing as it makes it easier to wash and dry them. In polymer terms, large molecular-weight polymers (large clothes) have a better affinity to tie into each other as opposed to their smaller molecular-weight counterparts (small clothes). This is called entanglement. This occurs after a certain molecular weight and affects the polymer properties in both the solution and solid states. Hydrogels Certain materials, when placed in excess water, are able to swell rapidly and retain large volumes of water in their structures. Such aqueous gel networks are called hydrogels. These are usually made of a hydrophilic polymer that is cross-linked either by chemical bonds or by other cohesion forces such as ionic interaction, hydrogen bonding, or hydrophobic interactions. Hydrogels behave like an elastic solid in a sense that they can return to their original conformation even after a long-term loading.A hydrogel swells for the same reason as its linear polymer dissolves in water to form a polymer solution or hydrosol. From a general physicochemical standpoint, a hydrosol is simply an aqueous solution of a polymer. Many polymers can undergo reversible transformation between hydrogel and hydrosol. When a hydrogel is made by introducing gas (air, nitrogen, or carbon dioxide) during its formation, it is called a porous hydrogel. A hydrogel swells in water or in any aqueous medium because of positive forces (polymer–solvent interaction, osmotic, electrostatic) and negative forces (elastic) acting upon the polymer chains. If a polymer structure is nonionic, the major driving force of swelling will be polymer–solvent interactions. As the ion content of a hydrogel increases, two very strong osmotic and electrostatic forces are generated within the hydrogel structure. The presence of ions inside the gel and the absence of the same ions in the solvent trigger a diffusion process (osmosis) by which water enters the polymer structure until the concentration of the ion inside the gel and the solvent becomes equivalent. In fact, the polymer diffuses into water to balance its ion content with the surrounding solution. Polymer chains carrying ions are charged either negatively (anionic) or positively (cationic). In either case, similar charges on the polymer backbone will repel each other upon ionization in an aqueous medium. This creates more spaces inside the hydrogel Superdisintegrants In pharmaceutical solid dosage forms, a superdisintegrant is generally used to help the dosage form with a proper disintegration. The concept behind this is the osmotic pressure that is generated by either hydrophilicity (as in vinyl pyrrolidone) or ionic (as in carboxymethyl cellulose) nature of the structure. Sodium starch glycolate (Explotab, Primojel, Vivastar P), cross-linked poly (vinyl pyrrolidone) (Crospovidone), and cross-linked sodium salt of carboxymethyl cellulose (Ac-Di-Sol, Croscarmelose) are widely used as a tablet and capsule disintegrant in oral dosage forms.  Osmotic Tablet and Pump Alza's Oros and Duros technologies are based on an osmosis concept. Oros provides 24 hr controlled drug release that is independent of many factors such as diet status. Tablets using Oros technology are made of two sections coated with a semipermeable material. The upper section contains drug and the lower section contains the osmotic agent either a salt or a water- soluble/swellable polymer. The membrane allows water or the aqueous medium to enter into the osmotic agent compartment. In the presence of water, osmotic pressure pushes the bottom compartment upward which in turn forces the drug through a laser-drilled orifice on top of the tablet. Since 1983, this technology has been used in a number of prescription and over- the-counter products marketed in the United States, including nifedipine (Procardia XL), glipizide (Glucotrol XL), methylphenidate, oxybutynin, and pseudoephedrine (Sudafed 24 Hour). Duros technology is utilized in implants that deliver drugs over a very long period. Leuprolide implant (Viadur) osmotic implant is based on Alza's Duros pump technology which delivers leuprolide acetate over a year long period. Polymers for Pharmaceutical Applications In a traditional pharmaceutics area, such as tablet manufacturing, polymers are used as tablet binders to bind the excipients of the tablet. Modern or advanced pharmaceutical dosage forms utilize polymers for drug protection, taste masking, controlled release of a given drug, targeted delivery, increase drug bioavailability. Apart from solid dosage forms, polymers have found application in liquid dosage forms as rheology modifiers. They are used to control the viscosity of an 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. In the biomedical area, polymers are generally used as implants and are expected to perform long-term service. This requires that the polymers have unique properties that are not offered by polymers intended for general applications  Polymers in Pharmaceutical and Biomedical Applications Water-Soluble Synthetic Polymers Poly (acrylic acid) Cosmetic, pharmaceuticals, immobilization of cationic drugs, base for Carbopol polymers Poly (ethylene oxide) Coagulant, flocculent, very high molecular-weight up to a few millions, swelling agent Poly (ethylene glycol) Mw