Pharmaceutical solids and preformulation importance of particle design

Question 1

Multi-particulates

• Powders: crystals, nanoparticles, microcapsules, microspheres
• Granules / agglomerates
• Pellets / spheroids / beads

Answer 1

Multi-particulates

• Powders: crystals, nanoparticles, microcapsules, microspheres
• Granules / agglomerates
• Pellets / spheroids / beads

Question 2

Final dosage form
• Capsules: hard, soft
• Tablets / caplets
• Others: films, gums

Answer 2

Final dosage form
• Capsules: hard, soft
• Tablets / caplets
• Others: films, gums

Question 3

Why Solid Dosage Form?

Answer 3

• Markedly better chemical stability
• Dry, does not promote microbial growth
• Lower bulk volume
• Ease of handling, added convenience
• Single chemical component possible

Question 4

Solid state solubility ranking

Ultra-micronization
polymorph
solvate
amorphous

Answer 4

LEAST SOLUBLE
1) polymorph
2) solvate
3) amorphous
4) ultra-micronization 
MOST SOLUBLE (Highest Chemical potential)

Question 5

technique to Determine structure of crystaline or amorphous material

Answer 5

1) Differential scanning calorimetry (DSC)
2) X-ray diffraction (XRD) by crystals — bragg eqn (nWAVELENGTH = 2dSINE o)
3) single crystal XRD
4) Powder- XRD

Question 6

DSC

Answer 6

Differential Scanning Calorimetry (DSC)

A thermoanalytical technique to measure the difference in the amount of heat required to increase the temperature of a sample and reference are measured as a function of temperature

Question 7

Crystal (Single Crystal XRD)

Answer 7

Single-crystal XRD is an analytical technique which provides detailed information about a crystal’s interior, including unit cell dimensions, bond-lengths, bond angles, ordering. Single crystal and details of site-XRD data analysis can provide the crystal structure.

Question 8

What are pre-formulation studies?

Answer 8

1) involve primary characterization of drugs substances and / or excipients for certain fundamental physical and chemical properties
2) Confirm supplier’s information and ensure quality. especially of raw materials
3) provide information that may dictate many of the subsequent events

Question 9

Applications/uses of preformualtion studies

Answer 9

1) to detect batch to batch variations of starting materials
2) enable better specifications to be drawn up for procuring materials, aimed at reducing cost or improving product quality.
3) an excellent database for the assessment of suppliers who can provide materials of consistent quality
4) retrospective study of process or product, improve specifications for raw materials .

Question 10

The physical aspects of raw materials are more likely than chemical properties to exert a greater influence on the granulation process as well as the quality and functionality of finished products.

Answer 10

The physical aspects of raw materials are more likely than chemical properties to exert a greater influence on the granulation process as well as the quality and functionality of finished products.

Question 11

Effect of particle shape

Answer 11

shape can have significant effects on the bulk properties of a powder.
spherical particles flow better, pack better and have lower surface to volume ratio

Question 12

surface area measurement by

Answer 12

1) gas permeability

2) gas adsorption

Question 13

determination of particle shape

Answer 13

1) micrometer
2) projected image
3) image analysis

most common is image analysis

• Sphericity = 4pi (AREA) / (perimeter)^2
  — 1 = spherical
  perimeter UP = less sphere
• roundness = (perimeter)^2 / 4pi Area
• — > 1 = less round
• Aspect ratio
  = Length / breadth
  ~2-3 = needle like
  up = more needle

Question 14

determine particle size

Answer 14

1) particle counting
2) particle size

1) size by group
2) get size of every particle and average it.

but only sphere can be described by 1 number.
Use equivalent sphere theory –> possible to gauge if particles become bigger or smaller, according to changes in volume or weight properties.

