Crystalline sodium phenytoin monohydrate

FIELD OF THE INVENTION

This invention relates to a crystalline form of sodium phenytoin monohydrate, to pharmaceutical formulations containing the same, and to methods for preparing and using the substance.

BACKGROUND OF THE INVENTION

Phenytoin is the generic name for 5,5-diphenyl-2,4-imidazolidinedione. It also is known as diphenylhydantoin. It is used extensively to treat convulsive disorders such as epilepsy. Because phenytoin is poorly soluble in aqueous mixtures, it cannot be effectively used in injectable solutions, or even in solid preparations for oral use. The compound generally is utilized as a sodium salt, which is readily soluble in water. However, even sodium phenytoin anhydrate rapidly dissociates into phenytoin, which then precipitates from aqueous solutions, thereby making uniform dosing difficult. Moreover, commercial production of sodium phenytoin anhydrate results in complex mixtures of polymorphic forms of the product, and the individual polymorphs exhibit different aqueous solubilities and dissolution rates, thereby further exacerbating dosing irregularities. To date, there has been no single crystal form of any phenytoin sodium capable of analysis by x-ray diffraction.

An object of this invention is to provide a new chemical substance that is a crystalline form of a monohydrate of sodium phenytoin. The new compound can be crystallized into a single crystal form which can readily be analyzed by x-ray diffraction. The sodium phenytoin monohydrate crystal form of this invention is stable for prolonged periods of time, and it exhibits excellent aqueous solubility characteristics, thereby allowing for improved uniformity of dosing. The new chemical compound is readily formulated for both oral and parenteral administration to humans for treatment of epilepsy and other convulsive disorders.

SUMMARY OF THE INVENTION

This invention provides a new chemical substance which is a crystalline form of sodium phenytoin monohydrate. The crystal form has a characteristic and unique x-ray diffraction pattern. The invention also provides a pharmaceutical composition comprising the crystalline sodium phenytoin monohydrate admixed with a carrier, diluent, or excipient therefor. The invention additionally provides a method for preparing the crystal form, as well as a method for treating convulsant disorders comprising administering an anticonvulsive effective amount of the crystal form. The crystal form can also be used to stabilize polymorphic mixtures of sodium phenytoin.

In a preferred embodiment, the sodium phenytoin monohydrate crystal form has the following distinctive x-ray pattern (2-theta values measured using CuK

α

radiation:

2-Theta

d (Å)

Relative Intensities (I)

12.1

7.3

100

27.2

3.3

80

22.7

3.9

73

15.5

5.7

71

18.4

4.8

67

20.3

4.4

60

21.2

4.2

54

6.2

14.2

49

In a more preferred embodiment, the crystal form of this invention is identified by the following 2-theta values measured using CuK

α

radiation: 12.1, 18.4, and 21.2.

In the most preferred embodiment, the crystal form is identified by the following unique 2-theta value measured using CuK

α

radiation: 12.1.

BRIEF DESCRIPTION OF FIGURES

FIG. 1

shows the intrinsic dissolution rate of sodium phenytoin monohydrate (SPM) relative to sodium phenytoin anhydrate (SPA).

FIG. 2

is the x-ray powder diffraction pattern on the 2-theta scale for sodium phenytoin anhydrate.

FIG. 3

is the x-ray powder diffraction pattern on the 2-theta scale for sodium phenytoin monohydrate.

FIG. 4

is the x-ray pattern of sodium phenytoin monohydrate calculated from single crystal data (P2

1

/c).

DETAILED DESCRIPTION OF THE INVENTION

The crystalline sodium phenytoin monohydrate provided by this invention is prepared by mixing sodium phenytoin with one molar equivalent or slight excess of water in dichloromethane, toluene, or methanol. The mixture typically is heated to a temperature of about 30° C. to about 40° C. for a period of time of about 30 minutes to about 3 hours or longer. The resulting suspension is cooled to about 25° C., and the crystalline sodium phenytoin monohydrate precipitates and can be collected by filtration. The crystalline product generally is dried for about 1 hour or more, preferably in a vacuum, at about 20° C. to about 30° C. The product so formed is highly stable and crystalline, and is highly water soluble.

The sodium phenytoin anhydrate which is the starting material for making the monohydrate of this invention is prepared by standard commercial processes. Specifically, phenytoin can be prepared by reacting benzophenone with ammonium carbonate in the presence of sodium cyanide. The phenytoin is then dissolved in sodium hydroxide solution, and the water is removed from the mixture by drying in a vacuum oven at a temperature of about 50° C. to about 100° C. The dried cake which results is a complex mixture of a large number of polymorphic forms of sodium phenytoin. The mixture of polymorphs leads to commercial preparations which exhibit inconsistent dissolution profiles, thereby causing irregular dosing characteristics from lot to lot in commercial preparations. We have now discovered that such polymorphic mixtures can be stabilized by adding the crystalline sodium phenytoin monohydrate of this invention at a level of about 1% to about 5% by weight. Such stabilization surprisingly leads to improved dissolution profiles and thus to more uniformity in dosing.

The following specific examples demonstrate the synthesis of the unique crystalline compound of this invention.

In the experiments, infrared spectra were obtained on a Perkin-Elmer 1600 FT IR spectrophotometer. Samples were prepared as KBr disks and scanned from 4000-400 cm

−1

. A polystyrene standard was run prior to sample analyses.

Solid-state, carbon-13 nuclear magnetic resonance (SSNMR) spectra were obtained on a Bruker AX-250, 250 MHZ spectrometer using high-power proton decoupling and cross-polarization with magic-angle spinning at approximately 5 kHz. The magic angle was adjusted using the Br signal of KBr by detecting the side bands as described by Frye and Maciel (

J. Mag. Res.

1982;48:125).

Approximately 300 mg of sample packed into a canister-design rotor was used for each experiment. The chemical shifts were referenced in the first sample to external tetrakis(trimethylsilyl)silane (methyl signal at 3.50 ppm) and subsequent samples were obtained at the same field settings.

Differential scanning calorimetry (DSC) experiments were performed on a Dupont DSC 2000 and thermogravimetric analyses (TGA) were performed on a Dupont TGA 2000. Nitrogen was used as the purge gas and heating rates were 10° C./minute. Standards were run prior to sample analyses; Sn for DSC and calcium oxalate for TGA.

Study of weight change under controlled humidity conditions, samples were placed in open vials, which were placed in closed controlled-humidity jars. Relative humidities were controlled using saturated aqueous salt solutions: 58% RH, NaBr; 75% RH, (NH

4

)

2

SO

4

; 76%, sodium acetate; 84% RH, KBr.

Dissolutions were carried out in a standard Van-Kel dissolution bath. The medium was either water, 90% water/10% ethanol, or 95% water/5% ethanol. For nonintrinsic dissolution experiments, SPM and SPA powders were sieved and fractions that passed through a 75 μm sieve were used. For intrinsic dissolution experiments, tablets were prepared in a standard Woods apparatus by compression of 400 mg of material at 3000 psig for 1 minute.

Each experiment was carried out by placing 900 mL of medium into one of the Van-Kel dissolution vessels and allowing it to equilibrate at 37° C. The test materials were added (powder or tablet) and samples were withdrawn by syringe at the specified times (see Table 4). Each sample was filtered through a 0.2μ nylon syringe filter. Three dissolution experiments were carried out for each lot of suspension.

EXAMPLE 1

Fifty grams of sodium phenytoin anhydrate was dissolved in 300 mL of dichloromethane containing 3.28 g of distilled water. The mixture was heated at reflux for 2 hours. The solution was cooled to 24° C., and the crystalline product was collected by filtration and air dried at 24° C. Karl Fischer analysis showed the crystalline product contained 6.20% water; theory for the monohydrate is 6.16%.

