Polymers and their Applications

• Synthetic and natural polymers are increasingly used in pharmaceutical and biomedical industries

Introduction to Polymers

• Polymers are crucial for pharmacists and scientists to understand for drug product development
• Understanding polymers helps in familiarizing with drug product functions
• Polymers also helps with the development of new formulations
• Familiarizing yourself with the function of drug products also potentially helps develop better delivery systems

History and Invention of Polymers

• Christian F. Schönbein created guncotton (cellulose nitrate) in 1845, the first semisynthetic polymer
• Guncotton's manufacturing process was modified due to its poor solubility, processability, and explosivity
• Modifications of guncotton led to polymers like Parkesine, celluloid, cellulose acetate and hydrolyzed cellulose acetate
• In 1872, Bakelite, a synthetic polymer, was invented composed of phenol and formaldehyde
• Other synthetic polymers include polyethylene, poly(vinyl chloride), polystyrene, polyamide, Teflon, and synthetic rubbers
• Polyethylene was originally used to make radar equipment and to insulate electrical parts for airplanes
• Synthetic rubber, which had a shorter production time than natural rubber, was used for tires and military supplies
• Teflon was used in atomic bombs to separate isotopes of uranium
• Nylon replaced silk in parachutes to avoid imports from Japan

Recent Applications of Polymers

• Polymers are used in devices for controlled drug delivery and organ replacement
• In oral delivery, polymers serve as coatings, binders, taste maskers, protective agents, drug carriers, and release controllers
• Targeted delivery to the lower gastrointestinal tract is possible using polymers that protect drugs from stomach acid
• Transdermal patches use polymers as backings, adhesives, or drug carriers
• Biodegradable polymers enable controlled delivery of proteins and peptides
• Most drugs contain at least one polymer to enhance product performance
• A key difference between earlier and pharmaceutical polymers is biocompatibility

Polymers in General

• The word "polymer" means "many parts"
• A polymer is a molecule made of repeating units
• Herman Staudinger coined the term "macromolecule" in 1922
• Polymers are distinct from macromolecules as they consist of repeating units
• Polymers are a subset of macromolecules
• Oligomers consist of 30-100 mers
• Polymers consist of over 200 mers
• The degree of polymerization (DP) equals the number of monomers in a chain

Types of Polymers

• Eudragit polymers are used in solid oral dosage forms
• Acrylic esters are used in Eudragit polymers.
• Eudragit polymers are used for sustained release, drug protection, and taste-masking
• Anonic and cationic monomers modify polymer solubility, swellability, and pH-dependent properties in Eudragit polymers

Polymer Properties

• Polymer properties can be altered by mixing or blending polymer systems commercially
• Polymer blends can be made via physical blending of two different polymers in molten form or solution
• Thermoplastic polymers are not resistant to sudden stresses
• Thermoplastic polymers break apart once impacted
• Adding a low glass transition temperature (Tg) polymer (i.e flexible polymer) such as rubber particles improve impacts by preventing crack growth

Interpenetrating Polymer Networks (IPNs)

• IPNs are composed of two or more polymer systems, but are not a simple physical blend
• Semi-IPNs are prepared by dissolving a polymer into a solution of another monomer
• An initiator and cross-linker is added to the solution, polymerizing and cross-linking the monomer
• The resulting structure has one cross-linked polymer interpenetrating into a non-cross-linked polymer system
• Two different monomers and their corresponding cross-linkers are polymerized and cross-linked in fully interpenetrated structures.
• Two cross-linked polymer systems interpenetrate one another
• Conducting cross-linking 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 complexion

IPN Polymer Structures

• Elastic superporous hydrogels are prepared using synthetic monomers such as acrylamide in the presence of a water-soluble polymer eg alginate
• Even though the cross-linked acrylamide polymer is not water soluble, the alginate component is
• In the second step, the semi-IPN prepared is further treated with cations

Molecular Weight and Polymer Properties

• Mechanical properties of a polymer generally increase with an increase in molecular weight
• Polymer melts and solutions become hard to handle as polymer weight increases
• Flow of polymer chains is affected by entanglement, so polymer chains are likely entangled at certain weights
• A result of entanglement causes poor polymer flow in solid and solution
• Successfully processing polymers in solid or liquid states require a working range of molecular weights

Polymer Topology and Isomerism

• The polymer structure's topology is described as linear, branched, or cross-linked
• Topology affects polymer properties in its solid form or solution state.
• Linear polymer chains are not chemically attached to each other, inst3ead intermolecular forces link polymer chains together
• A linear polymer can show dual behavior
• Chains in linear polymers can freely move, which makes the polymer have a low melting temperature
• Linear chains can likely approach each other in their solid state, which increases crystallinity and melting temperature

