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NIPTE Project Report
Adi Kaushal and Raj Suryanarayanan
University of Minnesota
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2
Outline
• Inter-conversion of the physical forms
• Wet massing – physical transformation
• Isomorphic desolvate - challenges with detection
Variable temperature XRD
• Wet massing followed by drying
• Implications on product characterization
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Form II and I Inter-conversion
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Negligible uptake of water by GBN form II (commercial sample) over a range of
RH (0 to 90 to 0 % RH in 10 % RH steps; 3 hrs at each RH)
Transformation of form II to form I not likely during handling at ambient RH
0
20
40
60
80
100
Sa
mpl
e S
enso
r R
H (
%)
100.0
100.2
100.4
100.6
100.8
101.0
Wei
ght (
%)
0 500 1000 1500 2000 2500 3000 3500 4000
Time (min)
Sample: GBN-profile-aSize: 12.3010 mgMethod: DCPD ramp
TGAFile: C:...\NIPTE\112408\GBN-profile-a.001Operator: adiRun Date: 2008-11-24 13:18Instrument: TGA Q5000 V3.5 Build 252
Universal V4.1D TA Instruments
Water Sorption (Form II)
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5
5 10 15 20 25 30 35
Two-Theta (deg)
x103
2.0
4.0
6.0
8.0
10.0In
tens
ity(C
ount
s)(1) [GBN-a2008-11-24 03.30.10PM.MDI] GBN-a, SCAN: 5.0/39.992/0.048/1(sec), Cu, I(max)=7031, 11/24/08 03:43p(2) [GBN-in water-a2008-12-04 06.12.12PM.MDI] GBN-in water-a, SCAN: 5.0/39.992/0.048/1(sec), Cu, I(max)=18280, 12/04/08 06:25p
Solid in contact with saturated aqueous solution – form I
GBN ‘as is’- form II
Inte
nsi
ty (
arb
itra
ry u
nit
s)
2 (deg)
Contact with Water
Solid in contact with saturated solution:
Instantaneous transformation of form II to form I – Implications on wet granulation
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Wet massing - granulation
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5 10 15 20 25 30
Two-Theta (deg)
x103
5.0
10.0
15.0
20.0
25.0
30.0
35.0
Inte
nsi
ty(C
ou
nts
)(1) [GBN-FIIgr-w-water-1g-250mcl-a2010-02-09 01.59.00PM.MDI] GBN-FIIgr-w-water-1g-250mcl-a, SCAN: 3.0/39.96/0.048/1(sec), Cu, I(max)=12225, 02/09/10 02:13p(2) [GBN-a2008-11-24 03.30.10PM.MDI] GBN-a, SCAN: 5.0/39.992/0.048/1(sec), Cu, I(max)=7031, 11/24/08 03:43p(3) [GBN MH attd 020509.MDI] GBN MH attd 020509, SCAN: 3.0/39.96/0.048/1(sec), Cu, I(max)=43995, 02/05/09 01:47p
GBN ‘as is’-form II
Wet granules
Inte
nsi
ty (
arb
itra
ry u
nit
s)
2 (deg)
Wet Mass During Granulation
Form II (1g) granulated with 0.3 ml water:
Wet mass shows pronounced transformation to form I
GBN - form I
I III
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5 10 15 20 25 30
Two-Theta (deg)
x103
2.0
4.0
6.0
8.0
10.0
Inte
nsity
(Cou
nts)
(1) [G1__020409-PU-DKT-GBN-water-Diosno-a2009-04-13 01.23.21PM.MDI] 020409-PU-DKT-GBN-water-Diosno-a, SCAN: 3.0/39.672/0.048/1(sec), Cu, I(max)=5140, 04/13/09 12:38p(2) [F_I__GBN-MH-022509-a2009-02-26 10.17.03AM.MDI] GBN-MH-022509-a, SCAN: 3.0/39.96/0.048/1(sec), Cu, I(max)=46383, 02/26/09 10:42a(3) [F_II__GBN-a2008-11-24 03.30.10PM.MDI] GBN-a, SCAN: 5.0/39.992/0.048/1(sec), Cu, I(max)=7031, 11/24/08 03:43p
Dried Granules: Diosna
2 (deg)
Inte
nsi
ty (
arb
itra
ry u
nit
