Stability of Rapidly Crystallizing Sulfonamides Glasses by Fast Scanning Calorimetry: Crystallization Kinetics and Glass-Forming Ability.

Production and evaluation of the kinetic stability of the amorphous forms of active pharmaceutical ingredients are among the current challenges of modern pharmaceutical science. In the present work, amorphous forms of several sulfonamides were produced for the first time using Fast Scanning calorimetry. The parameters, characterizing the glass-forming ability of the compounds, i.e. the critical cooling rate of the melt and the kinetic fragility, were determined. The cold crystallization kinetics was studied using both isothermal and non-isothermal approaches. The results of the present study will contribute to the development of approaches for producing amorphous forms of rapidly crystallizing active pharmaceutical ingredients.

Crystallization kinetics and glass-forming ability of rapidly crystallizing drugs studied by Fast Scanning Calorimetry.

The use of the amorphous forms of drugs is a modern approach for the enhancement of bioavailability. At the same time, the high cooling rate needed to obtain the metastable amorphous state often prevents its investigation using conventional laboratory methods such as differential scanning calorimetry, X-ray powder diffractometry. One of the ways to overcome this problem may be the application of Fast Scanning Calorimetry. This method allows direct determination of the critical cooling rate of the melt and kinetic parameters of the crystallization for bad glass formers. In the present work, the amorphous states of dopamine hydrochloride and atenolol were created using Fast Scanning Calorimetry for the first time. Critical cooling rates and glass transition temperatures of these drugs were determined. Based on the values of the kinetic fragility parameter, dopamine hydrochloride glass can be considered strong, while atenolol glass is moderately strong. Both model-based and model-free approaches were employed to determine the kinetic parameters of cold crystallization of dopamine and atenolol. The results were compared with the data from isothermal crystallization experiments. The Nakamura crystallization model provides the best description of the crystallization process and can be used to predict the long term stability of the amorphous forms of the drugs. The presented approaches may find applications in predicting the storage time and choosing the optimal storage conditions of the amorphous drugs prone to crystallization.

Kinetic stability of amorphous dipyridamole: A fast scanning calorimetry investigation.

One of the main tasks of modern pharmaceutics is enhancing the solubility of drugs. The approaches for solving this problem include producing active pharmaceutical ingredients in the amorphous state. However, the use of amorphous drugs requires the determination of their kinetic stability. The latter is often assessed using isothermal techniques, which are time-consuming. Alternatively, non-isothermal methods can be employed, allowing to determine the kinetic triplet more rapidly. Also, such techniques can be used to develop predictive models for storage stability. The production of the amorphous state itself typically requires fast cooling rates, which may not be easily accessible. Fast scanning calorimetry is a promising tool for the investigation of amorphous drug systems. In the present work, the crystallization of the model drug dipyridamole was investigated using the fast scanning calorimetry method. The kinetic stability of the amorphous form of the drug was evaluated using both, isothermal and non-isothermal methods. The Nakamura crystallization model was found to be applicable for the prediction of the temporal stability of the amorphous drug forms. The obtained results may find applications in the investigation of the kinetic stability of amorphous drug systems.

Kinetic stability of amorphous solid dispersions with high content of the drug: A fast scanning calorimetry investigation.

Formation of amorphous solid dispersions is an effective way to enhance the bioavailability of drugs. One of the main disadvantages of such systems is their low storage stability. Estimation and prognosis of storage stability of the amorphous solid dispersions are possible through modeling of the kinetics of crystallization by the Arrhenius equation and the resulting parameters, i.e., activation energy and pre-exponential factor. These parameters can be determined using the non-isothermal kinetics methods based on both model-fitting and model-free approaches using the differential scanning calorimetry data. In the present work, the formation of amorphous solid dispersions of the phenacetin model drug with polyvinylpyrrolidone of different molecular masses (3500-1.3 × 106 g·mol-1) was studied in a wide range of heating and cooling rates. The kinetic parameters of the crystallization process of the active pharmaceutic ingredient in the solid dispersions with increased drug content were determined. The dependence of the kinetic parameters of phenacetin cold crystallization on the molecular weight of the polymer is non-linear. The approaches used in the present work can find applications for the estimation of kinetic stability of amorphous pharmaceutical systems prone to crystallization.

[Age-related structural changes in the cells of the primary visual cortex of rats under high-intensity light exposure.]

