Hydroflumethiazide

Analytical Profiles of Drug Substances, 7

HYDROFLUMETHIAZIDE

Chester E . Orzech, Norris G . Nash, and Raymond D . Daley

297

Copyright @ 1978 by Academic Press, Inc. All rights of reproduction in any form reserved. ISBN 0-12-2608070

CHESTER E. ORZECH et al.

298

CONTENTS 1.

DESCRIPTION 1.1 Name, Formula, Molecular Weight 1.2 Appearance, Color, Odor

2.

PHYSICAL PROPERTIES 2.1 Infrared Spectra 2.2 Nuclear Magnetic Resonance Spectrum 2.3 U l t r a v i o l e t Spectre 2.4 Mass Spectrum 2.5 D i f f e r e n t i a l Thermal Analysis (mA) 2.6 Crystal Properties 2.7 S o l u b i l i t y 2.8 Ionization Constant 2.9 Fluorescence Spectra 2.10 Melting Points

3.

SYNTHESIS

4

STABILITY-DEGRADATION

.

5.

METABOLISM

6.

METHODS OF ANALYSIS 6.1 I d e n t i f i c a t i o n Tests 6.2 Elemental Analysis 6.3 Color iw tr ic Method 6.4 T i t r a t i o n Methods 6.5 Paper Chrometography 6.6 Column Chromatography 6.7 Ultraviolet Methods 6.8 Polarography 6.9 Thin Layer chromatography

7.

REFERENCES

299

HY DROFLIJMETHIAZIDE

.

1

DESCRIPTION

1.1 Name, Formula, Molecular Weight Hydrof lume t h i a t i d e is 3,4-dihydro-6-( t r i f luorome thy1)2H-1,2,4-benzothiad iaz ine- 7-sulfonamide 1,l-dioxide , also known as 6-trifluoromethyl-3,4-dihydro-7-sulfamoyl-2H-1,2,4benzothiadiazine 1,l-dioxide and as 3,4-dihydro-7-sulfamyl-6tr i f luorome thyl-l,2,4-benzothiadiaz ine 1,l-dioxide. Chemical Abstracts indexes i t a s 2H-1,2,4-benzothiadiazine-7-sulfonamide, 3,4-dihydro-6- ( t r i f luorome thy1)-, 1,l-dioxide. The CAS Regis t r y Number is [ 135-09-11.

Mol. Wt.:

331.29

1.2 Appearance, Color, Odor Hydrof lume t h i a z i d e is white t o cream colored, odor-

l e s s , powder o r c r y s t a l s .

2.

PHYSICAL PROPERTIES

2.1 I n f r a r e d Spectra The i n f r a r e d spectrum of hydrof lumethiazide NF Reference Standard Lot No. 69178 is s h o k i n Figure 1. The spect r u m was obtained i n a potassium bromide dispersion, using a B e c h n Model IR-12 spectrophotometer. A similar spectrum is observed when a mineral o i l or o t h e r d i s p e r s i n g medium is used, except f o r absorption bands of the medium. The spectrum is similar t o those a l r e a d y published (1,2). In addition to the absorption bands shown here, hydroflumethiazide exhibits weak but s h a r p bands a t 382, 338, and 315 cm-1, and very weak bands a t 267, 242, 230, and 218 cm-1, when the spectrum is obtained as a f a i r l y thick mineral o i l dispersion. Some of the absorption bands may be assigned as follows (3):

Figure 1.

Infrared Spectrum of Hydroflumethiaeide, Potasrium Braaide Pellet.