s)
Dry Granules(020409-PU-DKT-Diosno)
Form I(GBN-MH-022509-UM-AMK)
I III
Granules from Diosna (dried at RT):Form I persists in dried granules - Content ~80% (based on TGA)
Form II(GBN as received)
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Isomorphic Desolvate
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TGA: Form I and Partially Dehydrated Phase
GBN hydrate (form I) dehydrates slowly at RT – evident by TGA
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TGA: Form I and Dehydrated Phase
GBN hydrate (form I) dehydrates slowly at RT – evident by TGA
9.7%
0.2%
88
92
96
100
Wei
ght (
%)
30 50 70 90
Temperature (°C) Universal V4.1D TA Instruments
Form I after 12 months
Form I, freshly prepared
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DSC: Form I and Partially Dehydrated Phase
GBN hydrate (form I) dehydrates slowly at RT – evident by DSC
-3
-2
-1
0
1H
eat
Flo
w (
W/g
)
30 50 70 90
Temperature (°C)Exo Up Universal V4.1D TA Instruments
Form I after 12 months
Form I, freshly prepared
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DSC: Form I and Dehydrated Phase
GBN hydrate (form I) dehydrates slowly at RT – evident by DSC
-8
-6
-4
-2
0
2
4
Hea
t Flo
w (
W/g
)
30 60 90 120 150 180 210 240
Temperature (°C)Exo Up Universal V4.1D TA Instruments
Form I after 12 months
Form I, freshly prepared
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PXRD: Form I and Partially Dehydrated Phase
Dehydrated phase isomorphic to form I – PXRD may NOT be a reliable indicator of phase composition
2 (deg)
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PXRD: Form I and Dehydrated Phase
Dehydrated phase isomorphic to form I – PXRD may NOT be a reliable indicator of phase composition
5 10 15 20 25 30
Two-Theta (deg)
x103
5.0
10.0
15.0
20.0
25.0
30.0
35.0
40.0
45.0
Inte
nsi
ty(C
ou
nts
)
(1) [F_I__GBN-MH-022509-a2009-02-26 10.17.03AM.MDI] GBN-MH-022509-a, SCAN: 3.0/39.96/0.048/1(sec), Cu, I(max)=46383, 02/26/09 10:42a(2) [GBN-MH-020509-030210-a2010-03-02 01.22.47PM.MDI] GBN-MH-020509-030210-a, SCAN: 3.0/39.96/0.048/1(sec), Cu, I(max)=37648, 03/02/10 01:37p
2 (deg)
Inte
nsi
ty (
arb
itra
ry u
nit
s)
Form I after 12 months
Form I, freshly prepared
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ssNMR: Form I and Partially Dehydrated Phase
ssNMR can distinguish the isomorphic desolvate from form I
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Physical Stability of Isomorphic Desolvate
5 10 15 20 25 30
Theta(deg)
x103
5.0
10.0
15.0
20.0
25.0
30.0
35.0
40.0
45.0
Inte
nsity
(Cou
nts)
[GBN-MH-022509-a2009-02-26 10.17.03AM.MDI] GBN-MH-022509-a, SCAN: 3.0/39.96/0.048/1(sec), Cu, I(max)=46383, 02/26/09 11:42a[GBN-MH-022509-a 100709.MDI] GBN-MH-022509-a, SCAN: 3.0/34.968/0.048/1(sec), Cu, I(max)=57056, 10/07/09 04:51p[GBN-MH-022509-50C24hrs-a 100709.MDI] GBN-MH-022509-50C24hrs-a, SCAN: 3.0/34.968/0.048/1(sec), Cu, I(max)=7717, 10/07/09 04:08p
GBN MH 022509 (analyzed fresh)
GBN MH 022509 (analyzed after 6 mo)
GBN MH 022509 Post 50C/24 hrs
2 (deg)
Inte
nsi
ty (
arb
itra
ry u
nit
s)
Dehydrated phase resistant to transformation to other forms upon exposure to 50 °C
Is the isomorphic desolvate, physically stable in the timescales of our interest?