Branched Polymers

• Branched polymers have short or long side groups attached to the backbone of the polymer
• Branched polymer chains move with difficulty due to the steric hindrance induced by the side groups
• Branched polymer chains possess weaker intermolecular forces, which helps them move freely
• Chains in cross-linked polymers are chemically linked and restricted on the level of cross-linking
• Extremely cross-linked polymers structures have temperature degrading before chains starts to move
• Branched polymers have better solvent permeability due to their side groups
• Gum Arabic is a highly branched, water-soluble gum
• The solubility of a linear polymer will be sacrificed at the expense of swellability, if cross-linked
• A cross-linked polymer can swell in a solvent to an extent that is inversely related to the cross-linker amount

Isomerism

• Isomerism can be classified as structural, sequence, and stereoisomerism
• Gutta Percha natural rubber is a trans-polyisoprene as its synthetic counterpart is a cis-polyisoprene
• Trans and cis behavior result in a medium-crystal and amorphous behavior, respectively
• Cis and trans isomers of a polymer show different Tg and Tm values, such as polyisoprene and polybutadiene,.
• With sequence isomerism, monomers with pendant groups can attach in head-to-tail, head-to-head, or tail-to-tail conformation.
• Stereoisomerism applies to polymers with chiral centers
• There is 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 for stereoisomerism

Crystallinity and Amorphous Polymers

• Polymers display different thermal, physical, and mechanical properties based on polymer structure, weight, linearity, intra- and intermolecular interactions
• If the structure is linear chains can pack together in regular arrays
• Polypropylene chains fit together, so intermolecular attractions stabilize the chains into a regular lattice or crystalline state
• The crystal cells start to melt with high temp, and the whole polymer mass melts at a temperature suddenly
• Above the melting temperature, polymer molecules are always moving
• A structure of a polymer may not be able to make crystal formation as it is thermodynamically unfeasible, so the polymers will form glass rather than crystal domains
• A glass is a solid material in a noncrystalline state
• Amorphous structure is formed via rapid melting or with a lack of polymer structure regularity
• The rotation around single bonds of polymer chains will be very difficult at low temperatures, so the polymer molecules must adopt a disordered state and produce an amorphous structur
• Amorphous or glassy polymers do not display a sharp melting point; instead, they soften over a wide temperature range.
• Polystyrene and poly (vinyl acetate) are amorphous with melting ranges of 35°C to 85°C and 70°C to 115°C, respectively
• Poly (butylene terephthalate) and poly (ethylene terephthalate) are crystalline with melting range of 220 and 250°C to 260°C, respectively

Polymer Properties and Barrier Properties

• Polymer strength and stiffness increases with crystallinity
• Optical properties of a polymer are affected when crystallinity increases
• Optical properties start transparent and end opaque
• Crystallinity can increase a polymer's barrier properties
• Crystalline polymers display better barrier properties and durability
• Diffusion and solubility depend on crystallinity in a polymer and are important terms
• A less crystalline or amorphous polymer is preferred when the release of a drug or an active material is intended.
• Crystallinity in a polymer is also topology and isomerism, polymer molecular weight, intermolecular forces, and the rate of cooling
• Crystalline polymers can be anisotropic, and show different properties along longitudinal and transverse directions

Polymer Entanglement

• In polymer terms, large molecular-weight polymers have a better affinity to tie into each other as opposed to their smaller molecular-weight counterparts, which is entanglement
• Entanglement 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, and are usually made of a hydrophilic polymer that is cross-linked either by chemical bonds
• Hydrogels can be cross-linked by chemical bonds, ionic interaction, hydrogen bonding, or hydrophobic interactions
• Hydrogels act like an elastic solid, and returns to its original form even after loading for a long time period
• Hydrogels swells for the same reason as its linear polymer dissolves in water to form a polymer solution or hydrosol
• A hydrosol is an aqueous solution of a polymer
• Polymers can undergo reversible transformation between hydrogel and hydrosol
• A porous hydrogel can be made when created with a gas

Hydrogels and Swelling

• Hydrogels can swell in water or aqueous media
• Positive forces (polymer-solvent interaction, osmotic, electrostatic) and negative forces (elastic) act on polymer chains in hydrogels, causing swelling
• The hydrogel's major driving force for swelling is polymer-solvent interactions if polymer structure is nonionic
• Osmotic and electrostatic forces are generated within a hydrogel as ion content increases
• The presence of ions inside the gel and the absence of the ions in the solvent trigger a diffusion process that triggers water to enter
• The polymer diffuses into water to balance its ion content within the surrounding solution
• Charges on the polymer backbone repel each other, creating more space inside the hydrogel

