Biopharmaceutical & Pharmacokinetic Consideration in the Development of CRDDS

2. BIOPHARMACEUTICAL AND PHARMACOKINETIC
CONSIDERATION IN THE DEVELOPMENT OF CONTROLLED
RELEASE DRUG PRODUCTS.
BIOPHARMACEUTICS AND PHARMACOKINETICS

3. PRESENTED TO,
SIR MUHAMMAD FAROOQ

4. CONTENTS:
 Introduction
 Advantages
 Disadvantages
 Biopharmaceutical consideration
 Pharmacokinetic consideration

5. INTRODUCTION:
 Sustained release, sustained action, controlled release, extended action,
timed release dosage forms are the terms used to identify drug
delivery systems that are designed to achieve a prolonged therapeutic
effect by continuously releasing medication over an extended period of
time after the administration of single dose.
 The term “Controlled release” has become associated with those
systems from which therapeutic agents may be automatically delivered
at predefined rates over a long period of time. But, there are some
confusion in terminology between “Controlled release” and “Sustained
release.

6. CONT’D
 Sustained Release:
 The term sustained release has been constantly used to describe a
pharmaceutical dosage form formulated to retard the release of a therapeutic
agent such that its appearance in the systemic circulation is delayed or
prolonged and its plasma profile is sustained in duration.
 Sustained drug delivery tries to achieve zero order kinetics but follows first
order kinetics (concentration dependent). Slow first order release, drug release
from the dosage form is dependent on amount of drug in the delivery system
(i.e. concentration dependent).

7. CONT’D
 Controlled Release: This term on the other hand, has a meaning that goes
beyond the scope of sustained drug action.
 It also implies a predictability and reproducibility in the drug release kinetics,
which means that the release of drug ingredient from a controlled delivery
system proceeds at a rate profile that is not only predictable kinetically, but
also reproducible from one unit to another. An ideal controlled drug delivery
system is the one which delivers the drug at a predetermined rate, locally or
systematically for a specified period of time.
 Follows zero order release, drug release from the dosage form is independent
of amount of drug in the delivery system ( i.e. constant release rate).

8. An ideal controlled drug delivery system is the one which delivers the drug at
a predetermined rate, locally or systematically for a specified period of time.

9. BIOPHARMACEUTICAL CONSIDERATION OF CONTROLLED
RELEASE DOSAGE FORM
 Dose Size:
Size of the drug plays a major role in determining the size of the final finished product.
• In case, the dose already high, then formulating the same into controlled release will further increase the
overall dosage size & thereby reduced patient compliance.
• For drugs with an elimination half-life of less than 2 hours as well as those administered in large doses, a
controlled release dosage form may need to carry a prohibitively large quantity of drug.
 Stability of the drug
• Since most oral controlled release systems are designed to release their contents over much of the length
of GIT
 drugs that are unstable in the environment of the intestine
 drugs that are unstable in the environment of the stomach
• might be difficult to formulate into prolonged release system.
• In order to counter-act such problems, several modified-release methods have been adopted that restricts
the release at the required site of the GIT.

10.  Ionization and pKa of the drug
 Drug that remains is unionized state at absorption site is a good candidate.
 Drug that remains in ionized state (e.g. hexamethonium) are poor candidates.
• The Henderson-Hasselbalch eq. provides an estimate of ionized & unionized drug conc, by function of
Acidic drugs: pKa = - log10(Ka) = pH + log10([HA]/[A-])
Basic drugs: pKa = - log10(Kb) = pH + log10([HB+]/[B-])
Where:
Ka or Kb = ionization constant for acid/basic drugs
[HA] = conc. of unionized acid
[A-] = conc. of ionized acid
[HB+] = conc. of the unionized base
[B] = conc. of the ionized base
 Partition coefficient
The partition coefficient is defined as the fraction of drug in an oil phase to that of an adjacent aqueous phase.
A major criterion in evaluation of the ability of a drug to penetrate these lipid membranes (i.e., its membrane
permeability) in its apparent oil or water partition coefficient defined
As,
K= Co/Cw
Where,
Co = Equilibrium concentration of all forms of the drug in an organic phase at equilibrium.
Cw = Equilibrium concentration of all forms in an aqueous phase.

