ORAL DRUG DELIVERY SYSTEM

Dr. Wan Maznah Wan Ishak

Oral Drug Delivery Systems

Objectives
• To explain the structure and physiology of GIT
• To evaluate the physiological factors affecting oral
bioavailability
• To compare advantages and disadvantages of oral drug
delivery
ORAL DRUG
DELIVERY SYSTEM
Oral Route

• The oral route is preferred for administering drugs because:

• Very convenient
• Safe
• Suitable for life-threatening situations

• Disadvantages:
• Slower onset of response compared to intravenous route.
• Possible irregular and unpredictable absorption due to drug properties and
the gastrointestinal tract (GIT) anatomy and biochemistry.
Gastrointestinal Tract
Gastrointestinal Tract (GIT)
Gastrointestinal Tract (GIT)

• Drugs taken orally can be absorbed at various points from the mouth
to the rectum.

• Rate and extent of drug absorption in the GIT depends on:

• Environmental fluctuations (mainly pH changes)
• Biochemical variance (enzymes, transport proteins, cofactors)
• Anatomic differences (vascularity, epithelial thickness, surface area)
Gastrointestinal Tract (GIT)
• Drug absorption at the mouth:
• Drug is in solution form
• or in the form of orally disintegrating tablet (ODT)
• or retained in the oral cavity for an extended period.

• However, most orally administered drugs are swallowed too quickly to

be absorbed at the mouth mucous membranes.

• Can use sublingual (under the tongue) or buccal (between the cheek
and gum) methods to retain the tablet etc. for longer at the site.
• Also more easily absorbed in these locations due to thin mucous membrane
and high vascularity.
Gastrointestinal Tract (GIT)
Sublingual and Buccal Delivery Systems

• Used in situations that need quick response

• Ease of use
• Easy accessibility
• The rich of vasculature in these sites allow rapid absorption and a fast
onset of action
• Avoid first-pass hepatic metabolism
Gastrointestinal Tract (GIT)

• Most drugs taken orally are absorbed in the GIT.

• Absorption begins at the stomach.

• Drugs must cross the GIT epithelium to enter the blood stream.
• Penetration occurs via the paracellular and transcellular routes.

• Paracellular route:
• Between the epithelial cells
• Only for low molecular weight & highly hydrophilic drugs
• Not favoured because tight junctions between cells limits drug absorption.
Gastrointestinal Tract (GIT)

1) Paracellular route:
• Between the epithelial cells
• Only for low molecular weight & highly hydrophilic drugs
• Not favoured because tight junctions between cells limits drug absorption.

2) Transcellular route:
• Across the epithelial cells
• Occurs via:
• Passive diffusion
• Carrier mediated transport
• Pinocytosis
Gastrointestinal Tract (GIT)

1) Passive diffusion:
• Most common way of drug absorption
• Follows the concentration gradient (high to low)
• Depends on concentration gradient, lipid solubility, size and ionization of the drug
molecule.

2) Carrier mediated transport:

• Uses specialized carriers to transport the drug across the membrane.
• Can active transport (against the conc. gradient)
• Or facilitated diffusion (follows conc. gradient and doesn’t require energy)

3) Pinocytosis:
• Very small role in drug absorption
• Drug molecules are engulfed by the cell and released into the cell interior.
Physiologic Factors Affecting Oral
Bioavailability
Physiologic Factors Affecting Oral Bioavailability

• pH of the gastric (stomach) contents and pKa of the drug

• Stomach is not preferred site of drug absorption
• Stomach content is highly acidic (pH 1-3)
• Acidic condition can degrade some drugs
• The stomach is lined with thick mucous layer that slows drug absorption
• The faster drugs can pass through the stomach to the small intestines (gastric
emptying), the better it is.
 Physiologic Factors Affecting Oral Bioavailability

• Most drugs are absorbed at the small

intestines because:
• Very large surface area
• Due to many villi and microvilli
• Favourable membrane permeability
• Wider pH range (pH 5-8) allows absorption
of more types of drugs
• Therefore, the longer the drug stays in the
small intestines (intestinal transit time),
the better.
Physiologic Factors Affecting Oral Bioavailability

• Large intestines:
• Not favourable for drug absorption
• Includes the colon and rectum
• Major site for water resorption and production of feces
• Has much smaller surface area compared to small intestines.

