Capsules and Tablets

Dispensing (both repackaging and compounding)

different size multi-dose capsule vials (exp date of 1 yr) specially designed unit-dose packaging ("blister packs") (exp date of 1 yr) med packs -> exp date or 60 days

Compressed tablets

easier to manufacture than caps (up to 10,000 per min) influences tablet shape, size, and markings

hard capsule filling method - non aqueous liquids/semi solids

filled into the capsule body using a dropper or syringe locking capsules such as SNAP-FIT should be used alternatively the inner edge of the cap may be slightly hoisted with water before closing

Capsule shell excipients: colorants

gelatin and gelatin substitutes are typically clear and colorless next 2 are primarily pharmaceutical elegance natural colorants and synthetic FD&C and FD dyes and lakes (e.g. ferric oxide and FD&C Red no.3) are frequently used to add color opacifiers (e.g. titanium oxide) are commonly used to make capsules shells opaque

Miscellaneous fills

granules/pellets/beads small volume of non-aqueous liquids or semi-solids may be combined with inert powders or mixed with high MW melted (hardens at RT) polyethylene glycol and filled into the capsule large volumes of non-aqueous liquids or semi-solids may be filled directly into locking or sealed capsules small tablets or capsules to 1) separate incompatible ingredients 2) add remeasured amounts of potent drugs 3) blind competitor products during clinical trails

special hard capsules shells: snap-fit and coni-snap

grooves are made in booth the capsule body and cap to lock the capsules (minimize tampering and content loss but not easy to open for administration or compounding

capsule shell preparation methods

hard capsule shells pin bar mold pin (determines shapes/size) melted shell mixture soft capsule shells drug added / liquid or semi solid shell ribbons ribbons are fused and capsules cut out *for soft capsules, both shell preparation and filling occur in the same process

hard capsule shell sizes

hard capsule shells for human use are typically available in sizes 000 to 5 easy to prepare vs easier to swallow size 0,1,2 are most commonly used for oral administration size 000 may be used for rectal or vaginal administration

Capsule shell excipients: water

hard shells contain 13-16% and soft shells typically contain an even higher percentage (introduces some stability concerns)

Molded Tablets/ Tablet triturates (primary compounding)

the powder formulation is hoisted with a small amount of water(binder):ethanol(quicker drying) mixture (50:50) the damp mass is pressed into a calibrated mold using a spatula in order to form the tablets damp tablets are carefully removed and allowed to dry however the resulting tablets are often "soft" (little compression pressure) and rapidly disintegrate (increase in dC/dt)

hard capsule filling method - punch method

the powder formulation is triturated until uniform the uniform powder formulation is compressed into a flat bed of uniform thickness using a spatula the capsule body is repeatedly pushed into the compressed powder bed until it "feels" full powder is similarly added or removed until the appropriate weight is achieved

capsule fills: excipients - lubricants

to decrease the cohesion between the powder formulation and the capsule filling machinery (e.g. stearic acid and magnesium stearate)

Tablet preparation: excipients - lubricants

to decrease the cohesion between the powder formulation and the tablet filling machinery

Tablet preparation: excipients - glidants

to ensure that the powder formulation flows freely and uniformly

capsule fills: excipients - glidants

to ensure that the powder formulation flows freely and uniformly

Tablet preparation: excipients - diluents

to increase the bulk of the formulation and provide cohesion/compressibility which ensures proper tablet formation

capsule fills: excipients - diluents

to increase the bulk of the formulation and provide cohesion/compressibility, which ensures proper filling of the capsule

Tablet preparation: excipients - flavors, sweetners, and colorants

to mask taste and improve pharmaceutical elegance

capsule fills: excipients - binders

to promote particle adhesion within the powder formulation and improve compressibility

Tablet preparation: excipients - binders

to promote particle adhesion within the powder formulation which is critical for maintaining tablet integrity

Administration: Patient dosing

unit dosage form convenient and accurate administration -no need for patient to measure the dose -also, can be easily identifiable and very elegant limited dosing flexibility -size limitation based upon route of administration -fractional dosing difficult (tablet splitting can be done, but with caution)

Common types of coatings - compression coating

a powder coating is compressed around the tablet does not require any water or organic solvents, able to apply a thin and uniform coating, and enables alterations in dissolution characteristics but, a major limitation is the requirement of more specialized equipment

