W4 Pharmaceutical Powders (ZM) 17.10

Question 1

What are some examples of pharmaceutical powders? (5)

Answer 1

• Dusting powder (antifungals)
• Oral powder in sachets (dioralyte)
• Powders for reconstitution (abx- ciprofloxacin)
• Inhalation or insufflation products
• Bulk powders for tablets and capsules manufacture

Question 2

What differences are there between amorphous and crystalline?

Answer 2

Crystalline- Sucrose molecules align and form large ‘lattices’ of molecules, with a
regular repeating structure (Regular)
e.g. fudge, rock candy, fondant

Amorphous- Molecules of a different size and shape (glucose and fructose) get in the
way of the sucrose molecules and stop
crystals forming (Irregular)
e.g. lollipops, caramel, candy canes

Question 3

List some properties of crystalline solids:

Answer 3

• Molecules packed in a defined
  (long range) order
• Cool slowly to below melting point
• Melt ↔ freeze
• Polymorphs, solvates or hydrates,
  co-crystals

Question 4

List some properties of amorphous solids: (4)

Answer 4

• Molecules packed in a random
  (short range) order
• Rapid solidification/precipitation
• Glassy ↔ rubbery (transition)
• Moisture sensitive, dissolves faster

Question 5

What is polymorphism?

Answer 5

• Different molecular packing arrangements (of the same chemical substance) in the crystal lattice
• Differences in molecule orientation or conformation in lattice sites

Question 6

How can we check if something is crystalline or amorphous?

Answer 6

X-ray diffraction
if Crystalline: X-rays will be scattered only in certain directions (periodic arrangement of atoms)
if Amorphous: X-rays will be scattered in many directions

polymorphism will be inbetween

Question 7

What is Hygroscopicity?

Answer 7

The tendency of a solid substance to absorb moisture from the surrounding atmosphere

Question 8

Hydrate Vs Solvate:
What do these terms mean?

Answer 8

• If water is present in the crystal
  lattice= Hydrate
• Due to small molecular size of
  water and multidirectional hydrogen bonding capability of water
  Anhydrous = no water
• If solvents are present in the crystal lattice = solvate
• Ethanol → ethanolate
• DMSO (dimethyl sulfoxide) → DMSO solvate

Question 9

What are examples of a medicine that is a hydrate?

Answer 9

Lisinopril dihydrate
Each tablet contains lisinopril dihydrate equivalent to 10 mg anhydrous lisinopri

Question 10

What are the effects on drug distribution by salt formation? (ionic bond)
Example of a drug in its salt form?

Answer 10

Salt formation increases the solubility and dissolution* rates of acidic and basic drugs

*Dissolution is the process in which a substance forms a solution

Amlodipine besilate
-Each tablet contains amlodipine besilate equivalent to 10 mg of amlodipine

Question 11

What are co-crystals?

Answer 11

=Two or more molecules within the same crystal lattice
* In a definite stoichiometric ratio
* Not based on ionic bonds (like salts)

Question 12

Which 2 drugs can you combine to create a co-crystal?

Answer 12

Sildenafil and Aspirin:
Exerts 2 functions

• Sildenafil facilitates improved smooth muscle relaxation and increased blood flow in the human corpus cavernosum
• Aspirin has antiplatelet activity to
  combat heart attacks and strokes

Combined= Potential application in the treatment of erectile dysfunction in patients with cardiovascular complication

Question 13

Can you give examples of the solid states of a bulk drug which determines apparent solubility, and in turn governs the systemic
availability of that drug? (chemical)

Answer 13

Crystalline
Amorphous
Polymorphous
Hydrate or Solvate
Salt form
Co-crystal form

Question 14

What are the primary features of a powder? (physical) and their relevance? (3)

Answer 14

1. Particle size= Content uniformity, flow and mixing
2. Surface area= Dissolution rate
3. Shape= Content uniformity, flow and mixing

Question 15

What are the secondary features of a powder? (4)

Answer 15

1. Density (spaces between the solids)= Determines size of tablets and capsules
2. Porosity= Compressibility, permeability/water uptake of tablets
3. Flowability= Content uniformity
4. Compressibility= Essential to manufacture of tablets

Question 16

How is particle size expressed in large objects and small particles?

