Powders And Granules

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Definition: Powders and Granules

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USP Definition of Powders: "Powders are intimate mixtures of dry, finely divided drugs and/or chemicals that may be intended (oral powders) for internal or external (topical powders) use"

-Powders are mixtures

Granules: granules are prepared agglomerates of powders

e.g. bakery product: add water-->serves as glue--> powder becomes globules --> granules

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Properties of Powders

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As a dosage form, a powder is a mixture of "powdered" drugs and excipients

A dosage form, different from "powder" or "powdered" a physical state

Use as a dosage form is limited

Extensively used in most dosage forms

dosage form = pharmaceutical product in certain form

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Why Study Powders?

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1. Existing in powder form: active pharmaceutical ingredient (API) and excipient (inactive ingredient)

2. Pharmaceutical preparations: topical powder or sterile powder in vial

3. Starting material for
-solid dosage form - tablet, capsule
-liquid dosage form - powder for reconstitution
-semisolid dosage form - ointment or cream

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Characterization of Powders

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-Mainly physical
-Morphology (shape)
e.g. needle-shaped vs. spherical --> affect drug in diff. ways
-Purity
-Solubility
-Stability
-Particle size and distribution
-Uniformity (after mixing)
-Compatibility in blends

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Common issues with powders

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Powders can cause issues in:
-Dissolution rate - if powder is large particles --> diss. rate = slow. If powder is smaller particles --> diss. rate = faster
-Suspension
-Uniform distribution - need to have uniformity
-inhalation - powder needs to be light enough to go into lung but can't be too light otherwise it will be exhaled. If too large, can't suspend in air
-Poor flow
-Appearane

Thus, needs to characterize powder particle size and distribution.

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Characterize Powder Particle Size

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Sieve analysis: sieve number or mesh size - size

USP description
-very coarse: number 8
-coarse: number 20
-moderately coarse: number 40
-fine: number 60
-very fine: number 80

Granules: coarse to very coarse (8-40)

Increase in number - finer particles

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Characterize Powder Particle Size

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-Microscopy
-Sedimentation rate
-Light scattering
-Casacade impact - for aerosol

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Particle Size Reduction-Comminution

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Why reduce particle size?
-increase dissolution
-increase extraction
-increase uniformity
-enhance absorption

Mortar and pestle: trituration (grinding)

Levigation: grinding particles in oil with mortar and pestle. Ointment or paste preparation

Mills: cutting and sieving, e.g. FitzMill --> very common in industry

Pulverizer: grinding

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Blending Powders

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Blending: mixing powders to uniform

-Spatulation: small
-Trituration: small
-Sifting: industry
-Tumbling: industry
-Geometric dilution: blending potent drug in small equal portion of diluent, repeat steps till finish diluents --> used in industry and pharmacy

Mg stearate = lubricant

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Medicated Powders (Definition by Application)

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-Oral powder for reconstitution: for ease of swallow, or large dose, e.g., oral antibiotics liquid, label storage (2 weeks). Needs taste masking
-Dry powder inhalation
-Sterile dry powder: reconstitute with water for injection
-Vaginal douche: reconstitute with water, label "external use only"

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Example of Powder Applications (1 of 2)

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-Particles are important to suspensions
-Both the physical stability and bioavailability of suspensions can be related to the particles size
-Large particles can not be suspended for long
-Large particles may reduce the bioavailability

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Example of Powder Applications (2 of 2)

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-In inhalation aerosols, particle size is critical to achieve maximum penetration and deposition into the deeper airways of the lung
-85% of particles >5 micrometers are retained in the upper respiratory tract
-90% of particles in the 1-5 micrometer range are reained in the alveolae
-Particles <0.5 micrometers are exhaled
-Optimum particle: not too big, no too small sizes --> 5 micrometers

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Powders for external use (1 of 2)

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-Topical application: dusting powders
-Common diluents are starch and talc
-Easily applied in sifter-top shaker containers
-Most sifter-top containers are not "tight containers"
-Not volatile or sensitive to moisture components
-Examples: Methylbenzethonium Chloride Powder, USP --> not common. Historical product. Produced by trituration. Nystatin Topical Powder, USP

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Powders for external use (2 of 2)

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The mechanical irritation of topicals )dusting powders, creams and ointments) depends on particle size
-Particles pass through 325 mesh sieve (smaller than 45 micrometers) can minimize mechanical irritation

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Bulk and Divided Powders (Definition by Packaging) (1 of 2)

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-Bulk powders - nonpotent powders
-Antacids or laxatives: take with water
-Douche powders: wash with water, for vaginal use
-Topical powder: anti-infectives, antifungals
-Brewer's yeast powder: B complex vitamins
-Prepackaged
-Measuring tools: spoons or scoops

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Bulk and Divided Powders (Definition by Packaging) (2 of 2)

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-Divided Powder: for unit dose or each use
-Divide powder: weighing or block-and-divide
-Pack each divided portion in paper
-Select waxed or glassine paper in packing if moisture or air sensitive, or volatile

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Divided Powders

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Latin chartulae (pl._; Abbreviation: charts.
-'Powder Papers'
-After mixing, the powder blend is divided into individual units
-The portions are each placed on a small piece of paper, and folded to enclose (powder papers)
-Traditionally, the powder packets are dispensed in a cardboard "Powder Box"

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Granules

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-Granules are prepared agglomerates of powders
-Granulation is a size enlargement process
-Irregular shape, not spherical
-Size: usually 4-12 sieve number
-But vary dependent on applications
-Granules are larger and more porous than powder
-Starting material for
-solid dosage form - tablet, capsule
-liquid dosage form - powder for reconstitution

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Why Granules (1 of 4)

