To give knowledge about topic

1. Sustained and Controlled
Drug Delivery System
Presented By:
Ms. Harshada. R. Bafna
2/28/2024 HRB
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2. Syllabus content
Sustained and controlled drug delivery: Definition – Historical
development, advantages and disadvantages. Classification – details
of matrix and diffusion control systems. Model drug selection criteria
for SR & CR drug delivery system.
Biopharmaceutical aspects – steady state concept and concept of
maintenance dose & loading dose. Steady state diffusion, lag time,
diffusion cells. Dissolution: The diffusion layer model, drug release,
drug in polymer matrices, membrane control, reservoir type devices.
Evaluation of SR & CR Tablets only.
Brief introduction to polymers:- Introduction, classification, properties,
characterization. 2
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3. Introduction
The term “drug delivery systems’’refer to the technology utilized to
present the drug to the desired body site for drug release and
absorption.
Generations of dosage forms
1st gen. – Conventional (unmodified) release of drug.
2nd gen.– Controlled release of drug. (CR)
3rd gen. – Targeted distribution drug delivery systems.
3
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4. In the conventional therapy aliquot quantities of drugs are
introduced into the system at specified intervals of time with the
result that there is considerable fluctuation in drug concentration
level as indicated in the figure.
Conventional drug delivery system
HIGH
LOW
HIGH
LOW
4
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5. However, an ideal dosage regimen would be one, in which the
concentration of the drug, nearly coinciding with minimum
effective concentration (M.E.C.), is maintained at a constant level
throughout the treatment period. Such a situation can be graphically
represented by the following figure
CONSTANT LEVEL
5
Ideal dosage regimen
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6. 6
What is Sustain Release Dosage Form?
• Sustain release dosage form is defined as the type of dosage form
in which a portion i.e. (loading dose) of the drug is released
immediately, in order to achieve desired therapeutic response more
promptly, and the remaining (maintainence dose) is then released
slowly there by achieving a therapeutic level which is prolonged,
but not maintained constant.
• The basic goal of therapy is to achieve steady state blood level that
is therapeutically effective and non toxic for an extended period of
time.
• It may or may not be controlled release.
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7. 7
What is controlled Release Dosage Form?
• “Drug delivery system that are designed to release the drug at
predetermined rate, locally or systemically, for a specified period of
time.”
• Controlled release is perfectly zero order release that is the drug
release over time irrespective of concentration.
Injection
Toxicity level
Therapeutic Level
Controlled release
Time
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8. Rationality in designing this dosage form.
• The basic objective in dosage form design is to optimize the
delivery of medication to achieve the control of therapeutic effect
in the face of uncertain fluctuation in the in-vivo environment
in which drug release take place.
• This is usually concerned with maximum drug availability by
attempting
absorption.
• However,
to attain a maximum rate and extent of drug
control of drug action through formulation also
implies controlling bioavailability to reduce drug absorption
rates.
8
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9. Principle
• Immediate release conventional dosage form
Dosage Kr
form
Drug in
absorption
site
Ka Drug to Ke
target site
Drug
elimination
• Non immediate release dosage form (SR/CR)
Dosage Kr
form
Drug to Ke
target site
Drug
elimination
Here, Kr = 1st order release rate constant
Ka = 1st order absorption rate constant
Ke = 1st order elemination rate constant
The above criteria i.e. (Kr>Ka) is in case of immediate release, where
as in non immediate (Kr<Ka) i.e. release is rate limiting step. 9
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10. 10
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11. Difference between SR & CR
SR CR
1)Slow release of drug over extended
period of time.
1)Maintain a constant drug level in blood
or tissue.
2)Non site specific. 2)Site specific.
3)They show first order. 3)They show zero order.
4)Release of drug is conc. Dependent. 4)Release of drug is conc. independent.
5)Non predictable & reproducible. 5)Predictable & reproducible.
