DOSAGE FORM DESIGN:

BIOPHARMACEUTICAL
CONSIDERATION

JAVERIA M.RAFIQ SHEIKH

618-T, Regular session
Content

■ Basics of dosage form design

■ Drug considerations,
■ Drug product considerations,
■ Patient considerations,
■ Manufacturing considerations,
■ Pharmacodynamic considerations
■ Pharmacokinetic considerations.
 INTRODUCTION-Why we need a dosage form

■ Pharmaceutics - study on the: formulation, manufacture, stability, and effectiveness of

pharmaceutical dosage forms.

■ Pharmaceutical ingredients or excipient: -selective use of these non medicinal agents, uses include:
– Solubilization
– Thickening
– Stabilization
– To provide flavor
– Suspending agent
– Dilution
– Preservation
– Emulsification
– Color
– Increase appeal of product
– Closure forms
Need for a dosage form
■ To protect the drug substance from the destructive influences of atmospheric oxygen or
humidity. (Coated tablets)
■ To protect the drug substance from the destructive influence of gastric acid after oral
administration. (Enteric-coated)
■ To conceal the bitter, salty or offensive taste or odor of a drug substance. (Capsules,
Flavored syrups)
■ To provide liquid preparations of substances that are either insoluble or unstable in the
desired vehicle. (Suspension)
■ To provide clear liquid dosage forms of substances. (Syrups, Solutions)
■ To provide rate-controlled drug action. (Controlled-release tablets)
■ To provide optimal drug action from topical administration sites. (Ointments, Creams,
Transdermal patches)
■ To provide for insertion of a drug into one of the body’s orifices (Suppositories)
■ To provide placement of drugs directly in the bloodstream or body tissues (Injections)
■ To provide for optimal drug action through inhalation therapy (Inhalants, Inhalation
aerosols)
REQUIREMENTS OF DOSAGE FORM
Consideration of drug substances:
■ Physical, chemical & biological characteristics compatible with one another
■ stable,
■ efficacious,
■ attractive,
■ easy to administer and safe
■ manufactured under appropriate measures of quality control
■ packaged in containers to make product stable
■ labeled to promote correct use
■ stored under conditions to maximize shell life
Basics of dosage form design
 General consideration for dosage form design
■ Determine desired product type - framework for product development.
■ Develop and examine initial formulations of the product: - desired features:
– drug release profile
– bioavailability
– clinical effectiveness –
– pilot plant studies
– production scale-up.
■ master formula - formulation that best meets the goals of the product
■ Factors to consider before formulation of a medicinal agent in one or more dosage forms
– Therapeutic matters (nature of the illness)
– manner it is treated (locally or through systemic action)
– age and anticipated condition of the patient.
Drug considerations
For a drug to exert its biological effect, it must be
o Transported by the body fluids,
o Traverse the required biological membrane
barriers,
o Escape widespread distribution to unwanted areas,
o Endure metabolic attack,
o Penetrate in adequate concentration to the sites of
action,
o Interact in a specific fashion,
o Causing an alteration of cellular function.
Manufacturing considerations for drug
Pre-formulation Studies
■ 1. Physicochemical Description
• physical description: particle size, crystalline structure, melting point solubility
etc.
• Chemical properties: structure form reactivity
• purity of the chemical substance for: identification and for evaluation of its
chemical, physical, and biologic properties
■ 2. Microscopic Examination
– Indication of particle size and size range of the raw material along with the
crystal structure.
– Information generated in formulation processing attributable to changes in
particle or crystal characteristic changes of the drug molecules or particles.
■ 3. Melting Point Depression
Determines the:
– purity of the substance
– compatibility of various subs before inclusion in the dosage form –
– pure subs: sharp melting point –
– impure subs: depressed melting point
Pre-formulation Studies
■ 4. Phase Rule
– Phase diagrams constructed determines: - existence & extent of the presence of solid and
liquid phases in binary, ternary & other mixtures
– Particle Size - affects physical–chemical properties of drug subs’s:
■ dissolution rate
■ bioavailability
■ content uniformity
■ Stability
■ taste
■ texture
■ flow properties
■ absorption
■ sedimentation rate
■ 5. Polymorphism – substances can exist in more than one crystalline form
– Polymorphic forms – diff. physical-chemical properties (incl. melting pt. & solubility)
Evaluation of:
– crystal structure (microscopy, IR spectroscopy, thermal analysis, x-ray diffraction)
– polymorphism
– solvate form
Pre-formulation Studies
■ 6. Solubility
Process: Determined by equilibrium solubility method - excess amount of drug + solvent
= shaken at constant temp. over a prolonged period of time until equilibrium is obtained
1. Drug possess aqueous solubility - for therapeutic efficacy.
2. Insoluble compounds: incomplete/erratic absorption
■ 7. Dissolution Rate
Time for the drug to dissolve in the fluids at the absorption site (rate-limiting step in
absorption).
– Dissolution rate of drugs - increased by decreasing the particle size.
– for higher dissolution rate - use a highly water soluble salt of the parent
substance.
■ 8. Stability studies:
– conducted in the pre-formulation phase:
Solid-state of the drug alone
Solution phase
with the expected excipients
SUMMARY:

