factors affecting design of controlled release drug delivery systems (write-up)

CRDDS (DR. V. KUSUM MADAM)

BY-Suraj Choudhary

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BY-Suraj Choudhary

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FACTORS AFFECTING DESIGN OF CRDDS

1. Selection of drug candidate

2. Medical Rationale

3. Biological Factors

4. Physico-Chemical Properties

5. In vitro analysis

6. Formulation optimization

7. In vivo data generation

8. Discussion with Regulatory Authorities

9. Data submission to Regulatory Authorities for Marketing, Authorization / Approval.

1. Selection of Drug Candidate a. Very short or very long half-life:

In the design of CRDDS, it is necessary to determine the half-life of the drug candidate, as if

it will be either too high or too low, both cannot be considered.

In case of higher t1/2, such drugs have already the capability to remain in the body for longer

periods, so if formulated in CRDDS, then it’ll further enhance the same property & may lead

to toxicity.

Thereby, it is necessary to go for drugs which have optimum half life.

b. Significant first pass metabolism

The primary problem with the conventional dosage form, is their incapability to by-pass the

First pass metabolism.

Thereby most of the drug contents gets converted to their respective metabolites and becomes

inactive or gets converted to toxic forms, which affects severely.

In such case, by formulating it into CRDDS eliminates the problem.

But while formulating it in such form, it is necessary to consider the fate of the raw materials

used in the formulation and resistant to the First pass metabolism or have ability to bypass the

same.

c. Poor absorption throughout the GI tract

Most of the well versed molecules discovered so far have very poor absorption throughout the

GIT tract.

In such cases, formulation into a controlled release form, leads to increase in the release profile

and absorption phenomena progressively.

It is important to determine the solubility profile as thereby it’ll easier to determine the

targettted site of delivery.

d. Low solubility


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Drugs with lower solubility can be formulated in the form of CRDDS, so that it reaches to the

systemic circulation by-passing the barriers.

e. Large no. of dose

If the dose of the drug is higher or frequency of dosing is higher due to low bioavailability or

higher elimination rate, then the formulation of the same in the form CRDDS, expels out all

such problems and leads to patient compliance.

If the dose is too large then there are chances of formulation of bigger size that would not be

favourable as per patient compliance.

f. Narrow therapeutic window

For drugs with low therapeutic window, directly affects the frequency of dosing and

therapeutic effects which decreases fast.

So, in order to extend its therapeutic window, CRDDS is the ideal method.

It is difficult to produce such formulation with low therapeutic window, as it’ll not be there in

the site for longer time, so release pattern is required to be controlled properly.

2. Medical Rationale

a. Frequency of dosing

The major problem with the conventional therapy, is the frequency with which the drug is

administered to the patient.

Sometimes it exceeds above 3 times a day, which becomes problematic for them to take

continuously on time without skipping.

Such huge problem can be reduced if such drugs are formulated as CRDDS, which will release

the drug a defined rate and thereby maintain the drug concentration within the blood at steady

state.

b. Patient Compliance

The primary concern in the context of patient is their convenience about the drug intake

regimen.

Most of the conventional formulations due to low bioavailability, low duration of action, etc.

given many times which leads to changes of dose skip that may affect the patient health

directly.

Such concerns can be reduced in CRDDS, but we need to consider the route of administration,

size of the final product and patient viewpoint at the same time.

c. Drug intake

In this case, the formulation type directly affects the patient compatibility.

In case of very large dose of drug, the formulation size increases which may be a problem for

paediatric and geriatric patients to take.


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Thereby, CRDDS allows the efficiency of reducing the dose or changing the route of

administration with enhanced ease of therapeutic effects.

But we need to understand that how much of drug is required to be given, as it is too high, then

again CRDDS cannot be considered.

d. Fluctuations of serum concentration

Conventional dosage forms shows valleys and peaks in the plasma drug conc. vs time peak.

Such fluctuations causes increase or decrease of the therapeutic effect within the body, which

also affects the other systems.