HYDROFLUMETHIAZIDE

Absorption Bands, cm” 3380, 3260, 3170

301

Assignment N-H s t r e t c h

1300 t o 1350

-SO2- s t r e t c h ; -CF3 de format ion

1140 t o 1200

-SOz-

s t r e t c h ; -CF3 d e f o r m t ion

2.2 Nuclear Magnetic Resonance Spectrum The NER spectrum shown i n Figure 2 was obtained by dissolving A y e r s t- house reference standard hydroflume t h i a z i d e d59-1 i n ace tone-d6 containing te tram t h y l s i l a n e as i n t e r n a l reference. The s p e c t r u m was produced using a Varian EM-360 N M spectrometer. The peaks a t 7.42 ppm and 8.37 ppm a r e due t o the aromatic protons. The methylene protons are a t 5.00 ppm and the -NH protons a r e the broad peaks a t 6.70, 6.90, and 7.45 ppm. The s e r i e s of peaks a t 2.10 and 3.07 ppm are due t o the solvent. 2.3 U l t r a v i o l e t Spectra Figure 3 is the u l t r a v i o l e t absorption spectrum of NF Reference Standard hydrof lume t h i a z i d e , Lot No. 69178, in methanol. The spectrum was obtained on a Cary Model 14 spectrophotometer a t a concentration of 19.3 mg per l i t e r . Disc o n t i n u i t i e s i n the spectrum a r e due t o changes i n the absorbance range. The 277 t o 267 nm and the 222 t o 210 nm regions of the scan a r e on the 1.0 t o 2.0 absorbance range; the r e m i n d e r of the scan is on the 0.0 t o 1.0 range. Pilsbury and Jackson (4) compare u l t r a v i o l e t s p e c t r a

of hydroflumethiazide with those of other thiazides. They r e p o r t E ( l a , 1 cm) for hydroflumethiazide of 450 a t 276 nm a t pH 10, 580 a t 273 nrn a t pH 2.

Kracmar and Las tovkova (5,6) compare u l t r a v i o l e t s p e c t r a of hydroflumethiazide i n methanol, ethanol, 0.1E hydrochloric a c i d , and 0.lE potassium hydroxide t o the s p e c t r a of other thiazides. The a b s o r p t i v i t y (log 6 ) of hydroflumethiazide is reported a s 4.182 a t 275 nm i n 0.1E potassium hydroxide, 4.290 a t 273.5 nm i n 0,lE hydrochloric a c i d , 4.229 a t 272.5 nm i n ethanol, and 4.286 a t 272.5 i n methanol. Other u l t r a v i o l e t s p e c t r a l d a t a a r e those of DePaulis and Dipietromaria (7), who r e p o r t E ( R , 1 cm) of 560 a t 274 nm i n 70 percent ethanol; Fazzari ( 8 ) , r e p o r t i n g a n absorpt i v i t y of 45.4 l i t e r l g cm a t 273 nm i n 0.2E sodium hydroxide; and Sunshine (9), with s p e c t r a i n 0.lg hydrochloric a c i d and in 0.1E sodium hydroxide solution. The B r i t i s h Pharmacopeia

1

1

1

I

I

I

I

I

9

A

8

7

6

5

4

3

2

I

Figure 2.

Proton Mopetic Resonance Spectrum of Hydroflumethiazide, in Deuterated Acetane,

Figure 3.

Ultraviolet Spectrum of Hydroflumethiazide, 19.3 - / l i t e r ,

in Methanol.

CHESTER E. ORZECH et al.

304

1973 u l t r a v i o l e t i d e n t i t y test (10) corresponds t o an absorpt i v i t y of about 46 l i t e r / g cm a t 274 nm i n 0.OlK sodium hy-

droxide

.

2.4 Mnss Spectrum

Figure 4 is the low resolution mnss spectrum of hydroflumethiazide NF Reference Standard Lot No. 69178, obtained with an LKB 9000s mass spectromtter, ionization voltage 70 eV, source temperature 25OoC. Some of the peaks m y be assigned as follows (11): Molecular ion EH

m/e 331 m/e 331 m/e 303 m/e 303

-CHNH

-so -SO2

m/e 239

-NM

m/e 222

-so

m/e 222

-SO2

m/e 303 (*277.3) b

m/e 255

b

m/e 239

b

m/e 222 (*206)

e

m/e 174 m/e 158

m/e 69 2.5 Differential Thermal Analysis (DTA) The DTA curve i n Figure 5 was obtained w i t h a DuPont Model 900 instrument. The curve shows only a malting endothem a t 274OC with subsequent decomposition, 2.6 Crystal Properties

The powder d i f f r a c t i o n pattern is given i n Table I. This pattern was obtained w i t h 8 Norelco diffractometer, using nickel-filtered copper radiation. The pattern is similar t o one published by Corrigan and Timoney (12); they a l s o report the existence of a I t 1 c r y s t a l l i n e ethanol solvate. Kuhnert-Brandsti'tter e t a1 give information for the microscopic character iea tion of hydrof lume thiazide (13), as does Groenewegen (14).

