Topiramate

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Topiramate Comprehensive profile Nasr Y. Khalil, Haitham K. AlRabiah, Saad S. AL Rashoud, Ahmed Bari, Tanveer A. Wani Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia

Contents 1. General information 1.1 Nomenclature 1.2 Formulae 1.3 Elemental analysis 1.4 Appearance 1.5 Uses and applications 2. Methods of preparation 2.1 Using D-fructose as starting material 2.2 Using 2,3:4,5-bis-O-(1-methylethylidene)-β-D-fructopyranose as starting material 2.3 Using diacetone fructose (DAF) as starting material 2.4 Using chlorosulfonyl isocyanate as starting material 3. Physical characteristics 3.1 Optical activity 3.2 Solubility 3.3 Ionization constant 3.4 Thermal methods of analysis 3.5 Spectroscopy 4. Methods of analysis 4.1 United States Pharmacopeia compendial methods 4.2 Electrochemical methods of analysis 4.3 Spectroscopic methods of analysis 4.4 Chromatographic methods of analysis 4.5 Thermal behavior of topiramate 5. Pharmacokinetics, metabolism, and excretion 5.1 Pharmacokinetics 5.2 Metabolism 5.3 Excretion 6. Pharmacology 7. Stability References Profiles of Drug Substances, Excipients, and Related Methodology ISSN 1871-5125 https://doi.org/10.1016/bs.podrm.2018.11.005

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2019 Elsevier Inc. All rights reserved.

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1. General information 1.1 Nomenclature 1.1.1 Chemical name 2,3:4,5-bis-O-(1-methylethylidene)-β-D-fructopyranose sulfamate. 2,3:4,5-di-O-isopropylidene-β-D-fructopyranose sulfamate [1,2]. 1.1.2 Nonproprietary name Topiramate. 1.1.3 Proprietary names Tunisia: Epitomax, Ireland: Topamax, Pakistan: Apimat, Brainamax, Hong Kong: Apo-Topiramate, Topamax, South Africa: Toplep, Topirol, Epitoz, Sandoz Topiramate, Topamax, Topalex, Lebanon: Toramat, Topirate, Topirate, Nabian-K, Turkey: Xamate, N€ oromat, Topamax, Argentina: Zinalow, Topiramato Cevallos, Topitag, Neutop, Topamac, Topictal, Norway: Topiramat Bluefish, Topimax, Finland: Topiramat Orion, Australia: Topiramate, Topiramat Stada, Topiramat Sandoz, Topiramat Bluefish, Topiramat-ratiopharm, Tamate, Topamax, Topilex, Bulgaria: Topiramate Accord, Talopam, Tobanex, Egypt: Topiramate Sabaa, Conviban, Delpiramate, Nancydal, Topamax, United Kingdom: Topiramate Sandoz, Topiramate Actavis, Topiramate Accord, Topamax, Canada: Topiramate Sanis Health, Abbott-Topiramate, Apo-Topiramate, Auro-Topiramate, PMSTopiramate, RAN-Topiramate, Sandoz Topiramate, Teva-Topiramate, Topamax, France: Topiramate Zydus, Topiramate Sandoz Topiramate Biogaran, Topiramate EG, Topiramate Intas,Topiramate Mylan, Topiramate Arrow, Epitomax, Belgium: Topiramate EG, Topamax, Italy: Topiramato Accord Healthcare, Topiramato Bluefish, Topiramato Germed, Topiramato Doc Generici, Topiramato EG, Topiramato Mylan Generics, Topiramato Sandoz, Topiramato Tecnigen, Topiramato Tecnimede, Topiramato Teva, Sincronil, Topamax, Portugal: Topiramato Actavis, Topiramato Almus, Topiramato Accord, Topiramato Arrowblue, Topiramato Aurobindo, Topiramato Azevedos, Topiramato Bluefish, Topiramato Bluepharma, Topiramato Ciclum, Topiramato Cinfa, Topiramato Clindonim, Topiramato Farmoz, Topiramato Genedec, Topiramato Generis, Topiramato Germed, Topiramato Goldfarma, Topiramato GP, Topiramato Influben, Topiramato ITF, Topiramato Labesfal, Topiramato Mepha, Topiramato Mylan, Topiramato

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Normon, Topiramato Pharmagenus, Topiramato Ranbaxy, Topiramato Ratiopharm, Topiramato Sandoz, Topiramato Strachi, Topiramato Tecnimede, Topiramato Teva, Topiramato Tolife, Topiramato Tomix, Topiramato Vida, Topiramato Vitalion, Topiramato Wynn, Olandic, Pirepil, Topamax, India: Topamed, Topse, Topival, Epitop, Nuromate, Topamed, Spain: Topimylan, Topibrain, Topiramato Alter, Topiramato Cinfa, Topiramato Combix, Topiramato Davur, Topiramato Bluefish, Topiramato Kern Pharma, Topiramato Mylan, Topiramato Normon, Topiramato Pensa, Topiramato Pharma, Combix, Topiramato Pharmacia, Topiramato Pharmagenus, Topiramato Qualigen, Topiramato Ranbaxy, Topiramato Ratiopharm, Topiramato Sandoz Topiramato Stada, Topiramato Tarbis, Topiramato Tecnigen, Topiramato Teva, Topiramato Ur, Topiramato Zentiva, Acomicil, Epilmax, Fagodol, Topibrain, Japan: Topina, United States: Topiragen, Topiramate Actavis, Topiramate Accord Healthcare, Osymia, Qsymia, Topamax, Netherlands: Topiramaat Apotex, Topiramaat Arrow, Topiramaat Auro, Topiramaat Aurobindo, Topiramaat Bluefish, Topiramaat CF, Topiramaat Desitin, Topiramaat Glenmark, Topiramaat Mylan, Topiramaat PCH, Topiramaat Ratiopharm, Topiramaat Sandoz, Topiramaat Accord, Topiramaat Actavis, Topiramaat Torrent, Topepsil, Topitex, Topamax, Topamax, Topepsil, Topilept, Germany: Topiramat-1 A Pharma, Topiramat-Hormosan, TopiramatJanssen, Topiramat-neuraxpharm, Topiramat-CT, Topiramat SIGA, Topiramat STADA, Topiramat HEXAL, Topiramat Migr€ane STADA, Topiramat AL, Topiramat AL Migr€ane, Topiramat dura, TopiramatTEVA, Topiramat-TEVA, Topamax, Switzerland: Topiramat Actavis, Topiramat-Mepha Teva, Topiramat Spirig HC, Topamax, Denmark: Topiramat Actavis, Topimax, Topiramat Orion, Topiramat Hexal, Topiramat Bluefish, Topiratore, Topiratore, Topimax, Romania: Topiramat Actavis, Topilex, Topilept, Topiramat Teva, Topiramat Egis, Topiramat Bluefish, Torlepta, Topran, Letor, Nextop, Topamax, Topilex, Sweden: Topiramat Actavis, Topiramat-1A Pharma, Topiramat ratiopharm, Topiramat Orion, Topiramat Bluefish, Greece: Topiramat Actavis, Topiramat Teva, Topiramat Generics, Toramat, Topiref, Jadix, Letor, Pirantal, Topamac, Topepil, Iceland: Topiramat Actavis, Topiramat Bluefish, Topimax [3].

1.2 Formulae 1.2.1 Empirical formula, molecular weight and CAS number C12H21NO8S 339.359 97240-79-4 [1,2,4].

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1.2.2 Structural formula [1]

1.3 Elemental analysis [5] C: 42.47% H: 6.24% N: 4.13% O: 37.72% S: 9.45%

1.4 Appearance Solid, white crystalline powder with bitter taste [2].

1.5 Uses and applications Topiramate is classified as a sulfamate-substituted monosaccharide and is known as an anticonvulsant or antiepileptic drug. It is used alone or with other medications to prevent and control seizures (epilepsy). It is also used to prevent migraine headaches in children, for treatment of Lennox-Gastaut syndrome, and used in combination with phentermine for the treatment and management of obesity (under the name of QSYMIA®) and in the Treatment of Alcohol Use Disorders. Topiramate is given orally and the doses available are 25, 50, 100, 150 and 200 mg [6–11].

2. Methods of preparation 2.1 Using D-fructose as starting material D-Fructose,

an abundant and inexpensive monosaccharide, is first reacted with acetone to produce the thermodynamically more stable bisacetonide.

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From this intermediate, topiramate is synthesized through two routes: first route is condensation of the bisacetonide with sulfamoyl chloride in the presence of sodium hydride. Second route is by reacting the intermediate (bisacetonide) with sulfuryl chloride and pyridine in methylene chloride and then with sodium azide in acetonitrile to furnish azido sulfate, which is reduced with copper powder in methanol to obtain topiramate (Scheme 1) [12].