Such fluctuations have been eliminated by CRDDS, as it gives initial straight line in the graph

with further forms the steady state conc. throughout.

e. Reduced side effects

The formulation of CRDDS directly reduces the side effects as it localized or targets the site

of disease without getting accumulated to off-sites.

f. Sustained efficacy

Efficacy of the drug incorporated within the CRDDS have pronounced efficacy for

sustainable time compared to the conventional dosage forms.

3. Biological Rationale

a. Absorption

Absorption efficiency differs throughout the GIT, which directly affects the extent of drug

absorption from the site.

Most of the drugs are poorly soluble and poorly permeable, thereby less absorbable. Thus, in

such cases, the use of CRDDS, enables them to be carried out into the cell easily.

Even it enables some drugs to be get absorbed in stomach by creating a micro-environment

which was actually expected to be absorbed through intestine, but due to irritation have been

prevented.

b. Distribution

Distribution of drug from the conventional dosage form directly gets distributed throughout

the body, and gets accumulated to some of the off-sites, which may lead to toxicity.

Such instances can be prevented by CRDDS, which can be site-targetted and specific towards

the diseases condition area and thus preventing accumulation in other sites.

It also enables the complete drug to be reached to the required site, unlike the conventional

forms.

c. Elimination

There are so many drugs available, which accumulates in the organs like liver, pancreas, etc.

and becomes fatal sometimes.

Removal of such unwanted accumulated portion is quite hectic for the system due to slow

elimination rate.


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In such cases, CRDDS again plays a major role as the accumulation in off-sites are

comparatively negligible and also the released drug is easily expresses the action and then gets

eliminated safely.

d. Dose dependent Bioavailability

Due to low bioavailability of most drugs, higher and sometimes repeated doses are given at

certain intervals of time.

This leads to patient inconvenience and most importantly the changes of missing the dose.

Such problems can be eliminated by using the CRDDS as the tool.

e. Drug-Protein Binding

One of the major problem with conventional dosage form is the lesser availability of the drug

in the blood due to higher protein binding.

This binding decreases the action of drug and thereby the effective therapeutic effect

diminishes.

But in case of CRDDS, this problem can be eradicated by formulating it in several carriers

which will further help in delivering the drug in required quantity at the desired site.

f. Duration of Action (Half Life)

Many drugs have either too higher half-life or have very low half-life which creates huge

problem in conventional delivery systems.

In case of higher half-life, the CRDDS approach is not required, as it already have the ability

to remain in the body for longer periods.

For drugs with smaller half-life, the CRDDS approach directly helps in both extending the

release and at a steady rate for long hours.

g. Margin of safety

In conventional daosage form, the margin of safety is quite low compared to CRDDS, due to

accumulation at off-sites, less target specific, protein-binding, etc.

When it comes to safety, again the major concern comes is the elimination of the polymers and

other excipients used in the CRDDS without accumulation or side effects.

The types of polymers used must be biodegradable enough so that the alternate effects of its

metabolites are less and without toxic effects.

h. Disease Condition

Another parameter which defines the CRDDS, is the condition of the patient and the kind of

disease it have.

Generally the targeting and route of delivery system is determined by the type of disease

focussed.

4. Pharmaco-kinetic/Dynamic Considerations a. Dose Dumping


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With so many merits, still there is one of the major problem in case of CRDDS is the chances

of Dose dumping.

Dose dumping refers to the accidental release of the drug from the CRDDS which may lead to

toxicity.

If it a multiple dose drug delivery formulation, then it could fatal and may cause death.

Such case is possible if there is some error in the formulation aspect like inefficient coating,

polymer or excipient interaction, etc. or maybe because of problem in drug intake by the

patients or may be packaging errors.

So while formulating, it is necessary to assess the drug entrapment, coating efficiency, etc.

parameters for formulating a safer CRDDS.

b. First Pass metabolism

The major concern in case of CRDDS is the ability of such system to bypass the First-pass

metabolism.

