The medicinal chemistry of cyclo(Phe-4CI-Pro) and Cyclo(D-Phe-4CI-Pro)

Cyclic dipeptides have limited conformational freedom due to their diketopiperazine backbone and their small size. They are relatively simple to synthesise, making them ideal subjects for investigation into their biological effects. Cyclic dipeptides have also been known for their multitude of biological activities, including antimicrobial, anticancer and haematological properties. In this study the cyclic dipeptides, cyclo(Phe-4Cl-Pro) and cyclo(D-Phe-4Cl-Pro), were synthesised from their corresponding linear precursors using a modified phenol-induced cyclisation procedure. The phenol induced cyclisation procedure resulted in good yields and purity of the cyclic dipeptides. Quantitative analysis and evaluation of the physiochemical properties of the cyclic dipeptides was achieved using high-performance liquid chromatography, scanning electron microscopy, thermal analysis and X-ray powder diffraction. Structural elucidation of the cyclic dipeptides was done by means of infrared spectroscopy, mass spectroscopy, nuclear magnetic resonance spectroscopy and molecular modelling. The study‟s aim was to determine the biological activity of cyclo(Phe-4Cl-Pro) and cyclo(D-Phe-4Cl-Pro) with respect to their anticancer, antimicrobial, haematological and ant-diabetic studies. Anticancer studies revealed that cyclo(Phe-4Cl-Pro) and cyclo(D-Phe-4Cl-Pro) inhibited the growth of HeLa (cervical cancer), HT-29 (colon cancer) and MCF-7 (breast cancer) cancer cell lines. Both cyclic dipeptides also inhibited the growth of certain selected Gram-positive, Gram-negative and fungal microorganisms in the antimicrobial study. Although the inhibition of growth in the anticancer and antimicrobial studies was statistically significant, the clinical relevance is questionable, since the inhibition produced by both cyclic dipeptides was very limited compared to other pre-existing anticancer and antimicrobial agents. Both cyclic dipeptides caused a significant shortening of the APTT and PT clotting times and an increase in the fibrin and D-Dimer formation. Cyclo(D-Phe-4Cl-Pro) at a screening concentration of 12.5 mM and 3.125 mM, showed significant anti-platelet activity. Both cyclic dipeptides failed to produce any inhibition of the α-Glucosidase enzyme and very limited inhibition of the α-Amylase enzyme

The medicinal chemistry of cyclo(Phe-4CI-Pro) and Cyclo(D-Phe-4CI-Pro)

Cyclic dipeptides have limited conformational freedom due to their diketopiperazine backbone and their small size. They are relatively simple to synthesise, making them ideal subjects for investigation into their biological effects. Cyclic dipeptides have also been known for their multitude of biological activities, including antimicrobial, anticancer and haematological properties. In this study the cyclic dipeptides, cyclo(Phe-4Cl-Pro) and cyclo(D-Phe-4Cl-Pro), were synthesised from their corresponding linear precursors using a modified phenol-induced cyclisation procedure. The phenol induced cyclisation procedure resulted in good yields and purity of the cyclic dipeptides. Quantitative analysis and evaluation of the physiochemical properties of the cyclic dipeptides was achieved using high-performance liquid chromatography, scanning electron microscopy, thermal analysis and X-ray powder diffraction. Structural elucidation of the cyclic dipeptides was done by means of infrared spectroscopy, mass spectroscopy, nuclear magnetic resonance spectroscopy and molecular modelling. The study‟s aim was to determine the biological activity of cyclo(Phe-4Cl-Pro) and cyclo(D-Phe-4Cl-Pro) with respect to their anticancer, antimicrobial, haematological and ant-diabetic studies. Anticancer studies revealed that cyclo(Phe-4Cl-Pro) and cyclo(D-Phe-4Cl-Pro) inhibited the growth of HeLa (cervical cancer), HT-29 (colon cancer) and MCF-7 (breast cancer) cancer cell lines. Both cyclic dipeptides also inhibited the growth of certain selected Gram-positive, Gram-negative and fungal microorganisms in the antimicrobial study. Although the inhibition of growth in the anticancer and antimicrobial studies was statistically significant, the clinical relevance is questionable, since the inhibition produced by both cyclic dipeptides was very limited compared to other pre-existing anticancer and antimicrobial agents. Both cyclic dipeptides caused a significant shortening of the APTT and PT clotting times and an increase in the fibrin and D-Dimer formation. Cyclo(D-Phe-4Cl-Pro) at a screening concentration of 12.5 mM and 3.125 mM, showed significant anti-platelet activity. Both cyclic dipeptides failed to produce any inhibition of the α-Glucosidase enzyme and very limited inhibition of the α-Amylase enzyme