1

O -

o

1

I

o

I

o

~

O

o

I

o

I -

r--

o

o m a o r c c o m o n c u AlISN31NI 3 A I l W l 3 t l

4-0 o

I-

0

a a W

a a a

I

e

tn tn

a

I:

o

(I)

1

. U

Figure 5.

Differential Thermal Analysis Curve of Hydroflumethiazide.

HYDROFLUMETHIAZIDE

307

TABLE I

X-RAY POWDER DIFFRACTION PATTERN OF HYDROFLUMETHIUIDE

5.44 5.08 4.90 4.66 4.58 4.34 4.27 4.05 3.93 3.69 3.60 3.48 3.37 3.32 3.25 3.23 3.14 3.06 3.01 2.88 2.77 2.72

30

1

4 41 100 17 22 5

2 16 3 5 5 3 6 5 14 11 6 2 2 3

2.59 2.54 2.50 2.44 2.41 2.35 2.31 2.25 2.22 2.13 2.08 2.05 2.02 2.01 1.96 1.94 1.92 1.90 1.87 1.83 1.79 1.77

1 1 3 10

2 4 2 1

4

5 2 1 2 1 1 1 1 2

2 4 2 1

2.7 S o l u b i l i t y Some room temperature s o l u b i l i t i e s a r e a s followst Solvent

Me thano 1 Ethanol (957.)

Ethyl Acetate Ethyl Ether (anhydrous) Chloroform Ben2 ene Water Ace toni tr i l e Ace tone

Approximate S o l u b i l i t y , mg / m l

.

58 21.

11.

0.2 0.1 CO. 1 0.3 ( 1 5 ) 43

.

>loo.

CHESTER E. ORZECH et a].

308

Kobinger and Lund report that hydroflumethiazide is e a s i l y soluble i n the lower alcohols and ketoner, tetrahydrofuran, and pyridine. The p r r t i t i o n coefficient between e t h y l acetate or methyl isobutyl ketone and water i r about 30. It is also e a s i l y soluble i n b86eS (15). Hydroflumethiazide i8 soluble i n a mixture of polyethylene glycol 400, N-ma thyl-2-pyrrolidinoac, and water (40:5:55), or i n a mixture of polyethylene glycol 400, d i methylfonnamide, and water (40:5:55); the s o l u b i l i t i e s a r e 11.2 and 15.8 mg/ml, respectively (16). 2.8 Ionization Constant Kobinger and Lund report a pK1 of 8.9 and a pK2 of 10.7 a t room temperature (15). Smith e t a1 report a pK1 of 8.73, determined by rpectrophotomctry a t 273 nm, and of 8.79, determined by fluoronetry with e x c i t a t i o n a t 333 nm and emission a t 393 nm (17).

.

2 9 Fluorescence Spectra Hydroflumethiazide fluorescence ha6 an excitation maximum a t 333 nm and an emiosioa maximum a t 393 nm. Fluorercence is much more intenre a t pH 8 or les8 (17).

2.10 Melting Point8 Reported melting points range from about 200' t o 275OC (18-36, 38). The m l t i n g point i r specified as 270' t o 275'C i n NF XIV. 3.

SYNTHESIS

Hydrof lumethiazide ha8 been prepared by vrrious procedurer from t r i f luoroma thyl-5-aminobenzene-2 ,I-di8olforumide (18-28, 30, 32, 34-38), tr i f luoromethyl-5-8minobentene-2,4disulfonyl chloride (31, 33), or 6-(trifluoromcthyl)-7-~ulfamyl-l,2,4-benzothiadiatinc 1,l-dioxide (29). A few of these procedures including ryntheser of the s t a r t i n g material6 a r e outlined i n Figure 6. 4

.

STABILITY-DEGRADATION

Kobinger and Lund (15) reported 1 percent loss i n 24 hours in 0.1E hydrochloric acid a t 38*C, and 0.5 percent i n 24 hours i n 0 . E rodium hydroxide a t room temperature. However, boiling in 3E sodium hydroxide for 2 hour q w a t i t a t i v e l y conver tad hydrof lumethiazide t o 2,4-dirulfamyl-5-trif luoromc thylani 1ine

.

r

Figure 6. Synthesis of Hydrof lume thiazide

.

/.

clso/ 2. NQOH

1

,

1. (HCHOJn,

CHESTER E. ORZECH et al.

