Solid Dosage Forms - powders and granules Flashcards
What are powders?
Pharmaceutical dosage form in Heinrich a drug has been mixed with other powdered excipients e.g. Colouring, flavouring and sweetening agents (for oral use) to produce the final product
What are examples of solid dosage forms?
Powders
Granules
Tablets
What are granules?
Powder particles which have been aggregated using solvent to form large particles with a diameter of approx 2-4mm
What is different about granules used as a dosage form?
These granules are much larger than those prepared as an in-process material for tablet manufacture
What is an advantage of granules over powders ?
Granules have been designed to overcome problems associated with the use of powders such as segregation
What are the types of dispensed solid dosage form preparations and their uses?
Internal use:
Bulk powders or granules
Divided powders or granules (single preparations)
External use:
Dusting powders
Other:
Insufflations for ear/nose/throat administration
Antibiotic powders for reconstitution before use
What are the advantages of powders and granules?
More chemically stable than liquid dosage forms
Convenient form of dispersing drugs with large doses e.g. Antacids
Faster dissolution rate compared to tablets and capsules
What are the disadvantages of powders and granules?
Less convenient for patient to carry
Not suitable for administration of potent drugs with low doses
Difficult to mask unpleasant tastes
Not suitable for administration of drugs that are inactivated, not absorbed or destroyed in stomach or cause gastric irritation
What are the different classes of powders?
Bulk powders Divided powders Dusting powders Dry powder inhalers Powdered antibiotic for reconstitution
What are bulk powders?
A mixture of ingredients packed into large containers such as glass or jars.
- non potent
- can be dosed with acceptable accuracy and safety just by using measuring devices (e.g. Teaspoon, cup, etc)
- ingredients usually non toxic if they are given in large doses (e.g. Magnesium trisilicates and chalk in antacids)
What are divided powders?
Single doses of powdered medicinals which are individually wrapped in cellophane, metallic foil, or paper satchels.
What are dusting powders?
- Formulation used for therapeutics, prophylactic or lubricant purposes.
- for external use only
- requires good flow properties so they can be dusted over the skin
- dispensed in glass or metal containers with a perforated lid
- e.g. Baby powder
What are dry powder inhalers?
- used to extensively deliver active ingredients to lungs (e.g. in asthma & COPD )
- there are now a many commercial preparations available in the market as dry powders for inhalation in sophisticated devices e.g. Terbutaline
What are oral antibiotic powders?
- powders or granules intended for preparation of solution or suspension
- designed for patients who have difficulty swallowing whole tablets or capsules
- designed to overcome instability problems of some drugs
- reconstituted by adding water at time of dispensing
- reconstituted syrup or suspension has shelf life of 1-2 weeks
What are the different granule preparations?
Bulk granules
Divided granules
What are bulk granules?
- contain medicaments of low toxicity in high doses
- e.g. Methylcellulose used as bulk laxative (1-4g/day)
What are divided granules?
- small particles containing medicinal agent in a dry mixture usually composed of sodium bicarbonate, citric acid and tartaric acid
- releases gas in contact with water resulting in effervescence
What is micromeritics?
The science and technology of small particles
What is the unit of particle size most frequently used in micromeritics ?
μm
Why is particle size studied?
Particle size influences production of formulated medicines as solid dosage forms e.g. Tablets vs. Capsules
Powders with different particle sizes can have different flow and packing properties, affecting the production of tablets and capsules
Particle size affects rate of release of drug into solution and its bioavailability e.g. Griseofulvin
How is particle size of an individual particle defined?
If the particle is spherical, its size is expressed in diameter
If the particle is non spherical, the solid particle is often considered to approximate a sphere
The hypothetical sphere particle is expressed by its equivalent spherical diameter
What are the methods of determining particle size?
Sieving Microscopy Coulter counter/sensing zone counters Laser light scattering Sedimentation
How are the methods of determining particle size selected?
Based on The size range of sample If the sample is wet or dry If a manual or automatic determination is required The speed of analysis
What is sieving?
The oldest method of classifying powders and granules by particle-size distribution based on the intermediate size dimension (width)
Particle size analysis is carried out in the dry state
What are the limitations of using the sieve method?