Therefore:
A) Use graticule (perimeter diameter)
- common

B) use image analysis (projected area diameter)

Question 15

all Sizing methods and their size

Answer 15

1) Scales - venier, micrometer
(large particles (>05mm)

2) sieves - popular, robust (>10um)
3) microscopy/image analysis (5um - 5mm)
4) laser diffraction (5um-5mm)
5) laser scattering (0.001um - 5um)

Others:

sedimentation: gravity, sedimentation
(0. 05um - 150um)

SEM/image analysis (nm-um)

AFM/image analysis (nm-um)

Question 16

Microscopy

pros and cons

Answer 16

size determination

1) direct examination
2) cheap

3) not for quality or production control
- missing one 10um particles has the same effect as missing one thousand 1um particles
- need 10000 images to be statistically valid.

Question 17

Feret diameter

Answer 17

distance between two vertical lines tangent to the ends of the particle, or Feret’s diameter is the greatest distance possible between any two points along the boundary of a region of interest.

Question 18

Martin diameter

Answer 18

length of the horizontal line that appears to divide particle into halves.

Question 19

Sieves

pro and cons

Answer 19

1) economical
2) readily usable technique for large particles
3) allows separation into some size fractions if required.
4) robust method, for coarse powders.

5) Not possible for sprays and emulsions
6) difficult for very fine dry powders (under 40um)
7) cohesive and agglomerative materials are difficult to impossible to measure (<200um)

• the longer the measurement times, the smaller is the size as particles orienta themselves to fall through the sieve.

Question 20

Sieves size

Answer 20

consists of screens

apertures of different size with a root 2 progression.
divide by root 2

Question 21

techniques for sieving

Answer 21

1) wet sieving
2) hand sieving
3) machine sieving
4) air jet sieving

Question 22

Machine sieving procedure

Answer 22

1) weighed material on top sieve
2) Sieve shaker vibrated at a known amplitude for a fixed time
3) Each sieve removed from shaker
4) Amount on each sieve weighed = weight oversize.
5) cumulative distribution graph plotted.

Question 23

Air jet sieve

Answer 23

1) for sieving fine powders, < 200um
2) can be used with microsieves
3) weighed material placed on sieve of certain aperture size
4) particles smaller than aperture size passed through sieve.
5) material remaining on sieve weighed
6) process repeated with sieves of other aperture size
7) cumulative graph of percent weight oversize plotted.

Parallel methods.
1) weigh different powders

2) placed on sieve of different aperture size on different machine
3) plot graph

Sieve equivalent diameter = at 50% weight frequency

Span = D90 - D10 / D50

Question 24

Electrozone sensing

Answer 24

1) Difficult to measure emulsions and impossible to measure sprays.
2) Dry powder required to be in a suspension
3) measurement must take place in an electrolyte, difficult for organic materials
4) Requires calibration standards that are expensive and can change size in distilled water and electrolyte
5) it is slow for materials of relatively wide particle size and it it not easy to size particles below 2um
6) porous particles and dense materials pose additional problems.

7) works based on orifice obscuration
8) size ~ area ~ resistance
9) unaffected by optical properties, densities, colours and shapes of particles.

10) particles need to be insoluble, non-porous, non conductive
11) need reference size calibrator

Question 25

Laser diffraction general uses , note

Answer 25

• Low angle light scattering (LALLS)
• preferred standard to characterize particle and QC
• wide dynamic range (5um-5mm)
• flexible (can measure dry powder, sprays or particles in air/liquid.
• non destructive and non-intrusive methods and a volume distribution is generated, equal to weight distribution where density is constant.
• rapid,under a minute, repeatable and high resolution
• there is no need to calibrate against a standard but equipment performance can be easily verified.

Question 26

Laser diffraction principle

Answer 26

The laser diffractin method takes advantage of an optical principle which dictates that small particles in the path of a light beam scatter the light in characteristic, symmetrical pattern, a function of angle to the axis of the incident beam (‘flux pattern’) and the distribution of particle sizes can be deduced.