2.2 Using 2,3:4,5-bis-O-(1-methylethylidene)-β-Dfructopyranose as starting material Three reaction routes are presented for the preparation of topiramate starting from the readily available 2,3:4,5-bis-O-(1-methylethylidene)β-D-fructopyranose of the formula II. They only differ in the way the sulfamate ester group is formed. The three processes comprise the following chemical steps: In process A, the compound of formula II is reacted with sulfamoyl chloride of the formula ClSO2NH2 in the presence of sodium hydride using dimethylformamide (DMF) as solvent. In process B, reacting the compound of formula II and sulfuryl chloride yields a chlorosulfate ester of formula V, which is then treated with a metal azide of the formula MN3 and is finally reduced. In process C, the chlorosulfate ester of formula V obtained according to process B is reacted with ammonia in methylene chloride or in acetonitrile. The above processes A, B and C are summarized in the reaction scheme (Scheme 2). Process A has two major disadvantages. One disadvantage is said to be that it calls for a combination of NaH and DMF which has an uncontrollable exotherm and is therefore potentially explosive. Another disadvantage is that the process also uses highly toxic and corrosive chlorosulfonyl isocyanate to prepare the commercially unavailable sulfamoyl chloride (ClSO2NH2). There is an improvement in process C, in which the reaction of the chlorosulfate ester of the formula V and pressurized ammonia is carried out in tetrahydrofuran (THF).The above mentioned processes still suffer from the following disadvantages: According to process A, sulfamoyl chloride of the formula ClSO2NH2 is employed, which is commercially unavailable. It is prepared by the partial hydrolysis of chlorosulfonyl isocyanate. Since chlorosulfonyl isocyanate reacts violently with water, the procedure can be conducted safely only in laboratory scale. Sulfamoyl chloride is extremely unstable and has to be used promptly after its preparation. Moreover, the highly flammable sodium

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Scheme 1 Synthesis of topiramate from D-fructose.

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Scheme 2 Synthesis of topiramate using methylethylidene-fructopyranose as starting material.

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hydride is utilized in the second step. Therefore this process is less suitable for industrial scale manufacturing. According to process B, the chlorosulfate of the formula V is treated with the potentially explosive metal azide to obtain the azidosulfate of the formula VI. Azido compounds are dangerous to handle due to their explosive nature. Therefore they are not amenable to safe industrial application. In process C, reaction of the chlorosulfate of the formula V and ammonia yields the sulfamate ester of formula I. According to this process a low quality product of a moderate yield is obtained. However, an improvement is presented in which conduction of ammonolysis under pressure in THF results in better yield and quality. Upon reproduction of the improved process the compound of formula I was obtained in 80–85% yield. However, even repeated recrystallization sometimes failed to provide topiramate in pharmaceutical grade [13]. Thus, while the improved process C results in better yield of 80–85% and enhanced quality, nevertheless on reproducing the improved process, it was found that it is not possible to prepare in an acceptable quality and stable product even after repeated recrystallization. Topiramate thus obtained failed to pass the standard accelerated stability test, a discoloration (decomposition) being observed [14].

2.3 Using diacetone fructose (DAF) as starting material Reacting a compound of formula (II) known as diacetone fructose (DAF) with sulfuryl diamide (III) known as sulfamide, at an elevated temperature, in the presence of up to about 10% water, to yield the corresponding compound of formula (I) topiramate [13] (Scheme 3).

Scheme 3 Synthesis of topiramate using diacetone fructose as starting material.

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2.4 Using chlorosulfonyl isocyanate as starting material The compound of the general formula (IV) can be prepared by reacting chlorosulfonyl isocyanate compound of formula (I) with a compound of the general formula (II) wherein R1 and R2 are independently selected from saturated or unsaturated, straight, branched and/or cyclic alkyl, aryl or aralkyl, or R1 and R2 taken together with the nitrogen atom to which they are bound to form a saturated or unsaturated heterocycloalkyl. The intermediate compound of the general formula (V) can be prepared by reacting 2,3,4,5-bis-O-(1-methylethylidene)-β-D-fructopyranose of the formula (III) with a substituted aminocarbonylsulfamoyl chloride of the general formula (IV) wherein R1 and R2 are defined as above. The hydrolysis (Scheme 4) of the compound of the general formula (V) may, for example, be carried out in an aqueous solvent mixture, such as a mixture of water and a water-miscible organic solvent, such as acetone. The pH of the reaction mixture is preferably adjusted in the range of 2–5, preferably 3.5–4.5. The pH is maintained during hydrolysis of the compound of the general formula (V) by using an appropriate buffer solution, such as a sodium acetate/acetic acid buffer solution. The reaction may be conducted in a temperature range of, for example, 10–100 °C, preferably 70–90 °C. The hydrolysis reaction may be carried out at any suitable pressure, such as atmospheric pressure, or at elevated pressure (for example, between 1 and 5 bar, but more preferably in the range of between 1 and 2 bar) to increase the temperature of the reaction mixture [15].

3. Physical characteristics 3.1 Optical activity
34 degree/D (c ¼ 0.4 in methanol) [2].

3.2 Solubility Topiramate is most soluble in alkaline solutions with a pH of 9–10, including those containing sodium hydroxide or sodium phosphate. It is freely soluble in acetone, chloroform, dimethyl sulfoxide, and ethanol. The solubility in water is 9.8 mg/mL, and its saturated solution has a pH of 6.3 [2,4].

3.3 Ionization constant pKa ¼ 8.6 [2].

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Scheme 4 Synthesis of topiramate using chlorosulphonyl isocyanate as starting material.

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3.4 Thermal methods of analysis 3.4.1 Melting behavior The melting point is 125–126 °C [4]. 3.4.2 Differential scanning calorimetry Differential Scanning Calorimetric (DSC) analysis was performed using a Perkin Elmer DSC 8000 system. About 3.5 mg of sample was added placed in a 40 μL aluminum pan which was sealed and heated over the range of 40–170 °C at a heating rate of 10 °C/min. An empty aluminum pan was used as the reference standard. Analysis was carried out under nitrogen purge. As shown in Fig. 1, the thermogram consisted of a sharp endothermic peak at 126.27 °C, corresponding to its melting point.

3.5 Spectroscopy 3.5.1 Ultraviolet spectroscopy The analysis of topiramate by direct ultraviolet spectroscopic methods is not possible because the compound does not contain any chromophores that could yield absorbance bands above 190 nm. Therefore derivatization with different UV-absorbing or fluorescent moieties is employed before its analysis. 3.5.2 Vibrational spectroscopy The infrared absorption spectrum of topiramate was obtained using a Perkin Elmer spectrum BX system. As shown in Fig. 2, characteristic peaks at 3383 cm
1 (NH2 asymmetric stretching mode), 3213 cm
1 (broad, intermolecular hydrogen bonded, O-H stretching mode), 3113 cm
1 (aromatic C-H stretching mode), 3000.01 cm
1(CH3 asymmetric stretching modes) 2942 cm
1 (aliphatic C-H stretching mode), 1578 cm
1 (NH2 scissoring mode), 1458 cm
1 (CH2 stretching mode), 1379 cm
1 (in plane O-H bending mode),1045 cm
1 (ring C-O-C stretching mode) 641 cm
1 (O-C-O, C-OC bending mode), and the 574 cm
1 (SO3 stretching mode). 3.5.3 NMR spectrometry 3.5.3.1 1H NMR spectrometry

The 1H NMR spectrum of topiramate was scanned in DMSO-d6 on a Bruker NMR spectrometer operating at 700 MHz. Chemical shifts are expressed in δ-values (ppm), and coupling constants (J) are expressed in Hz (see Table 1 and Fig. 3).

Filename: Operator ID: Sample ID: Sample Weight: Comment:

D:\DSC data\Nasr Khall\TPRA.pdid Rais TPRA 3.500 mg

–10 Onset Y = –3.4229 mW Onset X = 124.13 °C

–5

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Heat Flow Endo Down (mW)

0

5 Area = 313.062 mJ Delta H = 89.4464 J/g 10

15 Peak = 126.27 °C 20

25 45 50

60

70

80

90

100 110 120 Temperature (°C)

130

140

150

160

170

3/8/2017 10:05:26 AM 1) Hold for 1.0 min at 40.00°C

Fig. 1 Differential scanning calorimetry thermogram of topiramate.

2) Heat from 40.00°C to 300.00°C at 10.00ºC/min

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Fig. 2 Infrared absorption spectrum of topiramate.