A large amount (at least 25g) of sample is required
It is difficult to sieve oily or other cohesive powders or granules that tend to clog the sieve openings
The sample needs to have good flow property or it will affect the measurement
If there is a lot of material greater than the sieve size, this will block the holes.
If the load is too large, this can also block the holes.
The sieves can be damaged or worn resulting in larger particles passing through
How are the sieves in the sieve method arranged?
They are arranged in a series with the coarsest sieve at the top and the pan at the bottom.
The holes in the sieve increase in size by a constant factor (usually double the size at the second sieve)
How is sieving conducted?
This technique requires a set of standard sieves arranged so that the largest sieve is at the top, and the smallest sieve is at the bottom with trays in between,
The sample is placed at the top shelf and allowed for the machine to shake the sieve vertically for a period of time.
After that you examine the sieves and retain the material for particle size analysis
What type of particles is the sieving method more suited for?
Larger particles. This is because the size range of this technique according to international standard organisations, can be from 45-1000μm
However, in practice, there are sieves with larger ranges from 5-125,000μm
There are also different types of sieves, PC, USP etc.
What kind of powders are defined as very coarse?
Those with a mesh opening size >1000 microns
And a mesh size diameter of 2-10
What kind of powders are defined as coarse?
Those with a mesh opening size of 355-1000 microns
And a mesh size diameter of 20-40
What kinds of powders are moderately coarse?
Those with a mesh opening size of 180-355 microns
And a mesh size number of 40-80
What type of powders are fine?
Those with a mesh opening size of 125-180 microns
And a mesh opening size of 80-120
What types of powders are very fine?
Those with a mesh opening size of 90-125microns
And a mesh size number of 120-200
What type of particle sizes is optical microscopy best suited to measure?
1-1000μm as this is the size range of microscopy
What are the requirements of particles measured by microscopy?
Particles must be suspended in a medium (not dissolved)
This medium must be viscous enough to prevent movement and separate particles without breaking agglomerates
What type of microscope is used to measure particle size?
Graduated microscope or graticule
What are the different kinds of diameters associated with microscopy?
da: projected area diameter
dp: projected perimeter diameter
df: feret’s diameter
dm: Martin’s diameter
What is the difference between dp and da?
The projected perimeter diameter is that of a circular perimeter around the particle
The projected area diameter is that of a circular area around a particle (i.e. The diameter of the bulk area of the particle)
What is the limitation of using feret’s diameter?
It is affected by the orientation of the sample
What are the limitations with microscopy?
Slow and tedious
Requires at least 500 particles
Eye strain
Phone to operator error
What are alternatives to optical microscopy?
Scanning electron microscopy
Transmission electron microscopy
How is a SEM used?
The sample is stained with heavy metal salts
The microscope images the sample surface by scanning it with a high energy beam of electrons through magnetic coils (instead of using light and lenses)
What are the range of particle sizes that is suitable to be studied using transmission electron microscopy?
0.001-0.005 μm
What are the range of particle sizes that can be used to study with scanning electron microscopy?
0.005-1000μm
What is a coulter counter?
An electrical stream sensing zone method.
This utilises the change in electric resistance to measure particle size and involves submerging electrodes into electrolytes.
How are particle sizes analysed using a coulter counter?
Powder samples are dispersed in an electrolyte to form a dilute suspension.
Samples must be thoroughly dispersed with no agglomeration
Particle suspension is drawn into a hollow glass tube surrounded by electrolytes.
There is a set of electrodes which monitor the potential differences between the two compartments
As an individual particle passes through the orfice between the compartment it displaces its own volume of electrolyte resulting in a potential change
The volume of electrolyte displaced is proportional to the size of the particle
Why must particles form a dilute suspension in electrolytes?
this enables each individual powder particle to pass through the orfice one at a time so that the potential detected is proportional to the size of that one passing particle. An average of particle sizes are then taken
What are the practical considerations associated with the coulter counter method?
