Aira Jhamaica Dimacale

Pharmaceutical Dosage

Chapter 6: Powders and Granules

Powders

Intimate mixtures of dry, finely divided drugs and/or chemicals used externally or internally

Medicated powder:

Internal use: oral powder

External use: topical powder

Uses of Medicated Powders in Therapeutics

To fabricate solid dosage forms as tablets and capsule

Blended with powdered fillers and other pharmaceutical ingredients

To make various liquid dosage forms

Dissolved or suspended in solvents or liquid vehicles

To prepare medicated ointments and creams

Incorporated into semisolid bases

Medicated Powders

Internal use:

Taken orally after mixing with water

Some are inhaled for local effects (laxatives) or systemic effect (analgesic)

External use:

Dusted on the affected area from sifter-type container or applied from powder aerosol

Should bear a label marked external use only

Solid Materials

Characterized to determine their chemical and physical features before the preparation of pharmaceutical products including:

Morphology, purity, solubility, stability, particle size, uniformity, compatibility with any other formulation components

For efficient production of a finished dosage form: optimum therapeutic efficacy, adjustment and control of powder’s particle size

Definition of Some Terms

Sieves

For pharmaceutical testing and measurement, reduction of particle size of powders

Made of wire cloth woven (not coated or plated) from brass, bronze, and other suitable wire

Granules

Prepared agglomerates of powdered particles

Contain one or more active ingredients with or without other ingredients

4-12 sieve size range

Granulations of powders used in tablet making (12-20 sieve range)

Opening of Standard Sieves

Sieve Number Sieve Opening Sieve Number Sieve Opening

2.0 9.50 um 70.0 212.00 um

3.5 5.60 um 80.0 180.00 um

4.0 4.75 um 100.0 150.00 um

8.0 2.36 um 120.0 125.00 um

10.0 2.00 um 200.0 75.00 um

20.0 850.00 um 230.0 63.00 um

30.0 600.00 um 270.0 53.00 um

40.0 425.00 um 325.0 45.00 um

50.0 300.00 um 400.0 38.00 um

60.0 350.00 um

Particle Size and Analysis

Particles of pharmaceutical powders range from:

Extremely coarse: about 10 mm to 1 cm in diameter

Extremely fine: approaching colloidal dimensions of 1 micron or less

Micromeritics

Science of small particles

Characteristics included: particle size, angle of repose, bulk volume, size distribution, porosity, apparent density, shape, true volume, bulkiness

USP Standings for Powders of Animals and Vegetable Drugs

USP Descriptive Terms

Sieve Size: All Particles Pass Through

Fineness

Very Coarse (No. 8) 8 Not more than (nmt) 20% through

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a no.60 sieve

Coarse (No.20) 20 Nmt 40% through a no.80 sieve

Moderately Coarse (No.40)

40 Nmt 40% through a no.80 sieve

Fine (No.60) 60 Nmt 40% through a no.100 sieve

Very Fine (No.80) 80 No limit to greater fineness

Purpose of Particle Size Analysis in Pharmacy

To obtain quantitative data of drug and other components used in pharmaceutical formulations on the size, distribution, and shape

Variety of Important Factors Particle Size can Influence

Dissolution rate of particles

Intended to dissolve

Drug micronization increases rate of drug dissolution and its bioavailability

Suspendability of particles

Intended to remain undissolved but uniformly dispersed in liquid vehicle

Example: fine dispersions have particles approximately 0.5 to 10 um

Uniform distribution of a drug substance in a powder mixture or solid dosage form

To ensure dose to dose content uniformity

Penetrability of particles

Inhaled for deposition deep in the respiratory tract

Example: 1 to 5 um

Nongrittiness of solid particles

In dermal ointments, creams, and ophthalmic preparations

Examples: fine powders may be 50-100 um in size

The Laser, Optics and Holography Rings

Sedimentation Rate

Particle size is determined by measuring the terminal setting velocity of particles through a liquid medium a gravitational and centrifugal environment

Range: 0.8 to 300 micrometers

Calculated using the Stoke’s Law

Methods for the Determination of Particle Size

Light energy diffraction or light scattering

Reduction in light reaching the sensor as the particle dispersed in a liquid or gas, passes through the sensing zone

Range: 0.2 to 500 micrometers

Laser holography

Particles individually imaged and sized

Pulsed laser fired through an aerolized particle spray and photographed in 3 dimensions (holographic camera)

Range: 1.4 to 100 micrometers

Cascade impaction

Principle: a particle driven by an air stream will heat a surface in its path but its inertia is sufficient to overcome the drag force that tends to keep it in the airstream

Particles separated into various size ranges by increasing the velocity of the airstream

Driven by an airstream will hit a surface in its path, provided that its inertia is sufficient to overcome the drag force that tends to keep in the airstreams

A single method may be sufficient.

