Oral Solid Dosage Forms

What is a tablet?

• A solid dosage form

• It comprises the API and excipients, all compressed into a single unit

• All components are solids

What is a capsule

• A solid dosage form

• It comprises an API and excipients loaded into a shell, which may be hard or soft

• The contents of the capsule may be solid or liquid

2 different types of capsules

Hard-shell capsules:

• Comprise two pieces, a body and a cap

• Made of e.g. starch or hydroxypropylmethylcelluose

• May have solid or liquid contents

Soft shell capsules:

• Consist of a single-piece shell, typically made of gelatin

• The contents are liquid

Why do we use solid dosage forms?

• Convenient and accurate dose

• Increased drug stability

• Simple and easy administration

• Altered drug release rates - IR or MR

• Mass production

Advantage of solid dosage forms in the context of doses

Can make a wide range of doses and a wide range of drug release profiles

2 problems with making tablets and capsules

1. Powder formulation

2. Segregation

Problems with tablets and capsules

Powder Flow

• Most APIs are crystalline materials

• This means the particles are irregular shaped

• This means they usually have poor flow properties

• So there is a lot of powder flow when making both tablets and capsules

Problems with tablets and capsules

Segregation

• Have to prevent segregation of different powders ie. Excipients and APIs

• To avoid this, particles must be the same size and shape

Problems with tablets and capsules

How can we solve the problems of powder flow and segregation?

Granulation

• Particles of varying shape and size are gathered into larger, uniform and permanent aggregates

• In which the original particles can still be identified

Problems with tablets and capsules

Granulation

We seek to make granules which…

• Have a narrow particle size distribution and a shape close to spherical

• Are easily fluidised and flow well

• Are easily compressible, and stable when compressed » for making tablets

• Are produced by a robust and reproducible process, with a clear end-point

Problems with tablets and capsules

Granulation

Benefits of granulation

• To improve flow properties of the material.

• To prevent segregation of the constituents in a powder mix (content uniformity).

• To increase bulk density = improves flow

• To reduce dust production (hazard)

• To improve compression characteristics

• To improve* dissolution rate » faster OR slower depending on desired properties

• For control of moisture content

Problems with tablets and capsules

Granulation

Components

2 routes of granulation

Powders:

• API

• Filler - provides bulk to the tablet

• Binder - sticks together API and excipients

• Disintegrant - breaks tablet/capsule up in the body, releasing drug

1. Dry granulation

2. Wet granulation

Problems with tablets and capsules

Granulation

Wet vs Dry granulation

Wet:

• Commonly used as more likely to produce good granules

• If needed, we can do wet granulation in solvents other than water, but water is preferred. We use the minimum amount we can

Dry:

• Dry granulation is necessary when the ingredients are sensitive to moisture or heat

Problems with tablets and capsules

Granulation - Wet

Process

1. Start with materials that have been ground to the same size

2. A binder is then added:

• Either added to the drug and diluent as a powder mix followed by mixing with water (dry binder)

• or as a pre-formed solution (wet binder)

• Binders are typically polymers like sucrose, starch, celluloses etc.

3. Granulating fluid added to make the wet mass

4. Chopper blade turns to break big lumps up

Problems with tablets and capsules

Granulation - Wet

What does the granulation fluid do?

• Sticks particles together in small aggregates

• Which then forms bigger granules

• Once granules are big enough, they are dried

Problems with tablets and capsules

Granulation - Wet

Properties of dried granules

• Porous structure

• Solid bridges between particles in the granules

Problems with tablets and capsules

Granulation - Wet

What does it mean if dried granules are more porous?

• More porous granules = dissolve faster BUT weaker mechanical strength

Problems with tablets and capsules

Granulation - Wet

How can we control the porosity and bridges between particles in the dried granules?

By controlling:

• Amount of binder added

• The length of time particles are granulated for

• The concentration of the powders in the system

Problems with tablets and capsules

Granulation - Wet

When can wet granulation go bad?

