Journal of Inclusion Phenomena and Macrocyclic Chemistry 50: 73-77, 2004.

Effects of 2-Hydroxypropyl-b-cyclodextrin on Polymorphic Transition
of Chlorpropamide in Various Conditions: Temperature, Humidity

and Moulding Pressure
YOH SONODA, FUMITOSHI HIRAYAMA, HIDETOSHI ARIMA
and KANETO UEKAMA*

Abstract
The amorphous complex of 2-hydroxypropyl-b-cyclodextrin (HP-b-CyD) with an oral hypoglycemic agent,
chlorpropamide (CPM), in a molar ratio of 1:1 was prepared by the spray-drying method. The effects of storage
(temperature and humidity) and moulding pressure on the polymorphic transition of CPM in HP-b-CyD matrix were
investigated, in comparison with those of the CPM polymorphs, Form A (stable form) and Form C (metastable
form). The formation of an amorphous complex of CPM with HP-b-CyD was confirmed by powder X-ray
diffractometry and differential scanning calorimetry. During storage at various temperature and humidity conditions,
the metastable Form C of CPM converted to the stable Form A, where the conversion proceeded according to the
Jander equation with an activation energy of 51 kJ/mol (25-60
C) and a reaction-order of 1.55 with respect to water
content (relative humidity (RH) 20-75%). No polymorphic transition of Form A crystals was observed under the
experimental conditions. In the case of the amorphous HP-b-CyD complex, Form C crystals were slowly produced,
but the further conversion of the resulting Form C to Form A was markedly suppressed in HP-b-CyD matrix. Upon
compression (2000 kg/cm2), Forms A and C were converted to amorphous CPM in a major portion and Forms C and
A, respectively, in a minor portion. The polymorphic transition behavior was clearly reflected in the dissolution rate
of CPM, i.e., (1) the dissolution rate was in the order of HP-b-CyD complex > Form C > Form A, and (2) the
dissolution rate of Forms A and C after the compression increased because of the conversion to amorphous state,
while the complex maintained the fast dissolving property even after the compression. The results indicated that HP-b-
CyD is useful not only for converting crystalline CPM to an amorphous substance, but also for maintaining the
metastable form with fast dissolution rate, Form C, over a long period.