Combination of methods preferred for certainty of size and shape parameters

Particle reduction points out: a decrease in particle size will result in an increase in the number of particles and total surface area (inversely proportional)

Comminution of Drugs

Pulverization by intervention

Reduction of particle size with the aid of a second agent that can be readily removed from the pulverized product

Example: camphor readily triturated with a few drops of alcohol or other volatile solvent (The pulverized camphor is readily recovered as the solvent evaporates.)

Levigation

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Separate fine particles from coarse by grinding in water

Reducing particle size forming a paste of the solid with a minimum amount of a levigating agent and then triturating the paste in a mortar or on slab with a spatula

Small-scale preparation of ointments

Reduce the particle size and grittiness of added powders

Mortar and pestle or ointment tile is used.

Trituration and levigating agent: insoluble powder (mineral oil and glycerine)

The basis of choice of levigating agent:

Ability to form a smooth paste with the substance

Compatibility with the product

*** Water cannot be used for levigating a substance for oleaginous ointment base.

Comminution of Drugs on a Large-Scale

Various types of mills and pulverizers

Example: FitzMill Comminutor

Used for particle reduction with attached containment system for protection of environment and prevention of product combination

Collection or containment system:

Protects the environment form chemical dust

Reduces product loss

Prevents product contamination

Mixing or Blending Powders Spatulation

Movement of spatula on a sheet of paper or ointment tile

Not suitable for large quantities of powders or powders containing potent substances

Suited to mixing solid substances that form eutectic mixtures (or liquefy when in close and prolonged contact with one another)

Examples that form eutectic mixtures when combined: phenol, thymol, camphor, aspirin, menthol, phenyl salicylate and other similar chemicals

Trituration To comminute and to mix powders Geometric dilution method

Used when a small amount of potent substance is mixed with a large amount of diluents

Ensure the uniform distribution of the potent drug

Indicated when the potent and other ingredients are:

o Same color o Visible sign of mixing is

lacking Examples: strychnine sulfate, arsenic, mercury

bichloride, atropine in convenient concentration using lactose as the diluents for use at the Rx counter

Sifting Powders mixed by passing through the sifters:

results in light, fluffy product Not acceptable for incorporation of potent

drugs into a diluent powder Tumbling (rotating chamber)

Use of machine or motorized equipment for industrial purposes

Time consuming Small scale preparations: spatulation,

trituration, siftingTwin Shell Blender

Mixes solid particlesBlending of Powders

The “V” blender: an efficient and versatile blending machine for mixing and lubrication process of dry powders homogeneously

The ribbon blender: an efficient and versatile blending machine for mixing dry granules and powders homogeneously

Routes in Administering Medicated Powders For internal use:

Taken orally after mixing with water For constitution with a liquid solvent or vehicle Some inhaled for local and systemic effects Others as injection Others as vaginal douche

For external use: Dusted on the affected area (sifter-type

container) or applied from powder aerosol Should bear a label marked external use only

or a similar label

For oral use has: Local effects (ex. laxatives) Systemic effects (ex. analgesic)

Faster rate of dissolution and absorption (immediate contact with gastric fluids)

Preferred than tablets and capsules by patients who have difficulty in swallowing solid dosage forms

Administered as powders Doses of some drugs are too bulky

(can’t be made into a capsule or tablet of convenient size)

Medicated Powders Advantages:

Faster rate of dissolution and absorption Ease in compounding For eutectic mixtures

Disadvantages: Can’t mask undesirable taste Inconvenient to carry Inaccuracy in dose

Aerosol Powders

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Administered by inhalation with the aid of dry-powder inhalers

Deliver micronized particles of medication in metered quantities 1um to 6um range in diameter

