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    Effect of precipitation inhibitors on supersaturation and solubility of furosemide
    (Marmara Univ, 2021) Gulsun, Tugba; Ozturk, Naile; Kara, Asli; Sahin, Selma; Vural, Imran
    Furosemide is a widely used diuretic drug for the treatment of edema associated with heart, liver cirrhosis, renal diseases and hypertension. It is a Class IV drug with low aqueous solubility and low permeability according to Biopharmaceutics Classification System (BCS). Furosemide was chosen as a model drug to examine the effect of polymeric precipitation inhibitors (PPIs) on the supersaturation and solubility. Solubility and concentration change of furosemide as a function of time at pH 1.2 and 6.8 were determined to show the effects of PPIs on furosemide solubility. The 24 h equilibrium solubility of furosemide was 0.017 +/- 0.004 and 3.62 +/- 0.201 mg/mL at pH 1.2 and pH 6.8 buffer solutions, respectively. PPI type and concentration (0.05%, 0.25%) did not increase furosemide solubility at pH 1.2. However, both hydroxypropylmethylcellulose (HPMC) and polyvinylpyrrolidoneK17 (PVPK17) at two concentrations increased furosemide solubility at pH 1.2 and 6.8. In addition, viscosity of solutions was in the range of 2.2-3.7 centipoise, and it was not influenced by PPIs concentrations. Our results showed that designing supersaturated formulations using PPIs can be useful and promising to enhance solubility of furosemide.
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    Preparation of nanosuspensions of a 1,4-dihydropyridine-based mixed L-/T-type calcium channel blocker by combined precipitation and ultrasonication methods
    (Elsevier, 2023) Pezik, Esra; Gulsun, Tugba; Gunduz, Miyase Gozde; Sahin, Selma; Ozturk, Naile; Vural, Imran
    M3, a condensed 1,4-dihydropyridine (DHP) derivative, targets both L- and T-type calcium channels and therefore, stands as a promising antihypertensive drug candidate. This study aims to improve the poor solubility of M3 using nanocrystal technology (a combination of precipitation and ultrasonication methods) to enhance its oral bioavailability. Pre-formulation studies were performed and M3 nanosuspensions were prepared using different stabilizers (polyvinyl pyrrolidone K30, polyvinyl alcohol, SoluPlus & REG;) and surfactants (poloxamer 188, poloxamer 407, sodium deoxycholate, sodium lauryl sulfate) at different concentrations (0.05, 0.1, 0.5, 1.0, 2.0%, w/v). The optimum nanosuspension formulation was freeze-dried using different cryoprotectants (mannitol, trehalose, glucose, sucrose, dextran) at different ratios (1.25, 2.5, 5.0%, w/v). It was determined that the most suitable cryoprotectant and ratio was 5.0% trehalose, resulting in nanocrystals with a size of 320.2 & PLUSMN; 15.3 nm and a zeta potential of -27.4 & PLUSMN; 0.1 mV. The physicochemical properties of M3, poloxamer 188, physical mixture and freeze-dried nanocrystals were evaluated by XRD, DSC and FT-IR analyses. Characterization studies showed amorphization of M3 in the freeze-dried nanocrystals prepared with poloxamer 188. The result of equilibrium solubility and permeability studies results indicated that M3 could be a BCS class 4 compound. Cell culture studies using Caco-2 cells showed that M3 had no significant toxic effect on the cells and had a Papp value of 2.2 x 10-7 cm/s. Compared to coarse M3 powder freeze-dried M3 nanocrystals showed a 200-fold increase in solubility and a 28.6-fold increase in apparent permeability. The cytotoxic effect of M3 was also reduced by using poloxamers as stabilizers in the formulation. M3 nanosuspensions were found to be a promising candidate for the oral administration of M3 for the potential treatment of hypertension due to the increase in solubility and permeability which could enhance its oral bioavailability.