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3.5.3.2

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Table 1 1H NMR of topiramate. Signal Location Shape

Integration

Identification

1

1.21

S

3H

CH3

2

1.34

S

3H

CH3

3

1.37

S

3H

CH3

4

1.47

S

3H

CH3

5

3.61

D.J ¼ 13.3

1H

CH

6

3.75

D.J ¼ 13.3

1H

CH

7

3.96

D.J ¼ 10.5

1H

CH

8

4

D.J ¼ 9.8

1H

CH

9

4.26

D.J ¼ 11.90 2H

CH2

10

7.64

D

NH2

1H

C NMR spectrometry

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The C NMR spectrum of topiramate was scanned in DMSO-d6 on a Bruker NMR spectrometer operating at 176.05 MHz. Chemical shifts are expressed in δ-values (ppm) relative to TMS as an internal standard (see Table 2 and Fig. 4). 3.5.4 Mass spectrometry The mass spectrum of topiramate was obtained using gas chromatography coupled with mass spectrometer (PerkinElmer® Clarus® 600) having an electroionization source. The base peak was m/z ¼ 43, and other prominent ions were m/z ¼ 324, 59, 69, and 110. Fig. 5 shows the Mass Scan of topiramate at m/z ¼ 340.23 [M + 1]+. 3.5.5 Thermogravimetric analysis (TGA) In a first run of TGA, a mass loss of 46.8% was observed around 180 °C, followed by a further mass loss of 20.8% in the interval 180–270 °C. Then, mass continues to reduce slowly until the temperature reaches 500 °C, when only 23% of the total mass was present (see Fig. 6). 3.5.6 X-ray diffraction pattern The X-ray powder diffraction pattern of Topiramate has been obtained using an Ultima IV X-ray diffraction system (Rigaku, Japan) and is shown in Fig. 7. The diffractometer was equipped with a scintillation detector, and

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Fig. 3 1H NMR spectrum of topiramate.

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Table 2 Signal

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C NMR spectrum of topiramate. Location

Identification

1

24.46

CH3

2

25.45

CH3

3

26.18

CH3

4

26.69

CH3

5

60.97

CH2

6

69.14

CH2

7

69.66

CH

8

70.16

CH

9

70.39

CH

10

101.02

Aromatic-c

11

108.64

Aliphatic-c

12

108.83

Aliphatic-c

the sample irradiated using copper (wavelength ¼ 1.5406 A˚) radiation. The sample was scanned over 3–60 degrees 2θ, at a scanning speed of 0.5 degree/min. A full data summary is compiled in Table 3.

4. Methods of analysis 4.1 United States Pharmacopeia compendial methods 4.1.1 Identification • Infrared absorption spectrum: Equivalent compared with a reference standard. • In the chromatogram obtained in the assay of the sample, the retention time of the major peak of the Sample solution corresponds to that of the Standard solution [1] 4.1.2 Organic impurities and related substances 4.1.2.1 Procedure: Liquid chromatography

Depending on the synthetic route, perform either “Procedure 2” or “Procedure 3.” If N-methyl topiramate is a potential related compound, either Procedure 1 or Procedure 3 is recommended [1].

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Fig. 4

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C NMR spectrum of topiramate.

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Fig. 5 Mass spectrum of topiramate.

College of Pharmacy - KSU Central Lab 116.1

100

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80

Weight % (%)

60

40

20

0

–20 50

100

150

200

Fig. 6 Thermogravimetric analysis thermogram of topiramate.

250 300 Temperature (°C)

350

400

450

500

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Fig. 7 X-ray powder diffraction pattern of topiramate.

4.1.2.1.1 Procedure 1 Identification solution: 0.2 mg/mL of USP topiramate. Related compound A RS in methanol. Standard solution A: 40 mg/mL of USP topiramate RS in methanol. Standard solution B: 0.08 mg/mL of topiramate from the Standard solution A and methanol.

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Topiramate

Table 3 Crystallographic data from the XRPD pattern of topiramate. ID Angle (degrees 2θ) Flex width d-value (Å) Intensity Relative intensity (%)

1

9.10

0.353

9.7099

353

22

2

12.00

0.471

7.3691

489

31

3

12.90

0.471

6.8569

92

6

4

15.20

0.353

5.8241

451

28

5

15.80

0.353

5.6043

1614

100

6

17.10

0.471

5.1811

375

24

7

18.10

0.824

4.8970

66

5

8

19.90

0.471

4.4579

364

23

9

20.80

0.588

4.2670

689

43

10 22.20

0.353

4.0010

153

10

11 23.30

0.471

3.8145

75

5

12 24.30

0.471

3.6598

170

11

13 25.70

0.353

3.4635

264

17

14 27.00

0.353

3.2996

78

5

15 27.70

0.588

3.2763

118

8

16 29.30

0.471

3.0456

119

8

17 30.40

0.353

2.9379

82

6

18 31.00

0.471

2.8824

103

7

19 31.70

0.353

2.8203

64

4

20 32.70

0.706

2.7363

199

13

21 33.50

0.471

2.6728

56

4

22 35.70

0.471

2.5129

240

15

23 36.70

0.353

2.4467

74

5

24 38.30

0.471

2.3481

68

5

25 45.30

0.471

2.0002

58

4

26 49.10

0.353

1.8539

57

4

27 50.20

0.471

1.8158

81

5

28 51.50

0.471

1.7730

67

5

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Standard solution C: 0.04 mg/mL of topiramate from the Standard solution A and methanol. Sample solution: 40 mg/mL of topiramate in methanol. Mode: Thin-layer chromatography adsorbent: 0.20-mm layer of chromatographic silica gel mixture, prewashed with methanol and air dried. Application volume: 20 μL. Developing solvent system: Acetonitrile, methanol, and 0.5 M sodium chloride (7:3:10). Spray reagent: Prepare a 30-mg/mL solution of phenol in alcohol and concentrated sulfuric acid (95:5). Analysis of samples: Standard solution B, Standard solution C, and Sample solution. Proceed as directed in the chapter. After elution, air-dry the plate, spray the plate with the Spray reagent, and let the plate air-dry. Then dry the plate for 10 min in an oven at 125 °C. The approximate RF values for topiramate and topiramate related compound A are 0.65 and 0.70, respectively. Disregard any spots at the origins of the chromatograms. Disregard any spot corresponding to topiramate related compound A because this impurity should be quantified using Procedure 2. Examine the plate using visible light and estimate the percentage of all secondary spots in the chromatogram of the Sample solution by comparing each spot with the principal spot from the chromatograms of the Standard solutions [1]. Acceptance criteria: Any single spot is not greater in size and intensity than the spot for Standard solution C; not more than (NMT) 0.1% of any individual impurity is found; and NMT 0.5% of total impurities by TLC is found [1]. 4.1.2.1.2 Procedure 2 Mobile phase: Proceed as directed in the assay procedure, preparing all solutions fresh before use. Sample solution: 40 mg/mL of Topiramate in mobile phase. Sonication may be used to aid dissolution. System suitability solution: 0.3 mg/mL each of USP Fructose RS and USP topiramate related compound A RS, in the Sample solution. Mode: Refractive index detector; Column: 5-μm packing L1 (4.6-mm  25-cm). The column temperature and the detector temperature are both 55 °C. The mobile phase flow rate is 0.6 mL/min, and the injection volume is 50 μL. The run time is not <5 times the retention time of

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the topiramate peak. The relative retention times for fructose, topiramate related compound A, and topiramate are 0.45, 0.9, and 1.0, respectively. System suitability criteria: The resolution between topiramate related compound A and topiramate is NLT 1.0. The relative standard deviation is NMT than 2.0% for the topiramate peak [1]. 4.1.2.1.3 Procedure 3 Mobile phase: Methanol and water (16:34). Standard solution: 10 mg/mL of USP Topiramate RS and 0.04 mg/mL of USP topiramate related compound A RS in mobile phase. Sample solution: 10 mg/mL of Topiramate in mobile phase. Chromatographic system: Refractive index Detector; Column: L15 packing (4.6 mm  150 mm; 5-μm); Column temperature 35 °C; Flow rate 1.5 mL/min; Injection size 50 μL. System suitability: The suitability requirements for the Standard solution are as follows: Resolution: NLT 1.0 between topiramate related compound A and topiramate. Relative standard deviation: NMT 2.0% for the topiramate peak for six replicate injections [1]. 4.1.3 Chromatographic assay Mobile phase: Acetonitrile and water (1:1) Standard solution: 2 mg/mL of USP Topiramate RS in mobile phase Sample solution: 2.0 mg/mL of Topiramate in mobile phase. Chromatographic system: Refractive index Detector; Column: L1 packing (4.6-mm  250 mm; 5-μm); Column and detector temperature 50 °C; Flow rate of 0.6 mL/min; Injection size: 20 μL. System suitability: The suitability requirements for the Standard solution are: Column efficiency NLT 1500 theoretical plates; Tailing factor NMT 2.0, Relative standard deviation NMT 2.0%. 4.1.3.1 Analysis

Samples: Standard solution and Sample solution: Calculate the percentage of C12H21NO8S in the portion of Topiramate taken: Result ¼ (Ru/Rs)  (Cs/Cu)  100. Ru ¼ peak response from the Sample solution

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Rs ¼ peak response from the Standard solution Cs ¼ concentration of USP Topiramate RS in the Standard solution (mg/mL) Cu ¼ concentration of Topiramate in the Sample solution (mg/mL) 4.1.3.2 Acceptance criteria

The assay is 98.0–102.0%, on an anhydrous basis.