6)Plot 6)Plot
11
MEC
MSC
Plasma
conc.
Time
MSC
MEC
Plasma
conc.
Time
MSC= Maximum Safe Conc. & MEC = Minimum Effective Conc.
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12. Controlled Drug Delivery System
CR dosage form may contain:
Loading dose: Release the drug immediately after administration
and follows first order kinetics.
Maintenance dose: Release the drug slowly and maintain the
therapeutic level for extended period of time. It follows zero order
kinetics.
12
Loading dose
Maintenance
dose
Dosage
form
Drug
blood
level
Time
Maintenance
dose
Loading dose
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13. Improved patient convenience and
frequent drug administration.
compliance due to less
Reduction in fluctuation in steady-state level and therefore better
control of disease condition.
Increased safety margin of high potency drug due to better
control of plasma levels.
Maximum utilization of drug enabling reduction in total amount
of dose administered.
Reduction in health care cost through improved therapy, shorter
treatment period.
M erits.
13
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14. 14
Less frequency of dosing and reduction in personnel time to
dispense, administer monitor patients.
Better control of drug absorption can be obtained, since the high
blood level peaks that may be observed after administration of a
dose of high availability drug can be reduced.
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15. Demerits..
Decreased systemic availability in comparison to immediate
release conventional dosage forms; this may be due to incomplete
release, increased first-pass metabolism, increased instability,
insufficient residence time for complete
absorption, pH dependent solubility etc.,
Poor in-vivo to in-vitro correlation.
release, site specific
Possibility of dose dumping due to food, physiologic or
formulation variable or chewing or grinding of oral formulation by
the patient and thus increased risk of toxicity.
15
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16. sustained release forms.
16
Retrieval of drug is difficult in case of toxicity, poisoning or
hypersensitivity reaction.
The physician has less flexibility in adjusting dosage regimens.
This is fixed by the dosage form design.
Sustained release forms are designed for the normal population
i.e. on the basis of average drug biologic half-life’s. Consequently
disease states that alter drug disposition, significant patient variation
and so forth are not accommodated.
Economics factors must also be assessed, since more costly
processes and equipment are involved in manufacturing many
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17. 17
Components of CRDDS
• Drug
• Polymers
-Ion exchange polymers e.g. polystyrene sulfonic acid
-Swellable polymers e.g. ethylene alcohol
-Bioadhesive polymers e.g. polycarbopol
• Excipients
-Diluents e.g.. Lactose
-Binders e.g.. Gelatin
-Disintegrants e.g.. Polyvinylpyrrolidone
-Lubricants and Glidents e.g.. Talc , stearic acid
-Colors , flavors and sweetener
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18. 18
Ideal Characteristics of drug
• Drugs which have half life between 2-8 hrs.
• Drugs which have therapeutic index greater than 10.
• Drugs which are undergo least first pass metabolism.
• Substances should have good aqueous solubility.
• Dose size should be 0.5-1.0 gm.
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19. Factors to be considered In S.R.Dosage forms.
2. Biological Factors
1. Absorption.
2. Distribution.
3. Metabolism.
4. Biological half
life.(excretion)
5. Margin of safety
6. Dosage size.
1. Physiological Factors:
1. Partition coefficient and
molecular size.
2. Aqueous Solubility.
3. Drug stability.
4. Protein binding.
5. Pka
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20. 1. Partition coefficient and molecular size.
Partition coefficient is the fraction of drug in an oil phase (C0) to
that of an adjacent aqueous phase (Cw).
K = C0 / Cw
Drug with high K value permeates faster gets deposited in tissues
and cause toxicity.
Drug with low K value do not permeate at all.
Therefore optimum a drug should possess optimum K value.
The relation between drug activity and K value can be given by
Hansch correlation
Physiological Factors
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21. 21
Hansch correlation
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22. 2. Aqueous Solubility & Pka.