Problems with tablets and capsules

Granulation - Dry

Process

• Mix drug and excipients

• Lubricant is added » helps powder flow through tablet machinery effectively

• Compressed to form a big lump

• Lump is broken up into granules

Problems with tablets and capsules

Granulation - Dry

Why is this process not very good?

Granules produced are not very regular and much less spherical = poor flow properties

Problems with tablets and capsules

Granulation

Pros and cons of wet granulation

Pros:

• Increases granule strength

• Can be used with a wide range of API concentrations

• Useful for APIs with poor flow properties

• Uniform distribution of drug and different colours

• Prevents segregation

• Produces tablet that are hard, non-friable and easy to coat

Cons:

• Many stages

• Long process times

• Expensive equipment

• Potentially hazardous dust

• Requires solvents » bad for water soluble drugs

• Drug is heated » bad for drugs which are not heat stable

• Migration of soluble components to granule surface

Problems with tablets and capsules

Granulation

Pros and cons of dry granulation

Pros:

• Less equipment so cheaper

• No expensive drying process

• No binders

• No heat or liquid » good for sensitive APIs

Cons:

• Multiple steps

• Produces irregular granules so poor powder flow

• Poor colour distribution

• Hazardous dust production

• Final tablets are softer than those from wet granulation and harder to coat

2 routes of making a tablet

1. Powder —> Granules —> Tablets (via granulation, then compression)

2. Powder —> Tablets (via direct compression)

Making Tablets

How do you make a tablet?

Take a powder and squash it:

• Die is filled with powder

• Lower punch is moved up and down to control how much powder fills the die

• Pressure is applied from upper punch and lower punch to squash all powders together to form a single unit

Making Tablets

What machine is used to make tablets in large-scale manufacturing?

Multi-station press

Making Tablets

Stages of powder compaction

As pressure is applied:

1. Loose packing

2. Dense packing - air removed, particles pushed close together

3. Elastic deformation - shape of particles changes, reverses when pressure is removed

4. Plastic deformation - permanent change in shape, tablet is formed

However, if too much pressure is applied:

5. Brittle fracture - tablet breaks into pieces

By which forces are tablets held together?

Non-covalent adhesive forces between particles - Van der Waals forces

2 types of compression characteristics of the drug/granules

1. Brittle fracture on compression

• Particles break on compression

• This creates a larger surface area for adhesion

2. Plastic deformation on compression

• Shape of particles changes permanently on compression

• Does not increase surface area

» we need to have a balance of these in our tablet

Why do we need both brittle fracture and plastic deformation in our tablet?

• Brittle fracture leads to more inter-particulate bonding = produces stronger tablets

• BUT the tablets are harder to remove from the die, and there may be problems with distintegration and drug release in the body

• Plastic deformation gives less inter-particulate bonding = produces weaker tablets

• BUT the tablets are easier to remove from the die, and have fewer dissolution problems

• We want a balance between brittle fracture and plastic deformation to get optimum tablets

Both the tablets and granules/powder can undergo brittle fracture. Explain what this means

• When pressure is applied, before a tablet is formed, some of the powder/granules might fragment » this is completely okay for the tablet formulation

• However, once the tablet is formed, if more pressure is applied the tablet will break up » not okay as cannot be packaged or used

Criteria of the powder and tablets for successful tablet formulation

The powder must:

• Flow well - to give a consistent tablet weight.

• Not segregate - to give a consistent dosage per tablet

• Be compressible - to form robust tablets.

• Be lubricated - to avoid sticking in the tableting machine.

And the tablets must:

• Disintegrate - i.e. break up to release the drug.

• Release the drug - determined by dissolution testing.

• Be fit for purpose - tablets that the patient can handle!

What powder criteria does granulation allow us to achieve and why (summary)

Allows the powder to:

• Flow well » forms spherical particles

• Not segregate » api and excipients stuck together

• Be compressible » right balance of brittle fracture and plastic deformation

How can tablets be made without granulation?