310

Fazzari (8) reported that less than 0.04 percent of the disulfonamide formed when hydroflumethiaside was stored for 5 hours i n 0.2E sodium hydroxide a t room temperature. 5.

METABOLISM

No reports of metabolic studies on hydroflunrethiazide were found. 6.

METHODS OF ANALYSIS 6 . 1 Identification Tests

Hydroflumethiazide is e a s i l y identified by the prope r t i e s described i n section 2 above. Where i d e n t i f i c a t i o n of hydroflumethiazide i n s o l i d formulations is necessary, i t can be extracted with a small volume of sodium hydroxide solution; the e x t r a c t is made s l i g h t l y acid t o precipitate the hydroflumethiazide, which can be washed with water and dried before further testing. Hydroflumethiazide can be extracted from a c i d i c aqueous solution with diethyl ether and recovered by evaporating the ether extract; the recovered material can be identified from i t s infrared spectrum, a s reported by Fazzari (8) and as directed i n NF XIV (39). Ethyl acetate and mcthyl isobutyl ketone a r e a l s o s u i t a b l e for extraction of hydroflumethiazide ( 1 5 ) . If the i d e n t i f i c a t i o n of 6 m P L l amounts of hydroflume thiaz ide is necessary, thin layer chromatography procedures are q u i t e specific. Several procedures for identifying thia-

zide diuretics, using t h i n layer chromatography ( 4 0 , 41, 4 2 , 4 3 , 44, 4 5 ) or paper chromatography (4), with various detection methods, have been reported. Ultraviolet absorption spectra i n acid and a l k a l i n e solution show comparatively small s h i f t s i n wavelength maxima in the case of hydroflumethiazide ( 4 ) , but may help t o d i f f e r e n t i a t e i t from somc other thiazides. Microscopic t e s t s for hydroflumethiazide a r e described by Croenewegen ( 1 4 ) and by Kuhnert-Brandstitter e t a 1 (13). 6.2 Elemental Analysis

The elemental composition of hydroflume thiazide is a8 follass :

311

HYDROFLUMETHIAZIDE Element

7. Theory

Carbon Hydrogen F luor ine N i tr ogen Oxygen Sulfur

29.00 2 -43 17.21 12.68 19.32 19.36

6.3 Colorimetric Method Bermlo (46) determined hydroflumethiazide by hydrolyzing i t to ~,4-disulfamyl-5-trifluoromet h y l a n i l i n e , diazot i z i n g the hydrolysis product and coupling to chromotropic a c i d or t o N-(1-naphthy1)e thylenediamine dihydrochloride. Kobinger and Lund (15) a l s o indicate that t h i s technique can be used f o r q u a n t i t a t i o n of hydroflumethiazide. 6.4 T i t r a t i o n Methods DePaulis and Diuietromaria (7) t i t r a t e d hvdroflumethiazide i n anhydrous eihylenediamine-solutionwiih sodium me thoxide i n benzene -methanol (85 :15), using a s a t u r a t e d solut i o n of azo v i o l e t i n benzene as indicator. Chiang (47) t i t r a t e d hydroflumethiazide i n dimethylformamide with sodium methoxide i n benzene-methanol s o l u t i o n , using a s a t u r a t e d s o l u t i o n of p-nitrobenzene-azo-resorcinol i n benzene a s i n d i c a t o r ; thymol blue indicator gave u n s a t i s f a c t o r y endpoints. Sugar and lactose i n t e r f e r e d , however. 6.5 Paper Chromatography

Adam and Lapiere (40) used two systems for paper chromatography of hydroflumethiazide: ( a ) Whatman No. 1 paper, with 1-pentanol, 12E a m o n i a , and water (80:20:60) a s mobile phase; (b) Whatman No. 1 paper impregnated w i t h formamide, with chloroform and 1-pentanol (80:20) a s mobile phase. The spots were detected using s h o r t wavelength u l t r a v i o l e t r a d i a t ion. Pilsbury and Jackson (4) a l s o used two s y s t e m t o d i f f e r e n t i a t e hydroflume thiazide from other thiazide diure tics: ( a ) Whatman No. 3 paper impregnated with t r i b u t y r i n , developing f o r 20 minutes a t 9OoC with pH 7.4 phosphate buffe r ; (b) Whatman No. 1 paper, with amyl alcohol and a m o n i a (9:l) a s mobile phase. The spots were located using s h o r t wavelength u l t r a v i o l e t r a d i a t i o n , and a l s o by spraying with 0.1E sodium hydroxide s o l u t i o n followed by a s a t u r a t e d solut i o n of sodium 1,2-naphthoquinone-4-sulfonate i n ethanol and water (1:l); the l a t t e r treatment develops a n orange-red color

312

with thiazides

.