EXAMPLE 2

Fifty grams of sodium phenytoin anhydrate was dissolved in 300 mL of dichloromethane containing 6.5 mL of distilled water. The solution was heated at reflux for 3 hours. After cooling the mixture to 24° C., the solid precipitate was collected by filtration and air dried for 48 hours at 24° C. to provide crystalline sodium phenytoin monohydrate. Karl Fisher assay established 6.2% water content.

EXAMPLE 3

Two hundred thirty-eight grams of sodium phenytoin anhydrate was dissolved in a mixture of 1000 mL of dichloromethane and 31 mL of distilled water. The mixture was heated at reflux for 3 hours, cooled to 24° C., and the precipitate was collected by filtration. The solid was dried in a vacuum at 25° C. for 6 hours to provide sodium phenytoin monohydrate. Karl Fisher analysis established water content of 6.35%, evidencing 1 mol of water.

EXAMPLE 4

Preparation of Sodium Phenytoin Monohydrate (Toluene Slurry)

A mixture of 100 g (0.36 mol) 6of sodium phenytoin anhydrate (SPA), 400 mL of toluene, and 6.6 mL (0.37 mol) of water was stirred rapidly under ambient conditions. After 2 days, about 1 mL of the slurry was filtered, and the resulting solid was found, by XRPD analysis (13-day turnaround), to consist of a mixture of SPA and sodium phenytoin monohydrate (SPM). An additional 0.66 mL (0.037 mol) of water was added, and the slurry was stirred overnight. About 1 mL of the slurry was filtered, and the resulting solid was found, by XRPD analysis (3-day turnaround), to consist of pure SPM. The solids were collected by filtration and allowed to dry in the air to give 93.7 g SPM.

EXAMPLE 5

The crystalline sodium phenytoin monohydrate provided by this invention has the following unique x-ray powder diffraction pattern when measured with a Siemans D-500 X-Ray Power Diffraktometer-Kristalloflex with an IBM-compatible interface, with software known as Diffrac AT (Socabim 1994). The x-rays are from CuK

α

radiation (20 mA, 40 kV, λ=1.5406 Å) (Slits I and II at 1°) electronically filtered by a Kevex Psi Peltier Cooled Silicon [Si(Li)] Detector (Slits: III at 1°, IV at 0.15°). A continuous theta-two theta scan at 6°/min (0.4 sec/0.04° step) from 4.00° to 40.00° was used. A silicon standard is run to check the x-ray tube alignment. The sample of crystalline monohydrate was pressed onto a zero-background quartz plate in an aluminum holder. The sample width was 15 mm. The foregoing analysis produced the following 2-theta data, spacings, and relative intensities.

2-Theta

Spacing, d(Å)

Relative Intensities, I/I

1

12.129

7.2909

100.00

27.227

3.2727

80.38

22.685

3.9165

72.60

15.542

5.6968

70.76

18.379

4.8234

67.28

20.259

4.3798

59.76

21.223

4.1830

53.97

6.214

14.2105

48.83

23.158

3.8377

40.99

17.195

5.1526

36.52

20.630

4.3019

34.49

31.173

2.8668

29.10

24.337

3.6544

27.54

32.827

2.7260

27.32

19.774

4.4861

27.15

16.373

5.4093

24.13

24.700

3.6013

24.02

17.537

5.0528

22.00

31.731

2.8177

21.75

28.668

3.1114

18.17

11.363

7.7805

17.00

28.969

3.0797

15.93

33.963

2.6374

15.15

29.399

3.0355

14.73

32.540

2.7494

14.52

23.856

3.7269

14.30

34.235

2.6171

13.95

35.808

2.5056

13.77

34.725

2.5812

13.24

28.167

3.1655

13.02

38.255

2.3508

12.60

36.386

2.4671

12.49

25.660

3.4687

12.03

26.323

3.3829

11.96

16.782

5.2785

11.75

In a preferred embodiment, the crystal form is identified by the following 2-theta lines:

2-Theta

d (Å)

Relative Intensities (I)

12.1

7.3

100

27.2

3.3

80

22.7

3.9

73

15.5

5.7

71

18.4

4.8

67

20.3

4.4

60

21.2

4.2

54

6.2

14.2

49

TABLE 1

SPM Behavior at Various Relative Humidities

Sample Weight in g (Change in

Sample Weight in g (Change in

Time

Starting Weight in g)

Time

Starting Weight in g)

(days)

58% RH

75% RH

84% RH

(days)

58% RH

75% RH

84% RH

0

1.5009

1.5360

1.5374

14

1.2938

1.3758

1.3855

(−0.2071)

(−0.1602)

(−0.1519)

1

1.2006

1.2358

1.2421

15

1.3045

1.3759

1.3857

(−0.3003)

(−0.3002)

(−0.2953)

(−0.1964)

(−0.1601)

(−0.1517)

2

1.1763

1.2405

1.2620

16

1.3123

1.3771

1.3880

(−0.3246)

(−0.2955)

(−0.2754)

(−0.1886)

(−0.1589)

(−0.1494)

3

1.1753

1.2928

1.3287

17

1.3255

1.3811

1.3928

(−0.3256)

(−0.2432)

(−0.2087)

(−0.1754)

(−0.1549)

(−0.1446)

4

1.1856

1.3258

1.3671

18

1.3323

1.3818

1.3949

(−0.3153)

(−0.2102)

(−0.1703)

(−0.1686)

(−0.1542)

(−0.1425)

5

1.2016

1.3707

1.3952

23

1.3452

1.3833

1.3986

(−0.2993)

(−0.1653)

(−0.1422)

(−0.1557)

(−0.1527)

(−0.1388)

7

1.2282

1.3862

1.3932

24

1.3446

1.3831

1.3991

(−0.2727)

(−0.1498)

(−0.1442)

(−0.1563)

(−0.1529)

(−0.1383)

8

1.2402

1.3840

1.3915

25

1.3439

1.3826

1.3989

(−0.2607)

(−0.1520)

(−0.1459)

(−0.1570)

(−0.1534)

(−0.1385)

10

1.2618

1.3813

1.3899

28

1.3421

1.3814

1.3980

(−0.2391)

(−0.1547)

(−0.1475)

(−0.1588)

(−0.1546)

(−0.1394)

11

1.2687

1.3797

1.3885

29

1.3450

1.3839

1.4013

(−0.2322)

(−0.1563)

(−0.1489)

(−0.1559)

(−0.1521)

(−0.1361)

12

1.2795

1.3778

1.3869

—

—

—

—

(−0.2214)

(−0.1582)

(−0.1505)

Percent Change Based on Average of Final Two

−10%

−10%

−9%

Weights

TABLE 2

SPA Behavior at Various Relative Humidities

Sample Weight in g (Change in

Sample Weight in g (Change in

Time

Starting Weight in g)

Time

Starting Weight in g)

(days)

58% RH

75% RH

84% RH

(days)

58% RH

75% RH

84% RH

0

1.5457

1.5093

1.5152

14

1.7917

1.8860

1.8931

(+0.2460)

(+0.3767)

(+0.3779)

1

1.5956

1.6010

1.6255

15

1.8047

1.8851

1.8923

(+0.0499)

(+0.0917)

(+0.1073)

(+0.2590)

(+0.3758)

(+0.3771)

2

1.6268

1.6597

1.6851

16

1.8144

1.8863

1.8930

(+0.0811)

(+0.1504)

(+0.1699)

(+0.2687)

(+0.3770)

(+0.3778)