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GBN form I - Isomorphic Desolvate
• Gabapentin hydrate converts to an anhydrous phase when allowed
to slowly dehydrate under ambient conditions
• TGA confirms dehydration - no appreciable changes in PXRD -
SSNMR distinguishes form I from the dehydrated phase
• Hydrate present in solid dosage form may convert to anhydrate
with subsequent release of water
• Possibility of isomorphic desolvate also indicated by variable
temperature XRD where the ‘hydrate pattern’ persists above the
temperature of complete dehydration in TGA
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Variable Temperature XRD
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Proposed phase transformations during heating of GBN monohydrate
Variable Temperature XRD - GBN form I
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• Form I dehydrates at elevated temperatures to a mixture of
polymorphs- form II, III and isomorphic desolvate
• PXRD pattern of form I persists above temperature of complete
dehydration in TGA – Indicative of isomorphic desolvate
• Though dehydration at such elevated temperatures may not be directly
relevant pharmaceutically, dehydration of form I over long term storage
or processing and under conditions of low water vapor pressure may
yield a mixture of polymorphic forms in the final product
Variable Temperature XRD - GBN form I
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Wet massing followed by drying
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In situ granule drying in XRD
• Gabapentin form II was wet granulated with water – wet mass
was filled into XRD holder and subjected to isothermal hold -
35 or 45 ° for about 3 hours.
– XRD was recorded at various time points
– TGA was performed on the resulting mass after ‘drying’ in XRD
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5 10 15 20 25 30
Two-Theta (deg)
x103
250
500
750
Inte
nsity
(Cou
nts)
(1) [GBN-WG-25C_1_25C.raw] GBN-WG-25C_2, SCAN: 3.0/34.9918/0.04991/77.5(sec), Cu(40kV,40mA), I(max)=336977, 05/02/10 03:03p(2) [GBN-WG-35C_1_0min.raw] GBN-WG-35C_1, SCAN: 3.0/34.9918/0.04991/77.5(sec), Cu(40kV,40mA), I(max)=342646, 05/02/10 03:03p(3) [GBN-WG-35C_3_30min.raw] GBN-WG-35C_3, SCAN: 3.0/34.9918/0.04991/77.5(sec), Cu(40kV,40mA), I(max)=363335, 05/02/10 03:04p(4) [GBN-WG-35C_5_60min.raw] GBN-WG-35C_5, SCAN: 3.0/34.9918/0.04991/77.5(sec), Cu(40kV,40mA), I(max)=362579, 05/02/10 03:05p
(5) [GBN-WG-35C_7_90min.raw] GBN-WG-35C_7, SCAN: 3.0/34.9918/0.04991/77.5(sec), Cu(40kV,40mA), I(max)=362740, 05/02/10 03:06p
(6) [GBN-WG-35C_9_120min.raw] GBN-WG-35C_9, SCAN: 3.0/34.9918/0.04991/77.5(sec), Cu(40kV,40mA), I(max)=360791, 05/02/10 03:07p
25 °C
35 °C – 0 min
35 °C – 30 min
35 °C – 60 min
35 °C – 120 min
35 °C – 150 min
Inte
nsity
(ar
bitr
ary
units
)
Two Theta (deg)
Isothermal XRD: Wet mass drying at 35 °C
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25
9.275%
85
90
95
100
105W
eig
ht
(%)
25 35 45 55 65 75 85 95
Temperature (°C)
Sample: GBN-WG-1-4_35C_postVTXRD-aSize: 3.2820 mgMethod: H@10cpm to 200C
TGAFile: G:...\GBN-WG-1-4_35C_postVTXRD-a.002Operator: adiRun Date: 2010-04-23 16:41Instrument: TGA Q500 V6.7 Build 203
Universal V4.1D TA Instruments
TGA: Wet mass dried at 35 °C
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5 10 15 20 25 30
Two-Theta (deg)
x103
50
100
150
200
250
300