Direct compression

Making Tablets

Direct Compression

• Direct compression is used if the drug is of low dosage and will flow well

• We add a compression aid - a bulking agent with good flow and compression properties

Examples of compression aids include:

• Microcrystalline cellulose (Avicel®) = plastic deformation excipient

• Dicalcium phosphate (Emcompress®) = brittle fracture excipient

• Spray dried lactose = brittle fracture excipient

Making Tablets

Direct Compression

Pros and Cons

Advantages:

• Two step process » blend and compress

• Improved stability

• No heat

• No water

Disadvantages:

• Require specialist (spray-dried) excipients = expansive

• Poor flow/compression properties

• Use of flow aid.

• Segregation (uniformity of dosage form)

• Size and density of API and excipients may be different = segregation

What is a film coat?

Thin outer layer that covers a tablet core

Film coatings are usually either:

• Sugar

• Polymer

Why do we film coat?

As a physical barrier:

• To protect the drug (moisture, light, O2 etc)

• To protect the user (some drugs are very potent)

For identification:

• Patients/HCPs can quickly identify a tablet based on colour

Taste-masking

To improve handling - if tablet is friable (easily broken)

To modify the rate of drug release

Example of very potent drugs that are film coated to prevent patient overdosing on these drugs e..g by licking fingers

• Finasteride

• Chlorambucil

What is an enteric film coat?

Where a film coat is designed to delay or modify drug release (usually by a polymer)

If we did not want a certain drug to dissolve in the stomach acid, what would we make the film coating out of?

A polymer with pH-dependent solubility

If a tablet is ‘gastro-resistant’…

This means it has an enteric coating

What should you tell patients when giving tablets which are enteric-coated?

• Do not break tablet in half

• Do not crush tablet

• Do not put tablet in juice etc (acidic = causes drug to be released early)

How can you tell whether a film coating of a tablet is made of sugar or polymers?

Sugar film coating are thicker than polymers

Sugar Film Coating

Properties

E.g. like M&Ms

• Thick coat (0.5-2mm) that covers imperfections

• Gives a shiny finish

• Masks bitter taste

• Not used to control drug release » sugar dissolves quickly at any pH

Sugar Film Coating

How is it made?

• Tablet cores are placed in a rotating drum

• Sugar syrup is sprayed into the drum

Usually multiple layers of sugar coating:

• Seal

• Sub-coat(s)

• Smoothing coats)

• Colour coat

• Polishing coat

• Printing coat (optional)

Polymer Film Coating

Properties

• Thin coat (20-200 um) that does not cover imperfections

• Gives a matte finish

• Masks bitter taster

• Can control drug release » polymer has pH dependent solubility

Polymer Film Coating

Basic film coat

• No pH-dependent dissolution

Typically comprises:

• HPMC » forms a high strength film

• HPC » gives good flexibility

• Titanium dioxide » makes the film opaque

• Dye

» all dissolved in water

Polymer Film Coating

Enteric film coat

• Designed to be insoluble at low pH

Typically comprises:

• Polymer - Cellulose acetate phthalate (Aquateric) OR Polymethacrylates (Eudragit)

• Plasticiser (like triacetin or PEG) » goes between polymer chains and makes the film more flexible

» Polymers are insoluble in water at certain pHs, so dissolved in ethanol

Polymer Film Coating

How is it made?

• Tablet cores are placed in a porous/perforated rotating drum

• Hot air enters to evaporate the ethanol

• Holes in the drum to let ethanol evaporate

Why is a porous drum used in polymer coating but not sugar coating?

• In polymer coating, solvent used is ethanol

• Pores allow ethanol to evaporate

What is drying?

The removal of water (or another solvent) to form a solid

What samples can be dried?

• Wet solid

• Suspension

• Solution

Are materials ever completely dry?