3

1.6671

1.7067

1.7465

17

1.8311

1.8900

1.8964

(+0.1214)

(+0.1974)

(+0.2313)

(+0.2854)

(+0.3807)

(+0.3812)

4

1.6901

1.7360

1.7834

18

1.8411

1.8906

1.8969

(+0.1444)

(+0.2267)

(+0.2682)

(+0.2954)

(+0.3813)

(+0.3817)

5

1.7120

1.7800

1.8368

23

1.8889

1.8890

1.8966

(+0.1663)

(0.2707)

(+0.3216)

(+0.3432)

(+0.3797)

(+0.3814)

7

1.7268

1.8620

1.9054

24

1.8944

1.8884

1.8956

(0.1811)

(+0.3527)

(+0.3902)

(+0.3487)

(+0.3791)

(+0.3804)

8

1.7354

1.8881

1.9065

25

1.8995

1.8875

1.8948

(+0.1897)

(+0.3788)

(+0.3913)

(+0.3538)

(+0.3782)

(+0.3796)

10

1.7550

1.8917

1.9016

28

1.9071

1.8842

1.8924

(+0.2093)

(+0.3824)

(+0.3864)

(+0.3614)

(+0.3749)

(+0.3772)

11

1.7624

1.8904

1.8995

29

1.9112

1.8863

1.8951

(+0.2167)

(+0.3811)

(+0.3843)

(+0.3655)

(+0.3770)

(+0.3799)

12

1.7749

1.8887

1.8964

—

—

—

—

(+0.2292)

(+0.3794)

(+0.3812)

Percent Change Based on Average of Final Two Weights

+24%

+25%

+25%

TABLE 3

SPM Behavior at Various Relative Humidities

Sample Weight in g (Change in

Sample Weight in g (Change in

Time

Starting Weight in g)

Time

Starting Weight in g)

(days)

58% RH

75% RH

84% RH

(days)

58% RH

75% RH

84% RH

0

1.5057

1.5013

1.5068

12

1.6543

1.7809

1.8167

(+0.1486)

(+0.1796)

(+0.3099)

1

1.5243

1.5483

1.5663

13

1.6612

1.7781

1.8158

(+0.0186)

(+0.0470)

(+0.0595)

(+0.1555)

(+0.2678)

(+0.3090)

2

1.5326

1.5943

1.6227

14

1.6690

1.7768

1.8123

(+0.0269)

(+0.0930)

(+0.1159)

(+0.1633)

(+0.2755)

(+0.3055)

3

1.5441

1.6399

1.6830

15

1.6776

1.7768

1.8064

(+0.0384)

(+0.1386)

(+0.1762)

(+0.1719)

(+0.2755)

(+0.2996)

4

1.5567

1.6832

1.7377

16

1.6851

1.7774

1.8029

(+0.0510)

(+0.1819)

(+0.2309)

(+0.1794)

(+0.2761)

(+0.2961)

5

1.5677

1.7218

1.7869

17

1.6917

1.7754

1.7984

(+0.0620)

(+0.2205)

(+0.2801)

(+0.1860)

(+0.2741)

(+0.2916)

6

1.5774

1.7565

1.8033

21

1.7233

—

—

(+0.0717)

(+0.2552)

(+0.2965)

(+0.2176)

7

1.5873

1.7887

1.7978

23

1.7380

—

—

(+0.0816)

(+0.2874)

(+0.2910)

(+0.2323)

8

1.5997

1.7765

1.8000

26

1.7582

—

—

(+0.0940)

(+0.2752)

(+0.2932)

(+0.2525)

10

1.6242

1.7738

1.8065

35

1.7613

—

—

(+0.1185)

(+0.2725)

(+0.2997)

(+0.2556)

11

1.6397

1.7781

1.8130

42

1.7568

—

—

(+0.1340)

(+0.2768)

(+0.3062)

(+0.2511)

Percent Change Based on Average of Final

+17%

+18%

+20%

Two Weights

TABLE 4

SPA Behavior at Various Relative Humidities

Sample Weight in g (Change in

Sample Weight in g (Change in

Time

Starting Weight in g)

Time

Starting Weight in g)

(days)

58% RH

75% RH

84% RH

(days)

58% RH

75% RH

84% RH

0

1.5087

1.5037

1.5023

12

1.7253

1.8234

1.8345

(+0.2166)

(+0.3197)

(+0.3322)

1

1.5350

1.5618

1.5735

13

1.7337

1.8208

1.8311

(+0.0263)

(+0.0581)

(+0.0712)

(+0.2250)

(+0.3171)

(+0.3288)

2

1.5597

1.6203

1.6353

14

1.7425

1.8189

1.8283

(+0.0510)

(+0.1166)

(+0.1330)

(+0.2338)

(+0.3152)

(+0.3260)

3

1.5880

1.6662

1.6975

15

1.7532

1.8183

1.8278

(+0.0793)

(+0.1625)

(+0.1952)

(+0.2445)

(+0.3146)

(+0.3255)

4

1.6098

1.7140

1.7521

16

1.7618

1.8176

1.8272

(+0.1011)

(+0.2103)

(+0.2498)

(+0.2531)

(+0.3139)

(+0.3249)

5

1.6198

1.7538

1.7972

17

1.7680

1.8154

1.8248

(+0.1111)

(+0.2501)

(+0.2949)

(+0.2593)

(+0.3117)

(+0.3225)

6

1.6295

1.7862

1.8192

21

1.7860

—

—

(+0.1208)

(+0.2825)

(+0.3169)

(+0.2773)

7

1.6420

1.8091

1.8298

23

1.7905

—

—

(+0.1333)

(+0.3054)

(+0.3275)

(+0.2818)

8

1.6574

1.8189

1.8324.

26

1.7905

—

—

(0.1487)

(+0.3152)

(+0.3301)

(+0.2818)

10

1.6884

1.8202

1.8300

—

—

—

—

(+0.1797)

(+0.3165)

(+0.3277)

11

1.7081

1.8224

1.8329

—

—

—

—

(+0.1994)

(+0.3187)

(+0.3306)

Percent Change Based on Average of Final Two

+19%

+21%

+22%

Weights

EXAMPLE 4

The rates of dissolution of SPM and SPA were compared. In preliminary nonintrinsic dissolution experiments both SPM and SPA were found to dissolve rapidly and extensively in water. These studies were conducted by slurrying sieved (<75 μm) sodium phenytoin powder in pure water and measuring the concentrations in solution at various times by HPLC. Unfortunately, solid crystallized from the solutions withdrawn for analysis as they cooled, rendering the data invalid for determination of dissolution rate. Even so, all of the samples withdrawn contained about 5 mg/mL of sodium phenytoin, including those withdrawn 5 minutes after the slurries were prepared. The amount of sodium phenytoin in samples withdrawn at extended reaction times (24 and 72 hours) appeared to be less than the amount found in the earlier samples. A decrease in the concentration of dissolved sodium phenytoin with time is consistent with the reported reaction of sodium phenytoin with acids, even carbonic acid formed by dissolution of atmospheric carbon dioxide in water, to give relatively water-insoluble phenytoin.

The dissolution rates of both SPM and SPA in water were high enough that differences could not be determined by nonintrinsic dissolution experiments in this medium. Since preliminary solubility studies indicated that sodium phenytoin is less soluble in ethanol than it is in water, it was decided to carry out intrinsic dissolutions in ethanol-water mixtures. For intrinsic dissolution experiments, the test material is compressed into a tablet and the tablet (still in the die) is lowered into the dissolution medium. In this way, a consistent surface area, the tablet face, is presented to the medium. In order to determine comparative dissolution rates of different solid forms by this method, it must first be established that solid form interconversion does not occur under the pressure used to make tablets. Therefore, tablets of SPM and SPA were prepared, removed from the die, crushed into powders, and examined by XRPD. According to XRPD analyses, no solid form interconversion occurred for either form.