11.  Aqueous Solubility
 Drugs with low Aqueous Solubility => Poor Candidate
CRDDS.
 Drugs with very high Aqueous Solubility => Poor
Candidate for CRDDS.
 Drugs which are suitable for CRDDS should have
Aq.solubilty <0.001mg/ml.
 Complex Formation
Complexation is one of the well-known method to entrap
the drug within a complexing agent like β-cyclodextrin
complex.
These complexes could be helpful in entrapping drugs of
very high molecular weight which have low diffusivity
through the membrane.
• From formulation point of view, this property also
facilitates in increasing the solubility of the drug in the

12.  Molecular size & Diffusivity
• In addition to diffusion through a variety of biological membranes, drugs in many CRDDS must
diffuse through a rate controlling membrane or matrix.
• The ability of drug to pass through membranes, it’s so called diffusivity, is a function of its
molecular size. • An important influence upon the value of diffusivity, D, in polymers is the
molecular size of the diffusing species.
• The value of D thus is related to the size and shape of the cavities as well as size and shape of
the drugs.
• Molecular size of the drug plays a major role when it comes to diffusion of the drug through a
biological membrane. 1. Mass spectroscopy (MS or LC-MS)
2. Fourier Transform IR- spectroscopy (FTIR)
• Diffusion of the drug from the matrix or encapsulated form determines the release rate of the
drug from the polymer.
• Diffusivity is the rate determining step in CRDDS.
 Polymer Structure
The diffusivity of a drug through a polymer is an important criterion in its selection for use in a
dosage form. The physical structure and chemical nature (for biodegradable polymers) of the
polymeric material are important parameters controlling drug diffusion coefficient and hence
release rate.

13. PHARMACOKINETIC CONSIDERATIONS OF CONTROLLED RELEASE
DOSAGE FORM
• Absorption:
 The release rate of drug is much slower than the rate of absorption. Kr >> Ka
 Drug should be uniformly absorbed throughout GI tract .Drug that are absorbed poorly and
at unpredictable rate are not good candidate for CRDDS.
 The absorption of drug should occur at a relatively uniform rate over the entire length of
small intestine. If a drug is absorbed by active transport or transport is restricted to a
specific region of intestine, CR preparation may be disadvantageous to absorption.
• Metabolism:
 Metabolism of the drug is either an inactivation of an active drug or conversion of an
inactive drug to an active metabolite.
 Drugs that are capable of either inducing or inhibiting enzyme synthesis, they are the poor
candidate for controlled release delivery system due to difficulty in maintaining uniform
blood levels.
 Drugs possessing variation in bioavailability due to the first-pass effect or intestinal
metabolism are not suitable for controlled release DDS.

14. • Distribution:
 The distribution of drugs into tissues and plasma can be important factor in the
overall drug elimination.
 Since it not only lowers the concentration of drug but it also can be rate limiting in its
equilibrium with blood and extra vascular tissue.
 The distribution includes the Binding of the drug to the tissue and blood protein.
 Volume of distribution is one of the imp parameter that describes the magnitude of
distribution as well as protein binding , the apparent volume of distribution at steady
state is considered to be most appropriate.
• Protein Binding :
 The characteristics of protein binding by a drug can play a significant role in its
therapeutic effect, regardless of the type of dosage form. Extensive binding to
proteins will be evidenced by a long half-life of elimination for the drug, and such
drugs generally do not require a controlled release dosage form.

15. • Elimination:
 The relationship between Clearance (Clt) and biological half-life (t1/2) is obtained as in
equation. t1/2= 0.693 Vd/CLt
The volume of distribution Vd and CLt affect t1/2. A decrease in clearance will increase the
biological half-life, changes in the volume of distribution will also cause similar changes in
biological half-life.
• Biological half life:
 Drugs with short half-life are best candidate for controlled release formulation. Drugs
which having shorter half-life less than 2 hours such as levodopa are poor candidates for
CRDDS. Drugs which having longer half-life more than 8 hours are also poor candidate in
CRDDS, since their effect is already sustained. Examples: Digoxin, Phenytoin.

16. • Margin of safety :
• Disease state:
Disease state is an important factor in considering a drug for controlled release system. In some
instances better management of the disease can be achieved by formulating the drug as
controlled release system.
E.g. Aspirin in Rheumatoid Arthritis
Nitroglycerin in the management of Angina pectoris
Safety of drug generally depends upon the therapeutic index. Larger the value of
therapeutic index of a drug safer is the drug. Drugs having less therapeutic index are
generally poor candidates for oral SR drug delivery system

17. ADVANTAGES OF CRDDS:
 Therapeutic advantage
 Reduction in Health care cost
 Patient comfort and compliance
 Reduction in Dose frequency

18. DISADVANTAGES OF CRDDS:
 Dose dumping
 Poor In-vitro In-vivo correlation
 Patient variation
 First pass clearance
 Removal of drug from system may be difficult
 Variable drug absorption

19. REFERENCES
• Shargel, L ., and Yu, A. , Applied Biopharmaceutics & Pharmacokinetics, 6th ed.,Appleton &
Lange, Stamford, CT, 2012
• Hui. H-W., Robinson, J.S., and Lee, V.H.L., Design and fabrication of oral controlled release
drug delivery systems, in Controlled Drug Delivery, Fundamentals and Applications, 2nd ed.,
Robinson, J.R. and Lee, V.H.L., Eds., 1987.

20. THANK YOU FOR LISTENING.