• First-pass hepatic metabolism

• Drugs absorbed in the GIT are transported to the liver via the hepatic portal
vein.
• Might be degraded by liver enzymes before entering the blood circulation and
reduce bioavailability.
Physicochemical Properties of Drugs
Physicochemical Properties of Drugs
• Oral drugs absorption process:
• Liberation (release) of the drug from the formulation
• Drug dissolution in fluids (very important)
• Drug permeation through the GIT membrane

• The absorption properties of orally administered drugs depends on

various drug properties:
• Particle size
• Polymorphism and hydration
• Partition coefficient
• pKa
Physiochemical Properties of Drugs
i) Particle size:
• Very important factor in oral drug formulation.
• Drug particle size affects the surface area, hence bioavailability.
• Smaller size = higher surface area = higher bioavailability
• Smaller size = faster rate of dissolution
• Smaller size = more stable suspension
Physicochemical Properties of Drugs

Characterized according to particle diameter (see USP Classification Table)

 Physicochemical Properties of Drugs

ii) Polymorphism and Hydration

• Polymorphism: ability of solid material to exist in more
than one form or crystal structure
• Drugs that are amorphous have better dissolution and
absorption compared to highly crystalline drugs
• Therefore, drugs that are crystalline but can turn into
amorphous after being administered are better in terms of shelf
life and bioavailability.

• Hydration: use of water as the solvent incorporated into

the drug’s crystalline structure
• Can be monohydrate, dihydrate, hemihydrate etc.
• Compounds with NO water molecules are called anhydrous.
• More hydration = better solubility
 Physicochemical Properties of Drugs
iii) Partition Coefficient
• Biological membranes are lipophilic
• Partition coefficient: a measure of the lipophilicity of a drug molecule.
• Higher partition coefficient = higher lipophilicity
• Higher lipophilicity = higher drug absorption through the membrane.
Physicochemical Properties of Drugs

iv) pKa of the Drug

• The chemical structure of many drugs are strongly affected by the surrounding
pH.
• Many drugs are weak organic acids/bases or their salts.
• Extent of drug ionization in solution depends on the solution’s pH and the drug’s
pKa.
• Acidic drugs are more easily absorbed in the stomach.
• Basic (pH) drugs are more easily absorbed in the intestines.
• Some acidic drugs are also absorbed in the small intestines due to the large
surface area and longer time spent in there.
 Water Solubility
Improvements of Solid Oral
Immediate Release Dosage
Forms
i) Salt Formation

• Water-soluble salt increases the dissolution rate in GIT tract

• To increase dissolution
• Weakly acidic drugs mixed with sodium or potassium salt (alkaline salt)
• Weakly basic drugs mixed with hydrochloric acid or other strong acid salt
(acidic salt)
• If free acid is converted to the sodium or potassium salt, the strong alkali
sodium or potassium cations exert a neutralizing effect
• The pH of the drug is raised for eg from pH 1-2 to pH 5-6 in the bulk medium of
stomach, resulting in alkaline microenvironment around the drug particle.
• This causes dissolution of acidic drug of higher pH which gives rise to overall
faster dissolution rates
ii) Polymorphism

• Many drugs can exist in more than one crystalline form depending on the
conditions (temperature, solvent, time) under which crystallization occurs.
• This property is referred to as polymorphism form is known as a polymorph
• At a given temperature and pressure, only one of the crystalline forms is
stable and the others are known as metastable forms
• A metastable polymorph exhibits a greater aqueous solubility and
dissolution rate, thus greater absorption than the stable polymorph
• The amorphous form of a drug has no crystalline lattice and therefore less
energy is required for dissolution, so the greater bioavailability.
iii) Formulation Factors