First pass metabolism refers to the absorption of the drug from the GIT and then reaching to

liver, where it gets converted to its active or inactive metabolites and recirculated back into the

GIT.

It is a type of metabolism process which leads to decreasing the drug ability to act and thereby

elimination.

So, the CRDDS system should be well enough to cope up in this scenario, or may be formulated

to deliver through other route with same efficiency.

c. Enzyme induction/inhibition on multiple dosing

Another important factor includes is the either induction or inhibition of body’s biological

enzymatic systems which may leads to certain adverse effects.

So, while formulating, it is necessary to understand the site and its other biological

considerations for proper delivery without adverse reactions on the normal processes running

within the body.

d. Urinary pH variability (on elimination)

Another problem includes the nature of the materials which have been used in the

formulations, as sometimes the change in urinary pH may occurs which may be toxic for the

urnary system and may lead to side effects.

e. Prolonged drug absorption

Some of the drugs requires more time in absorption which may leads to least absorption than

required and thereby decrease in potency.

f. Variability in GI motility

One of the major concern is the GI motility which differs based on conditions like food

presence, area of the GIT, type of formulation, etc.


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Thus, it is necessary to formulate the type of CRDDS, which manages the time and extent of

absorption based on the motility factors and time of GI emptying.

5. Physico-Chemical Considerations

a. Solubility & pKa

• The solubility of a solid substance is defined as…….

“ the concentration at which the solution phase is in equilibrium with a given solid phase

at a stated temperature & pressure.”

• To improve solubility:

Solvation Complexation

Hydration Recrystallization

Co-solvation Use of surface active agents

• NOTE: A classification is given as per the permeability & solubility profile, known as BCS

Classification.

• Determination of Solubility:

1. Semi quantitative method

2. Accurate-quantitative method

3. pH change method

• Absorption of poorly soluble drugs is often dissolution rate-limited.

• Such drugs do not require any further control over their dissolution rate and thus may not

seem to be good candidates for oral controlled release formulations.

• Controlled release formulations of such drugs may be aimed at making their dissolution

more uniform rather than reducing it.

b. Partition Coefficient

• The partition coefficient is defined as…….

“ the concentration ratio of unionized drug distributed between two phases at

equilibrium.”

• Given by the Noyes-Whitney’s Equation:

P = [𝐴]/([𝐴]∞)

• The logarithm (base 10) of the partition coefficient (log10P) is often used.

• For ionizable drugs, where the ionized species does not partition into the organic phase, the

APPARENT partition coefficient, (D), can be calculated as:……….

Acids : log10D = log10P – log10 (1 + 10 (pH-pKa))


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Bases : log10D = log10P – log10 (1 + 10 (pKa-pH))

• The octanol-water partition coefficient, (log10Pow), has been widely used as a measurement

for determining the relative lipophilicity of a drug.

• Drugs that are very lipid soluble or very water-soluble i.e., extremes in partition

coefficient, will demonstrate

either low flux into the tissues or

rapid flux followed by accumulation in tissues.

• Both cases are undesirable for controlled release system.

c. Mol.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, its so called diffusivity, is a function of its

molecular size (or molecular weight).

• 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) are generally used as the most common

methods to determine the molecular size of the drug.

2. Fourier Transform IR- spectroscopy (FTIR) is also used to determine the

molecular structure.

• 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.

d. 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.

e. Complexation

• Complexation is one of the well known method to entrap the drug within a complexing

agent like β-cyclodextrin complex.


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• 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 required solvent.

f. Ionization Constant

• This factor have important effects on a wide range of issues including, Dissolution,

Membrane partition, Complexation, Chemical stability & drug absorption.

• From the site of release of the drug, its absorption depends upon its ionization constant.

• And, it has been depicted that drugs in unionized form are absorbed faster than the ionized

species.