Intrinsic dissolution experiments were then carried out in 90% ethanol/10% water. The tablets dissolved very quickly in this medium, resulting in rapid deformation of the tablet faces. Occasionally pieces of solid broke free of the tablets and sank to the bottom of the dissolution vessel. Within 15-40 minutes the tablets had dissolved completely. Because of this behavior, consistent surface areas were not maintained during the course of the experiments. The result was a high degree of imprecision in the concentrations measured (Table 6). It appears that SPM dissolves more rapidly than does SPA, as shown in FIG.

1

.

TABLE 6

Intrinsic Dissolution Results in 90% Ethanol/10% Water

Time

Concentration (μg/mL)

Form

(min)

Run 1

Run 2

Run 3

Average

SD

c

RSD

d

SPM

a

1

2.42

2.21

5.26

3.30

1.70

51.67

5

44.78

25.24

48.38

39.46

12.46

31.54

10

99.18

70.05

107.91

92.38

19.82

21.46

15

—

120.28

153.22

136.75

23.29

17.03

20

166.11

—

—

166.11

—

—

SPA

b

1

1.73

1.68

3.36

2.26

0.96

42.36

5

11.71

12.24

19.91

14.62

459

31.39

10

23.27

23.84

57.43

34.84

19.56

56.13

20

47.05

60.83

144.62

87.17

52.81

62.74

40

112.23

139.74

193.12

148.36

41.13

27.72

a

SPM = sodium phenytoin monohydrate.

b

SPA = sodium phenytoin anhydrate.

c

Absolute standard deviation.

d

Relative standard deviation.

EXAMPLE 8

Methods were developed to determine, by X-ray powder diffraction (XRPD), the amount of SPM in SPA. Both SPM and SPA were sieved for use in quantitative method development. By using materials of the same particle size, demixing of mixtures prepared as standards will be minimized. In addition, use of small particle size materials will minimize preferred orientation effects.

SPM and SPA were each passed through a sieve stack. The SPM was somewhat, agglomerated, so large pieces were gently broken up before it was sieved. The sieve sizes and fractions collected are shown in Tables 7 and 8.

TABLE 7

Sieve Fractions Obtained of SPM

Fraction No.

Particle Size (μm)

Weight (g)

Starting Material (sample 34-89-3)

93.7

34-97-4

>300

30.8

34-97-5

300-212

12.7

34-97-6

212-150

7.79

34-97-7

150-106

6.31

34-97-8

106-75

3.25

34-97-9

<75

30.5

Total weight recovered

91.4

Mixtures were prepared using fractions of particle size <75 μm. These are listed in Table 9.

TABLE 9

SPM/SPA Mixtures

Sample

Amount SPM

Amount SPA

Percent SPM

No.

(mg)

(mg)

in SPA

39-3-1

0

100

0

39-3-2

11.2

212.7

5.0

39-3-3

22.7

163.3

10.0

39-3-4

45.2

180.8

20.0

39-3-5

67.5

157.5

30.0

Each mixture was analyzed by XRPD from 4-40 °2θ at a scan rate of 2°/minute. The resulting patterns were examined carefully to identify angular regions at which the peak heights varied in the order expected from the sample compositions.

Each mixture was then reanalyzed as follows: A weighed portion (about 150 mg) was loaded into the well of an aluminum sample holder. The weight was chosen to fill the holder well, which is 15×16×1 mm. The sample was scanned three times at 0.5°/minute over the region 11.4-12.6 °2θ. The sample was removed from the holder, reweighed, reloaded into the holder, and scanned three more times as above.

The peak height at 11.9 °2θ was determined by electronic subtraction of background counts and measurement of the intensity at the highest point of the remaining peak. The six measurements at each angle were divided by the weight of the samples that produced them and averaged. Thus each mixture afforded a value of peak height/weight (counts-per-second/mg, CPS/mg) for each of three peaks. These data are shown in Table 10.

TABLE 10

Peak Height Data Obtained for Mixtures of SPM in SPA

Sample

Percent

CPS/mg

a

at

SD

b

at

No.

SPM

11.9 °2θ

11.9 °2θ

39-3-1

0

0.14

0.09

39-3-2

5.0

2.22

0.12

39-3-3

10.0

4.38

0.24

39-3-4

20.0

8.75

0.28

39-3-5

30.0

13.06

0.15

A series of thirty measurements were made of background counts by scanning the region 11.4-12.6 °2θ for the sample of pure SPA. Backgrounds were electronically subtracted, the resulting numbers were averaged and divided by the weight of the sample to give a intensity/weight value of 0.16 counts-per-second/mg with a standard deviation of 0.10. The limit of detection (LOD) and limit of quantification (LOQ) were calculated as follows:

minimum detectable signal=0.16+3(0.10)=0.46 cps from the line equation of

FIG. 2

, percent SPM=(0.46−0.094224)÷0.43198=0.85% therefore, LOD=0.85% SPM in SPA

minimum quantifiable signal=0.16+10(0.10)=1.16 cps from the line equation of

FIG. 2

, percent SPM=(1.16−0.094224)÷0.43198=2.5% therefore, LOQ=2.5% SPM in SPA

EXAMPLE 9

Samples were analyzed by high-performance liquid chromatography (HPLC) on a BAS 480 HPLC system equipped with a UV/VIS detector and a TSP AS 100 autosampler, and controlled with INJECT software. A Phenomenex Hypersil C18 BDS column (5μ particle size, 4.6×150 mm) was used. The mobile phase was prepared by mixing water, methanol, and acetic acid in a 60:40:0.5 volume ratio. Analyses were carried out at a flow rate of 1 mL/minute with the UV/VIS detector set at 254 nm. The injection volume was 5 μL.

A calibration curve was constructed by making samples of known concentrations and analyzing them by HPLC. The data are shown in Table 11.

TABLE 11

HPLC Calibration Curve

Sample

Sodium Phenytoin

No.

Concentration (mg/mL)

Peak Area

22-85-5

0

0

22-85-4

18.7

54225

22-85-3

37.4

106197

22-85-2

74.8

212013

22-85-1

187.0

532380

A standard solution consisting of 74.8 μg/mL of sodium phenytoin in mobile phase was injected three times before and three times after each series of analyses. Each unknown sample was injected three times without dilution. The peak areas at 254 nm were recorded and averaged for each time point. The amount of sodium phenytoin in solution at each time point was calculated from the line equation of the calibration curve:

concentration (μg/mL)=(peak area−90.528)÷2844.8

EXAMPLE 10

Single Crystal Crystallography

Crystalline sodium phenytoin monohydrate was prepared as described in Example 4. The product was recrystallized several times in order to provide a pure large crystal of SPM (referred to below as C

15

H

13

NaN

2

O

3

and/or C

15

H

11

N

2

NaO

2

·H

2

O).

Data Collection

A colorless plate Of C

15

H

13

NaN

2

O

3

having approximate dimensions of 0.25×0.17×0.06 mm was mounted on a glass fiber in a random orientation. Preliminary examination and data collection were performed with Cu Kα radiation (λ=1.54184 Å) on an Enraf-Nonius CAD4 computer controlled kappa axis diffractometer equipped with a graphite crystal, incident beam monochromator.