Tube selection- microscope required to get an idea of the largest particle
Electrolyte - must conduct electricity without dissolving particles and be clean and particle free
In order for the powder particles to disperse ideally, a suitable concentration of particles is required, we also need a wetting agent, break up any aggregates. The sample must also be representative .
The probability of more than 1 particle passing through at a time must be less than 10%
What are the two types of light scattering?
Laser diffraction
Photon correlation
In both cases a laser light is used to measure the different size ranges of particles
What is laser diffraction?
This is also known as static light scattering and is based on the interaction of laser light with particles
What size range of particles is laser light scattering best suited to measure?
Those with a diameter of 1μm-1mm
What is Fraunhofer diffraction?
For particles much larger than the wavelength of light, any interaction with particles causes light to be scattered in a forward direction.
This phenomenon produces light intensity patterns which occur at regular angular intervals and are proportional to the particle diameter which is producing the scatter
How does the Fraunhofer diffraction phenomenon help determine the size of particles?
The composite pattern produced by different diameter particles can be considered to be the sum of all individual patterns produced by each particle the in the size distribution
Why is red laser light used?
Because blue light gives much shorter wavelengths and is used for submicron particles.
How is light diffraction conducted?
Red light is shown through the sample at a focal plane detector.
As particles go through the path of red light they scatter the light which is then collected at the different detectors (including the focal plane, angle and back detectors.)
The detectors computerise this into signals to interpret the particle size.
What are the advantages of laser light scattering?
It is easy to use,
Contains a built in computer (e.g. Malvern)
Can be used to detect the particle size of aerosols, liquids, dry powders
What is photon correlation spectroscopy?
This is used to study the size of very small particles (3μm-20nm)
This is based on Bronian motion and causes reflected light to flicker
The smaller the particle the higher the rate of flicker.
What is sedimentation related to?
Exponentially proportional to particle diameter
Inversely proportional to viscosity of the medium
Proportional to the density of the particle in relation to the density of the medium
It is also related to the gravity and friction constants
What is the friction constant?
18
What is the stoke diameter?
The diameter of a particle measured during sedimentation at a constant rate in laminar flow conditions.
How is sedimentation conducted to determine particle size?
Use a 550mL vessel containing a 10mL pipette sealed into the stopper.
Place a 1-2% suspension of particles in a medium containing a suitable deflocculation agent brought to the 550mL mark.
Shake to distribute particles uniformly
Place vessel in water bath to maintain temperature.
How is the sedimentation rate obtained?
A known volume of sample (10mL) is drawn slowly to avoid disturbance
The sample is dried and weighed to work out a concentration
The size distribution is determined by allowing a homogenous suspension to settle in a cylinder and taking samples from the settling suspension at a fixed horizontal level at fixed intervals of time.
What parameters affect the sedimentation rate?
There are also parameters which are not ideal and give inaccurate results when particle size is measured using sedimentation method.
e,g, turbulent flows
non spherical particles,
non infinite fluid (interaction of particles with liquid or device)
interaction between particles,
particles may fall in line,
method of sampling can also affect the sedimentation rate
What is the relationship between h and time?
H will reduce as the experiment continues due to the samples being drawn.
What is the exception of each sample containing a representative sample of the suspension?
Particles greater than a critical size as anything oversized will have already been settled.
How is particle size distribution presented graphically?
Via a frequency distribution curve where the number (or weight) of particles lying within a certain size range is plotted against the size range of mean particle size.
What is number in a frequency distribution curve?
Data collected by counting (microscopy)
What is the weight in a frequency distribution curve?
This is the data collected based on weight via sedimentation or sieving
Can a number distribution curve be converted to a weight distribution curve?
Yes. The reverse is also true however there can be significant differences in number and weight distributions even for the same sample.
What are the main types of frequency distribution curves?
Normally distributed (mean = mode)
Skewed (can be positive or negative. If negative, the frequency vs. Log particle diameter may be a bell shaped curve. This is also known as log-normal distribution)
Bimodal
Why is the shape and surface area of a particle improtant?
The shape affects the flow and packing properties of powders and has an influence on the surface area.
The surface area per unit weight or volume is an important characteristic when carrying out the surface adsorption and dissolution studies
What are the two main types of methods for determining surface area?