4.2 Electrochemical methods of analysis Mandil et al. [16] used differential pulse polarography (DPP) to determine topiramate in an aqueous medium. The method used phosphate buffer (0.01 M at pH 9.50), a dropping mercury electrode (DME), a static mercury drop electrode (SMDE), and a hanging mercury drop electrode (HMDE). The reduction peak for topiramate occurred in a potential range from 74 to 77 mV. Using the DME electrode the peak current was proportional to the concentration of topiramate over the range 1.36–19.04 μg/mL and 4.08–27.2 μg/mL when using the SMDE and HMDE electrodes. For DME the limit of quantitation was 1.36 μg/mL (relative standard deviation of 3.8%) and 4.08 μg/mL (respective RSD values of 2.8% and 4.5%) when using HMDE and SMDE. The proposed DPP method was used for the direct determination of topiramate in various pharmaceutical tablet formulations. It was reported that the difference between the expected and the found results was insignificant, with the RSD being <3.8%.

4.3 Spectroscopic methods of analysis 4.3.1 Flow injection spectrophotometric analysis Application of a sensitive and rapid flow injection analysis (FIA) method for determination of topiramate in pharmaceutical formulations has been investigated. The method, which was reported by Hadad et al. [17], is based on the reaction with ortho-phthaldehyde and 2-mercaptoethanol in a basic buffer solution, with measurement of absorbance at 295 nm under flow conditions. Variables affecting the determination (such as sample injection volume, pH, ionic strength, reagent concentrations, flow rate of reagent and other FIA parameters) were optimized to produce the most sensitive and reproducible results using a quarter-fraction factorial design, for five factors at two levels. The method has been optimized and fully validated in terms of selectivity, linearity range, limit of detection, limit of quantitation, precision, and accuracy. The method was successfully applied to the analysis of pharmaceutical preparations.

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4.3.2 Colorimetry Salama and co-workers optimized a selective, inexpensive and validated method for determination of topiramate as the bulk drug substance, and in drug products, as well as in the presence of pyridine [18]. The method was based on the reaction of the primary amino group of topiramate with ninhydrin reagent in ethanolic medium in the presence of 10% pyridine solution, yielding a colored product that was measured at 568 nm. The linearity range was found to be 50–300 μg/mL, with a mean recovery of 98–102%. All variables affecting the reaction conditions were thoroughly studied. The results were found to agree statistically, and the method was validated according to ICH guidelines. The proposed method is practical and valuable for the quality control laboratories for analysis of topiramate. Another colorimetric method has been developed by Kashyap et al. for the estimation of topiramate as the bulk drug substance, and in dosage forms [19]. The method was based on an oxidation-reduction reaction involving the formation of a blue colored complex between topiramate and ammonium molybdate in the presence of 2 M hydrochloric acid. When analyzed at a wavelength of 750 nm, the method demonstrated linearity over the range of 10–50 μg/mL. The method was validated based on ICH guidelines and is simple, sensitive, reliable, and reproducible. The high recovery and low relative standard deviation confirm the suitability of the method for the determination topiramate in pharmaceutical dosage forms, are therefore useful for the routine analysis of topiramate. 4.3.3 Fluorimetric methods Two highly sensitive, rapid, simple, economic and validated spectrofluorimetric methods have been developed by El-Yazbi et al., for determination of Topiramate and Levetiracetam in pharmaceutical tablets and in human plasma [20]. Topiramate and Levetiracetam were determined separately by derivatization using 4-chloro-7-nitrobenzofuran-2-oxo-1,3-diazole (NBD-Cl) and measured spectrofluorimetrically. The Relative fluorescence intensities were measured at λem/ex of 547/465 nm and 551/465 nm for Topiramate and Levetiracetam, respectively. While a binary mixture of Topiramate and Levetiracetam was determined by the fourth derivative synchronous fluorescence measurement after their reaction with NBD-Cl. In this method, the fourth derivative synchronous spectra were estimated as peak to peak measurement at 493–497 and 490.5–495 nm corresponding with zero-contribution of Levetiracetam and Topiramate, respectively. Linearity ranges for Topiramate and Levetiracetam in both

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methods were found to be 0.15–1.2 and 0.2–1.5 μg/mL, respectively. The different experimental parameters affecting the fluorescence of the two drugs were carefully studied and optimized. The proposed methods were validated in terms of linearity, accuracy, precision, limits of detection and quantification and other aspects of analytical validation. The proposed methods were successfully applied for the determination of the investigated drugs in human plasma samples obtained from healthy volunteers after single oral administration of the two drugs.

4.4 Chromatographic methods of analysis 4.4.1 Capillary electrophoresis(CE) A capillary electrophoresis (CE) method has been developed by KlockowBeck et al. [21], as an alternative method for the determination of the inorganic degradation products sulfate and sulfamate in topiramate drug product and drug substance, currently performed by ion chromatography. The anions were separated in a background electrolyte containing potassium chromate and boric acid, followed by indirect UV detection at a wavelength of 272 nm. By adding tetradecyltrimethylammonium bromide (TTAB) to the electrolyte, analysis was performed under co-electroosmotic flow conditions. Variations in injection volumes and migration times were compensated for by use of potassium nitrate as an internal standard. The validation of the method, which was performed according to ICH guidelines, comprises specificity, accuracy, linearity, precision, sensitivity and robustness. In addition, the results of an actual tablet sample analysis obtained by this CE method were statistically shown to be in close agreement with those obtained by an ion chromatographic method. The main advantages of this CE method were the shorter analysis time and that there was no requirement for background subtraction compared to the ion chromatography method. 4.4.2 High-performance liquid chromatography An important step during the development of high-performance liquid chromatography (HPLC) methods for quantitative analysis of drugs is choosing the appropriate detector. High sensitivity, reproducibility, stability, wide linear range, compatibility with gradient elution, non-destructive detection of the analyte and response unaffected by changes in the temperature/flow rate are some of the ideal characteristics of a universal HPLC detector. Because of the lack of chromophoric moieties on topiramate structure, Pinto et al. reported a variety of methods, with different detection techniques, which have been developed for the analysis of topiramate drug

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substance and formulations [22]. Those methods included derivatization with fluorescent moieties and UV-absorbing moieties, conductivity detection, evaporative light scattering detection, refractive index detection, chemiluminescent nitrogen detection and MS detection. Description of some of the analytical methods presented in the literature to analyze topiramate in the drug substance and in pharmaceutical formulations is presented below. 4.4.2.1 HPLC coupled with refractive index (RI) detector

Duong et al. developed a method in which a differential refractometer detector was used to analyze topiramate sprinkle capsule formulations [23]. The focus of the method was to evaluate the integrity of the polymeric outer coat of the formulation and to indirectly determine the extent of taste masking. The authors determined the content of topiramate after a washout procedure of the sprinkle formulation, which consisted of several steps of dipping the formulation into a specific basket of water and then analyzing the final solution. The integrity of the coating was directly related to the topiramate content. If the coating of the formulation was satisfactory, very low levels of topiramate would be observed. The method was validated and considered precise, linear over the range 3–60 μg/mL, and accurate. The authors applied the method to select the optimal coating conditions. Three formulations containing different amounts of polymeric coating (9%, 11% and 13%) were evaluated, and the integrity of the coating was indirectly determined by evaluating the topiramate content after the coating process. The method was able to differentiate between different coating levels, in which the higher level of coating resulted in a lower level of topiramate detected. The authors stated that 11% coating level of the polymeric coat was appropriate to taste masking. The method was also used to support the encapsulation of the formulation because the encapsulation process can cause fractures or breakage in the beads; therefore, the method was applied after coating and then again after the encapsulation. The resulting data were used to optimize the settings on the encapsulation equipment. The authors concluded that the developed method can be used during the formulation development in order to optimize the coating level and also to support the encapsulation effect of the formulation. In another study using HPLC with RI detection, Biro and co-workers presented three different methods to determine the levels of topiramate and its impurities using HPLC with RI detection [24]. In method 1, the authors used isocratic elution to separate and quantify topiramate and impurity 1 (2,3:4,5-bis-O-(1-methylethylidene)-β-D-fructopyranose). This method