Cell constants and an orientation matrix for data collection were obtained from least-squares refinement, using the setting angles of 25 reflections in the range 15<θ<11°, measured by the computer controlled diagonal slit method of centering. The monoclinic cell parameters and calculated volume are:

a=15.526(3), b=6.206(2), c=15.799(3)Å, β=115.50(2)°, V=1374.0 Å

3

.

For Z=4 and M

r

=292.27 the calculated density is 1.41 g·cm

−3

. As a check on crystal quality, omega scans of several intense reflections were measured; the width at half-height was 0.82° with a take-off angle of 3.0° indicating moderate crystal quality. From the systematic absences of:

h

0

l l=

2

n

0

k

0

k=

2

n

and from subsequent least-squares refinement, the space group was determined to be P2

1

/c (No. 14).

The data were collected at a temperature of 173±1 K using the ω-2θ scan technique. The scan rate varied from 1 to 16°/min (in omega). The variable scan rate allows rapid data collection for intense reflections where a fast scan rate is used and assures good counting statistics for weak reflections where a slow scan rate is used. Data were collected to a maximum 2θ of 136.3°. The scan range (in deg.) was determined as a function of θ to correct for the separation of the Kα doublet (ref 1); the scan width was calculated as follows:

ω scan width=0.82+0.330 tanθ

Moving-crystal moving-counter background counts were made by scanning an additional 25% above and below this range. Thus, the ratio of peak counting time to background counting time was 2:1. The counter aperture was also adjusted as a function of θ. The horizontal aperture width ranged from 2.4 to 3.8 mm; the vertical aperture was set at 4.0 mm. The diameter of the incident bear collimator was 0.7 mm and the crystal to detector distance was 21 cm. For intense reflections an attenuator was automatically inserted in front of the detector; the attenuator factor was 25.6.

Data Reduction

A total of 2680 reflections were collected, of which 2831 were unique.

Lorentz and polarization corrections were applied to the data. The linear absorption coefficient is 10.6 /cm for Cu Kα radiation. No absorption correction was made. Intensities of equivalent reflections were averaged. Six reflections were rejected from the averaging process because their intensities differed significantly from the average. The agreement factors for the averaging of the 132 observed and accepted reflections was 2.5% based on intensity and 2.2% based on F

o

.

Structure Solution and Refinement

The structure was solved using the structure solution program SHELX-86 (ref 2). The remaining atoms were located in succeeding difference Fourier syntheses. Except as noted in the table of positional parameters, hydrogen atoms were located and added to the structure factor calculations but not refined. The structure was refined in full-matrix least-squares where the function minimized was Σw(|F

o

|−|F

c

|)

2

and the weight w is defined as per the Killean and Lawrence method with terms of 0.020 and 1.0 (ref 3).

Scattering factors were taken from Cromer and Waber (ref 4). Anomalous dispersion effects were included in F

c

(ref 5): the values for ƒ and ƒ′ were those of Cromer (ref 6). Only the 1449 reflections having intensities greater than 3.0 times their standard deviation were used in the refinements. The final cycle of refinement included 202 variable parameters and converged (largest parameter shift was 0.24 times its esd) with unweighted and weighted agreement factors of:

R_{1} = \frac{\sum || F_{o} | - | F_{c} ||}{\sum | F_{o} |} = 0.049

R_{2} = \sqrt{\frac{\sum {w (F_{o} - F_{c})}^{2}}{\sum {wF}_{o}^{2}}} = 0.067

The standard deviation of an observation of unit weight was 1.83. There were 24 correlation coefficients greater than 0.50. The highest correlation coefficient was 0.60 between parameters 52 and 54. The highest peak in the final difference Fourier had a height of 0.75 e·Å

−3

with an estimated error based on δF (ref 7) of 0.07. The minimum negative peak had a height of −0.18 e·Å

−3

with an estimated error based on δF of 0.07. Plots of Σw(|F

o

|−|F

c

|)

2

versus |F

o

|, reflection order in data collection, sinθ/ω, and various classes of indices showed no unusual trends.

All calculations were performed on a VAX computer. Refinement was done using MolEN (ref 8). Crystallographic drawings were done using programs OR TEP (ref 9) and/or PLUTON (ref 10).

\begin{matrix} CRYSTALLOGRAPHIC  DATA  FOR C_{15} H_{11} N_{2} {NaO}_{2} \cdot H_{2} O \begin{matrix} {NaO}_{3} N_{2} C_{15} H_{13} & formula  weight  292.27 \\ a = 15.526 (3) Å & space  group {P2}_{1} / c (No. 14) \\ b = 6.206 (2) Å & T = 173 K \\ c = 15.799 (3) Å & λ = 1.54184 Å \\ β = 115.50 (2) & D_{calc} = 1.413 g \cdot {cm}^{- 3} \\ V = 1374 (1) Å^{3} & μ = 10.59 {cm}^{- 1} \\ Z = 4 & {R (F_{O})}^{a} = 0.049 \\ {R_{W} (F_{O})}^{b} = 0.067 \end{matrix} a_{R} = \frac{\sum || F_{o} | - | F_{c} ||}{\sum | F_{o} |} b_{R_{W}} = \sqrt{\frac{\sum {w (| F_{o} | - | F_{c} |)}^{2}}{\sum w | F_{o} |^{2}}} & □ \end{matrix}

CRYSTAL DATA AND DATA COLLECTION PARAMETERS

FOR C

15

H

13

N

2

NaO

2

.H

2

O

formula

NaO

3

N

2

C

15

H

13

formula weight

292.27

space group

P2

1

/c (No. 14)

a

15.526(3) Å

b

6.206(2) Å

c

15.799(3) Å

β

115.50(2)°

V

1374(1) Å

−3

Z

4

D

calc

1.413 g · cm

−3

crystal dimensions

0.25 × 0.17 × 0.06 mm

temperature

173 K.

radiation (wavelength)

Cu Kα(1.54184 Å)

monochromator

graphite

linear abs coef

1.059 mm

−1

absorption correction applied

none

diffractometer

Enraf-Nonius CAD4

scan method

ω-2θ

h, k, l range

−17 to 18, −7 to 0, −19 to 0

2θrange

5.56-136.26°

scan width

0.82 + 0.33 tanθ

take-off angle

6.00°

programs used

Enraf-Nonius MolEN

F

000

608.0

p-factor used in weighting

0.040

data collected

2680

unique data

2831

R

int

0.025

data with I > 3.0 σ(I)

1449

number of variables

202

largest shift/esd in final cycle

0.24

R(F

o

)

0.049

R

w

(F

o

)

0.067

goodness of fit

1.831

a

Flack H.D. Acta Crystallogr., Sect. A, A39, 876 (1983).