350
400
450
500
Inte
nsity
(Cou
nts)
(1) [GBN-WG-1-2-25C_1_0min.raw] GBN-WG-1-4-25C_1, SCAN: 3.0/34.9918/0.04991/77.5(sec), Cu(40kV,40mA), I(max)=194146, 05/02/10 03:13p(2) [GBN-WG-1-2-45C_2_0min.raw] GBN-WG-1-4-45C_2, SCAN: 3.0/34.9918/0.04991/77.5(sec), Cu(40kV,40mA), I(max)=230045, 05/02/10 03:14p(3) [GBN-WG-1-2-45C_4_30min.raw] GBN-WG-1-4-45C_4, SCAN: 3.0/34.9918/0.04991/77.5(sec), Cu(40kV,40mA), I(max)=241271, 05/02/10 03:15p(4) [GBN-WG-1-2-45C_8_90min.raw] GBN-WG-1-4-45C_8, SCAN: 3.0/34.9918/0.04991/77.5(sec), Cu(40kV,40mA), I(max)=208403, 05/02/10 03:16p(5) [GBN-WG-1-2-45C_9_120min.raw] GBN-WG-1-4-45C_9, SCAN: 3.0/34.9918/0.04991/77.5(sec), Cu(40kV,40mA), I(max)=192627, 05/02/10 03:16p
(6) [GBN-WG-1-2-45C_11_150min.raw] GBN-WG-1-4-45C_11, SCAN: 3.0/34.9918/0.04991/77.5(sec), Cu(40kV,40mA), I(max)=172581, 05/02/10 03:17p
25 °C
45 °C – 0 min
45 °C – 30 min
45 °C – 90 min
45 °C – 120 min
45 °C – 150 min
Inte
nsity
(ar
bitr
ary
units
)
Two Theta (deg)
Isothermal XRD: Wet mass drying at 45 °C
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27
1.069%
97.5
98.0
98.5
99.0
99.5
100.0
100.5W
eig
ht
(%)
25 45 65 85
Temperature (°C)
Sample: GBN-WG-post-VTXRD-aSize: 3.7440 mgMethod: H@10cpm to 220c
TGAFile: G:...\042210\GBN-WG-post-VTXRD-a.001Operator: adiRun Date: 2010-04-22 16:47Instrument: TGA Q500 V6.7 Build 203
Universal V4.1D TA Instruments
TGA: Wet mass dried at 45 °C
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28
90
92
94
96
98
100
102
Wei
ght (
%)
20 40 60 80 100
Temperature (°C)
GBN-WG-post-VTXRD-a.001––––––– GBN-WG-1-4_35C_postVTXRD-a.002– – – –
Universal V4.1D TA Instruments
TGA: Comparison
Dried at 35 °C
Dried at 45 °C
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29
Dehydrated Phase of Form I
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TGA: Dehydration of Form I
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PXRD: Dehydration of Form I
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0
20
40
60
80
Sa
mpl
e S
enso
r R
H (
%)
99.5
100.0
100.5
101.0
101.5
Wei
ght (
%)
0 5000 10000 15000 20000 25000
Time (min)
Sample: GBN MH 020509-121809-stepSize: 4.8330 mg
Comment: partially dehydrated
TGAFile: G:...\GBN MH 020509-121809-step.003Operator: adiRun Date: 2009-12-30 15:38Instrument: TGA Q5000 V3.10 Build 258
Universal V4.1D TA Instruments
Moisture Sorption: Dehydrated Phase
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TGA: Dehydrated Phase
99.0
99.2
99.4
99.6
99.8
100
100.2
100.4W
eigh
t (%
)
25 45 65 85 105
Temperature (°C)
Sample: GBN-MH-022509-ID-75RH-48h-aSize: 5.8620 mgMethod: H@ 10cpm to200C
TGAFile: G:...\GBN-MH-022509-ID-75RH-48h-a.001Operator: adiRun Date: 2010-04-29 10:21Instrument: TGA Q500 V6.7 Build 203
Universal V4.1D TA Instruments
Dehydrated phase exposed to 75% RH for 48 hours
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34
• Form I and isomorphic desolvate can form during processing
(granulation) of GBN
• PXRD is not a reliable indicator of phase composition because of its
inability to distinguish between the two forms
• The total water content may not be a reliable quality control
attribute. The mobility and distribution of water (lattice/free) may
be the critical determinants of product performance.
• In a formulation matrix, TGA and other characterization techniques
will have limited utility for obtaining phase information
Key Messages