Drug release and dissolution

+
Drug release and
dissolution

+
USP Disintegration Apparatus
Drug release and dissolution

+ The five types of dosage forms that can be
characterized by release in vitro
1. Solid oral dosage forms
2. Rectal dosage forms such as
suppositories
3. Pulmonary (lung delivery)
dosage forms ( orally inhaled
products)
4. Modified-release dosage
forms
5. Semisolid products such as
ointments, creams,and
transdermal products.

+

+ Drug release and dissolution

+
SUPAC
(Scale Up Post Approval Change) guidances
Biopharmaceutics Classification
System (BCS)

+
 Drug Product: A drug product is a finished dosage form (e.g.,
tablet and capsule) that contains a drug substance, generally,
but not necessarily in association with one or more other
ingredients (21 Code of Federal Regulations 314.3(b)).
 Drug Substance: An active ingredient that is intended to
furnish pharmacologic activity or other direct effect in the
diagnosis, cure, mitigation, treatment, or prevention of a
disease, or to affect the structure of any function of the human
body, but does not include intermediates used in the synthesis
of such ingredient (21 Code of Federal Regulations 314.3(b)).

+
 Drug release is the process by which a drug leaves a drug product
 Immediate release drug products allow drugs to dissolve with no intention of
delaying or prolonging dissolution or absorption of the drug
 Delayed release is defined as the release of a drug at a time other than
immediately following administration. (Enteric Coated)
 Enteric Coated: Intended to delay the release of the drug (or drugs) until the
dosage form has passed through the stomach. Enteric-coated products are
delayed-release dosage forms.
 Repeat action two single doses of medication; one for immediate release;
another one for modified release
 Targeted release drug release directed toward isolating or concentrating a
drug in a body region, tissue or site of absorption or for drug action

+
 Extended-release products are formulated to make the drug available over an extended
period after administration.
 Prolonged-release dosage forms Prolonged-release dosage forms are modified-release
dosage forms showing a slower release of the active substance(s) than that of a
conventional-release dosage form administered by the same route. Equivalent term:
extended-release dosage form.
 Pulsatile release involves the release of finite amounts (or pulses) of drug at distinct time
intervals that are programmed into the drug product.
 Modified-Release Dosage Forms: Dosage forms whose drug-release characteristics of
time course and/or location are chosen to accomplish therapeutic or convenience
objectives not offered by conventional dosage forms such as a solution or an immediate-
release dosage form OR Modified-release dosage forms are preparations where the rate
and/or place of release of the active substance(s) is different from that of a conventional-
release dosage form administered by the same route.
 Modified-release dosage forms include both delayed and extended-release drug products
 controlled release includes extended-release and pulsatile-release products.

+
1. Immediate release (IR)
2. Sustained Release (SR)
3. Sustained Action (SA)
4. Extended Release (ER)
5. Long Acting (LA)
6. Prolong Action (PA)
7. Controlled Release (CR)
8. Timed Release (TR)

+
Osmotically Controlled Systems

+ Dissolution
Dissolution
Dissolution refers to the process by which a solid phase (e.g., a tablet or
powder) goes into a solution phase such as water.
It is the process for which drug molecules leave the boundary surrounding the
dosage form and diffuses into the dissolution media.

+
Different controlled release systems
Time of release
Cumulative
release
Diffusion controlled release
Zero order (linear) release
Burst like release
Pulsatile release
Lag followed by
Burst release

+
Mechanism aspects of Oral drug
delivery formulation
1.Dissolution : 1.Matrix
2.Encapsulation
2.Diffusion : 1.Matrix
2.Reservoir
3.Combination of both dissolution & diffusion.
4.Osmotic pressure controlled system

+
Dissolution controlled systems
 In dissolution controlled systems, the rate controlling step is
dissolution.
 The drug is embedment in slowly dissolving or erodible matrix or by
coating with slowly dissolving substances
 There are basically two types of dissolution devices
Controlled Release Systems
Encapsulation dissolution controlled system
Matrix dissolution controlled
system
Soluble drug
Slowly
dissolving
matrix
Soluble drug
Slowly
dissolving or
erodible coat

+ Controlled Release Systems
Diffusion controlled systems
 Diffusion systems are characterized by release rate of drug is dependent on
its diffusion through inert water insoluble membrane barrier.
 There are basically two types of diffusion devices.
(I)Reservoir devices (II)Matrix devices

+
Dissolution & Diffusion Controlled Release
system
 Drug encased in a partially soluble membrane.
 Pores are created due to dissolution of parts of
membrane.
 It permits entry of aqueous medium into core &
drug dissolution.
 Diffusion of dissolved drug out of system.
Insoluble
membrane
Pore created by
dissolution of
soluble fraction of
membrane
Entry of
dissolution
fluid
Drug
diffusion