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was not able to separate the most polar impurity 2 (2,3-O-(1methylethylidene)-β-D-fructopyranose sulfamic acid), which was eluted with the solvent peak, nor impurity 4 (N-{[2,3:4,5-bis-O-(1-methylethylidene)β-fructopyranosyl] oxycarbonyl}-2,3:4,5-bis-O-(1-methylethylidene)-β-Dfructopyranose sulfamic acid), which was co-eluted with impurity 3 (2,3-O-(1-methylethylidene)-β-D-fructopyranose sulfamic acid) and other unknown impurities. Method 2 combined RI and UV detection with gradient elution to separate impurities 2, 3 and 4. In this method, impurity 2 (2,3-O-(1-methylethylidene)-β-D-fructopyranose sulfamic acid) was separated from the solvent peak and impurity 1 (2,3:4,5-bis-O(1-methylethylidene)-β-D-fructopyranose) in the isocratic part of the run, whereas impurities 3 (2,3-O-(1-methylethylidene)-β-D-fructopyranose sulfamic acid) and 4 (N-{[2,3:4,5-bis-O-(1-methylethylidene)-β-Dfructopyranosyl] oxycarbonyl}-2,3:4,5-bis-O-(1-methylethylidene)-βD-fructopyranose sulfamic acid) were eluted at a higher concentration of the organic modifiers. The authors did not determine the amount of impurity 1 using method 2, and topiramate was not seen in the chromatogram because it was eluted during the gradient elution part of the run in which RI detection was not possible. Method 3 consisted of anion exchange chromatography coupled simultaneously with UV and inverse RI detection to analyze the inorganic impurities sulfate and sulfamate. The chromatographic conditions were the same as described in the United States Pharmacopeia except for the detector. 4.4.2.2 HPLC with UV and fluorescence detection

A sensitive and simple high-performance liquid chromatographic method for analysis of topiramate, an antiepileptic agent, using 4-chloro-7nitrobenzofurazan (NBD-Cl) as pre-column derivatization agent, using a fluorescent detector was described by Bahrami and Mohammadi [25]. Following liquid-liquid extraction of topiramate and an internal standard (amlodipine) from human serum, derivatization of the drugs was performed by the labeling agent in the presence of dichloromethane, methanol, acetonitrile and borate buffer (0.05 M; pH 10.6). A mixture of sodium phosphate buffer (0.05 M; pH 2.4): methanol (35:65, v/v) was eluted as mobile phase and chromatographic separation was achieved using a Shimpack CLC-C18 (150  4.6 mm) column. In this method the limit of quantification of 0.01 μg/mL was obtained and the procedure was validated over the concentration range of 0.01–12.8 μg/mL. No interferences were found from commonly co-administrated antiepileptic drugs including phenytoin, phenobarbital, carbamazepine, lamotrigine,

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zonisamide, primidone, gabapentin, vigabatrin, and ethosuximide. The analysis performance was carried-out in terms of specificity, sensitivity, linearity, precision, accuracy and stability, and the method was shown to be accurate, with intra-day and inter-day accuracy from 3.4% to 10% and precise, with intra-day and inter-day precision from 1.1% to 18%. In another approach, the authors of the previous study developed a sensitive and specific high-performance liquid chromatographic method for quantitation of topiramate in human serum using 9-fluorenylmethyl chloroformate (FMOC-Cl) as fluorescence labeling reagent [26]. Topiramate was extracted from human serum by dichloromethane and derivatized by reaction with (FMOC-Cl) in the presence of borate buffer. Analysis was performed on a CN column with sodium phosphate buffer (pH 2.2) (containing 1 mL/L of trimethylamine) and methanol (52:48, v/v) as mobile phase. Amantadine was used as internal standard. The standard curve was linear over the range 20–5000 ng/mL of topiramate in human serum. The mean intra-day precision was from 10.5% (low concentration) to 1.2% (high concentration) and the within-day precision from 1.5% to 12.5% determined on spiked samples. The accuracy of the method was 96.5–107.5% (intra-day) and 98.4–105% (inter-day). The limit of quantification was 20 ng/mL of serum. This method was used in a bioequivalence study after administration of 2  25 mg topiramate in 24 healthy volunteers. In a third study, the same authors described a method which was designed to validate derivatization and analysis of topiramate in human serum with HPLC using UV detection [27]. The drug was extracted from human serum by liquid-liquid extraction (LLE) and subjected to derivatization with 9-fluorenylmethyl chloroformate. Analysis was performed on a phenyl column using a UV detector operated at the wavelength of 264 nm. A mixture of phosphate buffer (0.05 M) containing triethylamine (1 mL/L, pH 2.3) and methanol (28:72, v/v) at a flow rate of 2.5 mL/min was used as the mobile phase. No interference was found from the endogenous substances. Validity of the method was studied and it was found to be precise and accurate with a linearity range from 40 ng/mL to 40 μg/mL. The limit of quantification (LOQ) was 40 ng/mL of serum. The correlation coefficient between HPLC methods using fluorescence and UV detections was studied and found to be 0.992. The LOQ in this third method which was around 40 ng/mL, was twofold higher than the fluorescence detection method using FMOC-Cl. Nevertheless, it is still a sensitive method that has the advantage of being carried out using the most common detector available in laboratories for research and clinical analysis.

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Mohammadi et al. developed and validated a stability-indicating highperformance liquid chromatographic (HPLC) method for the quantitation and dissolution determination of topiramate in tablet dosage forms [28]. An isocratic separation was achieved using a phenyl column with a flow rate of 1 mL/min using UV detection at 264 nm. Topiramate has low UV absorbtivity and was subjected to derivatization with 9-fluorenylmethyl chloroformate (FMOC-Cl). The mobile phase for the separation consisted of acetonitrile: 50 mM sodium dihydrogen phosphate (NaH2PO4) containing 3% (v/v) triethylamine (pH 2.8) in a 48:52 (v/v) ratio. Topiramate was subjected to oxidation, hydrolysis, photolysis and heat for the purposes of stress testing. Separation was achieved for the parent compound and the degradation products in an overall analytical run time of approximately 15 min with the parent compound topiramate eluting at approximately 9.2 min. The method was linear over the concentration range of 1–100 μg/mL (r ¼ 0.9996) with limits of quantitation and detection of 1 and 0.3 μg/mL, respectively. In a similar way, a HPLC method for determination of topiramate in pharmaceutical formulations and in vitro dissolution studies, which avoids the use of RID detector was described by Majnooni and co-authors [29]. The method was based on derivatization of topiramate and an internal standard by reaction with 4-chloro-7-nitrobenzofurazan (NBD-CL), and reverse-phase chromatography using phenyl column and spectrophotometer detection at 264 nm. A mixture of phosphate buffer (0.05 M) containing triethylamine (0.1% (v/v), pH 2.3) and methanol (28:72, v/v) at a flow rate of 2.2 mL/min was used as mobile phase. The analysis performance was studied and the method was shown to be selective and linear for determination of topiramate in pharmaceutical formulations and dissolution studies. Li and Rossi developed a method to determine the sulfate and sulfamate contents in the drug substance and tablets by using an ion exchange chromatographic method with indirect UV detection [30]. The authors applied the method to stability studies of topiramate drug substance and tablets. The mobile phase consisted in a mixture of p-hydroxybenzoic acid (used as the chromophore) and methanol. The method was linear within the range 0.25–18.8 mol% for sulfate and 0.25–6.3 mol% for sulfamate. The recovery was determined for the degradation study, and it was related to the temperature and time the samples were submitted to degradation conditions. The recovery for samples at 70 °C was 96.6–98.3%.

