Dosage Form Design

Murat Kizaibek

The Need for Dosage Forms

The Need for Dosage FormsThe Need for Dosage Forms

• To provide the mechanism for the safe and convenient delivery of accurate dosage

• To protect the drug substance from the atmosphere

• To protect the drug substance from the gastric acid (EC tablet)

• To conceal the bitter, salty, or offensive taste or odor

• To provide liquid preparations of insoluble drugs

The Need for Dosage Forms (continued)The Need for Dosage Forms (continued)

• To provide clear liquid dosage forms (solutions)

• To provide rate-controlled drug action

• To provide topical drug action (ointments, creams, patches, ophthalmic, otic, nasal)

• To provide for insertion into body cavity

• To provide for placement into bloodstream

• To provide for inhalation therapy

General Considerations in

Dosage Form Design

• the nature of the illness

--normally (systemic use or oral) : tablet or capsule

--an emergency in which the patient may be comatose or

unable to take oral medication: injection

--motion sickness, nausea,and vomiting: tablets and skin

patches are used for prevention and suppositories and

injections for treatment.

• age

--infants and children younger than 5 years of age:

flavored liquid preparations

--young patient who has a productive cough or is vomiting,

gagging, or simply rebellious: injection, suppository

• anticipated condition of the patient

--patients who have difficulty in swallowing tablets whole:

chewable tablets

Design of Drug ProductsDesign of Drug Products

• Effectiveness

• Safety

• Reliability

• Stability

– Physical

– Chemical

– Microbiological

Design of Drug Products (continued)Design of Drug Products (continued)

• Pharmaceutical elegance

– Appearance

– Organoleptic properties

• Convenience

– Ease of use

– Dosing frequency

– Consumer acceptance

Preformulation StudiesPreformulation Studies

• Chemical characterization

• Physical characterization

Physical DescriptionPhysical Description

• Solids, liquids, gases

• Chemical Properties

– Structure, form, reactivity

• Physical Properties

– particle size, crystalline structure, melting point, solubility

• Biological Properties

– Ability to get to site of action and elicit a response

• Herbal medicines:

– powder of herbs or extracts, viscosity

Microscopic ExaminationMicroscopic Examination

• Particle size

• Particle size range

• Crystal structure

• Particle shape

Heat of VaporizationHeat of Vaporization

• the amount of heat required to

convert 1g of a liquid into the

vapor without a change in

temperature and is measured

in calories.

• Vapor pressure （ aerosol ）

• Volatile drugs can migrate

within a solid dosage form

• Personnel exposure

Melting PointMelting Point

• Purity determination

• Identity

The Phase RuleThe Phase Rule

• Phase diagrams

• Phase diagrams are valuable for

interpreting interactions between

two or more components, relating

not only to melting point depression

and possible liquefaction at room

temperature but also the formation

of solid solutions, coprecipitates,

and other solid-state interactions.

Particle SizeParticle Size

• Dissolution rate

• Bioavailability

• Content uniformity

• Taste

• Texture

• Color

• Stability

• Flow characteristics

• Sedimentation rates

The following characteristics of a drug substance are affected by the particle size distribution:

PolymorphismPolymorphism

• Crystalline form

• Amorphous form

• at least one third of all organic compounds exhibit polymorphism.

• Melting point variation

• Solubility differences

SolubilitySolubility

• Some aqueous solubility required for therapeutic efficacy

• Equilibrium solubility

• Solubility in different solvents

• Chemical modification of the drug into salt or ester forms

is frequently used to increase solubility.

Solubility and Particle SizeSolubility and Particle Size

• Small increases in solubility can be achieved by particle size reduction.

• Decreases in particle size may enhance dissolution rates.

Solubility and pHSolubility and pH

• pH can affect solubility.

DissolutionDissolution

• Dissolution may be rate-limiting step in the absorption of

poorly soluble drugs.

• Can affect onset, intensity, and duration of response and

control overall bioavailability of the drug from the dosage

form

Membrane PermeabilityMembrane Permeability

• pKa, solubility, and dissolution rate data can provide an indication of absorption.

pKa/Dissociation ConstantspKa/Dissociation Constants

• Extent of dissociation or ionization

• Dependent on pH of medium

• Can affect absorption, distribution, and elimination

Partition CoefficientPartition Coefficient

• Octanol:water partition coefficient often used in

formulation development

Drug and Drug Product StabilityDrug and Drug Product Stability

• Physical stability

• Chemical stability

• Shelf life of 2-3 years is generally desired

Drug Stability: Mechanisms of DegradationDrug Stability: Mechanisms of Degradation

• Hydrolysis, solvolysis

• Oxidation

• Other processes

Drug and Drug Product Stability: Kinetics and Shelf LifeDrug and Drug Product Stability: Kinetics and Shelf Life

• Chemical stability:active ingredient retains its chemical integrity

and labeled potency within the specified limits.

• Physical stability:appearance, palatability, uniformity, dissolution,

and suspendability

• Microbiological stability:microbial growth

• Therapeutic stability:The therapeutic effect remains unchanged.

• Toxicologic stability:No signifi cant increase in toxicity occurs.

Rate ReactionsRate Reactions

• Change of drug concentration with respect to time

ZERO-ORDER RATE REACTIONS

FIRST-ORDER RATE REACTIONS

C

t

lnC

t

C

t

Q10 Method of Shelf Life EstimationQ10 Method of Shelf Life Estimation

• Shelf life estimation

Reasonable estimates can often be made using the Q value of 3.

Enhancing Stability of Drug ProductsEnhancing Stability of Drug Products

• Excipients may be added to protect the drug

– Antioxidants

– Preservatives

– Chelating agents

– Buffering agents

Stability TestingStability Testing

• Done at each stage of product development

• Product containers and closures must be considered

• Temperature and humidity studies

• Light studies

• Changes in physical appearance, color, odor, taste, texture

• Chemical changes of drug degradation

• Pharmacist is last professional to check for quality and stability prior to dispensing

Herbal drugs: preformulation

• 1. processing

• 2. powder of extract or powder of plant material?

• 3. volatile?

• 4. taste or odor

• 5. solvent of extraction?

• 6. dense and hard materials

• 7.bioguided fractionation