Phase Solubility Diagrams Research Articles

Comparative analysis of solubilization and complexation characteristics for new antifungal compound with cyclodextrins. Impact of cyclodextrins on distribution process

From a pharmaceutical standpoint, cyclodextrin-based products have deservedly gained substantial market share due to their ability to improve undesirable physicochemical properties of drugs. In this study the solubility of a potenial antifungal compound (L-173) has been improved essentially by addition of β-cyclodextrin (β-CD), 2-hydroxypropyl-β-cyclodextrin (HP-β-CD), and heptakis(2,6-di-O-methyl)-β-cyclodextrin (DM-β-CD) in aqueous solutions (pH 2.0 and pH 7.4) at 298.15–313.15 K. The phase solubility diagrams were constructed. The stoichiometric ratio of the complexes was determined as 1:1. The stability constants of L-173 with all three CDs in acidic medium belong to the range optimal for the improvement of the bioavailability of hydrophobic drugs. DM-β-CD was assigned as the best solubilizer for L-173. The driving forces of the solubilization and complexation process were revealed by evaluating the thermodynamic parameters. The distribution behavior of L-173 in the 1-octanol/buffer and 1-hexane buffer systems at pH 2.0 and pH 7.4 in the presence of different CDs concentrations was studied. The reduction of the distribution coefficients with the increasing of CD concentration was detected due to complex formation. Based on the analysis of the solubility-distribution relationship, the L-173 partitioning between the biological tissues and penetration through the biological membranes in case when cyclodextrins are used as solubilizers was evaluated, and the optimal CD concentrations were proposed.

Preparation and in vitro characterization of rosuvastatin calcium incorporated methyl beta cyclodextrin and Captisol® inclusion complexes

Despite being the most effective hypolipidemic agent, poor physicochemical properties of Rosuvastatin calcium (RCa) remain challenging obstacles in the development of pharmaceutical dosage forms. Inclusion complexes (ICs) of RCa with cyclodextrin (CD) derivatives; methyl-beta-cyclodextrin (M-β-CD) and sulfobutylether-beta-cyclodextrin (SBE-β-CD; Captisol®) were formulated by kneading and freeze-drying (lyophilization) methods. Pysicochemical properties of ICs were evaluated by SEM, DSC, XRD, FT-IR, 1H-NMR analyses. Entrapment efficiency (EE), water solubility, in vitro release analyses were also performed. Safety and efficacy of the ICs were analyzed by cytotoxicity and permeation studies on Caco-2 cell lines. Both CDs indicated AL type phase solubility diagrams showing that [1:1] molar ratio. Apparent stability constants (K1:1) were found to be 60.93 M−1 for M-β-CD and 158.07 M−1 for Captisol®. High EE in the range of 93.50–105.40% was achieved. Molar solubility of RCa was increased 3.7- and 4.1-fold with M-β-CD and Captisol® ICs, respectively. In vitro release analyses have indicated the equivalence of dissolution profiles for M-β-CD and Captisol® based ICs to that of pure RCa (f2 > 50). Cytotoxicity studies on Caco-2 cell lines have revealed the safety of ICs for oral use. Permeability studies demonstrated that selected lyophilized F6 formulation has shown the best permeation rate with Papp value of 3.08 × 10−7 cm·s−1. Considering greater water solubility, lower toxicity, high efficiency of complexation as well as, RCa-like permeability and in vitro release behavior at pH 6.8; Captisol® based lyophilized F6 formulation was selected as the best IC to be used in oral dosage forms of RCa.

Coamorphization combined with complexation enhances dissolution of lurasidone hydrochloride and puerarin with synchronized release.

