National Institute for Pharmaceutical Technology and Education (NIPTE) Stability Group - Solid Form...

National Institute for Pharmaceutical Technology and Education

(NIPTE)

Stability Group - Solid Form Characterization

Eric Munson

Outline

• Samples of Gabapentin Analyzed

• Gabapentin - multiple forms

• Gabapentin monohydrate/desolvate

• Interconversion of forms upon analysis

• Identification - Form III in milled samples

• Gabapentin Lactam (primary degradation product)

Gabapentin as Received - SSNMR

O

OH

NH2

12

3

456

7

8 9

3

4

2

7(6,8)

(5,9)

Not shown: Carbon 1 at 179.5 ppm

Tentative NMR Assignments

Gabapentin as Received - SSNMR

1H T1 = 134 s

SSNMR of Gabapentin Forms

SSNMR of Gabapentin Forms - Effects of Recrystallization


5 10 15 20 25 30 35

Theta(deg)

x103

50

100

150

200

[Lot_A_UI-a2009-01-21 02.32.51PM.MDI] Lot_A_UI-a, SCAN: 5.0/39.992/0.048/1(sec), Cu, I(max)=44709, 01/21/09 02:46p[Lot_B_UI-a2009-01-21 02.50.49PM.MDI] Lot_B_UI-a, SCAN: 5.0/39.992/0.048/1(sec), Cu, I(max)=35959, 01/21/09 03:04p[Lot_C_UI-a2009-01-21 03.08.55PM.MDI] Lot_C_UI-a, SCAN: 5.0/39.992/0.048/1(sec), Cu, I(max)=110442, 01/21/09 03:22p

Lot B

Lot D

Lot A

Lot C

Inte

nsi

ty (

arb

itra

ry u

nit

s)

Two-Theta (deg)


5 10 15 20 25 30 35

Theta(deg)

0

2500

5000

7500

[Lot_A_UI-a2009-01-21 02.32.51PM.MDI] Lot_A_UI-a, SCAN: 5.0/39.992/0.048/1(sec), Cu, I(max)=44709, 01/21/09 02:46p[Lot_B_UI-a2009-01-21 02.50.49PM.MDI] Lot_B_UI-a, SCAN: 5.0/39.992/0.048/1(sec), Cu, I(max)=35959, 01/21/09 03:04p[Lot_C_UI-a2009-01-21 03.08.55PM.MDI] Lot_C_UI-a, SCAN: 5.0/39.992/0.048/1(sec), Cu, I(max)=110442, 01/21/09 03:22p

Lot B

Lot D

Lot A

Lot C

Inte

nsi

ty (

arb

itra

ry u

nit

s)

Two-Theta (deg)


Lot A, 20x Lot B, 20x

Lot C, 10x Lot D, 20x

SSNMR of Gabapentin Forms

SSNMR of Gabapentin Forms - Monohydrate

SSNMR of Gabapentin Forms - Milled Samples

Particles of bulk lactose monohydrate before processing

Lactose monohydrate cryoground for 60 minutes

120 100 80 40ppm

60 120 100 80 40ppm

60

Crystalline

Crystalline

Amorphous

Effect of Grinding on Forms

Bulk crystalline1H T1 = 243 s

Tablets1H T1 = 79 s

Spray-dried1H T1 = 4.1 s

120 100 80 40ppm

Lyophilized1H T1 = 3.8 s

60

O

OH

OH

H

HO

HH

HO

H

OH

O

OH

OH

H

HH

OHH

HO

H

Lubach, J. W.; Xu, D.; Segmuller, B. E., Munson, E. J. In Press J. Pharm. Sci. 2006.

Lactose 1H T1 Relaxation Data - SSNMR

Lubach, J. W.; Xu, D.; Segmuller, B. E., Munson, E. J. In Press J. Pharm. Sci. 2006.

Lactose 1H T1 Relaxation Data - SSNMR

Gabapentin Relaxation Times

Sample 1H T1

Gabapentin API (Form II) 134 s

122008-UI-SDD-1 (Lot A, Form III) 63 s

010909-UI-ZXZ-1 (Lot B) 128 s

122008-UI-SDD-2 (Lot C) 110 s

010909-UI-ZXZ-2 (Lot A) 131 s

031709-1-UI-SDD (15 min milling) 11.7 s




03009-KU-DBH (10 min cryogrinding) 7.3 s

Stability - High, Medium, Low

Degradation of Gabapentin Forms - Milled Samples

Gabapentin Relaxation Times

Sample 1H T1Initial

LactamAfter

Stability

GBN-MH-081309-UM-AMK-A 348 s 0.000 0.000

082909-1-UI-ZXZ (unmilled, no heat, no moisture) 134 s 0.000 0.000

082909-2-UI-ZXZ (milled, no heat, no moisture) 41 s 0.048 0.109

082909-3-UI-ZXZ (milled, heat, no moisture) 61 s 0.098 0.134

082909-4-UI-ZXZ (milled, heat, moisture) 63 s 0.051 0.060

082909-5-UI-ZXZ (HPC, unmilled) 130 s 0.003 0.011

082909-6-UI-ZXZ (HPC, milled, no heat, no moisture) 11 s 0.110 0.464

082909-7-UI-ZXZ (HPC, milled, heat, no moisture) 14 s 0.453 0.467

082909-8-UI-ZXZ (HPC, milled, heat, moisture) 11 s 0.088 0.119

Degradation of Gabapentin Forms - Milled Samples

Summary

National Institute for Pharmaceutical Technology and Education (NIPTE) Stability Group - Solid Form...

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