Pharmaceutical solids and preformulation importance of particle design Flashcards
Multi-particulates
- Powders: crystals, nanoparticles, microcapsules, microspheres
- Granules / agglomerates
- Pellets / spheroids / beads
Multi-particulates
- Powders: crystals, nanoparticles, microcapsules, microspheres
- Granules / agglomerates
- Pellets / spheroids / beads
Final dosage form
• Capsules: hard, soft
• Tablets / caplets
• Others: films, gums
Final dosage form
• Capsules: hard, soft
• Tablets / caplets
• Others: films, gums
Why Solid Dosage Form?
- Markedly better chemical stability
- Dry, does not promote microbial growth
- Lower bulk volume
- Ease of handling, added convenience
- Single chemical component possible
Solid state solubility ranking
Ultra-micronization
polymorph
solvate
amorphous
LEAST SOLUBLE 1) polymorph 2) solvate 3) amorphous 4) ultra-micronization MOST SOLUBLE (Highest Chemical potential)
technique to Determine structure of crystaline or amorphous material
1) Differential scanning calorimetry (DSC)
2) X-ray diffraction (XRD) by crystals — bragg eqn (nWAVELENGTH = 2dSINE o)
3) single crystal XRD
4) Powder- XRD
DSC
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
Crystal (Single Crystal XRD)
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.
What are pre-formulation studies?
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
Applications/uses of preformualtion studies
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 .
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.
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.
Effect of particle shape
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
surface area measurement by
1) gas permeability
2) gas adsorption
determination of particle shape
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
determine particle size
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)
all Sizing methods and their size
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)
Microscopy
pros and cons
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.
Feret diameter
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.
Martin diameter
length of the horizontal line that appears to divide particle into halves.
Sieves
pro and cons
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.
Sieves size
consists of screens
apertures of different size with a root 2 progression.
divide by root 2
techniques for sieving
1) wet sieving
2) hand sieving
3) machine sieving
4) air jet sieving
Machine sieving procedure
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.
Air jet sieve
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
Electrozone sensing
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
