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!