• The Henderson-Hasselbalch eq. provides an estimate of ionized & unionized drug conc, by

function of pH…………

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

g. Drug stability

• Since most oral controlled release systems are designed to release their contents over much

of the length of GI tract,

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.

h. Protein Binding

• It refers to the formation of complex with the blood proteins (like albumin) with the

absorbed drug.


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• This complex leads to….

Inhibition of therapeutic effect of such amount

Half-life is increased (compared to invitro studies)

Toxicity profiles elevated

• Thus, in most of the cases, protein binding is undesirable.

• Many drugs are highly protein binding (may be 95%), thus the need of formulating a

modified drug or drug delivery system starts.

NOTE: Generally, the values of diffusion coefficient for intermediate molecular weight drugs i.e., 150-

400 Dalton, through flexible polymers range from 10-6 to 10-9 cm2/sec, with values on the order

of 10-8 being most common.

NOTE: For drugs with molecular weight greater than 500 Dalton, the diffusion coefficients in many

polymers frequently are so small that they are difficult to quantify, i.e., less than 10-12 cm2/sec.

NOTE: Thus, high molecular weight of drug should be expected to display very slow release kinetics

in sustained release devices where diffusion through polymeric membrane or matrix is the release

mechanism.

APPROACHES FOR CRDDS DESIGN CONSIDERATIONS

Chemical approach

Biological approach

Pharmaceutical approach

PHARMACEUTICAL APPROACHES

A. Dissolution controlled Release

Encapsulation dissolution control

Matrix dissolution control

B. Diffusion Controlled Release

Membrane material

Solution-diffusion membrane

Rate of permeation

Drug diffusion coefficient in the polymer

Polymer/solution partition coefficient


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C. Dissolution-Diffusion Controlled (Combination)

DISSOLUTION CONTROLLED

INTRODUCTION:

• Control – Dissolution of the drug from the polymer matrix or encapsulated forms.

• The dissolution process at a steady state is described by Noyes Whitney equation:

dc / dt = k A/V (Cs – C)

dc / dt = (D/h) A (Cs – C)

where, dC/dt = dissolution rate

V = volume of the solution

k = dissolution rate constant

D = diffusion coefficient of drug through pores

h = thickness of the diffusion layer

A = surface area of the exposed solid

Cs = saturated solubility of the drug

C = conc. of drug in the bulk solution

• Of following types based on TECHNICAL SOPHISTICATION:

1. Matrix type

2. Encapsulation type

MATRIX TYPE :

• Matrix dissolution devices are prepared by compressing the drug with slowly dissolving carrier

into tablet

• Controlled dissolution by:

1. Altering porosity of tablet

2. Decreasing its wettability

3. Dissolving at slower rate

• First order drug release.

• There are 2 methods:

1. Congealing &

2. Aqueous dispersion method


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• The drug release is determined by dissolution rate of the polymer.

• Examples:

1. Dimetane extencaps,

2. Dimetapp extentabs.

ENCAPSULATION TYPE :

• The drug particle are coated or encapsulated by microencapsulation technique

• The pellets are filled in hard gelatin capsule, popularly called as ‘spansules’.

• Once the coating material dissolves the entire drug inside the microcapsule is immediately

available for dissolution and absorption.

• Here the drug release is determined by dissolution rate and thickness of polymer membrane

which may range from 1 to 200µ.

• Called as Coating dissolution controlled system.

• Dissolution rate of coat depends upon stability & thickness of coating.

• One of the microencapsulation method is used.

Examples:

1. Ornade spansules,

2. Chlortrimeton Repetabs

Drug Reservoir

Rate-Controlling surface

Drug

Soluble drug

Slowly dissolving or erodible coat


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DIFFUSION CONTROLLED

INTRODUCTION :

• This system is hollow containing an inner core of drug.

• The water insoluble polymeric material surrounds drug reservoir.

• The drug partitions into the membrane and exchanges with the surrounding fluid by diffusion.

• The release drug from a reservoir device follows Fick’s first law of diffusion.

