Study of the amorphous glibenclamide drug: analysis of the molecular dynamics of quenched and cryomilled material.

Glibenclamide (GCM) is an oral hypoglycemic agent of the sulfonylurea group used in the treatment of non-insulin-dependent diabetes. Crystalline GCM is characterized by low bioavailability, which is attributed to its poor dissolution properties. It prompted us to prepare this drug in its amorphous form as a means to enhance its dissolution characteristics. Two different methods were used to convert crystalline GCM into the glassy form: quench-cooling of the melt and cryogenic milling. To monitor solid-state properties of the amorphous samples, X-ray powder diffraction (XRD), infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), ultraperformance liquid chromatography (UPLC) and spectroscopy, and broadband dielectric spectroscopy (BDS) were applied. The results of UPLC separations along with associated infrared and NMR measurements unambiguously showed that the thermal degradation of the quenched GCM, as suggested in literature reports, does not occur. A similar analysis performed on the cryomilled material also did not indicate any chemical decomposition. On the other hand, both methods confirmed that the conversion to the amorphous form is connected with the amide-imidic acid tautomerism of the examined drug. Moreover it was shown that this transformation occurs regardless of the manner of amorphization. Finally, dielectric spectroscopy was employed to study the molecular dynamics of vitrified GCM. The analysis of the ε''(f) in terms of the KWW function from the dielectric measurements revealed the existence of an "excess wing" attributed to the true Johari-Goldstein process based on Ngai's coupling model. The dielectric properties of GCM obtained in the amorphous form both by rapid cooling of the melt and the cryogenic grinding of crystalline sample were also compared.

Molecular dynamics of the cryomilled base and hydrochloride ziprasidones by means of dielectric spectroscopy.

Cryomilling was applied to obtain amorphous forms of the base ziprasidone and its hydrochloride salt. Complete amorphization of both samples was confirmed by differential scanning calorimetry and X-ray measurements. As it turned out, cryogrinding is very effective way to obtain these drugs in the amorphous state, especially because melting of both ziprazidones accompanies significant chemical decomposition as revealed by ultra performance liquid chromatography examination. Consequently, the glassy state cannot be reached in conventional way, that is, by supercooling of melt. Broadband dielectric relaxation measurements were performed on both drugs to describe their molecular dynamics above as well as below their glass transition temperatures (T(g)). We found out that ziprasidone base and its hydrochloride salt differ in T(g) in the same way as it was previously reported for tramadol monohydrate and its hydrochloride. Moreover, our dielectric studies revealed that molecular mobility is not the main factor controlling kinetics of crystallization of both ziprasidones above their T(g) . Below the T(g) relaxation related to water as well as secondary relaxation process originating from the intermolecular interaction (Johari-Goldstein) were identified in the loss spectra of both materials. We have demonstrated that except of local mobility, water is the dominant factor moving both ziprasidones toward recrystallization process. Finally, we have also carried out solubility measurements to show that dissolution rate of the amorphous ziprasidones is much higher with respect to the crystalline samples.

Dielectric relaxation study on tramadol monohydrate and its hydrochloride salt.

Dielectric relaxation measurements as well as differential scanning calorimetry and X-ray diffraction investigations were performed on tramadol monohydrate and its hydrochloride salt. Examined samples do not crystallize during cooling and in consequence they reach the glassy state. In the case of the hydrochloride tramadol we are able to monitor alpha-relaxation process despite large contribution of dc conductivity to the loss spectra. It is the first such study on the salt of the drug. Up to now the dielectric spectroscopy has been regarded as useless in measuring such kind of API (active pharmaceutical ingredient). In this paper we also made some suggestions about the nature of the secondary relaxations in the amorphous tramadol monohydrate and its salt. The knowledge about the molecular mechanisms, which govern the observed secondary relaxations seems to be the key in predicting the stability of the amorphous form of the examined API. Finally additional dissolving measurements on the amorphous and crystal tramadol hydrochloride were performed. As a result we understood that dissolution properties of the amorphous form of the considered drug are comparable to those of crystalline one. However, we have found out that amorphous tramadol hydrochloride has greater ability to form tablets than its crystalline equivalent. This finding shows that amorphous drugs can be alternative even for the freely solved pharmaceuticals such as tramadol hydrochloride, because the former one has better ability to form tablets. It implies that during tabletting of the amorphous drugs there is no need to use any excipients and chemicals improving compaction properties of the API.

Molecular mobility in liquid and glassy states of telmisartan (TEL) studied by broadband dielectric spectroscopy.

The molecular relaxation in liquid and glassy states of Telmisartan (TEL) has been studied by Broadband Dielectric Spectroscopy (BDS) covering wide temperature and frequency range. Multiple relaxation processes were observed. Besides the primary alpha-relaxation, two secondary relaxations beta and gamma (labelled in order of decreasing time scale) have been reported. Well-separated beta-process observed above and below glass transition temperature T(g), has activation energy E(beta)=81.8 kJ/mol and was identified as intermolecular Johari-Goldstein (JG) process. The gamma-relaxation visible in dielectric loss spectra at very low temperatures is most likely non-JG relaxation. The temperature dependence of the relaxation times of alpha-process, measured over 11 orders of magnitude, cannot be described by a single Vogel-Fulcher-Tamman-Hesse (VFTH) equation. At temperature T(B)=475.8K the change in relaxation dynamics occurred, consequently a new set of VFTH parameters was required. From low temperature VFTH fits the glass transition temperature T(g) was estimated as T(g)=400.3 K and fragility index m=87 was calculated. Of particular interest was the time scale of molecular motion below the glass transition temperature. Our observation clearly indicates that the alpha-relaxation times at room temperature most probably would exceed 3 years and amorphous TEL should maintain physically and chemically stable over prolonged storage time.