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K. AdrjanowiczK. Adrjanowicz, Z. Wojnarowska, P. Wlodarczyk,, Z. Wojnarowska, P. Wlodarczyk, K. Grzybowska, K. Kaminski, M. Paluch K. Grzybowska, K. Kaminski, M. Paluch Institute of Physics, UniversityInstitute of Physics, University of Silelesia of Silelesia, Katowice, Poland, Katowice, Poland
H3CO
OH
NCH3
CH3
HCl
Tramadol Tramadol hydrochloride
Verapamil hydrochlorideCrystalline VH is soluble in water (i.e. 82 mg/mL at pH 2.32, 0.44 mg/mL at pH=7.32). More than 90% of the oral administer dose is absorbed from the gastrointestinal track, where pH is roughly 2-4. However only 10-20% out of these 90% absorbed from the digestive track get into circulatory system (pH blood about 7.34 – 7.43).
Tramadol HCL solubility ->300 mg/ml bioavailability -> 68–72% Increases with repeated dosing.
10-2 10-1 100 101 102 103 104 105 106
10-3
10-2
10-1
100
101
102
103
-relaxation
-relaxation
dc conduntivity
decreasing temperature
Tg=244 K
T=289 K T=245 K
T=4 K
di
elec
tric
loss
"
Freq. [Hz]
(a) T>Tg
T=223.15K T=133.15K
T=6K
T<Tg
10-1 100 101 102 103 104 105 106
10-3
10-2
diel
ectri
c lo
ss
"
Freq. / Hz
decreasing temperature
-relaxation
-relaxation
(b)
The glass transition temperature Tg was defined as a temperature at which =100s.
max
1
2 f
10 ( ) ,
2
KWW KWWJG c
c
t where
t ps
( ) exp[ ( / ) ]KWWt t
The Coupling Model prediction
Tramadol
3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5
-7
-6
-5
-4
-3
-2
-1
0
1
2
Tramadol monohydrate
-relaxationE
a=29.4kJ/mol
-relaxation
log
10
[s]
1000/T [K-1]
m=76
Tg=244 K0
0loglogTTTDP
The Arrhenius equation:
gT
gp
TTd
dm
log
Fragility
exp ao
ER T
Temperature VFT law:
Materials-process
-processFragility
mTg (BDS)
[K]
VFT Arrhenius
T0 (K) log ∞ DT (K) log 0 Ea (kJ/mol)
Tramadol 179.23.1-
18.110.513021211 -12.790.08 29.40.3 76 244
Tramadol
22 '''
''
M
22 "'
""
M
'''1
** iMMM
10-1 100 101 102 103 104 105 106
10-3
10-2
10-1
100
101
102
103
104
105
106
107
108
diel
ectri
c lo
ss
"
Freq. / Hz
T=520C
T=120oC
decreasing temperature
Tramadol HCl
10-2 10-1 100 101 102 103 104 105 106
10-3
10-2
10-1
100
101
102
103
104
105
106
107
108
10-1 100 101 102 103 104 105
2.0x10-3
3.0x10-3
4.0x10-3
T=383.15K T=321.15K
freq. [Hz]
Verapamil HCl
dc-conductivity
T > Tg
diel
ectr
ic lo
ss
''
T=233.15K T=133.15K
freq. [Hz]
T < Tg
-relaxatio
n
(b)(a)
10-2 10-1 100 101 102 103 104 105 106
1E-3
0.01
0.1
decreasing temperature T=383,15K T=323,15K
M"
Freq. / Hz
T>Tg
-relaxation
Verapamil hydrochloride
10 ( ) ,
2
KWW M KWW MJG c M
c
t where
t ps
( ) exp[ ( / ) ]KWW MMt t
The Coupling Model prediction
-4 -2 0 2 4 6-3.0
-2.5
-2.0
-1.5
-1.0
-0.5
0.0
log
M"
log Freq.[Hz]
JG
KWW
=0.65
Tramadol hydrochloride T=333K
-relaxation
The well-separated -process in TH is the Johari-Goldstein process
KWW-M=0.65
T=327.15KT=325.15KT=319.15KT=313.15KT=307.15K
10-3 10-2 10-1 100 101 102 103 104 105 106 107 108 109 1010
10-3
10-2
10-1
-2 0 2 4 6-3.0
-2.5
-2.0
-1.5
-1.0
-0.5
T=255.15K T=245.15K T=235.15K T=225.15Klo
g M
"
log shifted freq /Hz
M''
shifted freq. [Hz]
KWW-M
=0.61f0=2081Hz
10-3 10-2 10-1 100 101 102 103 104 105 106 107
0.01
0.1
freq. [Hz]
t=0kst=72 kst=43kst=86kst=151ks
excess wing
-relaxation
die
lect
ric
loss
''
The excess wing in VH is the JG process
Aging at T=313K
10log
( / ) g
MT T
g
dm
d T T
0
exp TM M
D
T T
2,6 2,8 3,0 3,2 3,4 3,6 3,8 4,0 4,2 4,4-8
-6
-4
-2
0
2
log[
/(s)
]
1000/T (K-1)
-relaxation
-relaxation
Tg=322.2K
m=76.8
Tramadol hydrochloride
0
0
log log PM M
D T
T T
Temperature VFT law:
expo
E
R T
The Arrhenius equation:
Fragility
Materials
-process-process
Fragilitym
Tg (BDS)
[K]
VFT Arrhenius
T0 (K) log ∞ DT (K) log 0
Ea
(kJ/mol)
Tramadol hydrochloride
2863
--
12.790.51473159
-14.560.3
2582 112 329
max
1
2M f
0.0025 0.0030 0.005 0.006 0.007
-6
-4
-2
0
2
1/T [K-1]
log
[ (
/s)]
-relaxationE
a=37.8 kJ/mol
-relaxationT
g=320.1K
m=87.9
-process-process
Fragility
m
Tg (BDS)
[K]
