Technologic Considerations of Creation Dosage Form of Original Substance 3,7-diazabicyclo[3.3.1]nonane

Introduction. An innovative pharmaceutical substance based on the 3,7-diazabicyclo[3.3.1]nonane derivative provides long-term activation of AMPA receptors and the production of neurotrophic factors, which makes it possible to use it for the treatment of cognitive impairments and rehabilitation of patients who have undergone acute brain hypoxia. Given that this substance is able to be absorbed through the walls of the gastrointestinal tract and pass through the blood-brain barrier, there are no restrictions on the development of an oral dosage form. In addition, the oral dosage form has significant advantages when used in geriatric and pediatric practice.Aim. The aim of the work was to carry out a comparative study of the possibility of using gelatin and hypromellose capsules for the development of the composition and technology for obtaining a dosage form containing a pharmaceutical substance based on a 3,7-diazabicyclo[3.3.1]nonane derivative.Materials and methods. The study of the «Dissolution» test of gelatinous and hypromellose capsules was carried out on an ERWEKA DT 720 «Paddle stirrer» apparatus at a stirrer rotation speed of 50 rpm in three media: pH 1.2, pH 4.5 and pH 6.8. The content of the substance in each sample was determined by high performance liquid chromatography with UV detection.Results and discussion. The results of the development and testing of capsules containing an original pharmaceutical substance of nootropic action based on a derivative of 3,7-diazabicyclo[3.3.1]nonane, which has low pharmaceutical and technological characteristics and is practically insoluble in water, are presented. The D/S value was ≥250.00 ml in each physiological pH range. The results of determining the dissolution of the developed dosage form in three media at pH values of 1.2, 4.5 and 6.8 showed a positive effect of the technology used on the solubility of the substance.Conclusion. A significant increase in the solubility of the practically insoluble substance of the 3,7-diazabicyclo[3.3.1]nonane derivative in the developed dosage form was shown, which is the result of the use of a well-founded complex of excipients and the technology of moisture-activated granulation. According to the results obtained, (77.60 ± 2.50) % of the substance passes into the dissolution medium with a pH of 4.5 in 45 minutes. The research results are used to develop a technological scheme for obtaining a finished dosage form, its indicators and quality standards.

The development of the physicochemical characteristics of the new original nootropic substance TST-9

Physicochemical properties of the original pharmaceutical substance TST-9 based on the 3,7-diazabicyclo[3.3.1]nonane derivative with the chemical name IUPAC 6-[4methoxy-3-(1H-pyrazol-1-ylmethyl) benzyl]-1,11-dimethyl-3,6,9-triazatricyclo[7.3.1.1]tetradecane-4,8,12-trion, were studied. TST-9 is used as an active substance for the development of the composition and technology for the preparation of an innovative oral drug. The pharmaceutical substance TST-9 is an amorphous white powder, odorless, soluble in chloroform, acetonitrile, methylene chloride, acetone, dimethyl sulfoxide, dimethylformamide and alcohol, sparingly soluble in diethyl ether, dioxane and is very slightly soluble in water, hexane, and heptane. The melting point ranged from 94°C to 96°C without visible decomposition of the substance. The microbiological purity corresponds to category 2.2. Residual organic solvents in the form of chloroform did not exceed 0.006%. The amount of impurities was not more than 0.15%. The loss in mass upon drying was not more than 0.5%. The “identity” was confirmed using nuclear magnetic resonance spectroscopy and HPLC with UV detection. The data obtained in the study will contribute to the further development of the dosage form, the choice of the route of administration and the dosage regimen, as well as the selection of analytical methods for analyzing the quality of the finished dosage form and the effective, high-precision determination of the content of the active substance and its likely decay products.

Collective Total Synthesis of PPAPs: Total Synthesis of Clusianone via Intramolecular Cyclopropanation

The total synthesis of clusianone was accomplished through the stereoselective construction of a bicyclo[3.3.1]nonane derivative via a three-step sequence which has been utilized for the total syntheses of nemorosone garsubellin A and hyperforin: intramolecular cyclopropanation formation of a geminal dimethyl group and regioselective ring opening of cyclopropane. Further elaboration including chemo- and stereoselective hydrogenation to generate the C7 stereogenic center and cross-metathesis to construct prenyl groups in the side-chains was employed to complete the total synthesis of clusianone.