Droperidol

Analytical Profiles of Drug Substances, 7

DROPERIDOL

Cusimir A . Junicki and Roger K . Ciipin

171

Copyright 0 1978 by Academic Press, Inc. All rights of reproduction in any form reserved. ISBN 0-12-260807-0

CASIMIR A. JANICKI AND ROGER K. GILPIN

172

TABLE OF CONTENTS 1.

Description 1.1

1.2 2.

Name, Formula, Molecular Weight Appearance, Color, Odor

Physical Properties 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8

Infrared Spectrum Nuclear Magnetic Resonance Spectrum Ultraviolet Spectrum Mass Spectrum Melting Range Differential Scanning Calorimetry Solubility PKa

3.

Synthesis

4.

Stability-Degradation

5.

Drug Metabolic Products and Pharmacokinetics

6.

Methods of Analysis 6.1

6.2 6.3 6.4 6.5 6.6

Elemental Analysis Nonaqueous Titrimetric Analysis Colorimetric Analysis Spectrophotometric Analysis Thin Layer Chromatographic Analysis Gas Chromatographic Analysis

7.

Determination in Biological Fluids

8.

Determination in Pharmaceuticals

9.

References

DROPERIDOL

173

1. Description 1.1

Name, Formula, Molecular Weight

Droperidol is l-El-[4-(4-Fluorophenyl)-4oxobutyl]-1,2,3,6-tetrahydro-4-pyridinyl~-l,3-dihydro-2H-benzimidazol-2-one. The parenteral product is known as INAPSINEB injection. It is also a component of INNOVARB and THALAMONALB injection.

0

1.2

White to light tan, odorless crystalline

powder. 2.

Appearance, Color, Odor

Physical Properties 2.1

Infrared Spectrum

The infrared spectrum is presented in Figure 1. The spectrum was obtained from a potassium bromide dispersion using a Perkin-Elmer 521 grating IR spectrophotometer. A list of the assignments made for some of the characteristic bands is given in Table I (1)

.

Table 1 IR Spectral Assignment for Droperidol 3060

-CH-

2950 2895

-CH2-

MICRONS 2.5

3

4

I

I

100

6

5 I

I

7 I

8

9

10

12

15

20

I

I

I

I

I

I

3040 I

I

-

w

80

i

6040-

a

* I-

20

-

0 4000

I

I

1

3500

3000

2500

2000

1800

1600

1400

1200 1000

800

600

CM'l

Figure 1.

The Infrared Spectrum of Droperidol, KBr Dispersion. Instrument; Perkin-Elmer 521

400

200

DROPERIDOL

175

2.2

1700

C=O ring

1685

C=O ring

1595 1500 1485

aromatic substitution

1235 828 745

p-substitution p-substitution o-substitution

Nuclear Magnetic Resonance Spectrum

The 90 mHZ spectrum of droperidol presented in Figure 2 was obtained in DMSO d6 at an approximate concentration of 98 mg/ml with tetramethylsilane as the internal standard. Spectral assignments are listed in Table I1 (1).

C

b

Table I1

P

n

NMR Spectral Assignments for Droperidol Characteristic of Chemical Shift (ppm) Multiplicity Proton 8 .O 7.25 6.8-7.2

multiplet mu1tiplet mu 1tip1et

5.9

mu1tip l et mu1tiplet

2.4-3.1

alb Cld (1 rm nl P k elf {glh

Figure 2.

The NMR Spectrum of D r o p e r i d o l i n CDC13 w i t h TMS a s I n t e r n a l Standard. I n s t r u m e n t ; Perkin-Elmer R-32

DROPERIDOL

177

3.25 1.8-2.2 10.5 2.3

mu1tiplet multiplet singlet

i j

r

Ultraviolet Spectrum

The ultraviolet absorption spectrum of dxoperidol obtained from a 9:1, 0.1 M hydrochloric acid: methanol solution is shown in Figure 3 . Droperidol exhibits two maxima, one about 245 nm (E: = 15,600) due to the butyrophenone part of the molecule and the second about 280 nm ( E = 7500) due to the benzimidazolinone part of the molecule. The W spectrum of droperidol obtained from a 9:1, 0.1 M Citric acid: methanol solution is very similar to the spectrum in Figure 3 . 2.4

Mass Spectrum

The mass spectrum obtained on a Finnigan model 10151, EI mass spectrometer is presented in Figure 4. The fragmentation patterns are discussed in a paper by Blessington ( 3 ) . 2.5

Melting Range*

A dried droperidol sample melts between 144O and 148OC, NF X I V Class 1 procedure. The existence of polymorphic forms plus a hydrated form is partially demonstrated by a melting point determination. The most stable polymorphic form melts between 146.5O - 148.5OC, with the least stable 142.5OC. The hydrate melts form between 139.8O at approximately 115OC followed by recrystallization and then remelting at approximately 14OOC (4).

