APowders & Granules
Powders
A powder is defined as a dosage form composed of a solid or
mixture of solids reduced to a finely divided state and intended
for internal or external use.
Composition
Properly prepared, powders have a uniform, small particle size
that has an elegant appearance. In general, powders are more
stable than are liquid dosage forms and are rapidly soluble,
enabling the drug to be absorbed quickly.
The properties of powders are related to the size and surface
area of the particles. For example, large particles that are
denser tend to settle more rapidly than do small particles;
particles that are more bulky will settle more slowly. This
characteristic must be considered in mixing or storing and
shipping, when powders of different particle size may become
segregated.
Another concern stems from the fact that powder dosage forms
have a large surface area that is exposed to atmospheric
conditions. Thus, powders should be dispensed in tight
containers. Further, because powders of small particle size
present a greater surface area to the atmosphere, they are
more reactive in nature and can adsorb larger quantities of
gases, such as carbon dioxide.
However, if the powder has a smaller particle size, it can
dissolve at a more rapid rate, unless adsorbed gases prevent
the water from surrounding the individual particles and wetting
them, thereby decreasing their wetting properties.
Topical Powders
Topical powders should have a
uniform, small particle size that
will not irritate the skin when
applied. They should be
impalpable and free flowing,
should easily adhere to the skin,
and should be passed through at least a No. 100-mesh sieve to
minimize skin irritation. The powder should be prepared so
that it adheres to the skin.
The powder should be prepared so that it adheres to the skin.
Highly sorptive powders should not be used for topical powders
that are to be applied to oozing wounds, as a hard crust may
form. A more hydrophobic, water repellent powder will prevent
loss of water from the skin and will not cake on the oozing
surfaces. Talc, or any other naturally derived product that is to
be used on open wounds, should first be sterilized to avoid an
infection in the area.
Topical powders usually consist of a base or vehicle, such as
cornstarch or talc; an adherent, such as magnesium stearate,
calcium stearate, or zinc stearate; and possibly an active
ingredient, along with an aromatic material. The powder should
provide a large surface area, flow easily, and spread uniformly.
The large surface area will aid in absorbing perspiration and
give a cooling sensation to the skin.
Insufflated Powders
Insufflated powders are finely divided powders that are
intended to be applied in a body cavity, such as the ears, nose,
vagina, tooth socket, or throat. When using an insufflator, or
“puffer,” the patient simply “puffs” the desired quantity of
powder onto the affected area or into the cavity. This device is
particularly appropriate for anti-infectives.
Physicochemical Considerations
Before the use of powders in the preparation of pharmaceutical
products, solid materials first are characterized to determine their
chemical and physical features, including morphology, purity,
solubility, flowability, stability, particle size, uniformity, and
compatibility with any other formulation components.
Drug and other materials commonly require chemical or
pharmaceutical processing to enable both the efficient production of
a finished dosage form and the optimum therapeutic efficacy. This
usually includes the adjustment and control of a powder’s particle
size.
In order to characterize the particle size of a given powder, the United
States Pharmacopeia (USP) uses these descriptive terms: very coarse,
coarse, moderately coarse, fine, and very fine, which are related to
the proportion of powder that is capable of passing through the
openings of standard sieves of varying fineness in a specified period
while being shaken, generally in a mechanical sieve shaker.
Granules typically
fall within the range
of 4- to 12-sieve size
Very coarse
Coarse
Moderately coarse
Fine
Very fine
➢ Dissolution rate of particles intended to dissolve; drug
micronization can increase the rate of drug dissolution and
its bioavailability.
➢ Suspendability of particles intended to remain undissolved
but uniformly dispersed in a liquid vehicle (e.g., fine
dispersions have particles ~0.5 to 10 μm).
➢ Uniform distribution of a drug substance in a powder
mixture or solid dosage form to ensure dose-to-dose
content uniformity.
➢ Penetrability of particles intended to be inhaled for
deposition deep in the respiratory tract (e.g., 1 to 5 μm).
➢ Lack of grittiness of solid particles in dermal ointments,
creams, and ophthalmic preparations (e.g., fine powders
may be 50 to 100 μm in size)
Comminution of drugs
On a small scale, the pharmacist reduces the size of chemical
substances by grinding with a mortar and pestle. A finer
grinding action is accomplished by using a mortar with a rough
surface (as a porcelain mortar) than one with a smooth surface
(as a glass mortar). Grinding a drug in a mortar to reduce its
particle size is termed trituration or comminution. On a large
scale, various types of mills and pulverizers may be used to
reduce particle size.
