PHYSICOCHEMICAL AND BIOLOGICAL
APPROACHES FOR SR/CR

FORMULATIONS

1 Presented by:
Pranay Mittal
M.PHARM 1st Semester
Department of Pharmaceutics
School of Pharmaceutical Sciences and
Research, Jamia Hamdard
New Delhi.

PHYSICOCHEMICAL APPROACH
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It includes the following factors:

a) Aqueous Solubility

b) Partition coefficient (P [O/W])

c) Drug pKa and ionization at physiological pH

d) Drug stability

e) Molecular weight and diffusivity

f) Protein binding

g) Dose size.

Aqueous Solubility:
3 Most of the drugs are weak acids or weak bases. Drugs with low water solubility will be difficult to incorporate into SR

mechanism. For a drug with high solubility and rapid dissolution rate, it is often quite difficult to retard its dissolution rate. A

drug of high water solubility can dissolve in water or GI fluid readily and tends to release its dosage form in a burst and thus is

absorbed quickly leading to a sharp increase in the blood drug concentration compared to less soluble drug. It is often

difficult to incorporate a highly water-soluble drug in the dosage form and retard the drug release, especially when the dose

is high. The pH-dependent solubility, particularly in the physiological pH range, would be another problem for SR formulation

because of the variation in the pH throughout the GIT and variation in the dissolution rate. The BCS allows estimation of the

likely contribution of three major factors which affect the oral absorption.

• Solubility

• Dissolution

• Intestinal permeability.

Class III (high solubility-low permeability) and Class IV (low solubility-low permeability) drugs are poor candidates for SR

dosage compound with solubility <0.1 mg/ml face significant solubilization obstacles and often compounds with solubility 10

mg/ml present difficulties to solubilization dosing formulation. In general, highly soluble drugs are undesirable for

formulation into SR product.

PARTITION COEFFICIENT
4 It is defined as the fraction of drug in an oil phase to that of an adjacent aqueous phase. It

influences not only the permeation of the drug cross the biological membranes but also diffusion

across the rate controlling membrane or matrix between the time when a drug is administered,

and when it is eliminated from the body, it must diffuse through a variety of biological

membranes that act primarily as lipid-like barriers.

A major criterion in evaluation of the ability of a drug to penetrate these lipid membranes 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.

In general, drugs with an extremely large value of K are very oil soluble and will partition into

5 membranes quite readily. The relationship between tissue permeation and partition coefficient for

the drug is generally defined with Hansch correlation which describe parabolic relationship between

the logarithm of its partition coefficient and logarithm of its drug activity.

Example:

The third generation dihydro-pyridines have an added additional property to this class of drugs: high

lipophilicity. Currently one of these drugs commercially available is Lercanidipine. As a result of the

lipophilic character this compound is relatively quickly cleared from the plasma building up within

phospholipid bilayer of cell membranes. The DHP thus accumulated can interact with its target, the

DHP site of target, the L-type calcium channel which lies within the double layer of the cell

membrane as well. This phenomenon explains the slow onset and long duration of action. The

sustained release of drugs which exhibit this type of property will offer no special advantages over

conventional dosage forms.

DRUG pKa and IONIZATION AT PHYSIOLOGICAL pH.
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 Drugs existing largely in an ionized form are poor candidates for oral SR DDS.

Absorption of the unionized drugs is well whereas permeation of ionized drug is

negligible because the absorption rate of the ionized drug is 3-4 times less than

that of the unionized drug.

 The pKa range for an acidic drug whose ionization is pH sensitive is around 3.0-

7.5 and pKa range for basic drug whose ionization is pH sensitive is around 7.0-

11.0 are ideal for optimum positive absorption.

 Drug shall be unionized at the site to an extent 0.1- 5%.

DRUG STABILITY
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 Drugs undergo both acid/base hydrolysis and enzymatic degradation when

administered oral route.

 Drugs that are unstable in gastric pH can be developed as slow release dosage

form and drug release can be delayed until the dosage form reaches the

intestine.

 Drugs that undergo gut wall metabolism and show instability in the small

intestine are not suitable for SR system.

 In such case, the drug can be modified chemically to form prodrugs, which may

possess different physicochemical properties or a different route of

administration should be chosen. For example CR of Nitroglycerin.