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4.4.2.3 HPLC coupled with conductivity detector

A method using conductivity detection and an anion exchange column to determine sulfate and sulfamate in raw material and topiramate tablets was described by Kornfeld et al. [31]. These workers used an anion suppressor between the analytical column and the conductivity detector to reduce hydroxide conductivity interference from the mobile phase. Sulfate and sulfamate were separated using isocratic elution; however, in order to separate sulfamate from the tablet excipients, a gradient elution was required. It was observed that modifications in the initial mobile phase composition changed sulfamate retention. This method was better than the previous method in which an indirect UV detection was used [30], because the method with conductivity detection was able to separate sulfamate from topiramate excipients via gradient elution. In addition, this method was more precise and provided lower limits of quantification. A hydroxideselective strong anion exchange column containing ethylvinylbenzene, divinylbenzene and alkanol quarternary ammonium moiety as the stationary phase was used. The selectivity of this column was optimized using a hydroxide eluent gradient and an automated potassium hydroxide eluent generator and no organic solvents. Due to the weak retention of sulfamate by this column, a weak potassium hydroxide eluent concentration gradient from 0.5 to 5 mM was initially used to separate this compound from the excipients. The strongly retained sulfate was later separated during the gradient at an eluent composition containing 38 mM potassium hydroxide. The method was accurate and precise and the linear ranges for sulfate and sulfamate were 0.5–10 and 0.1–10 μg/mL, respectively. 4.4.2.4 HPLC coupled with evaporative light scattering detector (HPLC-ELSD)

A chromatographic method with an Evaporative Light Scattering Detector (ELSD) was established by Hong and his co-workers, for the analysis of topiramate and its formulations [32]. The column used was a Waters C18 column (3.9 mm  150 mm; 5 μm particle size). The mobile phase was composed of methanol-water (35:65), the flow rate was at 1.0 mL/min, and the column temperature was 35 °C. The Alltech detector (ELSD 2000D) used in the analysis was equipped with a drift tube maintained at 100 °C, and a gas flow rate of 2.8 L/min. The linearity range was from 0.4 to 2.0 mg/mL, with a correlation coefficient (r) of 0.9983. The mean recovery of topiramate was 100.1%. The method is accurate, rapid and simple. It can be applied to the quality control of topiramate and its formulations.

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A chromatographic method using an Evaporative Light Scattering Detector (ELSD) was also established for the analysis of topiramate drug substance [33]. The authors evaluated five different mobile phase compositions, considering acetonitrile (ACN), methanol, water, and ammonium acetate solution as solvents. The optimized mobile phase was composed of ammonium acetate buffer-ACN (65:35). The method was linear over the range of 0.5–3.0 mg/mL. The main advantage of this method was the fast run time of 8 min, in which the topiramate retention time was 4 min. The authors did not present applications of the ELSD method to topiramate formulations. 4.4.2.5 HPLC coupled with electrospray ionization mass spectrometer (IC/ESI-MS)

An ion-exchange chromatograph/electrospray ionization mass spectrometer (IC/ESI-MS) was successfully used by Xiang et al. to identify organic and inorganic species present in topiramate tablets [34]. The column used was an Ion Pac AS5A column (150 mm  4.0 mm i.d.; 5 μm particles). The mobile phase was composed of water/50 mM sodium hydroxide solution (96/4) eluted at a flow rate of 1 mL/min. An ion suppressor was placed between the column and detectors to replace sodium ions in the mobile phase with hydrogen ions supplied by the suppressor. The ensuing combination of the hydrogen ions with the mobile phase hydroxide ions produces water and thus allows simultaneous ion detection by an ion conductivity detector and a mass spectrometer. Analytes, including lactate, glycolate, chloride, formate, sulfate, and oxalate, were unambiguously identified by matching the mass spectra and retention times with those of the authentic compounds. Due to its capability of detecting positive and negative as well as neutral species, ESI-MS provides valuable information which is not available with ion conductivity detection alone. Though the coupling of ion-exchange chromatography to mass spectrometry has been reported previously, this is the first demonstration of IC/ESI-MS for the identification of unknown species in real samples. Finally, with the use of deuterium/ carbon-13 labeling and MS/MS techniques, the authors have confirmed that oxalic acid (HOOC-COOH) is formed from formic acid (HCOOH) at the electrospray interface in the presence of the electric field. This observation not only confirms the identity of an unknown peak, but it also provides new insight into chemistry that can take place during electrospray ionization. Another rapid tandem mass spectrometric (MS/MS) method for quantification of topiramate in human plasma using topiramate-d12 (a labeled topiramate) as an internal standard (IS) was developed by Matar [35].

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The method was validated over the concentration range of 0.5–30 μg/mL (r > 0.99). Intra- and inter-run precisions of topiramate assay at three concentrations ranged from 0.7% to 7.8% with accuracy (bias) which varied from
10.0% to 2.1% indicating good precision and accuracy. Analytical recoveries of topiramate and IS from spiked human plasma were in the range of 84.1–90.0% and 90.0–111.0%, respectively. In another study, different methods for determination of topiramate in pharmaceutical formulation by high-performance thin-layer chromatography (HPTLC), UV-densitometry and liquid chromatography-mass spectrometry (LC-MS) have been developed by Koba and his co-workers [36]. HPTLC method as recommended by United States Pharmacopeia was performed using the silica plates, mobile phase composed of benzene: ethanol (5:2, v/v) and densitometric detection at 340 nm after topiramate visualization with the use of chemical reagent. Moreover, quantification was achieved in the concentration range of 0.25–4.0 μg/spot and with adequate precision (RSD ¼ 4.16%) and recovery (104.47%) using non-linear calibration curve by fitting to y ¼ a + b ln x. LC-MS method was performed using Zorbax SB-C18 column and isocratic elution mode with a mobile phase composed of acetonitrile:water (85:15, v/v) with 0.1% (v/v) formic acid at a flow rate of 0.5 mL/min. Moreover, the single quadrupole mass spectrometer employing ESI interface operated in the negative ion mode was used to quantify the topiramate at m/z ¼ 338.1. Proposed LC-MS method provided good results of precision (RSD ¼ 2.05%) and recovery (99.53%) in the concentration range of 0.25–10.0 μg/mL using linear y ¼ a + bx regression analysis. Additionally, no interferences were found from tablet excipients at the selected wavelength, mass-to-charge ratio and assay procedures. The developed methods found to be sufficiently precise and reproducible. A simple and fast method for the determination of topiramate in human plasma by high-performance liquid chromatography coupled with turbo ion spray mass spectrometry was presented by Contin and others [37]. Plasma sample pre-treatment was based on simple deproteinization by acetonitrile. Liquid chromatographic analysis was carried out on a reversed-phase column (C18, 125  4 mm i.d., 5 μm particles) using acetonitrile-ammonium acetate buffer (pH 6.3) as the mobile phase, at a flow rate of 0.8 mL/min. The retention time for topiramate was 2.1 min. The detector was a single quadrupole mass spectrometer coupled to a turbo ion spray ion source and a heated nebulizer probe, operating in the positive ion mode. Ion source temperature was off; voltage was +5800 V; nebulizer and curtain gas flow

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rates were 6 and 10 mL/min, respectively. Calibration curves for topiramate were linear over the range 1–20 μg/mL. Absolute recovery ranged between 92% and 95%. Intra- and inter-assay precision was <4%. The present procedure, omitting extraction and drying steps, seems to be faster and simpler than the previously reported analytical methods for topiramate and was demonstrated to possess adequate sensitivity for routine therapeutic drug monitoring in plasma from patients with epilepsy. In a different study Mohammadi et al. investigated the applicability of LC-MS/MS to optimize derivatization of topiramate with FMOC-Cl using reacted/intact drug ratio [38]. The authors re-optimized the method conditions using LC-MS/MS technique on the basis of reacted/free topiramate ratio as the new and more accurate index. In this new method, the authors optimized several factors including time and temperature of the reaction, pH and concentration of the used buffer, ratio of organic phase in the medium and removal of the excess reagent by glycine in order to obtain maximum yield of the product. In an earlier method in which FMOC-Cl was also used as derivitizing agent [26], there was no signal from intact topiramate and only the final product (FMOC-topiramate) appeared. Thus to optimize the reaction conditions for obtaining the highest derived yield, intensity of the final product peak was considered as a criteria for progression of the reaction. In LC-MS/MS system, however, both free and reacted topiramate were visible in the observed spectra. The results showed that, ratio of organic/aqueous phase had a dominant effect on the reaction, the most efficient temperature was 70 °C and the reaction was reversed following addition of the glycine. 4.4.2.6 HPLC with chemiluminescent nitrogen detection (CLND)

Styslo-Zalasik and Li [39] developed a HPLC method using the CLND to evaluate a liquid oral solution of topiramate. The authors stated that the RI detection method was not appropriate to evaluate a liquid oral solution of topiramate because this kind of formulation contains a large amount of water-soluble excipients that might co-elute with topiramate. They initially evaluated the viability of using capillary GC with flame ionization detection (FID); however, they indicated that this technique was not promising due to thermal instability observed for topiramate. Another approach evaluated by the authors was a reverse-phase HPLC method with light scattering detection, but the method was only suitable to analyze the drug substance. The detection of low levels of degradation products was not achieved. Impurity which contains NH2 moiety, was the only impurity selected to be monitored in the CLND method because it contains nitrogen. In addition,

