TD: Hydrogels

Question 1

What are hydrogels?

Answer 1

• Hydrogels are crosslinked polymeric systems (networks) swollen in water (or biological fluid)
• By definition, they have a high philicity for water (and low molecular weight polar solvents)
• They may absorb from a few percent of their weight to many thousands.
• They can be natural polymers (eg gelatine) or synthetic (‘man-made’).

Question 2

What are the applications of hydrogels

Answer 2

Pharmaceutical sciences

• Drug delivery - buccal, dermal, nasal, ocular, oral, parenteral, rectal, vaginal, subcutaneous, controlled or targeted drug release!

Biomaterials

• Prostheses
  
  • • contact lenses, vitreous body (eye)
  • artificial muscle
  • intraperitoneal barrier (prevents tissue adhesion following surgery)
  • arterial surfaces and tissue scaffolds

immunology

• Immunology
  
  • cell transport
  • protein purification (chromatography magnetoseparation)

Question 3

What are examples of natural hydrogels?

Answer 3

Polysaccharides:

Plant Cells:

• cellulose
• starch
• xanthan

Sea-weeds:

• carrageenan
• alginate

Crustanceans:

• chitin

Proteins

• Collagen (vertebrates)
• Gelatine (Vertebrates)
• Albumin (Eggs, blood)

Question 4

What are examples of synthetic hydrogels?

Answer 4

Poly(2-hydroxyethylmethacrylate) - HEMA

Poly(acrylic acid) - PAA

Poly(acrylamide) - PAM

Poly(methacrylic acid) - PMMA

Poly(vinyl alcohol) - PVA

Poly(N-vinyl-2-pyrrolidone) - PVP

Poly(ethylene glycol) - PEG

Question 5

What is the difference between hydrogels and gels?

Answer 5

hydrogels are a cross-linked network of hydrophilic polymers. They possess the ability to absorb large amounts of water and swell, while maintaining their three-dimensional (3D) structure [10]. This definition differentiates hydrogels from gels, which are polymeric networks already swollen to equilibrium, and the further addition of fluids results only in dilution of the polymeric network (chains dissolve)

Question 6

Describe the production of polymers from monomers

Answer 6

Peroxide catalyst breaks the C-C DB and produces free radicals which reatc in a random fashion with other unsaturated alekene molecules to produce long chains of substituted Carbon atoms

Question 7

What types of polymers can you get?

What polymerisation reactoins cause these?

Answer 7

Ziegler Natta uses metal catalysts

Question 8

Describe the production of hydrogels

Answer 8

Important to create a network structure - this is responsible for the swelling properties in water

Physical gels - do not require the formation of covalent chemical bodnds to join linear polymer chains together

Question 9

Describe formation of different polymer networks

Answer 9

Initator - small reactive molecule

1. Reactive side chain groups react to form a cross-linked structure

Trifunctional molecule reacts with reactive end-groups to form a structure

Question 10

Describe what type of cross-linking bonds can form

Answer 10

Question 11

Describe the types of network structures?

What is density of network?

Answer 11

Density network - distance between cross-linked molecular chains (often referred to as crossed-link mwt)

Physical entaglement - linear polymer chains become entangled - these restrict translational movement of polymer chains

The cross links involve prevent the network from completely dissolving in approp medium - but instead swell. They do not completely dissolve due to restricitve influence and presence of cross-links

Question 12

What are 2 classificatins of hydrogels?

Answer 12

• Chemical or neuteal
• Physical/reversible

Question 13

Describe chemical or neutral hydrogels

Answer 13

Question 14

Describe physical or reversible hydrogels

Answer 14

Question 15

Classification of hydrogels - ionic

Answer 15

Question 16

Describe the effect pores have on the drug and what factors affect pore size

Answer 16

Question 17

What are the equations for pore size?

Answer 17

Question 18

How do you calculate the degree of swelling

Answer 18

Question 19

What does diffusion of the solute depend on?

Answer 19

• solute concentration
• solute size
• degree of swelling
• molecular weight between crosslinks
• degree of crystallinity
• pore size

Question 20

What equation describes diffusion of the drug through hydrogels?

What is the relationship between diffusion, pore size and tourosity?

Answer 20

D proportional to pore size and D inverse prop to t

Question 21

How is Restriction coefficent calculated?

What do specific values mean?

Answer 21

Question 22

Describe complexation hydrogels

Answer 22

example of complexation hydrogel is polyacrylic acid

The free acid groups are associated in the unswollen state. The absorption of a suitable base e.g. NaOH neutralises the acid groups therfore forming -ve carboxylate groups. These repel each other therfore opening channels for the absorption and imbibing of water

Question 23

site-specicific drug delivery

Descrribe hydrogels as oral controlled release/M/R tablets.

Answer 23

In an acidic enviroment the PPMA has carboxylic acid groups which are non ionised and therefore associated by relatively strong H-bonds. between adjacent acid groups. When acid groups ionised by addition of base there is electrostatic repulsion between negative carboxylate anions which pushes the polymer chains apart. This allows the absorption and imbibing of water molecules which solvate the PPMA.