The experiment on 20 male Wistar rats has demonstrated that under light exposure 3 500 lux for 7 days on different-aged rats morphological changes are observed in the II, IV and V layers of the primary visual cortex. They manifest itself as percentage increase of reversibly and irreversibly altered neurons, mainly in the fourth layer in 18-month-old rats (p≤0,05). Thus, under light exposure in 18-month-old rats the percentage of hyperchromic wrinkled neurons runs up to to 6% (5; 8,5) and the percentage of neurons with total chromatolysis increases up to 10% (8,5; 14) in comparison with 1% (0,5; 14) and 6% (5; 8) in 3 month rats under light exposure, respectively (p≤0,05). The neural damage leads to the glial reaction, which is expressed by the percentage increase of glia with edema and swelling signs, hyperchromia without shrinkage of the nucleus and cytoplasm (p≤0,05), neuronophagy, and the intrusion of gliocytes into the neuron cytoplasm for initiation of intracellular repair. The destructive changes are characterized by hyperchromia of gliocytes with shrinkage of the nucleus and cytoplasm. The percentage of such gliocytes significantly increases in the IV layer in 18 month old rats under light exposure, in comparison with the indexes of young animals (p≤0,05).

Infradian Rhythm of the Content of Secretory Granules in Pinealocyte Cytoplasm in Mice and Rats.

The numerical density of secretory granules dense-core vesicles (DCV) in the cytoplasm of pinealocytes of the pineal gland was estimated by transmission electron microscopy in male white mice and Wistar rats. The 3-day biorhythm and lunaphase changes in the DCV content in the perikaryon and the processes of pinealocytes, which are manifested significantly in different seasons of the year, are established. The three-day biorhythm in adult male mice in comparison with younger male rats is not expressed uniformly in different phases of the moon. The in-phase manifestation of infradian biorhythms in different species of animals during the year with an unchanged daily photophase indicates the existence of common external synchronizers for mammals of these biorhythms that are not associated with the light/dark cycle.

Microspherical Particles of Solid Dispersion of Polyvinylpyrrolidone K29-32 for Inhalation Administration.

Inhalation administration is a promising alternative to the invasive drug delivery methods. The particle size required for ideal drug aerosol preparation is between 1 and 3 µm. The application of microspherical particles of solid dispersions enhances bioavailability of poorly soluble drugs due to the solubilization. In the present work, the spray drying process of the production of microspherical particles of solid dispersions of polyvinylpyrrolidone K29-32 with model hydrophobic drug, phenacetin, was optimized using the results of DSC, PXRD, and viscometry. The diameter of the obtained particles is within 1-3 µm range. The Gibbs energy of dissolution in water was shown to be negative for the mixture with polymer/phenacetin mass ratio 5 : 1. We have demonstrated that the optimal size distribution for the inhalation administration is obtained for microspherical particles produced using spray caps with 7.0 µm hole size. The dissolution rates of phenacetin from the produced microspherical particles were faster than that of drug powder. As evidenced by powder X-ray diffraction data, phenacetin stayed in amorphous state for 4 months in microspherical particles of solid dispersions. According to the obtained results, strategic application of the spray drying process could be beneficial for the improvement of the pharmaceutical properties of model drug, phenacetin.

Influence of nanosilver on the efficiency of Pisum sativum crops germination.

The study is aimed to investigate the impact of silver nanoparticles on germination of Pisum sativum pea seeds. The influence of synthesized silver nanoparticles on root length and percentage of germinated seeds was revealed. It was found that nanosilver treatment agents do not affect the germination of pea seeds negatively at low concentrations. Also, the treatment of pea seeds with silver nanoparticles provide a significant positive effect on the root length of pea seeds.

Pineal gland as an endocrine gravitational lunasensor: manifestation of moon-phase dependent morphological changes in mice.

We found that some morphological properties of the pineal gland and submandibular salivary gland of mice are significantly distinct at the new and full moon. We suppose that the differences are initiated by the displacements of the electron-dense concretions in the secretory vesicles of pinealocytes. This presumably occurs under the influence of the gravitational field, which periodically changes during different phases of the moon. It seems that the pinealocyte is both an endocrine and gravisensory cell. A periodic secretion of the pineal gland probably stimulates, in a lunaphasic mode, the neuroendocrine system that, in turn, periodically exerts influence on different organs of the body. The observed effect probably serves, within the lifelong clock of a brain, to control development and aging in time.

[Clinical and anamnestic analysis of multiple primary neoplasms with lesions of the endometrium in women of the Novosibirsk region].

