Comprehensive Study Notes — Tablets: Types, Excipients & Manufacturing

Tablet Classification Framework

Primary axis = Route of administration or therapeutic function
- Oral, buccal, sub-lingual, vaginal, rectal, implantable
Secondary axis = Drug-delivery system
- Conventional, immediate-release, controlled-release, sustained-release, extended-release, delayed-release, targeted, gastro-retentive, oro-dispersible, effervescent, chewable
Tertiary axis = Form / method of manufacture
- Compressed, multilayer, compression-coated, coated (film, sugar, enteric), molded, lyophilized, effervescent, etc.

Routes of Administration: Key Attributes

Oral ▸ systemic or local GI action, widest formulation latitude
Buccal & Sublingual ▸ rapid dissolution/absorption, avoid first-pass, typically molded or ODT
Vaginal / Rectal ▸ local/systemic, shape & pH-targeted excipients
Implantable ▸ long-term, sterile, zero-order or erosion controlled

Drug-Delivery System Concepts

Conventional IR ▸ tablet disintegrates quickly; onset < 30 min
Sustained vs Controlled
- Sustained = prolonged release but not necessarily constant rate
- Controlled = near-zero-order output to maintain target Cp window
Extended-release = ≥2× IR duration
Delayed-release = lag (e.g., enteric) followed by burst
Targeted / gastro-retentive = spatial control (stomach, colon, etc.)

Tablet Forms & Manufacturing Styles

Compressed (single punch or rotary) ▸ wet granulation, dry granulation/slugging, direct compression
Multiple-compressed ▸ layered (2–3) or compression-coated “tablet-in-tablet”
Molded (triturates / melt-in-mouth) ▸ low pressure, porous, dissolve rapidly; no disintegrant required
Lyophilized (freeze-dried ODT) ▸ solution frozen $-40\,^{\circ}\text C$ to $-80\,^{\circ}\text C$ then primary drying at $1{-}0.1\,\text{mbar},\,5\,^{\circ}\text C$ & secondary drying $25\,^{\circ}\text C,\,0.03\,\text{mbar}$
Effervescent ▸ acid–base pair; produces $\text{CO}_2$ in water

Molded Tablets (Details)

Soft, porous; rapid saliva penetration ➜ sublingual/buccal suitability
Typical excipients
- Water-soluble diluent (lactose, mannitol)
- Binder (starch, acacia, gelatin) at low level
- Flavors/sweeteners; often no disintegrant
Manufacturing stages
1. Mix API + excipients
2. Moisten with water/water-alcohol to plastic “dough”
3. Manual or automated molding-compression
4. Air or low-T oven drying
5. Ejection ⇒ fragile handling
6. Package (high barrier, dessicant)
Why no disintegrant?
- Minimal compression ➜ fragile
- Intrinsic porosity
- Water-soluble excipients promote disintegration

Lyophilized / Freeze-Dried Tablets (ODT)

Formulation components
- API, water-soluble filler (mannitol, lactose) for matrix
- Cryoprotectant (glycerol, sucrose)
- Disintegrant (crospovidone) & binder if needed
- Flavors/sweeteners for palatability
Process sequence
1. Prepare solution/suspension
2. Fill blisters/molds accurately
3. Rapid freeze $-40\rightarrow-80\,^{\circ}\text C$ at (~1000\,\text{mbar}) to lock structure
4. Primary drying (sublimation) under vacuum $1{-}0.1\,\text{mbar}$
- Remove 80–90 % water; shelf $5\,^{\circ}\text C$ + controlled heat
1. Secondary drying (desorption) $25\,^{\circ}\text C,\;0.03\,\text{mbar}$ until <2 % residual moisture
2. Back-fill with inert gas, seal blister

Standard Compressed Tablets

Made by wet granulation, direct compression, or double-compression (slugging/dry granulation)
Intended for rapid disintegration (local or systemic action)

Double Compaction (Slugging / Dry Granulation)

Stage-1: pre-compress large slugs → mill → granules
Stage-2: recompress granules to final tablets
Used for moisture/heat sensitive APIs, poor flow powders
Roller compaction variant (e.g., Chilsonator®)
- Key variables: hydraulic roll pressure, roll speed, feed-screw speed, roll gap
- Narrow gap & low speed = dense ribbons; wide gap/high speed = friable ribbons