-

2.6

Differential Scanning Calorimetry (DSC)

The DSC of droperidol is shown in Figure 5. melting endotherm is observed at 421°K (148OC) using a temperature program of 10°/minute. The DSC

A

*Data given as uncorrected values appearing in listed references.

1.0

0.8

w

0 2 4

0.6

m

a

2m

0.4

4

0.2

0

200

225

250 WAVELENGTH

Figure 3.

275

300

325

I nm I

The W Absorption Spectrum of Droperidol in 9:l 0.1a Hydrochloric Acid:Methanol.

u a

4J

@

c

H

0 k

a,

u

4J

w

rl

CASIMIR A. JANICKI AND ROGER K. GILPIN

180

1

1

1

,430

420

410

TEMPERATURE I"KI

Figure 5.

The,DSC of Droperidol. Instrument; Perkin-Elmer DSC-2. Heating Rate: 10' per min. ATM.: Nitrogen

DROPERIDOL

181

shows different metling peaks for the other polymorphic forms. The least stable polymorph has one peak about 416OK and the hydrate has two peaks at about 394OK and 418OK (4).

2.7

Solubility

The approximate solubilities obtained at room temperature are listed in Table I11 (1). Table I11 Approximate Solubilities of Droperidol Solvent

Solubility (g/lOO ml)

Acetic acid (0.1 M) Acetone Benzene Chloroform Dimethylformamide Ether Ethanol Hydrochloric Acid (0.1 M) Lactic Acid (0.1 M) Methanol 2-Propanol Propylene Glycol Tartaric Acid (0.1 Water 2.8

1.3 1.5

0.55

40 17 0.24 0.34 0.15 2.3

0.41 1.1 1.2 2.4

<0.001

&

The PKa of droperidol is 7.64 determined titrimetrically (1)

.

3.

Synthesis

Droperidol is synthesized by refluxing a mixture of 4-Chloro-l-(4-fluorophenyl)-l-butanone, sodium carbonate, 1-[1,2,3,6-tetrahydro-4-pyridinyl]-1,3-dihydro-2H-benzimidazol-2-one, and potassium iodide in a solvent of 4-methyl-2-pentanone. The droperidol is recrystallized from 1:l ethyl acetate: diisopropyl ether or alcohol ( 5 ) .

CASIMIR A. JANICKI AND ROGER K. GILPIN

182

0

A

A

""8" \ /

Fn i - C H 2 - C H 2 - C H z -

4.

Stability

-

Degradation

Although droperidol is sensitive to heat and light (6), it is stable for up to 5 years when stored in the dark at room temperature (1). Droperidol is slightly hygroscopic (1). When droperidol was refluxed overnight in 1M hydrochloric acid, it was found to undergo compiete hydrolysis (2). The hydrolysis is given in Figure 6. The major products are 1-[4-(4-fluorophenyl)-4-oxobutyll-4-piperidinone (I) and 1,3dihydro-2H-benzinidazolin-2-one (11). A solution of droperidol in monoglyme was refluxed overnight in 2M sodium hydroxide, and droperidol was recovered-unchanged. Droperidol solutions between p H 2 . 5 and 4 . 0 in Type I glass ampuls (tartaric acid of lactic acid) are very stable and have shown no loss of potency after a 5 year period at room temperature. These solutions were stable even after 7 months at 6OoC

DROPERI DOL

I

+

II HN

YNH 0

Figure 6 .

The Acid H y d r o l y s i s of D r o p e r i d o l .

CASIMIR A. JANICKI AND ROGER K. GILPIN

184

and even when exposed to sunlight. Solutions of droperidol containing fentanyl citrate in a 50:l ratio, with or without parabens, have been found to be stable for up to three years at room temperature when stored in Type I glass. In addition, solutions of droperidol containing fentanyl citrate in a 50:l ratio have been found to be compatible for up to 3 months with 1 mg/ml atropine sulfate ( 6 ) . 5.

Drug Metabolic Products and Pharmacokinetics

The butyrophenones used clinically are neuroleptics in the sense of Delay and Deniker ( 7 ) . Droperidol, an important member of the butyrophenones series of compounds, is characterized by its short onset of activity ( 8 , 9 ) and its rapid metabolism.* The metabolism of droperidol has been studied by a number of investigators in several species. These studies are catagorized below: Data presented

Species Rat, Dog & Man Sheep, Goat & Rat Mice, Dog & Cat Rat Dog & Rat Rat Man Man

References 7

10 10 11 9

12 13 8

A = Metabolic B = Pharmacokinetic C = Distribution D = Other (pharmacological, toxicological, etc.)