• The type of dosage form and its method of preparation or manufacture

can influence drug dissolution and bioavailability
• In solid dosage forms such as hard gelatin capsules or tablets, the
processes of disintegration and de-aggregation must occur before drug
dissolution can proceed at any appreciable rate
• No dissolution step for solution, while in suspension, drugs are rapidly
absorbed because of the large available surface are of the dispersed
solid.
• The dissolution and bioavailability of a given drug decrease in following
order
• Aqueous solutions > aqueous suspensions > hard gelatin capsules >
tablets
Conventional
Oral Delivery Systems
Conventional Oral Delivery Systems
• Includes:
• Tablets and capsules
• Liquids (clear solutions, suspensions and emulsions)
• Powders
• Majority are formulated as tablets, such as:
• Quick release
• Effervescent
• Disintegrating
• Buccal
• Sublingual
• May also be in granules or sprinkles (for paediatric use)
Conventional Oral Delivery Systems

• Liquids:
• Can be coloured and flavoured to be more appealing.
• More difficult to mask taste of drug.
• Transporting and accurate dosage are more difficult.
• Shorter shelf life due to aqueous medium.
Powders
• Powders:
• Advantages: good stability compared to tablets and liquids and flexibility in
dosage.
• Two forms:
• Bulk powders: patients have to measure the drug dose themselves
(inaccurate)
• Divided powders: Individual doses pre-wrapped in packets or sealed
pouches (more accurate but more resources needed to manufacture).

• Most powdered drugs are reconstituted in liquid and dispensed by

pharmacists.
• Largely been replaced by capsules and tablets.
Conventional or Immediate Release Tablets
• Tablets are the most used because:
• Accepted by patients and doctors
• Ease of manufacturing
• Can be modified to the desired
biopharmaceutical profiles.

• Can come in many shapes, sizes and

colours:
• Round, oblong, triangular, cylindrical, square
etc.
• Easier for patients to distinguish different
drugs
• Some are scored to easily break into smaller
portions.
• Can be etched for identification
Conventional or Immediate Release Tablets

• Process of drug delivery in tablets:

• Conventional tablets are disintegrated in the stomach or intestine into
smaller granules.
• Granules then undergo dissolution or breakdown into smaller particles in
the GIT.
• Dissolution is governed by pH of GIT, pKa of drug, drug particle size (see
previous section).
• Dissolved drug molecules cross the gastrointestinal membranes and enter the
systemic circulation.
Conventional or Immediate Release Tablets
• Other ingredients in tablets:
• Binders: mechanically hold the ingredients together, e.g. starches, cellulose,
lactose.
• Disintegrants: helps breakup tablet into granules/smaller particles and
increase porosity of tablet to increase surface area, e.g., starch, crospovidone.
• Diluents: increase the bulk of tablet so that is appropriate for handling and
processing. Usually inert, cheap and palatable e.g., lactose, calcium
phosphate, cellulose.
• Lubricants: facilitate the smooth passage of tableting material through the
compression machine when manufacturing the tablet, e.g., magnesium
stearate, talc and silica.
• Colourings and flavouring agents: make the drug more appealing and help to
differentiate the products.
• Coatings: (see next subsection)
Tablet Coating
• Three main types of tablet coating:
• Film
• Sugar
• Enteric

• Film-coated tablets for rapid release

• Usually use cellulose derivatives and methacrylic acid copolymers.
• Contains:
• Plasticizer (makes the coat flexible and elastic, e.g. PEG),
• Glossant (adds shine e.g. beeswax)
• Surfactant (facilitate film spreading during coating process, e.g.,
polysorbate 80).
Tablet Coating

• Sugar:
• Applied to improve palatability and aesthetic appeal of tablet
• Might alter the shape, size and weight of tablet.

• Enteric-coated (EC) products:

• Minimize exposure of drug to acidic pH in stomach
• Protects drug from degradation
• Decrease gastric side effects of drugs (ulcers, perforations and bleeding)
• Most commonly used is cellulose acetate phthalate.
• Coats the core of the formulation and only dissolves at higher pH (> pH 5)
when the tablet exits the stomach into the small intestine.
Sprinkles, Granules and Effervescent Tablets

• Solid formulations can also come in these forms.