MOLECULAR WEIGHT AND DIFFUSIVITY
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i. Diffusivity is defined as the ability of a drug to diffuse through the

membrane. Diffusivity depends on size and shape of the cavities of the

membrane.

ii. The diffusion co-efficient of intermediate drug molecular weight is 100-

400 Daltons through flexible polymer range is 10−6-10−9 cm2/seconds.

iii. Molecular size or weight is indirectly proportional to the diffusibility.

Drugs with larger molecular are a poor candidate for oral SR system.

PROTEIN BINDING
9 It is well-known that many drugs bind to plasma proteins with concomitant influence on the duration

of drug action. Since blood proteins are four the most part re-circulated and not eliminated, drug

protein binding can serve as the depot for drug producing a prolonged release profile, especially if a

high degree of drug binding occurs. The drug interaction and the period of binding with mucin-like

protein also influence the rate and extent of oral absorption.

DOSE SIZE
For orally administered systems, there is an upper limit to the bulk size of the dose to be

administered. In general, a single dose of 0.5-1.0 g is considered maximal for a conventional dosage

form. This also holds for sustained-release dosage forms. Those compounds that require large dosing

size can sometimes be given in multiple amounts or formulated into liquid system. Another

consideration is the margin of safety involved in the administration of large amounts of a drug with

narrow therapeutic range.

10 BIOLOGICAL APPROACH

 It includes the following factors:

 Absorption

 Distribution

 Metabolism

 Elimination half-life/Duration of action

 Margin of Safety/ Therapeutic Index

 Side effect

 Disease

ABSORPTION:
11 The rate, extent, and uniformity of absorption of a drug are important factors when considering its formulation into an

extended release system. The most critical incase of oral administration is Kr<<<Ka. Assuming that the transit time of

drug through the absorptive area of GIT is between 9-12 hours, the maximum absorption half-life should be 3-4 hours.

This corresponds to a minimum absorption rate constant Ka value of 0.17-0.23/hr necessary for about 80-95% absorption

over a 9-12 hours transit time.

For a drug with a very slow rate of absorption (Ka<<0.17/hr), the first order release rate constant Kr less than 0.17/hr

results in unacceptably poor bioavailability in many patients. Therefore slowly absorbed drug will be difficult to be

formulated into extended release systems where the criterion Kr<<<Ka must be met (Rudnic & Schawartz., 2000).

If the drug were erratically absorbed because of variable absorptive surface of gastrointestinal tract, design of the

sustained/controlled release product would be more difficult or prohibitive. Ex: The oral anticoagulant – Dicoumarol, Iron

• Drugs absorbed by active transport system are unsuitable for sustained/controlled drug delivery system:

Methotrexate, Enalapril, Riboflavin, Pyridoxine, 5-Fluorouracil, 5-Bromo uracil, Nicotinamide, Fexofenadine, Methyl-dopa.

• Drugs absorbed through amino acid transporters in the intestine: Cephalosporines, Gabapentin, Baclofen, Methyl-

dopa, Levo-dopa.

• Drugs transported through Oligo – peptide transporters: Captopril, Lisinopril, Cephalexin, Cefadroxil, Cefixime.

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• Drugs required to exert a local therapeutic action in the stomach are unsuitable for sustained /controlled drug delivery.

Ex: Misoprostol, 5-fluorouracil, Antacids, anti-helicobacter pylori agents.

Absorption Window

Some drugs display region specific absorption which is related to differential drug solubility and stability in different regions

of G.I.T, as a result of changes in environmental pH, degradation by enzymes, etc. These drugs show absorption window,

which signifies the region of G.I tract where absorption primarily occurs. Drugs released from sustained/controlled release

systems, after absorption window has been crossed goes waste with little/ negligible absorption. Hence absorption

window can limit the bioavailability of orally administered compounds and can be a major obstacle to the development of

sustained/controlled release drugs (Stanley S., 2005 and Sanjay., 2003).

Examples of Drugs exhibiting the site specific absorption in stomach or upper parts of small intestine(absorption window)

are:

Acyclovir, Captopril, Metformin, Gabapentin, Atenolol, Furosemide, Ranitidine, Levo-dopa Sotalol, Salbutamol, Riboflavin,

Sulphonamides, Loratadine, Cephalosporines, Tetracyclines Verapamil, Thiamine, Sulpiride, Baclofen, Nimesulide,

Cyclosporine, Quinolines.