When the acid gropus are solubilised the polymer network can swell and form a weak gel network stricture. Provided the pore size is greater than the hydrodynamic radius of the drug then the diffusion of the drug can readily occur

Question 24

Describe the mechanism of drug release using hydrogels as oral M/R tablets

Answer 24

It is the swelling and deswelling of the network structure that permits or prevents the diffusion of drugs.

The low pH of the stomach acid causes the complexation of the carboxylic acid groups. This effectively reduces the pore size of the hydrogel to below that of the hydrodynamic radius of the drug. This effectively traps the drug molecules in the voids resulting from the strong H-bonding. This protects the drug from the acidic conditions but no diffusion is possible.

The decomplexation of carboxylic acid groups by exposure to a less acidic and more neutral enviroment permits the swelling of the network and the free difussion of the drug.

This property also allows for site specific drug delivery to the colon where the the carboxylic acid groups are decomplexation and the hydrogel swells and allows drug diffusion.

The hydrophillic properties of PEG allow for adheration to the intestinal lumen and a path for drug to follow to its target site

Question 25

Describe hydrogels for modulated delivery - thermosensitive

Answer 25

In its open form PIPAAm is a good vehicle for the release of drugs. When temp is increased above a cirtical temperature the hydrophobic isopropyl groups agglomerate and are held together by hydrophobic-hydrophobic attractions. This closes the open chain stucture and the drug is trapped. However when temp decreased the structure relaxes and the drug becomes mobile again and can diffuse

Question 26

Describe thermo-sensitve hydrogels drug release for poly(IPAm-co-RMA)

Answer 26

The coploymer has been produced as a bead containg the drug. When temp increased the isoppropyl groups on the surface complex with each other and an impermeable skin fomrs on the outside of the hydrogel bead. This process is reversible by simply lowering the temperature and this allows for a pulsitile release than can be on or OFF

Question 27

Describe the following graph based on thermo-sensitive modulated drug release of a hydorgel

Answer 27

Inital temperature is 30C and ~10% of total drug content is released over 4hr. The temp remains same for another 20hr. After this temp lowered to 20C and release continues. At higher temp the bulk of drug is trapped in unswollen/OFF state. At lower temp drug release continues as normal

Question 28

Descfribe

Answer 28

The drug from inside the hydrogel has to diffuse to the outside of and this pw is more toruse than the pw of drug close to surface. As T increase it causes a skin to form on the ourside of the hydrogel and this squeezes a small amount of drug out the surface of the hydrogel. This small release is short-lived and then goes into OFF mode. This cycle is repeated for 8r and a pulsatile relase is obtained. Over time the release subsides as the drug reserviour is depleted

Question 29

Describe the formation of the neutral hydrogel poly(methylacrylate)

Answer 29

The student should remember that neutral or chemical hydrogels are not complexation hydrogels, nor are they physical or ionic hydrogels. Neutral hydrogels have covalent, chemical crosslinks such as the example of poly(vinyl alcohol) or PVA illustrated in the last lecture, that can swell but not completely dissolve due to the restricting cross links that tie the network together. The first example of a neutral hydrogel given is that of poly(methacrylamide). The liquid (monomer) can be placed in a suitable mould and polymersied by the action of heat and/or a catalyst. In this example, the catalyst is actually a radical initiator called AIBN for short. The action of heat cleaves the nitrogen double bond to produce two moles of IBM radicals. These radicals activate the carbon-carbon double bonds in the monomer causing a radical polymerisation reaction that results in long cross-linked polymer chains of poly(methacrylamide). When the cross-linked po lymer is removed from the mould in which it was made,it has a shape memory. It will swell and expand in water but always maintain its cast shape.

Question 30

Describe the formation of the neutral hydrogel polymer shown below:

Answer 30

The polymer as that of a cross-linked polyurethane made from the reaction of a difunctional isocyanate and poly(ethylene glycol) of molecular weight eight thousand grams per mole. Just think about that for a moment. One mole of the poly(ethylene glycol) weighs eight kilograms! The cross-linking agent is a trifunctional alcohol that can react with isocyanate groups, the urethane or carbamate reaction is shown bottom left. Polyethylene glycol is melted at 80 degrees C and mixed with the diisocyanate and hexanetriol. A small quantity of ferric chloride is added as a catalyst.This mixture is injected into a suitable mould and the reaction takes place. Once the reaction is complete and the cooled polymer demoulded, a chemically cross-linked polymer network that can swell in water is produced in the desired shape.

Question 31

Describe the steps in making the previous neutral hydorgel

Answer 31

Question 32

Describe hydrogels as subcutanrous implants

Answer 32

The slide exemplifies the process for producing a monolithic, neutral hydrogel device containing drug, using the chemistry described in the previous slide. The regents are heated and mixed in the presence of a catalyst and cast to appropriately sized and shaped moulds. Once de-moulded, the unswollen polymer is placed in a reservoir containing a water soluble drug. The polymer swells in the solution, absorbing the drug. Thereafter, it is dried and returns to its cast shape and size. In this state, it is ready to be implanted subcutaneously, to swell in the biological fluid and release its contents by a diffusional process. Hormonal delivery is a popular use for this neutral hydrogel.

Question 33

problems with subcutaneous implants and solution

Answer 33

Implant attacked by immune system. Can coer with biocompatable membrane (hydrogel)