Levigation is the process of reducing the particle size of a solid
by first forming a mass of the solid with a liquid and then
grinding the mixture in a mortar with a pestle or on a slab with
a spatula.
Levigation is convenient for the comminution of medicinal
agents which are to be incorporated into fatty bases for the
preparation of semisolids.
Blending powders
When two or more powdered substances are to be combined to
form a uniform mixture, it is best to reduce the particle size of each
powder individually before weighing and blending. Depending on
the nature of the ingredients, the amount of powder, and the
equipment, powders may be blended by spatulation, trituration,
sifting, and tumbling.
➢ Spatulation is blending small amounts of powders by movement
of a spatula through them on a sheet of paper or an ointment
slab. It is not suitable for large quantities of powders or for
powders containing potent substances, because homogeneous
blending is not as certain as other methods. Very little
compression or compacting of the powder results from
spatulation, which is especially suited to mixing solid substances
that form eutectic mixtures (or liquefy) when in close and
prolonged contact with one another. To diminish contact, a
powder prepared from such substances is commonly mixed in
the presence of an inert diluent, such as light magnesium oxide
or magnesium carbonate, to separate them physically.
➢ Trituration may be employed both to comminute and to mix
powders. If simple admixture is desired without the special need
for comminution, the glass mortar is usually preferred. When a
small amount of a potent substance is to be mixed with a large
amount of diluent, the geometric dilution method is used to
ensure the uniform distribution of the potent drug. This method
is especially indicated when the potent substance and other
ingredients are of the same color and a visible sign of mixing is
lacking.
➢ Sifting by passing the powders through sifters like those used in
the kitchen to sift flour. Sifting results in a light, fluffy product.
This process is not acceptable for the incorporation of potent
drugs into a diluent powder.
➢ Another method of mixing powders is tumbling the powder in a
rotating chamber. Special small-scale and large-scale motorized
powder blenders mix powders by tumbling them. Mixing by this
process is thorough but time consuming. Such blenders are
widely employed in industry, as are mixers that use motorized
blades to blend powders in a large vessel.
Medicated Powders
Some medicated powders are intended to be used internally and
others, externally. Most powders for internal use are taken orally
after mixing with water or in the case of infants in their infant
formulas. Some powders are intended to be inhaled for local and
systemic effects. Other dry powders are commercially packaged for
constitution with a liquid solvent or vehicle, some for administration
orally, others for use as an injection, and still others for use as a
vaginal douche.
Medicated powders for external use are dusted on the affected area
from a sifter-type container or applied from a powder aerosol.
Powders intended for external use should bear a label marked
“external use only”.
Medicated powders for oral use may be intended for local effects
(e.g., laxatives) or systemic effects (e.g., analgesics) and may be
preferred to counterpart tablets and capsules by patients who have
difficulty swallowing solid dosage forms.
The doses of some drugs are too bulky to be formed into tablets or
capsules of convenient size, so they may be administered as
powders. For administration, they can be mixed with a liquid or soft
food.
Powders taken orally for systemic use may be expected to result in
faster rates of dissolution and absorption than solid dosage forms,
because there is immediate contact with the gastric fluids.
A primary disadvantage of the use of oral powders is the undesirable
taste of the drug.
Some medications, notably antibiotics for children, are intended for
oral administration as liquids but are relatively unstable in liquid
form. They are provided to the pharmacist by the manufacturer as a
dry powder or granule for constitution with a specified quantity of
purified water at the time of dispensing. Under labeled conditions of
storage, the resultant product remains stable for the prescribed
period of use, generally up to 2 weeks.
Sterile dry powders intended to be constituted with sterile water of
injection prior to administration by injection.
Some medicated powders are
administered by inhalation with the
aid of dry powder inhalers (DPIs),
which deliver micronized particles of
medication in metered quantities. A
DPI is a device used to administer an
inhalation powder in a finely divided
state suitable for oral inhalation by the
patient.
Most of these products are used in the treatment of asthma and
other bronchial disorders that require distribution of medication
deep in the lungs. To accomplish this, the particle size of the
micronized medication is prepared in the range of 1 to 6 μm in
diameter.
In addition to the therapeutic agent, these products contain inert
propellants and pharmaceutical diluents, such as crystalline alpha-
lactose monohydrate, to aid the formulation’s flow properties and
metering uniformity and to protect the powder from humidity.
Dispensing of Powders
Medicated powders may be provided to the patient as bulk powders
or as divided powders.
Bulk Powders
These are limited to those powders which are non-toxic and can be
measured safely in a spoon by the patient as well as for the dusting
powders.