Based on the study of 60 women who were treated at the gynecology department of the Novosibirsk Regional Oncology Dispensary from 2003 to 2013 with a diagnosis of primary multiple synchronous and metachronous neoplasia with endometrial lesion it was found that the most common risk factors for this disease could be considered: overweight and obesity; late age at onset of menarche; late age of menopause; concomitant cardiovascular diseases and disorders of the endocrine metabolism.

Morphological changes in the pineal gland of rats under conditions of long-term exposure to bright light.

Changes in the diurnal light cycle affect the morphofunctional state of the pineal gland. The volume of the nucleus, Golgi apparatus, and mitochondria in pinealocytes decreases after 45-day exposure to bright light. After 90 days, the degree of nuclear polymorphism increased, the specific volume of the Golgi apparatus returned to normal, the volume of the granular endoplasmic reticulum decreased, while the volume of lysosomes, free ribosomes, and polysomes increased. These changes reflect plasticity of pinealocytes and adaptation of the gland to long-term 24-h light exposure.

Plasticity of secretory neurons in the supraoptic and paraventricular nuclei of the hypothalamus on exposure to light.

Light and electron microscopic methods were used to analyze changes in secretory neurons in the supraoptic (SON) and paraventricular (PVN) nuclei in the hypothalamus in 100 adult male rats at time points from the first minutes to 180 days after 48 hours of full-time exposure to bright light. At the early time points after exposure, the cellular formulae of the SON and PVN shifted towards functionally active neurons with minimal quantities of secretory granules, large nuclei and nucleoli, low RNA contents, small numbers of rough endoplasmic reticulum cisterns, vacuoles, and lysosomes in the perikarya. The number of cells depositing secretion was greater than in controls at 24 h in the SON and PVN and at 10 days in the SON. Normalization of the cellular formula and the structural organization of the protein-synthesizing apparatus of PVN neurons occurred at 10-30 days, with normalization in the SON at 30-180 days. These data provide evidence that the range of plasticity of neurons in the PVN on exposure to full-time bright light was more significant than that in the SON.

Estrogen-metabolizing gene polymorphisms in the assessment of female hormone-dependent cancer risk.

Allelic variants of cytochrome P450: CYP1A1, CYP1A2, CYP19 (Aromatase) and II-phase enzyme Sulfotransferase (SULT1A1) genes are associated with a high risk of hormone-dependent cancers. We estimated a frequency of these allelic variants in the female Caucasian population of the Novosibirsk region of Russia and their association with the elevated risk of ovarian and endometrial cancer. A DNA bank of gynecologic oncology patients, patients with benign gynecologic diseases and healthy women was created, and the following single nucleotide polymorphisms (SNPs) were examined: CYP1A1 M1 polymorphism, that is, T264 --> C transition in the 3'-noncoding region; CYP1A2*1F polymorphism, that is, C734 --> A transversion in CYP1A2 gene; C --> T transition (Arg264Cys) in exon 7 of CYP19; SULT1A1*2 polymorphism, that is, G638 --> A transition (Arg213His) in SULT1A1 gene. A positive correlation of C allele of CYP1A2*1F and G allele of SULT1A1*2 with hormone-dependent cancers in women was found. Thus, these genes are appropriate candidates for studying the contribution of genetic factors to endocrine disorder and environmentally determined diseases susceptibility. In contrast, no association of CYP19 and CYP1A1 polymorphisms with increased cancer risk was revealed.

[Plasticity of neuroendocrine transducers under the combined influence of the radiation and light exposure].

The structural changes of neurons of the rat hypothalamic supraoptic (SON) and of paraventricular (PVN) nucleus after 48 h of bright light exposure, of 5 Gy whole-body X-irradiation and of their combination subjected to the analysis by means of light-optic and of electron microscopy for the estimation of radimodificated effect of light exposure lasted 24 h a day and plasticity of neuroendocrine transducers interacted with the optic sensory system. The structural changes of neurons of the SON after combined action are less considerable and more prolonged in comparison with the PVN that loas defermined by their direct connection with the optic sensory system via the retinohypothalamic tract.

[Plastisity of secreteory neurons of hypothalamic supraoptic and paraventricular nuclei during light exposure].