Coamorphous systems have gained increasing interests due to their ability to enhance solubility and dissolution of poorly soluble drugs. In the current study, coamorphous system of lurasidone hydrochloride (LH), a BCS class II drug, with puerarin (PUE) was prepared by the solvent-evaporation method. The observation of a single Tg at 65.8°C in differential scanning calorimetry thermogram and the absence of crystalline diffraction peaks in powder X-ray diffraction pattern indicated the formation of coamorphous LH-PUE. Compared to physical mixture of amorphous LH and amorphous PUE, peak shifts in FTIR with principal component analysis indicated potential intermolecular hydrogen bonding formed between the carbonyl group of LH and the hydroxyl group of PUE in the coamorphous system. In comparison to crystalline/amorphous LH and PUE, the coamorphous system exhibited significantly enhanced dissolution with synchronized release behavior of LH and PUE, which was mainly due to the complexation formation between LH and PUE in solution proved by fluorescence quenching test and phase-solubility diagram. In addition, coamorphous LH-PUE showed superior physical stability over pure amorphous LH and PUE under both long-term and accelerated storage conditions.

Capsaicin-Cyclodextrin Complex Enhances Mepivacaine Targeting and Improves Local Anesthesia in Inflamed Tissues.

Acidic environments, such as in inflamed tissues, favor the charged form of local anesthetics (LA). Hence, these drugs show less cell permeation and diminished potency. Since the analgesic capsaicin (CAP) triggers opening of the TRPV1 receptor pore, its combination with LAs could result in better uptake and improved anesthesia. We tested the above hypothesis and report here for the first time the analgesia effect of a two-drug combination (LA and CAP) on an inflamed tissue. First, CAP solubility increased up to 20 times with hydroxypropyl-beta-cyclodextrin (HP-β-CD), as shown by the phase solubility study. The resulting complex (HP-β-CD-CAP) showed 1:1 stoichiometry and high association constant, according to phase-solubility diagrams and isothermal titration calorimetry data. The inclusion complex formation was also confirmed and characterized by differential scanning calorimetry (DSC), X-ray diffraction, and 1H-NMR. The freeze-dried complex showed physicochemical stability for at least 12 months. To test in vivo performance, we used a pain model based on mouse paw edema. Results showed that 2% mepivacaine injection failed to anesthetize mice inflamed paw, but its combination with complexed CAP resulted in pain control up to 45 min. These promising results encourages deeper research of CAP as an adjuvant for anesthesia in inflamed tissues and cyclodextrin as a solubilizing agent for targeting molecules in drug delivery.

β-cyclodextrin inclusion complexes with vitamin A and its esters: A comparative experimental and molecular modeling study

Cyclodextrin (CD) complexation has emerged as a promising approach for enhancing the solubility or/and stability of hydrophobic small molecule substances. Here the inclusion complexes of Vitamin A (VA), Vitamin A acetate (VAA), and Vitamin A palmitate (VAP) with β-cyclodextrin (β-CD) were prepared by co-precipitation with freeze-drying methods. Results from FT-IR, NMR, and SEM confirmed the formation of inclusion complexes. Phase solubility diagrams showed a molecular ratio of 2:1, 1:1, and 1:1 for β-CD complexes with VA, VAA, and VAP, respectively. Among these vitamins tested, free VA has the lowest thermal stability, but it was the highest after embedding with β-CD. β-CD:VA also showed a better water solubility. Although VAP achieved the highest increase rate in water solubility among the three vitamins after embedding with β-CD, water solubility of β-CD:VAP was still relatively small due to the poor water solubility of free VAP in nature. The obtained results revealed that β-CD complexation is more suitable for vitamin A than the other two vitamin A esters in promoting thermal stability and water solubility.On the basis of these experimental studies, we furthermore performed molecular docking simulations to predict possible binding mode and binding affinities of three vitamins with β-CD. Gibbs free energy changes (ΔG°) of β-CD:VA with 2:1 molecular ratio was lowest, which explained the enhanced thermal stability of VA by β-CD encapsulation. This work is useful for enlarged applications of β-CD inclusion complexes with vitamin A and its esters.