Superdisintegrants

• Superdisintegrants help solid dosage forms disintegrate
• Superdisintegrants have osmotic pressure by either hydrophilicity or ionic structure
• Sodium starch glycolate, cross-linked poly (vinyl pyrrolidone), and cross-linked sodium salt of carboxymethyl cellulose are disintegrants used

Osmotic Tablet and Pump

• Alza's Oros and Duros operate on osmosis concepts
• Oros provides 24 hr release that is independent from diet
• Tablets using this technology are made of sempiermeable material on two sections
• Membrane allows water to enter the osmotic agent compartment
• The upper section contains drug and the lower section contains the osmotic agent
• Osmotic pressure pushes the bottom section upward, which will force the drug with the water through a laser-drilled orifice on the tablet's top
• Nifedipine (Procardia XL), glipizide (Glucotrol XL), methylphenidate, oxybutynin, and pseudoephedrine (Sudafed 24 Hour) use this technology
• 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

• Polymers are used as tablet binders to bind the excipients in tablet manufacturing
• Modern forms utilize polymers for drug protection, masking, delivery, and increase drug bio availability
• They are used to control the viscosity of aqueous solutions, and suspend or granulate
• Major polymer use is in controlled drug release
• In biomedicine, they are generally used as implants and are need them to perform for long-term service

Polymers in Pharmaceutical and Biomedical Applications

• Water-Soluble Synthetic Polymers include:
  • 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 <10,000; liquid (Mw <1000) and wax (Mw >1000), plasticizer, base for suppositories
  • Poly (vinyl pyrrolidone) Used to make betadine (iodine complex of PVP) with less toxicity than iodine, plasma replacement, tablet granulation
  • Poly (vinyl alcohol): Water-soluble packaging, tablet binder, tablet coating
  • Polyacrylamide: Gel electrophoresis to separate proteins based on their molecular weights, coagulant, absorbent
  • Poly (isopropyl acrylamide) and poly (cyclopropyl methacrylamide): Thermogelling acrylamide derivatives, its balance of hydrogen bonding, and hydrophobic association changes with temperature

Cellulose-Based Polymers

• Ethyl cellulose: Insoluble but dispersible in water, aqueous coating system for sustained release applications
• Carboxymethyl cellulose: Superdisintegrant, emulsion stabilizer
• Hydroxyethyl and hydroxypropyl celluloses: Soluble in water and in alcohol, tablet coating
• Hydroxypropyl methyl cellulose: Binder for tablet matrix and tablet coating, gelatin alternative as capsule material
• Cellulose acetate phthalate: Enteric coating
• Hydrocolloids include:
  • 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
  • Carrageenan: Modified release, viscosifier
  • Chitosan: Cosmetics and controlled drug delivery applications, mucoadhesive dosage forms, rapid release dosage forms
  • Hyaluronic acid: Reduction of scar tissue, cosmetics
  • Pectinic acid: Drug delivery
• Water-Insoluble Biodegradable Polymers include:
  • (Lactide-co-glycolide) polymers: Microparticle-nanoparticle for protein delivery
• Starch-Based Polymers Include:
  • Starch: Glidant, a diluent in tablets and capsules, a disintegrant in tablets and capsules, a tablet binder
  • Sodium starch glycolate: Superdisintegrant for tablets
• Plastics and Rubbers include:
  • Polyurethane: Transdermal patch backing, blood pump, artificial heart, vascular grafts, and foam in biomedical and industrial products
  • Silicones: Pacifier, therapeutic devices, implants, medical adhesive for transdermal delivery -Polycarbonate: Case for biomedical and pharmaceutical products
  • Polychloroprene: Septum for injection, plungers for syringes, and valve components
• Additional Polymers include:
  • 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 -Polystyrene: Petri dishes and containers for cell culture -Polypropylene: Tight packaging, heat shrinkable films, containers
• Water-Soluble Synthetic Polymers:
  • Poly (vinyl chloride): Blood bag, hoses, and tubing
  • Polyethylene: Transdermal patch backing for drug in adhesive design, wrap, packaging, containers -Poly (methyl methacrylate): Hard/soft contact lenses -Acrylic acid and butyl acrylate copolymer: High/Low Tg pressure-sensitive adhesives for transdermal patches
  • Vinyl acetate and methyl acrylate copolymer: High cohesive strength pressure-sensitive adhesive for transdermal patches
  • Ethylene vinyl acetate and polyethylene terephthalate: Transdermal patch backing
  • Polyethylene and polyethylene terephthalate: Transdermal patch backing
  • Transdermal patch backing (when ethylene vinyl acetate copolymer is incompatible with the drug)
• Methocel polymers including pure methylcellulose and hydroxypropyl-substituted methylcellulose display thermogelling property in water
• More methyl causes better water solubility so cloud point temperature shifts higher and is dependent on methyl substitution
• Methocel viscosity relies on polymer molecular weight rather than methy/ydroxypropyl content