Since drugs must be in solution before they can be absorbed,
compounds with very low aqueous solubility usually suffer oral
bioavailability problems, because of limited GI transit time of
undissolved drug particles and limited solubility at the absorption site.
E.g. Tetracycline dissolves to greater extent in the stomach than in the
intestine, therefore it is best absorbed in the intestine.
for drugs with poor aqueous solubility, it will be difficult to
incorporate into sustained release mechanism.
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23. Aqueous solubility
The aqueous solubility of the drug influences its dissolution rate
which in turn establishes its concentration in solution and hence the
driving force for diffusion across the membranes as shown by
Noyes-Whitney’s equation which under sink condition that is
dc/dt= D.A.Cs
Where dc/dt = dissolution rate
D = dissolution rate constant
A = total surface area of the drug particles
Cs = aqueous solubility of the drug
In above equation dc/dt will be constant ifAis constant
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24. Drug with low aqueous solubility have low dissolution rate and its
suffer oral bioavailability problem.
The aqueous solubility of weak acid and bases are controlled by
pKa of the compound and pH the medium.
For weak acids
St= So (1+10pH-pKa )
Where St = total solubility of weak acid.
So = solubility of unionized form
Ka=Acid dissociation constant
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25. For Weak Bases
St = So (1+10pKa-pH )
Where, St = total solubility of weak base
So = solubility of free base form
Example: If a poorly soluble drug was consider as a suitable
candidate for formulation into sustained release system. Since
weakly acidic drugs will exist in the stomach pH 1-2 , primarily in
the unionized form their absorption will be favored from this acidic
environment on the other hands weakly basic drugs will be exist
primarily in the ionized form (Conjugate Acids) at the same site,
their absorption will be poor. in the upper portion of the small
intestine the pH is more alkaline pH 5-7 and the reverse will be
expected for weak acids
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26. 3.Drug stability.
The stability of drug in environment to which it is exposed, is
sustained/controlled release systems, drugs that are unstable
another physico-chemical factor to be considered in design at
in
stomach can be placed in slowly soluble forms or have their release
delayed until they reach the small intestine.
Orally administered drugs can be subject to both acid, base
hydrolysis and enzymatic degradation.
Degradation will proceed at the reduced rate for drugs in the solid
state compared to liquid dosage forms.
For drugs that are unstable in stomach, systems that prolong
delivery ever the entire course of transit in GI tract are beneficial.
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27. Compounds that are unstable in the small intestine may demonstrate
decreased bioavailability when administered form a sustaining dosage
from. This is because more drug is delivered in small intestine and
hence subject to degradation.
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28. 4.Protein binding.
It is well known that many drugs bind to plasma protein with the
influence on duration of action.
Drug-protein binding serve as a depot for drug producing a prolonged
release profile, especially it is high degree of drug binding occurs.
Extensive binding to plasma proteins will be evidenced by a long
half life of elimination for drugs and such drugs generally mostly
require a sustained release dosage form.
However drugs that exhibit high degree of binding to plasma
proteins also might bind to bio-polymers in GI tract which could have
influence on sustained drug delivery.
The presence of hydrophobic moiety on drug molecule also increases
the binding potential.
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29. The binding of the drugs to plasma proteins(e.g. Albumin)
results in retention of the drug into the vascular space the drug
protein complex can serves as reservoir in the vascular space for
sustained drug release to extra vascular tissue but only for those
drugs that exhibited a high degree of binding.
The main force of attraction are
A) Vander-walls forces ,
B) hydrogen binding,
C) electrostatic binding.
In general charged compound have a greater tendency to bind a
protein then uncharged compound, due to electrostatic effect.
E.g., amitriptyline, coumarins, diazepam, digoxide, dicaumarol,
novobiocin.