Positional Parameters and Their Estimated Standard Deviations

for C

15

H

11

N

2

NaO

2

.H

2

O

Atom

x

y

z

U(Å

2

)

Na

0.97607(9)

0.0179(3)

0.3015(1)

0.0316(4)

O2

0.8076(2)

−0.0403(4)

0.3437(2)

0.0345(8)

O5

0.9334(2)

−0.6319(5)

0.2681(2)

0.0316(7)

O100

1.0613(3)

0.1041(7)

0.4512(3)

0.093(2)

N1

0.8879(2)

−0.2958(5)

0.2989(2)

0.0242(8)

N4

0.8027(2)

−0.5897(5)

0.3007(2)

0.0229(8)

C2

0.8187(3)

−0.2284(6)

0.3231(2)

0.024(1)

C3

0.7533(2)

−0.4171(6)

0.3235(2)

0.0195(9)

C5

0.8789(2)

−0.5134(6)

0.2882(2)

0.023(1)

C31

0.7501(2)

−0.4451(6)

0.4191(2)

0.022(1)

C32

0.7060(3)

−0.2986(8)

0.4534(3)

0.052(1)

C33

0.7040(3)

−0.3245(9)

0.5404(3)

0.057(2)

C34

0.7446(3)

−0.4921(8)

0.5926(2)

0.043(1)

C35

0.7871(5)

−0.6411(9)

0.5588(3)

0.077(2)

C36

0.7904(4)

−0.6151(8)

0.4727(3)

0.059(2)

C37

0.6565(2)

−0.3846(6)

0.2490(2)

0.022(1)

C38

0.6129(3)

−0.5512(7)

0.1889(2)

0.032(1)

C39

0.5252(3)

−0.5233(8)

0.1209(3)

0.041(1)

C310

0.4796(3)

−0.3291(9)

0.1108(3)

0.045(1)

C311

0.5209(3)

−0.1640(8)

0.1688(3)

0.042(1)

C312

0.6088(3)

−0.1883(7)

0.2372(2)

0.030(1)

H4

0.794(2)

−0.727(6)

0.306(2)

0.03(1)*

H32

0.6753(7)

−0.178(2)

0.4175(5)

0.085

H33

0.6739(7)

−0.221(2)

0.5614(6)

0.093

H34

0.7441(6)

−0.510(2)

0.6508(5)

0.072

H35

0.817(1)

−0.760(2)

0.5964(6)

0.114

H36

0.8199(8)

−0.719(2)

0.4514(6)

0.093

H38

0.6435(5)

−0.683(1)

0.1953(5)

0.058

H39

0.4942(5)

−0.635(2)

0.0804(6)

0.072

H101

1.112(6)

0.12(2)

0.498(6)

0.22(4)*

H102

1.048(3)

−0.02(1)

0.490(4)

0.11(2)*

H310

0.4183(6)

−0.313(2)

0.0625(6)

0.077

H311

0.4889(6)

−0.033(2)

0.1615(6)

0.074

H312

0.6379(5)

−0.074(1)

0.2773(5)

0.061

Starred atoms were refined isotropically

U_{eq} = \frac{1}{3} \sum_{I} \sum_{j} U_{ij} a_{i}^{*} a_{j}^{*} a_{i} \cdot a_{j}

Hydrogens included in calculation of structure factors but not refined

B

isoH

=1.3B

isoC

Anisotropic Temperature Factor Coefficients - B's

for C

15

H

11

N

2

NaO

2

.H

2

O

Name

B

11

B

22

B

33

B

12

B

13

B

23

B

eqv

Na

2.44(5)

2.20(6)

3.38(5)

−0.33(5)

1.76(3)

−0.37(5)

0.0316(4)

O2

3.21(10)

1.42(11)

3.47(10)

−0.29(9)

1.38(8)

−0.46(9)

0.0345(8)

O5

2.20(8)

2.78(13)

3.17(9)

0.31(9)

1.79(6)

0.01(9)

0.0316(7)

O100

8.0(2)

7.4(2)

3.55(16)

1.0(2)

−0.39(16)

−1.35(17)

0.0931(17

N1

1.94(10)

1.65(13)

2.44(10)

−0.34(10)

1.22(8)

0.19(10)

0.0242(8)

N4

1.92(9)

1.25(12)

2.92(10)

−0.24(10)

1.68(7)

−0.23(10)

0.0229(8)

C2

2.35(13)

1.62(15)

1.45(12)

−0.07(13)

0.51(9)

−0.09(12)

0.0242(10

C3

1.62(11)

1.63(15)

1.54(11)

0.09(12)

0.84(8)

0.08(12)

0.0195(9)

C5

1.81(11)

2.17(16)

1.48(11)

0.16(13)

0.68(8)

0.37(13)

0.0231(10

C31

1.72(11)

2.07(16)

1.45(11)

−0.17(12)

0.73(8)

−0.02(12)

0.0219(10

C32

5.01(18)

5.3(2)

2.56(14)

3.01(18)

2.23(11)

1.09(17)

0.0518(14

C33

4.65(17)

7.1(3)

2.46(14)

2.3(2)

2.13(11)

0.5O(19)

0.0571(15

C34

4.39(17)

4.2(2)

1.69(13)

−0.75(18)

1.41(11)

0.06(16)

0.0431(13

C35

11.8(3)

3.8(2)

2.62(16)

2.2(3)

3.12(17)

1.13(18)

0.077(2)

C36

8.7(3)

3.1(2)

2.25(15)

2.4(2)

2.44(14)

0.72(16)

0.0589(16

C37

1.88(11)

2.14(16)

1.52(11)

−0.19(12)

1.05(8)

0.01(12)

0.0220(10

C38

2.53(13)

3.2(2)

1.89(12)

−0.53(15)

1.12(9)

−0.05(14)

0.0316(11

C39

2.63(14)

5.0(2)

1.76(13)

−1.22(17)

0.57(11)

−0.28(16)

0.0412(13

C310

2.05(14)

6.0(3)

2.28(14)

−0.37(1.8)

0.61(11)

0.68(17)

0.0452(14

C311

2.35(13)

5.0(2)

2.75(14)

1.38(16)

1.30(10)

1.20(16)

0.0419(13

C312

2.37(13)

2.99(19)

2.00(12)

0.57(14)

1.09(9)

0.21(14)

0.0304(11

The form of the anisotropic temperature factor is:

exp[−0.25(h

2

a*

2

B

11

+k

2

b*

2

B

22

+l

2

c*

2

B

33

+2hKa*b*B

12

+2hla*c*B

13

+2klb*c*B

23

)]

where a*, b*, and c* are reciprocal lattice constants.

Table of Refined Temperature Factor Expressions - Beta's

for C

15

H

11

N

2

NaO

2

.H

2

O

Name

B

11

B

22

B

33

B

12

B

13

B

23

Na

0.00310(6)

0.0143(4)

0.00416(6)

−0.0019(3)

0.00440(9)

−0.0021(3)

04(11)

O2

0.00408(13)

0.0092(7)

0.00427(13)

−0.0017(5)

0.00344(19)

−0.0026(5)

04(11)

O5

0.00280(10)

0.0180(8)

0.00390(11)

0.0018(5)

0.00448(15)

0.0001(5)

04(11)

O100

0.0102(3)

0.0483(16)

0.00437(19)

0.0059(12

−0.0010(4)

−0.0076(10)

04(11)

N1

0.00247(12)

0.0107(8)

0.00300(13)

−0.0019(6)

0.00306(19)

0.0010(6)

04(11)

N4

0.00245(12)

0.0081(8)

0.00359(13)

−0.0014(6)

0.00421(18)

−0.0013(6)

04(11)

C2

0.00299(16)

0.0105(10)

0.00178(14)

−0.0004(7)

0.0013(2)

−0.0005(7)

04(11)

C3

0.00207(13)

0.0106(10)

0.00190(13)

0.0005(7)

0.0021(2)

0.0004(7)

04(11)

C5

0.00230(14)

0.0141(11)

0.00181(13)

0.0009(8)

0.0017(2)

0.0021(7)

04(11)

C31

0.00220(14)

0.0134(11)

0.00178(13)

−0.0010(7)

0.0018(2)

−0.0001(7)

04(11)

C32

0.0064(2)

0.0346(16)

0.00314(17)

0.0173(10

0.0056(3)

0.0061(9)

04(11)

C33

0.0059(2)

0.046(2)

0.00302(17)

0.0132(12

0.0053(3)

0.0028(11)

04(11)

C34

0.0056(2)

0.0275(14)

0.00208(16)

−0.0043(10

0.0035(3)

0.0003(9)

04(11)

C35

0.0150(4)

