DDS Lecture 19 Content

Powder considerations

• particle size and analysis

• comminution of drugs

• blending powders

Medicated Powders

• aerosol powders

• bulk and divided powders

Granules

• Effervescent granulated salts

• fusion method

• wet method

Powder particle size and analysis

• very coarse

• coarse

• mod. coarse

• fine

• very fine

• as particle gets smaller (coarse → fine), sieve number gets larger

Very coarse

• #8 sieve

• 2360 mcm

Coarse

• #20 sieve

• 850 mcm

Mod. Coarse

• #40 sieve

• 425 mcm

Fine

• #60 sieve

• 250 mcm

Very fine

• #80 sieve

• 180 mcm

Particle size considerations

• dissolution

• suspendability of suspensions

• uniformity of mixtures in liquids

• penetrability of particles for inhalation

• non-grittiness for ointments, creams, gels

• if uniform, will aid in mixing and distribution

• finer particles may migrate to bottom

• larger particles may migrate to top

• differences may change the color intensity of a powder

• especially important in dermatologicals

Comminution of drugs

• process of reducing the particle size of a solid substance to a finer state of subdivision

• stone mills: original implement

• mortar and pestle: symbol of pharmacy

Manual methods of comminution

• Trituration

• Levigation

• Pulverization by intervention

• Mills

Trituration

• to rub to pieces

• pill tile and spatula

• mortar and pestle

  • porcelain

  • wedgewood

  • glass

Levigation

• make smooth

• triturating while moistening with a liquid in which powder is insoluble

• common levigating agent: propylene glycol

Pulverization by intervention

• comminution by utilizing a solvent that can be easily removed

• ex. solvent: alcohol

Mills

• ball mills

  • closed

  • continuous

• roller mills

• cutter mills

• hammer mills

• colloid mills

Blending/Mixing

• process that tends to result in a randomization of dissimilar particles within a system

• can use small scale (compounding) or large scale (manufacturing) blending equipment

Small-scale blending equipment

• pill tile and spatula

• mortar and pestle

• bottle/container

• plastic baggie

Small-scale blending equipment requirement

• easily cleanable

• dust tight

• provide complete discharge/recovery

Equipment categories

• batch mixing

• continuous mixing

• tumblers

  • double cone blender

  • twin shell blender

• paddle blenders

  • blade and paddle blender

Powder applications

• dentifrices

• insufflations

• powder aerosols

Dentifrices

powders used to clean teeth

Insufflations

• intended for application to body cavities

• tooth sockets, ears, nose, throat, vagina

Powder Aerosols

• antiperspirants, deodorants, feminine hygiene sprays, body sprays, insufflations, dry lubricants

Bulk powders

• intended to be administered in dosage quantities that are safe for the patient to measure

• should pass through a 100 mesh sieve

• dusting powders, aerosols, dentrifices, antacids, laxatives, dietary nutrient supplements, douches

Dusting powder characteristics

• homogenous

• free from potential of causing local irritation

• flow easily

• spread uniformly

• cling to skin upon application

• generally dispensed in sifter-top containers

Divided Powders

• chartulae, charts, powder papers, powders

• single doses of the powdered drug mixture individually enclosed in paper, cellophane, or metallic foil wrappers or packets

• sufficiently potent to require pre-measured doses

Advantages of divided powders

• allows physicians to prescribe a precise amount of the drug

• more stable than the liquid form of many drugs

• dissolve more rapidly than compressed solid dosage forms

• rapid dissolution leads to faster blood levels and possibly less GI irritation

Powder applications

• easily alter dose

• clinical studies easy to prepare and alter

• infants/young children (“sprinkles”)

• bulky drugs

• rapid onset of action

• good bioavailability

• stable

Disadvantages of powders

• not suitable for bitter, nauseating, or corrosive drugs

• preparation is time-consuming, therefore more costly

• exposure of powder to atmospheric conditions

Preparation of powders

• spatulation

• trituration

• sifting

• tumbling

Methods to divide powder mixture into unit dose

• weighing each powder

• blocking and dividing

• powder measures

• volumetric template

Hygroscopic

• substances that absorb moisture from air

• must keep in tight container

Deliquescent

• substances that absorb moisture from the air to the extent that they liquefy by partially or wholly forming a solution

