Name:

Pharmaceutical Dosage

Chapter 7: Capsules

Capsules and Tablets

Preferred when administered orally by adults: conveniently carried, readily identified, easily taken

Variety of dosage strengths, providing: Flexibility to the prescriber Accurate individualized dosage for the patient

Pharmaceutical Standpoints

Solid dosage forms: Manufactured efficiently and productively Packaged and shipped at lower cost and with less

breakage More stable Have longer shelf life than liquids

Disadvantages of Tablets and Capsules

Swallowing Formulation difficulties Some have poor bioavailability or poor water solubility Some have irritant effect on the GIT when taken orally

Key Features of a Good Tablet or Capsule

Stability of the active drug Accurate dose Uniformity (weight, amount of active ingredient, coating

thickness, etc) Consistent performance (manufacturing parameters,

pharmacokinetics) Appropriate disintegration and dissolution Can withstand packaging, shipping, handling without

breakage Masking of taste and odor Pharmaceutically elegant Production economically sound

Overview of Capsules

Capsules Medicinal agents and/or inert substances

enclosed in a small shell of gelatin Swallowed wholly

Open capsule or crushed tablets Mixed with food or drink (children or patients

who are unable to swallow solid dosage forms)

Solid Dosage Forms that must be Left Intact

Enteric coated tablets To pass through the stomach for drug release and

absorption in the intestine Extended-release dosage forms

Provide prolonged release of the medication Sublingual or buccal tablets

To dissolve under the tongue or in the mouth

Alternative Products if Patients cannot Swallow an Intact Solid Dosage Form

Chewable tablet Instant dissolving tablet Oral liquid Oral or nasal inhalation solution Suppository Injection

Characteristics

May be swallowed whole by patient May be inserted into the rectum for drug release and

absorption from site The content may be removed from the gelatin shell and

employed as pre measured medicinal powder, the capsule shell being use to contain a dose of the medicinal substance.

Ex: Theo-dur Sprinkle Elegance Ease of use Portability Tasteless shell to mask the unpleasant taste/ odor Permits physician to prescribe the exact medication needed

buy the patient Conveniently carried Readily identified Easily taken Tasteless when swallowed Commonly embossed or imprinted on their surface the

manufacturer’s name and product code readily identified Available in variety of dosage strength Provide flexibility to the prescriber and accurate

individualized dosage for the patient Packaged and shipped by manufacturers at lower cost, less

breakage than liquid forms More stable and longer shelf life

Hard Gelatin Capsules

Also referred to as “DFC” Dry Filled Capsule, manufactured into two sections, the capsule body and a shorter cap

Manufacture most of the commercially available medicated capsules

Employed in clinical drug trials For extemporaneous compounding of

prescriptions Contains 13% to 16% moisture Manufactured form:

Gelatin Titanium dioxide (opacifying agent) 0.15% SO2 (prevents decomposition of gelatin) Colorants

Empty Capsule Shells

Made of gelatin, sugar and water Hard or soft Softened (made elastic or plasticized) by adding glycerin or

polyhydric alcohol like sorbitol) Can be: clear, colorless, tasteless Colored with various FD&C and D&C dyes Made opaque by adding agents like titanium oxide

Gelatin

Obtained by partial hydrolysis of collagen from the skin, white connective tissue and bones of animals

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Properties: Stable in air (dry) Subject to microbial decompositions when

moistened Insoluble in cold water, softens through

absorption of up to 10 times its weight of water Soluble in hot water and in warm gastric fluid A protein, digested by proteolytic enzymes and

absorbed High humidity: additional moisture is absorbed

Becomes distorted and lose their rigid shape

Remedy: use desiccant material (silica gel, slay, or activated charcoal)

Extreme dryness: moisture is lost Becomes brittle and crumble when

handled

Gelatin Capsule

Dissolves and exposes its contents Unsuitable for aqueous liquids (softens gelatin and

distorted, resulting in leakage of contents)

