261 PHT Slids Powder, Granuls, Caps, Supp

7/28/2019 261 PHT Slids Powder, Granuls, Caps, Supp

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POWDERS AND GRANULES

As a pharmaceutical preparation, a powder (latin , pulvis) is a mixture of finely divideddrugs and / or chemicals in dry form

Powders are subdivided solids which are classified according to the size of theiconstituent particles which range from <1.25 μm to 1.7 mm in diameter.

It may be prepared from a naturally occurring dried vegetable drug, or it may be aphysical admixture of two or more powdered pure chemical agents.

A drug powder may be mixed with other powdered excipients depending upon theintended use of the product.

Advantages of powdered products :

• Are preferred by some patients (infants and young children) who are unable to

swallow the solid dosage forms.

• Stability and shelf-life.• Convenient form to dispense drugs with a large dose

• Faster dissolution and absorption rate than tabletor capsules.

• Can be applied to many body cavities such as ears, nose, tooth socket, throat

• Can be made into many different dosage formulations (capsules, tablets,powders for reconstitution, dusting powders, bulk powders, powders forinhalation, etc.)

Disadvantages of powders:• Less convenient to carry (bulk powder)

• Masking of unpleasant taste is a problem

• Potent drug with low dose

• Not suitable form for drug inactivated in the stomach

• Difficulty of protecting hygroscopic and deliquescent

Or aromatic materials.

Dispensed preparations1- Bulk powders (non toxic medicament with a large dose).2- Divided powders (separately wrapped)

3- Dusting powders for external use4- Insufflations (potent drug as: sodium cromoglycate).

Preparations requiring further treatment at time of dispensing: Oral antibiotisyrups

Powder for injection

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Agglomeration, granulation and pelletizing processes involve the wetting and mechanicalhandling of particulates. An open and porous agglomerate structure changes to a moreclosed and grain-like granule structure as the degree of wetting and mixing is increased.Particulates engineering involves the control of moisture and energy input to achieve adesired change in structural and other properties.

By improving:

• free floability• ease of handling• visual

appearance

• ease of compaction

By adjusting:

• bulk density• solubility rate

• shape and size distribution

By reducing:

• fines (dustcontent

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Particle Size AnalysisThe particle size of drug and other powders is determined and influences thesubsequent physical performance of the medicine and the pharmacologicaperformance of the drug.

1- Particle size influence the production of formulated medicine assolid dosage forms.

2- Powders with different particle size have different flow andpacking properties. Flow property& particle size.3- Particles having small dimensions will tend to increase the rate o

dissolution.4- Particle size influence suspendability of particles intended to

remain undissolved but uniformly dispersed in a liquid vehicle5- Particle size cam\n influence penetrability of particles intended to

be inhaled to reach into the respiratory tract.6- Particle size influences grittiness of solid particles in derma

ointment, cream and ophthalmic preparations.

Methods for determination of particle size:1- Sieving2- Microscopy3- Sedimentation (Andreasen pippett)4- Light energy diffraction5- Laser light scattering6- Electronic sensing zone (Coulter Counter)

Powder FlowReasons for producing free–flowing pharmaceutical powders include:

1- Uneven powder flow can result in excess entrapped air within powderswhich may promote capping or lamination.

2- Uneven powder flow can result from excess fine particles in a powdewhich increase particle-die wall friction, causing lubrication problemsincrease dust contamination risks.

3- Uniform fed from bulk storage containers into the feed mechanisms otableting or capsule-filling equipment, allowing uniform particlepacking which improve weight uniformity.

Angle of repose:tan ө = h/rh= the height of the powder coner= the radius of the powder cone

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Cohesion: occurs between like surfaces such as component particles of a bulksolid,

Adhesion: occurs between two unlike surfaces, between particle and a hopperwall.

Particle size effectsParticle shape

Particle densitySurface texturePorosity

Improvement of powder flowability1- Alteration of particle size and size distribution2- Alteration of particle shape and texture3- Alteration of surface forces4- Formulation additives: flow activators5- Moisture control

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Blending Powders

Depending on: the nature of the ingredientsamount of powderequipment available

Powders can be blended by:

1- Spatulation: for small amounts of powders, there is no reduction inparticle size2- Geometric: used to help ensure that small amounts of the ingredients

usually potent drugs, are uniformly distributed throughout the powdemixture.

3- Trituration: it gives more intimate mixing than other methods. Idescribes the grinding of two or more substances in a mortar tointimately mix them.