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-Good flow: large size than powder --> powder is coming in steadily --> powders cannot achieve this but granules can
-Compressibility: contains binder
-Uniformity: drug and excipient are binded --> porous has more compressibility
-Making tablets or filling capsules
-Advantage in feeding high-speed equipment

-Form plug when making capsules
-Need to mix powder well to makes granules

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Why Granules (2 of 4)

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-Larger size than powders
-Less surface area per unit weight than powders (the smaller, the larger surface area)
-More stable to atmospheric moisture or oxygen
-Less likely to cake in the container than powders

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Why Granules (3 of 4)

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-granulation may improve drug dissolution (e.g. from a tablet)
-enhancing wettability due to hydrophilic nature
-the hyrophilic binder, which covers particle
-more porous, capillary action (sucking) readily wetted vs powder
-attract water due to above mechanisms and can enhance the ability of hydrophobic, poorly soluble drugs to be wetted by dissolution fluids.

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Why Granules (4 of 4)

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Generally difficult to mix low dose drugs to uniformity
-Wet granulation can ensure content uniformity
-In wet granulation, drugs can be dissolved or dispersed in binder solution
-Adding liquid phase helps dispersion of low dose drug to ensure content uniformity
-After drying, drug is locked in granules
-This feature is important to achieve content uniformity for tablets or capsules.

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Granules

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-May be dispensed in bulk as a dosage form for oral administration, e.g. antibiotics, antacid, dietary supplement etc.
-Widely used as an intermediate for making compressed tablets. Powders may also be granulated prior to filling into capsules (flow and uniformity)

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Granule Composition

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Main composition
-active ingredient
-diluent - makes up bulk volume
-binder - if no binder, one dry --> becomes loose
-flavor (powder for reconstitution)
-color (powder for reconstitution)

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Granule Preparation: Wet Granulation

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Fluid in wet granulation: high shear or fluid bed dryer.
High (or low shear) mixer process
-Moist and mix powders to form liquid bridge among powders
-Powders stick together in lumps
-Wet lumps pass through sieve
-Wet granules are tray dried in oven or dried in fluid bed dryer
-Pass dried granulation through sieve

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High Shear Granulator

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-Revolutionized pharm. industry
-Collette Gral Type
-High speed
-Bowl

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Granule Preparation: Wet Granulation

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Fluid bed dryer process
-Fluid bed dryer is a conical shaped equipped to perform all steps
-Air suspends powders for mixing
-Spay granulation fluid to moist and mix powders to form liquid bridge among powders
-Wet granules are dried by suspending in hot air

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Fluid Bed Granulation

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-Requires balance of inlet air temperature and feed rate
-Higher inlet air temperature cause rapid evaporation of the binder solution and results in smaller, friable granules
-Lower inlet temperatures, drying is slower (particles star wetter longer); produces larger, denser, stronger granules
-Higher feed rates increases the 'evaporative load' and slows drying; tends to produce larger, denser and stronger granules
-Lower feed rates tend to produce smaller, friable granules

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Caution

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Wet granulation is not practical for drugs sensitive to water or heat (hydrolysis)

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Granule Preparation: Dry Preparation: Dry Granulation

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-No fluid in dry granulation: roller compactor or slugging
-Roller compactor method:
1. Compact powders to ribbons
2. Break ribbons to granules of desired size

-Slugging Method:
1. Compact powders to large tablets or slugs (about 1 inch in diameter)
2. Break slugs to granules of desired size

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Dry Granulation - Slugging

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-Older process
-Mix with dry binders
-Compress into large crude tablets (slugs) on a special heavy duty slugging press
-Mill the slugs to form granules
-Slugging is slow and may require double lubrication (could slow drug dissolution)

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Dry Granulation - Roller Compaction

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-Powder blend is compressed between rollers to form a cake (ribbon)
-Cake milled to form granules
-Compact formation facilitated by
*increased time under pressure facilitates bonding between particles
*use of highly compactible excipients that can effectively function as dry binders
*Microcrystalline cellulose

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Granules Applications

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-Granules have broad applications due to good flow, compressibility, uniformity
-Manufacturing tablet, or capsule
-More porous, readily wetted vs powder
-Packaged as a powder for reconstitution (antibiotics)
-More stable vs powder (small surface area to humidity)

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Granules Applications

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-Reconstituted antibiotics
-Bulk laxatives, e.g. Senokot Granules (granules contain standardized senna concentrate)
-Bulk analgesics, e.g., effervescent granules such as Bromo Seltzer

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Powder for Reconsitution Dose Calculation

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Refer to slides

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Effervescent Granulated Salts (1 of 2)

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Package granules for high dose, masking taste, ease of swallow
-Main ingredients: acid, base, and the active ingredient
-Acid: combination of citric acid and tartaric acid to avoid stickiness (citric acid) or crumbling (tartaric acid)
-Base: sodium bicarbonate
-Granulate to control the rate of solution and effervescence

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Effervescent Granulated Salts (2 of 2)

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-Carbon dioxide forms with placed in water
-Carbonation helps mask the unpleasant taste of drugs
-Granular form (as opposed to powder form)
-Dissolves more slowly and provides a more controlled reaction
-More stable to atmosphere

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Effervescent Granules: Fusion Method

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-No water added
-Water is in citric acid crystal (citric acid monohydrate)
-Mix powder
-Dry at 34-40 degrees Celsius to release water from citric acid crystal, trigger chimical reaction
-Water released and chemical reaction product (water and CO2) granulate powders upon mixing
-Sieve
-Dry at 54 degrees Celsius
-Air tight packaging

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Effervescent Granules: Wet Method

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-Binding agent: water and alcohol
-Powers are anhydrous
-Granulate with just enough water without triggering effervescence
-Sieve
-Dry
-Package