Dosage Forms: Exam 3- Solids (Oral)

Discuss the advantages of powdered dosage forms

POWDERS

• Advantages

  • Absorbed more rapidly than tablets or capsules

  • Easy to give large doses

    • As compared to a tablet with 1 g of active ingredient plus excipients

  • Easier to swallow than tablets or capsules

  • More chemically stable than liquids or preparations

Discuss the disadvantages of powdered dosage forms

POWDERS

• Disadvantages

  • Can’t mask unpleasant taste or odors

  • Inconvenient to handle

  • Can be expensive to manufacture

    • Powders have explosion risk—> may need special handling equipment

  • Dose inaccuracy (bulk powders)

  • Problematic if drugs is hygroscopic or deliquescent

Methods of blending powders: Spatulation

BLENDING POWDERS

• Spatulation

  • Mixing 2 or more powders together with a spatula

  • Not suitable for large quantities

    • Why?

  • Very little compaction or compression results from this method

  • Homogenous blending is not as certain

  • Especially good for eutectic mixtures

Methods of blending powders: Trituration

BLENDING POWDERS

• Trituration

  • Powders are mixed using mortar and pestle

  • Results in:

    • Blending

    • Particle size reduction

    • Reduced powder bulkiness (with heavy trituration)

  • Choice of mortar

    • Blending only: glass
      Blending and size reduction: porcelain or Wedgwood

Methods of blending powders: Geometric dilution

BLENDING POWDERS

• Geometric dilution

  • Very useful for achieving a uniform distribution of potent drugs

    • Start with the ingredient present in the smallest amount

    • Add additional ingredients in order of quantity required by approximately doubling the portion being mixed with each addition

Methods of blending powders: Sifting

BLENDING POWDERS

• Sifting

  • Mixing by passing through a sifter (sieve)

  • Useful when powders are in the same particle size range

    • Otherwise, stratification will result

Methods of blending powders: Tumbling

BLENDING POWDERS

• Tumbling

  • Mixing by placing powders in a large container that rotates

Describe methods of granule preparation discussed in class.

GRANULE PREPARATION

• Two types of granulation

  • Wet

  • Dry

• For both types, first steps are:

  • Weigh all materials

  • Blend powders to make a uniform mixture

Identify the steps involved in: Wet granulation

• Weigh all materials

• Blend powders to make a uniform mixture

• Moisten the desired powder or blended powder mixture

• Mix

• Pass dough through screen of appropriate mesh size to produce the desired particle size range

• Air dry or use heat

Identify the steps involved in: Dry granulation

• Weigh all materials

• Blend powders to make a uniform mixture

• Compact

  • Roller compaction: form ribbons of compressed material

  • Slugging: form oversized tablets

• Size by grinding compacted material (ribbons or slugs)

Describe methods of granule preparation discussed in class: Wet granulation

WET GRANULATION

• Water is most frequently used solvent

  • Relatively inexpensive

  • Limited ecological impact

  • Non-flammable

  • Disadvantages:

    • Takes longer to dry:

      • Potential problems with heat-sensitive drugs

    • Causes hydrolysis in susceptible products

• Organic solvents sometimes used

  • During processing of water-sensitive drugs

  • When short drying time is needed

  • Disadvantages

    • Flammable—> expensive safety precautions are needed

    • Solvents/solvent potentially harmful to workers, environment

    • Expensive

Describe methods of granule preparation discussed in class: Dry graunulation

DRY GRANULATION

• Powder particles are aggregated under high-pressure

• Used primarily with drugs that:

  • Are moisture sensitive

  • Do not compress well after wet granulation

• Done by

  • Slugging

  • Roller compaction

Explain how granules differ from powders

GRANULES

• Prepared agglomerates of smaller particles

  • In general, irregular in shape

  • Behave as single particles

  • Size ranges 2-4 mm (sieve #4-12)

  • Uses:

    • As a dosage form in itself

    • As intermediate step in the process of tableting

Explain why granules are preferred to powders in pharmaceutical processing. (e.g. density is increased, dust is reduced or eliminated)

ADVANTAGES OF GRANULATION

• Granules flow better than powders

• More stable than powders

• More easily wetted by solvent

• Higher density

  • Occupy less volume per weight—> more convenient storage and shipping

• Larger particle size

• Prevents individual powder ingredients from segregating

• lead to elimination of dust

  • With toxic materials, leads to decreased risk of toxic dust

  • Less powder explosion risk

• Improves compression properties of powder blend

Discuss the advantages of capsules as a dosage form

CAPSULES AS A DOSAGE FORM

• Advantages

  • Dose accuracy

  • Easy to administer

  • Dosage flexibility

  • Ability to include combinations of drugs

  • Ability to mask unpleasant tastes and odors

  • Moore chemically stable than liquid preparations

  • Drugs with poor compressibility can be filled into a capsule

Discuss the disadvantages of capsules as a dosage form

CAPSULES AS A DOSAGE FORM

• Disadvantages

  • Sensitive to moisture

    • Loss of moisture to environment or hygroscopic capsule contents can make the capsule brittle