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30. Biological Factors
1. Absorption.
Absorption of drug need dissolution in fluid before it reaches to
systemic circulation. The rate, extent and uniformity in absorption
of drug are important factor when considering its formulation in to
controlled release system. Absorption= dissolution
The characteristics of absorption of a drug can be greatly effects
its suitability of sustained release product. The rate of release is
much slower than rate of absorption. The maximum half-life for
absorption should be approximately 3-4 hr otherwise, the device
will pass out of potential absorptive region before drug release is
complete.
Compounds that demonstrate true lower absorption rate constants
will probably be poor candidates for sustaining systems.
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31. Also drug absorbed by specialized transport are poor candidates
for Sustained release preparations e.g., riboflavin
The rate limiting step in drug delivery from a sustained-release
system is its release from a dosage form, rather than absorption.
Kr <<< Ka
Reason for poor absorption
a) Poor aq. Solubility
b) Small K value
c) Acid hydrolysis
d) Metabolism
e) Site specific absorption
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32. 2. Distribution:
The distribution of drugs into tissues can be important factor in
the overall drug elimination kinetics.
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, consequently apparent volume of distribution assumes
different values depending on time course of drug disposition.
For design of sustained/ controlled release products, one must
have information of disposition of drug.
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33. Two parameters that are used to describe distribution
characteristics are its
A) apparent volume of distribution and
B) the ratio of drug concentration in tissue to that in plasma at the
steady state the so- called T/P ratio.
The apparent volume of distribution Vd is nearly a proportional
constant that release drug concentration in the blood or plasma to
the amount of drug in the body.
In case of one compartment model
Vd = dose/C0
Where, C0= initial drug concentration immediately after an IV
bolus injection
In case of two compartment model.
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34. Vss = (1+K12/K21)/V1
Where:
V1 = volume of central compartment
K12= rate constant for distribution of drug from central to peripheral
K21= rate constant for distribution of drug from peripheral to central
Vss= estimation of extent of distribution in the body
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35. To avoid ambiguity inherent in the apparent volume of
distribution as an estimation of the amount of drug in the body.
The T/P ratio is used.
The amount of drug in the body can be calculated by T/P ratio as
given bellow.
T/P = K12 (K21-β)
Where, β = slow deposition constant
T= amount of drug in peripheral to central compartment
Thus it can be noted that,
T/P estimates relative distribution of drugs between compartment
Vss estimates extent of distribution of drug in the body
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36. 3. Metabolism:
There are two areas of concern relative to metabolism that
significantly restrict sustained release formulation.
1.If drug upon chronic administration is capable of either inducing
or inhibition enzyme synthesis it will be poor candidate for
sustained release formulation because of difficulty of maintaining
uniform blood levels of drugs.
2.If there is a variable blood level of drug through a first-pass
effect, this also will make preparation of sustained release product
difficult.
Drug that are significantly metabolized before absorption, either
in lumen of intestine, can show decreased bio-availability from
slower-releasing dosage forms.
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37. Example
1. Drugs undergoing intestinal metabolism: nitroglycerin, levodopa
2.Drugs undergoing first pass metabolism: lidocaine, phenacetin,
propranolol
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38. 4. Biological half life.
The usual goal of sustained release product is to maintain
therapeutic blood level over an extended period, to this drug must
enter the circulation at approximately the same rate at which it is
eliminated. The elimination rate is quantitatively described by the
half-life (t1/2)
t1/2 = 0.693 V/ Cls = 0.693 VAUC/dose
Since, Cls = dose/AUC
Where, V= apparent volume of distribution,
Cls = systemic clearance
AUC =Area under curve
Therapeutic compounds with short half life are excellent candidates
for sustained release preparation since these can reduce dosing
frequency.
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39. Drugs with half-life shorter than 2 hours. Such as e.g.:
Furosemide, levodopa are poor for sustained release formulation
because it requires large release rates and large dose compounds
with long half-life.
More than 8 hours are also generally not used in sustaining forms,
since their effect is already sustained.
E.g.; Digoxin, Warfarin, Phenytoin etc.
