Post on 18-Jan-2016
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
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)
SSNMR of Gabapentin Forms - Effects of Recrystallization
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)
SSNMR of Gabapentin Forms - Effects of Recrystallization
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
SSNMR of Gabapentin Forms - Milled Samples
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
031709-2-UI-SDD (30 min milling) 14.4 s
031709-3-UI-SDD (45 min milling) 11.2 s
031709-4-UI-SDD (60 min milling) 23.6 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