AGRIS BĒRZIŅŠ , TOMS RĒĶIS, ANDRIS ACTIŅŠ, INESE SARCEVIČA DEPARTMENT OF CHEMISTRY, UNIVERSITY OF LATVIA DESOLVATION OF DROPERIDOL ISOSTRUCTURAL SOLVATES
A G R I S B Ē R Z I Ņ Š , T O M S R Ē Ķ I S ,
A N D R I S A C T I Ņ Š , I N E S E S A R C E V I Č A
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
DESOLVATION OF DROPERIDOL
ISOSTRUCTURAL SOLVATES
Background
2Department of Chemistry, University of Latvia
Introduction
3
Droperidol is known to exist in: Two polymorphic forms Y and Z a,b
Dihydrate c
Nonstoichiometric hydrate 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.
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.
Droperidol hydrates
Droperidol hydrates - conclusions
5
Droperidol dihydrate typical stoichiometric hydrate complicated dehydration process
Droperidol hemihydrate typical nonstoichiometric hydrate Dehydration gives isomorphic dehydrate
Outline
6
Preparation and characterization of solvates Crystallization Characterization Crystal structure determination
Droperidol ethanol and methanol solvates Sorption-desorption isotherms Systematic lattice parameter changes
Desolvation kinetics Desolvation by controlling PXRD pattern Kinetic parameters from isothermal experiments Solvent exchange experiment
Conclusions
Preparation and characterization of solvates Crystallization Characterization Crystal structure determination
Droperidol ethanol and methanol solvates Sorption-desorption isotherms Systematic lattice parameter changes
Desolvation kinetics Desolvation by controlling PXRD pattern Kinetic parameters from isothermal experiments Solvent exchange experiment
Conclusions
Solvent Phase Solvent PhaseA
prot
icpo
lar acetone Z 1,4-dioxane -
acetonitrile Solvate ethylacetate Z
n-buthylacetate Z nitromethane Solvate
cyclohexanon - 3-pentanone Zdichloromethane Solvate
Hyd
roge
nbo
nddo
nors
Acetic acid Solvate Methanol Solvate
1-butanol Z 1-pentanol -
Carbon tetrachloride Z 1-propanol Z
Chloroform Solvate 2-propanol Z
Cyclohexanol - Water DH/NSTHEthanol Solvate
Electron pair donors / Aromatic apolar or lightly polarterc-buthylmethyl ether Z toluene Z
tetrahydrofurane Z/Y
Solvent Phase Solvent PhaseA
prot
icpo
lar acetone Z 1,4-dioxane -
acetonitrile Solvate ethylacetate Z
n-buthylacetate Z nitromethane Solvate
cyclohexanon - 3-pentanone Zdichlorlomethane Solvate
Hyd
roge
nbo
nddo
nors
Acetic acid Solvate Methanol Solvate
1-butanol Z 1-pentanol -
Carbon tetrachloride Z 1-propanol Z
Chloroform Solvate 2-propanol Z
Cyclohexanol - Water DH/NSTHEthanol Solvate
Electron pair donors / Aromatic apolar or lightly polarterc-buthylmethyl ether Z toluene Z
tetrahydrofurane Z/Y
Crystallization of droperidol
7
PXRD patterns of solvates
8
Desolvation of solvates
9
Crystal structure of solvates
10
Parameter Solvent
Water a Ethanol b Methanol Nitrometane Acetonitrile Ethanol
Stoichiometry 0.5 0.5 0.5 0.5 0.5 0.5
Space group P-1 P-1 P1 P1 P1 P-1
a, Å 6.2842(15) 6.083(3) 6.0671(2) 6.06730(10) 6.0870(2) 6.08400(10)
b, Å 10.1473(8) 10.296(1) 10.2183(4) 10.1884(3) 10.2177(3) 10.2978(3)
c, Å 16.1854(2) 16.018(2) 16.2078(8) 16.4237(5) 16.2642(6) 16.1737(5)
α, o 102.554 100.93(1) 101.3130(10) 99.8303(13) 101.2051(11) 100.9299(10)
β, o 91.917(14) 92.72(2) 93.208(2) 92.2880(12) 92.7447(10) 92.6382(10)
γ, o 99.316(12) 96.27(2) 96.996(2) 95.6243(18) 96.7569(19) 95.9415(15)
V, Å3 991.614 976.735 974.654 993.864 982.777 987.346
Z, Z` 2, 1 2, 1 2, 2 2, 2 2, 2 2, 1
T, K 293 193 193 193 193 193
R 5.09 5.81 6.18 6.42 5.55 6.80
a) A. Actins, R. Arajs, S. Belakovs, L. Orola, M. Veidis, J Chem Crystall, 38 (2008) 169-174.b) C.L. Klein, J. Welch, L.C. Southall, Acta Crystallographica Section C, 45 (1989) 650-653.
Crystal structure of solvates - water
11
a) A. Actins, R. Arajs, S. Belakovs, L. Orola, M. Veidis, Journal of Chemical Crystallography, 38 (2008) 169-174.