Treatment of asthma and other bronchial disorders Contain inert propellants and pharmaceutical diluents

such as crystalline alpha-lactose monohydrate To aid the formulation’s flow properties and

metering uniformity To protect the powder from humidity

Mechanical devices used: pressurized aerosols, spinhaler (cromolyn Na from capsules), blowers or insufflators

Powders to various parts of the body after depression of rubber bulb causing turbulence in the vessel forcing the powder out through the orifice in the tip

Insufflator Powder is placed in the vessel. When the rubber bulb is depressed, internal turbulence

disperses the powder and forces it from orifice.Insufflations

Finely divided powders introduced into the body cavities such as the ears, nose, throat, tooth sockets and vagina

Examples: Norisodrine Sulfate Aerohaler Cartridge

(Abbott): specialized equipment or inhalation Cromolyn Sodium Powder: relieve bronchial

asthmaTypes of Powders

Bulk powders Dispensing powder medication in bulk

quantities (nonpotent substances) Bulk powders available in prepackaged

amounts: Anatacids (ex. sodium bicarbonate)

and laxatives (ex. Psyllium: Metamucil)o Taken by mixing with water or

other beverage before swallowing

Douche powders (ex. Massengil Powder): dissolved in warm water by the patient for vaginal use

Mediacated topical anti-infectives: for external application to the skin (ex. bacitracin zinc and polymyxin B sulfate) or antifungals (ex. tolnaftate)

Non-medicated: Brewer’s yeast powder containing B-complex vitamins and other nutritional supplements

Divided Powders Form of individual dosing units (block

and divide method) Dispensed in chartulae (folded papers),

metal foil, small heat-sealed or resealable plastic bags

Based on the amount to be taken or used at a single time

Examples: headache powders, powdered laxatives, and douche powders

Properly blended using the geometric dilution method for potent substances

Block and divide method For nonpotent powders Entire amount of prepared powder on

a pill tileo With a large spatula divided

into equal amounts

Forms rectangular or square block of powder

Having uniform depth Each block transferred to a powder

paper and wrapped Geometric dilution method

Powders properly blended Small amount of potent substances

mixed with large amount of diluents Ensures uniform distribution of the

potent drug (same color with other ingredients and visible sign of mixing is lacking)

No powder in the folds, and should not escape with moderate agitation

Label placed on the container or affix a label of directions to each paper

Cellophane or plastic envelopes (moisture resistant resulting in uniform packaging) To enclose individual doses or units Used than folded individual powder

papers Advantages of divided powders:

Flexibility Rapid therapeutic effect Stability Ease of administration

Disadvantages of divided powders: Time consuming to prepare Not well suited for dispensing of

many unpleasant tasting hygroscopic drug

Inaccuracy

Papers that may be used Simple bond paper: opaque paper

with no moisture resistant properties Vegetable parchment: opaque

moisture resistant Glassine: glazed transparent moisture

resistant Waxed paper: transparent waterproof

paper Powders containing:

Hygroscopic and deliquescent materials: waterproof or waxed paper

Limited barrier against moisture is necessary: glassine and vegetable parchment papers

Volatile components: waxed or glassine papers

Neither volatile nor ingredients adversely affected by air moisture: white bond paper

Examples of finely divided powders: Oral powders: supplied as finely as

divided powders or effervescent granules

Douche powders: generally dissolved in warm water for vaginal use

Medicated or non-medicated powders: for external application

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usually dispensed in sifter cans for convenient application the skin

Dentifrices or dental cleansing powders

Denture powders: for dentifrices or foe adhesive to hold dentures

Douche Powders Products completely soluble and are intended to be

dissolved in water prior to use as antiseptic or cleansing agent for body cavity

Components: Boric acid or borax Astringents as K alum, ammonium alum,

ZnSO4

Antimicrobial as oxyquinoline sulfate or povidone iodine

Quaternary ammonium compounds as benzethonium chloride

Detergents as sodium lauryl sulfate Oxidizing agents as sodium perborate Salts as sodium citrate, sodium chloride Aromatic as menthol, thymol, eucalyptol,

methyl salicylate and phenol Packaging: may be in a wide mouth glass jar to protect

from volatile constituents and by bulk powder boxesDentifrices

Form of bulk powder, generally containing flavors, soap or detergent, mild abrasive and a polishing agent