Among the bulk powders available are:
a) Antacids (e.g., sodium bicarbonate) and laxatives (e.g.,
Metamucil) which the patient takes by mixing with water or
another beverages before swallowing;
b) Douche powders (e.g., Massengill powder), dissolved in warm
water by the patient for vaginal use;
c) Medicated powders for external application to the skin, usually
topical anti-infectives (e.g., bacitracin zinc and polymyxin B
sulfate) or antifungals (e.g., tolnaftate); and
d) Multivitamins and nutritional supplements powders.
In some cases, a small measuring scoop, spoon, or other device is
dispensed with the powder for measuring the dose of the drug.
Dispensing powder medication in bulk quantities is limited to non
potent substances. Powders containing substances that should be
administered in controlled dosage are supplied to the patient in
divided amounts in folded papers or packets.
Divided Powders
After a powder has been properly blended (using the geometric
dilution method for potent substances), it may be divided into
individual dosing units based on the amount to be taken or used at a
single time.
Each divided portion of powder may be placed on a small piece of
paper (Latin chartula; abbrev. chart.; powder paper) that is folded to
enclose the medication.
Depending on the potency of the drug, the pharmacist decides
whether to use weighing method or blocking and dividing method.
Several kinds of papers may be used:
a) Simple bond paper;
b) Vegetable parchment, a thin, semiopaque paper with limited
moisture resistance;
c) Glassine, a glazed, transparent paper, also with limited moisture
resistance; and
d) Waxed paper, a transparent waterproof paper.
The selection of the type of paper is based primarily on the nature of
the powder. If the powder contains hygroscopic or deliquescent
materials, waterproof or waxed paper should be used.
Powders containing volatile components should be wrapped in
waxed or glassine papers. Powders containing neither volatile
components nor ingredients adversely affected by air or moisture
are usually wrapped in a white bond paper.
Problems associated with powder dosage form
Eutectics
Some powders may become sticky or pasty, or they may liquefy
when mixed together, such as acetanilide, aspirin, camphor and
chloral hydrate.
To keep the powders dry, one can mix them with a bulky powder
adsorbent such as light magnesium oxide or magnesium carbonate.
Also, these powders should be triturated very lightly by using a
spatula for mixing rather than a mortar and pestle. The latter will
cause compression and make the problem worse. It may also be
advisable to double wrap the papers.
Hygroscopic and deliquescent powders
Hygroscopic powders will absorb moisture from the air. Deliquescent
powders will absorb moisture from the air to the extent that they
will partially or wholly liquefy. These problems must be overcome for
the powder to be acceptable to the patient and usable.
The best approach is to dispense the ingredients in tight containers
and incorporate a desiccant packet when necessary. The patient
should be instructed to store the powder in a dry place in a tightly
closed container.
To lessen the extent of the problem, the compounding pharmacist
can in some situations dilute the powder with an inert drying
powder to reduce the amount of surface area exposed to the
moisture. Examples for hygroscopic and deliquescent powders are
ammonium bromide, calcium bromide, hyoscyamine hydrobromide
and hyoscyamine sulfate.
Efflorescent powders
An efflorescent powder like alums, atropine sulfate, caffeine, citric
acid and codeine is a crystalline powder that contains water of
hydration or crystallization. This water can be liberated either during
manipulations or on exposure to a low-humidity environment. If this
occurs, the powder will become sticky and pasty, or it may even
liquefy.
One approach is to use an anhydrous salt form of the drug, keeping
in mind the potency differential between its anhydrous form and it’s
hydrated form. Another method is to include a drying bulky powder
and to use a light, noncompacting method of mixing the powders.
Explosive Mixtures
Some combinations of powders like bromine & alcohol, chlorates &
bisulfites as well as chloric acid & bromides may react violently when
mixed together. Special precautions must be taken if it is necessary
to prepare a formulation containing these mixtures.
Incorporation of liquids
A liquid that is to be incorporated into a dry powder can be adsorbed
onto an inert material (carrier) such as lactose or starch and then
geometrically introduced into the bulk of the powder. Pasty material
can be added to dry powder by mixing it with increasing quantities
of the powder, which will dry out the paste.
It is best to add some materials by preparing an alcoholic solution
and spraying it evenly on the powder, which has been spread out on
a pill tile. The alcohol, or another suitable solvent, should then be
allowed to evaporate, leaving the ingredient uniformly dispersed.
This method may be especially suitable for high-potency drugs or
flavoring agents because it minimizes the possibility that clumps of
active drug will develop in the powder blend.
Granules
Granules are defined as a dosage form
composed of dry aggregates of powder
particles that may contain one or more
APIs, with or without other ingredients.