Changes of secreteory neurons of hypothalamic supraoptic (SON) and paraventricular nuclei (PVN) were analyzed using light and electron microscopy in 100 adult male rats from the first minutes up to 180 days after their round-the-clock 48 hours-long exposure to bright light. At the early stages after the exposure, SON and PVN cellular formula was changed in favor of functionally active neurons containing few secretory granules, large nucleus and nucleoli, low RNA content, sparse complexes of rough endoplasmic reticulum, vacuoles and lysosomes in their perikarya. After 24 hours in both SON and PVN and after 10 days in SON the number of cells accumulating secretion was greater than that in control group. Normalization of the cellular formula and of the structural organization of protein-synthesis apparatus in PVN secretory neurons took place at days 10-30, while those ones in SON--at days 30-180. The results obtained suggest that the range of plasticity in PVN neurons in animals exposed to continuous bright light is larger than that in SON neurons.

[Ultrastructure of the pinealocytes in rats exposed to light and radiation]. / Ul'trastruktura pinealotsitov u krys pri vozdeistvii sveta i radiatsii.

Changes in pinealocytes (PC) were analysed using quantitative electron microscopy in 240 adult male rats from first minutes up to 180 days after their continuous exposure to bright light (CLE) for 48 hours, X-ray irradiation (XRI) or their combination (CE). After CLE early changes of PC included the reduction of rough endoplasmic reticulum (RER), Golgi complex and synaptic ribbons. At 24 hours and 10 days PC secretory activity was increased, while their ultrastructural organization was normalized by 30-180 days. 10 days after XRI degenerative changes were detected in PC that included dilation, fragmentation and vacuolization of RER cisterns, mitochondrial swelling, appearance of large vacuoles and osmiophilic inclusions, increase in lysosome content. Volume density of mitochondria and RER was lower, while that of Golgi complex was higher than in control. PC ultrastructure was restored 30-180 days after XRI. Following CE, the changes in PC ultrastructural organization were more significant at all time interval studied than after the action of single factors. The results obtained indicate that CLE increased the extent of postradiation changes in PC ultrastructural organization during the early time intervals after XRI and at the peak of radiation sickness development.

[Functional morphology of suprachiasmatic nuclei neurons of rat hypothalamus after the combined influence of x-irradiation and light exposure]. / Funktsional'naia morfologiia neironov superkhiazmaticheskikh iader gipotalamusa krys posle kombinirovannogo vozdeistviia rentgenovskogo izlucheniia i sveta.

For estimation of light radiomodification and cellular neuroadaptation of the circadian pacemarker, the morphological changes of suprachiasmatic nuclei (SCN) neurons of rat hypothalamus after 48-hours bright light exposure, the single 5 Gy whole-body X-irradiation and their combination were subjected to analysis. The dynamics of reactive and reparative changes has got a phasic character. Temporary desynchronous changes were developed in the course of the early period. Age morphological changes after X-ray and combined irradiation were discovered in the remote period. The plastic diapason of ventrolateral division (SCNv) is more considerable in comparison with dorsomedial division (SCNd). The synergism of X-irradiation and light exposure was discovered in SCNd.

[Structural changes in the granular duct epitheliocytes and terminal areas of the submandibular glands induced by exposure to light and radiation in rats]. / Strukturnye izmeneniia épiteliotsitov granuliarnykh vyvodnykh protokov i kontsevykh otdelov podnizhnecheliustnykh zhelez krys pri vozdeistvii sveta i radiatsii.

This investigation was aimed at the evaluation of radiomodifying effect of round-the-clock light exposure on the salivary glands. The changes of morphometric parameters of granular duct epitheliocytes and acinar cells in rat submandibular glands were analyzed by means of light and electron microscopy after 48 h of light exposure by 3500-lux cool white fluorescent lamps, single 5 Gy whole-body X-irradiation and their combination. Early changes of granular duct epitheliocytes after light and combined exposure were more significant in comparison with those on acinar cells. On the 10-th day after combined irradiation reduction of nucleoli and endoplasmatic reticulum in the duct cells was more pronounced as compared with similar period following light and X-ray irradiation. Long-term morphological changes in the glands after X-ray and combined irradiation were similar. It is concluded that radiation and round-the-clock light exposure act synergistically.

[Aroma-forming substance from a culture of the mold fungus Penicillium roqueforti during growth on milk curds]. / Aromatobrazuiushchie veshchestva kul'tury plesnevogo griba Penicillium roqueforti pri roste na molochnom sgustke.

Production of aroma-forming substances by Penicillium roqueforti strains no. 31 and no. 541-A grown on curd was studied. The data showed that the strain no. 541-A is the most promising producer of cheese flavor. The flavor acquired a soily scent after a long-term (4-5 days) cultivation, which may hamper the use of these cultures (particularly, no. 31) in the food industry.