Adsorption methods
Permeability methods
What are adsorption methods?
Based on the fact that the amount of gas or liquid solute adsorbed onto the sample or powder to form a monolayer is a direct function of the surface area of the sample
What are permeability methods?
Based on the fact that the rate at which a gas or liquid prime as a bed of powder is related to the surface area exposed to the permeant
What are the different types of particle shapes?
Equation Acicular Columnar Plate Flake Lath
What must characterisation of particle size also include for irregularly shaped particles?
Information on particle shape
How is acicular described?
Slender, needle like particle of similar width and thickness
How is columnar described?
Long thin particle with a width and thickness greater than acicular particles
How is a flake described?
Thin flat particle of similar length and width
How is plate described?
flat particle of similar length and width but with a greater thickness than a flake particle
How is lath described?
Long thin blade like particle
How is equant described?
Particle of similar length, width and thickness, includes both cubical and spherical particles
What is an example of a fundamental property?
Particle size distribution
Surface area
What are derived properties?
Properties which e based on the fundamental properties
What are the derived properties of powders?
Porosity Packing arrangements Density Flow properties Dissolution Compaction
What are the different types of density?
Bulk density
True density
Granule density
How is bulk density determined?
From bulk volume and weight in a graduated cylinder
What is true denstiy?
Density of a solid exclusive of the voices and pores
How is granule density determined?
By displacement of mercury.
Nb: mercury does not penetrate into pores smaller than 10μm
What is porosity?
The void volume divided by the bulk volume (ε=v/Vb
Where void volume = bulk volume - true volume of particles
What are the theoretical porosity of powder beds of uniform sized spheres?
26% for closest packing (rhombohedral)
48% for loosest packing (cubic)
What are the porosity ranges for real powders?
Expected porosity is between 26-48%
Practically most powders are 30-48%
The range is due to real powders being not spherical or uniform
What is the angle of repose?
This is the maximum angle that can be obtained between the free standing surface of a powder heap and the horizontal plane.
Tanφ= 2h/D
= the coefficient of friction between the particles.
What is the angle of repose for a powder with excellent flow properties?
25-30 degrees
What is the angle of repose for a powder with good flow properties?
31-35 degrees
What is the angle of repose for a particle with fair (unaided) flow properties?
36-40 degrees
What is the angle of repose for a powder with passable (may hang up) flow properties?
41-45
What is the angle of repose for a powder with poor (must agitate, vibrate) properties?
46-55
What is the angle of repose for a powder with very poor flow properties?
56-65degrees
What is the angle of repose for a powder with very very poor flow properties?
> 66 degrees
What does flow property depend on?
The particle particle interaction which in turn depends on
Particle size Shape Porosity Density Surface Moisture content
How can flow properties be improved?
Altering particle size and size distribution Altering particle shape or texture Altering surface forces Altering Formulation additives Altering process conditions
How can altering particle size and size distribution improve flow properties?
Coarse particles are less cohesive than fine particles (larger particles may flow better)
The fraction of fines is incorporated
How does altering particle shape or texture improve its flow property?
Spherical particles flow better
How does altering surface forces improve flow property?
Reducing electrostatic charges will reduce frictional contacts
How does altering the formulation additives change the flow properties?
Addition of flow activators, glidants etc, will reduce adhesion and cohesion
E.g. Talc, starch, magnesium stearate, colloidal silicon dioxide
Addition of magnesium oxide adsorbs the moisture when flow is impaired by increased moisture content
How does the alteration of process conditions improve flow property?
Use of specific techniques and equipment like vibration assisted hoppers, force feeders will improve flow properties
What is compactibiltiy?
The propencity of a powder to form a coherent tablet and thus represent a critical powder property in successful tableting operations
What does a high compactibiltiy refer to ?
Tablets with a high esi stance to fracture, cap or laminate (good quality tablets)
Does a granule have better compactibility than powders?
Yes
What does dissolution consist of ?
Solubilisation and diffusion
What happens in dissolution?
The solid particles get solvated or dissolved at the liquid interface
Solubilised drug migrates through the saturated liquid layer into the bulk of the solution diffusion
