Synthesis, Characterization, and Intrinsic Dissolution Studies of Drug-Drug Eutectic Solid Forms of Metformin Hydrochloride and Thiazide Diuretics.
ABSTRACT: The mechanochemical synthesis of drug-drug solid forms containing metformin hydrochloride (MET·HCl) and thiazide diuretics hydrochlorothiazide (HTZ) or chlorothiazide (CTZ) is reported. Characterization of these new systems indicates formation of binary eutectic conglomerates, i.e., drug-drug eutectic solids (DDESs). Further analysis by construction of binary diagrams (DSC screening) exhibited the characteristic V-shaped form indicating formation of DDESs in both cases. These new DDESs were further characterized by different techniques, including thermal analysis (DSC), solid state NMR spectroscopy (SSNMR), powder X-ray diffraction (PXRD) and scanning electron microscopy-energy dispersive X-ray spectroscopy analysis (SEM-EDS). In addition, intrinsic dissolution rate experiments and solubility assays were performed. In the case of MET·HCl-HTZ (χMET·HCl = 0.66), we observed a slight enhancement in the dissolution properties compared with pure HTZ (1.21-fold). The same analysis for the solid forms of MET·HCl-CTZ (χMET·HCl = 0.33 and 0.5) showed an enhancement in the dissolved amount of CTZ accompanied by a slight improvement in solubility. From these dissolution profiles and saturation solubility studies and by comparing the thermodynamic parameters (ΔHfus and ΔSfus) of the pure drugs with these new solid forms, it can be observed that there was a limited modification in these properties, not modifying the free energy of the solution (ΔG) and thus not allowing an improvement in the dissolution and solubility properties of these solid forms.
Project description:Lovastatin (LOV) is a drug used to treat hypercholesterolemia. Recent studies have identified its antioxidant effects and potential use in the treatment of some types of cancer. However, the low bioavailability related to its poor water solubility limits its use in solid oral dosage forms. Therefore, to improve the solubility of LOV three eutectic systems of LOV with the carboxylic acids benzoic (BEN), salicylic (SAL) and cinnamic (CIN) were obtained. Both binary phase and Tammann diagrams were constructed using differential scanning calorimetry (DSC) data of mixtures prepared from 0.1 to 1.0 molar ratios. Binary mixtures and eutectics were prepared by liquid-assisted grinding. The eutectics were further characterized by DSC and powder X-ray diffraction (PXRD), Fourier-transform infrared spectroscopy (FT-IR) and scanning electron microscopy (SEM). The LOV-BEN, LOV-SAL and LOV-CIN system formed a eutectic at an LOV mole fraction of 0.19, 0.60 and 0.14, respectively. The systems exhibited improvements in LOV solubility, becoming more soluble by five-fold in the LOV-SAL system and approximately four-fold in the other two systems. Considering that the solubility enhancements and the carboxylic acids used are generally recognized as safe by the U.S. Food and Drug Administration (FDA), the LOV eutectic systems are promising materials to be used in a solubility enhancement strategy for pharmaceutical product formulation.
Project description:Pterostilbene (3,5-dimethoxy-4'-hydroxystilbene, PTB) is a natural dietary stilbene, occurring primarily in blueberries and Pterocarpus marsupium heartwood. The interest in this compound is related to its different biological and pharmacological properties, such as its antioxidant, anti-inflammatory, and anticarcinogenic activities and its capacity to reduce and regulate cholesterol and blood sugar levels. Nevertheless, its use in therapy is hindered by its low aqueous solubility; to overcome this limitation we studied the feasibility of the use of cyclodextrins (CDs) as solubility-enhancing agents. CDs are natural macrocyclic oligomers composed of α-d-glucose units linked by α-1,4 glycosidic bonds to form torus-shaped molecules, responsible for inclusion complex formation with organic molecules. In particular, the aim of this study was to evaluate the feasibility of complexation between PTB and native CDs using various preparative methods. The isolated solid products were characterized using differential scanning calorimetry (DSC), simultaneous thermogravimetric/DSC analysis (TGA/DSC), Fourier transform infrared (FT-IR) spectroscopy, and X-ray diffraction (XRD) on powder and single crystals. The results indicated little or no evidence of the affinity of PTB to complex with α-CD using the kneading method. However, with β-CD and γ-CD thermal analysis revealed an interaction which was also corroborated by FT-IR and <sup>1</sup>H-NMR spectroscopy. With β-CD, a hydrated complex of PTB was isolated and its characterization by single-crystal XRD revealed, for the first time, the mode of inclusion of the PTB molecule in the cavity of a CD. To complement the solid-state data, liquid-phase studies were carried out to establish the effect of CDs on the aqueous solubility of PTB and to determine the complex stoichiometries and the association constants for complex formation. Phase-solubility studies showed A<sub>L</sub>-type profiles for α- and β-CD and a B<sub>S</sub> profile for γ-CD, with K<sub>1:1</sub> values of 1144, 4950, and 133 M<sup>-1</sup> for α-CD·PTB, β-CD·PTB, and γ-CD·PTB, respectively. The stoichiometry of CD·PTB complexes, determined by Job's method, revealed for each system a 1:1 molar ratio. The dissolution rate of PTB was approximately doubled just by employing simple physical mixtures, but the best performance was achieved by products obtained via kneading and co-precipitation, which effected the complete dissolution of PTB in 40 and 20 min for β-CD and γ-CD, respectively.
