Emma (Injectables)

Question 1

Viscosity

Answer 1

“An expression of the resistance of a fluid to flow”
The higher the viscosity the greater the resistance (more force required to make the liquid flow).
Macromolecules affect the viscosity of a solvent. The effect is large even at low concentrations because big molecules affect the fluids flow over a long range.
Viscosity studies can provide information on the shape of particles in solution (shape of particles dictate how it will flow). They can also provide quality control of batches.
Linked to rheology. Rheology is measuring the flow and viscosity is resistance to the flow.

Question 2

Newtonian fluids

Answer 2

The higher the viscosity of a liquid, the greater the shearing stress required to produce a certain rate of shear.
In newtonian fluids, viscosity does not change with increasing shear rate. Viscosity is constant.
Very few things are Newtonian in flow but some examples are water, honey, pharmaceutical dosage forms with high water content.

Question 3

Viscosity in pharmacy

Answer 3

• The viscosity of creams and lotions may affect the rate of absorption of the products by the skin. This is due to the effect of viscosity on the rate of diffusion of the active ingredients-the more viscous it is, the harder it is for the active ingredient to move out of the cream.
• A greater release of active ingredients is generally possible from softer, less viscous bases.
• The rate of absorption of an ordinary suspension differs from thixotropic suspensions.
• Thixotropy is useful in the formulation of pharmaceutical suspensions and emulsions. They must be poured easily from containers (low viscosity). (If you shape a thixotropic solution it needs time to go back to its original shape)
  Example- the oral contraceptive pill thickens cervical mucus
  Depo injections- once injected they revert to a state that is thicker which means it takes longer to break down and release the active ingredient

Injectables- parenteral delivery
- Intravenous (IV)
- Intramuscular (IM)
- Subcutaneous (SC)
- Intradermal (ID)/Intracutaneous (IC)
(Parenteral means administration other than through the GI tract)
A parenteral drug is defined as a sterile product that is suitable for administration by injection, internal irrigation, or for use in dialysis procedures.

Question 4

Why does viscosity matter?

Answer 4

In parenteral delivery the drug must flow.
The flow conditions within a fluid can affect heat and mass transfer and rate of dissolution (if it doesn’t flow properly the API might sediment out which can change the concentration of the drug which changes the dose).
Macromolecules affect the viscosity of a solvent. This matters when delivering large drug molecules as they can affect the flow. (e.g. carbohydrates and proteins i.e. insulin)

Question 5

Liquid flow on surfaces

Answer 5

Velocity of fluid in a drop depends on region. (Faster flow further away from the surface).
If it is close to the wall of the strings the velocity is much lower than in the bulk due to intermolecular interactions.
The liquid interacts with the surface of material (adsorption).

Question 6

Adsorption vs absorption

Answer 6

Adsorption is a surface effect. The process of adsorption is used to decrease accumulation of an adsorbate at an interface. It can be on the walls of a syringe, needle, or dialysis tubing. This can reduce the potency of the drug product administered.
Absorption is the penetration of one component throughout another.

Question 7

Adsorption issued in practice

Answer 7

Adsorption of proteins onto surfaces is a fast process and depends on concentration, charge, temperature, and hydrophobicity.
Adsorption of proteins on polymer surfaces often catalyses their unfolding and aggregation (-decreases potency).
Administration of therapeutic proteins through polypropylene (PP) syringes often results in loss of proteins because of their adsorption.

Blood tubing, such as in dialysis procedures, has to be extensively analysed to prevent activation and destruction of blood components. - The material can trigger the clotting cascade.
An initially adsorbed protein later on the material surface is the main trigger of adverse reactions such as
- the activation of coagulation via intrinsic pathway
- the activation of leukocytes, which results in inflammation
- the adhesion and activation of platelets
As a result the number of blood cells can decrease and a thrombus can form. This can result in pulmonary embolism.

Question 8

Insulin adsorption (BNF)

Answer 8

• The adsorption of insulin to the surfaces of IV infusion solution containers, glass and plastic, tubing, and filters has been demonstrated.
• Estimates of the loss range up to about 80% for the entire infusion apparatus, although varying results using differing test methods, equipment, and procedures have been reported. Estimates of adsorption of around 20 - 30% are common.
• !!The percent adsorbed is inversely proportional to the concentration of insulin!!
  Other important factors are the amount of container surface area and the fill volume of the solution. The amount of insulin adsorbed varies directly with the available surface area and indirectly with the ratio of fluid volume to container capacity (i.e. fill a smaller container rather than half fill a large container).
• The container material is a factor, with glass possibly adsorbing insulin more extensively than some plastics.
• Other factors influencing the extent of insulin adsorption include the type of solution, type and length of administration set, rate of infusion, temperature, previous exposure of tubing to insulin, and presence of albumin human, whole blood, electrolytes, and other drugs. (This means they may need to go in temperature and pressure controlled containers if you are shipping them across the world. In hospital you need to check what else has been through the IV line before administering insulin through it).