CHESTER E. ORZECH et

.

01.

6 6 Column Chromatography Fazzari ( 8 9 48) used a &sic celitt@ column to purify

t a b l e t e x t r a c t s prior t o u l t r a v i o l e t quantitation. So& e t a1 ( 4 3 ) used non-ionic resin colunms t o recover and clean up thiazides i n urine prior t o thin layer chromatography.

Hydroflumethiazide can be separated and quantitated by columa chromatography with a gravity fed eluant as follows (49 1: Sephade@ LH-20, 23 cm x 1.2 em I.D. Me thanol-cyclohexane-chloroform-ace t i c acid (40r30t30:l vol/vol) Elution Volum: 72 t o 117 m l Column: Eluant:

-

Fluorescence 333 nm excitation, 380 nm emission About 100 u g of hydroflumethiazide

Quantitation:

Sample:

Pressurized liquid chromatography can a l s o be used t o determine hydroflumethiazide. The following system is s u i t able (49): Column:

W t e r s y-Boadapal@ 30 cm x 4 m I.D. pre-packed coltrmn Solvent: Methanol 0.02g pH 7.4 phosphate buffer (2:8 vol/vol) Pressure: 1500 p s i Plow Ratet 1 m l h i n u t e sample: About 1 u g Detection: Schoeffel Variable Wavelength Ultrav i o l e t Detector, 280 nm

-

6.7 Ultraviolet Me thods

Identification of hydroflrwethiazide by u l t r a v i o l e t absorption was discussed ihsections 2.3 8nd 6;l. Fazzari (8) developed a p a r t i t i o n chromatographyu l t r a v i o l e t method for hydroflumcthiazide i n drug formulations. The compound i r h e l d on an alkaline C e l i t 8 colunm, which is washed with chloroform and ether, then eluted with a c e t i c acid in ether. The eluate is then extracted with 0.21 sodium hydroxide and the strength of the sample is determined by the absorptivity a t 273 fun. This method is now the NF assay procedure for hydroflumethiazide tablets (39).

HYDROFLUMETHIAZIDE

313

Other i n v e s t i g a t o r s (4, 5, 6, 7) have described the use of u l t r a v i o l e t absorption measurements t o determine hydro-

flume t h i a z ide.

6.8 Polarography

Polarographic s tudies on the reduction of hydroflumet h i a z i d e have been reported (50, 51, 52, 53). These are p r i marily s t u d i e s of the reduction of the trifluoromethyl group or sulfonamide group, although Lund (51) r e p o r t s the a s s a y of hydroflume t h i a z i d e i n urine by polarography. 6.9 Thin Layer Chroma tographr

Table I1 lists t h i n layer chromatography systems for hydroflumethiazide. Hydroflu& thiazide can be iocated on the p l a t e by examination under an u l t r a v i o l e t lamp, or by any of the s p r a y reagents described (42, 43, 44, 45, 54). Garceau e t a1 (55) reported a q u a n t i t a t i v e t h i n l a y e r chromatography procedure with fluorometric d e t e c t i o n , for the determination of hydroflumethiazide i n urine and plasma. The l i m i t of d e t e c t i o n was reported t o be 10 ng of drug per m l of plasma. ACKNOWLEDGMENTS The writers wish t o thank Dr. B. T. Kho f o r h i s review of the manuscript, Dr. G. S c h i l l i n g of Ayerst Research Laboratories f o r h i s mass s p e c t r a l data and i n t e r p r e t a t i o n , the l i b r a r y s t a f f f o r t h e i r literature search, and Mrs. B. Juneau f o r typing the p r o f i l e .

CHESTER E. ORZECH et al.