+ Controlled Release Systems
Osmotic pressure controlled system

Swelling vs. Erosion
Diffusion controlled
systems and / or
Dissolution &
Diffusion Controlled
Release system
Dissolution
controlled systems

+
 Drug dissolution and release commonly fall into two groups:
 zero-order release and first-order release.
 Typically in the pharmaceutical sciences, zero-order release is achieved
from non-disintegrating dosage forms such as topical or transdermal
delivery systems, implantable depot systems, or oral controlled release
delivery systems oral osmotic tablets matrix tablets with low-soluble
drugs

zero-order release
tKQQt 00 
where Q is the amount of drug released or dissolved (assuming that release
occurs rapidly after the drug dissolves)
Q0 is the initial amount of drug in solution (it is usually zero),
and K0 is the zero-order release constant.
tKQt 0
“Constant” release is defined in this context as the same
amount of drug release per unit of time

First-order release.
Kt
Q
Q
eQQ tkt
t  
)ln(
0
0
Where
Qt is the amount of drug released or dissolved
Q0 is the initial amount of drug in the device
and K is the First-order release constant.

+
Absorption depends some what on
1- The rate of disintegration of the dosage forms
2- Deaggregation of the granules
3- More importance is the dissolution rate of the solid drug.
Frequently, dissolution is the limiting or rate-controlling step in the absorption of drugs
with low solubility
Dissolution

Mathematical model for drug dissolution
Noyes-Whitney equation

+
Chemical photography of drug release

 The equation describes
the rate of release of the
drug from its solid state.
)(
)(
CCs
Vh
DS
dt
dC
CCs
h
DS
dt
dM


M: mass of solute dissolved in time t.
D: is the diffusion coefficient.
S: is the surface area of dissolution. (concentration of a saturated solution)
h: is the diffusion layer thickness
Cs: is the solubility of drug in the dissolution medium.
C: is the concentration of drug in the bulk.
V: is the volume of solution.
dC/dt is the dissolution rate,

+ An aqueous diffusion layer or stagnant liquid
film of thickness h exists at the surface of a solid undergoing dissolution.
This thickness, h, represents a stationary layer of solvent in which the solute
molecules exist in concentrations from Cs to C
h
Cd
DSK
dt
dM
h
CrCd
DSK
dt
dM




Cs
Vh
DS
dt
dC
Cs
h
DS
dt
dM
C


 0
)(
)(
CCs
Vh
DS
dt
dC
CCs
h
DS
dt
dM

 Under sink conditions
C<<<<CS the equation
becomes
Cs
V
S
K
dt
dC
KSCs
dt
dM

 h
D
K 
K dissolution
rate constant

Calculate the dissolution rate of a hydrophobic drug having the following
physicochemical characteristics:
surface area = 2.5 x 103 cm2
saturated solubility = 0.35 mg/mL (at room temperature)
diffusion coefficient = 1.75 x 10-7 cm2/s
thickness of diffusion layer = 1.25 μm
[Note: need to convert to cm, so 1 μm = 1 x 10-4 cm and 1.25 x 10-4 cm]
conc of drug in bulk = 2.1 x 10-4 mg/mL
Example:
)( CCs
h
DS
dt
dM

    sec/22.1
1025.1
101.235.0105.21075.1
4
437
mg
x
xxx
dt
dM


 


+
 A preparation of drug granules weighing 5.5 gm and having a total surface area of
2800 cm2 is allowed to dissolve in a 500 ml of water at 25oC. After the first
minute, 0.76 gm have dissolved. The saturation solubility (Cs) of the drug is 15
mg/ml.
a) Calculate the dissolution rate constant (K = D/h)
case 1 dM/dt =KS (Cs-Ct) =
(0.000336 cm /sec)(5000 cm2)(15- 1.52 mg/ml)
dM/dt = 22.646mg/sec
case 2 dM/dt =KS (Cs) =
(0.000302 cm /sec)(5000 cm2)(15mg/ml)
dM/dt = 22.65 mg/sec
case 1: not sink condition dM/dt =KS (Cs-Ct)
dM/dt =0.76gm / 60 seconds = 0.01267 gm/sec X 1000= 12.67 mg/sec
S = 2800 cm2
Cs = 15 mg/ml
Ct = 0.76 gm / 500 ml = 0.00152 gm/ ml X 1000 = 1.52 mg/ml
12.67 mg/sec = K (2800 cm2) (15 mg/ml - 1.52 mg/ml)
K = 0.000335cm /sec
500 ml is the volume of stomach
case 2 : In the case of sink condition dM/dt =KS Cs
12.67 mg/sec = K (2800 cm2) x15 mg/ml K = 0.000302cm /sec
b) If the diffusion layer thickness (h) is 0.005 cm, calculate the diffusion coefficient (D).
K = D/h
D = K X h
case 1 D = 0.000335 cm /sec X 0.005 cm = 1.6 X10-6 cm2/ sec
case 2 D = 0.000302 cm /sec X 0.005 cm = 1.6 X10-6 cm2/ sec
c) Suppose that surface area was increased to 5000 cm2, what would be the dissolution rate.