Cellulose Based Polymer Properties

• Cellulose: Water-insoluble due to excessive hydrogen bonding H and CH3
• Methyl cellulose: soluble in cold water; swells slow in cold water; insoluble in ethanol, water, and salt
• Ethyl cellulose: Water-insoluble; impermeable barrier, commercially available from Dow,
• Carboxymethyl cellulose: Water-soluble; FMC Corp. supplies cross-linked CMC as tablet superdisintegrant
• Hydroxyethyl cellulose: Soluble in water and in alcohol
• Hydroxypropyl cellulose: Water-soluble at low temperature; film-coating application
• Hydroxypropyl methylcellulose: Soluble in water below 60°C and in organic solvents; HPMC coating replaced sugar coating with a shorter coating time

Hydrocolloids and Guams

• Hydrocolloids or gums originate from a variety of sources, they are hydrophilic and contain very long polymeric chains and groups
• Gums are very attractive in processes and behave differently across different types of aqueous solutions
• Gums display property such as thickening and gelling in drug encapsulation applications
• Gums such as guar, and alginate are used in thickening/gelling in encapsulation
• Synthetically, gums can be blended to provide superior properties through synergy.
• Since gums are from natural sources they make the job of pharmaceutical suppliers difficult
• Gums are a good platform for bacteria
• Chitosan can be used as an excipient and made from lobster shells and investigated in delivery for adhesive properties
• Chitosan is cationic and can be mixed with cellulose to form a masking for bad tastes such as caffeine

Chitosan Toxicity and Properties

• Chitosan is safe and has negligible cytotoxicity, so lower molecular weight (oligosaccharide) is preffered
• Synthetic protein can be exposed to denaturation or deactivation during the production process, so chitosan is made to complex anionic polymers
• Gels based on chitosan and ovalbumin protein are used in pharms
• Protonated can allow permeabaility in peptide drugs, while a sorbitol ester can act as nonic emulser such as cream

Polymers in Drug Delivery

• Taste masking, controlled release, stability, and increased bioavailability are all results pharmaceutical polymers use
• Monolithic delivery system that has a matrix and drug is affected by drug conc and relaxation of the polymers
• Exemplified by alprazolam

Alternative Drug release

• Release is provided by swelling with a polymer matrix, or a porous/non porous membrane
• While nonporous is driven by diffusion, porous allow for an extra path
• Membrane systems can generally be modified via the use of plasticizers or thickness to create a sustained release

Polmeric Functionality

• Polymers can be pH dependent
• Anionic polymers are generally designed for delivery passed the stomach from a pH of below two (duodenum)
• Eudragit is used to show for where the dissolution takes place and there are different versions based on the type (Eudragit L 30D)
• Kollicoat MAE 30 DP is a combination of ethy and acrylic is a 30% dispersion
• Neutral polymers are insoluble

Degradability in Polyerms

• Drug can be a consequence form polymer erosion such through swelling or in bulk through hydrolytic or functional conditions
• The polymer will be released at a surface depending on the erosion rate
• Biodegradable polymers are classified as both natural and based. Synthetic like Polyssacharides can be uses
• Exemplified by:
  • Prostrate Cancer, the eligard is injected, while atridoz in injectabl as it is bioabsorbable

Polymer Properties and Matrix Swelling

• Matrix is controlled by swell and erode,
• Matrixs depends on if the product is weak and if a hydrogel can swell
• Ion-Exchange Resins, polyermer materials with 2 char: aqueous medium to swell, complexable

Polymer Application

• Drugs can be both anionic or cationic, by the addition of moisture
• The duv cross linked posseses a high swelling and can be affect by ph (or temp)
• Used to main tool to contrl release with blending and are macromolecules chain and groups

Explore the history and diverse applications of polymers. This includes early challenges with guncotton, the advantages of synthetic rubber, and the role of polymers in wartime technologies like polyethylene and nylon parachutes. Furthermore, understanding the use of polymers like Eudragit in drug delivery systems.