*Although it is rapidly metabolized, droperidol has a relatively long duration of activity.

DROPERIDOL

185

The most commonly reported pathway for metabolism of droperidol is oxidative N-dealkylation giving rise to 4-fluoro-y-oxobenzenebutanoic acid and 1-(1,2,3,6-tetrahydro-4-pyridiny1)-1,3-dihydro2H-benzimidazol-2-one, followed by rapid metabolism of 4-fluoro-oxobenzenebutanoic acid to 4-fluorobenzeneacetic acid and its glycine conjugate, N-(4fluorobenzoyl) glycine (7,8,11,12), the most important of the urinary metabolites (7,121. These proposed metabolic pathways are summarized in Figures 7 and 8 . 6.

Methods of Analysis 6.1

Elemental Analvsis

E1ement Carbon Hydrogen Nitrogen Oxygen Fluorine 6.2

Theory

%

69.64 5.84 11.08 8.43 5.01

Nonaqueous Titrimetric Analysis

The nonaqueous titration procedure of analysis is the official method listed in the National Formulary XIV (14). An accurately weighed 300 mg sample of droperidol is dissolved in 30 to 40 ml of glacial acetic acid. After addition of anaphtholbenzeine indicator, the solution is titrated with a previously standardized 0.1M - HC104 solution to an end point. 6.3

Colorimetric Analysis

Haemers and Van Den Bossche (15) have described a general procedure for the quantitative determination of several butyrophenones, one of which was droperidol. Their procedure involves the reaction of butyrophenones with 3,5-dinitrobenzoic acid in an alkaline medium, resulting in the formation of a red complex. Using this procedure, the amount of droperidol in an injectable (2.5 mg/ml) form was determined.

DROPERIDOL

-

I

4 f Iuoro-y -ox0 benzenebut anoic acid 1- 11,2.3, 6-tetrahydro-

4-pyridinyl l -1 .3-dihydro5-step degradation

4-fluorobenzeneacetic

Figure 7.

2H-benzirnidazol-2-one

acid

Pathway in the Metabolic Disposition of Droperidol.

DROPERIDOL

187

Fe!-CH2-CH2-C-OH

I

8

4- f iuoro-y -oxobenzenobutrnoic acid

4-f iuorobenzoneacetic acid

Figure 8.

Pathway in the Metabolic Disposition of Droperidol.

CASIMIR A. JANICKI AND ROGER K. GILPIN

188

The method was found to be useful for both aqueous and alcoholic solution. 6.4

Spectrophotometric Analysis

Spectrophotometric determination of droperidol by a non-specific procedure involving the extraction of the compound into 0.1M hydrochloric acid and reading it at 246 nm has been reported (16). The effect of the amount of ether and extraction time on the purified drug was reported. A specific assay method for determining droperidol by itself or in the presence of fentanyl citrate (2) involves a double extraction procedure prior to recording the W spectrum. The initial droperidol solution is diluted with water to contain 0.15 mg/ml droperidol. Fifteen ml of the diluted droperidol solution is added to 10 ml of a pH 6 phosphate buffer, 10 ml of a 1% sodium bisulfite solution, and extracted with 15 ml of chloroform. Five ml of the chloroform layer are re-extracted into 50 ml of 0.1M citric acid and the W spectrum recorded from 235 to 300 nm.

6.5 Solvent System

Thin Layer Chromatographic Analysis Absorbent Silica Silica Silica Silica Silica Silica Silica Silica Silica

Detection Technique Rf

Gela Gela Gela Gela Gel 60Fb Gel Gb Gel GC Gel GC Gel Q4Fd

3, 4 3, 4 3, 4 31 4

1, 2 3 2

11 2 4

.75 .44 .45

.80

.46 .78 .58 .25 .59

Ref 17 17 17 17 1 1 6 2

18

Solvent Systems A B

Acetone (100) Benzene: acetone: petroleum ether: ammonium hydroxide (10:10:10:2)

DROPERIDOL

C

D

E

F G

H I

189

Acetone: petroleum ether (7:3) n-Butanol: isopropanol: acetic acid: water (3:3:2:4) Ethyl acetate: chloroform: methanol: 0.1M sodium acetate buffer, pH=4.7 (54:23:18:5) Chloroform: methanol: ammonium hydroxide (91:8 : 1) Methanol: 0.1M - sodium acetate buffer, pH=4.7 (95:5) Chloroform: methanol (95:s) Ethyl acetate: methanol: ammonium hydroxide ( 8 5 : 10:3 ) Detection Techniques

1 2 3 4

Ultraviolet light Iodine staining Dragendorff Reagent Iodoplatinate Reagent Adsorbents

a

b C

d

Unspecified Merck Analtech Quantum Industries 6.6

Gas Chromatographic Analysis

Droperidol has been reported to be unsuited for gas chromatographic analysis due to oncolumn decomposition (17). 7.