    • Absorption of moisture from environment can make the capsule sticky

  • Cross-linking of reactive aldehyde groups with gelatin

  • Not suitable for aqueous and alcoholic preparations

    • These solvents can dissolve the capsule shell unless the formulation is extensively revised

List and describe the purpose of the components of a capsule shell

CAPSULES

• An edible package made from gelatin or other suitable material which is filled with drug and excipients

  • Produces a unit dosage, mainly for oral use

  • From the Latin capsula, meaning a small box

Identify what types of ingredients can be incorporated into hard capsules

HARD GELATIN CAPSULES

• Composition of capsule shell:

  • Gelatin

    • Source of collage

  • Plasticizers: increase flexibility of the shell

  • Water

  • Coloring agents

  • Opaquants

  • Sometimes include:

    • Flavoring agents

    • Sweeteners

• Composition of powder content mixture:

  • Active ingredients

  • Diluent

  • Lubricants or glidants

  • Wetting agents

• HGC can also be filled with:

  • Granules

  • Pellets

  • Non-aqueous liquids

  • Semi-solids

Describe situations when an alternative to gelatin would be useful in a hard capsule shell.

NON-GELATIN CAPSULES

• Reasons for alternative shells

  • Gelatin is unsuitable for certain populations

    • Strict vegetarians

    • Those with religious or cultural restrictions

      • Why?

    • Those with food allergies (alternatively shells typically dairy, corn, and wheat free)

  • Some drugs react with gelatin

    • HPMC is inert

  • HPMC has lower moisture content than gelatin

    • Prevents hydrolysis of extremely moisture-sensitive drugs from the moisture in the capsule shell

LICAPS

• 2-piece hard capsules

  • Specially designed for secure containment of liquids and semi-solids

  • Uses Fusion Technology for sealing

  • Vegetarian: Kosher and Halal certified

    • HPMC based

  • Free of gluten and other allergens

  • At this point, appear to be used only in the vitamin or supplement industry

• Advantages

  • No plasticizers or preservatives

  • Reduced changes for drug oxidation

  • Dual release is possible:

    • Capsule in capsule

    • Pellets dispersed in an immediate-release liquid formulation

    • Allows for isolation of incompatible actives until delivery

Describe situations in which a soft gelatin capsule would be useful

SOFT GELATIN CAPSULES

• Available in different shapes

• Useful when:

  • Active ingredient is liquid

  • Active ingredient is suspended or dissolved in liquid vehicle

  • Active ingredient or formulation is semisolid

Identify what types of ingredients can be incorporated into soft gelatin capsules

SOFT GELATIN CAPSULES

• Liquids that may be contained in soft gelatin capsules:

  • Oil

  • Non-aqueous, water-miscible liquids such as PEG 400

• Liquids that may NOT be contained in soft gelatin capsules without extensive reformulation

  • Water

  • Alcohol

• Composition of capsule shell:

  • Gelatin or other suitable material

    • Plant cellulose

    • HPMC

  • Glycerin of polyhydric alcohols (such as sorbitol)

Identify what excipient functions may be included in capsule formulations

SOFT GELATIN CAPSULES

• One-step manufacturing process

  • Liquid would escape from shell if done in multiple steps

Discuss the advantages of tablets as a dosage form

TABLETS

• Advantages

  • Dose accuracy

  • Easy to administer

  • Rapid and reasonably inexpensive production

  • More chemically stable than liquid dosage forms

  • Easy to mask unpleasant tastes and odors

  • May be colored, flavored, imprinted

Discuss the disadvantages of tablets as a dosage form

TABLETS

• Disadvantages

  • Some drugs are not compressible—> can’t formulate

  • If coating is required, processing is more expensive

  • Some patients may have difficulty in swallowing

Recognize and describe the unique properties of the various types of tablets discussed in class: Immediate release tablets

IMMEDIATE RELEASE TABLETS

• Regular tablets that, when administered orally, disintegrate in the stomach and release drug for absorption

• Can be prepared using different technologies

  • Single compression

  • Multi compression

Recognize and describe the unique properties of the various types of tablets discussed in class: Compressed tablets

COMPRESSED TABLETS

• Requires only a single compression step

• Wide variety of shapes possible

Recognize and describe the unique properties of the various types of tablets discussed in class: Multi-compressed tablets

MULTI COMPRESSED TABLETS

• Require more than one compression step

• Require special machinery

• Can be used to prepare modified release products

• Allows incompatible layers of drug to be separated

• Types of multi-compressed tablets

  • Multiple-layer tablets:

    • Compress additional granulation onto a previously compressed layer

      • Layer

        • Immediate release or sustained release

        • Drug A or drug

Recognize and describe the unique properties of the various types of tablets discussed in class: Types of multi-compressed tablets

TYPES OF MULTI COMPRESSED TABLETS

• Multiple-layer tablets:

  • compress additional granulation onto a previously compressed layer

  • Layers

    • Immediate release or sustained release

    • Drug A or drug B

• Press-coated tablets:

  • Compress another granulation layer around the entire compressed table

  • Tablet within tablet

Recognize and describe the unique properties of the various types of tablets discussed in class: Sugar-coated tablets

SUGAR-COATED TABLETS

• Coating is water-soluble

• Coating:

  • Protects from humidity

  • Improves taste

    • Taste masking

    • Sweet taste of coating istelf

  • Enhances appearance

  • Coating is usually thick, adds size

    • Premarin (conjugated estrogens): thin coating

Recognize and describe the unique properties of the various types of tablets discussed in class: Film coated tablets

FILM-COATED TABLETS

• Coated with polymeric film

  • May be water-soluble or water-insoluble

  • Thin

  • Provides taste masking

  • Improve stability of the drug

Recognize and describe the unique properties of the various types of tablets discussed in class: Enteric-coated tablets

ENTERIC-COATED TABLETS

• Coated with polymeric film that resists disruption in the stomach

• Drug is released in the intestine

• Example

  • Enteric-coated aspirin
    

Recognize and describe the unique properties of the various types of tablets discussed in class: Sublingual tablets

SUBLINGUAL TABLETS

• Flat, oval tablets

• Dissolve under the tongue

• Absorbed through the oral mucosa

• Erode quickly

• Rapid drug absorption

Recognize and describe the unique properties of the various types of tablets discussed in class: Buccal tablets

BUCCAL TABLETS

• Flat, oval tablets

• Placed in buccal cavity (between the cheek and gum)

• Dissolves in the buccal region

• Absorbed through oral mucosa

• Typically erode and release drug more slowly than sublingual

• Example:

  • Fentora (fentanyl citrate buccal tablet)

Recognize and describe the unique properties of the various types of tablets discussed in class: Mucoadhesive buccal tablets

MUCOADHESIVE BUCCAL TABLETS

• Formulated from materials that adhere to mucous membranes

  • Allows product to remain in place for an extended period

• Example:

  • Oravig (miconazole buccal tablet)

  • Instructions: tablet should be placed against the upper gum just about the incisor tooth and held in place with slight pressure over the upper lip for 30 seconds to ensure adhesion

  • Dissolves in buccal region

    • Locally treats oropharyngeal candidiasis

  • erodes and release drug slowly

Recognize and describe the unique properties of the various types of tablets discussed in class: Effervescent tablets

EFFERVESCENT TABLETS

• Compressed granular effervescent salts

• Contain drug which dissolves rapidly after adding water

  • Formulation has both dry acid and base components

  • Dissolve and react to produce effervescence (CO2)

    • Helps in taste making

    • Rapid action is possible

  • Example

    • Alka Seltzer products

Recognize and describe the unique properties of the various types of tablets discussed in class: Chewable tablets

CHEWABLE TABLETS

• Disintegrate rapidly when chewed

• Creamy, flavored base

  • Usually mannitol

• Useful for:

  • Children

  • Adults who have difficulty swallowing

Recognize and describe the unique properties of the various types of tablets discussed in class: Rapid-dissolve tablets

RAPID-DISSOLVE TABLETS

• Formulated to have pleasant taste and mouth feel

• Do not require chewing

• Disintegrate within 45 seconds when placed in mouth

• Dissolved tablet than swallowed

  • Oral, not sublingual or buccal product

• Useful for:

  • Children

  • Adults who have difficulty swallowing

  • Situations in which water is not readily available

  • Ensuring medication compliance (psychiatric patients)

Recognize and describe the unique properties of the various types of tablets discussed in class: Tablet triturates

TABLET TRITURATES

• One historical example

  • Mercury bichloride tablets

    • Dissolved in water to be used as an external antiseptic

    • Other poisonous substances were also provided as tablet triturates

      • Arsenic

      • Atropine

• Hypodermic tablets

  • Subset of tablet triturates

  • Physicians used during house calls if needed an injectable solution

  • Resulting solutions were not sterile

Recognize and describe the unique properties of the various types of tablets discussed in class: Modified release tablets

MODIFIED RELEASE TABLETS

• Any tablet in which drug release is modified as compared to an immediate-release product

• Categorized into

  • Delayed release

  • Sustained release

  • Controlled or extended release

List and describe the function of the components present in a tablet (active ingredient, diluent, etc) given an ingredient list.