Question 9

Liquid flow in pipes

Answer 9

Osborne Reynolds performed an experiment to study the flow of fluids.
He introduced a dye into the flowing stream of water at various points and determined there were three regions:
- Laminar flow region
- Turbulent flow region
- Transition flow region

Question 10

Laminar flow

Answer 10

• This was seen in the low flow (low velocity) region. The dye formed a smooth, thin straight streak down the pipe and there was no mixing.
• In this region, the pressure drop per unit length is proportion to flow rate.
• All the motion is in the axial direction (direction of flow) and is called laminar because the fluid appears to move in layers or lamina.

Question 11

Turbulent flow

Answer 11

• This was seen in the high flow (high velocity) region. The dye was rapidly mixed throughout the entire pipe.
• The rapid, haphazard motion in all directions in the pipe along with the axial flow caused rapid mixing of the dye.

Question 12

Transition flow

Answer 12

• Reynolds observed a region of unreproducible results between the laminar and turbulent flow regions.
• The switch from laminar flow to turbulent flow may result from ‘outside disturbances’. These can include roughness of the pipe wall and equipment vibration which cause the switch from the stable flow conditions of laminar flow to turbulent flow. (Can turn back into laminar flow).
• In the transition region, the flow is either turbulent or laminar and depending on the conditions it alternates between these.
• The pressure drop in this region is very difficult to measure as it oscillates between higher and lower values.

Question 13

Velocity distribution across pipes

Answer 13

Lamina moving at different speeds. The ones closest to the edge are moving slowly while those near the centre are moving quickly.
- Flow is fastest in the middle of the pipe and slowest near the wall
- At the actual surface of the pipe wall, the velocity of the fluid is zero

Question 14

Reynolds number

Answer 14

Reynolds determined there were two forces acting on the fluid in flow:
- Inertial (velocity) forces – tend to maintain flow in its general direction.
- Viscous forces – tend to retard the general motion of fluid and introduce eddies.

Reynolds claimed that the fluid flow changes with the change in these forces and the type of flow depends on their ratio.
He developed the dimensionless Reynolds number to quantify this.
Re = Inertial force/ Viscous force
(Inertial force = density of fluid * velocity of fluid * pipe diameter.
Viscous force = viscosity of the liquid)

Laminar flow Re = <2100 (Low Reynolds number)
Transition flow Re= 2100-4000
Turbulent flow Re = >4000 (High Reynolds number)

Question 15

Hagen- Poiseuille’s Law

Answer 15

The Hagen–Poiseuille equation is the physical law that gives the pressure drop in an incompressible and Newtonian fluid in laminar flow flowing through a long cylindrical pipe of constant cross section.
In this case, the pipe is a needle and small increases in the radius of the needle can significantly reduce the pressure required to deliver the drug.
Needle gauge is key; although a finer needle means easier and less painful insertion, it also has a smaller bore so requires more pressure.
If an injector device is fitted with a 27 G needle (bore size 0.191 mm) and the needle is changed to a 30 G (bore size 0.140 mm) of the same length, the plunger force needed to give the same flow rate (and therefore the same injection duration) has to increase by 350%.
A balance has to be struck between insertion pain and force required to administer the dose effectively.

Question 16

Injectable viscosity

Answer 16

• In effective sustained release and SC injections, the concentration of protein is usually increased, causing an increase in viscosity (long-acting/ultra-long acting insulins- forms a depot).
• The increase in viscosity creates significant challenges in injectability, since high viscosity requires high injection force. This, in turn, affects how an auto-injection system needs to be designed to achieve optimum performance.
• A drug injected through a small needle (e.g. 27 G), with a 10s injection time rate, will have a shear rate inside of the needle which is estimated to be 160,000 s-1 (high).
• It is important to note that at this specific shear rate, the viscosity of the drug can be significantly different than if it was at a lower shear rate.

Question 17

Relevance to pharmacy

Answer 17

Stokes law equation can be modified to include Reynolds number to study the rate of sedimentation in a suspension
The viscosity and injection speeds (flow rates) have an impact on perceived injection pain.

