Biopharmaceutic considerations in drug product design

1. Mohammad Asim
20/MPH/DIPSAR/2019
1
Biopharmaceutics Considerations in Drug Product Design
Biopharmaceutics drug product performance is defined as the release of the drug substance from
the drug product either for local drug action or for drug absorption into the plasma for systemic
therapeutic activity. Advances in pharmaceutical technology and manufacturing have focused on
developing quality drug products that are safer, more effective, and more convenient for the
patient. Biopharmaceutics examines the interrelationship of
i. The physical/chemical properties of the drug, the dosage form (drug product) in which the
drug is given.
ii. The route of administration on the rate and extent of systemic drug absorption.
iii. The importance of the drug substance and the drug formulation on absorption.
iv. In vivo distribution of the drug to the site of action.
Biopharmaceutics considerations in drug product design include-
1. Pharmacodynamics consideration
o Therapeutic objective
o Toxic effects
o Adverse effect
2. Drug considerations
o Particle size
o pKa & pH profile
o Polymorphism
o Hygroscopicity
o Partition coefficient
Drug
consideratio
ns
Pharmacodynam
ic considerations
Drug product
considerations
Patient considerations
Manufacturing considerations

2. Mohammad Asim
20/MPH/DIPSAR/2019
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o Excipient interaction
o pH stability profile
o Solubility
3. Drug product considerations
o Pharmacokinetics of drug
o Bioavailability consideration
o Route of administration
o Desired dose of drug
o Dosing frequency
4. Patient considerations
o Acceptability & Compliance of drug product
o Cost
5. Manufacturing considerations
o Availability of raw materials
o Stability
o QC
Pharmacodynamic considerations
Evaluation of the drug effect in the body and its mechanism of action. Therapeutic considerations
include desired pharmacodynamics and pharmacologic properties of the drug, including the
desired therapeutic response and the type and frequency of adverse reactions to the drug.
Therapeutic objective influences the design of the drug product, route of drug administration, dose,
dosage regimen, and manufacturing process.

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20/MPH/DIPSAR/2019
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E.g., An oral drug used in the treatment of an acute condition is generally formulated in order to
achieve rapid release of the drug and to show rapid onset of action. If more rapid drug absorption
is desired, then an injectable drug formulation might be formulated.
E.g. In the case of nitroglycerin, which is highly metabolized if swallowed, a sublingual tablet
formulation allows for rapid absorption of the drug from the buccal area of the mouth for the
treatment of angina pectoris. In order to reduce unwanted systemic side effects, locally drugs such
as inhaled drugs have been developed.
Drug considerations
Physicochemical properties of drug that are considered in drug product design are
Particle size
o Reduction in the particle size results in a number of advantages:
o Enhance the surface area effectively.
o Once the surface area of the particle enhances, it increases the penetration of water into the
particles and eventually increases drug dissolution rate.
Solubility-pH profile
o Gives rough estimation of the completeness of dissolution for a dose of a drug in stomach
/small intestine
o Basic drug is more soluble in an acidic medium, forming a soluble salt.
o Acid drug is more soluble in the intestine, forming a soluble salt at the more alkaline pH.
o Acidic and alkaline pH influence the rate of decomposition of most drugs.
o Solubility may be improved with the addition of an acidic or basic excipient.

4. Mohammad Asim
20/MPH/DIPSAR/2019
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Stability-pH profile
o Many drugs are stable between pH 4 and 8
o Some drug - has pH-dependent stability profile
o e.g. In acidic medium, erythromycin decomposition occurs rapidly, whereas in
neutral/alkaline, the drug is relatively stable.
Polymorphism
o Polymorph - lower aqueous solubility than the amorphous forms, cause product -
incompletely absorbed.
o Amorphous drug (non-crystalline form) - dissolves more rapidly/highest apparent
solubility or dissolution rate - high free energy compared to the crystalline
o Amorphous solid dispersion (ASD) - technologies for improving BA of poorly water-
soluble compounds.
o Change in crystal form - cause problems in manufacturing the product.
o E.g. change in the crystal structure of the drug - cause cracking in a tablet, problem in tablet
compression
o The order for dissolution of different solid dosage forms drugs;
Amorphous > Meta-stable > stable
Excipient interactions
o Should be pharmacodynamically inert
o However, it may change the suitability of drug substance and BA of drug from the dosage
form

5. Mohammad Asim
20/MPH/DIPSAR/2019
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o Affect the dissolution kinetics of the drug, either by altering the medium in which the drug
is dissolving or by reacting with the drug itself
o Chemical instability / chemical interactions with certain excipients will also affect the type
of drug product and its method of fabrication.
Drug products considerations
Bioavailability consideration
o Rate: The amount or rate of drug absorption from the given dosage form.
o Duration: how long does the drug present into the blood stream
o Due to poor bioavailability of some drugs, alternative route of drug administration or
higher dose may be needed.
Desired dose of drug
o Optimal dosage that gives desired effect with minimum side effects
o The potency of the drug, determines the plasma concentration of the drug required for the
desired therapeutic effect
o The desired final drug size manufactured is determined by main two factors: the dose of
the drug and the excipients.
Dosing frequency
o Empirical approach - involves certain quantity of drug and therapeutic response
o Kinetic approach - therapeutic & toxic effects on drug related to amount of drug in body /
plasma concentration of drug at the receptor site
o Drug clearance and drug concentration of plasma.

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o Pharmacokinetic evaluation - determine the levels of drug attained from multiple dosing
estimation
o If the drug has a short half-life which means high clearance from the body, then the duration
of action of the drug will become shorter and hence the frequency of drug administration
must be increased.
Route of administration
Dosage forms Onset actions
I.V injections Seconds
I.M and S.C injections, Buccal, Aerosols Minutes
Injections, solutions, suspensions, powders, capsules,
granules, tablets, modified release
Minutes-hours
Enteric coated formulations Several hours
Depot injections, implants Days to weeks
Topical preparations Varies
Patient considerations
o Must be acceptable to the patient
o Cost of products
o Age, urine pH, condition being treated, existence of other disease states, patients’
background

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o Poor patient compliance may result from poor product attributes, such as
 Swallowing difficulty
 Unacceptable odor
 Bad medicine taste
 Dosing frequency /unusual dosage requirements
 Side effects /allergic reaction
Manufacturing considerations
o Product quality and performance
o Quality control important components for drug product manufacturing – dissolution &
drug release tests
o Stability – long term stability of drug product – critical attribute of overall product quality
o Lower cost
o Availability of raw materials