J = - D dc/dx

Where, J = flux, amount/area-time

D = diffusion coefficient of drug in the polymer, area/time

dc/dx = change in conc. with respect to polymer distance

• Of following types based on TECHNICAL SOPHISTICATION:

1. Reservoir Devices

2. Matrix Devices

RESERVOIR DEVICES :

• The drug core is encased by a water-insoluble polymeric materials.

• The mesh (i.e., the space between macromolecular chains) of these polymers, through which

drug penetrates or diffuses after partitioning, is of MOLECULAR LEVEL.

• The rate of drug release is dependent on the rate of drug diffusion but not on the rate of

dissolution.

• In short, mass transport phenomena at molecular level occurs.

• TYPES:

a) Spherical type

b) Slab type


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• Types based on Methods of Preparation :

o Coated Beads/Pellets

o Microencapsulation

1. Coated Beads/Pellets

• BEADS/PELLETS

Coating of drug solution onto preformed cores.

Covering of core by an insoluble (but permeable coat).

NOTE: Pan Coating or air-suspension technique is generally used for coating.

NOTE: Pore forming additives may be added to the coating solution.

2. Microencapsulation

• This technique used to encapsulate small particles of drug, solution of drug, or even gases in a

coat (usually a polymer coat).

• Generally, any method that can induce a polymer barrier to deposit on the surface of a liquid

droplet or a solid surface can be used to form microcapsules.

Rate controlling Steps :

• Polymeric content in coating,

• Thickness of coating,

• Hardness of microcapsule.


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• Techniques:

a) Coacervation (Polymers: gelatin, acacia, PA, EC, etc.)

b) Interfacial polymerization (Polymers: polyurethanes, polyamides, polysulfonamides,

polyphtalamides, etc.)

c) Solvent evaporation

d) Others (thermal denaturation, hot melt, spray-drying, salting out, etc.)

MATRIX DEVICES :

• A matrix or monolithic device consists of an inert polymeric matrix in which a drug is uniformly

distributed.

• Drugs can be dissolved in the matrix or the drugs can be present as a dispersion.

NOTE: Matrix may be HOMOGENEOUS or POROUS with water filled pores.

• State of presentation of this form affects the various release patterns:

1. Dissolved drug (Fick’s Second law)

2. Dispersed drug (Fick’s First law)

3. Porous matrix (Higuchi’s theory for porous form)

4. Hydrophilic matrix (gelation & diffusion)

• Types based on Methods of Preparation:

1. Rigid Matrix Diffusion

o Materials used are insoluble plastics such as PVP & fatty acids.

2. Swellable Matrix Diffusion

a. Also called as Glassy hydrogels (Popular for sustaining the release of highly water

soluble drugs)

b. Materials used are hydrophilic gums.

Examples : Natural- Guar gum, Tragacanth.

Semisynthetic -HPMC, CMC, Xanthum gum.

Synthetic -Polyacrilamides.

RECENT MARKET TRENDS

• Products in market:

Cordicant -uno®


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Madopar DR

SULAR ER

• This technology controls amount, timing and location of release in body.

• Formulation with predictable and reproducible drug release profile.

• Controls rate of drug diffusion throughout release process, ensuring 100% release Products

REFERENCES

1. Chien Y W; Novel Drug Delivery Systems; Informa Healthcare, 2nd Edition, 2009.

2. Siegel R A and Rathbone M J; Overview of Controlled Release Mechanisms; Advances in

Delivery Science and Technology, 2012.

3. Bhowmik D, et.al; Recent trends in scope and opportunities of control release oral drug

delivery systems; Critical review in pharmaceutical sciences, (1): 2012.

4. Ummadi S, Shravani B; Overview on Controlled Release Dosage Form; International Journal of

Pharma Sciences, 3(4); 2013.

factors affecting design of controlled release drug delivery systems (write-up)

Health & Medicine

formulation of crdds

form of crdds

form crdds

drug concentration

large dose of drug

plasma drug

drug contents

low therapeutic window