■ Pharmaceutics - study on the: formulation, manufacture, stability, and effectiveness

of pharmaceutical dosage forms.
■ Pharmaceutical ingredients or excipient: -selective use of these non medicinal
agents,
■ On the basis of different requirements and need dosage form are design keeping
drug consideration and other in mind.
■ Pre-formulation studies are done priory to decide a suitable dosage form for a drug.
REFERENCES:

■ HARISHANKARSAHU/pharmaceutical-dosage-forms
■ https://www.slideshare.net/MERHAJ/dosage-form-design-31245254
■ Biopharamaceutics and Clinical pharmacokinetics by Milo Gibaldi
■ Applied biopharmaceutics and pharmacokinetics Textbook by Leon Shargel
■ Pharmacokinetic-pharmacodynamic modeling and simulation Book by Peter L. Bonate
■ Essentials of Biopharmaceutics and Pharmacokinetics Book by Ashutosh Kar
■ Pharmacokinetics: Principles and Applications by Mehdi Boroujerdi
■ Basic Pharmacokinetics by Mohsen A. Hedaya
■ Clinical Pharmacokinetics: Concepts and Applications by Malcolm Rowland, Thomas N. Tozer
■ Biopharmaceutics and Pharmacokinetics Book by A. P. Pawar and J. S. Kulkarni
■ https://accesspharmacy.mhmedical.com/content.aspx?bookid=513&sectionid=41488032
DOSAGE FORM DESIGN:
BIOPHARMACEUTICAL
CONSIDERATION

JAVERIA M.RAFIQ SHEIKH

618-T, Regular session
Content

■ Basics of dosage form design

■ Drug considerations,
■ Drug product considerations,
■ Patient considerations,
■ Manufacturing considerations,
■ Pharmacodynamic considerations
■ Pharmacokinetic considerations.
 INTRODUCTION-Why we need a dosage form

■ Pharmaceutics - study on the: formulation, manufacture, stability, and effectiveness of

pharmaceutical dosage forms.

■ Pharmaceutical ingredients or excipient: -selective use of these non medicinal agents, uses include:
– Solubilization
– Thickening
– Stabilization
– To provide flavor
– Suspending agent
– Dilution
– Preservation
– Emulsification
– Color
– Increase appeal of product
– Closure forms
Patient considerations
Effect of Food

■ The presence of food in the GI tract affects the bioavailability of oral drugs.

■ Some effects of food on the bioavailability of the oral drugs include:

• Delay in gastric emptying time
• Stimulation of bile flow
• Change in the pH of GI tract
• Alter in splanchnic blood flow
• Change in luminal metabolism of drug substances
• Physical/chemical interaction of metal with drug substances
Absorption:
• Absorption of some antibiotics decreases when administered with food (e.g.
penicillin, tetracycline)
• Absorption of some lipid soluble drugs increases when administered with food. e.g.
metazalone.
Bile flow
• The presence of food in the GI lumen stimulates the flow of bile which increases
the solubility of fat soluble drugs by forming micelle.
pH:
• The presence of food in the stomach lowers the pH which causes acidic drugs to
remain in non-ionized form – helps in absorption. They may help some basic drug in
dissolution as well.
Irritation
• Drugs irritating to GI mucosa (e.g: erythromycin, aspirin, NSAIDs etc) given with
food to reduce the irritation by decreasing the rate of drug absorption.
Non-disintegration:
• In the presence of food, enteric coated and non-disintegrating drug products can
not reach the duodenum rapidly, thus they delay drug release & systemic drug
absorption.
AGE:

■ In children & infants: Gastric pH is high, membrane permeability & BBB

permeability is high, protein binding is less therefore it helps drug
absorption.

