1. Adi Kaushal and Raj Suryanarayanan University of Minnesota
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
New slide. 2

3. Form II and I Inter-conversion3

4. Water Sorption (Form II)
Safe to use form II in ambient RH conditons
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

5. Intensity (arbitrary units)
Contact with Water
Solid in contact with saturated aqueous solution – form I
GBN ‘as is’- form II
Intensity (arbitrary units)
2 (deg)
Implications on wet granulation process
Solid in contact with saturated solution:
Instantaneous transformation of form II to form I – Implications on wet granulation

6. Wet massing - granulation6

7. Wet Mass During GranulationII I
Intensity (arbitrary units)
GBN - form I
GBN ‘as is’-form II
Form II granulated with water (amounts mentioned) was analyzed immediately after.
Wet mass is primarily form I (hydrate) with very little form II remaining.
Characteristic peaks of form II and I are indicated by boxes
Wet granules
2 (deg)
Form II (1g) granulated with 0.3 ml water:
Wet mass shows pronounced transformation to form I

8. Dried Granules: DiosnaII I
Form II
(GBN as received)
Intensity (arbitrary units)
Form I
(GBN-MH UM-AMK)
Even after drying form I (hydrate) is retained.
During wet massing, is all of II transformed to I? (depending upon amount of water used, most is transformed to form I)
During drying, is I transformed back to II? Possibly some of I is transformed back to II. (again depends on the drying condition)
This is one of the granules that we received from Purdue. This one shows a dominant presence of hydrate. Other examples showed lower or no form I in the dried granules.
Dry Granules
( PU-DKT-Diosno)
2 (deg)
Granules from Diosna (dried at RT):
Form I persists in dried granules - Content ~80% (based on TGA) 8

9. Isomorphic Desolvate

10. TGA: Form I and Partially Dehydrated Phase
TGA provides a reasonable idea of dehydration – however, utility of TGA may be limited when analyzing a formulation matrix. Other formulation components are likely to interfere with water content determination and interpretation.
GBN hydrate (form I) dehydrates slowly at RT – evident by TGA

11. TGA: Form I and Dehydrated Phase
Form I after 12 months
Form I, freshly prepared
TGA provides a reasonable idea of dehydration – however, utility of TGA may be limited when analyzing a formulation matrix. Other formulation components are likely to interfere with water content determination and interpretation.
GBN hydrate (form I) dehydrates slowly at RT – evident by TGA 11

12. DSC: Form I and Partially Dehydrated Phase
TGA provides a reasonable idea of dehydration – however, utility of TGA may be limited when analyzing a formulation matrix. Other formulation components are likely to interfere with water content determination and interpretation.
Form I after 12 months
Form I, freshly prepared
GBN hydrate (form I) dehydrates slowly at RT – evident by DSC 12

13. DSC: Form I and Dehydrated Phase
Form I after 12 months
Form I, freshly prepared
TGA provides a reasonable idea of dehydration – however, utility of TGA may be limited when analyzing a formulation matrix. Other formulation components are likely to interfere with water content determination and interpretation.
GBN hydrate (form I) dehydrates slowly at RT – evident by DSC 13

14. PXRD: Form I and Partially Dehydrated Phase
PXRD, which is a routinely used for obtaining phase information is NOT reliable in this case.
Importance of using a combination of techniques.
2 (deg)
Dehydrated phase isomorphic to form I –
PXRD may NOT be a reliable indicator of phase composition

15. PXRD: Form I and Dehydrated Phase
Form I after 12 months
Form I, freshly prepared
Intensity (arbitrary units)
PXRD, which is a routinely used for obtaining phase information is NOT reliable in this case.
Importance of using a combination of techniques.
2 (deg)
Dehydrated phase isomorphic to form I –
PXRD may NOT be a reliable indicator of phase composition 15

16. ssNMR: Form I and Partially Dehydrated Phase
Boxed area shows peaks specific to the two forms.
ssNMR can distinguish the isomorphic desolvate from form I

17. Physical Stability of Isomorphic Desolvate
GBN MH (analyzed fresh)
GBN MH (analyzed after 6 mo)
GBN MH Post 50C/24 hrs
2 (deg)
Intensity (arbitrary units)
Once isomorphic desolvate is formed, it may be resistant to further transformation to other forms (e.g. form II).
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 XRD19

20. Variable Temperature XRD - GBN form I
A snapshot of proposed phase transformation when hydrate (form I) is heated in a VTXRD.
Form I gives- form II, III and isomorphic desolvate
Proposed phase transformations during heating of GBN monohydrate

21. Variable Temperature XRD - GBN form I
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

22. Wet massing followed by drying22 22

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 23 23

24. Isothermal XRD: Wet mass drying at 35 °C
35 °C – 150 min
Intensity (arbitrary units)
35 °C – 120 min
35 °C – 60 min
35 °C – 30 min
Form I is obtained readily by wetmassing, and is retained in the dried granules. This conclusion is based on TGA (next slide)
35 °C – 0 min
25 °C
Two Theta (deg) 24 24

25. TGA: Wet mass dried at 35 °C25 25

26. Isothermal XRD: Wet mass drying at 45 °C
45 °C – 150 min
45 °C – 120 min
Intensity (arbitrary units)
45 °C – 90 min
45 °C – 30 min
45 °C – 0 min
25 °C
Two Theta (deg) 26 26

27. TGA: Wet mass dried at 45 °C27 27

28. TGA: Comparison
Dried at 45 °C
Dried at 35 °C 28 28

29. Dehydrated Phase of Form I29 29

30. TGA: Dehydration of Form I
Form I was prepared by dissolving form II in water:IPA mixture at RT and cooling to -20C. Crystalliztion can take a few days. The crystal were stored at ambient temperature in a capped vial.
Take home message: Hydrate can dehydrate gradually at room temperature; the timescale of dehydration is months 30 30

31. PXRD: Dehydration of Form I31 31

32. Moisture Sorption: Dehydrated Phase
While the hydrate (form I) has a tendency to lose the lattice water (in timescales of months), the reverse process, i.e. sorption of water by the dehydrated phase will not occur readily.
Since it looses water very slowly, will the uptake water also be very slow. In other words, these results may be different if the system is allowed to equilibrate for a longer timeperid. 32 32

33. TGA: Dehydrated Phase Dehydrated phase exposed to 75% RH for 48 hours
See the comments in the earlier slide.
Dehydrated phase exposed to 75% RH for 48 hours 33 33

34. Key Messages
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
This slide may go towards the end of presentation with the summary. We are emphasizing points 3 and 4