Crystal structure of solvates - ethanol
12a) C.L. Klein, J. Welch, L.C. Southall, Acta Crystallographica Section C, 45 (1989) 650-653.
Crystal structure of solvates - methanol
13
Crystal structure of solvates - acetonitrile
14
Outline
15
Preparation and characterization of solvates Crystallization Characterization Crystal structure determination
Droperidol ethanol and methanol solvates Sorption-desorption isotherms Systematic lattice parameter changes
Desolvation kinetics Desolvation by controlling PXRD pattern Kinetic parameters from isothermal experiments Solvent exchange experiment
Conclusions
Sorption-desorption isotherms
16
n(solvent)/n(droperidol)
X(solvent), %
Sorption-desorption isotherms of droperidol solvates
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
0 20 40 60 80 100
WaterEthanolMethanol
0
0.1
0.2
0.3
0.4
0.5
0.6
0 2 4 6
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
0 20 40 60 80 100
WaterEthanolMethanol
X(solvent), %
n(solvent)/n(droperidol)
Sorption-desorption isotherms
17
n(solvent)/n(droperidol)
X(solvent), %
Sorption-desorption isotherms of droperidol solvates
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
0 20 40 60 80 100
WaterEthanolMethanol
Sorption-desorption isotherms
18
n(solvent)/n(droperidol)
X(solvent), %
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0 20 40 60 80 100
Methanol
Langmuir
Disordered solvent
Global model 1
Sorption-desorption isotherms
19
n(solvent)/n(droperidol)
X(solvent), %
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0 20 40 60 80 100
Ethanol
Crystallographic vacantlocation modelDisordered solvent
Global model 2
PXRD pattern changes of ethanol solvate
20
Ethaol mass fraction, %
PXRD pattern change and crystal structure
21
Lattice parameter changes
22
α
Lattice parameter changes
23
β γ
Outline
24
Preparation and characterization of solvates Crystallization Characterization Crystal structure determination
Droperidol ethanol and methanol solvates Sorption-desorption isotherms Systematic lattice parameter changes
Desolvation kinetics Desolvation by controlling PXRD pattern Kinetic parameters from isothermal experiments Solvent exchange experiment
Conclusions
Desolvation in air – methanol solvate
25
Desolvation in air– nitromethane solvate
26
Desolvation kinetics in nitrogen flow
27
00.10.20.30.40.50.60.70.80.9
1
0 200 400 600 800 1000
Water
Methanol
Ethanol
time, min
Conversion degree α
Desolvation kinetics in nitrogen flow
28
00.10.20.30.40.50.60.70.80.9
1
0 100 200 300 400 500
Ethanol
Acetonitrile
Nitromethane
time, min
Conversion degree α
Desolvation kinetics in nitrogen flow
29
00.10.20.30.40.50.60.70.80.9
1
0 50 100 150 200
Crystals I
Crystals II
Pulverized
Pulverized II
time, min
Conversion degree α
Kinetic parameter calculation
30
Model free approach: Calculation of activation energy by isoconversional methods Kinetic model determination
0
20
40
60
80
100
120
0 0.2 0.4 0.6 0.8 1
Friedman
Advanced isoconversional
Model free approach: Calculation of activation energy by isoconversional methods Kinetic model determination
Conversion degree α
Activation energy, kJ
Kinetic parameter calculation
31
Model free approach: Calculation of activation energy by isoconversional methods Kinetic model determination
00.5
11.5
22.5
33.5
44.5
5
0 0.2 0.4 0.6 0.8 1
F(3/2)F2D2D3D4D535.49402442
Conversion degree α
g(α)/g(0.5)t(α)/t(0.5)
Kinetic parameter calculation
32
Model free approach: Calculation of activation energy by isoconversional methods Kinetic model determination
0
0.5
1
1.5
2
2.5
3
0 0.2 0.4 0.6 0.8 1
F(3/2)F2D2D3D4D5Exp
Conversion degree α
g(α)=kt
Kinetic parameter calculation
33
Modelistic approach: Kinetic model determination/selection Calculation of rate constants and activation energy
00.10.20.30.40.50.60.70.80.9
1
0 200 400 600
70 oC100 oC
Conversion degree α
time, min
Solvent exchange
34
Conclusions
35
Droperidol forms isostructural solvates with water, ethanol, methanol, acetonitrile, nitromethane, chloroform and dichloromethane.
Systematic lattice parameter change depending onsolvent content was observed for water, ethanol andmethanol.
Desolvation kinetic was analysed. Kinetic modelbased on diffusion mechanism should be used.
A c k n o w l e d g m e n t s :• E u r o p e a n S o c i a l F u n d f o r a s c h o l a r s h i p t o
A . B ē r z i ņ š a n d L a t v i a n A c a d e m y o f S c i e n c e s G r a n t .
• J S C G r i n d e k s f o r d r o p e r i d o l s a m p l e s
Thank you for your attention!