Comprehensive Study Notes – Capsules (Hard & Soft Gelatin)

INTRODUCTION TO CAPSULES

• Capsules = solid dosage forms in which drug is enclosed in a hard or soft soluble shell, usually gelatin.
• Name derived from Latin “capsula” = small container.
• Fill materials can be powders, liquids, semisolids; usually swallowed whole (oral), but rectal/vaginal use possible.

HISTORICAL MILESTONES

• 1730 – De Pauli (Vienna) developed oval capsules to mask turpentine taste (gout therapy).
• 1834 – Joseph Duplanc & Francois Mothes patented one-piece olive-shaped gelatin capsules closed with concentrated warm gelatin.
• 1846 – Jules Lehuby proposed two-piece capsules by dipping silver-coated metal pins into gelatin.
• 1931 – Colton designed a machine to mass-produce hard-gelatin caps & bodies.

ADVANTAGES OF CAPSULE DOSAGE FORM

• Tasteless, odorless, attractive; convenient to administer & carry.
• Enables combination of powders; masks unpleasant taste/odor.
• Dose & drug combination easily varied by prescriber.
• Economical; lower manufacturing breakage than liquids.
• Gelatin dissolves readily at gastric pH → rapid drug release.

DISADVANTAGES

• Unsuitable for liquids that dissolve gelatin (aqueous or hydro-alcoholic).
• Concentrated solutions requiring dilution may irritate stomach.
• Not ideal for efflorescent (soften shell) or deliquescent (brittle shell) drugs.

CAPSULE SIZES & SHAPES

• Largest human size: No. 000; smallest: No. 5 (veterinary sizes larger exist).
• Standard shape: symmetrical bullet.
• Size–volume–length reference:
• 000 → $1.37\,\text{mL},\;26.3\,\text{mm}$
• 00 → $0.95\,\text{mL},\;23.7\,\text{mm}$ … down to 5 → $0.15\,\text{mL},\;11.9\,\text{mm}$

RAW MATERIALS FOR CAPSULE PRODUCTION

• Gelatin (major component)
• Water $12\%-16\%$ (varies with storage RH)
• Sugar
• Colorants:
– Water-soluble dyes (e.g.
erythrosine)
– Pigments (e.g.
iron oxides, titanium dioxide)
• Sulfur dioxide $\le15\,\text{ppm}$ – antioxidant during manufacture.
• Preservatives (e.g.
parabens) against microbial growth.
• Excipients for fills: diluents (lactose, mannitol, sorbitol, starch), lubricants & glidants (talc, Mg/Ca stearate), wetting agent (sodium lauryl sulfate), disintegrants, anti-dusting oils.

GELATIN: SOURCE, PREPARATION & PROPERTIES

• Hydrolytic extract of animal collagen (bones, hides, pork skin).
• Key properties: non-toxic, soluble in body fluids, good film-former, mobile 40\%\;\text{w\/v} solutions at $50^{\circ}\text{C}$ , thermo-reversible sol⇌gel near room T.

Industrial Preparation

Type A (acid process, pI ≈ $9$ ) – mainly pork skin.
Type B (alkali process, pI ≈ $4.7$ ) – mainly bovine bones.
Flow: cleaning → acid/alkali conditioning → extraction at $50{-}60^{\circ}\text{C}$ in stages → filtration → evaporation → sterilization → drying (ribbon or tunnel) → blending → shipping.

Quality Parameters

• Bloom value (gel strength) $50{-}300$ ; ↑bloom → ↑gel strength.
• Viscosity: 6.67 % sol @ $60^{\circ}\text{C}$ , $20{-}70\,\text{mP·s}$ .
• Foamability: better for pig skin grades.
• Melting point: inverse to bloom; low-bloom types melt faster in mouth.
• Color/clarity (turbidimeter), no odor.
• Electrical conductivity critical for photographic grades.
• pH (1 % solution) $4.5{-}6.5$ .

TWO BROAD CAPSULE TYPES

• Hard Gelatin Capsules (HGC, “two-piece”, dry-filled).
• Soft Gelatin Capsules (SGC, “one-piece”, liquid\/semisolid filled).