• Have similar excipients to tablets but differ in method of administration.
• Sprinkles & granules:
• Aggregated powders
• Sprinkles are commonly used to give drugs to babies/children who can’t
swallow tablets
• Granules are convenient to administer drug in large doses.
Sprinkles, Granules and Effervescent Tablets

• Effervescent tablets:
• Must be dissolved in water before use
• Effervescence: reaction in water between an acid and a base that produces
carbon dioxide (seen as bubbles).
• Most commonly used acid is citric acid.
• Most common bases are sodium bicarbonate and potassium bicarbonate.
• Usually added artificial sweeteners to improve taste.
• Also widely used for paediatric patients.
Orally Disintegrating Tablets (ODT)

• ODTs combine ease of swallowing of liquid formulations and convenience of

tablets.
• ODTs are NOT intended to be swallowed.
• These tablets disintegrate instantly on the tongue in seconds resulting in rapid
onset of action.
• Ideal drug for ODTs are high potency, quick action e.g., Zomig-ZMT for migraine.
• Mainly for pediatric, geriatric, bedridden and mentally disabled patients who
can’t swallow or chew tablets.
• ODTs are less shelf stable and require careful handling because they disintegrate
easily.
Thin Films
• Some drugs can come in the form of
thin films or strips.
• Uses various biocompatible polymers.
• Also instantaneously melt or dissolve
on the tongue.
• Convenient, easy to use and doesn’t
need water.
• Useful for geriatric and pediatric
patients.
Hard Gelatin Capsules
• Drugs and excipients are enclosed
within a gelatin shell.
• Designed to be swallowed.
• Can have various colours and sizes to
improve aesthetic appeal and ease of
identification.
• Must be stored in tightly controlled
humidity.
Soft Gelatin Capsules
• Allows delivery of small quantity of liquid as
a solid formulation.
• Used for drugs that are not very soluble in
water.
• Drugs are dissolved in non-aqueous vehicle
and encapsulated.
• Soft gelatin capsules can also carry
suspensions, pastes or powders.
• Must be swallowed whole and not
compounded or cut into smaller portions.
Solutions, Suspensions & Emulsions
• In addition to the drug, solutions, suspensions and emulsions also
contain:
• Buffers: maintain pH
• Preservatives: prevents microbial growth, e.g. methyl parabens, propyl
parabens.
• Sweeteners: Enhances taste and increase viscosity, e.g. sucrose, fructose,
mannitol.
• Colouring agents: Enhance aesthetic appeal. Must be inert and stable.
• Flavouring agents: mask unpleasant taste of drugs.
Solutions

• Solutions: clear and homogenous liquid products containing one or more solutes
dissolved in a single or mixture of solvents.
• Most important factor in formulation is the solubility of the drug (solute) (see USP
table next page).
• Preparation of solution involves precise weighing, mixing and measuring of
ingredients in a specific order.
• May require heating (must be careful not to damage the ingredients).
• Most commonly used solvents are water, glycerin, ethanol and propylene glycol
depending on the drug’s solubility in the solvent.
• A mix of water and ethanol (hydroalcoholic mixture) is used to dissolve both
hydrophilic and lipophilic molecules.
Solutions

Table of USP Definitions of Solubility Type

Suspensions
• Suspension: a heterogenous liquid preparation containing fine particles of
solutes uniformly distributed throughout a vehicle.
• Must consider two issues:
• Sedimentation of drug particles (settling to the bottom)
• Redispersibility of sedimented particles (can it be resuspended)
• Ideal suspensions should have drug particles that are well segregated and good
flow properties.
• Highly viscous suspensions are not ideal because they are hard to pour and
unpleasant to swallow.
• Some drugs are more stable in suspension and taste better.
Suspensions
Emulsions
• Emulsion: a dispersed system containing two or more immiscible liquid phases
(oil and water).
• Is a type of colloid.
• The dispersed phase (internal phase) is distributed in small liquid globules
throughout the dispersion vehicle (external phase).
• Two types:
• Water in oil (w/o)
• Oil in water (o/w)
• Requires the use of emulsifying agents to create stable emulsions.
• Increase viscosity and prevent aggregation of dispersed globules.
• Mainly used for oral drugs with objectionable taste.
Emulsions