0.0246(16)

0.0032(2)

0.0127(15

0.0078(4)

0.0064(10)

04(11)

C36

0.0111(3)

0.0198(14)

0.00277(18)

0.0140(12

0.0061(4)

0.0041(9)

04(11)

C37

0.00240(14)

0.0139(11)

0.00187(13)

−0.0011(7)

0.0026(2)

0.0000(7)

04(11)

C38

0.00322(16)

0.0211(13)

0.00233(15)

−0.0031(9)

0.0028(2)

−0.0003(8)

04(11)

C39

0.00335(18)

0.0322(16)

0.00217(16)

−0.0070(10

0.0014(3)

−0.0016(9)

04(11)

C310

0.00261(18)

0.0392(18)

0.00280(18)

−0.0022(10

0.0015(3)

0.0038(10)

04(11)

C311

0.00299(17)

0.0328(16)

0.00339(17)

0.0079(9)

0.0033(3)

0.0068(9)

04(11)

C312

0.00302(16)

0.0194(12)

0.00246(15)

0.0033(8)

0.0027(2)

0.0012(8)

04(11)

The form of the anisotropic temperature factor is:

exp[−(β

11

h

2

+

22

k

2

+β

33

l

2

+

12

hk+β

13

hl+

23

kl)].

Anisotropic Temperature Factor Coefficients - U's

for C

15

H

11

N

2

NaO

2

.H

2

O

Name

B

11

B

22

B

33

B

12

B

13

B

23

Na

0.0309(6)

0.0278(8)

0.0429(6)

−0.0041(6)

0.0223(4)

−0.0046(7)

04(11)

O2

0.0406(13)

0.0180(14)

0.0440(13)

−0.0037(12)

0.0174(10)

−0.0058(12)

04(11)

O5

0.0279(10)

0.0352(16)

0.0402(11)

0.0040(11)

0.0227(8)

0.0002(12)

04(11)

O100

0.101(3)

0.094(3)

0.045(2)

0.013(3)

−0.005(2)

−0.017(2)

04(11)

N1

0.0245(12)

0.0209(16)

0.0309(13)

−0.0043(13)

0.0155(10)

0.0023(13)

04(11)

N4

0.0243(11)

0.0158(15)

0.0370(13)

−0.0031(12)

0.0213(9)

−0.0029(13)

04(11)

C2

0.0297(16)

0.0205(19)

0.0184(15)

−0.0009(16)

0.0065(12)

−0.0012(15)

04(11)

C3

0.0205(13)

0.0206(19)

0.0195(14)

0.0012(15)

0.0107(10)

0.0010(15)

04(11)

C5

0.0229(14)

0.028(2)

0.0187(14)

0.0020(17)

0.0087(1l)

0.0046(16)

04(11)

C31

0.0218(14)

0.026(2)

0.0183(14)

−0.0021(16)

0.0092(10)

−0.0003(15)

04(11)

C32

0.063(2)

0.067(3)

0.0324(18)

0.038(2)

0.0282(14)

0.014(2)

04(11)

C33

0.059(2)

0.089(4)

0.0311(18)

0.029(3)

0.0270(14)

0.006(2)

04(11)

C34

0.056(2)

0.054(3)

0.0214(16)

−0.010(2)

0.0179(14)

0.001(2)

04(11)

C35

0.149(4)

0.048(3)

0.033(2)

0.028(3)

0.040(2)

0.014(2)

04(11)

C36

0.110(3)

0.039(3)

0.0286(19)

0.031(3)

0.0309(18)

0.009(2)

04(11)

C37

0.0239(14)

0.027(2)

0.0192(13)

−0.0024(16)

0.0133(10)

0.000l(15)

04(11)

C38

0.0320(16)

0.041(3)

0.0240(16)

−0.0067(19)

0.0142(12)

−0.0006(17)

04(11)

C39

0.0333(18)

0.063(3)

0.0223(17)

−0.015(2)

0.0072(13)

−0.004(2)

04(11)

C310

0.0260(17)

0.077(3)

0.0289(18)

−0.005(2)

0.0077(14)

0.009(2)

04(11)

C311

0.0297(17)

0.064(3)

0.0349(18)

0.018(2)

0.0165(13)

0.015(2)

04(11)

C312

0.0301(16)

0.038(2)

0.0253(16)

0.0072(17)

0.0138(12)

0.0027(17)

04(11)

The form of the anisotropic temperature factor is:

exp[−2π(h

2

a*

2

U

11

+k

2

b*

2

U

22

+l

2

c*

2

U

33

+2hka*b*U

12

+2hla*c*U

13

+2klb*c U

23

)]

where a*, b*, and c* are reciprocal lattice constants.

Table of Bond Distances in Angstroms

for C

15

H

11

N

2

NaO

2

.H

2

O

Distance

Distance

Na—O5

2.267(3)

C3—C31

1.541(5)

Na—O5

2.320(3)

C3—C37

1.471(5)

Na—O100

2.223(5)

C31—C32

1.382(6)

Na—N1

2.370(3)

C31—C36

1.329(6)

O2—C2

1.244(5)

C32—C33

1.397(6)

O5—C5

1.260(5)

C33—C34

1.308(7)

O100—H101

0.8(1)

C34—C35

1.371(7)

O100—H102

1.06(8)

C35—C36

1.393(7)

N1—C2

1.353(5)

C37—C38

1.369(5)

N1—C5

1.361(5)

C37—C312

1.396(6)

N4—C3

1.451(5)

C38—C39

1.334(6)

N4—C5

1.365(5)

C39—C310

1.371(7)

N4—H4

0.87(4)

C310—C311

1.340(7)

C2—C3

1.552(5)

C311—C312

1.335(6)

Numbers in parentheses are estimated standard deviations in the least significant digits.

Table of Bond Angles in Degrees

for C

15

H

11

N

2

NaO

2

.H

2

O

Angle

Angle

O5—Na—O5

116.8(1)

N4—C3—C37

111.7(3)

O5—Na—O100

89.8(2)

C2—C3—C31

112.7(3)

O5—Na—N1

132.4(1)

C2—C3—C37

109.8(3)

O5—Na—O100

113.4(2)

C31—C3—C37

110.3(3)

O5—Na—N1

97.2(1)

N1—C5—N4

112.1(4)

O100—Na—N1

106.9(2)

C3—C31—C32

122.7(4)

Na—O5—Na

108.5(1)

C3—C31—C36

120.6(4)

Na—O5—C5

131.4(3)

C32—C31—C36

116.7(4)

Na—O5—C5

119.7(3)

C31—C32—C33

122.3(5)

Na—O100—H101

152(8)

C32—C33—C34

120.2(5)

Na—O100—H102

106(4)

C33—C34—C35

118.2(4)

H101—O100—H102

86(8)

C34—C35—C36

122.0(5)

Na—N1—C2

105.3(3)

C31—C36—C35

120.6(5)

Na—N1—C5

147.7(3)

C3—C37—C38

118.8(4)

C2—N1—C5

106.8(3)

C3—C37—C312

121.8(4)

C3—N4—C5

111.3(3)

C38—C37—C312

119.4(4)

C3—N4—H4

126(3)

C37—C38—C39

119.3(4)

C5—N4—H4

122(3)

C38—C39—C310

120.3(4)

N1—C2—C3

111.7(3)

C39—C310—C311

121.5(4)

N4—C3—C2

98.0(3)

C310—C311—C312

119.2(5)

N4—C3—C31

113.8(3)

C37—C312—C311

120.3(4)

Numbers in parentheses are estimated standard deviations in the least significant digits.

