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

This document was presented at PPXRD -Pharmaceutical Powder X-ray Diffraction Symposium

Sponsored by The International Centre for Diffraction Data

This presentation is provided by the International Centre for Diffraction Data in cooperation with the authors and presenters of the PPXRD symposia for the express purpose of educating the scientific community.

All copyrights for the presentation are retained by the original authors.

The ICDD has received permission from the authors to post this material on our website and make the material available for viewing. Usage is restricted for the purposes of education and scientific research.

ICDD Website - www.icdd.comPPXRD Website – www.icdd.com/ppxrd

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)

14

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)

17

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

23

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

24

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)

28

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

29

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.

A c k n o w l e d g m e n t s : • R i g a T e c h n i c a l U n i v e r s i t y I n s t i t u t e o f I n o r g a n i c

C h e m i s t r y • L i ā n a O r o l a • 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!