TABLET COMPOSITION

• May or may not have all of the following excipients

  • Depends on:

    • Properties of active ingredients

    • Intended use

  • These excipients may be found in capsule formulations also

• Common Tablet Components

  • Active ingredient

  • Diluent

  • Granulating agent

  • Disintegrant

  • Lubricant

  • Glidant

  • Coloring agents

  • Flavors

  • Opacifying agents

  • Coating agents

Define the following excipient functions in tablets. Identify which of these excipient functions are also found in capsules: Diluent (tablet or capsule)

DILLUENT (TABLET OR CAPSULE)

• Inert filler used to create

  • Desired bulk

  • Flow properties

  • Compression characteristics needed for tablet or capsule manufacture

  • Must be compatible with the drug

Define the following excipient functions in tablets. Identify which of these excipient functions are also found in capsules: Direct compression diluents

DIRECT COMPRESSION DILUENTS

• Special case excipient

• Used in direct compression formulations to allow proper compression characteristics without adding a granulation step

Define the following excipient functions in tablets. Identify which of these excipient functions are also found in capsules: Chewable tablet diluents

CHEWABLE TABLET DILUENTS

• Special case excipient

• Must have good mouth feel and taste

  • Mannitol

  • Powdered sugar (sucrose)

Define the following excipient functions in tablets. Identify which of these excipient functions are also found in capsules: Granulating agents or binders

GRANULATING AGENTS OR BINDERS

• Used to cause adhesion of powder particles in tablet granulations

  • Impart cohesive properties to powder

Define the following excipient functions in tablets. Identify which of these excipient functions are also found in capsules: Tablet disintegrants

TABLET DISINTEGRANTS

• Allow tablet to break apart

  • Absorb water, and either swell or dissolve

  • Usually between 5-15% (w/w) of formulation

• Super-disintegrants

  • Effective @ low levels

  • 2-4% (w;w)

  • Cross-linked, so swell more effectively

Define the following excipient functions in tablets. Identify which of these excipient functions are also found in capsules: Lubricants

LUBRICANTS

• Three roles identified with lubricants- understand the differences:

  • True lubricant role

  • Anti-adherent role

  • Glidant role

• Substantial overlap between these roles; one excipient might serve more than one of the functions

Define the following excipient functions in tablets. Identify which of these excipient functions are also found in capsules: Lubricants- true lubricant role

LUBRICANTS: TRUE LUBRICANT ROLE

• Decrease friction at the interface between a tablet’s surface and the die wall during ejection

• Reduce wear on punches and dies

• Too much can “water-proof” the tablet→ poor disintegration; dissolution

  • What effect will this have on drug absorption?

Define the following excipient functions in tablets. Identify which of these excipient functions are also found in capsules: Lubricants- antiadherent role

LUBRICANTS: ANTIADHERENT ROLE

• Prevent powders or granules sticking to tablet punch faces, or capsule machine dosators, tamping pins, etc.

  • Similar and overlapping functions with true lubricants

Define the following excipient functions in tablets. Identify which of these excipient functions are also found in capsules: Lubricants- glidant role

LUBRICANTS: GLIDANT ROLE

• Improves flow properties of powder mixtures during capsule and tablet processing

  • Reduces friction between the particles

  • Pure glidants do not reduce die-wall friction

What might happen if too much lubricant is included in a capsule or tablet formulation? Too much granulating agent? Too much binder?

• Too much can “water-proof” the tablet→ poor disintegration; dissolution

List the steps in manufacturing tablets.

TABLET MANUFACTURING

• 3 Methods

  • Direct compression

  • Wet granulation

  • Dry granulation

List the steps in manufacturing tablets: Direct compression

DIRECT COMPRESSION

• Make tablets without making granules first

  • Ingredient must be compressible

  • If drug itself isn’t very compressible, large amounts of diluent must be used

• Steps:

  • Weigh raw materials

  • Mix raw materials

  • Compress mixture

List the steps in manufacturing tablets: Wet and dry granulations

WET AND DRY GRANULATIONS

• Granule formation discussed earlier in lecture packet

• Granules for tableting can be produced via wet or dry granulation

  • Wet granulation: granules sized by screening wet dough before drying

  • Dry granulation: granules sized by grinding compacted ribbons or slugs

• Once granules of the correct size have been produced

  • Add lubricant

  • Mix Compress

List the steps in manufacturing tablets: Compression

COMPRESSION

• Occurs in a tableting machine

• Single punch:

  • Not particularly large-scale production

    • Slow

    • Only produces one tablet per revolution

• Multi-station

  • Method used in industry

  • Rapidly produces large volumes of tablets

Describe the reasons for tablet coating

COATING AGENTS

• Protect the tablet from decomposition

• ALL coatings mask unpleasant taste, odor, or appearance

• Provide easier swallowing

• In some cases:

  • Control the site of drug release

  • Protect the drug from the gastric environment

  • Protect the gastric environment from the drug

  • Prolong drug release

  • Prevent interaction of incompatible ingredients

• Examples

  • Sugar coating

    • Liquid glucose

  • Film coating

    • Hydroxyethyl cellulose

    • Hypromellose

  • Enteric coating

    • Cellulose acetate phthalate

List the types of tablet coatings available and identify an appropriate type of coating for a specific problem or situation: Sugar coating

SUGAR COATING

• Tablet is coated with layers of sugar, color, and flavor

• Can double the size of a tablet

• Positives

  • Masks unpleasant tastes and odors

  • Produces a very attractive product

• Problems

  • Time consuming

  • Requires skilled personnel

  • Coating varies from batch to batch and sometimes within the batch

List the types of tablet coatings available and identify an appropriate type of coating for a specific problem or situation: Tablet polishing agent

TABLET POLISHING AGENT

• Used to impart an attractive sheen to sugar-coated tablets

  • Example

    • Carnauba wax

    • White wax

List the types of tablet coatings available and identify an appropriate type of coating for a specific problem or situation: Film coating

FILM COATING

• Tablet is coated with a thin layer or membrane of a plastic-like material

  • Forms a skin-tight coating of the material over the tablet

  • Coating solution can be aqueous or non-aqueous

  • Polymer=film former

• Mask unpleasant tastes and odors

List and describe the function of the components present in a tablet coating: Alloying substance

ALLOYING SUBSTANCE

• Component in film coatings

  • Provides water solubility or permeability to the film to ensure penetration by body fluids and therapeutic availability to the drug

List and describe the function of the components present in a tablet coating: Plasticizer

PLASTICIZER

• Component of film-coating solutions used to make fil more pliable, enhancing the spread of coating over tablets, beads, and granules

• Adds flexibility and durability to the film

• Example:

  • Diethyl phthalate

  • Glycerin

  • Triethyl citrate

List and describe the function of the components present in a tablet coating: Opaquant

OPAQUANT

• Used to render a coating opaque

• May be used alone or with a colorant

• Example:

  • Titanium dioxide

List and describe the function of the components present in a tablet coating: Film coating- additional components

FILM COATING: ADDITIONAL COMPONENTS

• Surfactants

  • Enhances spreadability of the film during application

• Sweeteners; flavors; aromas

  • Enhance patient acceptability

• Glossants

  • Provide luster

  • Do not require an additional polishing step

List and describe the function of the components present in a tablet coating: Enteric coating

ENTERIC COATING

• Type of film coating that permits a tablet (or capsule) to pass from the stomach to the intestine before it begins to integrate and dissolve

  • Resists breakdown in gastric fluid

  • Masks unpleasant tastes and odors (though not primary purpose)

  • Material used:

    • Polyvinyl alcohol (PVA) phthalate

    • Hydroxypropyl methylcellulose (HPMC) phthalate

    • Cellulose acid phthalate (CAP)

List and describe the function of the components present in a tablet coating: Sustained release coating

SUSTAINED RELEASE COATING

• Coating alters the release profiles of the active ingredient from the tablet

  • Release of drug is slow, but prolonged

  • Different types of polymers are used

  • Types depend on:

    • Release profile desired

    • Type of drug

List and describe the function of the components present in a tablet coating: Gelatin coated tablet

GELATIN COATED TABLET

• Gelatin used as a coating agent

  • Makes tablet appear like a capsule

  • Primarily used for aesthetic appeal

List and describe the function of the components present in a tablet coating: Tablet coatings- Given the same base tablet, would film coating or sugar coating lead to a larger final product? Why?

Compare and contrast soluble and lake dyes: Compare

COLORING AGENTS

• Improves aesthetic appeal

• Assists in product identification

  • Makes the appearance distinctive

• Masks color variation in ingredients (especially capsules and tablets)

• Examples:

  • Soluble dyes

  • Lake dyes

Compare and contrast soluble and lake dyes: Soluble dyes

SOLUBLE DYES

• Chemical compounds that exhibit their coloring power when dissolved in a solvent

• Synthetics are available in a wide range of shades or hues with higher coloring power than natural pigments

• Natural dyes less frequently used pharmaceutically, but are frequently seen in foods