Distribution
13 The distribution of a drug into vascular and extra vascular spaces in the body is an important factor in the

overall elimination kinetics. Apparent volume of distribution and ratio of drug in tissue to plasma (T/P)

concentration are used to describe the distribution characteristics of a drug.

For drugs which have apparent volume of distribution higher than real volume of distribution i.e., drugs

which are extensively bound to extra vascular tissues eg: chloroquine, the elimination half life is decreased

i.e. the drug leaves the body gradually provided drug elimination rate is limited by the release of drug

from tissue binding sites and that drug is released from the tissues to give concentrations exceeding the

threshold level or within the therapeutic range, one can assume that such drugs are inherently sustained.

The larger the volume of distribution, the more the drug is concentrated in the tissues compared with the

blood. It is the drug in the blood that is exposed to hepatic or renal clearance, so that when the distribution

volume is large these mechanisms have fewer drugs to work on. By contrast, if the volume of distribution is

small, most of the drug in the body is in the blood and is accessible to the elimination process.

Table 1 shows drugs with apparent volume of distribution higher than total volume of distribution. To avoid

the ambiguity inherent in apparent volume of distribution as estimation of amount of drug in body, the T/P
14 ratio is used. If the amount of drug in central compartment ‘P’ is known, the amount of drug in peripheral

compartment ‘T’ and hence the total amount of drug in the body can be calculated by

T/P = k12 (k 21 – β)

Where, β = slow disposition rate constant

Table 1 Drug with apparent volume of distribution higher than total volume of distribution

DRUG App. Vol. Distribution(lts)

Chloroquine 12950

Digoxin 500

Doxepin 1400

Flurazepam 1540

Haloperidol 1400

Azythromycin 2170

Amiodarone 4620

Metabolism:
Metabolism of drug can either inactivate an active drug or convert an inactive drug to active metabolite. Complex metabolic

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patterns would make the S.R/C.R design much more difficult particularly when biological activity is wholly or partly due to a

metabolite as in case isosorbide 2, 5-dinitrate. There are two areas of concern related to metabolism that significantly restrict SR

product design. First, if a drug upon chronic administration is capable of either inducing or inhibiting enzyme synthesis, it will be

a poor candidate for a SR/CR product because of the difficulty of maintaining uniform blood levels of a drug. Second, if there is a

variable blood level of a drug through either intestinal metabolism or through first pass effect, this also will make formulation of

SR dosage form difficult, since most of the process are saturable, the fraction of the drug loss would be dose dependent and that

would result in significant reduction in bioavailability if the drug is slowly released over a extended period of time.

Fluctuating drug blood levels due to intestinal metabolism upon oral dosing: Examples: Salicylamide, Isoproterenol,

Chlorpromazine, Clonazepam Hydralazine and Levodopa.

Fluctuating drug blood levels due to first pass hepatic metabolism upon oral dosing: Ex: Nortriptyline, phenacetin, morphine,

propranolol.

Fluctuating blood levels due to enzyme induction are poor candidates for Sustained/controlled Release dosage forms:

Ex: Griseofulvin, Phenytoin, Primidone, Barbiturates, Rifampicin, Meprobamate, Cyclophosphamide.

Fluctuating blood levels due to enzyme inhibition are poor candidates for Sustained/Controlled Release dosage forms:

Ex: Isoniazid, Cimetidine, Amiodarone, Erythromycin, Fluconazole, Ketoconazole, MAO–inhibitors, Para-aminosalicyclic acid,

Allopurinol, Coumarins.

Elimination Half Life:
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Half life is the time taken for the amount of drug in the body (or the plasma concentration) to fall by half and

is determined by both clearance (Cl) and volume of distribution (VD)

t1/2 = 0.693xVd/Cl

Half life is increased by increasing in volume of distribution or a decrease in clearance, and vice-versa. The larger the

volume of distribution the more the drug is concentrated in the tissues compared with the blood. If the volume of

distribution is small, most of the drug in the body is in the blood and is accelerated to the elimination process.

For drugs that follow linear kinetics, the elimination half-life is constant and does not change with dose or drug

concentration.

