Multicomponent solid forms of the BCS class IV drug furosemide (FSM) were obtained upon liquid assisted grinding with coformers anthranilamide (ANT), 4-toluamide (TOL), 2-picolinamide (PCM), ...piperazine (PPZ), 2,3,5,6-tetramethylpyrazine (TMPZ), pyrazine (PYZ), 2-picolinic acid (PIC), isoniazid (INZ), and theophylline (THP), and identified with powder X-ray diffraction. Solid forms FSM–TMPZ (2:1), FSM–ANT (1:1), FSM–PPZ (1:1), and FSM–TOL ethanol solvate (1:1:1) were further characterized with single crystal X-ray diffraction and differential scanning calorimetry; a sesquihydrate structure for FSM–PCM (1:1:1.5) was additionally confirmed with thermogravimetric analysis. The thermodynamically stable form I of FSM contains O–H···O acid···acid and N–H···O sulfonamide dimer synthons and chains. These synthons are modified in the cocrystals/salts sometimes leading to changes in physicochemical properties. The FSM–PPZ (1:1) salt converted to a thermodynamically more stable form FSM–PPZ (2:1) within 1 h. The apparent solubility of FSM–PPZ (1:1) salt is ∼3 times higher than the equilibrium solubility of the thermodynamically stable FSM–PPZ (2:1) salt. The solubilities of FSM–TMPZ and FSM–ANT are comparable to FSM, and this could be linked to coformer solubility. The metastable FSM–PCM sesquihydrate exhibited unusually high FSM concentration in solution as a function of time and as monitored in a slurry experiment. This prolonged presence of FSM in solution is rationalized by a synthon-extended-spring-and-parachute model. Our rationale starts with Nangia’s explanation of the apparently high solubility of pharmaceutical cocrystals based on the simple spring-and-parachute model of Guzman et al. and later detailed by Brouwers et al. We go on to suggest that certain heteromolecular aggregates might well persist in soluble amorphous forms leading to a higher persistence of the drug in solution. Cocrystals/salts with higher solubility show higher values of initial diffusion/flux. A few bases when used as coformers render stable salt/cocrystals that resulted in low solubility/diffusion. In the new solid forms of FSM studied here, solubility and flux are seen to go hand in handan observation of import in drug absorption.
An elastic organic crystal, 2,6-dichlorobenzylidine-4-fluoro-3-nitroaniline (DFNA), which also shows thermosalient behavior, is studied. The presence of these two distinct properties in the same ...crystal is unusual and unprecedented because they follow respectively from isotropy and anisotropy in the crystal packing. Therefore, while both properties lead from the crystal structure, the mechanisms for bending and thermosalience are quite independent of one another. Crystals of the low-temperature (α) form of the title compound are bent easily without any signs of fracture with the application of deforming stress, and this bending is within the elastic limit. The crystal structure of the α-form was determined (P21/c, Z = 4, a = 3.927(7) Å, b = 21.98(4) Å, c = 15.32(3) Å). There is an irreversible phase transition at 138 °C of this form to the high-temperature β-form followed by melting at 140 °C. Variable-temperature X-ray powder diffraction was used to investigate the structural changes across the phase transition and, along with an FTIR study, establishes the structure of the β-form. A possible rationale for strain build-up is given. Thermosalient behavior arises from anisotropic changes in the three unit cell parameters across the phase transition, notably an increase in the b axis parameter from 21.98 to 22.30 Å. A rationale is provided for the existence of both elasticity and thermosalience in the same crystal. FTIR studies across the phase transition reveal important mechanistic insights: (i) increased π···π repulsions along 100 lead to expansion along the a axis; (ii) change in alignment of C–Cl and NO2 groups result from density changes; and (iii) competition between short-range repulsive (π···π) interactions and long-range attractive dipolar interactions (C–Cl and NO2) could lie at the origin of the existence of two distinctive properties.
A new multicomponent solid consisting of an antibacterial (norfloxacin) and an antimicrobial (sulfathiazole) was made and characterized with single crystal X-ray diffraction, PXRD, FTIR, and DSC. The ...title salt shows enhanced solubility in different pH buffers and improved diffusion as well as release and inhibition of bacterial and fungal species relative to the parent drugs. The enhanced in vitro biological properties of the drug–drug salt hydrate may be attributed to the higher extent of its supersaturation with respect to the individual components, which leads to higher diffusion rates.