Forms: paste, powder, liquid, and block and solid Use: with a tooth brush for the purpose of cleansing the

accessible surfaces of the teeth Composition: abrasives such as calcium carbonate,

calcium phosphate, calcium sulfate, insoluble sodium metaphosphate, hydrated Al2O3, MgCO3, and phosphates, NaHCO3, and NaCl

Dentifrices contain non-carbohydrates sweetening agents but a few contain sugar

Dusting Powders

Non-toxic preparations for local application and therefore no systemic effect

Dispensing: should be dispensed in a very fine state of subdivision to enhance effectiveness and minimized irritation

Packaging: available in sifter type containers or pressure aerosols, the latter more expensive but protects from air, moisture and contamination

Uses: lubricants, absorbents, antiseptics, antipruritics, astringents, and antiperspirant

Official powdered vegetable drugs: Powdered Belladona Extract NF Powdered Digitalis Extract Powdered Ipecac USP Powdered Opium USP Powdered Rauwolfia Serpentina NF

Official powders: Ampicillin Soluble Powder: dry mixture of the

ampicillin and diluents and stabilizing Polymixin B Sulfate and Bacitracin Zinc Topical

Powder, USP: used as a topical anti-infective Compound Cloquinol Powder, USP: mixture of

cloquinol lactic acid, zinc stearate and lactose vaginal insufflations as an anti-chomonal

Nystatin Topical Powder USP: employed as a topical dusting powder in the treatment of the mycotic infections

Tolnaftate Powder USP: treatment of fungal infection

Official powders for topical use: Absorbable Dusting Powder: gloves lubricants Compound Iodochlorohydroxyquin Powder, NF:

vaginal insufflations as antimicrobial Methylbenzenthonium Chloride Powders, NF: local

anti-infectives for diaper rash in infantsGranules

Prepared aggromalates of smaller particles of powder Irregularly shaped but may be spherical 4-12 sieve size range, although granules of various mesh

sizes may be prepared depending upon their application Provide a pleasant vehicle for selected drug products

with bitter, salty taste Prepared by: wet method, dry method Examples:

Pricipen (ampicillin): for oral suspension (for reconstitution)

Senokot granules: for laxative Effervescent products as Bromo Seltzer K-Lyte: granulations of effervescent products

compressed into tablet

Preparation of granules: Wet Method:

One basic wet methodo Moisten the powder or powder

mixtureo Pass the paste through a

screen of the mesh size (to produce the desired size of granules)

o Granules are placed on drying trays and dried by air or under heat. Granules periodically moved on the drying trays to prevent adhesion into a large mass.

Another type of wet method Fluid bed process: particles

in a conical shaped equipment dispersed and suspended; liquid excipient sprayed and the product dried

Granules or pellets of defined particle size formed

Dry Granulation Method Dry method or fusion method:

material passed through a roll compactor then through a granulating machine

Also called slugging: compression of powder or a powder mixture under 8000-12000 pounds of pressure (depending on physical properties of powder)

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Increases particle density and improves powder flow

Milling equipment: used to improve flow, reduce segregation, enhance drying, and limit wide particle size distribution

Characteristics of granules which are advantageous over powders:

Flow well More stable to atmospheric humidity Less likely to cake or harden upon standing Easily wetted by liquids

Effervescent granulated salts Granules or coarse to very course powders

containing a medicinal agent in a dry mixture Composition: sodium bicarbonate, citric acid,

tartaric acid If water is added: effervescence If tartaric only: loose firm If citric only: pasty Pleasant vehicle to mask of bitter and salty

tastes Example: sodium phosphate: cathartic Two methods of preparation:

Dry method or fusion method: binding agent for the powder mixture: one molecule or water present in each molecule of citric acid

Wet method: binding agent: water added to alcohol as the moistening agent not the water of crystallization from the citric acid: forming the pliable mass for granulation

o Examples: Zantac Efferdose tablets

o Lactinex granules: mixed culture of Lactobacillus acidophilus and Lactobacillus bulgaricus in 1g packets

o Treatment of uncomplicated diarrhea, usually mixed with water, beverages, sprinkled on food or eaten plain

Dry and wet methods: Objectives of using the method:

o To determine the proper formula for the preparation that will result in effective effervescent and effect of the product

o Efficient use of the acids and base present

o Stable granulationo Pleasant taste

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