314

TABLE XI THIN LAYER CHROMATOGRAPHY SYSTEMS FOR HYDROFLUMETHIAZIDE

Absorbent

Solvent Sys tern

u

Alumina G S i l i c a Gel G

Ethyl Acetate E t h y l Ace ta teBenzene (80: 20) Ethyl Acetate Ethyl Acetate-ater (98: 2 E t h y l Ace tate-Wa ter (197: 3) Toluene-Xylene-l,4Dioxane-2-Propanol25% Amnonia (1:1:3:

0.36

40

0.41 0.46

40 40

0.52

41

S i l i c a Gel G Alumina GF254 S i l i c a Gel DSFS S i l i c a Gel GF

S i l i c a Gel G S i l i c a Gel G S i l i c a Gel G S f l i c a Gel F254 S i l i c a C e l F254 Silica G e l

G25-22

*Not Recorded

3:2)

Benzene-B thyl Acetate (2:8) Ethyl AcetateMe thanol- Anmonia (85:10:5) Ethyl AcetateBenzene (8:2) Ethyl Acetate Ethyl Acetate E t h y l AcetateMethanol-0. !l Annnonia (96:2:2)

Oa

53

Reference

41

0.43

42

NR*

43

NR*

43

0.78 0.45 0.45

54 44 45

0.52

55

HYDROFLUMETHIAZIDE

315

REFERENCES 1.

2. 3. 4. 5. 6.

7. 8. 9. 10.

11.

12. 13. 14. 15. 16. 17. 18. 19. 20.

21. 22.

0. R. Samnul, W. L. Brannon, and A. L. Hayden, J. A s s . Offic. A n a l . Chem. 47, 918-991 (1964). E. G. C. Clarke ( e d i t o r ) , " I s o l a t i o n and I d e n t i f i c a t i o n of Drugs", The Pharmaceutical Press, London, 1969, page 743. L. J. Bellamy, "The Infrared Spectra of Complex Molecules", t h i r d e d i t i o n , John Wiley & Sons, New York, 1975, pp. 372 and 406-7. V. B. P i l s b u r y and J. V. Jackson, J. Pharm. Pharmacol. 18, 713-20 (1966). J. Kracmar and M. Lastovkova, Pharmazie 25, 464-70 (1970). J. Kracmar and M. Lastovkova, Cesk. Farm. 20, 287-98 (1971); C.A. 76, 1448785. D. DePaulis and C. Dipietromaria, Boll. chim. farm. 99, 15-19 (1960); C.A. 54, 9 2 0 7 ~ . F. R. Fazzari, J. Ass. Offic. Anal. Chem 53, 582-4 (1970) I. Sunshine ( e d i t o r ) , "Handbook of Analytical Toxicology", The Chemical Rubber CO., Cleveland, Ohio, 1969, page 222. " B r i t i s h Pharmacopoeia 1973", Her Majesty's S t a t i o n e r y Office, London, 1973, page 232, G. S c h i l l i n g , A y e r s t Research Laboratories personal comnunica tion. 0. I. Corrigan and R. F. Timoney, J. Pharm. Pharmacol. 26, 838-40 (1974). M. Kuhnert-Brandstgtter, A. Kofler, R. Hoffman, and H.-C Rhi, Sci. Pharm, 33, 205-30 (1965); C.A. 64, 7966g. H. Groenewegen, Pharm.Teekblad 95, 345-50 (1960); C.A. 55, 87670. W. Kobinger and F. J. Lund, Acta Pharmacol. Toxicol. l5, 265-74 (1959); C.A. 53, 14332e. S. Ueda, Japan. Patent No. 25,692 (1963); C.A. 60, 9107f. R. B. Smith, R. V. Smith, and C. J. Yakatan, J. Pharm. Sci. 65, 1208-11 (1976). CIBA Ltd., B r i t . Patent No. 861,367 (1961); C.A. 55, 199691. C, T. Holdrege, R. B. Babel, and L. C. Cheney, J. Am. Chem. SOC. 81, 4807-10 (1959). F. Lund and W. 0. Godtfredsen, Brit. Patent No. 863,474 (1961); C.A. 55, 19971b. R, S e l l e r i a n 7 0 . Caldini, Ann. Chim. (Rome) 5 0 , 170-6 (1960); C.A. 54, 22676~. H. L. Yale, K. Losee, and J. Bernstein, J. Am. Chem. Soc. 82, 2042-6 (1960).

-

-

-

.

,

-

-

-

-

CHESTER E. ORZECH et 01.