Answer 16

Large, geometric objects
= Size described in 3D

Small, irregular particles:
= 3D size description impractical, only one dimension (e.g. average diameter) is used

Question 17

What are some equivalent diameters?

Answer 17

• dp= Projected perimeter diameter
• da = Projected area diameter
• dF = Feret’s diameter
• dM = Martin’s diameter
• ds = Sieve diameter
• dv = Diameter of equivalent volume sphere
• dsa = Diameter of equivalent surface area sphere
• dmass = Diameter of equivalent mass sphere

Question 18

Equivalent diameters:
What are Stokes, Aerodynamic and Hydrodynamic diameters?

Answer 18

1. dst = Stokes’ diameter
   * Diameter of a sphere with the same density and settling velocity as the particle
2. dae = Aerodynamic diameter
   * Diameter of a sphere with the same terminal velocity in air or some other relevant fluid as the particle
3. dhyd = Hydrodynamic diameter
   * Diameter of a sphere that diffuses at the same rate in a liquid as the particle

Question 19

Which equivalent diameter should I choose for paint pigment particles?

Which equivalent diameter should I choose for aerosol deposition in the lungs?

Which equivalent diameter should I choose for sedimentation properties of the material

Answer 19

1. Projected area diameter
2. Aerodynamic diameter
3. Stokes’s diameter

Question 20

What are two particle shapes?

Answer 20

Solid irregular particles
Porous irregular particles

*porosity= exposing surface area

Question 21

What are some particle shape terminologies for 1D, 2D and 3D shapes?

Answer 21

1D= Acicular or Rod-shaped
2D= Dendritic or Flaky
3D= Porous or Angular/irregular or Spherical or Rounded

Question 22

How does particle shape matter?

Answer 22

1. Good flowability = easy mixing
   (spherical + rounded)
2. Tendency to interlock, increased mechanical strength
   (Acicular, Rod-shaped, Angular/irregular)
3. Cohesive effects due to greater surface area (flaky)

Question 23

Surface area equations:

Answer 23

for a sphere: SA= 4πr^2

for a rectangle:
Surface area =
2(length × width) +
2(width × height) +
2(length × height

Question 24

Specific surface area per weight unit (Sw)
equation:

Answer 24

Weight-specific surface area
= [surface area/weight]

Question 25

Specific surface area per volume unit (Sv) equation:

Answer 25

Volume-specific surface area = [surface area/volume]
A small particle may be best described as matter of a small size with an immensely high surface-to-volume ratio

Question 26

Noyes-Whitney Equation

Answer 26

A greater surface area leads to an increase in dissolution rate and improved
bioavailability

• 𝑑𝐶/𝑑𝑡 = the rate of dissolution of the drug particles
• D = the diffusion coefficient of the drug in solution in the GI fluids
• A = the effective surface area of the drug particles in contact with the GI fluids
• Cs = the saturation solubility of the drug in solution in the diffusion layer
• C = the concentration of the drug in the gastrointestinal fluids
• h = the thickness of the diffusion layer around each drug particle

Question 27

Surface area measurement (of irregular particles) setup and process:

Answer 27

Brunauer–Emmett–Teller (BET) theory
* Stephen Brunauer, Paul Hugh Emmett, and Edward Teller

1. Powder is filled into a vacuum-sealed chamber
2. Small amounts of nitrogen gas (or krypton or argon) are added to the chamber
3. The nitrogen molecules adsorb to the
   the surface of the powder (until the entire
   surface (including all accessible pores) is
   covered
4. Pressure transducers sense the amount of gas adsorbed from which the surface
   area can be calculated

Question 28

How does the determination of particle size, shape and surface area help to inform the drug manufacturing process?