• the simplest flux pattern, a monomodal dispersion of spheres, consists of a central bright spot (AIRY DISK), surrounded by concentric dark and bright rings whose intensity diminishes further from the centre of the pattern, that is at higher scattering angles.
  The scattering angle at which the first dark ring, or diffraction minimum, occurs, depends on the size of the particles; the smaller the particle, the higher the angle of the first dark ring (or alternatively, the larger the size of the Airy disk)
• As particle size approace wavelength of light ==> some light are scattered FORWARD (BIG PARTICLE)
• SMALL PARTICLE have more curvature = more diffraction = LIGHT DIFFRACTION SIDE WAY.

Question 27

Light scattering

Answer 27

Also known as dynamic light scattering and quasi-elastic light scattering.
- APPLICABLE to particles suspended in liquid, which are in a state of random movement due to brownian motion
( ~2-3um)

• the pace of the movement is inversely proportional to size (smaller particles, faster movement or diffusion) and the pace can be detected by analyzing the time dependency of light intensity fluctuations scattered from particles when they are illuminated.

BIG particles reflect more light and move slower therefore light decay is slower.

Question 28

Surface area determination

Answer 28

1) gas permeability
2) gas adsorption

1) gas passes thru a column of particles.
if SA increase = more resistance = more time needed to pass the column

(packing of column is impt factor)

2) BET theory

Question 29

Brunauer-Emmett-teller (BET) theory

Answer 29

1) All air are evacuate out
2) cool to boiling point of nitrogen

3) introduce N2
4) N2 adsorb on surface and form monolayer (At cryogenic temp, weak molecular attractive forces will cause gas molecules to be adsorbed)

specific surface area can be derived from amount of adsorbate required for monolayer absorption, with Avogadro constant (6.022 x 10^23/mol) and the effective cross-sectional area of one adsorbate molecule.

By ideal gas law; measuring pressure, can determin volume of gas adsorbed (adsorption isotherm)

From crosssectional area of adsorbed gas molecule, SA and pore size distribution can be derived.

Question 30

True
particle 
real 
absolute 
skeletal DENSITY  =

Answer 30

Weight / true volume of solid (volume without voids)

Question 31

Bulk density:

Answer 31

weight / volume occupied.

1) poured: freely settled
2) Tapped: post-tapped
3) Envelope: Bulk density without inter-agglomerate voids.

Question 32

Gas pycnometry

Answer 32

to get density

Vs = Vc + Vr / (1-P1/P2)

Vs = sample volume
Vc = Volume of empty sample chamber
(known from a prior calibration step)
Vr = Volume of the reference volume (again known from a prior calibration step)

P1 is the first pressure (ie the sample chamer only)
P2 is the second (lower) pressure after expansion of the gas into the comined volumes of sample chamber and reference chamber.

He an inert small gas is usually used

Question 33

Envelope density

Answer 33

Also known as geometric density.

Involves the determination of the geometric space occupied within the envelope of a solid material or aggregate,
including any interior voids, cracks or pores.

The volume of irregularly shaped samples can be determined by dry powder displacement using a free-flowing powder and a measuring cylinder.

PARTICLES SIZE should ideally EXCEED 2mm for best results.

envelope density is the mass of an object divided by its volume where the volume includes that of its internal pore and small cavities.

The unique displacement measurement technique that uses a quasi-fluid composed of small, rigid spheres, freely flowing and referred as free-flow filler.

A test sample of known weight is placed in a bed of the free-flow filler of known volume,
and the filler is agiated to gently blend nd completely embed the sample. The displacement volume is determined; and is considered as the equivalent volume of the sample.

Question 34

Solubility of drugs and excipients affect _____

Answer 34

F
Rate of drug release
therefore therapeutic efficacy

Question 35

Factors that affected solubility determination

Answer 35

Normally determined from saturated solution.

Factors:

1) Technique/ methodology
2) Temp ctrl
3) Eq point — take long time to establish
4) Supersaturation: crystal form

5) impurities
- LESS pure = more soluble
- MORE pure = less soluble

(MUST be 99.9% pure)