• Can lead to problems during wet granulation

  • Soluble colors may migrate during drying step

  • If multiple colors are used, they might migrate at different rates

  • Uneven coloring (or mottling) results

  • Can be diminished by absorbing onto additives such as starch or talc

Compare and contrast soluble and lake dyes: Lake dyes

LAKE DYES

• Aluminum salts of FD&C water soluble dyes absorbed to alumina substrate

  • Available in 6 basic colors

    • Yellow, orange, pink-red, orange-red, green-blue, royal blue

    • Blends are available to provide more colors

• Insoluble and color by dispersion

  • Particle size is very critical to coloring capacity

  • Smaller particle size leads to increased surface area for reflected light

• Advantages

  • Because they are insoluble, the drying stages of processing may be performed more quickly

  • Opaque

    • Mottling is reduced

    • Overcoloring is not a problem; only 1 shade of color will result

    • Color is more reproducible

    • Full-color development requires fewer applications

      • Time savings

      • Lower raw material costs

Define the various tablet and film coating defects discussed in class

TABLET DEFECTS

• Capping

  • AKA splitting

  • Top of tablet separates from bottom

• Lamination

  • Separates into layers

• Picking

  • Small fragments of film flake from the tablet surface

• Peeling

  • Larger sections of film flake or peel from the tablet surface

Define the various tablet and film coating defects discussed in class: Orange peel effect

COATING DEFECTS

• Orange peel effect

  • Roughness of tablet surface

  • Contributing factors:

    • High atomization pressure and extended spray time

    • Coating droplets drying before they spread completely over the tablet surface

Define the various tablet and film coating defects discussed in class: Twinning and mottling

COATING DEFECTS

• Twinning

  • 2 or more tablets sticking together

  • Most common with capsule-shaped tablets

  • Due to slow pan speed or high spray rate

• Mottling

  • Uneven color distribution on tablet surface

Define the various tablet and film coating defects discussed in class: Bridging and infilling

COATING DEFECTS

• Bridging

  • Coating film contracts and lifts off the tablet surface, suspending across the score line or tablet logo

• Infilling

  • Score line or tablet logo is filled with coating

Define the various tablet and film coating defects discussed in class: Chipping and erosion

COATING DEFFECTS

• Chipping

  • Portion of coating and sometimes tablet chips off

  • Due to high pan speed, friable tablet core, or poor choice of plasticizer

• Erosion

  • Disfiguration of the core tablet when subjected to the coating solution for too long at at time

Define the various tablet and film coating defects discussed in class:

TABLET AND COATING DEFFECTS

• May require

  • Changes in excipients (in tablet or coating)

  • Different punch design

  • More robust tablet

  • Change in pan speed

  • Change in coating application speed

Explain why tablet hardness, friability, disintegration, and dissolution testing are used to assess quality in tablet manufacturing: Tablet hardness (breaking force)

• TABLET HARDNESS (BREAKING FORCE)

  • Force required to crush a tablet

    • Resistance to chipping, abrasion or breakage under conditions of coating, storage, transport and handling depends on this

    • Too hard —>

      • Tablet may not disintegrate or dissolve in specified time

    • Too soft —>

      • Tablet wont’ withstand handling

    • Load before fracture of common tablet types:

      • Oral: 4-10 kg

      • Chewable: 3 kg

      • Some sustained release: 10-20 kg

Explain why tablet hardness, friability, disintegration, and dissolution testing are used to assess quality in tablet manufacturing: Table friability

TABLET FRIABILITY

• Related to hardness

• Evaluates durability

  • Ability to withstand abrasion in handling, packaging and shipping

• Tablets are weighed and placed in tumbling device

  • Weighed before and after a specified # of rotations

  • Weight loss should not exceed 1%

Explain why tablet hardness, friability, disintegration, and dissolution testing are used to assess quality in tablet manufacturing: Disintegration time

DISINTEGRATION TIME

• A measure of the time required under a given set of circumstances for a group of tablets to disintegrate into particles

  • Placed into baskets with mesh at bottom

  • Agitated in a bath of suitable liquid

  • Particles must become small enough to go through the mesh

• Many USP monographs specify disintegration time

  • Less than 30 minutes for most tablets

  • Usually not required for capsules unless enteric coated

    • Why?

Explain why tablet hardness, friability, disintegration, and dissolution testing are used to assess quality in tablet manufacturing: Dissolution time

DISSOLUTION TIME

• Conducted to determine the amount of drug dissolved from the dosage form at certain time intervals

  • A drug must be present in solution to be fully absorbed

  • Disintegration DOES NOT imply dissolution

  • The dissolution of a drug from a dosage form is indicative of the availability of the drug for absorption in vivo

• Vessel contains dissolution medium

  • Usually simulated gastric or intestinal fluid

  • Stirred at a predetermined rate

  • Dosage unit must be submerged completely in the dissolution medium

• Different methods (most common*)

  • USP type 1 apparatus: basket*

    • Stainless steel cylindrical basket of 40-mesh cloth attached to shaft

    • Dosage unit is placed in the dry basket and submerged

    • Can be used with dosage units that float

      • More common with capsules

  • USP type 2 apparatus: paddle*

    • Paddle attached to shaft is used as stirring element

    • Dosage unit is allowed to sink to the bottom of the vessel before blade rotation begins