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topiramate may have different degradation products in solution formulations compared with solid dosage forms. The method development was focused mainly on optimizing detector parameters. The final conditions were pyrolysis furnace 1050 °C, dryer membrane 85 °C and flow rates for oxygen, argon, make up and ozone were 250, 150, 50 and 25 cm3/min, respectively. The method showed a validated linearity range of 32–4800 ng of topiramate and excellent precision (system repeatability). The limit of quantitation was determined to be 0.1% (w/w) for the topiramate degradation product. 4.4.3 High-performance thin-layer chromatography (HPTLC) An economic and rapid high-performance thin-layer chromatographic (HPTLC) method was developed and validated by Parmar and co-workers [40], for the quantitative determination of topiramate in plasma, brain homogenate and pharmaceutical formulation. The simple extraction method was used for the isolation of topiramate from formulation, plasma and brain homogenate samples. HPTLC separation was achieved on an aluminumbacked layer of silica gel 60F254 plates using toluene:acetone (5.0:2.0, v/v) as mobile phase. Spots of developed plates were visualized by spraying of reagent [3.0% phenol in the mixture of ethanol:sulfuric acid (95:5, v/v)]. Quantitation was achieved by densitometric analysis at 340 nm over the concentration range of 1000–5000 ng/spot. The method was found to give compact spot for the drug (Rf: 0.61  0.018). The regression analysis data for the calibration plots showed good relationship with a correlation coefficient of 0.9983. The minimum detectable amount was found to be 165 ng/spot, whereas the limit of quantitation was found to be 500 ng/spot. Statistical analysis of the data showed that the method is precise, accurate, reproducible and selective for the analysis of topiramate. The developed method was successfully employed for the estimation of topiramate in samples of equilibrium solubility study, diffusion study, microemulsion formulation and suspension formulation (developed in-house), rat plasma and rat brain homogenate samples. 4.4.4 Gas chromatography (GC) method An accurate and robust method involving liquid-liquid extraction and capillary gas chromatographic (GC) assay with nitrogen phosphorus detection (NPD) was developed and validated for the quantitative determination of topiramate in human plasma, urine, and whole blood [41]. The galactopyranose analog of topiramate was used as the internal standard. A DB-5, fused silica capillary column (J&W Scientific, Folsom, CA) was used, yielding typical retention

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times of 4.95 min for topiramate and 5.32 min for the internal standard in human plasma. The assay involved organic extraction with methyl t-butyl ether (MTBE) from base, a back extraction into acid and a second extraction in MTBE. The organic solvent was evaporated, and the residue was redissolved and injected for analysis. The standard curve was validated from 0.5 to 50 μg/mL for human plasma and whole blood, and from 1.0 to 50 μg/mL for urine. Peak area ratios of drug to internal standard were determined and used to construct a standard curve. The resulting chromatograms showed no endogenous interfering peaks with the respective blank human fluids. Chromatograms corresponding to topiramate and the internal standard produced sharp peaks that were well resolved. This assay showed good accuracy with a precision of 5%. Two minor human metabolites of topiramate did not interfere with the assay. This assay was successfully applied to determine the pharmacokinetics of topiramate during the development of this drug.

4.5 Thermal behavior of topiramate The thermal behavior of some sulfone-containing drugs, namely, dapsone (DDS), dimethyl sulfone (MSM), and topiramate (TOP) in drug substances, and products were investigated by Salama et al. [42], using different thermal techniques. These included thermogravimetry (TGA), derivative thermogravimetry (DTG), differential thermal analysis (DTA), and differential scanning calorimetry (DSC). The thermogravimetric data allowed the determination of the kinetic parameters: activation energy (Ea), frequency factor (A), and reaction order (n). The thermal degradation of dapsone and topiramate was followed a first-order kinetic behavior. The calculated data evidenced a zero-order kinetic for dimethyl sulfone. The relative thermal stabilities of the studied drugs have been evaluated and followed the order DDS > TOP > MSM. The purity was determined using DSC for the studied compounds, in drug substances and products. The results were in agreement with the recommended pharmacopeia and manufacturer methods. DSC curves obtained from the tablets suggest compatibility between the drugs, excipients and/or co-formulated drugs. The fragmentation pathway of dapsone with mass spectrometry was taken as example, to correlate the thermal decomposition with the resulted MS-EI. The decomposition modes were investigated, and the possible fragmentation pathways were suggested by mass spectrometry.

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5. Pharmacokinetics, metabolism, and excretion 5.1 Pharmacokinetics Topiramate is well absorbed from the gastrointestinal tract, with peak plasma levels being usually attained in 2–3 h. The drug is negligibly (9–17%) bound to plasma proteins and is eliminated partly by renal excretion in unchanged form and partly by oxidation and hydrolysis. In healthy volunteers, the halflife is about 20–30 h, but elimination rate is accelerated in patients taking concomitant enzyme-inducing drugs such as phenytoin, carbamazepine and barbiturates. Topiramate has no major effects on plasma levels of concurrent anticonvulsants, except for a rise in plasma phenytoin in occasional patients. In double-blind add-on trials in refractory partial epilepsy, a significant reduction in seizure frequency has been demonstrated in over 40% of topiramatetreated patients (vs about 10% of those treated with placebo), a response rate which compares favorably with that observed with other new antiepileptic drugs. Dosages found to be effective in add-on controlled trials ranged between 200 and 1000 mg/day, although most patients were likely to benefit from receiving 400 mg/day or less [43]. Topiramate has a favorable pharmacokinetic profile with rapid absorption, good bioavailability. The bioavailability exceeds 80% following an oral dose and is not significantly affected by food. Linear pharmacokinetics was noted, along with a relatively long halflife and limited pharmacokinetic drug interactions. Concomitant ingestion of food delays the time required to reach peak plasma topiramate levels by about 2 h, but the extent of absorption is not significantly altered. In practice, topiramate can be administered regardless to meal time. It distributes into all tissues, including the brain [44–46]. However, topiramate can reduce the estrogen component of oral contraceptive medications [47].

5.2 Metabolism Topiramate is not extensively metabolized and is primarily eliminated unchanged in the urine (approximately 70% of an administered dose). Six metabolites have been identified in humans, none of which constitutes >5% of an administered dose. The metabolites are formed via hydroxylation, hydrolysis, and glucuronidation [48–50].

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5.3 Excretion In healthy volunteers and when used as a monotherapy, 55–66% of the administered dose of topiramate is excreted unchanged in urine. This indicates that urinary excretion is a major route of elimination. Its half-life is 20–30 h. Elimination is faster in patients receiving concurrent medication with enzyme-inducing anticonvulsants, in whom the extent of biotransformation becomes more prominent. Under such conditions the topiramate pharmacokinetics differ significantly from those during topiramate monotherapy and the fraction of the dose excreted unchanged in urine falls to 30% This suggests that metabolic clearance of topiramate increases when enzyme-inducing anticonvulsants such as phenytoin, barbiturates or carbamazepine are co-administered with topiramate [51]. In addition, a study was conducted to identify the factors influencing topiramate pharmacokinetics in a large population of adult patients with epilepsy using population pharmacokinetic analysis [52]. Demographic and clinical variables tested as potential covariates were age, sex, body weight, height, serum creatinine, creatinine clearance (CLcr), total bilirubin, prothrombin time, albumin, aspartate transaminase (AST), alanine transaminase (ALT), daily dose and concomitant medications with phenytoin(PHT), clobazam, carbamazepine(CBZ), valproic acid, lamotrigine, levetiracetam, oxcarbazepine (OXC), pregabalin, clonazepam, and phenobarbital (PB). The apparent clearance of topiramate increased with co-medication of PHT, CBZ, OXC, and PB. This population pharmacokinetic model can be applied for optimizing topiramate dosage regimens in actual clinical practice. In separate studies, potential pharmacokinetic interactions of topiramate (TPM) with phenytoin (PHT), carbamazepine (CBZ), and valproate (VPA) were evaluated by Bourgeois [53]. TPM was added to the baseline antiepileptic drug (AED) at a dosage of up to 800 mg day
1, after which the baseline drug was discontinued, when possible. Addition of TPM produced no change in plasma levels of CBZ or CBZ epoxide (CBZ-E). Modest increases in PHT plasma levels in 6 of 12 patients treated with PHT and TPM, and a small mean decrease in VPA levels noted in patients receiving VPA with TPM, was considered unlikely to require adjustments in the dosage of the concomitant AED when TPM is added or discontinued. When patients were changed from concomitant therapy with PHT or CBZ to TPM monotherapy, TPM clearance was reduced by approximately 50%, suggesting that an adjustment in TPM dose may be required when PHT