4- Sifting: produce a light fluffy product.5- Tumbling: us a large container which rotates by a motorized process.

Powder Comminuation

1- facilitate crude drug extraction,2- aid in formulation of pharmaceutically acceptable dosage forms,3- increase the dissolution rate,4- enhance the drug absorption,5- reduce the bulk volume of a material to improve transportation

efficiency.

On small scale use mortar and pestlesTrituration Levigation

I- Cutting methods: Cutter millsFor fibrous crude drugs: roots, peels, barksProducing coarse degree of size reduction of driedgranulations.

II- Impact methods: Hammer mill

Vibration mill

III- Compression method: Mortar and pestleEnd-runner and edge runnerMills

IV- Attrition method: Roller mill

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CAPSULES(Capsula: small box)

Capsules are solid dosage forms in which medicinal agents and /or inertsubstances are enclosed within a small shell of gelatin.

Capsules first appeared in USP XII in 1942.

Advantage of encapsulation:

• Taste concealment (unpleasant taste)

• Elegance, smooth slippery, easily swallowed shell

• Nice presentation of the drug

• Portability, convenient

• Light weight

• Rapid drug release

• Can be used for the extemporaneous compounding of prescriptions.

Capsules are made of hard or soft gelatin shell

Hard gelatin capsules

The empty capsule shells are made from a mixture of gelatin, plasticizer, sugaand water (and may contain FD&C dyes and / or opacifying agent, preservativeenteric agent, flavour).

Capsules are not suitable:

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• For drugs that are very soluble: as salts (potassium chloride, potbromide, ammonium chloride).

• For efflorescent or deliquescent materials.

Gelatin: is obtained by partial hydrolysis of collagen obtained from bones, skin,connective tissue of animals.

1- Non-toxic, used in food stuff.2- Readily soluble in biological fluid at body temp.3- Good film forming material4- Undergoes a reversible phase change at a little high temp.

• Bloom or gel strength of gelatin: It is a measure of the cohesive strength of the cross-linking which occur between the gelatin molecules and isproportional to the molecular weight of the gelatin

Bloom is determined by measuring the wt in grams required to move aplastic plunger, 0.5 inches in diameter, 4 mm into a 6.66 % gelatin gel that

has been held at 10°C for 17 hours.

Bloom would be within the range of 150-250 Bloom grams.

• Viscosity of gelatin also determined on a 6.66% conc. of gelatin inwater, is a measure of the molecular chain length and determines themanufacturing characteristics of the gelatin film.

The viscosity range for gelatin can be from 25-45 millipoise.

• Iron is always present in the raw gelatin, gelatin used in themanufacturing of soft gelatin capsules should not contain more than 15% ofthis element, because its effect on FD&C dyes and possible colour reactionswith organic compounds.

• Plasticizers: Glycerol, sorbitol, propylene glycol.

The ratio by weight of dry plasticizer to dry gelatin determine the harness ofthe gelatin shell.

• Colorants

Soluble dyes Insoluble pigmentsTitanium dioxide The oxides of iron

• PreservativesAre added to capsules as an in-process aid to prevent microbiologicalcontamination during manufacturing.

Sizes of hard gelatin capsule shell:

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Eight sizes are generally used:

No.5 4 3 2 1 0 00 000

Smallest largest

Volume 0.13 0.2 0.27 0.37 0.48 0.67 0.95 1.36

The capacity of the capsule is dependent on the density andcharacteristics of the powders in the application.

Veterinary capsules are available in sizes No. 10, 11, 12.

The capsule size selected should be slightly larger than that needed tohold the powder to provide a full capsule.

Capsule fill weight= tapped density of formulation ×

capsule volume

All formulations for filling into capsules must:1- be able to accurately dosed into the capsule shell

(accurate, ease of filling, elegance).2- release their contents in an available form to the patient (good

bioavailability).

Types of materials for filling into hard gelatin capsules:

1- Dry solid: powders, granules, tablets, pellets2- Semisolids: pastes, thermosoftening

Formulation factors affecting release from hard gelatin capsules:1- Active ingredient

- Solubility- Melting point- Crystalline form- Particle size

2- Diluent 3- Glidants and lubricant4- Wetting

Steps for preparation of filled hard gelatin capsules:1- Developing the formulation and selecting the size capsule.

2- filling the capsule shells.3- Capsule sealing (optional).4- Cleansing and polishing the filled capsules.