Measurements and theoretical simulations of phase equilibria in the quaternary systems NaBr + KBr + SrBr2 + H2O, NaBr + MgBr2 + SrBr2 + H2O and their subsystems at 273.15 K

Since various mineral elements (such as sodium, potassium, strontium, bromine) are rich in underground brine in Sichuan Basin of China, to utilize the bromine resources rationally, the phase equilibria of the quaternary systems NaBr + KBr + SrBr2 + H2O, NaBr + MgBr2 + SrBr2 + H2O and their subsystems at 273.15 K were studied with the means of isothermal dissolution equilibrium method. The research systems are three ternary systems (NaBr + SrBr2 + H2O, KBr + SrBr2 + H2O and MgBr2 + SrBr2 + H2O) and two quaternary systems (NaBr + KBr + SrBr2 + H2O and NaBr + MgBr2 + SrBr2 + H2O). The corresponding solubility phase diagrams of the research systems listed above were plotted based on the measured experimental data.The experimental results indicate that there is no formation of solid solution or double salts in five systems. Five phase diagrams all belong to hydrate type I and contain one invariant point. In three ternary systems, there are two isothermal solubility curves and two crystallization fields, and the equilibrium solid phases are NaBr•2H2O and SrBr2•6H2O in the ternary system NaBr + SrBr2 + H2O, KBr and SrBr2•6H2O in the ternary system KBr + SrBr2 + H2O, and MgBr2•6H2O and SrBr2•6H2O in the ternary system MgBr2 + SrBr2 + H2O, respectively. There are three isothermal solubility curves and three crystallization fields in two quaternary systems. The equilibrium solid phases are NaBr•2H2O, KBr, and SrBr2•6H2O in the quaternary system NaBr + KBr + SrBr2 + H2O. In the quaternary system NaBr + MgBr2 + SrBr2 + H2O, the salts NaBr•2H2O, MgBr2•6H2O and SrBr2•6H2O coexist at the invariant point.The unreported mixing ion-interaction parameters of Pitzer equations θMg, Sr, ΨMg, Sr, Br, ΨNa, Sr, Br, and ΨK, Sr, Br are fitted with the solubility data at 273.15 K. The Pitzer ionic interaction model and the required parameters were employed to predict the solubilities of salts in five systems. The calculated results show that the predicted values are in accordance with the measured data, which verify the reliability of the selected parameters.

Comparison of the solubility and dissolution rate of gliclazide-β-cyclodextrin inclusion complexes prepared by liquid/ liquid extraction and neutralization

The solid complexes of gliclazide and β-cyclodextrin were prepared by 2 methods, liquid/liquid extraction and neutralization. The phase-solubility diagram was used to calculate the stability constant of gliclazide and β-cyclodextrin. According to the molar stoichiometry, the complex of gliclazide with β-cyclodextrin was prepared following the 1:1 ratio. The interaction between gliclazide and β-cyclodextrin was analyzed by Fourier-transform infrared spectroscopy and differential scanning calorimetry. The dissolution rate of gliclazide from the complex made by liquid/liquid extraction was faster than those from neutralization method, physical mixtures and pure drug. The mean particle size of two complexes was smaller with a narrower size distribution than those of physical mixtures and β-cyclodextrin. The results indicate that liquid/liquid extraction method, as well as neutralization method, provides some signs of improvement in the solubility and dissolution rate of gliclazide.

Voltammetric/UV–Vis study of temozolomide inclusion complexes with cyclodextrin derivatives

Temozolomide (TMZ) – a chemotherapeutic agent possessing cytotoxic activity is used in single or combined therapies of human glioma. Difficulties in these applications, connected with low solubility and stability of temozolomide lead us to study the inclusion complexes between TMZ, and three cyclodextrins: β-cyclodextrin (βCD), monodeoxy-6-monoamino-β-cyclodextrin hydrochloride (βCDamine), and β-cyclodextrin containing galactosamine and triazole ring in the side group (βCDgal). The voltammetric and spectroscopy studies showed the improvement of the drug solubility and formation of stable complexes. Higuchi and Connors method was used to determine the solubilities of the drug in the presence of the selected cyclodextrins. Phase solubility diagrams showed increase of TMZ solubility and 1:1 stoichiometry of the complexes formed. The stability constant of TMZ- βCDgal complex was pH – dependent, larger at pH 7.4 (corresponding to the pH of the body fluids), than at pH 5.5, characteristic for the cancer cells environment. βCDgal ligand was an effective complexing agent for TMZ due to additional strong proton-acceptor π-π interactions between the triazole ring of the cyclodextrin and the ring of TMZ. The increased solubility and sustainability of TMZ complexes with βCDgal allow to propose this cyclodextrin as a promising TMZ carrier for further studies in the biological cell environment.