• No

• Water may still be on the surface or within cells

• Water is important for materials for maintaining their structure

Why do we dry materials?

• To improve physical properties e.g. powder flow, compressibility » dry powders will flow better than wet powders (less clumping)

• To improve stability by reducing:

  • Hydrolysis

  • Polymorph conversion

  • Growth of microorganisms

  • Reducing efflorescence » fat crystallising out of a material

Why do we not completely dry materials?

Some water content is needed for good compression

4 methods of drying

1. Tray-drying

2. Fluidised-bed drying

3. Spray-drying

4. Freeze-drying

Tray Drying

Method

Advantages

Disadvantages

• Sample (wet powder) is spread thinly on a tray in a convective oven

• Hot, turbulent air is then passed over the sample

Advantages:

• Cheap and easy to use

Disadvantages:

• Can take up to 24h to dry

• Limited sample mass (a few kg)

• Low surface area of solid

Fluidised-bed Drying

Method

Advantages

Disadvantages

• Hot, turbulent air passed in from below the powder bed

• If air flow is high enough, particles aerosolise and become fluidised

• Filter bag prevents powder particles from leaving the top of the dryer, and has small holes to allow the air out

Advantages:

• Very rapid drying (ca. 30 mins)

• Energy efficient

• Can handle large masses (ca 100s kg)

• Can smooth particles

Disadvantages:

• Risk of dust explosion

Spray Drying

Method

Advantages

• For drying solutions / suspensions

• Hot air and solution/suspension passed through a nozzle at the same time

• Sample becomes an aerosol

• Aerosol droplets dried in a vortex of hot air

• As the droplets dry = become denser = falls to the bottom of the spray dryer

Advantages:

• Very rapid drying (1-2s for each droplet to dry)

• Energy efficient

• Can run continuously

• Produces spherical particles

• Often makes material amorphous = dissolve fast

Freeze Drying

Method

Advantages

Disadvantages

• Based on the fact that water has a triple point - where solid, liquid and gas intersect

• Water is able to go straight from a solid to a gas = sublimation

• Solution/suspension inserted into freeze dryer at atmospheric pressure (10⁵ Pa) and room temperature » point 1 on the diagram

• Under these conditions, water is a liquid

• The sample is frozen » reduce temperature, keep pressure the same » point 1 to point 2

• A vacuum is initiated, causing pressure to drop below 610Pa » point 2 to point 3

• Increase temperature back to room temperature » point 3 to point 4

• Frozen water sublimes and becomes a gas, which is removed

Advantages:

• No rise in temperature, so good for heat sensitive samples

• Makes highly porous, amorphous material = very fast dissolution

Disadvantages:

• Expensive to operate

• Small samples (usually in glass vials)

Which is the only drying method where temperature is not increased above room temperature?

Freeze drying

Which solvent, other than water, has a triple point and can be freeze dried

T-butanol

Diluents

What are diluents?

Bulking agents

• Added to increase bulk and make the tablet a practical size for compression

• Diluents used in direct compression need to have similar particle size to the drug, and good compressibility

• With insoluble drugs, need to add hydrophilic diluents

• The diluents must have good compatibility with the drug

Diluents

Examples

• Lactose monohydrate

• Microcrystalline cellulose

• Dicalcium phosphate dihydrate

• Pregelatinised starch

• Mannitol

• Calcium sultate

• Corn starch

Disintegrants

What are disintegrants?

Facilitate the break up of tablets into individual granules/particles upon contact with water

Mechanisms of action

• Wicking - capillary forces promoting rapid water uptake

• Swelling

• Release of gases upon contact with water

• Melting at body temperature

• Enzymatic destruction of binder

Disintegrants

Examples

Normal disintegrants

• Starches (corn, pre-gelatinised)

• Alginates

Super disintegrants

• Cross-linked carboxymethylcellulose 2-6% (Ac-di-sol)

• Sodium starch glycolate 2-8% (Explotab)

• Crospovidone 2 - 6% (Kollidon CL or Polyplasdone)

Disintegrants

When do you use a normal or super disintegrant?