Hydrochlorothiazide (HCT) is a diuretic and a BCS class IV drug with low solubility and low permeability, exhibiting poor oral absorption. The present study attempts to improve the physicochemical ...properties of the drug using a crystal engineering approach with cocrystals. Such multicomponent crystals of HCT with nicotinic acid (NIC), nicotinamide (NCT), 4-aminobenzoic acid (PABA), succinamide (SAM), and resorcinol (RES) were prepared using liquid-assisted grinding, and their solubilities in pH 7.4 buffer were evaluated. Diffusion and membrane permeability were studied using a Franz diffusion cell. Except for the SAM and NIC cocrystals, all other binary systems exhibited improved solubility. All of the cocrystals showed improved diffusion/membrane permeability compared to that of HCT with the exception of the SAM cocrystal. When the solubility was high, as in the case of PABA, NCT, and RES cocrystals, the flux/permeability dropped slightly. This is in agreement with the expected interplay between solubility and permeability. Improved solubility/permeability is attributed to new drug–coformer interactions. Cocrystals of SAM, however, showed poor solubility and flux. This cocrystal contains a primary sulfonamide dimer synthon similar to that of HCT polymorphs, which may be a reason for its unusual behavior. Hirshfeld surface analysis was carried out in all cases to determine whether a correlation exists between cocrystal permeability and drug–coformer interactions.
Access to reliable electricity is crucial for rural development and improving the quality of life in remote areas. Standalone photovoltaic PV systems and hybrid power systems HPS are promising ...solutions for rural electrification. However, frequency stabilization is a critical challenge in such systems, and conventional control techniques are inadequate. This work proposes a novel approach to optimize the PID controller gains for the standalone PV-based isolated HPS (IHPS). The student psychology-based optimization algorithm (SPBOA) and quasi-oppositional-based whale optimization algorithm (QOWOA) are employed to enhance the performance of the IHPS models separately. The objective function considered is the integral of time absolute error (ITAE), and the frequency response profile is studied in the presence of the proposed SPBOA and QOWOA-based PID controllers. The results show that the proposed SPBOA outperforms the QOWOA in terms of reducing the ITAE by nearly 5% and minimizing the peak and settling time of the frequency response by 5%-7% in different scenarios. The transient responses of the systems to different input conditions are also analyzed, indicating that both the IHPS-I and IHPS-II models are feasible for remote rural electrification. Overall, the proposed approach offers an efficient solution to optimize the PID controller gains for frequency stabilization in standalone PV and HPS. The results demonstrate the benefits of using the SPBOA and QOWOA algorithms to enhance the performance of the systems, making them suitable for remote rural electrification.
Sildenafil is a drug used to treat erectile dysfunction and pulmonary arterial hypertension. Because of poor aqueous solubility of the drug, the citrate salt, with improved solubility and ...pharmacokinetics, has been marketed. However, the citrate salt requires an hour to reach its peak plasma concentration. Thus, to improve solubility and bioavailability characteristics, cocrystals and salts of the drug have been prepared by treating aliphatic dicarboxylic acids with sildenafil; the N-methylated piperazine of the drug molecule interacts with the carboxyl group of the acid to form a heterosynthon. Salts are formed with oxalic and fumaric acid; salt monoanions are formed with succinic and glutaric acid. Sildenafil forms cocrystals with longer chain dicarboxylic acids such as adipic, pimelic, suberic, and sebacic acids. Auxiliary stabilization via C–H···O interactions is also present in these cocrystals and salts. Solubility experiments of sildenafil cocrystal/salts were carried out in 0.1N HCl aqueous medium and compared with the solubility of the citrate salt. The glutarate salt and pimelic acid cocrystal dissolve faster than the citrate salt in a two hour dissolution experiment. The glutarate salt exhibits improved solubility (3.2-fold) compared to the citrate salt in water. Solubilities of the binary salts follow an inverse correlation with their melting points, while the solubilities of the cocrystals follow solubilities of the coformer. Pharmacokinetic studies on rats showed that the glutarate salt exhibits doubled plasma AUC values in a single dose within an hour compared to the citrate salt. The high solubility of glutaric acid, in part originating from the strained conformation of the molecule and its high permeability, may be the reason for higher plasma levels of the drug.