Studies on spectral characterization and solubility of hydroxypropyl β-cyclodextrin/iloperidone binary and ternary complexes using different auxiliary agents

The antipsychotic drug Iloperidone (ILO) suffers from drawbacks of low solubility and poor bioavailability. In order to overcome such problems, we proposed to prepare binary and ternary complexes using kneading method and further compared for their ability to improve the solubility of ILO. Based on preliminary studies and phase solubility diagram, 1:1 ratio of drug and Hydroxypropyl β-cyclodextrin (HPβCD) was selected. Tartaric acid (TA) and Kolliphor P-188 (KP) were selected as auxiliary agents (AAs) for ternary systems. Significant improvements in the stability constant and complexation efficiency were seen in the phase solubility studies for TA in comparison to KP. Complexation was studied using PXRD, DSC, FT-IR and NMR. Apparent changes in the crystallinity of ILO were observed from PXRD and DSC studies, suggesting formation of complexes. The interactions in the inclusion complexes were confirmed by FT-IR and 1HNMR. Saturation solubility and in vitro dissolution studies showed increase in the drug solubility and release from the complexes compared to the pure drug alone. These studies suggest some interaction between AAs, ILO and HPβCD in ternary complexes. Thus, the present study led to the conclusion that AAs positively enhance solubility of the drug ILO and consequently may improve bioavailability.

Improvement of the Solubility and Evaluation of the Physical Properties of an Inclusion Complex Formed by a New Ferulic Acid Derivative and γ-Cyclodextrin.

Ferulic acid derivative 012 (FAD012) is a ferulic acid (FA) derivative. The current study prepared a solid dispersion of FAD012 and γ-cyclodextrin (γCD) and ground it using a three-dimensional ball mill (3DGM) to prepare an inclusion complex. This study also assessed the physicochemical properties such as solubility of that complex. A Job’s plot indicated that FAD012 and γCD formed an inclusion complex at a molar ratio of 1:1. Phase solubility diagrams revealed that FAD012 produced a BS diagram. According to PXRD, FAD012 produced a diffraction peak at 2θ = 7.0° and γCD produced a diffraction peak at 2θ = 9.1°. Those two peaks were not produced by the 3DGM, but new peaks (2θ = 7.3 and 16.5°) were evident. DSC patterns revealed an endothermic peak due to the melting of FAD012 at 190 °C, but no endothermic peaks were evident with the 3DGM. NIR spectra of the 3DGM indicated that the methyl group of FAD012 produced a higher peak and that the OH groups of γCD produced a higher peak. 1H-1H ROESY NMR spectra (D2O) revealed cross peaks for protons of the methyl group of FAD012 and a proton (H-3) in the cavity of γCD, so FAD012 presumably interacts with the wide opening of the γCD torus. A solubility test (25 °C) indicated that solubility improved about 5-fold for the 3DGM in comparison to the solubility of FAD012 alone (about 140 μg/mL). Based on these findings, an FAD012/γCD complex was formed by cogrinding, and its solubility improved. These observations are expected to expand the usefulness of cogrinding of FAD012 with γCD using a 3D ball mill.

