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Dibucainea 0.70 605 0.51 75 132 5 8
Droperidola 0.73 627 0.53 22 108 6 8
Flurbiprofena 0.69 315 0.55 46 61 13 7
Nifedipinea 0.72 198 0.47 17 33 36 9
D( )salicina 0.69 364 0.93 23 58 14 4
Tolazamidea 0.65 99 0.68 3 18 281 2
Aceclofenac 0.66 131 0.56 45 25 69 8
Clotrimazole 0.72 566 0.40 40 97 7 11
Felodipine 0.76 404 0.49 5 66 12 5
Fenofibrate 0.72 369 0.75 34 76 10 2
Ibuprofen 0.65 255 0.60 92 58 14 10
Indomethacin 0.73 356 0.61 9 58 14 5
Itraconazole 0.75 4643 0.39 3 731 1 8
Ketoconazole 0.75 473 0.60 5 78 10 5
Ketoprofen 0.73 318 0.78 32 61 13 5
Loratadine 0.76 497 0.33 31 84 9 10
Miconazole 0.76 322 0.63 27 61 13 4
Nilutamide 0.72 620 0.43 28 106 7 9
Nimesulide 0.70 583 0.66 2 103 7 3
Pimozide 0.66 1070 0.35 1 170 4 8
Probucol 0.75 581 0.49 3 101 7 3
Procaine 0.70 309 1.00 47 69 11 1
Ritonavir 0.81 781 0.60 2 127 5 7
Trg calculated using Tm and Tg values in Kelvin.
a
Class (II) molecules.
From the calculated fragility and strength para- crystallization was absent for each molecule in one of
meters, it is clear there is no correlation between the triplicate runs conducted. These observations
these parameters and the GS parameters listed in indicate that class (III) molecules have both high GFA
Table 8. The majority of the class (II) compounds are upon cooling as well as high glass stability upon
moderately fragile, as seen in previous studies,44 with reheating above Tg. Fragility and strength para-
a few compounds falling into the fragile category. The meters (Table 9) for each class (III) molecule were
combined fragility and strength parameters and GS calculated as described above. All of the molecules
parameters suggest that celecoxib, droperidol, and had calculated fragility and strength parameters
nifedipine should have the highest GFA, while indicative of either moderately fragile or fragile
acetaminophen and flurbiprofen should have the liquids, with the range of values similar to those
lowest GFA amongst the class (II) molecules; again seen for class (II) compounds. Due to the lack of
the experimental evidence does not support this crystallization during reheating, GS parameters for
conclusion. class (III) molecules could not be calculated. The
reduced glass transition temperature (Trg) values are
shown in Table 9, and similar to both class (I) and
Class (III) Molecules
class (II) molecules, it is difficult to find a reliable
Molecules within this class, similar to class (II) correlation between Trg and GFA for molecules within
molecules, exhibit high relative GFA upon cooling this class for example, the compounds that crystal-
from the undercooled melt state. However, unlike lize upon slow reheating do not have lower Trg values
class (II) molecules, crystallization was not observed than the other compounds in this class. Furthermore,
during reheating at a slow heating rate (28C min 1) although the Trg values on average are lowest for
for the majority of the molecules, and was absent at class (I) [0.69 0.02] and highest for class (III)
moderate heating rates for all systems (108C min 1). [0.73 0.04] molecules, these differences were not
Crystallization upon reheating at 28C min 1 was statistically different, thus Trg is clearly not an
observed for nilutamide and nimesulide; however, infallible predictor of crystallization tendency.
DOI 10.1002/jps JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 9, SEPTEMBER 2010
3800 BAIRD, VAN EERDENBRUGH, AND TAYLOR
In summary, in contrast to inorganic systems observed for the class (I) molecules, most notably
where there is some evidence that GFA and GS lidocaine and tolbutamide and to a lesser extent
parameters correlate with crystallization behavior, flufenamic acid, chlorpropamide, atenolol, and 4-
none of these parameters tested showed a strong biphenylcarboxaldehyde. For the class (III) mole-
correlation with the observed crystallization behavior cules, moderate deviations were observed for aceclo-
in this study, either within or between classes of fenac, nilutamide, nimesulide, ketoprofen, ibuprofen,
molecules, suggesting these parameters may not be and procaine. Class (II) molecules are distributed in
ideal to predict the GFA or GS of organic molecules. between class (I) and (III) molecules, with some
preference for the right hand side of the plot. Outliers
for this class include acetaminophen, dibucaine, and
Evaluation of the Influence of Physical and Molecular
D( )salicin. Hence from this plot it is apparent that by
Properties on Crystallization Behavior
using the 1st and 2nd components, this PCA model
Given the limited value of the above parameters in
allows a reasonable discrimination between class (I)
predicting the GFA and GS of our set of organic
and class (III) molecules. The 3rd component, on the
molecules, it was of interest to determine if a better
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