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.