Additives

Desiccant To protect against the absorption of atmospheric

moisture Dried silica gel Clay Activated charcoal

Diluents or filter To produce the proper capsules fill volume Provide cohesion to the powders For the transfer of the powder blend into the

capsule shells Lactose Microcrystalline cellulose Starch

Excipients Added for Capsule Fill

Wetting agents (Li2CO3) Added to capsule formulation to enhance drug

dissolution Absorbent

Separates interacting agents Absorbs any liquefied material that may form

Magnesium carbonate Kaolin or light MgO

Disintegrants To assist the break up and disintegration of the

capsule’s contents in the stomach Pregelatinized starch Croscarmellose Sodium starch glycolate

Lubricant or glidant Enhances flow properties

Silicon dioxide Magnesium stearate Stearic acid or talc (about 0.25-1%)

Surface active agent (surfactant) To facilitate wetting by GI fluids

Sodium lauryl sulfate

Fixed or Volatile Oils

Do not interfere with stability of the gelatin shells

Eutectic Mixture of Drugs

Mixtures of agents that have a propensity to liquefy when admixed

Methods to Track the Passage of Capsules and Tablets through the GIT to Map their Transit Time and Drug Release Patterns

Gamma scintigraphy Gamma ray emitting radiotracer incorporated into

the formulation with gamma camera coupled to a data recording system

Pharmacoscintographic evaluation IVIVC for bioavailability of immediate release

products Combination of scintigraphy and pharmacokinetic

studies Assesses integrity and transit of time of enteric

coated tablets through the stomach to the intestines

Drug and dosage form evaluation in new product development

Heidelberg capsule (No. 0 gelatin capsule) pH sensitive (non indigestible radio telemetric

device) A non-radioactive means to measure solid dosage

forms (fasting and non fasting human subjects) Gastric pH, gastric emptying time,

gastric residence time

Manufacture of Hard Gelatin Capsule Shells

Manufactured in 2 sections: Capsule body Shorter cap

Drug Absorption Depends on a Number of Factors

Solubility of the drug Type of product formulation (immediate release, modified

enteric) Gastrointestinal contents Physiologic character and response

Innovations to Provide Distinctions (Distinctive Looking Capsules)

Pulvules End of the body-producing peg is tapered while

leaving the cap-making peg rounded Spansule capsules

Capsules with the ends of both the bodies and caps highly tapered

Innovations in Capsule Shell Designs

Snap-fit Two halves of capsule shells positively joined

through locking grooves in the shell walls Ensure reliable closing of the filled capsule

Coni-snap Rim of the capsule body is tapered slightly, not

straight Reduces the risk of the capsule rims touching or

joining

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Eliminates splitting (telescoping) and/or denting of capsule shell

Coni-snap supro Rim is tapered, upper capsule part extends

(rounded edge of lower surface is visible) Opening is difficult, lower surface less gripping

to pull 2 halves apart Increases security of contents and integrity of the

capsule Eliminates splitting (telescoping) and/or denting

of capsule shell

***Check the book: coni-snap capsule parts, coni-snap and coni-snap supro capsule sizes (as in actual size of capsule in relation to a quart)

Capsule Sizes

000 15 grains 972mg (largest)00 10 grains 648mg0 7.5 grains 486mg1 5 grains 324mg2 4 grains 259mg3 3 grains 194mg4 2 grains 130mg5 1 grain 64.8mg (smallest)

Preparation of Filled Hard Gelatin Capsules

Formulation development and preparation and selection of capsule size

Filling the capsule shells Capsule sealing (optional) Cleaning and polishing of filled capsules

Examples of Fill in Hard Gelatin Capsules

Powder or granulate Pellet mixture Paste Capsule Tablet

Developing the Formulation and Selection of Capsule Size

Goals in preparing a capsule: Accurate dosage Good availability Ease of filling and production Stability Elegance

Dry Formulations

Blended thoroughly (active and inactive components) to ensure uniformity of powder mix for the fill

Care in Blending

Lack of homogeneity for low dose drugs Results in significant therapeutic consequences

Preformulation Studies

Determine whether all of the formulation’s bulk powders Effectively blended together Require reduction of particle size

