Methylphenidate Hydrochloride

METHYLPHENIDATE HYDROCHLORIDE Gandharva R. Padrnanabhan 1. Description 1.1 Name, Formula, Molecular Weight 1.2 Appearance 2. Physical and Chemical Properties 2.1 Infrared Absorption Spectrum 2.2 Nuclear Magnetic Resonance Spectrum 2.3 Ultraviolet Absorption Spectrum 2.4 Mass Spectrum 2.5 Optical Rotation 2.6 Melting Range 2.7 Differential Scanning Calorimetry 2.8 Thermogravirnetric Analysis 2.9 Solubility 2.10 X-Ray Diffraction 2.11 Polymorphism 2.12 Partition Coefficient 2.13 Dissociation Constant 3. Synthesis 4. Stability-Degradation 5. Drug Metabilism and Pharrnacokinetics 6. Toxicity 7. Methods of Analysis 7.1 Identification 7.2 Elemental Analysis 7.3 Nonaqueous Titration 7.4 Phase Solubility Analysis 7.5 Thin-layer Chromatography 7.6 High Pressure Liquid Chromatography 7.7 Gas Chromatography 7.8 Gas Chromatography-Mass Spectrometry (GC-MS) 7.9 Colorimetric Methods 7.10 Infrared 7.11 Reineckate Salt 8. References 9. Acknowledgment

474 474 474 474 474 474 477 479 479 48 1 48 1 48 1 48 1 483 483 483 483 485 485 486 486 486 486 486 486 487 487 489 49 1 492 493 494

495 495 497

GANDHARVA R. PADMANABHAN

474

1.

Description 1.1. Name, Formula, Molecular Weight Methylphenidate hydrochloride is methyl a-phenyl2-piperidineacetate hydrochloride, (Rfc,Rfc)- (+) .

C14H19N02.HCl 1.2

Molecular Weight 269.71

Appearance Methylphenidate hydrochloride occurs as a white, odorless, fine, crystalline powder.

2.

Phvsical and Chemical ProDerties 2.1.

Infrared Absorption Spectrum The infrared spectrum of a mineral oil suspension o f methylphenidate hydrochloride is shown in Figure 1. The spectral assignments are listed in Table 1. TABLE 1

1

Wavenumber, cm-l 703, 737 1602 2300

2700

Assignment Monosubstituted benzene Aromatic Stretch Secondary Amine Salt

1739

C=O Stretch

-

C-0 Stretch

1150 2.2

-

I

1170

Nuclear Magnetic Resonance SDectrum (NMR) The NMR spectrum of methylphenidate hydrochloride i s shown in Figure 2. The spectrum was determined on a Perkin-Elmer R-24B 60 MHz spectrometer at ambient temperature. The sample was dissolved in a 1:l mixture o f deuterated chloroform and deuterated dimethylsulfoxide containing tetramethylsilane as an internal standard. The spectral assignments are shown in Table 2.

E

I 0 Q

N 0

I

>

a

?

0

W 0

0

8 8

: 8 2

2

;

a

3

2

3

‘D

8

f

8

7 8

I 1

0

m

U

I

-0 N

7

0 -N

N

0 .U

0

0

.W

0

.a,

0 0

W

METHYLPHENIDATE HYDROCHLORIDE

477

TABLE 2 No. of

Chemical Shift 6 (PPd

Multiplicity

7.1

-

7.6

Broad Singlet

Phenyl protons

4.0

-

4.4

Doublet

-CH-COOCH, -

3.6

-

3.8

Singlet

-0cg3

Assignment

Protons

I

I

2.8

- 3.6

Broad Mu1 tiplet

-N

Solvent

'CH2-

2.4

-

2.7

Broad Multiplet

1.0

-

1.9

Broad Multiplet

2.3.

CH/ -

Ultraviolet Absorption Spectrum The W spectrum of methylphenidate hyd,rochloride (1 mg/mL) in methanolic 0.1N HC1 exhibits maxima and minima as shown in Table 3 and Figure 3 . TABLE 3

A max, nm

A 1% 1cm

264

6.1

165

25 7

7.7

208

25 2

5 -9

159

247

4.5

122

A min. at

&

263 nm, 255 nm, 249 nm and 245 nm.