    • Dosage unit must not float

  • USP type 3 apparatus (FYI): reciprocating cylinder

  • USP type 4 apparatus (FYI): flow-through cell

Define rapid dissolve tablets

RAPID DISSOLVE TABLETS

• Frequently referred to as Oral Disintegrating Tablets (ODT)

• Disintegrate in the mouth within 30 seconds

• More convenient to carry and take than oral liquids

• FDA considers to be a new dosage form

  • Must get approval even if product is already on the market as a conventional release tablet

Advantages of rapid dissolve tablets

ADVANTAGES

• Good for patients that have issues with oral dosage forms

  • Elderly—> hand tremors, difficulty in swallowing

  • Very young—> difficulty in swallowing

  • Mentally challenged patients

  • Developmentally disabled patients

  • Uncooperative patients

  • Patients required reduced liquid intake

  • Patients experiencing “sudden attacks” that prevent easy swallowing

  • Animals

Disadvantages of rapid dissolve tablets

DISADVANTAGES

• Taste masking can be challenging for some drugs

  • Why?

• Friability

• Manufacturing costs

• Stability of the product

Define rapid dissolve films

RAPID DISSOLVE FILMS

• Thin film that incorporates the drug

• Disintegrates within seconds in contact with water or saliva

• Drug then swallowed or absorbed by buccal mucosa

• Contains:

  • Drug (1-25%)

  • Water-soluble polymers (40-50%)

  • Softener (0-20%)

  • Fillers (0-40%)

  • Flavors or sweeteners

• Potential uses:

  • Good for drugs requiring fast onset of action

    • Antiemetics

    • Migraine medication

    • Sleep medication

    • Opioid dependence (Suboxone)

  • Good for local treatment of oral cavity

  • Dissolves before sick child or uncooperative patient can spit out

Rapid dissolve films: Advantages

ADVANTAGES

• Very rapid dissolution

• Inexpensive to make

• Can theoretically be compounded

  • How do you think this would compare to the molded ODT compounds?

Rapid dissolve films: Disadvantages

DISADVANTAGES

• Poor taste masking, even for rapid dissolve products

• Low drug loading capacity

List and compare the methods of manufacturing rapid-dissolve products

RAPID DISSOLVE TECHNOLOGY

• Most products use one or more of the following processing technologies

  • Lyophilized foam

  • Compression

  • Sublimation

  • Candy-floss method

  • Spray-drying

  • Tablet molding

List and compare the methods of manufacturing rapid-dissolve products: Lyophilized form

LYOPHILIZED FORM

• Tablets are prepared by foaming a mixture of drug and excipients

  • Foam is poured into a mold

  • Product is then freeze-dried

  • Mold serves as a unit dose dispensing package

  • Resulting tablets have amorphous, porous structure

    • Similar in texture to meringue (but foamed texture of meringue set by heating, rather than by freeze-drying)

• Advantages

  • Extremely rapid dissolution

    • Within a few seconds of being placed on the tongue

• Disadvantages

  • Very soft

    • Packaging material must be peeled away, exposing the tablet

  • Relatively expensive

  • Time-consuming

  • May not be stable under enviornmental stresses (heat or humidity)

• Matrices used:

  • Usually gelatin or sugar-based excipients such as mannitol

  • May have improved stability if use:

    • At least 50% mannitol

    • 0.07-3.2% natural gum (acacia, guar, xanthan)

• Examples

  • Claritin, Reditabs (loratadine)

    • Seasonal allergies

  • Zofran ODT (ondansetron)

    • Brand name has been discontinued; generics available

    • Nausea and vomitting

List and compare the methods of manufacturing rapid-dissolve products: Compression

COMPRESSION

• Formulations contain

  • Super-disintegrant

  • Small amount of effervescent material

• MOA

  • Super-disintegrant pulls moisture into tablet

  • Effervescent material starts dissolving

  • Facilitates tablet breakup

• Tablets are a little thinner than standard tablets

  • Larger surface area exposed to saliva

  • Packaged in firm molded plastic package to prevent breakage

    • Tablets are thin and fragile

• Advantages

  • Rapid dissolution

    • 30-45 seconds

    • Not as fast as some methods

• Disadvantages

  • Water-insoluble disintegrants

    • Mouthfeel and swallowability issues

  • Effervescent materials are sensitive to moisture

    • Need protective packaging

• Examples

  • Triaminic soft chew- cough and cold

    • No longer available

  • Zomig-ZMT (zolmitriptan)- migraine

    • Brand names ODT has been discontinued; generics available

List and compare the methods of manufacturing rapid-dissolve products: Sublimination