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or CBZ is discontinued from TPM-treated patients. A slight increase in plasma TPM levels during monotherapy compared to concomitant therapy with VPA was considered clinically insignificant and not likely to require TPM dosage adjustment. In another study, oral clearance of digoxin was slightly increased when TPM was added, resulting in a small decrease in peak plasma levels of digoxin. In vitro studies conducted on a number of specific cytochrome P450 isoforms showed an effect of TPM only on the CYP2Cmeph isoform. The risk for clinically meaningful changes in plasma levels of traditional AEDs when TPM was added to or discontinued from concomitant regimens appeared to be minimal. However, adjustments in TPM dosages are likely to be needed when potent enzyme inducers, such as PHT or CBZ, are added or discontinued. Chronic renal and hepatic impairment can affect the clearance of topiramate. Therefore, it is necessary to establish dosage guidelines for topiramate in chronic renal impairment, end-stage renal disease (ESRD) undergoing hemodialysis, or chronic hepatic impairment patients. In those patients the elimination half-life is longer. The dose of topiramate may have to be reduced and usually half of the dose is recommended for moderate-severe renal impairment and ESRD. Supplemental dose may be required during hemodialysis. Dose adjustments might not be required in moderate-severe hepatic impairments [54].

6. Pharmacology Topiramate, a sulfamate-substituted monosaccharide, was licensed in the United Kingdom in 1995 as adjunctive therapy in patients with intractable partial epilepsy [55]. Clinical evidence suggests that topiramate is a potent antiepileptic drug with a broad spectrum of activity and corroborates the significant efficacy observed in predictive animal models of epilepsy, i.e., maximal electroshock, intravenous pentylenetetrazole, genetic (spontaneous epileptic rat and DBA/2 mouse) and amygdala kindling models. Pharmacological evidence indicates that topiramate may act via several mechanisms including: modulation of voltage-dependent sodium channels, potentiation of gamma-aminobutyric acid (GABA) inhibition, block of excitatory neurotransmission, and possibly modulation of voltage- and receptor-gated calcium ion channels. Topiramate not only prevents seizure spread but it also elevates seizure threshold. Carbonic anhydrase inhibiting properties have also been demonstrated but they are not considered to be relevant to

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anticonvulsant activity. This combination of pharmacological properties is unique among currently available antiepileptic drugs and may explain why topiramate is effective in both partial and generalized seizures, and why it is proving efficacious in numerous intractable syndromic epilepsies. This indicates that topiramate (TPM) has multiple probable sites of action, including sodium channels, GABA receptors, and glutamate (AMPA) [56]. Brandes et al. conducted a study to assess the efficacy and safety of topiramate for migraine prevention [57]. A 26-week, randomized, doubleblind, placebo-controlled study was conducted during outpatient treatment at 52 North American clinical centers. Patients were aged 12–65 years and had a 6-month history of migraine (International Headache Society criteria) and 3–12 migraines a month but no >15 headache days a month during a 28-day prospective baseline phase. After a washout period, patients meeting entry criteria were randomized to topiramate (50, 100, or 200 mg/day) or placebo. Topiramate was titrated by 25 mg/week for 8 weeks to the assigned or maximum tolerated dose, whichever was less. Patients continued receiving that dose for 18 weeks. Topiramate was found to have significant efficacy in migraine prevention within the first month of treatment, an effect maintained for the duration of the double-blind phase. In another study Silberstein established the efficacy of topiramate in migraine prevention (prophylaxis) in two multicenter, randomized, doubleblind, placebo-controlled, pivotal trials [58]. Topiramate has received regulatory approval for use in adults for migraine prophylaxis (prevention) in the United States and numerous other countries, including France, Ireland, Switzerland, Brazil, Taiwan, Spain, and Australia. Treatment with 100 or 200 mg/day of topiramate was associated with significant reductions in the frequency of migraine headaches, number of migraine days, and use of acute medications. No increase in efficacy was observed between 100 and 200mg/day of topiramate. Based on efficacy and tolerability, 100 mg/day of topiramate should be the initial target dose for most patients. The most common adverse events were paresthesia, fatigue, decreased appetite, nausea, diarrhea, weight decrease, and taste perversion. Topiramate is a first-line migraine preventive drug and should especially be considered as a preferred treatment for all patients who are concerned about gaining weight, who are currently overweight, or who have coexisting epilepsy. Ferrari et al. [59] explained that topiramate was approved for the prophylaxis of migraine where it should act as a neuromodulator. They added that topiramate is an important option for the prophylaxis of migraine and is of proven efficacy and tolerability. It has also been studied in chronic migraine

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with encouraging results, even in patients with medication overuse. However, in migraine prevention its efficacy is comparable to the other first-line drugs. Mathew and Kilcoyne [60] mentioned that topiramate could be used in the pediatric population for the management of Lenox-Gastaut syndrome, also as pain medicine for the management of chronic migraine prophylaxis and in treatment of neuropathic pain of diabetic neuropathy, migraines, and cluster headache therapy. In a study dealing with Anti-Epileptic Drugs and Hormonal Treatments, Johnston and Crawford [61] mentioned that contraceptive failure occurs with the use of antiepileptic drugs (AEDs) through induction of hepatic P450 microsomal enzyme. Many of the older generation of AEDs cause enzyme induction (barbiturates, phenytoin, and carbamazepine), whereas some of the newer AEDs tend not to. They added that there is evidence that topiramate and perampanel are less potent inducers and may interact with the oral contraceptive (OC) in a dose-dependent manner. Simeone et al. [62] demonstrated that activation of Cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA) prevents inhibition of non-N-methyl-D-aspartate (NMDA) glutamate receptors by the anticonvulsant topiramate. Using two-electrode voltage-clamp techniques, they demonstrated that PKA activity also modulates topiramate potentiation of recombinant GABA(A) receptors expressed in Xenopus laevis oocytes. PKA activators, dibutyryl-cAMP and forskolin, attenuate topiramate potentiation, whereas the PKA inhibitor H-89 increases topiramate potentiation. Thus, endogenous PKA activity and receptor phosphorylation states may contribute to topiramate treatment efficacy. Scozzafava et al. [63] stated that the discovery of the clinically used anticonvulsants topiramate (TPM) and zonisamide (ZNS) induced weight loss in obese, epileptic patients, afforded the validation of the mitochondrial carbonic anhydrases as targets for the development of antiobesity drugs. Actually TPM is already approved for this therapy. Such compounds are the lead molecules in this field and an intense research is on the way in order to develop new compounds based on the selective inhibition of mitochondrial CA isoforms. Supuran [64] explained that topiramate, which is used as an antiepileptic drug possessing potent anticonvulsant effects due to a multifactorial mechanism of action, was also observed to have a side effect on obese patients causing loss of body weight, although no pharmacological explanation of this phenomenon has been provided.

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Cerminara and co-authors [65] reported that topiramate does not seem to be associated with serious adverse effects and is also well tolerated in pediatric patients. Only few cases of hypohidrosis have been described. The authors presented one young patient with complex partial seizures who was medicated with topiramate when she developed fatigue, headache, intermittent hyperthermia, inability to produce sweat secretion, and dryness of the skin. Reduced sweat response was determined using the Wescor Macroduct collection procedure. Topiramate was discontinued, and within 3 weeks a repeat sweat test was completely normal. At that time, clinical signs had also disappeared. Hypohidrosis is an uncommon and reversible side effect reported in association with topiramate therapy. It is rare in patients on monotherapy. This side effect might be attributed to an autonomic dysfunction by inhibition of isoenzymes of carbonic anhydrase localized in human eccrine sweat glands. Other common adverse effects of topiramate are CNSrelated and include dizziness, fatigue, visual disturbances, ataxia, mental slowing and impaired concentration. Paresthesias, anorexia, weight loss and increased risk of nephrolithiasis have been also reported. Many of these effects are related to dose and/or to rate of dose titration.

7. Stability Exposure to moisture and heat leads to degradation of topiramate in its solid dosage forms. Topiramate in particular is very sensitive to water (i.e., humidity). Upon contact with humidity, topiramate degradation is accelerated because the degradation products have a catalytic effect on the degradation process itself. Degradation of topiramate tablets is readily detected by changes in physical appearance (discoloration of tablet color to brown or black) and by the formation of sulfate ions and organic degradation compounds, which can be readily detected by standard techniques. Topiramate should therefore be well protected from moisture [66].

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