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The thermal and NMR results are consistent with an increase in mobility at the surface of the amorphous materials. The eff ect of surface area on molecular mobility and crystallization is confi rmed by the reversible thermal properties of the amorphous materials, as well as the relaxation times obtained from the NMR analyses.


Characterization of Micronized APIs


The high energy particle attrition achieved during micronization is expected to generate disorder that generally resides on the surface of the particle and demonstrates high surface area. The characterization of micronization-induced disorder can often be challenging due to the small amount that is formed relative to the predominantly crystalline particle. In the following section, DSC, GVS, SSNMR and XRPD are used to examine the surface and structural changes associated with process-induced disorder.


Figure 1. DSC traces for (a) amorphous griseofulvin and (b) amorphous compound A. The eff ect of preparation method on crystallization is noted.


temperature of the non-ground amorphous sample. Similar thermal behavior was observed for both systems, where the higher surface area amorphous samples demonstrated crystallization onset below the glass transition of the lower surface area samples, presumably due to enhanced mobility at the surface [6].


SSNMR was used to confi rm the increase in molecular mobility for high surface area amorphous materials. 13 amorphous griseofulvin and 19


C NMR was used to characterize F NMR was used to characterize


, are generally expected to be shorter for molecules with higher mobility since they would return to equilibrium more rapidly. The T1


values are consistent with higher mobility in the high surface area samples demonstrated by shorter relaxation times, as shown in Table 1.


T1ρ Table 1. T1 and T1ρ values obtained from 13 Griseofulvin melt quench


Griseofulvin melt quench, ground Compound A desolvated


Compound A desolvated, ground F data (Compound A). C and 19 F NMR analysis


for amorphous griseofulvin and compound A, respectively. T1


T1ρ


1.60 ± 0.12 s 0.74 ± 0.18 s 21.87 ± 2.87 s 18.82 ± 3.33 s


Errors are estimated from fi tting of multiple peaks in the 13 measurements of the 19


78 ± 13 ms 45 ± 13 ms


31.11 ± 0.77 ms 16.14 ± 0.75 ms


C data (griseofulvin) or from replicate


Table 2. Summary of DSC and GVS Results for Micronized APIs Griseofulvin Compound B Compound C


micronized sample exotherm onset


amorphous sample glass transition (Tg


) ΔT1


cycle 1 uptake at 50%RH cycle 2 uptake at 50%RH


1Temperature diff erence between Tg of micronized API


65°C 90°C 25°C


0.20% 0.12%


100°C 118°C 18°C


0.46% 0.13%


of bulk amorphous and crystallization onset 135°C 170°C 35°C


0.80% 0.48%


amorphous compound A. High and low surface area amorphous samples were analyzed for both compounds. The nuclear spin-lattice relaxation time, T1 T1ρ


, and spin-lattice relaxation in the rotating frame, and


Figure 2. Comparison of DSC traces for bulk amorphous (solid lines) and micronized (dashed lines) APIs. The arrows indicate the Tg


of the bulk amorphous and crystallization onset for the micronized samples.


The DSC traces for three diff erent crystalline micronized APIs all exhibit small exothermic events with onsets below the bulk glass transition temperature known for each compound, as shown in Figure 2. Since compound A is a solvate, a similar assessment of the crystallization of micronized API could not be completed due to the desolvation event in the DSC trace. The exothermic transitions observed for the micronized samples are consistent with a small amount of amorphous content generated on the surface of high surface area micronized particles. As


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