Stability And Desolvation Kinetics Of Droperidol Hydrates ... · agris bĒrziŅŠ, andris actiŅŠ,...
Transcript of Stability And Desolvation Kinetics Of Droperidol Hydrates ... · agris bĒrziŅŠ, andris actiŅŠ,...
A G R I S B Ē R Z I Ņ Š , A N D R I S A C T I Ņ Š , E D G A R S S K A R B U L I S
D E P A R T M E N T O F C H E M I S T R Y , U N I V E R S I T Y O F L A T V I A
STABILITY AND DESOLVATION KINETICS
OF DROPERIDOL HYDRATES AND AN
ETHANOL SOLVATE, STUDIED BY POWDER
X-RAY DIFFRACTOMETRY AND
DIFFERENTIAL THERMAL
ANALYSIS/THERMOGRAVIMETRY
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Background
2
Department of Chemistry, University of Latvia
Introduction
3
Droperidol is known to exist in: Two polymorphic forms a,b
Dihydrate c
Hemihydrate a,b
Ethanol solvate d
HN
N
O
NO
F
a) M. Azibi, M. Draguet-Brughmans, R. Bouche, Pharmaceutica Acta Helvetiae, 57 (1982) 182-188. b) A. Actins, R. Arajs, S. Belakovs, L. Orola, M. Veidis, Journal of Chemical Crystallography, 38 (2008)
169-174. c) N.M. Blaton, O.M. Peeters, C.J. De Ranter, Acta Crystallographica Section B, 36 (1980) 2828-2830. d) C.L. Klein, J. Welch, L.C. Southall, Acta Crystallographica Section C, 45 (1989) 650-653.
Droperidol hydrates
4
Dihydratea Hemihydrateb,c
a) N.M. Blaton, O.M. Peeters, C.J. De Ranter, Acta Crystallographica Section B, 36 (1980) 2828-2830. b) A. Actins, R. Arajs, S. Belakovs, L. Orola, M. Veidis, Journal of Chemical Crystallography, 38 (2008) 169-174. c) L. Orola. Synthesis, structure and properties of crystalline forms of some active pharmaceutical ingredients.
PhD Thesis, Riga Technical University, (2010) 170 p.
Outline
5
Droperidol hydrates Sorption-desorption isotherms Dehydration products Dehydration kinetics Lattice parametres of droperidol hemihydrate
Droperidol ethanol solvate Similarity with hemihydrate Lattice parametres of droperidol ethanol solvate Desolvatation kinetics
Conclusions
Desorption-sorption isotherms - dihydrate
6
0
0,5
1
1,5
2
0 20 40 60 80 100RH, %
desorption after equilibriumdesorption before equilibriumsorption
n(H2O)/n(droperidol)
Desorption-sorption isotherm of droperidol dihydrate in 25 oC temperature
Desorption-sorption isotherms - hemihydrate
7
n(H2O)/n(droperidol)
Desorption-sorption isotherm of droperidol hemihydrate in 25 oC temperature
00,10,20,30,40,50,60,70,80,9
1
0 20 40 60 80 100RH, %
a) J.R. Authelin. International Journal of Pharmaceutics 303 (2005) 37–53
Dehydration products - dihydrate
8
50 oC 3 50 oC 2 50 oC 1 30 oC
70 oC
0
100
200
300
400
3 10
d=20
,318
97
d=10
,080
95
d=7,
0913
2
d=6,
5272
8
d=6,
0286
3
d=10
,201
55
d=9,
6258
5
d=8,
1544
7
2Θ, o
Dehydratation of droperidol dihydrate sample A by heating
Z
dihydrate
Dehydration products - dihydrate
9
0
100
200
300
400
500
600
700
3 10
d=20
,146
78
d=17
,227
64
d=8,
5618
0
d=7,
0733
9
d=6,
5326
9
d=6,
0336
0
d=6,
3507
8
d=10
,031
86
2Θ, o
Dehydratation of untreated droperidol dihydrate sample C by heating
Z Y
Dehydration products - hemihydrate
10
Dehydratation of droperidol hemihydrate by lowering relative humidity (1)
Dehydration products - hemihydrate
11
Dehydratation of droperidol hemihydrate by lowering relative humidity (2)
Droperidol hydrates - conclusions
12
Droperido dihydrate typical stoichiometric hydrate complicated dehydration process
Droperidol hemihydrate typical nonstoichiometric hydrate Dehydration gives isomorphic dehydrate
Dehydration kinetics – dihydrate (1)
13
0
0,1
0,2
0,3
0,4
0,5
0,6
0,7
0,8
0,9
1
0 10 20 30 40 50 60
54,950,441,746,026,832,337,458,4
time, min
Con
vers
ion
deg
ree
α
Dehydratation kinetic curves of droperidol dihydrate sample A in nitrogen flow with sample mass 5 mg
Dehydration kinetics – dihydrate (3)
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0
0,05
0,1
0,15
0,2
0,25
0,0 20,0 40,0 60,0 80,0
MKSA3/2MKSR2MKSA2MKSR3
Least square summ
Temperature, oC
