Do amorphous troglitazones prepared from two diastereomer-pairs have the same molecular mobility and crystallization rate at the surface?

The surface of amorphous compounds crystallizes faster compared to the bulk. This suggests that molecules at the surface have high molecular mobility. Crystallization behavior is affected by various factors including molecular weight and glass transition temperature (T(g)). In this study, we focus on troglitazone which is composed of diastereomers, RR/SS and RS/SR, as model compound, because each diastereomer has the same molecular weight and similar chemical structure. Troglitazone is isolated into each diastereomer, and both amorphous prepared from RR/SS and RS/SR showed similar T(g) (around 60°C). The surface relaxation of each amorphous troglitazone prepared from two diastereomers, RR/SS and RS/SR, was determined to compare surface molecular mobility, using inverse gas chromatography under dry conditions. As a result, amorphous prepared from RS/SR, showed the shorter surface relaxation time at 40°C (temperature below T(g)), which means it has higher molecular mobility than that from RR/SS at the surface although both have the same molecular weight and similar T(g). Microscopy analysis was conducted to observe the crstallization behavior at the surface of amorphous troglitazone in conditions of high temperature and humidity. Micrographs showed that crystallization area at the surface of amorphous prepared from RS/SR, which showed the shorter surface relaxation time, increased faster than that of the amorphous prepared from RR/SS. Although the reason for the difference in the surface relaxation time of each amorphous troglitazone could not be determined, factors such as the difference of configuration might affect the difference.

Evaluation of solid dispersions on a molecular level by the Raman mapping technique.

Troglitazone containing two asymmetric carbons has four isomers. Crystalline troglitazone consists of two crystalline diastereomer-pairs, RR/SS and RS/SR, which have different melting points. Using a closed melting method, troglitazone-polyvinylpyrrolidone solid dispersions with various crystallinities were prepared. Raman spectroscopy and its mapping technique were applied to discriminate between the crystalline RR/SS, crystalline RS/SR and amorphous form of troglitazone in solid dispersions. The results of the Raman mapping of solid dispersions showed the co-existence of crystal and amorphous forms, and which diastereomer-pairs remained as crystals, in addition to the distribution of the drug. Moreover, the distribution of PVP could be illustrated from the Raman mapping data. Thus, Raman spectroscopy and its mapping technique are useful tools to evaluate crystal and amorphous states, including discrimination of crystalline diastereomer-pairs in solid dispersions. In addition, by describing the distribution of the drug and the carrier, it could be guessed how drug crystals become amorphous during preparation from the point of view of the distribution of the amorphous form of the drug substance and the carrier.

Effect of physical properties of troglitazone crystal on the molecular interaction with PVP during heating.

This study examined the effect of physical properties of troglitazone drug substance on the molecular interaction with polyvinylpyrrolidone K30 (PVP) during preparation by a closed melting method. Milling was conducted using impact and jet mills to change the physical properties of troglitazone, such as particle size, specific surface area, surface free energy and acidic-basic parameters. Solid dispersions (SDs) prepared from milled troglitazone, irrespective of milling method, showed almost 100% dissolution when not less than 7.5% of water was added during heating. SDs prepared from unmilled troglitazone showed almost 100% dissolution when not less than 12.8% of water was added during heating. Physical mixture (PM) containing unmilled troglitazone must be heated above at least 50 degrees C higher than the glass transition temperature (T(g)) of PVP to obtain an SD showing 100% dissolution, while PMs containing milled troglitazone could be heated above only 20 degrees C higher than the T(g) of PVP to obtain an SD showing 100% dissolution. The melting points of troglitazone in PMs containing milled troglitazone, irrespective of milling method, were lower than those in PMs containing unmilled troglitazone. These results indicated that specific interaction could occur more easily during heating between milled troglitazone and PVP during preparation by a closed melting method. In addition, Fourier transform infrared study indicated that hydrogen bonding could occur between the N-H of troglitazone and the C=O of PVP.

Effects of water content in physical mixture and heating temperature on crystallinity of troglitazone-PVP K30 solid dispersions prepared by closed melting method.

Troglitazone, which possesses two asymmetric carbons, is obtained as a mixture of four isomers present in equal amounts. Troglitazone (Lot T003) has two melting points, about 120 and 175 degrees C. To increase the bioavailability of insoluble troglitazone, troglitazone-polyvinylpyrrolidone K30 (PVP) solid dispersions (SDs) were prepared with water by a unique closed melting method. In this study, the effects of the water content in the physical mixture (PM) and the heating temperature on the apparent crystallinity of troglitazone in SDs prepared by this method were investigated. When the water content in the PM was controlled at 3%, although the apparent crystallinity of troglitazone in the SD prepared by heating at 105 degrees C did not decrease (99%), that of the SDs prepared by heating at 130 and 150 degrees C were reduced to 54 and 11%, respectively. This result indicated that the meltage of troglitazone varies depending on the heating temperature. The apparent crystallinity of troglitazone in the SDs decreased with increase in water content in the PM. In particular, SDs prepared by heating at 130 and 150 degrees C showed 0% apparent crystallinity when the water content in the PM were more than 13 and 8%, respectively. When the heating temperature used was higher than the glass transition temperature of PVP plasticized with water, troglitazone crystals were dissolved in the rubbery PVP. Therefore, even if the heating temperature is lower than the melting point of troglitazone during preparation, controlling the water content in the PM at a high level can produce a troglitazone SD with 0% apparent crystallinity.

Uniformity and physical states of troglitazone in solid dispersions determined by electron probe microanalysis and microthermal analysis.

Solid dispersions of troglitazone with PVP K30 in a weight ratio of 1:2 were prepared by the closed melting method. Solid dispersions that exhibit different degrees of crystallinity (0 and 36%) were prepared by changing the charged amount of water, which functions as a plasticizer for PVP K30. Electron probe microanalysis (EPMA) and microthermal analysis (micro TA) of the solid dispersions were performed to investigate the uniformity and physical state of troglitazone in the solid dispersions. The EPMA study confirmed that troglitazone was dispersed homogeneously in the sample whose apparent crystallinity was 0%. However, the sample with a 36% crystallinity was heterogeneous. The micro TA study showed that the sample with a 36% crystallinity was present in two states, crystal and amorphous. EPMA and micro TA would be useful tools to confirm the uniformity and physical states, respectively, of solid dispersions.