Low solubility = use super disintegrant to speed up disintegration and drug dissolution

Strong granule = use superdisintegrant to speed up disintegration

Disintegrants

When do we add a disintegrant?

Option 1: Add all disintegrant prior to granulation

Option 2 (Preferred/Most common): Split addition

• 2/3 added prior to granulation

• 1/3 added to the dry granules before compression

Examples of common excipients used in tablet formulation

Microcrystalline Cellulose (MCC) - 90 microns:

• Excellent compactability and flow

• Limited disintegration properties

Starch 1500

• Adds bulk to the tablets

• Good compactability, flow and lubricity

• Disintegration property

Lubricants

Purpose of lubricants

Examples

Reduces friction between powder and tableting tools

E.g.

• Mg stearate / Ca stearate

• Polyethylene glycol

Lubricants

When is the lubricants added

• Whether tablets are made by:

  • Direct compression, or

  • Wet/dry granulation

• The lubrication step is essentially the same:

  • Lubricant is added at the final blending stage, just before compression

Lubricants

Advantages

• Reduce friction between powder/granules and dies and punches

• Prevent material from sticking to equipment

• Ensure smooth tablet ejection

• Low shear mixing → avoids excessive coating

• Minimum effective amount → typically 0.25–1%

• Short mixing time → limits negative effects

Lubricants

What happens if there is too much lubrication?

• Particles become over-coated

• Results in:

  • Soft tablets (reduced hardness)

  • Poor dissolution (water cannot penetrate easily)

• This happens because lubricants repel water and weaken particle bonding

Lubricants

What happens if there is too little lubrication?

• High friction during compression

• Leads to:

  • Sticking – material sticks to punch faces

  • Picking – part of the tablet surface is pulled off

• Causes defective tablets and equipment issues.

Glidants

Purpose of glidants

Examples

To improve powder flowability

E.g. Colloidal silicon dioxide

Examples of interactions between APIs and excipients

E.g.

• Lactose and primary or secondary amines → Maillard reaction

• CaHPO, is alkaline, so need to consider pH stability of drug

What must happen to all excipients before direct compression

Must be spray dried to ensure they are spherical, so they mix and flow well

Possible problems after tablet manufacturing

Weight variation

• Caused by variation of flow of powder into the die

• Leads to variation in drug content

Solution:

• Improve flow properties

• Reduce compression speed

Possible problems after tablet manufacturing

Segmentation of granules/powder

• Leads to variation in drug content

Solution: improve powder flow properties

Possible problems after tablet manufacturing

Capping / Lamination

• Caused by excessive elastic recovery

• Moisture content may be too high or low

Solution:Add excipients to give more brittle fracture

Possible problems after tablet manufacturing

Sticking

• Bits of formulation stick to the punches

• Causes by small/irregular particles or high moisture content

Solution: increase the amount of lubricant/lubrication time

Possible problems after tablet manufacturing

Picking

• Tablets pick up bits of powder on the surface

• Causes by small/irregular particles or high moisture content

Solution: increase the amount of lubricant/lubrication time

Possible problems after tablet manufacturing

Chipping / Cracking

Caused by:

• large particle size

• high elastic recovery

• high humidity

Possible problems after tablet manufacturing

Poor dissolution properties

Caused by:

• Particle size

• High moisture content

• Low binding

• Segregation

How are tablets made to be easy to swallow?