HARD GELATIN CAPSULES (HGC)

Structure

• Two telescoping cylinders: longer body + shorter cap.

Empty-Shell Manufacturing (Industrial)

Dipping – stainless steel pins dipped in $\approx50^{\circ}\text{C}$ gelatin.
Spinning – rotate pins to distribute film & prevent beading.
Drying – cool air kilns drive evaporation to form rigid shells.
Stripping – bronze jaws remove shells from pins.
Trimming & Joining – knives cut to tolerance $\pm0.15\,\text{mm}$ ; cap & body re-joined.
Polishing – a) pan polishing, b) cloth dusting, c) brushing.
• Finished EMC $13\%-16\%$ ; store at RH $40\%-60\%$ .

Filling Methods

• Hand-operated or bench devices (200–300 holes): load → separate caps → fill powder → tamp → replace caps → lock.
• Punch (manual) – push body into powder cake repeatedly.
• Semi-/Automatic machines (e.g.
Osaka, Zanasi, Hofliger-Karg) follow steps:

Rectification (orientation)
Separation (vacuum splits cap\/body)
Filling (mechanisms below)
Cap replacement & locking
Ejection & cleaning (up to $1.6\times10^5$ caps\/8 h)

Filling Principles

• Auger fill – rotating auger meters powder into moving bodies.
• Vibratory fill – perforated plate vibrates to feed powder.
• Piston-tamp – pistons compress powder into slugs then insert; compression $50{-}200\,\text{N}$ .
• Dosator & dosing-disc variants; vacuum-fill for special powders.

Locking & Sealing

• Banding (colored gelatin band), moistening with warm gelatin, spot-welding, thermal welding $40{-}45^{\circ}\text{C}$ , or use of Coni-Snap® grooves for snap-fit.

Finishing & Sorting

• Polishing options (as above); Rotosort system handles $\approx1.5\times10^5$ cap\/h.

Storage & Stability

• EMC target $13{-}16\%$ ; brittleness < $12\%$ , softness > $18\%$ .
• QUALI-V® (HPMC) capsules available for moisture\/animal-free needs.

SOFT GELATIN CAPSULES (SGC)

Definition & Composition

• One-piece hermetically sealed soft shell containing liquid, suspension, or semisolid fill.
• Typical gel mass: gelatin $35{-}45\%$ , plasticizer (glycerin or sorbitol) $15{-}25\%$ , water $\sim40\%$ , dyes, pigments (e.g.
$\text{TiO}_2$ ), flavors, sugar (≤ 5 %).
• Plasticizer : gelatin (dry) ratio 0.3–1.8 controls hardness.
• Residual shell moisture $6{-}10\%$ .

Applications

• Oral dosage, suppositories, single-dose topical\/ophthalmic (tubes or aplicaps).

Advantages

• Encapsulate non-aqueous liquids; rapid bioavailability; elegant, portable, taste masking.
• Variety of shapes (round, oval, oblong, tube, miscellaneous), sizes from <200 mg to >1 g fill.
• Specialty designs: chewable, modified release, captabs.

Fill Vehicle Selection

Water-immiscible, low-volatility oils (vegetable, mineral, MCTs, acetylated glycerides).
Water-miscible, non-volatile PEGs (enhance dissolution).
• Must flow by gravity ≤ $35^{\circ}\text{C}$ ; gelatin sealing temp $37{-}40^{\circ}\text{C}$ .
• Emulsions avoided (water separates → shell failure).

Manufacturing Methods

Plate process – two gelatin sheets, vacuum draw, fill pockets, second sheet, press-seal & cut.
Rotary-die (R.P.
Scherer) – continuous ribbons form, wedge injects fill, opposing dies seal & cut; simultaneous formation & fill; most common.
Accogel – for powder fills/tablet in capsule: measuring roll → die roll → sealing roll.
Reciprocating-die – vertical ribbons, fills injected between dies traveling up & down.