Determination in Biological Fluids

Presently, there are no published chemical methods for determining droperidol in blood or urine. However, a radiochemical assay method has been published (13). Tritium-labeled droperidol is synthesized according to the method of Soudijn a1 (19). Total radioactivity in urine or et plasma samples containing tritium-labeled droperido1 is determined by counting directly in a 20% ethanol-toluene scintillator or a 20% Beckman BBS3-toluene scintillator, respectively. The intact droperidol from blood or urine is obtained by

190

CASIMIR A. JANICKI AND ROGER K. GILPIN

extracting an alkaline solution of the urine or plasma with freshly seeded chloroform ( 2 5 pg of unlabeled droperidol per ml of chloroform). A portion of the chloroform layer is transferred to a scintillator vial, evaporated to dryness, and the radioactivity determined using a 20% ethanol-toluene scintillator. The remainder of the chloroform layer is evaporated to dryness, and the residue redissolved in a small volume of chloroform. The entire chloroform sample is spotted onto a Silica G plate and developed with 91:8:1 chloroform: methanol: ammonium hydroxide. The droperidol spot (Rf between 0.6-0.7) is scraped and placed into a scintillation vial. Twenty percent ethanol-toluene scintillator is added and the radioactivity determined. The counting efficiency is not affected by the variation in the amounts of silica gel present in the counting vials. 8.

Determination in Pharmaceuticals

Chekova proposed a method for solutions containing parabens, which involved the dilution of the dosage form with 0.1M hydrochloric acid and removing the parabens with-an ether extraction. The W spectrum of the hydrochloric acid solution is recorded. Haemers and Van den Bossche reacted droperidol with 3,5-dinitrobenzene to form a colored complex, which is used for the quantitative determination of droperidol in dosage forms. Both these methods suffer from the fact that they are not specific for intact droperidol. The specific ultraviolet assay method for droperidol, described in section 6.4, is the preferred assay. The assay is modified slightly when the dosage form contains parabens. After the droperido1 is extracted into citric acid, the citric acid is washed with diethyl ether. This removes any W interferences in the citric acid due to the parabens (6).

DROPERIDOL

191

References 1.

Demoen, Paul, Janssen Pharmaceutica, Beerse, Belgium, unpublished data.

2.

Janicki, C.A., Brenner, R.J.,Schwartz, 57, 451. B.E., J. Pharm. Sci., 1968, -

3.

Blessington, B., Org. Mass Spectrom, 1971, 5, 1113. c

4.

Van Rompay, J., Janssen Pharmaceutica, Beerse, Belgium, unpublished data.

5.

Janssen, P.A.J., and Gardocki, J.F.,U.S. Patent 3,141,823, (1964).

6.

Janicki, Casimir,A., McNeil Laboratories, unpublished data.

7.

Janssen, P.A.J., Proc. Eur. SOC. Study 9, 107. Drug Tox., 1967, -

8.

DiMascio, A., Butyrophenones in Psychiatry, A. DiMascio and R . I . Shader Eds., Raven Press, New York, N . Y . , 1972, 11-23.

9.

Janssen, P.A.J., in "Psychopharmacological Agents", Vol.11, M. Gordon, Ed., Academic Press, New York, N.Y., 1967, 199-248.

10.

in "The Application of Shephard, N.W., Neuroleptanalgesia in Anesthetic and Other Practice", N.W. Shephard, Ed., Pergamon Press, London, G.B., 1965, 1-27.

11.

Soudijn, W., Van Wijngaarden, I., Janssen, P.A.J., Int. Anesthesiol. Clin., 12, 145. 1974, -

12.

Soudijn, W., Van Wijngaarden, I., 1, Allewijn, F., Eur. Pharmacol., 1967, 47.

CASIMIR A. JANICKI AND ROGER K. GILPIN

192

13.

Cressman, W.A., Plostnieks, J., Johnson, P.C., Anesthesiology, 1973, 3 8 , 363.

-

14. National Formulary XIV, Mack Printing Co., Easton, Pa., 1975, 245. 15.

Haemers, A . , Van Den Bossche, W., J. 21, 245. Pharm. Pharmacol., 1969, -

16.

Chekova, L.P., Shemyakin, F.M., Molnar, L.N., Farmatsiya (Moscow) 1972, 21, 41. -

17.

Quaglio, M . P . , Cavicchi, G . S . , Murglia, M., Boll. Chin. Farm., 1971, 110, 385. -

18.

Gilpin, R.K., McNeil Laboratories, unpublished data.

19.

Soudijn, W., Van Wijngaarden, I., J. Labelled Compds., 1968, 4, 159.