+
 When surface area is 2800 cm2: dM/dt = 12. 67 mg/sec
 When surface area is 5000 cm2: dM/dt = 22.65 mg/sec
 Surface area: leads to increase dissolution rate.
How to utilize Noyes Whitney equation to enhance solubility:
dM/dt =(D/h)S (Cs-Ct)
1) Increase surface area by decreasing particle size.
Effective surface area is area in direct contact with water.
Reduced particle size leads to increased surface area leading to
increased effective surface area and increased solubility.
2) Mechanical stirring leads to reduced diffusion layer thickness

+
 Derivation of equations Noyes-Whitney it was assumed that h
and S were constant
But this is not the case.
 The static diffusion layer thickness is altered by the force of
agitation at the surface of the dissolving tablet
 The surface area, S, obviously does not remain constant as a powder,
granule, or tablet dissolves, and it is difficult to obtain an accurate
measure of S as the process continues.

+
 Applies for dissolution of powder drugs:
 Assumptions:
 Spherical particles.
 Shape remains spherical during dissolution.
 All particles have the same size.
(uniform size)
Hixson-Crowell cube root equation

+


kCs
d
M
k
tMM t
23
1
0
3
1
3
1
0


M0: original mass of drug particles
Mt: mass of drug particles remaining at time t
κ: cube rate dissolution constant
k= D/ h

+
2
4 rr radius and surface area and
if the radius is reduced by dr, the volume change is
3
3
4
rV 
drrdV 2
4 drrNdV 2
4 For N particles
The surface area of N particles is 2
4 rNS 
the infinitesimal mass change Noyes–Whitney law,
KSCsdtdM 
drug's density multiplied by the infinitesimal volume change, ρ dV, can be set
equal to dM
KSCsdtdV   Substituted S and
dV KCsdtrNdrrN 22
44  
KCsdtdr   t
KCs
rr

 0
Integration
dt
KCs
dr
tr
r
 
00


+ t
KCs
rr

 0
the cube root dNM
3
1
3
1
6 














Volume of a
spherical particle
3
6
1
dV 
Mass for N
particles
3
6
dNM 


d =2r




kCs
d
MkC
N
tMM
S
t
22
6
3
1
0
3
1
3
1
3
1
0














Equations 1
t
tkC
NMM s
t 


 


















2
6
3
1
3
1
3
1
0

+
the estimated time for complete
dissolution, τ (i.e., when r = 0)
DCs
r
2
2
0
 Dissolution time

+ Example (1)
A specially prepared tolbutamide powder of fairly uniformly sized particles with a
diameter of 150 μm weighed 75 mg. Dissolution of the drug was determined in
1000 mL of water at 25°C as a function of time. Determine the value of κ, the
cube-root dissolution rate constant, at each time interval and calculate the
average value of κ.
M0
1
3
- Mt
1
3
=kt

+
In clinical practice, diazepam injection (a sterile solution of
diazepam in a propylene glycol– ethanol–water cosolvent
system) is often diluted many fold with normal saline
injection. An incipient precipitation of diazepam occurs
invariably upon addition of saline followed by complete
dissolution within 1 min upon shaking.
DCs
r
2
2
0
 
Example (2)

+
More Complex Models of Dissolution:
Convective Diffusion

+
 Release of water soluble and poorly soluble Drugs
 Drugs are dispersed homogeneously throughout the matrix of an erodible
tablet
 Drug release from ointment base.
 Diffusion of dispersed solid drug.
Higuchi (Equation)

+
 The drug is assumed to
dissolve in the polymer matrix
and to diffuse out from the
surface of the of the device
 As the drug released, the
distance for diffusion becomes
increasingly greater
 The boundary that forms
between the drug and empty
matrix therefore recedes into
the tablet as drug is eluted

+ Mathematical model for drug dissolution
Higuchi (Equation)
  2
1
2 tCCADQ SS
  2
1
2
2
1