Project description:In this study, the phase diagram of the ternary system of ezetimibe-simvastatin-fenofibrate was established. It has been proven that the ternary composition recommended for the treatment of mixed hyperlipidemia forms a eutectic system. Since eutectic mixtures are characterized by greater solubility and dissolution rate, the obtained result can explain the marvelous medical effectiveness of combined therapy. Considering that another well-known method for improving the aqueous solubility is amorphization, the ternary system with eutectic concentration was converted into an amorphous form. Thermal properties, molecular dynamics, and physical stability of the obtained amorphous system were thoroughly investigated through various experimental techniques compared to both: neat amorphous active pharmaceutical ingredients (considered separately) and other representative concentrations of ternary mixture. The obtained results open up a new way of selecting the therapeutic concentrations for combined therapies, a path that considers one additional variable: eutecticity.
Project description:Telmisartan suffers from low oral bioavailability due to its poor water solubility. The research work presents a formulation of solid dispersed (SD) telmisartan formulation as a ternary mixture of a drug, a polymeric carrier (poly(vinylpyrrolidone) (PVP) K30), and an alkalizer (Na<sub>2</sub>CO<sub>3</sub>). The preparation method, which was lyophilization of an aqueous solution containing the ingredients, was free from any organic solvent. The developed SD formulations resulted in a significant improvement in <i>in vitro</i> dissolution (>90% drug dissolution in 15 min) compared to pure telmisartan. Solid-state characterization by scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and X-ray diffraction (XRD) studies indicated the conversion of crystalline telmisartan into an amorphous form. Fourier transform infrared (FTIR) spectroscopy revealed the drug-polymer interaction that was responsible for reducing the chances of recrystallization. A short-term stability study showed that selected SD formulations were stable in terms of <i>in vitro</i> dissolution and retained their amorphous structure in ambient and accelerated conditions over 2 months. Selected formulations (drug/PVP K30/Na<sub>2</sub>CO<sub>3</sub> as 1:1:2 or 1:2:2 weight ratio) resulted in >2.48 times relative oral bioavailability compared to marketed formulations. It was considered that the incorporation of an alkalizer and a hydrophilic polymer, and amorphization of telmisartan by lyophilization, could enhance <i>in vitro</i> dissolution and improve oral bioavailability.
Project description:Low aqueous solubility and poor bioavailability are major concerns in the development of oral solid-dosage drug forms. In this study, we fabricated surface-attached solid dispersion (SASD) to enhance the solubility, bioavailability, and photostability of methotrexate (MTX), a highly lipophilic and photo-unstable drug. Several MTX-loaded SASD formulations were developed for spray-drying using water as the solvent, and were investigated for their aqueous solubility and dissolution kinetics. An optimized ternary SASD formulation composed of MTX/ sodium carboxymethyl cellulose (Na-CMC)/sodium lauryl sulfate (SLS) at 3/0.5/0.5 (<i>w</i>/<i>w</i>) had 31.78-fold and 1.88-fold higher solubility and dissolution, respectively, than MTX powder. For SASD, the in vivo pharmacokinetic parameters AUC and C<sub>max</sub> were 2.90- and 3.41-fold higher, respectively, than for the MTX powder. Solid-state characterizations by differential scanning calorimetry and X-ray diffraction revealed that MTX exists in its crystalline state within the spray-dried SASD. The MTX-loaded SASD formulation showed few physical changes with photostability testing. Overall, the results indicate that the spray-dried MTX-loaded SASD formulation without organic solvents enhances the solubility and oral bioavailability of MTX without a significant deterioration of its photochemical stability.
Project description:The objective of this study was to formulate aripiprazole (ARI)-loaded pH-modulated solid dispersions (SD) to enhance solubility, dissolution, and bioavailability via hot-melt extrusion (HME) technology. Kollidon® 12 PF (PVP) and succinic acid (SA) were selected after solubility screenings of various polymers and acidifiers. Several formulations, varying in screw speed and drug/polymer/acidifier ratios, were extruded using an 11?mm twin-screw extruder and were investigated for the effect of these variables. Scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and X-ray diffraction (XRD) were used to perform solid-state characterizations of the pure drug and extrudates. The aqueous solubility and dissolution were evaluated for the pure drug and milled extrudates. Among the prepared formulations, N6 was chosen for in vivo absorption studies. Solid-state characterization demonstrated the transformation of the crystalline ARI to an amorphous state in the formulations. Each formulation showed increased solubility and dissolution compared to the drug powder. The oral bioavailability (Cmax and AUC0-12) of N6 was significantly improved when compared to the pure ARI. This novel study not only discusses the incorporation of acidifiers in SDs but also the preparation of SDs using HME technology as effective techniques to improve drug release and bioavailability.