Enhancement of loading and oral bioavailability of curcumin loaded self-microemulsifying lipid carriers using Curcuma oleoresins

The therapeutic applications of curcumin, a phenolic compound extracted from Curcuma species, is limited due to poor bioavailability. To enhance the bioavailability, self-microemulsifying drug delivery systems (SMEDDS) with curcumin were prepared. Ethyl oleate, Tween 80, and Transcutol® P with surfactant: co-surfactant ratio of 2:1 w/w was selected based on the solubility and pseudo-ternary phase diagrams. The optimized formulation (S-Eo3) was evaluated for use of spice oleoresins as curcumin bioenhancers. The oleophilic phase of curcumin containing SMEDDS formulations was then successfully modified by using bioactive oleoresins extracted from two Curcuma species, viz. C. longa (S-CL1) and C. aromatica (S-CA1). The curcumin content in S-Eo3, S-CL1, and S-CA1 were 69.6 ± 0.23, 82.4 ± 0.62, and 88.8 ± 0.46 mg/g, respectively. Thus, by the partial modification of oleophilic phase of SMEDDS with spice oleoresin (acting as bioenhancer) resulted in ∼88 k improvement of curcumin aqueous solubility. The pharmacokinetic study in male Wistar rats showed that the relative bioavailability of curcumin in S-CL1 and S-CA1 were 26- and 29-fold vis-à-vis 22-fold in S-Eo3 compared to curcumin suspension. All the SMEDDS formulations were stable for three months as established by ICH guidelines.

Applying Different Techniques to Improve the Bioavailability of Candesartan Cilexetil Antihypertensive Drug.

PurposeThe objective of this study was to compare different techniques to enhance the solubility and dissolution rate, and hence the bioavailability of candesartan cilexetil.MethodsTo achieve this target, various techniques were employed such as solid dispersions, inclusion complexes, and preparation of candesartan nanoparticles. Following the preparations, all samples were characterized for their physicochemical properties, and the samples of the best results were subjected to further bioavailability studies.ResultsResults of dissolution studies revealed an increase in the dissolution rate of all samples. The highest dissolution rate was achieved using solid dispersion of the drug with PVP K-90 (1:4). Physicochemical investigations (XR, DSC, and FT-IR) suggested formation of hydrogen bonding and changing in the crystalline structure of the drug. Regarding the inclusion complexes, more stable complex was formed between HP-β-CD and CC compared to β-CD, as indicated by phase solubility diagrams. Antisolvent method resulted in the preparation of stable nanoparticles, as indicated by ζ potential, with average particle size of 238.9 ± 19.25 nm using PVP K-90 as a hydrophilic polymer. The best sample that gave the highest dissolution rate (CC/PVP K-90 1:4) was allowed for further pharmacokinetic studies using UPLC MS/MS assay of rabbit plasma. Results showed a significant increase in the bioavailability of CC from ~15% to ~48%.ConclusionThe bioavailability of CC was significantly improved from ~15% to ~48% when formulated as SDs with PVP K-90 with 1:4 drug:polymer ratio.

Improvement of stability due to a cyclamen aldehyde/β-cyclodextrin inclusion complex

Cyclamen aldehyde (Cya) is an essential oil component with an aldehyde group. The current study examined an inclusion complex of Cya and β-cyclodextrin (βCD) and assessed its physicochemical properties, volatility, and stability. Phase solubility diagrams and 1H NMR spectroscopy indicated that Cya and βCD in a co-precipitate (CP) form a complex at a molar ratio of 1/1. Powder X-ray diffraction (PXRD) patterns revealed crystal diffraction peaks due to βCD (2θ = 8.8°, 12.5°, and 20.8°) for the PM and new diffraction peaks (2θ = 11.7° and 17.5°) for the CP. Thermogravimetry (TG) measurements indicated that Cya decreased about 18.2% in a physical mixture (PM) and about 4.4% in the CP. FT-IR and NIR spectroscopies indicated that the spectra produced by the methyl groups and isopropyl group (5908 cm−1) of Cya and by the hydroxyl groups (4756 cm−1) in the cavity of βCD shifted. {1H–1H} NOESY NMR spectra revealed couplings for the protons of the isopropyl group (1.05 ppm) and the protons of the βCD cavity (H-3: 3.66 ppm). These findings indicated that the isopropyl group of Cya is included in the wider opening of the βCD torus. Diffusion-ordered two-dimensional NMR spectroscopy (DOSY) indicated that the CP (Cya/βCD) had a diffusion coefficient of 3.21 × 10−5 cm2/s and that βCD had a diffusion coefficient of 3.25 × 10−5 cm2/s, so the CP (Cya/βCD) had colligate properties like those of βCD. A stability test at a temperature of 40 °C and RH of 82% revealed that Cya decreased about 7.4% in 7 d, but at least 29% of the CP (Cya/βCD) was retained. At a temperature of 25 °C and RH of 84%, Cya decreased about 9.7% in 7 d, but at least 76.5% of the CP (Cya/βCD) was retained. These findings indicated that formation of a complex by the CP (Cya/βCD) should reduce the volatility of Cya and improve its stability.