They may be swallowed as such, dispersed
in food, or dissolved in water.
Granules are frequently compacted into
tablets or filled into capsules, with or
without additional ingredients.
As indicated previously, granules are prepared agglomerates of
smaller particles of powder. They are irregularly shaped but may be
prepared to be spherical. They are usually in the 4- to 12-mesh sieve
size range, although granules of various mesh sizes may be prepared
depending upon their application.
Granules are prepared by wet
methods and dry methods. One basic screening
wet method is to moisten the powder
or powder mixture and then pass the
resulting paste through a screen of
the mesh size to produce the desired
size of granules. The granules are
placed on drying trays and are dried
by air or under heat. The granules are
periodically moved about on the
drying trays to prevent adhesion into
a large mass. Another type of wet
method is fluid bed processing.
Fluidized bed dryer
The dry granulation method may be
performed in a couple of ways. By one
method, the dry powder is passed through a
roller compactor and then through a
granulating machine.
An alternative dry method, termed slugging, is
the compression of a powder or powder
mixture into large tablets or slugs on a Roller Compactor
compressing machine under high pressure,
depending on the physical characteristics of
the powder. The slugs are generally flat-faced Slug
and are about 2.5 cm (1 inch) in diameter. The 2.5cm
slugs are granulated into the desired particle
size, generally for use in the production of
tablets. The dry process often results in the
production of fines, that is, powder that has
not agglomerated into granules.
Granules flow well compared to powders. Because of their flow
properties, granulations are commonly used in tablet making to
facilitate the free flow of material from the feeding container (or
hopper) into the tablet presses. Granules have other important
characteristics. Because their surface area is less than that of a
comparable volume of powder, granules are usually more stable to the
effects of atmospheric humidity and are less likely to cake or harden
upon standing. Granules also are more easily wetted by liquids than are
certain light and fluffy powders (which tend to float on the surface) and
are often preferred for dry products intended to be constituted into
solutions or suspensions.
Effervescent Granulated Salts
An effervescent dosage form, frequently tablets
or granules, contains ingredients that, when in
contact with water, rapidly release carbon
dioxide. The dosage form is dissolved or
dispersed in water to initiate the effervescence
prior to ingestion. Effervescent salts are granules
or coarse to very coarse powders containing a
medicinal agent in a dry mixture usually
composed of sodium bicarbonate, citric acid,
and tartaric acid. When added to water, the
acids and the base react to liberate carbon
dioxide, resulting in effervescence. The resulting
carbonated solution masks undesirable taste of
any medicinal agent.
Using granules or coarse particles of the mixed powders rather than small
powder particles decreases the rate of solution and prevents violent and
uncontrollable effervescence. Sudden and rapid effervescence could
overflow the glass and leave little residual carbonation in the solution.
Using a combination of citric and tartaric acids rather than either acid
alone avoids certain difficulties. When tartaric acid is used as the sole
acid, the resulting granules readily lose their firmness and crumble.
Citric acid alone results in a sticky mixture difficult to granulate.
Effervescent granules are prepared by two general methods: (a) the dry
or fusion method and (b) the wet method.
a) Dry or Fusion Method
In the fusion method, the one molecule of water present in each
molecule of citric acid acts as the binding agent for the powder mixture.
Before mixing the powders, the citric acid crystals are powdered and
then mixed with the other powders of the same sieve size to ensure
uniformity of the mixture. The sieves and the mixing equipment should
be made of stainless steel or other material resistant to the effect of the
acids. The mixing of the powders is performed as rapidly as is practical,
preferably in an environment of low humidity to avoid absorption of
moisture and a premature chemical reaction. After mixing, the powder
is placed on a suitable dish in an oven at 34°C to 40°C. During the
heating process, an acid resistant spatula is used to turn the powder.
The heat releases the water of crystallization from the citric acid. This
causes the softened mass of powder to become somewhat spongy, and
when it has reached the proper consistency (as bread dough), it is
removed from the oven and rubbed through a sieve to produce
granules of the desired size. A No. 4 sieve produces large granules, a No.
8 sieve prepares medium size granules, and a No. 10 sieve prepares
small granules. The granules are dried at a temperature not exceeding
54°C and are immediately placed in containers and tightly sealed.
b) Wet Method
The wet method differs from the fusion method in that the source of
binding agent is not the water of crystallization from the citric acid but
alcohol used as the moistening agent, forming the pliable mass for
granulation.
Just enough liquid is added (in portions) to prepare a mass of proper
consistency; then the granules are prepared and dried in the same
manner as previously described.