For drugs that follow non-linear kinetics, the elimination half-life and drug clearance both change with dose or drug

concentration Drugs with short half-lives (<2hrs) and high dose impose a constraint on formulation into

sustained/controlled release systems because of the necessary dose size and drugs with long half-lives (>8hr) are

inherently sustained (Birkett,1998). Sustained release products for drugs with intrinsically long biologic half-lives are

available. As expected, little or no therapeutic advantages have been demonstrated in these products over

conventional dosage forms. Examples: Meprobamate (11.3 hr), Amitriptyline (21 hr).

Duration of Action:
17 It is the time period for which the blood levels remain above the MEC and below the MSC levels (or) more specifically

within the therapeutic window. Drugs acting for long duration are unsuitable candidates for formulation into S.R/C.R

forms. The long duration of action of ACE inhibitors is determined by Plasma half-life and the Affinity of binding to

tissue ACE (Taylor S.H., 1990). Drugs with short plasma half- life but high tissue binding such as quinapril are active

for 24 hrs. Other drugs such as lisinopril have weaker tissue ACE binding but much long plasma half life is also long

acting.

In contrast captopril which has relatively short duration of action has weaker tissue ACE binding and short plasma

half life. Proton pump inhibitors forms covalent bond with parietal cells and is irreversible and inhibits acid secretion

for life period of bonded parietal cell (18-24 hr).

Receptor occupation, Tissue binding, Half life, Metabolism, Partition coefficient Irreversible binding to cells are some

parameters which are responsible for long duration of action of drugs.

Since inhibition lasts for 24 hr or more these proton pump inhibitors are dosed once daily and offer no significant

advantage if formulated in sustained release dosage form.

Margin of Safety/ Therapeutic index:
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 Margin of safety of a drug can be described by considering therapeutic index, which is the ration of

median toxic dose and median effective dose.

Therapeutic index = TD50/ED50

 A drug is considered to be relatively safe with therapeutic index more than 10 i.e., larger the ratio the

more safe is the drug. Margin of the safety of the drugs determined on the basis of therapeutic index is

the range of plasma concentration in which the drug is considered to the safe and therapeutically

effective.

 The drugs with narrow therapeutic indices the release pattern should be more precise to maintain the

plasma concentration within the narrow therapeutic and safety range. The unfavorable therapeutic index

of a drug can be overcome by suitable employment of the SR mechanisms.

Side Effect: The side effects of the some drugs are mainly developed due to fluctuation in the

19 plasma concentrations. The incidences of side effects can be minimized by controlling the concentration within

therapeutic range at any given time. The SR drug delivery is the most widely used to incidences of the GI (local)

side effects rather than a systemic side effect of the drug. The drug properties which induce local or systemic

side effect can be circumvented or modified by their incorporation in a suitable oral SR delivery system that

employs a specific controlled release mechanism.

DISEASE STATE: Disease state and circadian rhythm are not drug properties, but they are

equally important as drug properties in considering a drug for SR.

For example:

• Aspirin is a drug of choice for rheumatoid arthritis though it is not suitable for SR dosage form. Still, aspirin SR

dosage form could be advantageous to maintain therapeutic concentrations, particularly throughout the night,

thus alleviating(to decrease) morning stiffness.

• Asthma attacks are commonly occurring before bedtime, due to a low cortisol level. The highest cortisol level

occurred between 12 midnight and 4 a.m. These variations entail for the design an oral SR delivery in

accordance to circadian rhythm.

References:
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 Karna Sudhir*, Chaturvedi Shashank, Aggrawal Vipin, Alim Mohammaad, ‘’Formulation
Approaches For Sustained Release Dosage Forms’’, Asian Journal Of Pharmaceutical And Clinical
Research, Vol 8 Issue-5,2015.

 Mamidala R.K, Ramana Vamshi, Sandeep, Yamsani M.R,” Factors Influencing the Design and
Performance of Oral Sustained/Controlled Release Dosage Forms”, International Journal of
Pharmaceutical Sciences and Nanotechnology, Vol 2, Issue-3, 2009.

 Chein YW, “Novel Drug Delivery System”, Revised and Expanded, 2nd ed, New York: Marcel
Dekker; 2005.

 Aulton ME, “Aulton’s Pharmaceutics – The Design and Manufacture of Medicine”, 3rd ed, New
York: Churchill Livingstone; 2007.

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