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