SUBLIMINATION

• Volatile excipients are added to other tablet ingredients

  • Urethane

  • Urea

  • Ammonium carbonate

  • Ammonium bicarbonate

  • Benzoic acid

  • Phthalic acid

  • Naphthalene

  • Camphor

• Mixture is compressed into tablets

• Volatile materials are removed during the manufacturing process via sublimation

• Porous structure results

• Advantages

  • Exhibit good mechanical strength

  • makes porous tablet that allows quick water penetration

    • Quick disintegration

    • 10-20 seconds

• Disadvantages

  • Fragile formulation; needs proper packaging

List and compare the methods of manufacturing rapid-dissolve products: Candy floss method

CANDY FLOSS METHOD

• Not all sugar-based excipients have ideal characteristics for rapid-dissolve

  • Dissolution rates

  • Compressibility

  • Compactibility

• Use spinning machine to convert sorbitol or sucrose into candy floss

  • Improves above characteristics

  • Mill, blend, and compress

• Advantages

  • Can hold large amount of drug

    • EZ chew: 1000 mg

    • Flash dose: 600 mg

  • Potentially good taste masking ability

    • Very product-dependent

• Disadvantages

  • High processing temperature

    • Drug must be heat-stable

List and compare the methods of manufacturing rapid-dissolve products: Spray drying

SPRAY DRYING

• Solvent is evaporated rapidly

  • Can produce highly porous, fine powders

• Disintegrate within 20 seconds

• Formulations contain:

  • Support agents: gelatin

  • Bulking agents: mannitol

  • Super-disintegrants: sodium starch glycolate or croscarmellose sodium

  • pH adjusters to enhance disintegration or dissolution: citric acid or sodium bicarbonate

• Advantages

  • Forms highly porous powder

  • Dissolves rapidly

• Disadvantages

  • Use of solvent

  • Expensive technology

List and compare the methods of manufacturing rapid-dissolve products: Tablet molding

TABLET MOLDING

• Prepared using water-soluble ingredients

  • Tablet dissolves rapidly and quickly

• Less compact than compressed tablets

• Porous structure enhances dissolution

• Advantages

  • Rapid dissolution

  • Can be compounded

    • Do you forsee any problems with this?

• Disadvantages

  • Binding agent must be added to increase mechanical strength

    • Sucrose

    • Acacia

    • PVP

  • Poor taste masking abilities, even compared to other ODT types

Can Actiq (or generic equivalent) and Fentora be used interchangeably? Why or why not?

FENTANYL ACTIQ

• Brand name has been discontinued, but similar generics remain

• Appearance

  • Off-white lollipop

  • Large Rx symbol on stick

• Requires special packaging

  • Open with scissors

  • Reduces risk of accidental overdose by child (looks like candy)

• Absorbed via the buccal mucosa

• Provides almost instant relief

• Effects last only about 15 minutes

  • Typically long enough to relieve breakthrough pain

  • Patient can control rate of drug delivery

    • Remove and dispose of when pain relief is felt

FENTORA

• Fentanyl buccal tablet

• Onset in 15 minutes

• Provides pain relief for ~60 minutes

• Higher bioavailability than Actiq

  • F=0.65 (vs F=0.47)

  • Do NOT use interchangeably

Explain the mechanism by which Fentora has enhanced rate and extent of absorption.

FENTORA

• Uses OraVescent drug delivery technology

  • Effervescent reaction

  • Is thought to enhance rate and extent of buccal absorption

Define troches / lozenges / pastilles

TROCHES; LOZENGES; PASTILLES

• Solids containing the medicinal agent in a suitably flavored base

  • Intended to be slowly dissolved in the mouth

  • Usually for localized effect

  • Some may be chewable

  • Often made in the pharmacy

    • Melt the ingredients

    • Mix

    • Pout into molds

Define troches

TROCHES

• Technically only refers to compressed lozenges

• In practice, “troche” and “lozenge” are used interchangeably

Define pastilles

PASTILLES

• Softer texture

• Contain high percentage of sugar or a combination of gelatin and sugar

• Molded

• Slowly dissolved in mouth or chewed

Advantages of troches; lozenges; pastilles

ADVANTAGES

• Easy to give to patients who have difficulty swallowing

• Pleasant to taste

• Extends time drug is in contact with oral cavity

• Can prepare in pharmacy with minimal equipment

Disadvantages of troches; lozenges; pastilles

DISADVANTAGES

• Children may mistake for candy

• Ingredients must be heat stable

Describe what products troches; lozenges; pastilles are used for

USES

• Especially good for relief of minor sore throat pain and irritation

  • Cough drops

• Drug categories

  • Local anesthetics

  • Antibiotics; antibacterials

  • Analgesics