• should be in tight container

Efflorescent powders

• crystalline substances that become powdery and liberate their water of crystallization

• should be in tight container

Water of imbibition

• colloidal substances may absorb large amounts of water and retain the appearance of dry powders

• may cause problems in weighing

• water content varies with humidity

• ex. cellulose, starch, agar, gelatin

• need to know moisture content at first weigh

Eutectic Mixtures

• a proportion of components that will give the lowest melting point

  • lower melting point than individual MP’s of its components

• a mixture of components with a melting point less than room temperature

  • components are solid before mixing together, liquid when mixed together

• ex. aspirin, betanaphthol, camphor, chloral hydrate, menthol, phenol, salol, thymol

Avoiding Eutectics

• dispense powders separately

• add absorbent powder (talc, starch, lactose, calcium phosphate)

• keep ingredients separated as much as possible

  • do not store closely together

• make eutectic, then add absorbent to incorporate the liquid

Explosive mixtures

• when triturating an oxidizing agent with a reducing agent (using mortar and pestle)

• try to avoid

Oxidizing agents

• potassium chlorate/nitrate/permanganate

• sodium peroxide

• silver nitrate

• silver oxide

Reducing agents

• charcoal

• hypophosphites

• sulfur

• sulfides

• tannic acid

• volatile oils

Dusting powder

• applied to intertriginous areas as covering to protect the skin from chafing of friction and moisture

• vehicles: bentonite, kaolin, kieselguhr, magnesium carbonate, starch

  • absorb secretions, dry area, and impart cooling effect

• adhesive powders: aluminum stearate, kaolin, magnesium stearate, zinc oxide, zinc stearate

Granules

• particles ranging from 4-10 mesh in size

• not intended for use with potent drugs because of inherent error when a patient measures the dose with a teaspoon, scoop, etc

• good for unstable drugs

• ex. antibiotics for reconstitutions

Granule preparations

• prepared by moistening blended powders and passing the mass through a screen or granulator

• granules air or oven dried

• flavors can be sprayed on the granules and then dried

Effervescent granules

• contain mixtures of citric acid, tartaric acid, or sodium biphosphate with a bicarbonate and a medicinal agent

• carbonated solution is pleasant vehicle and lessens the bitter and salty taste of salts

• dispensed in packets of wide-mouth bottles

• do not want them to effervesce too quickly as they will overflow the container during mixing

• ex. Lactinex, Bassoran, Zantac

Capsule Advantages

• mask odor and/or taste of unpleasant drugs

• easy to prepare

• can vary dosage and combination of drugs

Capsule definition

• unit doses of powder, semisolid or liquid drugs enclosed within either a hard or soft envelope or shell

• can be hard gelatin or soft gelatin capsule

  • depends on glycerin content (higher = softer)

  • soft capsule: good for liquid

Capsules with special names

• kapseals

• spansules

• ped caos

• minimicrospheres

Capsule applications

• place on tongue and swallow with liquid

• dissolve contents in water or mix contents with food

• rectal and vaginal

Capsule disadvantages

not suitable for administering very soluble ionic salts (potassium chloride, ammonium chloride) bc it can interact with the shell

Capsule preparations

1. comminution

2. blending

3. determine capsule size

   1. based on dose

4. add additional diluent prn

5. encapsulate

6. clean

7. quality control

8. package and label

Comminution for capsules

• similar particle size

• mortar and pestle

• pill tile and spatula

• mill

• levigation

• pulverization by intervention

• other

Blending

• uniform distribution of actives in matrix

• mortar and pestle

• pill tile and spatula

• bottle

• plastic bag

• use of tracer/color

Human capsule sizes

• (from big to small)

• 000 (1.37 ml)