To improve swallowability, tablets are often given a special film coating. This coating is formulated to:

• Be smooth and slippery

• Show low bioadhesion (does not stick to the mouth or throat)

Coating composition

• Polymers:

  • Hydroxypropyl methylcellulose (HPMC)

  • Polyvinyl alcohol (PVA)

  • These form a smooth, flexible film with low adhesion

• Plasticisers:

  • Polyethylene glycol (PEG)

  • Plasticisers increase flexibility and prevent cracking

• Colorants:

  • Improve appearance and aid product identification

2 types of capsules

Hard (shell) capsule

• Two piece capsules which include a "body" and "cap"

• Capsule materials: Gelatin or Hydroxypropyl methylcellulose (HPMC) or Starch

• Contents may be solids or liquids

• Three stage manufacturing process: i) shell, ii) contents, ili) filling

Soft (shell) capsule

• One piece

• Capsule material: Gelatin

• Contents are liquids

• Two stage manufacturing process: i) contents, ii) shell manufacture and filling combined

Capsule Sizes

• There are 8 standard capsule sizes, ranging from: 000 (largest) → 5 (smallest)

• As the capsule size number increases, the capsule volume decreases

How to estimate fill weight for hard capsules

Fill weight ≈ capsule body volume × tapped bulk density

Tapped bulk density is used because it reflects how powder behaves after settling, which is closer to real capsule filling conditions.

How to estimate fill volume for soft capsules

Fill volume depends on the density of the liquid in the capsule

Hard Capsules

How are hard gelatin capsule shells manufactured?

• Gelatin dissolved in hot water (60°C to 70°C)

• Colour is added as necessary

• Stainless steel pins (fingers) dipped into the gelatin solution

• the coating on the pins will become one part of the capsule

• the pins are rotated to ensure constant thickness of coating

• the coating is dried, removed and trimmed

• the two halves of the capsules are joined together

Hard Capsules

What is the standard moisture content for hard gelatin capsules?

What is the recommended storage conditions?

• Standard moisture content: 13% to 16% w/w

• Storage conditions: 50% relative humidity at 21°C

Hard Capsules

Why do we use hard capsules compared to tablets?

• No water involved in the dry powder mix → prevent hydrolysis

• No heat involved in the dry powder mix → good for heat-sensitive drugs

• No compression involved in filling of dry powder mix → avoid possible changes of physical state (amorphous v crystalline, polymorphic changes) → prevent change in dissolution profile

Hard Capsules

Why may HPMC be used as a capsule material instead of gelatin?

Used to improve performance and stability of formulations, especially for:

• Poorly soluble APIs » better solubilisation

• Aldehyde-containing formulations » avoids gelatin cross-linking and disintegration issues

• Modified-release formulations

• Moisture-sensitive drugs » lower moisture content than gelatin, better stability)

Soft Capsules

How are soft gelatin capsule shells manufactured?

Preparation of the ribbon

• Gelatin dissolved in hot water

• Plasticisers added (eg glycerol, sorbitol, PEG, propylene glycol)

• Colour is added as necessary

• A gel "ribbon" is formed

Preparation and filling of the capsules

• Two gel ribbons are placed on the rollers

• Ribbons are partially sealed to provide a "cup"

• The liquid is added to the cup

• The ribbons are sealed above the fill, making an intact capsule

• The capsules are dried

Soft Capsules

Why do we use soft shell capsules compared to tablets?

For poorly water soluble drugs

• Drug is in solution in the fill

  • Avoids dissolution step in the gastro-intestinal tract

  • Promotes bioavailability, especially if in a self-emulsifying formulation

Excipients in a capsule filling

• Diluents (filler)

• Lubricants, which reduce powder-to-metal adhesion

• Glidants, which improve powder flow

• Wetting agents, which improve water penetration

• Disintegrants, which produce disruption of the powder mass

Hard Capsules

Limitations of filling for hard capsules

• React with shell material

• Contains high levels of moisture

• Volume of unit dose exceeds the capsule size available

Hard Capsules

Different types of fillings for hard capsules

• Powders

• Granules » improve mixing, reduce segregation

• Pellets » enable controlled release and combination drugs

• Mini-tablets » different drugs or release rates in one capsule

• Non-aqueous liquids » oils or oil/surfactant systems for very poorly water-soluble drugs; may be liquid or molten-filled solids