VFT Arrhenius
T0 (K) log ∞ -M DT log ∞-M E (kJ/mol)
258.04 0.83 -15.010.12 4.090.09 -15.090.26 37.80.8 88 320.1
tamadol hydrochloride, T=333,15K verapamil hydrochloride, T=329,15K
10-2 10-1 100 101 102 103 104 105 106 107
1E-3
0.01
0.1 f0
for werapamil hydrochloride calculated from the CM
verpamil hydrochloride
KWW=0.61
M"
Freq.[Hz]
tramadol hydrochloride
KWW=0.65
tramadol hydrochlorideJGprocess
We link an opposite trend to crystallization of both pharmaceuticals with different local molecular mobility.
The ability of amorphous pharmaceuticals to crystallization might be correlate to the asymmetric distribution of structural relaxation time, described by the KWW parameter - Shamblin S.L., Hancock B.C., Dupuis Y., Pikal M.J., J.Pharm.Sci., 89, 417-427 (1999)
It was affirmed that amorphous tramadol hydrochloride compacted better than crystalline. Amorphous tramadol hydrochloride requires about 30% less pressure force than the drug in crystalline state to obtain tablets with similar physical parameters
No significant differences between amorphous and crystalline tramadol hydrochloride in intrinsic dissolution test rate were observed
Cooperation:Department of Pharmaceutical Technology, Medical University of Gdansk, Hallera 107, 80-416, Gdansk, PolandW. Sawicki , P. Lepek , R. Lunio, J. Mazgalski
Solubility
(mg/ml)
water phosphate buffer 6,8 0,1N HCl
cryst. amorph. cryst. amorph. cryst. amorph.
25º C
71.16 ±
3,41
260.92 ±
2,17
106.98 ±
2,48
385.14 ±
2,49
47.68 ±
3,58
228.59 ±
9,55
37º C
529.17 ±
19,09
589.78 ±
11,67
371.89 ±
15,84
411.86 ±
6,89
498.45 ±
18,97
581.18 ±
7,90
Solubility and intrinsic dissolution rate obtained for amorphous verapamil hydrochloride are much better than that derived for crystalline API.
It was found the statistically significant difference between IDR calculated for crystalline and amorphous form. The obtained results amounted to 7,61 and 8,89 mg*min-1*cm-1 for crystalline and amorphous form respectively.
Cooperation:Department of Pharmaceutical Technology, Medical University of Gdansk, Hallera 107, 80-416, Gdansk, PolandW. Sawicki , P. Lepek , R. Lunio, J. Mazgalski
2. Chemical transition of drug from monohydrate into hydrochloride salt results in significant increase of its glass transition. As a consequence it is possible to prepare its oral dosage form completely amorphous in the room temperature and even human body temperature.
1. We showed that dielectric spectroscopy can be satisfactorily used to follow dynamics of hydrochloride salts, despite theirs ionic character. Up to know BDS was used to measure only pure API’s, while in the case of their salts this experimental technique failed because of great contribution of the dc conductivity to the loss spectra.Presentation of the dielectric data in modulus representation enabled us to get valuable information about dynamics of the investigated system
4. Amorphous drugs can be alternative even for the well solved pharmaceuticals
3. Both analyzed by us compounds differ in separation of JG relaxation. Thus, we relate completly opposite trend to crystallization of both pharmaceuticals with different local molecular mobility.
The authors are deeply thankful for the financial support The authors are deeply thankful for the financial support of their research within the framework of the project of their research within the framework of the project entitled /From Study of Molecular Dynamics in entitled /From Study of Molecular Dynamics in Amorphous Medicines at Ambient and Elevated Amorphous Medicines at Ambient and Elevated Pressure to Novel Applications in Pharmacy/, which is Pressure to Novel Applications in Pharmacy/, which is operated within the Foundation for Polish Science Team operated within the Foundation for Polish Science Team Programme co-financed by the EU European Regional Programme co-financed by the EU European Regional Development Fund.Development Fund.