NIPTE Project Report
description
Transcript of NIPTE Project Report
NIPTE Project Report
Adi Kaushal and Raj Suryanarayanan
University of Minnesota
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
3
Form II and I Inter-conversion
4
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)
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
6
Wet massing - granulation
7
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
8
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)
Isomorphic Desolvate
10
TGA: Form I and Partially Dehydrated Phase
GBN hydrate (form I) dehydrates slowly at RT – evident by TGA
11
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
12
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
13
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
14
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)
15
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
16
ssNMR: Form I and Partially Dehydrated Phase
ssNMR can distinguish the isomorphic desolvate from form I
17
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?
18
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
19
Variable Temperature XRD
20
Proposed phase transformations during heating of GBN monohydrate
Variable Temperature XRD - GBN form I
21
• 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
22
Wet massing followed by drying
23
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
24
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
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
26
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
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
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
29
Dehydrated Phase of Form I
30
TGA: Dehydration of Form I
31
PXRD: Dehydration of Form I
32
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
33
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
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