Project description:A solid self-nanoemulsifying drug-delivery system (solid SNEDDS) has been explored to improve the solubility and dissolution profile of glipizide. SNEDDS preconcentrate was systematically optimized using a circumscribed central composite design by varying Captex 355 (Oil), Solutol HS15 (Surfactant) and Imwitor 988 (Co-surfactant). The optimized SNEDDS preconcentrate consisted of Captex 355 (30% w/w), Solutol HS15 (45% w/w) and Imwitor 988 (25% w/w). The saturation solubility (SS) of glipizide in optimized SNEDDS preconcentrate was found to be 45.12 ± 1.36 mg/ml, indicating an improvement (1367 times) of glipizide solubility as compared to its aqueous solubility (0.033 ± 0.0021 mg/ml). At 90% SS, glipizide was loaded to the optimized SNEDDS. In-vitro dilution of liquid SNEDDS resulted in a nanoemulsion with a mean droplet size of 29.4 nm. TEM studies of diluted liquid SNEDDS confirmed the uniform shape and size of the globules. The liquid SNEDDS was adsorbed onto calcium carbonate and talc to form solid SNEDDS. PXRD, DSC, and SEM results indicated that, the presence of glipizide as an amorphous and as a molecular dispersion state within solid SNEDDS. Glipizide dissolution improved significantly (p < 0.001) from the solid SNEDDS (∼100% in 15 min) as compared to the pure drug (18.37%) and commercial product (65.82) respectively.
Project description:Pharmaceutical eutectics are solid mixtures, where the crystals of active pharmaceutical ingredients (APIs) are finely divided in the phase-separated microstructures. The size reduction makes the eutectic formation a viable option to improve the dissolution rate of the poorly soluble APIs. In the present study, ibuprofen, naproxen, and sorafenib were investigated in terms of their phase behaviors with fatty alcohols, such as tetradecanol, octadecanol, and docosanol. Among the studied APIs, only ibuprofen was able to form eutectics with the fatty alcohols, and this was in agreement with the feasibility prediction based on the van 't Hoff equation and solubility parameters. In vitro release behavior was significantly improved for the ibuprofen/octadecanol eutectic mixture, although the practical insolubility of octadecanol in water was the opposite of the outstanding hydrophilicity of usual eutectic formers. The feasibility prediction and the choice of eutectic formers in the present study will be useful in advancing the utility of the pharmaceutical eutectics.
Project description:The preparation of new active pharmaceutical ingredient (API) multicomponent crystal forms, especially co-crystals and salts, is being considered as a reliable strategy to improve API solubility and bioavailability. In this study, three novel imidazole-based salts of the poorly water-soluble salicylic acid (SA) are reported exhibiting a remarkable improvement in solubility and dissolution rate properties. All structures were solved by powder X-ray diffraction. Multiple complementary techniques were used to solve co-crystal/salt ambiguities: density functional theory calculations, Raman and <sup>1</sup>H/<sup>13</sup>C solid-state NMR spectroscopies. In all molecular salts, the crystal packing interactions are based on a common charged assisted <sup>+</sup>N-H<sub>(SA)</sub> ? O<sup>-</sup><sub>(co-former)</sub> hydrogen bond interaction. The presence of an extra methyl group in different positions of the co-former, induced different supramolecular arrangements, yielding salts with different physicochemical properties. All salts present much higher solubility and dissolution rate than pure SA. The most promising results were obtained for the salts with imidazole and 1-methylimidazole co-formers.
Project description:Poor aqueous solubility of eplerenone (EPL) is a major obstacle to achieve sufficient bioavailability after oral administration. In this study, we aimed to develop and evaluate eplerenone nanocrystals (EPL-NCs) for solubility and dissolution enhancement. D-optimal combined mixture process using Design-Expert software was employed to generate different combinations for optimization. EPL-NCs were prepared by a bottom-up, controlled crystallization technique during freeze-drying. The optimized EPL-NCs were evaluated for their size, morphology, thermal behavior, crystalline structure, saturation solubility, dissolution profile, <i>in vivo</i> pharmacokinetics, and acute toxicity. The optimized EPL-NCs showed mean particle size of 46.8 nm. Scanning electron microscopy revealed the formation of elongated parallelepiped shaped NCs. DSC and PXRD analysis confirmed the crystalline structure and the absence of any polymorphic transition in EPL-NCs. Furthermore, EPL-NCs demonstrated a 17-fold prompt increase in the saturation solubility of EPL (8.96 vs. 155.85 µg/mL). The dissolution rate was also significantly higher as indicated by ∼95% dissolution from EPL-NCs in 10 min compared to only 29% from EPL powder. EPL-NCs improved the oral bioavailability as indicated by higher AUC, <i>C</i><sub>max</sub>, and lower <i>T</i><sub>max</sub> than EPL powder. Acute oral toxicity study showed that EPL-NCs do not pose any toxicity concern to the blood and vital organs. Consequently, NCs prepared by controlled crystallization technique present a promising strategy to improve solubility profile, dissolution velocity and bioavailability of poorly water-soluble drugs.