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40. 6. Margin of safety:
In general the larger the volume of therapeutic index safer the
drug.
Drug with very small values of therapeutic index usually are
poor candidates for SRDF due to pharmacological limitation of
control over release rate .e.g.- induced digitoxin, Phenobarbital,
phenytoin.
= TD50/ED50
It is imperative that the drug release pattern is precise so that the
plasma drug concentration achieved in under therapeutic range.
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41. 7. Dosage size.
In general a single dose of 0.5 - 1.0 gm is considered for a
conventional dosage form this also holds for sustained release
dosage forms.

42. Natural polymers
eg. Xanthan gum,
polyurethanes,
Guar gum,
polycarbonates,
Karaya gum
etc
Semi synthetic
polymers
eg. Celluloses such as
HPMC, NaCMC,
Ethyl
cellulose etc.
Synthetic polymers
eg. Polyesters,
polyamides,
polyolefins etc
Classification of polymers
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43. Sr.no Polymer characteristics Material
1. Insoluble, inert Polyethylene, polyvinyl chloride, methyl acrylates-
methacrylate copolymer, ethyl cellulose.
2. Insoluble, erodable Carnauba wax
Stearyl alcohol,
Stearic acid,
Polyethylene glycol.
Castor wax
Polyethylene glycol monostearate
Trigycerides
3. Hydrophilic Methylcellulose, Hydroxyethylcellulose, HPMC,
Sodium CMC, Sodium alginate, Galactomannose
Carboxypolymethylene.
Classification Of Polymers Used In Sustained Release Drug Delivery Systems
According To Their Characteristics:
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44. 44
Factors affecting the design of CRDDS
1. Physicochemical properties of drug
2. Route of administration
3. Target sites
4. Acute or chronic therapy
5. The disease state
6. The patient
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45. 45
Oral Controlled Drug Delivery
1. Diffusion-controlled drug release
a. Reservoir devices
b. Matrix devices
2.Dissolution-controlled drug release
a. Encapsulation dissolution control
b. Matrix dissolution control
3. Dissolution and diffusion controlled drug release
4. Ion exchange resins-drug complexes
5. Osmotic controlled drug release
6. Altered density formulation
7. Delayed release system
a. Intestinal release system
b. Colonic release system
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46. Diffusion Controlled Drug Release
Polymeric content in
coating
Thickness of coating
Hardness of
microcapsule
Diffusion of
dissolved drug through
the matrix
Rate controlling factors
46
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47. Reservoir devices
Product Active ingrediant
Nico 400 capsule Nicotinic acid
Nitro Bid capsule Nitroglycerin
Measurin capsule Acetyl salicylic acid
Bronkodyl capsule Theophylline
Matrix devices
Product Active ingrediant
Ferro gradumet tablet Ferrous fumarate
Procan tablet Procainamide Hcl
Desoxyn tablet Methamphetamine Hcl
Diffusion Controlled Drug Release
47
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48. Dissolution Controlled Drug Release
Rate controlling
factors
Solubility &
thickness of coat
Dissolution of
dispersed drug
through medium
48
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49. 49
Product Active ingredient
Quinidex Quinidine sulphate
Nicobid Nicotinic acid
Chlor trimeton Chlorpheniramine maleate
Matrix dissolution control
Encapsulation dissolution control
Product Active ingrediant
Benzedrine Amphetamine sulpahte
Thorazine Chlorpheniramine Hcl
Diamox Acetazolamide
Ferro sequels Ferrous fumarate
Dissolution Controlled Drug Release
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50. Dissolution and Diffusion Controlled
Drug Release
Drug core is enclosed with a partially soluble membrane.
Dissolution of part of membrane allows for diffusion of
contained drug through pores in the polymer coat.
