Kimura K, Hirayama F, Uekama K
The Faculty of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto 862-0973, Japan.
J Pharm Sci. 1999 Apr;88(4):385-91. doi: 10.1021/js980376z.
Burger's two polymorphs of tolbutamide (TB), an oral hypoglycemic agent, were obtained by spray-drying the drug dissolved in a mixed solvent of ethanol/dichloromethane (Form IV) and allowing Form IV to stand at constant temperatures and humidities (Form II). These polymorphs were characterized by various physical methods [e.g., powder X-ray diffractometry, differential scanning calorimetry, infrared spectrometry, and solid-state carbon-13 nuclear magnetic resonance (13C NMR) spectroscopy] and compared with two other TB polymorphs Forms I and III. The 13C NMR spectra showed that the chemical shift and the peak shape of resonance associated with the toluene and n-butyl moieties of TB were different for each of the four polymorphs, whereas the carbonyl carbon was unchanged, indicating different conformations and molecular motions of the toluene and n-butyl moieties in the solid states. Form IV converted itself to Form II within 3 h when it was stored at 45 degrees C and 75% relative humidity (RH) and, in turn, Form II transformed to Form I at higher temperatures. The conversion of Form IV to Form II proceeded according to a zero-order equation (Polany-Winger equation), and that of Form II to Form I according to a first-order equation. The increase in RH accelerated the polymorphic transition of Form IV. Both the apparent dissolution rate and the solubility of Form IV were nearly identical with those of Form II, because the former changed to the latter during the dissolution, but their dissolution rates and solubility were higher than those of Forms I and III. These dissolution characteristics of TB polymorphs were reflected in the oral absorption behavior in dogs; that is, the bioavailability increased in the order Form I < Form III < Form II approximately Form IV.
口服降糖药甲苯磺丁脲（TB）的两种多晶型物是通过将溶解在乙醇/二氯甲烷混合溶剂中的药物进行喷雾干燥得到的（晶型IV），并使晶型IV在恒定温度和湿度下放置（晶型II）。这些多晶型物通过各种物理方法进行表征[例如，粉末X射线衍射法、差示扫描量热法、红外光谱法和固态碳-13核磁共振（13C NMR）光谱法]，并与另外两种TB多晶型物晶型I和晶型III进行比较。13C NMR光谱表明，对于四种多晶型物中的每一种，与TB的甲苯和正丁基部分相关的共振的化学位移和峰形都不同，而羰基碳不变，这表明固态中甲苯和正丁基部分的构象和分子运动不同。当晶型IV在45℃和75%相对湿度（RH）下储存时，它会在3小时内自行转变为晶型II，反过来，晶型II在更高温度下会转变为晶型I。晶型IV向晶型II的转变按照零级方程（波兰尼-温格方程）进行，晶型II向晶型I 的转变按照一级方程进行。相对湿度的增加加速了晶型IV的多晶型转变。晶型IV的表观溶解速率和溶解度与晶型II几乎相同，因为前者在溶解过程中转变为后者，但它们的溶解速率和溶解度高于晶型I和晶型III。TB多晶型物的这些溶解特性反映在犬的口服吸收行为中；也就是说，生物利用度按晶型I <晶型III <晶型II≈晶型IV的顺序增加。