After optimization obtained least square sums for most appropriate kinetic models for droperidol dihydrate sample A with sample mass 5 mg
Dehydration kinetics – dihydrate (4)
15
Ea, kJ∙mol-1
80 m
L 2 m
g untre
ated
200
mL 5 m
g
< 67
µm
300
mL
10 m
g
< 40
µm
65
70
75
80
85
90
95
A B C
D-AD-CD-B
With optimization method calculated activation energy values for droperidol dihydrate samples
Dehydration kinetics – hemihydrate (1)
16 Dehydratation kinetic curves of grinded and ungrinded droperidol nonstoichiometric hydrate
0
0,1
0,2
0,3
0,4
0,5
0,6
0,7
0,8
0,9
1
0 5 10 15 20 25 30 35 40
22 (grinded)28 (grinded)40 (grinded)37 (ungrinded)46 (ungrinded)58 (ungrinded)
time, min
Con
vers
ion
deg
ree
α
Dehydration kinetics – hemihydrate (1)
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30,00
35,00
40,00
45,00
50,00
55,00
60,00
65,00
70,00
grinded 5 mgungrinded, 5 mggrinded, 200 mg
Ea, kJ∙mol-1
With optimization method calculated activation energy values for droperidol nonstoichiometric hydrate samples
Hemihydrate water content influence on lattice parameters
18 a) A. Actins, R. Arajs, S. Belakovs, L. Orola, M. Veidis, Journal of Chemical Crystallography, b) 38 (2008) 169-174.
19
Hemihydrate water content influence on lattice parameters (2)
20
Hemihydrate water content influence on lattice parameters (3)
21
Hemihydrate water content influence on lattice parameters (4)
Droperidol ethanol solvate
22
Ethanol solvate Nonstoichiometric hydrate
Inte
nsity
, cou
nts
0
1000
2000
3000
4000
2Θ, o 5 10 20 30
PXRD patterns of droperidol nonstoichiometric hydrate and ethanol solvate
Droperidol ethanol solvate structure
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Structure of droperidol ethanol solvate a
a) C.L. Klein, J. Welch, L.C. Southall, Acta Crystallographica Section C, 45 (1989) 650-653.
Sorption-desorption isotherm
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0
0,1
0,2
0,3
0,4
0,5
0,6
0,7
0 20 40 60 80 100
global modeldisordered ethanolLangmuir model
n(EtOH)/n(droperidol)
X(EtOH), % Sorption-desorption isotherm of droperidol ethanol solvate
a) J.R. Authelin. International Journal of Pharmaceutics 303 (2005) 37–53
Lattice parameter changes
25
Lattice parameter changes (2)
26
Desolvatation kinetics
27
0,00
0,10
0,20
0,30
0,40
0,50
0,60
0,70
0,80
0,90
1,00
0 50 100 150 200
Con
vers
ion
degr
ee α
t, min
65 °C70 °C75 °C80 °C50 °C60 °C40 °C45 °C
Desolvatation kinetic curves of droperidol ethanol solvate
Desolvatation kinetics (2)
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𝛼 = 1 − (𝐴𝑒−𝑘𝑎𝑡 + 𝐵𝑒−𝑘𝑏𝑡)
R² = 0,9994
0
0,1
0,2
0,3
0,4
0,5
0,6
0,7
0,8
0,9
1
0 0,2 0,4 0,6 0,8 1α
Bifunkcionālais modelis
A stadija
B stadija
Biphasic model, component A 𝑬𝒂 =(55±4) kJ·mol-1
Biphasic model, component B 𝑬𝒂 =(67±5) kJ·mol-1
α
Component A and B weight in kinetic curves of droperidol ethanol solvate
Biphasic model
Component A
Component B
a) U.J. Griesser , A. Burger. International Journal of Pharmaceutics 120 (1995) 83-93
Conclusions
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Droperidol dihydrate is stoichiometric and its hemihydrate actually is nonstoichiometric hydrate.
Dehydration-hydration of nonstoichiometric hydrate is reversible while that of dihydrate is irreversible.
Dehydration of dihydrate can be described with Avrami-Erofeev while dehydartataion of nonstoichiometric hydrate can be described with first order kinetic model.
Conclusions (2)
30
Nonstoichiometric hydrate’s and ethanol solvate’s lattice parametres systematically changes depending on solvent content in the structure.
Most effective hydrogen bond structure in nonstoichiometric hydrate is for hemihydare stoichiometry.
Almost maximum ethanol content in ethanol solvate are reached when ethanol content in atmosphere is about 5%.
Ethanol solvate desolvatation can be described with biphasic model.
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