Rate controlling factor
Fraction of soluble
polymer in the coat
50
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51. Ion Exchange Resins-Drug Complexes
Product Active ingredient
Biphetamine capsule Amphetamine
Tussionex capsule , tablet Hydrocodone phenyl toloxamine
Ionamin capsule Phenteramine
Resin+
-Drug-
+X-
Resin-
-Drug+
+Y+
Resin+
-X-
+Drug-
Resin-
-Y+
+Drug+
51
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52. Osmotic Controlled Drug Release
Rate controlling factor
Orifice diameter
Membrane area
Membrane thickness
Membrane permeability
Drug solubility
52
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53. Altered Density
Drug can be mixed with
heavy inert material.
The weighted pellet can
be covered with a diffusion
controlled membrane.
Globular shells can be
used as a carrier.
The coating of mixture of
drug and polymers is given
to the undercoat of the
shell.
53
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54. An Example of Extended Release
Formulation of Bupropion
54
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55. Recent Trends
Products in market
Medopar DR
Sular ER
55
Geomatrix (SKY Pharma)
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56. Multiparticulate Drug Delivery System
Marketed products
Coreg CR
(Carvedilol phosphate)
56
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57. • Dissolution is a process in which a solid substance solubilizes in a
given solvent i.e. mass transfer from the solid surface to the liquid
phase.
• It involves two steps :-
1. Solution of the solid to form stagnant film or diffusive layer which is
saturated with the drug
2. Diffusion of the soluble solute from the stagnant layer to the bulk of the
solution; this is rate determining step in drug dissolution.
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59. The earliest equation to explain the rate of dissolution when the
process is Diffusion-controlled and involves no chemical reaction
was given by Noyes and Whitney:
Where,
dC/dT = Dissolution rate of the drug
K = Dissolution rate constant(First order)
Cs = Concentration of drug in the stagnant layer (also called
as the saturation or maximum drug solubility
Cb = Concentration of drug in the bulk of the solution at
time t.
……1
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60. • The eq.1 was based on Ficks second law of diffusion.
• Nernst and Brunner incorporated Ficks first law of diffusion and
modified the Noyes-Whitney΄s eq. to:
dC/dt=DAKw/o(Cs-Cb)/Vh
Where,
D
A
Kw/o
V
H
= Diffusion coefficient (diffusivity) of the drug
= Surface area of the dissolving solid
= water/oil partition coefficient of the drug
=Volume of dissolution medium.
=Thickness of the stagnant layer
(Cs-Cb) =Concentration gradient for diffusion of drug.
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61. Conc.
of
dissolved
drug
Time
zero order dissolution
under sink condition
first order dissolution
under non-sink condition
Dissolution rate under non-sink and
sink conditions.
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63. 63
References
1.Lachman Leon, Lieberman H.A and Kanig J.L., “The Theory and
Practice of Industrial Pharmacy”, 3rd edition, Varghese publishing
House Bombay, pg no. 430-456.
2.Khar R.K., Vyas S.P. “Controlled Drug Delivery”, 1st edition, 2002,pg
no.1-50 .
3.Brahmanker D.M. and Jaiswal S.B. “Biopharmaceutics and
Pharmacokinetics A Treatise”, Vallabh Prakashan, 1st edition, 1995,
pg.no.335-357.
4.Dr. Ali J. , Dr. Khar R. K., “A Textbook of Biopharmaceutics &
Pharmacokinetics ”, 2nd edition, Birla publication, pg no.225-251.
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64. 64
5.Jain N.K., “Controlled and Novel Drug Delivery”, CBS publication
2002, pg.no.676-698.
6.Remington, “The Science and Practice of Pharmacy”, 20th
edition,
Vol. I, pg.no.903-913.
7.Lee V.H., Robinson J.R, “Controlled Drug Delivery Fundamentals
and Application” , Marcel Dekker, New York, pg.no.71-121, 138-171.
8.Aulton M. E., “Pharmaceutics – The Design and Manufacture of
Medicines” , Churchill Livingstone New York, Page no.575.
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