This paper describes an application of quasi-oppositional harmony search (QOHS) algorithm to design the scaling factor (SF) based fuzzy-classical controller (such as PI/PD/PID) for frequency and ...power control of an isolated hybrid power system (IHPS). The considered IHPS model is comprised of a wind turbine generator, a diesel engine generator and an energy storage device (such as superconducting magnetic energy storage (SMES), in this case). Traditionally, SF, membership functions and control rules are obtained in fuzzy logic controllers (FLCs) by trial and error method or are obtained based on the experiences of the designers or are optimized by some traditional optimization techniques with some extra computational cost. To overcome all these problems of FLCs, classical controllers have been integrated in this paper with the FLC. QOHS algorithm is applied to simultaneously tune the SFs (the only tunable parameter of FLC), the gains of the classical controllers and the tunable parameters of the SMES device to minimize frequency and power deviations of the studied IHPS system against various load demand and wind change. Different considered controller configurations of the IHPS are SF based FLC (termed as Fuzzy-only), SF based FLC with proportional-integral (PI) (named as Fuzzy-PI) controller, SF based FLC with proportional-derivative (PD) (abbreviated as Fuzzy-PD) controller and SF based FLC with proportional-integral-derivative (PID) (designated as Fuzzy-PID) controller. Simulation results, explicitly, show that the performance of the Fuzzy-PID controller based IHPS is superior to Fuzzy-only, Fuzzy-PI and Fuzzy-PD controller based IHPS configuration in terms of overshoot, settling time and the proposed Fuzzy-PID controller is robust against various wide range of load changes.
•Load frequency stabilization of IHPS is studied under different three scenarios.•Impact of SMES as frequency stabilization is studied.•Impact of WTG in frequency stabilization is studied connected ...with thermal system.•QOHS algorithm is used to tune the PID and SMES controller gains.
This paper investigates the load frequency control (LFC) of two different configurations of power system model. The first one is worked as an isolated hybrid power system (HPS) (IHPS) while the second one is a grid tied HPS (GHPS). In IHPS, the power generating units are diesel engine generator (DEG), wind turbine generator (WTG) and solar thermal power generation (STPG). It is considered in such a way that the generation persists throughout the day with uninterrupted power supply. The energy storage device used in this work is superconducting magnetic energy storage (SMES). The three scenarios considered in isolated mode are (a) HPS with one DEG, one WTG and one STPG, (b) HPS with one DEG and one STPG and (c) HPS with one DEG and one WTG. As concerned to GHPS, a combination of WTG and steam thermal power plant is considered. A conventional proportional-integral-derivative (PID) controller has been used as supplementary control mechanism. The PID controller gains and the tunable parameters of the SMES are tuned by the use of quasi-oppositional harmony search (QOHS) algorithm. Initially, integral of time absolute error based objective function is minimized and, subsequently, three performance indices such as integral of absolute error, integral of square error and integral of time square error are calculated to test the designed efficiency of the proposed QOHS based PID controller. The transient responses of systems pertaining to step and random changes in the load demand are analyzed. The simulated results obtained by the QOHS algorithm reveals that it may be imposed to boost LFC performance of the power system.
•High pressure Raman spectroscopic measurements have been carried out on Cinnarizine up to 15.3 GPa.•The compound develops broader bands with pressure with some modes changing from ∼0.9 GPa.•Change ...in dω/dP values indicate phase changes around ∼2.7, ∼5, ∼7.5 ∼9 and ∼1112 GPa.•Most of the modes show irreversible changes with pressure with pressure and do not recover at all after decompression of the sample whereas other vibrational modes involving rings 1,2 and 3 do show partial recovery after decompression.•Pressure induced phase transition below 1 GPa and ensuing disorder could have an effect on the solubility, dissolution and pharmacokinetics of the solid drug.•As tableting pressures are around 0.20.5 GPa, it is likely that a tableted form could have a different profile and they need to be checked for physicochemical behavior and PK/PD.
Raman spectra of Cinnarizine in the 35–3400 cm-1 region were studied at high pressures up to 15.3 GPa, using a Diamond Anvil Cell. Broadening of bands is observed starting from ∼0.9 up to ∼11–12 GPa pressures as evidenced by the changes in the Raman spectra of some modes. Plots of frequency vs pressure of bands, show increase of frequency with pressure for most of the bands and the slopes, dω/dP, of some bands show clear changes around ∼2.7, ∼5, ∼7.5 ∼9 and ∼11–12 GPa indicating phase transformation caused by changes in structure and chemical bonds at these pressures. The present article describes high pressure effects on cinnarizine studied by Raman Spectroscopy and is supported by density function theoretical calculations.
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