Lec 16- Monolithic systems

Question 1

DiffusionControlled devices

Monolithic systems

Answer 1

• Drug is uniformly dispersed within water insoluble matrix
• matrix
  
  • solid drug dispersed with a matrix
    
    • 0.5 (v/v)- simple monolithic dispersion
    • 5-20% - complex monolithic daspersion
    • >20% - Monolithic matrix system

Question 2

diffusion control devices

monolithic systems

Answer 2

• Matrix devices
• Drug is homogenous we dispersed in insoluble matrix
  
  • Solid dispersion or solution
• Relatively easy to manufacture-mix and compress
• No danger of dose-dumping
  
  • Because matrix is insoluble the drug can’t penetrate it so won’t dose dump
  • Even if you cut the tablets the resulting parts will stil undergo slow release

Question 3

diffusion -controlled devices

monolithic systems

Answer 3

• Release rate depends on
  
  • matrix
  • loading
  • geometry
• Rate of release continuously falls as drug is depleted
• Lower loading is generally possible

Question 4

Simple monolithic dispersions

release of drug

Answer 4

• The interface between dispersed dissolved drug migrates inwards
• The rate of release decreases over time with this system
• In saturated solution- is in the soluble phase
• Solid drug travels inwards- toward the centre of the tablet- this increases the time for dissolution as there is a concentrated solution increase, therefore the pathlength between the water and insoluble tablet will mean that the release rate is far slower

Question 5

Monolithic dispersion- release equation

Answer 5

• Route t release holds over most of the delivery profile

Question 6

Monolithic dispersions

Release profile

Answer 6

• Opposite to zero order as time goes release rate decreases

Question 7

Monolithic dispersions

Release profile- Root t

Answer 7

• The closer the relation between Mt vs SqR t (closer to R=1) shows that the formulation is monolithic
  
  • Same for rate v 1/SqR t

Question 8

Monolithic dispersions

Effect of loading

Answer 8

• Small dependent on loaded
• drug release is dependent on the initial concentration of the drug
• Because release kinetics equation contains the C₀ (initial concentration) therefore as it increases release rate increases

Question 9

Complex monolithic dispersions

Answer 9

• 5 to 20% drug (v/v) Loading
  
  • depletion of drug near surface these cavities in matrix
  • cavities filled with external fluid-water-filled pores
  • provides rapid bypass diffusional barrier through matrix
  • Pores not connected
  • pores increase overall permeability at later times
  • Increase in loading increases permeability
• Release rate follows 1/Sqroot t
  
  • Faster than that predicted for simple dispersions

Question 10

Complex monolithic dispersions (5-20%)

Development of pore structure

Answer 10

• The white pores are not connected

Question 11

Complex monolithic dispersions

Release enhancement by pore structure

Answer 11

Question 12

Complex monolithic dispersions

Release dependent upon loading

Answer 12

• Release of chloramphenicol from EVA polymer
• Rate increases with loading- as the pores connect leaving multiple routes the water can enter or drug can exit

Question 13

Monolithic matrix systems

Answer 13

• >20% (v/v) drug loading
  
  • Particles are in contact with one another
  • Depletion of drug leaves cavities in matrix
  • Cavities fill with external fluid (water)
  • Provides rapid by-pass pores
  • Pores connect to form continuous channels
  • Channels increase overall permeability at later times
  • Much drug is released by diffusion through channels

Question 14

Monolithic matrix systems

Development of channel structures

Answer 14

Question 15

Monolithic matrix systems

Release enhancement by channel structure

Answer 15

• With higher concentrations of drug within the monolithic system when dissolution occurs and the drug exists the solution this means that pores are left which can be used as channels to enhances further drug release
• In high concentration monolithic tablets there are many pores which combine together to create far more paths to further aid drug release

Question 16

Monolithic matrix systems

Answer 16

• Useful for delivery of poorly diffusible drugs
• Simple preparation
• Release model analogous to simple monolithic dispersions

Question 17

Monolithic systems- preparation

Answer 17

• Insoluble matrices
  
  • Inert polymers
    
    • PVC, Polyethylene, ethylcellulose, acryclic resins
  • Lipophilic compounds
    
    • Hydrogenated vegetable oil, microcrystalline wax
      
      • Not in common use, often contain channeling agent

Question 18

Inert polymer matrices

Answer 18

• Gradumet technologies (Abbott)
  
  • Ferrograd, Ferrograd C, Ferrograd Folic
  • Gradument
    
    • Inert plastic matrix, honeycombed with thousands of narrow passages containg drug and a soluble channelling agent (highly soluble material within the matrix, dissolve very quickly causing and enhancing drug release
  • Methyl acrylate and methyl methacrylate matrix passes unchanged through GI tract into the stools

Question 19

Wax matrix

Answer 19

• Imdur (isosorbide mononitrate)
  
  • Drug granules suspended paraffin wax matrix
  • Directly compressed into a tablet
  • Wax broken down by enzyme in GI tract
  • Good for water soluble drugs
  • Tablets may be divided

Question 20

Nitro-Dur

Answer 20

• Homogenous daspersion of GTN/Lactose triturate in matrix
• Release is mainly controlled by the skin
• Why have a patch as a monolithic patch
  
  • Allow patch to be cut (fentanyl)
  • No dose dumping
  • Easier and cheaper to make

Question 21

Fentanyl patches

Answer 21

• Dose titration
• Cutting patches renders them unlicensed, fentanyl 25 mcg patches are often cut in practice to achieve a 12.5 mcg dose
• The formulation of the patch determines whether it may be safely cut or not
• Reservoir patches may not be cut

Question 22

Deponit

Dual action

Answer 22

• Deposit is a reservoir gradient-controlled matrix system
• Designed to compensate for non-zero order in the matrix system
• Multilayered matrix holding GTN in a concentration gradient (High concentration absorbed onto lactose, low free drug concentration)
  
  • This gives a constant rate of release (most monolithic the release decreases as time goes on)
• Matrix is a lattice of fixed lactose crystals to which GTN molecules are adsorbed
• High degree of control over delivery
• Has advantages of the reservoir and monolithic systems

Question 23

Problem 1

Controlled-release product

• In a dissolution experiment, the mass of drug released from a controlled delivery device (Mt) at various intervals was found to be as follows
• Determine the model which satisfies this release profile and suggest the type of device that may have been use

Answer 23

• Plot Mt v t= non-linear
• Plat Mr v Square root of t = linear
• This is the characteristic of a monolithic device (drug inside an insoluble matrix)