316

24. 25. 26. 27. 28

c. Novello, S. C. b e l l , E. L. A. Abrams, C. Ziegler, and J. M. Sprague, J. Org. Chem. 25, 970-81 (1960). L. H. Werner, A. Halamandaris, S. Ricca, Jr., L. Dorfman, and G. DeStevens, J. Am. Chem. SOC. 82, 1161-6 (1960), W. J. Close, L. R. Swett, L. E. Brady, J. H. Short, and M. Vernsten, J. Am. Chern. SOC. 82, 1132-5 (1960). G. DeStevens and L. H. Werner, Swiss Patent No. 385,869 (1965); C.A. 63, 8383g. H. Hoehn, Ger. Patent No. 1,118,788 (1961); C.A. 57, 2236a. G. DeStevens and L. H. Werner, Ger. Patent No. 1,147,233 (1963); C.A. 60, 1778b. A. Kongsted, Dan. Patent No. 92,966 (1962); C.A. 58, 9108a. Z. Foldi, D. Heidt, and R. Koenig, Hung. Patent No. 143,398 (1962); C.A. 58, 68470. R. B. Margerison, A. C. Shabica, and J. B. Z i r g l e r , Ger. Patent No. 1,093,370 (1962); C.A. 56, 5987a. H. L. Yale and J. Bernstein, Fr. Patent No. 1,330,713 (1963); C.A. 60, 1777g. L. C. Cheney and C. T. Holdredge, Fr. Patent No. 1,368,708 (1964); C.A. 62, 9157c. J. Klosa and H. Voigt, J. Prakt. Chem. l6, 264-76 (1962); C.A. 2,5689c. D. A. Johnson, U.S. Patent No. 3,007,948 (1962); C.A. 56, 5889e. CIBA Ltd., Brit. Patent No. 880,652 (1962); C.A. 56, 7340a. F. C. N w e l l o , Fr. Patent No. 1,393,953 (1965); C.A. 63, 8383c. Merck and Co., Inc., B r i t . Patent No. 948,069 (1964); C.A. 60, 15895d. "The National Formulary", 14th ed., Mack Publishing Co., Easton, Pa., 1975, page 329ff. R. Adam and C. L. Lapiere, J. Pharm. Belg. l9, 79-89 8134f. (1964); C.A. M. Duchene and C. L. Lapiere, J. Pharm. Belg. 20, 275-84 (1965); C.A. 64, 79701. R. Neidlein, H. K r u l l , and M. Meyl, Deut. Apoth.-Ztg. 105, 481-2 (1965); C.A. 66, 4075511. 0. Soh, J. Simoa, M. A. Hanna, G. G h a l i , and R. Tolba, J. Chromatogr. 87, 570-5 (1973). M. I. Walash and S. P. Agarwal, J. Drug Res. 2, 217-25 (1973); C.A. 8 l , 68646t. S. P. Agarwal, M. I. Blake, Indian J. Pharm. 35, 181-3 (1973); C.A. 80, 63904~. J. Bermjo, Galenica Acta (Madrid) l 4 ., 255-64 (1961); C.A. 56, 10286e. H. C. Chiang, J. Pharm. Sci. 5 0 , 885-6 (1961).

F.

23

.

29. 30. 31, 32. 33 34 35 36

. . .-

37. 38

.

39. 40 41. 42. 43

.

44. 45. 46. 47.

fi,

HYDROFLUMETHIAZIDE

48

.

49.

51. 52 53 54 55

.

. ..

317

F. R. Fazzari, J. Ass. Offic. Anal. Chem. 55, 161-2 (1972). G. J. Krol and R. E. Pickering, Ayerst Laboratories Inc., personal comunication. H. Lund, Acta Chem. Scand. l3, 192-4 (1959); C.A. 54, 22676a. H. Lund, Abhandl. Deut. Akad. Wiss. Berlin, K1. Chem., Ceol., Biol. 1964 ( l ) , 434-42; C.A. 62, 8674d. A. I. Cohen, B. T. Keeler, N. H. Coy, and H. L. Yale, Anal. Chem. 34, 216-19 (1962). 0. Menousek, 0. Exner, and P. Zurnan, Collect. Czech. Chem. Coamun. 33, 4000-7 (1968); C.A. 70, 33765b. B. G. Osborne, J. Crhometogr. 70, 190-3 (1972). Y. Garceau, I. Davis, and J. Hasegawa, J. Pharm. Sci. 63, 1793-5 (1974).

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L i t e r a t u r e surveyed through March, 1976.