Direct Compression

Blend API with highly compressible, free-flowing excipients
- Microcrystalline cellulose (Avicel pH101/pH102)
- Spray-dried lactose, anhydrous lactose
- Pregelatinized starch, sodium starch glycolate, croscarmellose
Advantages: minimal steps, no heat/moisture; risk of segregation for low-dose drugs due to density differences

Superdisintegrants & Disintegration Principles

Superdisintegrants: croscarmellose sodium, sodium starch glycolate, crospovidone (2–5 %)
Mechanisms
- Swelling, wicking, capillarity/porosity, deformation recovery, heat of wetting, effervescence

Multiple-Compressed Tablets

Layered tablets or compression-coated
- 2- or 3-layer for separating incompatible APIs or repeat/prolonged action
- Compression-coated: press core first, press outer layer around it
Slower machine speed than standard tablets; light compression between stages, full compression last
Raw materials for coatings
- Fillers: MCC, lactose
- Polymers: HPMC, sodium alginate, CAP (enteric)
- Lubricants: Mg stearate
- Disintegrants: croscarmellose, SSG
- Colorants (TiO₂), flavors

Chewable Tablets

Designed to be chewed prior to swallowing (large dose antacids, pediatric use)
Large amount of base (e.g., CaCO₃); particle size reduction upon chewing improves acid neutralising capacity
Usually flavored, sweetened; minimal disintegrant

Coated Tablets

Sugar & Chocolate Coating (Traditional vs Modern)

Classical process: seal → sub-coat (+50–100 % weight) → syrup/color smoothing → polishing; doubled tablet weight; artisan skill
Sealants: shellac, zein – moisture barrier
Modern: water-soluble polymers (HPMC, PVA), automated spray, side-vented pans, weight gain ≤50 %, process <1 day; plasticizers (PEG, PG) enhance flexibility

Film Coating

Early systems: organic-solvent polymer (e.g., HPMC) + plasticizer + surfactant; airless spray → 1-2 h cycle
Regulatory & cost pressures ➜ aqueous systems
- Immediate-release films: HPMC, HPC + plasticizer
- Controlled-release: ethyl cellulose aqueous dispersion (Aquacoat® 30 % EC)
Spray technologies
- Air spray: compressed-air atomization
- Airless: hydraulic (500–3000 psi) atomization
Plasticizers: PEG 400, propylene glycol; Surfactants: sodium lauryl sulfate, Tween-80
Water-soluble vs water-insoluble film polymers
- Soluble: HPMC, sodium alginate
- Insoluble: EC, HPMCP, CAP, Eudragit® L30 D-55 (enteric), Eudragit® RL/RS (controlled)

Enteric / Delayed-Action Tablets

Goal: remain intact to $\text{pH} \le 4$ , dissolve at $\text{pH}\,4{-}8$ (duodenum → ileum)
Enteric polymers share phthalate esters; insoluble in acid (COOH non-ionized) → ionize (COO⁻) in intestine to hydrate & rupture
- Cellulose acetate phthalate (CAP)
- Polyvinyl acetate phthalate (PVAP)
- Hydroxypropyl methylcellulose phthalate (HPMCP)
Additional breakdown: esterase hydrolysis of ester bonds, bile salt surface activity
Cellulose acetylation reaction example:
$\text{Cellulose} + \text{(CH}<em>3\text{CO)}</em>2\text{O} \xrightarrow{H<em>2SO</em>4} \text{Cellulose acetate} + \text{CH}_3\text{COOH}$

Controlled & Sustained Release Matrices

Hydrophobic: ethylcellulose, polymethacrylates (Eudragit RL/RS), polyvinyl alcohol
Hydrophilic swellable: HPMC, HEC, PEO, sodium alginate, xanthan gum, Carbopol
Design aims: zero-order (controlled) vs prolonged first-order (sustained)

Tablets for Oral Cavity (Troches, Lozenges, Buccal/Sublingual)

Lozenges: usually hard-candy fusion or molding; dissolve 15–30 min; deliver anesthetic, antiseptic, antitussive
Troches: compressed, slower dissolve; designed not to disintegrate quickly

Tablet Size, Density & Patient Handling

Round ingestible tablets: $3/16{-}1/2\,\text{in}$ (4.8–12.7 mm)
Weight range $120{-}700\,\text{mg}$ for density $0.5{-}1.5\,\text{g/cm}^3$
Oval shapes allow >800 mg; tablets <4.8 mm difficult for elderly manipulation
Low-density APIs require larger tablets; high-density APIs enable smaller forms

Excipient Functionality

Diluents / Fillers (selection highlights)

