Pharmaceutical solids and preformulation importance of particle design Flashcards Preview

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


• 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


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



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.

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)

sedimentation: gravity, sedimentation
(0.05um - 150um)

SEM/image analysis (nm-um)

AFM/image analysis (nm-um)


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.


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


Laser diffraction general uses , note

- 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.


Laser diffraction principle

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.


Light scattering

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.


Surface area determination

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


Brunauer-Emmett-teller (BET) theory

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.


skeletal DENSITY =

Weight / true volume of solid (volume without voids)