GANDHARVA R . PADMANABHAN

478

Figure 3: Ultraviolet Absorption Spectrum of Methylphenidate Hydrochloride

0.8

0.7

0.6

0.5 a, 0

c

m

g

0.4

0

n

Q

0.3

0.2

0.1

0.0

Wavelength , Nanometer

METHYLPHENIDATE HYDROCHLORIDE

2.4

479

Mass Spectrum The low resolution mass spectrum of methylphenidate hydrochloride obtained at 70 ev using a solid probe insertion is shown in Figure 4 . The spectrum was run on a Kratos MS25 spectrometer interfaced with a data handling system. Table 4 illustrates the prominent fragments and their masslcharge ratios. TABLE 4

';The spectrum is known to vary due toethermal decomposition (27).

2.5

Optical Rotation Although the methylphenidate hydrochloride molecule has two asymmetric carbon atoms, the drug exhibits no optical activity as it is a racemic mixture. The diastereoisomer of the drug, (R",Sf:) isomer, is also referred to as "erythro isomer". The conformations of methylphenidate hydrochloride and its (&:,Sf<) isomer have been documented (1-2). Due to the low efficacy of the (R';,S$;) isomer (1) the amount of this diastereoisomer is controlled in the drug to a level of 1%or less (3).

GANDHARVA R. PADMANABHAN

480

Figure4: Low Resolution Mass Spectrum of Methylphenidate Hydrochloride 100

90

80

70

-

>

.-

60

v)

C

a,

c

c a,

> .c

m a, a:

50

40

30

20

10

I 0 160

MassIC harge

180

200

220

24C

METHYLPHENIDATE HYDROCHLORIDE

2.6

48 1

Melting Range Methylphenidate hydrochloride melts between 224OC and 226OC when tested according t o the USP XX Class Ia procedure.

2.7

Differential Scanning Calorimetry (DSC) The DSC thermogram of methylphenidate hydrochloride shows a melt endotherm between 1 9 5 O C and 235OC with a melting point, with decomposition, o f approximately 22OOC when the thermogram was followed in a DuPont Model 900 instrument at a scan rate o f 1O0C/minute (Figure 5).

2.8

Thermogravimetric Analysis (TGA) The TGA of methylphenidate hydrochloride exhibited a weight loss of 0.34% between 3OoC and 15OOC. Above 1 5 O O C a rapid weight loss due to decomposition and/or sublimation was observed.

2.9

Solubility Approximate solubilities in different solvents were determined after equilibrating 10 mg (more, if necessary, to obtain a saturated solution) of the drug at room temperature with 1 mL o f solvent.

TABLE 5 Solvent

I

Solubi1ity (mg/mL)

Water

> 100

0.1N - HC1

> 100 > 100 > 25

Methanol Ethanol Acetonitrile Chloroform n-Hexane Ethyl Acetate Ether 95% Ethanol

Petroleum Ether Acetone

5.3

> 100 < 0.01 0.08

< 0.01 > 50 < 0.01 0.9

GANDHARVA R. PADMANABHAN

482

Figure!? DSC Scan of Methylphenidate Hydrochloride

I

400

I

I

450

Temperature O

500 K

METHYLPHENIDATE HYDROCHLORIDE

2.10

483

X-Rav Diffraction The x-ray powder diffraction pattern obtained for mehylphenidate hydrochloride is shown in Figure 6 . The data were collected on a GE Model XRD-spectrogoniometer using Cu K (1.542AO) with a Ni filter (Y as a radiation source.

2.11

Polymorphism No polymorphism has been reported for methylphenidate hydrochloride.

2.12

Partition Coefficient The following partition coefficient data were obtained when 50 mL o f 0.1 and 1.0 mg/mL of methylphenidate hydrochloride in appropriate aqueous solutions at room temperature were partitioned individually with 50 mL of indicated organic s o l vents. Heptane-pH 7. 4 buffer data was obtained from the literature ( 4 ) .

TABLE 6 Aqueous Phase

Organic Phase

Partition Coefficient"

0.1N HC1

Chloroform

+ o

pH 7 Buffer

Chloroform

22.7 20.5

0.1N HC1

Ether

3 0

pH 7 Buffer

Ether

1 . 7 k0. 2

pH 7 . 4 Buffer

Heptane

0.63

7,;

= Concentration in organic phase/concentration in aqueous phase.

2.13 Dissociation Constant A pKa value of 9.0 was obtained for the dissociation of the protonated secondary amine function by potentiometric titration method. A value of 8.9 was also obtained (5) for the pKa by the nonlogarithmic method of Benet and Goyan (6).