Relationship Between Phase Solubility Diagrams and Crystalline Structures During Dissolution of Cimetidine/Cyclodextrin Complex Crystals

Cyclodextrins (CDs) form complex crystals with drugs and improve physicochemical properties of drugs. However, only few reports have summarized relationships between crystal structures of drug/CD and dissolution behavior. In this study, we developed cimetidine (CIM)/CD complex crystals to achieve sustained drug release and investigated the relationship between the dissolution behavior of CIM/CD complexes and their crystal structures. CIM and 3 types of CDs (α-, β-, and γ-CD) formed a complex crystal when subjected to solvent mixing. The CIM/CD complexes had a highly reduced dissolution rate compared to that of the physical mixture of CIM and CD. β-CD improved the solubility of CIM, whereas γ-CD decreased its solubility. Based on the phase solubility diagram, CIM and α-, β-, and γ-CD indicated A-type positive (AP) and AL deviation, and B-type limited solubility (BS) profiles, respectively. In γ-CD, the saturated concentration of CIM decreased owing to the formation of a low-solubility complex with CIM. CIM/α-CD formed cage-type crystals, and CIM/β-CD and CIM/γ-CD formed channel-type crystals. The dissolution rate constant (k) of CIM/α-CD and CIM/β-CD were 0.045 and 0.04 h−1, respectively. CIM/γ-CD and CIM/β-CD displayed channel-type crystals; however, the channel-type crystals of CIM/γ-CD were stabilized by the presence of additional water molecules.

Stent coating by electrospinning with chitosan/poly-cyclodextrin based nanofibers loaded with simvastatin for restenosis prevention

The main cause of failure of angioplasty stenting is restenosis due to neointimal hyperplasia, a too high proliferation of smooth muscle cells (SMC). The local and sustained delivery of selective pleiotropic drugs to limit SMC proliferation seems to be the hopeful solution to minimize this post surgery complication. The aim of this study is to develop a stent covered by nanofibers (NFs) produced by electrospinning, loaded with simvastatin (SV), a drug commonly used for restenosis prevention. NFs were prepared from the electrospinning of a solution containing SV and a mixture of chitosan (cationic) and β-cyclodextrin (CD) polymer (anionic) which form together a polyelectrolyte complex that makes up the NFs matrix. First, the SV/CD interactions were studied by phase solubility diagram, DRX and DSC. The electrospinning process was then optimized to cover a self-expandable NiTiNOL stent and the mechanical resistance of the NFs sheath upon its introduction inside the delivery catheter was considered, using a crimper apparatus. The morphology, coating thicknesses and diameters of nanofibers were studied by scanning electron microscopy. The SV loading rates on the stents were controlled by the electrospinning time, and the presence of SV in the NFs was confirmed by FTIR. NFs stability in PBS pH 7.4 buffer could be improved after thermal post-treatment of NFs and in vitro release of SV in dynamic conditions demonstrated that the release profiles were influenced by the presence of CD polymer in NFs and by the thickness of the NFs sheath. Finally, a covered stent delivering 3 µg/mm2 of SV within 6 h was obtained, whose efficiency will be investigated in a further in vivo study.

Short-Stability Study of Rifaximin-Based Samples.