 

t
CCAD
dt
dQ SS
A>>>>Cs
 2
1
2 tADCQ S
2
1
2 






t
ADC
dt
dQ S
dQ/dt the rate of drug released per unit area
Cs is the solubility or saturation concentration of drug in the matrix
A is the total concentration dissolved and undissolved, of drug in the matrix. OR
Total amount of drug in a unit volume of the matrix OR
The initial drug concentration
Q amount of the drug release in time t per unit area
D, the diffusion coefficient of the drug in the matrix

+ Release from Granular Matrices: Porosity and Tortuosity
 
2
1
2 





 tCCADQ SS


Sink
condition
OR
A>>>>Cs
2
1
2 





 tADCQ S


dQ/dt the rate of drug released per unit area
Cs is the solubility or saturation concentration of drug in the matrix
A is the total concentration dissolved and undissolved, of drug in the matrix. OR
Total amount of drug in a unit volume of the matrix
Q amount of the drug release at time t per unit area
D, the diffusion coefficient of the drug in the matrix;
ε is the porosity of the matrix and
τ is the tortuosity of the capillary system,

+
 Porosity is the fraction of matrix that exists as pores or channels into
which the surrounding liquid can penetrate
 Tortuosity is introduced to this equation to account for an increase in
the path length of diffusion due to branching and bending of the
pores as compered to shortest ‘straight –through’ pores
 Tortuosity tends to reduce the amount of drug release in a given
interval of time

+
T(hr) Concent.
Drug
release
mg/ml
0 0
2 0.42
4 0.59
6 0.74
8 0.876
10 0.98
2
1
tQ 
The dissolution in 500 ml water data are found in the table below.
0
100
200
300
400
500
600
0 1 2 3 4 5 6 7 8 9 10
mgdrrugrelease
t (hr)
Amount drug
release Mg
(in 500ml)
Qt
0
210
295
370
438
490
T^(1/2)
0.000
1.414
2.000
2.449
2.828
3.162
K
mg*^(1/2)/hr
148.4924
147.5
151.0519
154.8564
154.9516

+
T(hr) Concent.
Drug
release
mg/ml
Amount drug
release Mg
(in 500ml)
Qt
T^(1/2) K
mg*^(1/2)/hr
0 0 0 0.000
2 0.42 210 1.414 148.4924
4 0.59 295 2.000 147.5
6 0.74 370 2.449 151.0519
8 0.876 438 2.828 154.8564
10 0.98 490 3.162 154.9516
2
1
tQ 
The dissolution in 500 ml water data are found in the table below.
0
100
200
300
400
500
600
0.00 0.50 1.00 1.50 2.00 2.50 3.00 3.50
mgdrugrelease
t (hr)^(1/2)

+ Mathematical model for drug dissolution
zero-order release
tKQt 0 first-order release.
Kt
Q
Q
eQQ tkt
t  
)ln(
0
0
)(
)(
CCs
Vh
DS
dt
dC
CCs
h
DS
dt
dM

 tMM t  3
1
3
1
0
Higuchi (Equation)   2
1
2 tCCADQ SS
2
1
ktQ    2
1
2 SS CCADk 

+
T(hr) Qt
Drug
release mg
0 0
1 10.02
2 19.8
3 28.78
4 38.54
5 49.05
6 58.78
7 67.99
8 78.12
9 88.04
10 97.58
KtQt 
hrmgK /749.9
7
24.68
29
8.1904.88




0
10
20
30
40
50
60
70
80
90
100
0 1 2 3 4 5 6 7 8 9 10 11
t(hr)
Qtmgdrugrelease
K=
(Qt)/t
Mg/hr
10.02
9.90
9.59
9.64
9.81
9.80
9.71
9.77
9.78
9.76
K=9.78
Mg/hr
Average
zero-order release equation

+
tMM t  3
1
3
1
0
T(hr) Concent.
Drug
release
mg/ml
0 0
2 0.159
4 0.288
6 0.39
8 0.468
10 0.528
3
1
3
1
0 tMM 
A 0.625 g af paracetamol powder was dissolved in 1000 ml of water. The dissolution data are
found in the table below.
0
100
200
300
400
500
600
0 2 4 6 8 10 12
mgdrugrelease
t( hr)
Average K= 0.397
Amount drug
release
Mg / 1lt
Wt
0
159
288
390
468
528
Amount of
undissolved
drug
Mt=625-Wt
0
466
337
235
157
97
0.000
0.797
1.591
2.379
3.155
3.955
K
mg*^(1/3)/hr
0
0.399
0.398
0.396
0.394
0.396

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