Lactose (monohydrate, anhydrous, spray-dried) – inexpensive, compressible; Maillard risk with amines
Mannitol, sorbitol – non-carbohydrate sugar alcohols (cooling effect)
MCC – compressible & wicks water ➜ secondary disintegrant function
Starch (native/pregelatinized), sucrose, dicalcium phosphate
Spray-dried lactose: 80–90 % crystalline + 10–20 % amorphous; amorphous phase plastically deforms & is hygroscopic ⇒ better compressibility but moisture uptake risk

Maillard Reaction Incompatibility

Amino drugs + lactose + Mg stearate ➜ Schiff base → Amadori → AGEs (brown discoloration, potency loss)
$\text{R-NH}_2 + \text{CHO} \rightarrow \text{R-N=CH-} + \cdots$
Mitigation: use anhydrous lactose (<0.5 % H₂O) or non-reducing filler (mannitol)

Binders / Adhesives

Natural gums: acacia, tragacanth (10–25 % solutions)
Gelatin (protein), starch paste (hydrolyzed to dextrins), sucrose or liquid glucose (50–74 % solutions)
Modified cellulose derivatives: HPMC, HPC, ethylcellulose (alcoholic), polyvinylpyrrolidone (PVP)

Disintegrants (full list snapshot)

Alginic acid, CMC-Na, MCC, croscarmellose Na, crospovidone, guar gum, magnesium aluminum silicate, polacrilin potassium, SSG, starch
Use intra- &/or extra-granular to break both tablet & granule

Lubricants / Glidants / Antiadherents

Stearates: Mg, Ca, Zn stearate (0.25–2 %)
Stearic acid (less efficient), hydrogenated oils
Talc (Ca/Mg silicate) – glidant, antiadherent
Colloidal silicon dioxide (Aerosil®) – glidant, lubricant synergy

Colors, Flavours, Sweeteners

FD&C or D&C water-soluble dyes added in granulating fluid
Lake pigments (insoluble) for coating or dry blend
Artificial sweeteners: saccharin (500× sucrose, bitter, carcinogenic concern); aspartame (stable only dry)

Comminution & Compressibility Theory

Hooke’s law region slope = Young’s modulus; yield point indicates onset of plastic flow; area under curve = energy to fracture
Plastic deformation (MCC, SD lactose) promotes interparticle bonding; brittle fracture (talc, sugar) risks lamination
Moisture acts as lubricant at low %; excess moisture ➜ sticking/capping
Stratification risk when API/diluent bulk density mismatch (critical for low-dose)

Direct Compression vs Wet vs Dry Granulation

Direct compression: minimal steps; limits – flow, segregation, API %
Dry granulation: slugging or roller compaction; suitable for moisture/heat sensitive; variables = roll pressure, gap, speed
Wet granulation: binder liquid bridges → pendular → funicular → capillary → (avoid) droplet stage; capillary negative pressure binds particles
- Wet screening/milling increases SA for drying; overly wet mass ⇒ slow drying & hard aggregates → fines during dry milling
- Drying mechanisms: fusion (PEG, PVA), recrystallization (sucrose), curing (glutaraldehyde)
High-shear mixer-granulators (Lödige, Diosna, Gral) integrate dry mix, granulate, and wet massing with chopper; amperage feedback to detect end-point

Practical Example: 30 % Ethyl Cellulose Aqueous Dispersion (Aquacoat)

Dissolve EC (30 g/100 mL final) in ethanol 5–10 % w/v
Prepare water phase + 0.5–2 % Tween 80
Emulsify organic phase into water under high shear
Gently evaporate solvent at $40{-}50\,^{\circ}\text C$ or rotary vacuum
Adjust volume, store sealed

Roller Compactor Process Variables (Dry Granulation Recap)

Hydraulic pressure ↑ → ribbon density ↑
Roll gap narrow ↑ → compaction ↑, risk over-hard
Roll speed fast ↑ → residence ↓, density ↓
Feed-screw speed controls throughput & deaeration

Glossary of Key Numeric References

Lyophilization freeze temp: $-40\rightarrow-80\,^{\circ}\text C$
Primary drying pressure: $1{-}0.1\,\text{mbar}$
Secondary drying residual moisture target: < $2\%$
Enteric solubility threshold: $\text{pH}\approx4$ stomach; dissolves \text{pH}>5
Superdisintegrant use-level: $2{-}5\%$ of tablet weight
Tablet size practical limits: $4.76{-}12.7\,\text{mm}$ diameter