Table of Torsion Angles in Degrees

Angle

O100—Na—N1—C2

72.90

(0.26)

O100—Na—N1—C5

−102.12

(0.43)

Na—N1—C2—O2

−1.34

(0.41)

Na—N1—C2—C3

179.34

(0.21)

C5—N1—C2—O2

175.88

(0.33)

C5—N1—C2—C3

−3.44

(0.36)

Na—N1—C5—O5

−3.01

(0.63)

Na—N1—C5—N4

177.75

(0.30)

C2—N1—C5—O5

−177.99

(0.31)

C2—N1—C5—N4

2.77

(0.37)

C5—N4—C3—C2

−1.00

(0.32)

C5—N4—C3—C31

−120.23

(0.32)

C5—N4—C3—C37

114.08

(0.33)

H4—N4—C3—C2

166.43

(2.61)

H4—N4—C3—C31

47.21

(2.63)

H4—N4—C3—C37

−78.49

(2.63)

C3—N4—C5—O5

179.78

(0.29)

C3—N4—C5—N1

−0.97

(0.37)

H4—N4—C5—O5

11.83

(2.49)

H4—N4—C5—N1

−168.92

(2.45)

O2—C2—C3—N4

−176.61

(0.31)

O2—C2—C3—C31

−56.58

(0.45)

O2—C2—C3—C37

66.79

(0.42)

N1—C2—C3—N4

2.73

(0.34)

N1—C2—C3—C31

122.76

(0.32)

N1—C2—C3—C37

−113.87

(0.33)

N4—C3—C31—C32

−179.71

(0.37)

N4—C3—C31—C36

0.13

(0.55)

C2—C3—C31—C32

69.83

(0.48)

C2—C3—C31—C36

−110.33

(0.45)

C37—C3—C31—C32

−53.26

(0.50)

C37—C3—C31—C36

126.58

(0.44)

N4—C3—C37—C38

22.63

(0.47)

N4—C3—C37—C312

−156.39

(0.34)

C2—C3—C37—C38

130.24

(0.36)

C2—C3—C37—C312

−48.77

(0.45)

C31—C3—C37—C38

−104.97

(0.38)

C31—C3—C37—C312

76.01

(0.44)

C3—C31—C32—C33

−179.56

(0.42)

C36—C31—C32—C33

0.60

(0.70)

C3—C31—C36—C35

−179.62

(0.47)

C32—C31—C36—C35

0.22

(0.74)

C31—C32—C33—C34

−0.19

(0.77)

C32—C33—C36—C35

−1.02

(0.79)

C33—C34—C35—C36

1.86

(0.87)

C34—C35—C36—C31

−1.48

(0.91)

C3—C37—C38—C39

−179.76

(0.36)

C312—C37—C38—C39

−0.72

(0.58)

C3—C37—C312—C311

179.97

(0.38)

C38—C37—C312—C311

0.95

(0.59)

C37—C38—C39—C310

0.58

(0.63)

C38—C39—C31—C311

−0.67

(0.68)

C39—C310—C311—C312

0.89

(0.68)

C310—C311—C312—C37

−1.03

(0.64)

Table of Atomic Multiplicities

for C

15

H

11

N

2

NaO

2

.H

2

O

Name

Multiplicity

Name

Multiplicity

Name

Multiplicity

Na

1.000

C312

1.000

H102

1.000

N1

1.000

C32

1.000

H32

1.000

N4

1.000

C33

1.000

H33

1.000

O2

1.000

C34

1.000

H34

1.000

O5

1.000

C35

1.000

H35

1.000

O100

1.000

C36

1.000

H36

1.000

C2

1.000

C37

1.000

H38

1.000

C3

1.000

C38

1.000

H39

1.000

C5

1.000

C39

1.000

H310

1.000

C31

1.000

H4

1.000

H311

1.000

C310

1.000

H101

1.000

H312

1.000

C311

1.000

REFERENCES

1. “CAD4 Operations Manual”, Enraf-Nonius, Delft, 1977

2. G. M. Sheldrick, SHELXS86.

A Program for the Solution of

—

Crystal Strtuctures.,

Univ. of Gottingen, Germany, 1985.

3. R. C. G. Killean and J. L. Lawrence,

Acta Crystallogr.,

Sect B, 25, 1750 (1969).

4. D. T. Cromer and J. T. Waber, “International Tables for X-Ray Crystallography”, Vol. IV, The Kynoch Press, Birmingham, England, 1974, Table 2.2B.

5. J. A. Ibers and W. C. Hamilton,

Acta Crystallogr.,

17, 781(1964).

6. D. T. Cromer, “International Tables for X-Ray Crystallography,” Vol. IV, The Kynoch Press, Birmingham, England, 1974, Table 2.3.1.

7. D. W. J. Cruickshank,

Acta Crystallogr.,

2, 154 (1949).

8. C. K. Fair, MolEN Structure Determination System, Delft Instruments, Delft, The Netherlands (1990).

9. C. K. Johnson,

ORTEPII,

ReportORNL-5138, Oak Ridge National Laboratory, Tennessee, USA (1976).

10. A. L. Spek,

PLUTON.

Molecular Graphics Program. Univ. of Ultrecht, The Netherlands (1991).

The crystalline sodium phenytoin monohydrate provided by his invention is useful as an anticonvulsant agent, especially for treating all forms of epilepsy. The compound can be formulated for convenient oral or parenteral administration. The crystals can be admixed with conventional carriers and excipients such as sucrose, polyvinylpyrrolidone, stearic acid, starch, talc, magnesium stearate and the like, and encapsulated into gelatin capsules, or if desired, the formulation can be pressed into tablets. The crystalline monohydrate can additionally be dissolved in sterile aqueous solutions such as isotonic saline or 5% aqueous glucose for parenteral administration, for example, by intravenous infusion. The pharmaceutical formulations of this invention typically will contain from about 10% to about 90% by weight of the monohydrate, for instance from about 30 mg to about 3000 mg per dosage unit. The monohydrate can be formulated with polymers and the like that are routinely utilized to retard release so as to have slow release dosage forms.

The monohydrate of this invention can additionally be added to sodium phenytoin that is produced by commercial processes such as those described above. By adding from about 1% to about 10% by weight of the monohydrate, commercial preparations of sodium phenytoin are stabilized such that their rate of dissolution are made more uniform, thereby resulting in more consistent dosing profiles of such commercial preparations.

As noted above, the crystalline sodium phenytoin of this invention is biologically effective to control generalized tonic-clonic (grand mal) and complex partial (psychomotor, temporal lobe) seizures. The compound can be utilized alone or in combination with other anticonvulsant agents, for instance gabapentin and the like. The invention, therefore, further provides a method for treating anticonvulsant disorders in humans comprising administering an anticonvulsant effective amount of the sodium phenytoin monohydrate. Such effective amounts will be a daily dosage of from about 30 mg to about 3000 mg, and preferably about 100 mg to about 1000 mg per day for a typical adult patient.

Number	Name	Date
2242775	Bywater	May 1941
2409754	Henze	Oct 1946
2409755	Henze	Oct 1946
2409756	Henze	Oct 1946
2684371	Levy	Jul 1954
4304782	Dumont et al.	Dec 1981
4642316	Fawzi et al.	Feb 1987
4696814	Kao et al.	Sep 1987

Crystalline sodium phenytoin monohydrate

Information

Patent Number

Date Filed

Date Issued

Inventors

Original Assignees

Examiners

Agents

CPC

US Classifications

Field of Search

US

International Classifications

Abstract

Description

Claims

Parent Case Info

PCT Information

US Referenced Citations (8)

Non-Patent Literature Citations (1)

Provisional Applications (1)