GANDHARVA R. PADMANABHAN

484

Figure 6: X-Ray Powder Diffraction Pattern of Methylphenidate Hydrochloride

8.3

I

35

I

30

I

25

1

20

Degrees Two Theta

I

15

I

10

I

5

METHYLPHENIDATE HYDROCHLORIDE

3.

485

Synthesis Methylphenidate hydrochloride is prepared by the following sequence of reactions. a-Phenyl-2-pyridineacetonitrile is hydrolyzed in diluted sulfuric acid to a-phenyl2-pyridineacetamide. The acetamide is isolated and then hydrogenated over a catalyst to yield racemates of diastereoisomeric mixtures of a-phenyl-2-piperidineacetamide. The diastereoisomeric piperidineacetamide racemate mixture is converted t o (R>t,R$C) racemate by heating in sodium hydroxide solution and then to a-phenyl-2-piperidineacetic acid by heating in sulfuric acid solution. The acetic acid derivative is converted to the acid chloride and then, without isolation, reacted with methanol to yield the methyl ester free base which is then converted to methylphenidate hydrochloride (7).

4.

Stability-Degradation The drug is relatively stable in acidic solutions but is degraded extensively in basic solutions. The degradation occurs via the hydrolysis of the methyl ester to the free acid, a - p h e n y l - 2 - p i p e r i d i n e a c e t i c acid (8-10). pH of Solution 1.7 3.7

3.5 4.9 4.1 5.7

8.9 9.2

Time (hours)

% Methylphenidate HC1 Remaining

100

20

100

100

20

100

100

300

95

100

20

84

100

300

51

100

20

49

100

20

0

30

20

87

Temperature

1 2 2 2

2

3 4

4

OC

'0.1N HC1 2Phthalate Buffer 3Phosphate Buffer 4Borate Buffer

The methyl ester of phenylacetic acid has been reported as one of the products when the drug substance was subjected to thermal degradation.

GANDHARVA R . PADMANABHAN

486

5.

Drug Metabolism and Pharmacokinetics a-Phenyl-2-piperidineacetic acid, the lactam acid and several other unidentified polar compounds have been reported as metabolites in guinea pig, dog and human urine ( 4 , 11-13). p - H y d r o x y p h e n y l - 2 - p i p e r i d i n e a c e t i c acid and its methyl ester were also reported as metabolities in dog and rat urine ( 1 4 ) . The products of metabolism involving oxidiation, hydrolysis and conjugation processes in rats and dogs have also been reported ( 3 0 ) .

6. Toxicity

A typical sample

o f methylphenidate hydrochloride active drug gave an oral LD50 value o f 350 mg/kg with deaths (9/10) at 1000 mg/kg when a 7.5% solution was administered to male rats (15).

7.

Methods o f Analysis 7.1

Identification Two identity tests are given in the LISP XX, one an infrared absorption test and the other a test for chloride.

7.2

Elemental Analysis The following elemental composition was obtained for methylphenidate hydrochloride when a 2 mg sample was employed for analysis with a PerkinElmer, Model 240 CHN Analyzer.

7.3

Element

Theory, %

Found, %

Carbon Hydrogen Nitrogen

62.33

62.35 7.57 5.12

7.47 5.19

Nonaqueous Titration

Methylphenidate hydrochloride may be titrated in glacial acetic acid containing mercuric acetate with perchloric acid in glacial acetic acid as titrant. The titration can be carried out potentiometrically or with p-naphtholbenzein as indicator.

METHYLPHENIDATE HYDROCHLORIDE

487

Although the titration as such is not specific for the intact drug in presence of its major degradation compound, a - p h e n y l - 2 - p i p e r i d i n e a c e t i c acid, the procedure can be made specific by extracting the drug from a pH 9 buffer with chloroform and then titrating the free base with perchloric acid without the addition of mercuric acetate ( 1 6 ) . 7.4

Phase Solubility Analysis Phase solubility analysis of methylphenidate hydrochloride has been carried out using the following systems: System I A mixture of 93 mL of benzene and 7 mL of anhydrous ethanol Approximate solubility: 14 mg/mL Solvent:

System I1

A mixture of

90 mL of benzene and 10 mL of methanol Approximate solubility: 65 mg/mL at 3OoC

Solvent:

System I11 Solvent: n-Butanol Approximate solubility: 7.5

13 mg/mL at 3OoC

Thin-layer Chromatography

A number of thin-layer chromatographic systems have been developed for the identification and the determination of the drug and compounds related to the drug. System I

Adsorbent:

The following system may be employed particularly to control the (R?:, Ssc) isomer content in the drug ( 3 ) . Silica Gel G plate, 250p thickness

Mobile Phase :

A mixture containing

Detection System :

Dragendorff spray reagent (0.7 g of bismuth subnitrate dissolved in 40 mL of 20% glacial acetic acid and then diluted successively with 40 mL of 40% KI solution, 120 mL of glacial acetic acid and 250 mL of water).

190 mL of chloroform, 10 mL of methanol and 1 mL of concentrated ammonium hydroxide.

GANDHARVA R. PADhlANABIIAh’

System I1

The following system may be employed particularly when a-phenyl-2-piperidineacetic acid hydrochloride content in the drug has to be established (3).

Adsorbent :

Silica Gel G plate, 250p thickness

Mobile Phase :

A mixture containing 65 mL of chloro-

Detection System:

1. Irradiation o f the dried plate with high-intensity W for 10 minutes followed by visualization under longwave W source.

form, 25 mL of methanol and 5 m L of acetic acid.

2. Heating for 10 minutes at 1 0 5 O C after spraying with 3.5% phosphomolybdic acid in isopropanol.

Other Systems: The following systems have also been employed for the analysis of methylphenidate hydrochloride. System I11

Chloroform/Methanol (9:l); Silica Gel GF; Iodine Spray and UV Detectors (17).

System IV

Acetone/25% Ammonium Hydroxide (99:l); Silica Gel GF; Iodine spray and W detection Systems (17).

System V

Methanol/25% Ammonium Hydroxide (99:l); Silica Gel GF; Iodine Spray and W Detection Systems (17).

Svstem VI

Ethanol/Glacial Acetic Acid/Water (5:3:2); Silica Gel GF; Iodine Spray and W Detection Systems (17).

System VII

Chloroform/Methanol ( 8 4 : 1 6 ) ; Silica Gel G: Chlorine/o-Tolidine Detection System (18).

System VIII

n-Propanol/pH 4.0 Citric AcidPhosphate Buffer (9:l); Alumina Plate; Iodoplatinic Acid Spray Detection System ( 1 9 ) .

METHYLPHENIDATE HYDROCHLORIDE

489

System IX

Chloroform/Methanol ( 1 : l ) ; Silica Gel GF: Iodine Spray and W Detection Systems (17).

System X

Chloroform/Methanol/Concentrated Ammonium Hydroxide ( 9 : l : l ) ; Silica Gel GF; Acetic acid-Commercial Chlorine Bleach-Phenothiazine Spray Reagent and Shortwave W Detection Systems (20) *

System XI

Chloroform/Methanol/Concentrated ammonium Hydroxide (7:5:1); Silica Gel GF; Detection Systems Same as in System

x

System XI1

(20).

Acetone/Methanol containing 0.5% HCl ( 1 : l ) ; Silica Gel GF: Detection Systems same as in System X ( 2 0 ) .

System XI11 - Concentrated Ammonium Hydroxide/ Ethanol/Water (16:100:12); Silica G e l GF; Detection System not reported.

7.6

Svstem XIV

Methanol/Formic Acid ( 9 : l ) ; Silica Gel GF: Detection System not reported.

System XVI

Ethyl AcetateIAcetic Acid/Water/Hydrochloric Acid (55:35:2:2); Silica Gel G; Detection System not reported.

High Pressure Liquid Chromatography The following two systems have been reported (21) for the quantitation of the (R;b,S$C) isomer in methylphenidate hydrochloride samples. System I Mobile Phase :

A mixture containing 85 mL of chloro-

Column:

100 cm x 2.1 mm steel column drypacked with Sil-XB (Perkin-Elmer).

Detection:

W (254 nm)

form, 13.5 mL o f cyclohexane, 1 . 5 mL of ethanol, and 0 . 5 mL of concentrated ammonium hydroxide.

Temperature: Ambient

GANDHARVA R. PADMANABHAN

490

System I1 Mobile Phase:

A mixture containing 80 mL of chloro-

Column :

50 cm x 2.1 mm (i.d.) MicroPak-SI-10 (Var ian)

Detection:

UV (254 nm)

Sample :

Inject 20 pL of isolated free base in chloroform

Temperature:

Ambient

form, 20 mL of cyclohexane and 1.5 mL of ethanol.