Capsule shell excipients: gelatin

a protein obtained by partially hydrolyzing collagen from the skin, cognitive tissue, and bones of animals most common material used to prepare capsule shells ideal since it is solid at room temperature but rapidly melts and dissolves after administration and is easily hydrolyzed (primarily amide bonds) by digestive enzymes and an acidic pH gelatin substitutes (potential needs) include starch and hydroxypropylmethylcellulose

hard capsule filling method - hand operated capsule filling machines

can fill ~24-300 capsules at once and ~200 to 2000 capsules per hour uniformity is highly dependent upon flow, therefore, diluents have a good flow (e.g. anhydrous lactose and microcrystalline cellulose) and/or glints should be used (especially since not all capsules are individually weighted)

special hard capsule shells: cone-snap supro

capsule cap is longer than a conventional capsule

elastic deformation

causes powder particles to fracture, which decreases tablet integrity

Special hard capsule shells - pulvules

closed end of the capsule is tapered (easier swallowing?)

Administration: Route of administration - Vaginal/Rectal

Possible advantages over suppositories (described based on preparation vs. administration) -easier to mass product -less stability issues -more convenient administration

Tablets

Solid dosage forms containing medicinal substances with or without suitable diluents, and classified as either compressed or molded

Capsules

Solid dosage forms in which the drug is enclosed within a hard or soft soluble container or "shell"

Performance - Tablet hardness and friability (chipping)

Tablets must be 1) hard enough to resist damage during transport and storage but 2) soft enough to disintegrate and release their active ingredients dependence (increasing each increases hardness) -powder compressibility -amount of binders in the powder formulation (hardness may also increase over time as the binder becomes more effective) -compression pressures used during tableting Tablets must break apart and disintegrate to release their active ingredients; however, capsule shells simply need to dissolve to release their contents, which are minimally compressed Therefore, capsules generally result in quicker dissolution rates (may quicken onset and increase amount absorbed), particularly soft shells which typically contain liquids

Tablet coatings - potential advantages

-Decreased damage during transport & maintenance of tablet integrity -Improved product stability during storage Protection of "handlers" from toxic ingredients -Improved pharmaceutical elegance & product identity -Masking of taste & odor -Smoother surface / easier to swallow -Provide modified-release mechanisms

Performance - Excipients (used to increase dC/dt after administration)

-Disintegrants to overcome any substantial cohesion (esp. tablets; also help offset the effect of binders) of the powder formulation (e.g. pregelatinized starch, croscarmellose, and sodium starch glycolate) -Surfactants(also help offset the effects of lubricants, which are typically hydrophobic, and therefore decrease dC/dt) to facilitate wetting of the powder formulation (e.g. sodium lauryl sulfate) -Alloying substances to provide water solubility and permeability, especially to non-hydrophilic coatings (e.g. polyethylene glycol) -Effervescent agents to increase disintegration & dissolution rates

some products may disintegrate/dissolve in the mouth

-typically without additional water (added convenience and accuracy) -drug may be absorbed through the oral mucosa (quicker onset and avoids first-pass) ex. sublingual

Performance - special tablets

1. Chewable: requires a low hardness to allow for chewing (increases SA -> increases dC/dt) dilantin infatabs have a slightly onset of action than dilantin kapseals 2. dispersible: typically have a low hardness as well since a fast dC/dt is desired 3. Orally disintegrating/dissolving: prepared with very water-soluble ingredients (often hygroscopic) and have a very low hardness therefore, require a special packing (often individual blister packs) to prevent breakage and water exposure

Capsule Preparation: Capsule shells

Hard capsule shells -typically oblong in shape -two pieces (cap and body) soft capsules shells -multiple shapes -single enclosed system

