Dosage - Chapter 6

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Aira Jhamaica Dimacale

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Pharmaceutical Dosage Chapter 6: Powders and Granules

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Granules

Powders 

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Prepared agglomerates of powdered particles

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

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Contain one or more active ingredients with or without other ingredients

Medicated powder:

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4-12 sieve size range

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

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Internal use: oral powder

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External use: topical powder Opening of Standard Sieves

Uses of Medicated Powders in Therapeutics 

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Blended with powdered fillers and other pharmaceutical ingredients

To make various liquid dosage forms 

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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

To fabricate solid dosage forms as tablets and capsule

Dissolved or suspended in solvents or liquid vehicles

To prepare medicated ointments and creams 

Incorporated into semisolid bases

Medicated Powders 

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Internal use: 

Taken orally after mixing with water

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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

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Should bear a label marked external use only

Particle Size and Analysis 

Solid Materials 

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

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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 particle size

Definition of Some Terms 

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Particles of pharmaceutical powders range from: 

Extremely coarse: about 10 mm to 1 cm in diameter

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Extremely fine: approaching dimensions of 1 micron or less

Micromeritics 

Science of small particles

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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 Terms

Descriptive

Sieves 

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

colloidal

Very Coarse (No. 8)

Sieve Size: All Particles Pass Through

Fineness

8

Not more than (nmt) 20% through 1

a no.60 sieve Coarse (No.20)

20

Nmt 40% through a no.80 sieve

Moderately (No.40)

40

Nmt 40% through a no.80 sieve

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Methods for the Determination of Particle Size 

Coarse

Fine (No.60)

60

Very Fine (No.80)

80

No limit to greater fineness

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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 

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Dissolution rate of particles 

Intended to dissolve

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Drug micronization increases rate of drug dissolution and its bioavailability

Suspendability of particles 

Intended to remain undissolved but uniformly dispersed in liquid vehicle

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Example: fine dispersions approximately 0.5 to 10 um

have

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

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Range: 0.2 to 500 micrometers

Laser holography 

Particles individually imaged and sized

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

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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

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

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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

particles

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

Light energy diffraction or light scattering

Nmt 40% through a no.100 sieve

Purpose of Particle Size Analysis in Pharmacy 

Calculated using the Stoke’s Law

To ensure dose to dose content uniformity

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Penetrability of particles 

Inhaled for deposition deep in the respiratory tract

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Example: 1 to 5 um

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)

Nongrittiness of solid particles 

In dermal ointments, creams, and ophthalmic preparations

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

Comminution of Drugs 

The Laser, Optics and Ho lography Rings

Pulverization by intervention 

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

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

Sedimentation Rate 

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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

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Levigation 

Separate fine particles from coarse by grinding in water

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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

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Small-scale preparation of ointments

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Reduce the particle size and grittiness of added powders

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Mortar and pestle or ointment tile is used.

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

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The basis of choice of levigating agent:

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Ability to form a smooth paste with the substance

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Compatibility with the product

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*** 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 

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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

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Reduces product loss

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Prevents product contamination

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: Same color o Visible sign of mixing is o 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, sifting Twin Shell Blender Mixes solid particles  Blending 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  

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 

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Inconvenient to carry Inaccuracy in dose

Aerosol Powders 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  asthma Types 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) Taken by mixing with water or o 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 

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Entire amount of prepared powder on a pill tile With a large spatula divided o into equal amounts rectangular or  Forms 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 

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Douche powders: generally dissolved in warm water for vaginal use Medicated or non-medicated powders: for external application 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 boxes Dentifrices 

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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 

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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

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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 infants

Granules   

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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 method  Moisten the powder or powder o mixture Pass the paste through a o screen of the mesh size (to produce the desired size of  granules) Granules are placed on o 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 5

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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) 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 forming the pliable mass for granulation Examples: Zantac o Efferdose tablets Lactinex granules: mixed o culture of Lactobacillus acidophilus and Lactobacillus bulgaricus in 1g packets Treatment of  o uncomplicated diarrhea, usually mixed with water, beverages, sprinkled on food or eaten plain Dry and wet methods:  Objectives of using the method:  To determine the proper o formula for the preparation that will result in effective effervescent and effect of  the product Efficient use of the acids o and base present Stable granulation o Pleasant taste o

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