Other processes to achieve homogeneity

Methods in Reducing Particle Size

Milling Particles ranging from 50-1000 micrometer

Micronization Drugs of lower dose or when smaller particles are

required Particles ranging from 1-20 micrometer

Filling Hard Capsule Shells

Use punch method Steps:

Count the capsules Powder encapsulated placed on a sheet of

clean paper or a glass or porcelain plate Powder mixed formed into a cake depth of

approximately ¼ to 1/3 the length of the capsule body

Empty capsule punched vertically into the powder cake until filled

Process of Capsule Filling

Milling or sieving of all ingredients Blending

Powder blender or empty capsules Capsule filler Capsule deduster or cleaner Capsule injection screen Capsule check-weighing system or reject Finished capsules Packaging

***Check book: profill system

Capsule Sealing

For the manufacturers: Sealing the joint between the 2 capsule parts

using: Colored band of gelatin (KAPSEALS,

Parker Davis) Heat welding process

o Fuses the capsule cap to the body through the double wall thickness at their juncture (distinctive “ring” around the capsule)

Liquid wetting agent (liquid sealing-water and ethanol sprayed around the seam area), followed by thermal bonding

Extemporaneouslyo Warm gelatin solution,

lightly coating the inner surface of the cap prior to placement on the filled capsule body

Cleaning and Polishing Capsules

Small scale By rubbing with a clean gauze or cloth

Large scale

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Cleaning vacuum affixed to the capsule-filling machines (removes any extraneous material) using Accela-Cota apparatus

Some Medications Commercially Prepared into Soft Gelatin Capsules

Acetazolamide: Diamox: Carbonic anhydrase inhibitor Cyclosporine: Sandimmune: Immunosuppressive Cyclosporine: Neoral: Immunosuppressive Digoxin: Lanoxicaps: Cardiac glycoside Ethosuximide: Zarontin: Anticonvulsant Ranitidine HCl: Zantac Geldose: Histamine H2 receptor

inhibitor

Preparation of Soft Gelatin Capsules

Plate process Uses set of molds to form capsules

Rotary die process Most commonly used Rotary die machine Liquid gelatin flowing from an overhead tank

into two continuous ribbons brought together between rotating die

More efficient and productive Results in bicolored capsules Very accurate filling (+/-1-3%)

Reciprocating die process Norton capsule machine

Similar to rotary die (gelatin ribbons are formed) Differs in encapsulating process

Produced, filled and sealed in a continuous operation

Accogel capsule machine Stern Machine Unlike the other fill dry powders into soft elastic

capsules Also use liquids or liquids and powders as fill Used to cover tablets with a gelatin film (geltabs) Variety of shapes, sizes, color possible

Utilization of Soft Gelatin Capsules

To contain a variety of liquid, pastry and dry fills

Uses of Soft Gelatin Capsules

Water-immiscible volatile and nonvolatile liquids Vegetable and aromatic oils, aromatic and

aliphatic hydrocarbons, chlorinated hydrocarbons, ethers, esters, alcohols and organic acids

Water-miscible nonvolatile liquids Polyethylene glycols and nonionic surface active

agents as polysorbate 80 Water-miscible and relatively nonvolatile compounds

Propylene glycol and isopropyl alcohol (depending on factors as concentration used and packaging conditions)

Soft Medications Commercially Prepared into Soft Gelatin Capsules

Acetazolamide: Diamox sequels: Carbonic anhydrase inhibitor

Cyclosporine: Sandimmune, Neoral: Immunosuppressive Ethosuximide: Zarontin: Anticonvulsant Ranitidine HCl: Zantac Geldose: Histamine H2 receptor

inhibitor

Liquids that cannot be Encapsulated into a Soft Gelatin Capsule

Easily migrate through capsule shell like materials with water above 5%

Low molecular weight Water soluble and water volatile organic compounds

(alcohols, ketones, acids, amine, and esters)

Solids that may be Encapsulated into a Soft Gelatin Capsule

Solutions in a suitable liquid solvent, suspensions, dry powders, granules, pellets or small tablets