Soft Gelatin Capsules or Soft elastic gelatin (SEG)

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Pharmaceutical applications:1- As an oral dosage form for human or veterinary2- As a suppository dosage form for rectal or vaginal use3- As a specialty package in tube form, for single dose application of topical and

ophthalmic preparations; rectal ointments; ear and nose drops.

Rotary die process machine (Scherer), Iron mold were used for shaping the capsule.

SGC are used to hermetically seal and encapsulate liquids, suspensions, pastymaterials and dry powders.

Advantages of SGC as a dosage form:1- A compression stage is not included.2- The dose content uniformity is optimized, with reduction of the cost through the

use of smaller overages.3- Protection of sensitive drug from oxidation and hydrolysis.4- The drug is dissolved or dispersed in vehicle which provide high surface area and

good bioavailability.

The choice of Plasticizer is related to the type and nature of the capsulated materialswhile the ratio (hardness of shell) chosen usually is related to the end use of theproduct or to the geographical area.

Plasticizer concentration can be expressed as:parts of dry plasticizer : 1 part of dry gelatin.Range (0.3-1.0) : 10.3.0.5 oral products having an oil vehicle0.4.0.6 oil fill with added surfactant0.6.1.0 completely water-miscible vehicle,

tube shaped, squeeze-out type cap1.5 vaginal supp The ratio by weight of water to dry gelatin can vary from 0.7-1.3 water to 1.0 part of dry gelatin, depending on the viscosity of the gelatin used.

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The nature of the capsule contents:

Liquid vehicles:1- water-immiscible, volatile and non-volatile liquids as vegetable and aromatic

oils, chlorinated hydrocarbons, ethers2- water-miscible, non-volatile liquids as PEG, and non-ionic surfactants as Tween

80

3- water-miscible and relatively non-volatile liquids: alcohol (isopropyl alcohol),propylene glycol and glycerol, polglycerols, sugar esters, glyceryl esters.

Suspensions:Insoluble drugs can be dispersed (with suspending agents and surfactants) in the

above vehicles or combination of vehicles.

Limitation for fill materials:Excipients containing high conc. of water > 5% or other gelatin solvents.Emulsions (o/w or w/o)Extremes of pH: < 2.5 attack gelatin hydrolysis and leakage

> 7.5 have a tanning effect on the gelatinAldehydes, ketones, acid, amines, esters

Quality Control Tests for capsules:1- Disintegration tests2- Dissolution tests for capsules3- Weight variations4- Content uniformity (85% - 115 %)5- Moisture permeation test (single-unit and unit-dose container).

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Suppositories

Is a medicated solid dosage form intended for use in the rectum, vagina(pessaries).- Latin word : suppositorium

Rectal route for drug administration is used when:

1- The patient is not able to make use of the oral route.2- The drug is less suited for oral administration3- The drug with an unacceptable taste.

Drawbacks of rectal route:1- Slow, incomplete absorption2- Inter, intra-subject variation.3- Large scale production is a problematic

Uses of rectal route:i- Local effect (constipation, hemorrhoids)

ii- Systemic effect (analgesic, antibacterial, antispasmodics, sedative.

- The rectum is part of the colon, ends with acircular muscle, the anus.

- The total volume of mucus is 3 ml.Factors affecting absorption from the rectum:1- Physiological factors:- Fluid available- Properties of rectal fluid- Content of the rectum- Motility of the rectal wall

2- Physicochemical characteristics of drug:- Lipid/water partition coefficient- Drug particle size- Degree of ionization- Amount of drug

Drug in vehicle drug in colon fluid absorption through therectal mucosa.

Formulation of suppositories:Supp. are in different shapes, sizes 1- 4 g

Adult supp. 2gChildren supp. 1gVaginal supp. (globular, oviform shape) 3-5 g

Types of suppository base:1- Glycerides-type fatty bases2- Water-soluble bases

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Requirements of the optimum base:1- Melt at, or just below body temp. or dissolve in body fluid2- Rapid solidification after preparation3- Be miscible with many ingredients4- Non-toxic, non-irritant5- Resistant to handling6- Enough volume of contraction to permit removal from the mould

7- Stable on heating above its m.p8- Low acid value, low iodine value9- Physically, chemically stable on storage10- With high water number

Fatty vehicles (bases)Natural : Cocoa butter (Theobroma oil)It is a yellowish-white, solid, brittle fat, smells and tastes like chocolateCharacter of cocoa butter supp base:

1- Non-irritant, bland2- Smells and tastes like chocolate

3- Miscible with many ingredients4- Rapid melting, rapid solidification when cooled5- Melting range 30-35º C (solid at R.T.)6- Iodine value 34-38 (rancidity)7- Acid value < 5

Disadvantage of cocoa butter as a supp. base:1- It exhibits marked polymorphism, this is attributed to the highproportion of unsaturated triglycerides.