Factors contribution to subcutaneous injection site pain:
- Product related factors
- Formulation- ingredients, pH, buffers
- Delivery volume
- Needle gauge size
- Device type
- Injection related factors:
- Injection speed
- Fluid viscosity
- Injection angle/technique
- Temperature of produce
- Allergens
- Injection frequency
- Injection site
- Patient related factors
- Low body weight
- Injection anxiety
- Pain catastrophising
- Nocebo effect
- Female
- Fibromyalgia
- Depression
- Arthritis
- Patient expectations
- Patient movement during injection

Question 18

Shear rate also affects the biologic
(https://www.chemistryworld.com/news/tiny-shear-forces-have-big-effect-on-protein-reactions/4014482.article?utm_campaign=cw_shared&utm_medium=email&utm_source=website

https://pubs.acs.org/doi/10.1021/jacs.1c0368)

Answer 18

• This research showed that tiny shear forces proteins experience inside blood vessels can dramatically increase their reaction rates.
• ‘It has previously largely been assumed that these modest levels of shear would have little effect on the chemical reactivity of the protein…but …that this is not necessarily the case.’
• The proteins’ macromolecular shape is changed with shear stress and this could affect the action of therapeutic antibodies.
• Studying trastuzumab, the monoclonal antibody developed to treat breast cancer, showed that ‘some of these antibodies may be partially dissociated under these shear stress conditions’.

Question 19

Polymers used in pharmacy

Answer 19

• There are many polymers used in pharmacy for many different applications.
• Their inclusion in a liquid formulation can alter the properties – often this is desirable and why they are included. (They can make the injection flow more smoothly- Macromolecules affect the viscosity of a solvent)
• Sometimes the active ingredient is a polymer – a protein or carbohydrate/polysaccharide.
• We need to know what effect this polymer will have on the formulation

Question 20

Polymers used in pharmacy- Carbopol

Answer 20

• Carbopol polymersare polymers of acrylic acid cross-linked with polyalkenyl ethers or divinyl glycol.
• The structure can be viewed as a network formed by polymer chains being interconnected via cross-linking through covalent bonds or hydrated salt bridges.
• It is frequently employed in the cosmetics, pharmaceutical, paint, and food industry as a thickening, suspending, dispersing, and stabilizing agent.

Question 21

Polymers used in pharmacy- Dextrans

Answer 21

• Dextrans are complex branched polysaccharides consisting of many glucose molecules composed of chains of varying lengths (from 3 - 2000 kDa).
• Used as replacement for blood plasma and as a solvent e.g. for iron salts.
• Dextrans have an inhibitory effect on thrombocyte aggregation and coagulation factors and are used as volume expanders.

Question 22

Measurement of viscosity

Answer 22

Viscosities are measured in several ways.
Capillary viscometers
- Also known as Ostwald viscometers or Ubbelohde type viscometers.
- Shear rate varies throughout experiment
- Temperature control
- Used for polymer or micelles in solution
Start point – The solution is drawn above this point and then allowed to fall under gravity.
End point – The length of time it takes the solution to go from the start to end point allows the viscosity to be calculated.
The temperature is measured.
Various viscosities can be calculated e.g.
- Kinematic viscosity
- Relative viscosity
- Specific viscosity
- Reduced viscosity
- Intrinsic viscosity
- Inherent viscosity

Units- viscosity is usually reported in centipoise (cP).

Question 23

Tonicity

Answer 23

• Tonicity modifiers (e.g. dextrose, sodium chloride or potassium chloride) are commonly used to achieve isotonicity in a parenteral formulation.
• An isotonic solution has an equal amount of dissolved solute in it compared to the solution it is being introduced into such as blood for IV injection.
  
  • Typically in humans and most other mammals, the isotonic solution corresponds to 0.9% w/v sodium chloride or 5% w/v dextrose.
  • An isotonic solution has an osmotic pressure close to that of the body fluids which minimises patient discomfort and damage to the RBCs.
• A hypertonic solution contains higher concentrations of dissolved substances than RBCs which causes them to shrink.
• A hypotonic solution contains lower concentrations of dissolved substances than the RBCs causing them to swell and possibly burst.

Question 24

Hagen-Poiseuille’s law in blood vessels

Answer 24

• Can also be used to calculate pressure difference in arteries and capillaries.
• There are three primary factors that determine the resistance to blood flow within a single vessel:
  
  1. Vessel diameter (or radius)
  2. Vessel length
  3. Viscosity of the blood
• Of these three factors, the most important is vessel diameter. The reason for this is that vessel diameter changes because of contraction and relaxation of the vascular smooth muscle in the wall of the blood vessel. Very small changes in vessel diameter lead to large changes in resistance.
• Vessel length does not change significantly and blood viscosity normally stays within a small range