Adi Kaushal and Raj Suryanarayanan University of Minnesota NIPTE Project Report Adi Kaushal and Raj Suryanarayanan University of Minnesota

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

Form II and I Inter-conversion 3

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

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

Wet massing - granulation 6

Wet Mass During Granulation II 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

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

Isomorphic Desolvate

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

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

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

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

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

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

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

Physical Stability of Isomorphic Desolvate GBN MH 022509 (analyzed fresh) GBN MH 022509 (analyzed after 6 mo) GBN MH 022509 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?

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

Variable Temperature XRD 19

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

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

Wet massing followed by drying 22 22

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

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

TGA: Wet mass dried at 35 °C 25 25

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

TGA: Wet mass dried at 45 °C 27 27

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

Dehydrated Phase of Form I 29 29

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

PXRD: Dehydration of Form I 31 31

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

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

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