COMPARISON: HARD vs SOFT GELATIN CAPSULES

Hard (HGC)
• 4–5× less gelatin; only gelatin + water shell (no plasticizer).
• Separate manufacture & filling; can fill two formulations sequentially (two-stage release).
• Heat-resistant (fill materials ≤ $75^{\circ}\text{C}$ ); stable in hot climates.
• Thinner wall → faster disintegration; minimal product migration.
• Fixed external dimensions → easier packaging.
Soft (SGC)
• Need 4–5× more gelatin + plasticizer; filling & sealing simultaneous (rotary dies).
• Filling temp limited $\le35^{\circ}\text{C}$ (high-m.p. solids unsuitable).
• Walls thicker, glycerin plasticizer can enhance diffusion & sticking; variable dimensions depending on fill weight.
• Slower disintegration; prone to tackiness in hot humid conditions.

CAPSULE SHELL – ADDITIVES & FUNCTIONS

• Gelatin Type A/B – film former.
• Plasticizers (glycerin, sorbitol) – impart elasticity.
• Preservatives (methyl-/propyl-paraben, sorbic acid $0.2\%$ ) – microbial control.
• Solvents/Oils – shine.
• Opacifiers ( $\text{TiO}_2$ $0.2{-}1.2\%$ ) – light protection.
• Colorants – FD&C, natural lakes.
• Flavors (ethyl vanillin $0.1{-}2\%$ ) – palatability.
• Sugars (sucrose ≤ 5 %) – chewable.
• Acids (fumaric ≤ 1 %) – reduce aldehydic tanning.
• Thickening agents (methyl cellulose) – viscosity control.

QUALITY CONTROL / EVALUATION TESTS

Physical Tests

• Weight variation – 20 capsules; individual weight 90–110 % of mean.
• Disintegration – HGC ≤30 min, SGC ≤60 min in $37\pm2^{\circ}\text{C}$ water; pass if no residue (16 / 18 units).

Chemical Tests

• Content uniformity – 10 of 30 units assay; 9 must be 85–115 %, none outside 75–125 %. If failure, assay remaining 20; overall 27 / 30 within 85–115 %.
• Dissolution – USP apparatus I; 1000 mL deaerated water $36.5{-}37.5^{\circ}\text{C}$ , 100 rpm; Q = ≥70 % API in 45 min unless monograph states otherwise.
• Assay of API (per monograph).
• Stability studies (ICH conditions) – evaluate EMC, potency, dissolution.
• Moisture permeation (USP) – packaged unit with desiccant pellets; mass gain indicates moisture ingress.

PACKAGING & STORAGE

• Pack in tight glass or plastic containers at ≤ $30^{\circ}\text{C}$ , RH $40{-}60\%$ .
• Strip packs (Al\/plastic) provide hermetic seal; blister packs allow push-through.
• Other options: plastic bottles with screw caps, clamshell blisters (fold-over plastic, no heat), cardboard blister cards, bulk plastic pails or zip-locked pouches (require outer cartons for shipping).
• Shelf-life greater in unopened glass than strips; opposite once opened.

PRACTICAL & ETHICAL CONSIDERATIONS

• BSE\/TSE risk → shift to porcine or HPMC (vegetarian) shells.
• Environmental moisture control critical – avoid patient exposure to extremes.
• Tamper-evident sealing (banding, printing) enhances consumer safety.
• Accurate labeling of animal origin, allergens, colorants required for informed patient choice.

NUMERICAL & FORMULA SUMMARY

• Gelatin EM solutions mobile at $50^{\circ}\text{C}$ when 40\%\,w\/v.
• EMC targets: shells $13{-}16\%$ , finished SGC $6{-}10\%$ .
• Bloom strength range $50{-}300$ ; Viscosity $20{-}70\,\text{mP·s}$ .
• Hard cap sizes: 000 (1.37 mL) down to 5 (0.15 mL).
• Disintegration criteria met if ≥16 / 18 units pass; content uniformity 27 / 30.
• Compression force for Piston-Tamp $50{-}200\,\text{N}$ .