• 00 (0.95 ml)

• 0 (0.68 ml)

• 1 (0.5 ml)

• 2 (0.37 ml)

• 3 (0.3 ml)

• 4 (0.2 ml)

• 5 (0.13 ml)

Veterinary Capsule sizes

• from big to small

• 7 (1.5 oz)

• 10 (1 oz)

• 11 (0.5 oz)

• 12 (0.25oz)

• 13 (0.125 oz)

Encapsulation methods

• individual hand filling

• capsule machine filling

• filling capsules with a semisolid mass

• filling capsules with liquids

Cleaning capsules

• minimize traces of dust, moisture

• de-dusting using cloth, screen, or salt bottle

• most cleaning procedures are effective only if capsules have been kept clean and dry

Considerations for developing capsule formulation and selecting capsule size

• accurate dosage

• good bioavailability

• ease of filling and production

• stable

• elegant

Capsule Physicochemical considerations

• incompatibilities

• hygroscopic

• deliquescent

• eutectic

• use of diluents/adsorbents

Capsule special applications and considerations

• potent powders

• tablet with a capsule

• capsule within a capsule

• altered-release capsules

  • omeprazole: suspended-release

• rapid-release capsules

Capsule special problems

• deliquescent powders

• eutectic mixtures

• potent powders

• tablet with a capsule

• masses/semisolids

• oils

Filling hard capsule shells

• punch method

• capsule machine

• automated machines

What can fill hard gelatin capsules?

• powder or granule

• pellet mixture

• paste

• capsule

• tablet

Punch method

• with empty capsules in loader tray, tray is placed on top of filler units

• loader insets the capsules into the filling unit and is removed and the top plate is lifted to separate the caps from the bodies

• powder is placed on the unit and the capsule bodies are filled

• top plate is returned to the unit and the caps are placed on filled capsule bodies

Capsule sealing

• kapseals

• gelatin bands

• heat welded or thermally coupled

• Z-weld’s gelatin seal fuses the two capsule halves to create a one piece capsule that is tamper evident

Cleaning and polishing capsules

• cleaning vacuum

• clean gauze or cloth

• goal: remove powder from outside

Preparation of soft gelatin capsules

• plate process

• molds

• rotary die process

  • gelatin ribbons

• not made by compounding pharmacy

Use of soft gelatin capsules

• water-immiscible volatile and nonvolatile liquids

• water-miscible nonvolatile liquids

• water-miscible and relatively nonvolatile compounds

• NOT for powders (dosing concerns)

Capsule quality control

• drug content: measured by HPLC drug assay

• fill weight

• disintegration

• dissolution

• stability

Added substances to capsules

• harmless

• do not exceed minimum amounts required

• do not impair bioavailability

• do not interfere with compendial assays and tests

Containers for dispensing capsules

• tight

• well-closed

• light-resistant

Disintegration test for capsules

• basket rack assembly

• 37C water or suitable fluid

• disintegrate completely into a soft mass with no palpable firm core and only some fragments of the gelatin shell

• mimic stomach environment

Dissolution test for capsules

• paddle method: use for tablets

• basket method: use for capsules

Capsule Content Uniformity

• 9 of 10 within 85-115%

• none outside of 70% to 125% of label claim

• additional testing required if they are outside

Capsule labeling requirement

quantity of each active ingredient in each dosage unit

Capsule stability testing

• intrinsic stability of active drug molecule

• environmental factors: temperature, humidity, light, formulative, components, and container and closure system

Capsule BUD

• USP 795

• 6 months if prepared from USP/NF ingredients

• 25% of remaining expiration dating if prepared from commercial products

  • unless evidence available to support other dating

Capsule packaging/storage

room temp (generally, determined by API)

Capsule patient counseling

• capsules 0-5 are not difficult to swalloe

• larger capsules: use syrup, honey, liquid candy to help patient swallow

• caution when emptying contents to food, etc

Capsule administration

• place on tongue and swallow with liquid

• dissolve contents in water or mix contents with food