■ While in elderly patient there is altered gastric emptying, decrease

intestinal surface area, decrease gastric blood flow & higher incidence of
achlorhydria so it inhibits drug absorption.
EFFECT OF DISEASE STATE

Changes in –
1. Intestinal blood flow
2. Gastrointestinal motility
3. Changes in stomach emptying time
4. Gastric pH
5. Intestinal pH
6. Permeability of gut wall
7. Bile secretion
8. Digestive enzyme secretion
9. Alteration of normal GI flora
EFFECT OF DISEASE STATE

• Patient with Parkinson’s disease have difficulty swallowing & greatly diminished
GI motility

• Patient on tricyclic antidepressants & antipsychotic drugs reduce GI motility

which delay drug absorption

• In achlorhydric patient weak-base drugs remain undissolved in stomach

because no adequate acid

• In patient with acid reflux disorder, Proton Pump Inhibitor such as

omeprazole, render stomach achlorhydric, may affect drug absorption

• HIV-AIDS patients are prone to a number of GI disturbances e.g.

increased gastric transit time, diarrhea
Biopharmaceutical rational design
of drug product
BIOPHARMACEUTICAL CONSIDERATION

■ The physical and chemical properties of the drug substance

■ The route of drug administration, including the anatomic and physiologic nature of
the application site (eg, oral, topical, injectable, implant, transdermal patch, etc)
■ Desired pharmacodynamic effect (eg, immediate or prolonged activity)
■ Toxicological properties of the drug
■ Safety of product
PHARMACOKINETIC CONSIDERATION
PHARMACOKINETIC CONSIDERATION

■ Important Pharmacokinetics parameters:

– Clearance (cL)
– Volume of distribution (Vd )
– Half-life (t1/2)
– Bioavailability (F%)
– Protein binding (fu )
Pharmacodynamic considerations
Pharmacodynamic considerations
■ The nature of the clinical indication, disease or illness against which the drug is
intended is an important factor when selecting the range of dosage forms to be
prepared.
■ Factors such as the need for systemic or oral therapy duration of action required,
and whether the drug will be used in emergency situations, need to be considered.
■ Patients requiring urgent relief from angina pectoris, a coronary circulatory problem,
place tablets of nitroglycerin sublingually for rapid drug absorption directly into the
blood capillaries there.
■ What potential adverse effect it can cause/how to deal with them as well
■ What are indication and contra-indication of drug
■ What potential drug interaction should be avoided along with taken in an account
regarding drug-food interaction.
SUMMARY:

■ Patient considerations: Different patient consideration are taken in an account to

design proper dosage form
■ Pharmacodynamic considerations: what a drug dose to body, keeping this thought in
mind we make choice of appropriate dosage for suitable condition
■ Pharmacokinetic considerations: what body does to drug, making sure that the
proper effect is produced by drug within system on the basis of that dosage form is
selected.
REFERENCES:

■ HARISHANKARSAHU/pharmaceutical-dosage-forms
■ https://www.slideshare.net/MERHAJ/dosage-form-design-31245254
■ Biopharamaceutics and Clinical pharmacokinetics by Milo Gibaldi
■ Applied biopharmaceutics and pharmacokinetics Textbook by Leon Shargel
■ Pharmacokinetic-pharmacodynamic modeling and simulation Book by Peter L. Bonate
■ Essentials of Biopharmaceutics and Pharmacokinetics Book by Ashutosh Kar
■ Pharmacokinetics: Principles and Applications by Mehdi Boroujerdi
■ Basic Pharmacokinetics by Mohsen A. Hedaya
■ Clinical Pharmacokinetics: Concepts and Applications by Malcolm Rowland, Thomas N. Tozer
■ Biopharmaceutics and Pharmacokinetics Book by A. P. Pawar and J. S. Kulkarni
■ https://accesspharmacy.mhmedical.com/content.aspx?bookid=513&sectionid=41488032