The validation of a simple, robust, stability-indicating rp-hplc method for the simultaneous detection of lamivudine, tenofovir disoproxil fumarate, and dolutegravir sodium in bulk material and pharmaceutical formulations

An effective analytical method is requisite to ensure the accurate identification and quantification of drug(s), either in bulk material or in complex matrices, which form part of finished pharmaceutical products. For the purpose of a pharmaceutical formulation study, it became necessary to have a simple, yet robust and reproducible reversed-phase HPLC method for the simultaneous detection and quantification of lamivudine (3TC), tenofovir disoproxil fumarate (TDF), and dolutegravir sodium (DTG) in bulk form, complex polymeric matrices, and during drug release studies. A suitable method was developed using a Kinetex® C18, 250 × 4.6 mm column as stationary phase and a mobile phase consisting of 50 : 50 v/v methanol and water with 1 mL orthophosphoric acid, with a flow rate of 1.0 mL/min and column temperature maintained at 35°C. A detection wavelength of 260 nm and an injection volume of 10 μL were used. ,e method was validated according to the International Conference on Harmonization (ICH) guideline Q2 (R1), and the parameters of linearity and range, accuracy, precision, specificity, limit of detection (LOD), limit of quantification (LOQ), robustness, and stability were all determined. Acceptable correlation coefficients for linearity (R2) of >0.998 for each of the three drugs were obtained. ,e LOD was quantified to be 56.31 μg/mL, 40.27 μg/mL, and 7.00 μg/mL for 3TC, TDF, and DTG, respectively, and the LOQ was quantified as 187.69 μg/mL, 134.22 μg/mL, and 22.5 μg/mL for 3TC, TDF, and DTG, respectively. In relation to all the determined validation parameters, this method proves to be suitable for the accurate identification and quantification of the three ARVs, either alone or in combination, as well as when incorporated into polymeric matrices. Furthermore, the method proves to be suitable to detect degradation of the compounds

The stabilization of amorphous zopiclone in an amorphous solid dispersion

Zopiclone is a poorly soluble psychotherapeutic agent. The aim of this study was to prepare and characterize an amorphous form of zopiclone as well as the characterization and performance of a stable amorphous solid dispersion. The amorphous form was prepared by the well-known method of quenchcooling of the melt. The solid dispersion was prepared by a solvent evaporation method of zopiclone, polyvinylpyrrolidone-25 (PVP-25), and methanol, followed by freeze-drying. The physico-chemical properties and stability of amorphous zopiclone and the solid dispersion was studied using differential scanning calorimetry (DSC), infrared spectroscopy (FT-IR), thermogravimetric analysis (TGA), scanning electron microscopy (SEM), hot-stage microscopy (HSM), X-ray diffractometry (XRD), solubility, and dissolution studies. The zopiclone amorphous solid-state form was determined to be a fragile glass; it was concluded that the stability of the amorphous form is influenced by both temperature and water. Exposure of amorphous zopiclone to moisture results in rapid transformation of the amorphous form to the crystalline dihydrated form. In comparison, the amorphous solid dispersion proved to be more stable with increased aqueous solubilityNorth-West University, South Africa (Potchefstroom Campus) as well as the National Research Foundation (NRF) of South Afric

Different amorphous solid-state forms of roxithromycin: a thermodynamic and morphological study