α form, melting at 24º C, β′ form m.p 28-31º C,

stable β, melts 34-35 º C, γ form, melting at 18 º C

Prolonged heating above the critical temp. 35 º C causes the formation of theunstable crystals with resulting lowered m.p.

2- It can rancidify (unsat. Fatty acid, oleic acid)3- Insufficient contraction at cooling, so lubrication is important.4- Poor water absorptive power5- Some drugs as volatile oils, phenol, chloral hydrate lower the m.p of

cocoa butter. Addition of wax and spermaceti can correct this condition.7 parts of cocoa butter and 1 part of spermaceti.

Synthetics fatsVegetable oils are modified by esterification, hydrogenation and

fractionation at different melting range to obtain the desired product.

Semi synthetic type of fatty vehicles (termed adeps solidus). Composed of mixed triglycerides of saturated fatty acid and mono, diglycerides.

Witepsol H15, Witepsol W35, Suppocires- Lubrication of mold is unnecessary, not affected by overheating.- Appreciable quantities of aqueous solution can be incorporated

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m.p Acidcontent

Hydroxyl no Iodine no

Cocoa butter 31-34º C < 5 0 34-38 Adeps solidus 33-37.5ºC < 2 < 5-30 < 3

Disadvantage:1- These bases become brittle if cooled too rapid2- The viscosity of the synthetic fats, is lower than that of cocoa butter,there is a great risk of the active ingredients sedimentation during preparationleading to a lack of uniformity.

Water-soluble vehiclesThey comprise the classical glycerol-gelatin or soap bases, PEG.

1- Glycerinated gelatin glycerol 70%

gelatin 20%purified water to 100%It dissolves in the rectal fluid rather than melted.Is a useful suppository base for vaginal use. It is suitable for use with a widerange of medicaments: alkaloids, boric acid, zinc oxide, ichthammol.Glycerinated gelatin supp. are translucent, resilient and gelatinous solids.

Mold calibration 1.2 g of base occupy the same volume a 1g cocoa butter base.It must be kept in well-closed containers in a cool place, a preservative shouldbe added

2- Polyethylene glycol polymers (Macrogols)May be used singly or two or more PEGs with different M.Wt mixed in variousproportions to yield product of satisfactory hardness and dissolution time.They are chemically stable, miscible with water, they may be safely stored atroom temp. they will not support mould growth, no laxative effect.

Disadvantages of PEGs supp. base:i- They are hygroscopic, attract water resulting in a painful sensation for apatient (add 10% water during manufacture).ii- Incompatible with several drugs, plastics.iii-Become brittle if cooled rapidly and on storage

iv- Crystal growth may cause irritation (waxy coat or local anesthetic may beused).

Methods of preparation:1- Fusion molding(density calculations and mold calibrations are required)Density factor = weight of drug

weight of base displaced

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Displacement value: is the number of parts by weight of drug which displaces 1part by weight of the base.

2- Compression molding: preparation of supp. from grated mass of supp. baseand medicaments which is forced into a special compression mold. Thismethod avoids the sedimentation of insoluble solids in the supp base, it is too

slow for large scale production.

Dispensing supp.In boxes lined with waxed paper or in plastic containerOr separately wrapped in metal foil.

Labeling supp."Store in a cool place""For rectal use only"Don't swallow

Suppositories

Specific problems in formulating suppositories

1- Moisture in suppositories

2- Hygroscopicity

Glycerinated gelatin and polyethylene glycol

3- Incompatibilities ( PEG)

4- Viscosity (sedimentation of suspended particles, 2% aluminum

monostearate, cetyl, stearyl or myristyl alcohols o stearic acid areadded to improve the consistency of suppositories).

5- Brittleness (Tween 80, glycerin, propylene glycol impart plasticity).

6- Volume contraction

7- Lubricants or mold release agents

8- Rancidity & antioxidants

Quality control test for suppositories:1- Appearance 6- Content uniformity2- Disintegration 7- Mechanical strength3- Weight variation4- Melting behaviour5- Drug release

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261 PHT Slids Powder, Granuls, Caps, Supp