Common types of coatings - film coatings

Thin, smooth coating of a polymer material Most common type of coating Quicker to apply than sugar or gelatin coatings, No significant increase in product size, The polymer material is flexible and therefore highly resistant to damage, And enables alterations in dissolution characteristics But, the excipients are more complex: -film former or polymer material to provide the base of the coating (e.g. cellulose acetate phthalate [hydrophobic] and hydroxypropyl methyl cellulose [hydrophilic]) -plasticizer to provide coating flexibility (e.g. castor oil [hydrophobic], glycerin, and polyethylene glycol [hydrophilic both]) - Surfactants or wetting agents to decrease surface tension, which ensures a thin, uniform coating (e.g. polysorbate 80) - Anti-foaming agents to ensure a smooth coating (e.g. simethicone emulsion) - Colorants, Flavors, Sweeteners, Glossants(polished surface) (e.g. carnuba and candelilla wax) to ensure pharmaceutical elegance -solvents to dissolve the coating ingredients and enable application (e.g. water [extended drying time/ stability concerns], alcohol-acetone [safety, environmental, and coat issues])

USP preparation requirements - content uniformity

active ingredient content is determined using an "official" assay method required for 1) uncoated tablets and hard capsules having at least one dosage strength < 50mg and 2) all coated tablets (coating weight may vary) general requirement most units within 75%-125% all within 65-135% of labeled claim

plastic deformation

allows powder particles to deform around each other, which increases tablet integrity

USP preparation requirements - weight variation

assumes homogeneous mixing, so the active ingredient content is based upon formulation may be used in place of content uniformity for 1) uncoated tablets and hard capsules if the dosage unit contains >50mg of drug comprising >50% of the total weight may be used for all soft capsules (better assumption w liquid and semi solid fills) general requirement most units within 85%-115% all within 75-125% of labeled claim

hard capsule filling method - pharmaceutical manufacturers use ____________ that may fill up to __________________ per hour (coni snap)

automated machinery, 165000 capsules

hard capsule filling method - hard capsule sealing

banding seals the capsule cap and body with a band of gelatin or gelatin substitute (similar to locking capsules) heat welding. seals the capsule cap and body by applying heat at a small spot to melt and fuse the two halves

special hard capsules shells - spansules

both closed ends of the capsule shell are tapered

Administration: Route of administration - Oral

by far the most common route of administration typically swallowed whole with a glass of water -easy to mask taste (no/little contact with taste buds) -but may be difficult to swallow (tablets typically more so than capsules) -and might lodge in the esophagus (may result in irritation/ulceration) some products are designed to be chewed some products are to be mixed with beverages (potential convenience and accuracy issues)

Capsule shell excipients: plasticizers

increase flexibility to enable preparation of soft capsule shells (enables multiple shapes) also creates a smoother and shinier shell surface (easier to swallow, increased pharmaceutical elegance) examples include polyethylene glycol and glycerin

ultimately a loss of tablet integrity typically displays itself in one of the following ways

lamination - striations on the tablet surface capping - top of the tablet separates from the rest of the tablet

Stability

little/no water present and limited exposure to environment (USP compounded DNUB dates - solid [6 mon/25% rule] - liquid filled capsules (intended for duration of use or 30 days)) However, capsule shells (especially soft shells) 1) contain some water and 2) may absorb more water from humid environments also causing them to become sticky and distorted (store in dry environments/may use desiccants) Antioxidants (e.g. citric acid) and preservatives (e.g. sodium benzoate and methylparaben) may also be included within the capsule shell and/or the powder fill formulation Conversely, capsule shells may lose excessive water to very dry environments causing them to become brittle However, the plasticizers within soft capsule shells often act as humectants, which minimizes water loss from these shells

Common types of coatings - sugar coating

multi-step process done within a series of rotating coating pans and with a stream of warm air to dry the tablets between each coating sucrose improves taste and is very water soluble (no effect on dC/dt) but, coating is tedious and time-consuming, highly variable, may not be used with water-sensitive ingredients (coating solution is aqueous) offers little resistance to damage (sucrose has a low yield stress) and causes a significant increase in tablet size (swallowing more difficult)

Common types of coatings - gelatin coating

tablets are 1) often capsule shaped (i.e. caplets) and 2) dipped into a melted gelatin mixture combines the shape and "slicker" surface of capsules with the greater compression of tablets (swallowing made less difficult, but coating causes a moderate increase in size) also more tamper/loss resistant than capsules and no effect upon dC/dt but may not be used with water sensitive ingredients

chewable, dispersible, and orally disintegrating tablets do overcome swallowing concerns but

taste masking becomes more difficult still a choking hazard for <4 yr old