Compendial Requirements for Capsules

Added substances may only be used: Harmless in the quantities used Do not exceed the minimum amount required to

provide their intended effect Do not impair the product’s bioavailability

therapeutic efficacy or safety Do not interfere with requisite compendial assays

and tests

Comparison Between Hard and Soft Capsules

Property Hard Capsule Soft Capsule

Shell Made of gelatin, sugar and powder

Gelatin, plasticizer (glycerin) or polyhydric alcohol (sorbitol) water and etc., colorants

Manufacturing processes

Shells produced separately from the fill

Continuous dipping, drying, removing and joining of capsules as peg containing plates rotate in and out of gelatin bath

Shells and fill made and combined on one and the same process line

By: plate process, rotary die process and reciprocating die process

Content Dry powders or granules, pellet mixture, paste, small capsule and tablets

Liquids and semi-liquids, suspensions, pasty materials, dry powders and

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preformed tablets

Formulation technology

13%-16% moisture content

Moisture proof packaging needed

Encapsulation using succinylated gelatin

More moisture Water content

of fill not more than 5%

Addition of titanium dioxides or iron oxides for light sensitive shells

Packed in aluminum blisters

Encapsulation uses succinylated, glycerol-free shell formulation, addition of PVP to the fill

Containers for dispensing capsules Tight Well-closed Light-resistant

In glass or plastic containers Some with packets of desiccant (prevents

absorption of excessive moisture) Unit dose and strip packaging of solid

dosage forms provides:o Sanitary handling of the

medicationso Ease of identificationo Security in accountability for

medications Disintegration test fop capsules

Uses basket rack assembly, immersed 30 times per minute into a thermostatically controlled fluid (37oC) and observed over the time described in the individual monograph

To satisfy the test, the capsules disintegrate completely into a soft mass having no palpably firm core and only some fragments of the gelatin shell

Dissolution test for capsules USP Apparatus I (stainless steel basket on a stirrer

shaft) and USP apparatus II ( using paddle as the stirrer): same apparatus for immediate release tablet

If the capsule shells interfere with the chemical analysis before proceeding with the sampling and chemical analysis: Contents of a specified number of capsules can

be removed Empty capsule shells dissolved in the dissolution

medium Weight variation

Hard Capsules Individual weight of 10 capsules – weight of

empty shells = net weight of performed assay for content of active ingredient according to monograph

Soft capsules

Same as above, cut open the capsule and the content is removed by dissolving with suitable solvent

Content uniformity Amount of active ingredient (determined by assay)

must be: Within 85% to 115%of the label claim for 9-

10 dosage units No unit outside the range of 70% to 125% of

label claim Additional test are needed when 2-3 dosage

units are outside of the desired range but within the stated extremes.

Weight variation and content uniformity: uniformity of dosage units can be determined

Content labeling requirement Express the quantity of each active ingredient in per

dosage unit Stability testing

Factors like temperature, humidity, light, formulative components and other container closure system using long term and accelerated stability tests

Moisture permeation test For single unit and unit-dose containers to assure

suitability for packaging Uses color revealing desiccant pellet for color change

and weight changes

Examples of some official capsules: Table 7.2: memorize

Inspection

Visual or electric inspection To detect any flaws in the integrity and appearance of

the capsules Defective caps should be rejected. CGMP regulations if number of production flaws is

excessive The cause must be investigated, documented and steps

undertaken to correct the problem.Counting

Community pharmacy Counting small numbers of solid dosage units:

specifically designed trays are used Spatula used to count and sweep the dosage units into

the trough until the desired number is reached Tray must be wiped clean after every use to prevent

batch-to-batch contamination Industrial scale

Use of automated pieces of equipment dosage units into bulk containers

Packaging

Caps are packaged in: Glass or in plastic containers Some containing packets of desiccant ( prevent

absorption of excessive moisture) Unit dose and strip packaging of solid dosage forms

Provides sanitary handling of the medications Ease of identification Security in accountability for medication

Storage

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Caps should be stored in tightly capped containers in a cool, dry place.

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