The following system has been employed for the quantitation of methylphenidate in serum samples (22). System I11 Mobile Phase :

pH 3.5 Phosphate bufferlhigh purity

Column:

VBondapak C18 (Waters) (4 mm x 30 cm)

acetonitrile (80:ZO).

Temperature: 4OoC Flow Rate:

1.6 mL/minute

Detection:

UV (192 run)

Internal Standard :

4,5-Diphenylimidazole

The following system has been employed for the determination of a - p h e n y l - p i p e r i d i n e a c e t i c acid in serum samples (23). System IV Mobile Phase :

pH 3.8 Phosphate bufferlacetonitrile (83:7)

Column:

VBondapak C18, (Waters) (4 mm x 30 cm)

Temperature:

4OoC

Flow Rate:

2.0 mL/minute

Detection: Inte rna1 Standard

w

(192 nm)

a,a-Dimethyl-p-methylsuccinimide

METHYLPHENIDATE HYDROCHLORIDE

7.7

49 1

Gas Chromatography The f o l l o w i n g system h a s been employed f o r t h e a n a l y s i s of t h e d r u g s u b s t a n c e i n plasma. System I Column:

8 f t x 4 mm i . d . w i t h 5% XE-60 on Gas Chrom Q (100 - 120 mesh)

Temperature:

Column - 15OoC; D e t e c t o r I n j e c t o r - 185O

-

Detector:

Flame i o n i z a t i o n

Carrier:

N i t r o g e n 70 cc/minute

Sample :

I s o l a t e d f r e e b a s e d i s s o l v e d i n DMF

185';

The f o l l o w i n g system ( 1 9 ) h a s been employed f o r i d e n t i f i c a t i o n of t h e d r u g i n b l o o d and u r i n e samples. System I1 Column:

5 ft x O . D . (3mm i . d . ) g l a s s column, 2% H i E f f 3A (Applied S c i e n c e ) on Gas Chrom Q (100 - 120 mesh).

Temperature:

Column - 140'C; D e t e c t o r p o r t e d ; I n j e c t o r - 220OC

Detector:

Flame I o n i z a t i o n

Carrier:

N i t r o g e n a t 75 mL/minute

-

n o t re-

The f o l l o w i n g system h a s been employed f o r t h e a n a l y s i s of s e v e r a l d r u g s i n c l u d i n g methylphenidate hydrochloride. System I11 Column:

8 f t x l/8" g l a s s column w i t h 15% XF-1112 on Chromosorb X-HMDS

Temperature:

I n j e c t o r - 200OC; Column - Program 60' - 180' a t 4O/minute; D e t e c t o r not reported.

Detector:

Flame i o n i z a t i o n

Carrier:

N i t r o g e n 25 mL/minute

The f o l l o w i n g system has been employed t o q u a n t i t a t e (R",S") isomer i n m e t h y l p h e n i d a t e h y d r o c h l o r i d e samples ( 2 5 ) .

GANDHARVA R. PAUMANABHAN

Svstem IV Column:

200 cm x 2 mm i . d . glass column with 3% OV-225 on Gas Chrom Q (80 - 100 mesh).

Carrier Gas:

Nitrogen 30 mL/minute

Detector:

Flame ionizaton detector

Temperature:

Column - 125OC; Detector - 200OC; Injector - 200OC

Sample:

Isolated free base in chloroform

The following system was employed for the identification of the drug in a tablet formulation. System V

7.8

Column:

8' x 4 mm i.d. with 5% XE-60 on Gas Chrom S (100 - 120 mesh)

Temperature:

Column - 13OOC; Injector - 158OC; Flame Ionization Detector - 175OC

Carrier Gas:

Nitrogen 60 cclminute

Sample :

Isolated free base in dimethylformamide

Gas Chromatography

-

Mass Spectrometry (GC-MS)

Sensitive methods for the analysis of methylphenidate hydrochloride and its hydrolytic degradation compound have been reported using GC-MS with selected ion monitoring for separation and detection. The following experimental conditions were used for the analysis of the drug and its metabolite in blood and urine samples. Method I (27) Column:

6 ft x 2 mm i.d. glass column containing 3% OV-1 on Gas Chrom-Q (100 - 120 mesh)

Detection:

GC-MS selected ion monitoring m/e=91

METHYLPHENIDATE HYDROCHLORIDE

Method I (27)

493

(Continued)

Temperature:

I n j e c t o r , d e t e c t o r , c a p i l l a r y res t r i c t o r , s e p a r a t o r and l i n e of s i g h t p r o b e - 225OC; Column - 165OC; MS E l e c t r o n Impact Source - 1 7 5 O C .

