NIPTE Project Report

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

6. Wet massing - granulation

7. Wet Mass During Granulation I I II Intensity (arbitrary units) GBN - form I GBN ‘as is’-form II Wet granules 2 (deg) Form II (1g) granulated with 0.3 ml water: Wet mass shows pronounced transformation to form I

8. Dried Granules: Diosna I I II Form II (GBN as received) Intensity (arbitrary units) Form I (GBN-MH-022509-UM-AMK) Dry Granules (020409-PU-DKT-Diosno) 2 (deg) Granules from Diosna (dried at RT): Form I persists in dried granules - Content ~80% (based on TGA)

9. 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 Form I after 12 months Form I, freshly prepared GBN hydrate (form I) dehydrates slowly at RT – evident by TGA

12. DSC: Form I and Partially Dehydrated Phase Form I after 12 months Form I, freshly prepared GBN hydrate (form I) dehydrates slowly at RT – evident by DSC

13. DSC: Form I and Dehydrated Phase Form I after 12 months Form I, freshly prepared GBN hydrate (form I) dehydrates slowly at RT – evident by DSC

14. PXRD: Form I and Partially Dehydrated Phase 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) 2 (deg) Dehydrated phase isomorphic to form I – PXRD may NOT be a reliable indicator of phase composition

16. ssNMR: Form I and Partially Dehydrated Phase ssNMR can distinguish the isomorphic desolvate from form I

17. GBN MH 022509 Post 50C/24 hrs GBN MH 022509 (analyzed after 6 mo) Intensity (arbitrary units) GBN MH 022509 (analyzed fresh) 2 (deg) Physical Stability of Isomorphic Desolvate 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. Variable Temperature XRD - GBN form I 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 drying 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

24. Isothermal XRD: Wet mass drying at 35 °C 35 °C – 150 min 35 °C – 120 min Intensity (arbitrary units) 35 °C – 60 min 35 °C – 30 min 35 °C – 0 min 25 °C Two Theta (deg) 24

25. TGA: Wet mass dried at 35 °C 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

27. TGA: Wet mass dried at 45 °C 27

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

29. Dehydrated Phase of Form I 29

30. TGA: Dehydration of Form I 30

31. PXRD: Dehydration of Form I 31

32. Moisture Sorption: Dehydrated Phase 32

33. TGA: Dehydrated Phase Dehydrated phase exposed to 75% RH for 48 hours 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