The striking impact that different preparation methods have on the characteristics of amorphous solidstate forms has attracted considerable attention during the last two decades. The pursuit of more extensive knowledge regarding polyamorphism therefore continues. The aim of this study was firstly, to investigate the influence of different preparation techniques to obtain amorphous solid-state forms for the same active pharmaceutical ingredient, namely roxithromycin. The preparation techniques also report on a method utilizing hot air, which although it is based on a melt intermediary step, is considered a novel preparation method. Secondly, to conduct an in-depth investigation into any physico-chemical differences between the resulting amorphous forms and thirdly, to bring our findings into context with that of previous work done, whilst simultaneously discussing a well-defined interpretation for the term polyamorphism and propose a discernment between true polyamorphism and pseudo-polyamorphism/ atypical-polyamorphism. The preparation techniques included melt, solution, and a combination of solution-mechanical disruption as intermediary steps. The resulting amorphous forms were investigated using differential scanning calorimetry, X-ray powder diffraction, hot-stage microscopy, scanning electron microscopy, and vapor sorption. Clear and significant thermodynamic differences were determined between the four amorphous forms. It was also deduced from this study that different preparation techniques have a mentionable impact on the morphological properties of the resulting amorphous roxithromycin powders. Thermodynamic properties as well as the physical characteristics of the amorphous forms greatly governed other physico-chemical properties i.e. solubility and dissolutionNational Research Foundation (NRF) of South Africa(Grant no.: TTK13020718661); Centre of Excellence for Pharmaceutical Sciences (Pharmacen) at the North-West Univer- sity Potchefstroom, South Afric

The Effect of Isoniazid–Maltitol Solid Dispersions on Aqueous Solubility and Permeability

Maltitol (MAL) is a well-known polyol with potential pharmaceutical applications. Unlike other polyols, its utilization as a carrier for solid dispersions (SDs) has not been adequately investigated. This research studied the feasibility of MAL as an SD carrier to enhance the biopharmaceutical properties of a BCS class I/III drug, isoniazid (INH). SDs of INH–MAL were prepared by the fusion method, and physicochemical characteristics were investigated to determine the solid-state habit, solubility and permeation enhancement of INH. Fourier-transform infrared (FT-IR) spectroscopy demonstrated significant peak broadening for the SDs consisting of a higher MAL concentration. Powder X-ray diffraction indicated a decrease in degree of crystallinity with increasing MAL concentration. Hot-stage microscopy (HSM) and scanning electron microscopy (SEM) revealed that INH–MAL molar ratios affect the type of SD prepared via the fusion method. Results from the equilibrium solubility studies indicated significant INH solubility improvement (p < 0.05) with SDs in comparison with the pure drug and physical mixtures. The artificial membrane permeation assay (PAMPA) of INH was positively affected by the presence of MAL. The results of the study indicated the potential for MAL as a carrier in the preparation of SDs for the solubility and/or permeability enhancement of drugs

A Comprehensive Review of Cross-Linked Gels as Vehicles for Drug Delivery to Treat Central Nervous System Disorders

Gels are attractive candidates for drug delivery because they are easily producible while offering sustained and/or controlled drug release through various mechanisms by releasing the therapeutic agent at the site of action or absorption. Gels can be classified based on various characteristics including the nature of solvents used during preparation and the method of cross-linking. The development of novel gel systems for local or systemic drug delivery in a sustained, controlled, and targetable manner has been at the epitome of recent advances in drug delivery systems. Cross-linked gels can be modified by altering their polymer composition and content for pharmaceutical and biomedical applications. These modifications have resulted in the development of stimuli-responsive and functionalized dosage forms that offer many advantages for effective dosing of drugs for Central Nervous System (CNS) conditions. In this review, the literature concerning recent advances in cross-linked gels for drug delivery to the CNS are explored. Injectable and non-injectable formulations intended for the treatment of diseases of the CNS together with the impact of recent advances in cross-linked gels on studies involving CNS drug delivery are discussed