Carrier:

Helium 40 mL/minute

MS E I Source: 70 e v Method I1 (28) Column:

0 . 9 m x 2 mm i . d . g l a s s column w i t h 3% OV-17 on Gas Chrom Q

Detection:

GC-MS S e l e c t e d I o n Monitoring m/e=180

Temperature:

I n j e c t o r - 250OC; Column - 170OC; Membrane S e p a r a t o r - 1 7 O o C ; T r a n s f e r l i n e - 25OOC

C a r r i e r Gas:

H e l i u m 35 mL/min

MS E I Source: 70 e v

7.9

Sample :

Derivatized with t r i f l u o r o a c e t i c anhydride

Interna 1 Standard:

E t h y l e s t e r a n a l o g of methylphenid a t e HC1.

C o l o r i m e t r i c Methods 7.9.1

P i c r a t e Method Methylphenidate h y d r o c h l o r i d e can be asayed by t h e p i c r a t e i o n - p a i r e x t r a c t i o n method ( 3 ) . The sample i s e x t r a c t e d i n t o a d i l u t e d s u l f u r i c a c i d s o l u t i o n , mixed w i t h a p i c r i c a c i d s o l u t i o n , pH a d j u s t e d t o 5 . 0 and t h e n e x t r a c t e d a s a p i c r a t e i o n - p a i r w i t h chloroform. The e x t r a c t e d drug i s q u a n t i t a t e d c o l o r i m e t r i c a l l y by measuring absorbance a t 405 nm. The method i s s p e c i f i c f o r t h e drug i n p r e sence of i t s h y d r o l y t i c d e g r a d a t i o n compound.

GANDHARVA R . PADMANABHAN

494

7.9.2

Bromcresol Purple Methylphenidate hydrochloride also forms a colored complex with bromcresol purple at pH 5.0. The complex can be extracted with chloroform and the content of the drug quantitated by measuring the absorption of the acidified extract at 420 nm. The hydrolytic degradation compound does not interfere.

7.9.3

Hydroxamic Acid In basic solution, methylphenidate forms a hydroxamic acid with hydroxylamine (29)

This hydroxamic acid forms a red complex with ferric ion in acidic solutions which can be quantitated colorimetrically by measuring the absorbance at 500 nm. The degradation compound does not interfere with the assay. However, the method is subject to interference from excipients in drug formulations such as lactose. 7.9.4

1,2-Naphthaquinone Sulfonic Acid An automated procedure has been reported for the determination of methylphenidate hydrochloride in tablet formulations based on the formation of a yellow-colored complex with 1,2-naphthaquinone sulfonic acid. The complex is extracted into chloroform and the drug quantitated by the measurement of absorption maximum o f the complex at 400 nm.

7.10 Infrared Methylphenidate hydrochloride has been assayed in certain tablets by extracting the drug from the tablet matrix, by adjusting the pH to about 9.0 and then extracting immediately with chloroform. By measuring the IR absorption at 1720 cri' of the concentrated extract, the drug content can be quantitated. The method has also been applied to a syrup formulation assay.

METHYLPHENIDATE HYDROCHLORIDE

7.11

495

Reineckate Salt Methylphenidate hydrochloride has been determined gravimetrically by precipitating the reineckate salt of the free base by the addition of ammonium reineckate, NH4[Cr(NH3)2(SCN)4] to the drug in solution.

8.

References

1. Rometsch, R . , US Patent, 2,838,519 (1958).

2. Shafiee, A. and Hite, G., J. Med. Chem., 1 2 , 266, 520 ( 1 9 6 9 ) ; Shafiee, A . , Marathe, S . , BhatkarTR. and 5 6 , 1689 (1967). Hite, G., J. Pharm. Sci., 3. The United States Pharmacopeia, Twentieth Revision, Mack Printing Company, Easton, PA, 1980, page 522. 4 . Faraj, B.A.,

Israili, Z.H., Perel, J.M., Jenkins, M.L., Holzman, S . G . , Cucinell, S.A. and Dayton, P.G., J. Pharniacol. Exp. Ther., __ 191, 535 (1974).

