Kinetic release of theophylline from

modified release oral pharmaceutical

dosage forms
 1. Introduction & Aim

➢ The dissolution kinetics of drugs from modified release

formulations is often complex and cannot be analyzed
using classical kinetic equations

➢ In some instances we have to use complex kinetic

models, consisted in simultaneous or consecutive basic
kinetic processes, not necessary having the same order

➢ The aim of this study was to analyze the kinetic release of

theophylline from three modified release pharmaceutical
formulations using complex kinetic models
2. Experimental
➢ Three pharmaceutical dosage forms containing
theophylline were analyzed:

➢ Teotard 200 (modified release capsule, 200 mg

theophylline, Krka)
➢ Theo SR 200 (modified release capsule, 200
mg theophylline, GSK)
➢ Teofilina SR 200 (modified release capsule,

200 mg theophylline, Terapia)

2. Experimental
Dissolution conditions:

➢ Apparatus no. 2 (paddle), PharmaTest PT-DT7

➢ Dissolution media:
➢ 1000 ml sol HCl pH 1.2 for first 2 hr
➢ from 2 hr to 24 hr: pH 6.8 (100 ml 0.1 M Na2HPO4
+ 10 ml NaOH 5 M)
➢ Rotation speed: 50 rpm
➢ Temperature: 37 ± 0.5 0C
2. Experimental
Sampling:

➢ Sampling: between 0 and 24 hr: 40 samples (every 20

min until 4 hr, every 30 min until 10 hr, then at every 1
or 2 hr)

➢ Concentration of theophylline from samples was

analyzed by HPLC with fluorescence detection (Ex/Em
277/ 340 nm)
3. Results: The dissolution profiles:
100
90
80
70
60 Teofilina SR 200

50 Teotard 200

40 Theo SR 200

30
20
10
0
0 2 4 6 8 10 12 14 16 18 20 22 24
pH=1.2 pH=6.8 Time (hr)
3. Results: The dissolution profiles:
100
90
80
70
60
50
Teofilina SR 200
40
30 Theo SR 200
20
10 pH=1.2 pH=6.8
0
0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6
Time (hr)
3. Results: Modelisation:
100
90
80
70 Modelisation:
60 Teofilina SR 200

50 Teotard 200

40 Theo SR 200 M1. 1st order release

30 M2. Higuchi
20
M3. Peppas
10
0
M4-6. complex models
0 2 4 6 8 10 12 14 16 18 20 22 24
Time (hr)
pH=1.2 pH=6.8

????
kinetics
3. Results: Complex Models:
100
90
80
Modelisation:
70
60 complex models only
50
Teofilina SR 200
40
30 Theo SR 200
M4. mixed 0 and 1st order
20 M5. mixed 1st and 1st order,
10
mechanism A
0
0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6 M6. mixed 1st and 1st order,
Time (hr)
pH=1.2 pH=6.8 mechanism B
M4. mixed 0 and 1st order
f*D, k0 (tced), tlag1
(1-f)*D, k1, tlag2
3. Results: Complex Models:
M5. mixed 1st and 1st order, M6. mixed 1st and 1st order,
mechanism A mechanism B

f*D, k1, tlag1 f*D, k1, tlag1

v=f(f*D) v=f(D)

(1-f)*D, k2, tlag2 (1-f)*D, k2, tlag2

v=f((1-f)*D v=f((1-f)*D)
3. Results:
Model selection: Akaike criteria AIC= f (N, SSR, p)
Product/ Akaike Index
Model Kinetics Teotard 200 Theo SR 200 Teofilina SR 200
1 1st order 192.6 - -
2 Higuchi 279.2 - -
3 Peppas 263.1 - -
4 0 and 1st 181.6 112.5 50.7
5 1st and 1st, A 135.7 111.5 84.13
6 1st and 1st, B 197.8 107.18 60.3
3. Results:
Modeling dissolution profile of theophilline for Teotard 200:
100
90
Product=Teotard 200

Observed
Model:
80
Predicted
Mixer order kinetics (1st and
70
60
1st order, mechanism A)
50
40
Tlag Calculated parameters :
30
(2) Parameter Units Value CV
20
TLAG hr 0.05 7.1
10 1st order
K1 hr-1 0.18 7.48
0 kinetic
0 5 10 15 20 25 t1/2 (kin 1) hr 3.83 -
process
T ime (hr) % kin 1 % 76.60 4.54
TLAG hr 6.76 3.16
1st order
K1 hr-1 0.15 6.33
kinetic
t1/2 (kin 1) hr 4.65 -
process
% kin 1 % 23.40 -
3. Results:
Modeling dissolution profile of theophilline for Teofilina SR 200:
100
90
Product=Teofilina SR 200
Model:
80
Observed Mixer order kinetics (1st and 0
Predicted
70 order)
60 Tlag1 Calculated parameters:
50
40 Parameter Units Value CV SEM
30 Tced O TLAG0 hr 0.05 2.3
0 order
TCED0 hr 3.16 1.77
20 kinetic
% kin 0 % 54.50 2.11
10 process
k0 %/hr 17.25 -
0 TLAG1 hr 2.12 0.46
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 1st order
K1 hr-1 1.85 4.11
kinetic
Time (hr) t1/2 (kin 1) hr 0.37 -
process
% kin 1 % 45.50 -

k0=Amount %/ t release
t1/2=0.693/k
3. Results:
Modeling dissolution profile of theophilline for Teofilina SR 200:
100
90
Product=Teofilina SR 200 Model:
80 Mixer order kinetics (1st and 0
Tlag1
70 order)
60
Calculated parameters:
50
40
Parameter Units Value CV SEM
TLAG0 hr 0.05 2.3
30 Tced O 0 order
TCED0 hr 3.16 1.77
kinetic
20 % kin 0 % 54.50 2.11
process
10
k0 %/hr 17.25 -
TLAG1 hr 2.12 0.46
0 1st order
K1 hr-1 1.85 4.11
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 kinetic
t1/2 (kin 1) hr 0.37 -
Time process
% kin 1 % 45.50 -

k0=Amount %/ t release
t1/2=0.693/k
3. Results:
Modeling dissolution profile of theophilline for Theo SR 200:
100
90
Product=Theo SR 200 Model:
80
Observed
Predicted
Mixer order kinetics (1st and
70 1st order, mechanism B)
60 Tx Calculated parameters:
50
40
Parameter Units Value CV
1st order TLAG hr 0.00 1.22
30
kinetic K1 hr-1 0.18 8.79
20 process t1/2 (kin 1) hr 3.96 -
10 1st order Tx hr 2.25 2.08
0 kinetic K1 hr-1 1.07 6.31
0 1 2 3 4 5 6 process t1/2 (kin 1) hr 0.65 -
Time (hr)
4. Conclusions:
➢Three pharmaceutical formulations containing
theophylline were analyzed
➢The drug dissolution profiles from both formulations were
successfully fitted by complex kinetic models
➢All the kinetic processes were characterized by calculating
the corresponding parameters

In vitro modeling is a powerful tool which can be used :

➢In drug formulation, when a custom dissolution profile is
needed
➢In the study and assessment of release mechanism of drug
from pharmaceutical formulations