5 . Smith, J. and Piskorik, H., CIBA-GEIGY, Personal

Communication.

6 . Benet, L.Z. and Goyan, J.E., J. Pharm. Sci., 1179 (1965).

54,

7 . Weisz, I. and Dudas, A., Monatsch., 9 1 , 840 (1960)

8. Portoghese, P.S. and Malspeis, L., J. Pharm. Sci., 5 0 , 494 (1961). 9 . Siegel, S . , Lachman, L. and Malspeis, L., J. Pharm

Sci. , @, 431 (1959).

10.

Rometsch, R., CIBA-GEIGY, Personal Communication.

11. Bartlett, M.F. and Egger, H.P., Fed. Proceedings,

537 (1972).

31,

12. Sheppard, H., Tsien, W.H., Rodegker, W. and Plummer, A . J . , Toxicol. Applied Pharmacol., 2, 353 (1960).

496

GANDHARVA R. PADMANABHAN

13.

Dayton, P.G., Read, J.M. and Ong, V., Fed. Proceedings, 3 1 , 1822 ( 1 9 7 2 ) .

14.

Faraj, B.A. and Jenkins, M.L., Pharmacologist, 15, 155 (1973).

15.

Jeffrey, K. and Traina, V.M., CIBA-GEIGY, Personal Communication.

16.

The Pharmacopeia of the United States of America, Eighteenth Revision, Mack Printing Company, Easton, PA, 1970, page 432.

17.

Galla, M.M. and Macek, T.J., U.S.P. Reference Standards Committee Collaborative Report, September 29, 1970.

18.

Yachontov, L.N., Mashkovski, M.D., Levkoeva, E.I., Altshuler, R.A., Tubina, I.C., Turchin, K.F., Flashurian, U.D., Tulenev, A.K., Potonova, P.G., Voljina, O.H. and Gorobsetskij, L.S., Khim-Farm. Zh., 8 , 3 (1974).

19.

Schubert, B., Acta Chemica Scand., 2 4 , 433 ( 1 9 7 0 ) .

20 *

Lovering, E . G . , Drug Research Laboratories (Canada) Private Communication, July 28, 1976.

21.

Padmanabhan, G.R., Fogel, G., Mollica, J.A., O'Connor, 3, 1079 J.M. and Strusz, R., J. Liquid Chromatography, (1980).

22.

Solidin, S.J., Chan, Y.-P.M., Hill, B.M. and Swanson, J.M., Clin. Chem., 25, 401 ( 1 9 7 9 ) .

23.

Soldin, S.J., Hill, B.M., Chan, Y.-P.M., Swanson, J.M. and Hill, J.G., Clin. Chem., 25, 5 1 (1979).

24.

Noirfalise, A. and Grosjean, M.H., J. Chromatog., 37, 1979 ( 1 9 6 8 ) .

25.

Blichler, W. and Senn, H., CIBA-GEIGY, Personal Comrnunication.

26.

Mollica, J.A. and Strusz, R.F., CIBA-GEIGY, Personal Communication.

27.

Milberg, R.M., Rinehart Jr., K.L., Sprague, R.L. and Sleator, E.K., Biomedical Mass Spec., 2, 2 ( 1 9 7 5 ) .

METHYLPHENIDATE HYDROCHLORIDE

497

28.

G a l , J . , Hodshon, B . J . , P i n t a u r o , C . , Flamm, B.L. and Cho, A . K . , J . Pharm. S c i . , 66, 866 ( 1 9 7 7 ) .

29.

Goddu, R . F . , LeBlanc, W.F. and Wright, C . M . , Anal. Chem., 2 7 , 1251 ( 1 9 5 5 ) . g r a w y a , M.S. and Ghourab, M . G . , J . Pharm. S c i . , 5 9 , 1331 (1970).

30.

E g g e r , H . , B a r t l e t t , F . , D r e y f u s s , R . and K a r l i n e r , J . , I n Press.

9.

Acknowledgment The a u t h o r e x p r e s s e s a p p r e c i a t i o n t o I n g r i d Becue, R i c h a r d Brown and J a n e Johnson f o r h e l p i n p r e p a r a t i o n of t h i s m a n u s c r i p t .