Rifaximin is an oral antimicrobial with a daily dose ranging from 600 to 800 mg. It is classified as Class IV in the Biopharmaceutic Classification System. Thus, rifaximin-based samples were developed by complexation to β-cyclodextrin using a phase solubility diagram, and malaxation and decreasing particle size using wet milling. Concomitant to the pharmaceutical technology, a stability studywas undertaken with the objective of verifying the integrity of the drug. The stability of the new samples were studied for 6 months, without interruption, under controlled conditions of temperature and humidity in a climatic chamber. They were analyzed simultaneously by HPLC and microbiological turbidimetry at zero, 3, and 6 months. Two of the samples follow second reaction order and one follows zero reaction order. Microbiological analysis proved to be important in assessing the potency of rifaximin in one of the samples, and its results were more consistent than the results by HPLC. The rifaximin-based samples were stable under controlled temperature and humidity conditions and the physical-chemical and microbiological methods were able to evaluate their behavior during the 6-month study. It is worth considering the development of these products, since the design process of formulation and pharmaceutical technology is financially more attractive than the development of new drugs that require high levels of investment in research and development, innovation of public policies, and regulatory actions.

Oral Bioavailability Enhancement of Amisulpride: Complexation and its Pharmacokinetics and Pharmacodynamics Evaluations.

Many CNS drugs have low bioavailability due to their poor water solubility of extensive first-pass metabolism and hence have less effectiveness. The present study aims to enhance the solubility and oral bioavailability of poorly watersoluble antipsychotic drug Amisulpride (AMS) through complexation with 2-hydroxypropyl β- cyclodextrin (HPβCD). It has slow and erratic absorption after oral administration. This report describes the study of the phase solubility diagram, preparation of the inclusion complex and tablet of prepared inclusion complex, characterization of the physico-chemical properties of the inclusion complex and tablet. In-vitro study (100 % drug release in 15 minutes), and in-vivo study of an AL-type (linear type) phase solubility diagram indicated a complex of AMS-HP-β-CD with the constant complex formation of 13245 M-1 at 37°C. The complex formation was confirmed by DSC, IR, and X-ray diffraction. The extent of absorption of the complex was determined in rats and was compared with that of pure drug and the market product. The peak plasma concentration of pure drug was 30.05 ± 1.3 ng/ml (Cmax) at 60 ± 3 min, whereas with the market product the value was 54.85 ± 1.2 ng/ml at 40 ± 1 min and with AMS-HPβCD inclusion complex the value was 79.01 ± 1.5 ng/ml. The AUCtot of the pure drug was 2980.34±3.6, the market product was 7238.73±2.9 and of the inclusion complex was 11871.1±2.8. Pharmacodynamic studies in mice showed improved effectiveness of drug compared to pure drug. The oral bioavailability of AMS was improved from 48% to 78%.

Exploiting Ternary Solubility Phase Diagrams for Resolution of Enantiomers: An Instructive Example

AbstractTernary phase diagrams are essential research tools in several scientific fields. They provide fundamental understanding and guidance in designing separation experiments. While their utility and relevance is undisputed in the chemical and chemical engineering community, yet much progress remains to be done in understanding and exploiting ternary phase diagrams for crystallization‐based chiral separation purposes. A guide in the interpretation of the ternary solubility phase diagram of a chiral molecule to design the separation of its enantiomers is provided. On the basis of the discussion of fundamental relationships in the phase diagram, basic enantioseparation experiments are performed forD‐/L‐methionine in water exploiting the characteristic shift of the eutectic composition in the chiral system. The rational approach followed in separation process design is described together with the experimental procedures applied and the results obtained.

Characterization of an aryl piperazine/2-hydroxypropyl-β-cyclodextrin association, a complex with antidiabetic potential

This study explores the molecular association between 4-(thiophen-2-yl)-1-(4-(4-(trifluoromethyl)phenyl)piperazin-1-yl)butan-1-one (RTC1), an antidiabetic compound recently reported by our research group with challenging aqueous solubility, and 2-hydroxypropyl-β-cyclodextrin (HPBCD). The formation of a RTC1/HPBCD complex resulted in improved solubility. A phase-solubility diagram was used to determine the complex stability constant and stoichiometric ratio. 2D 1H NMR spectroscopy was utilized to study the molecular interaction between RTC1 and HPBCD in the complex. Differential scanning calorimetry and scanning electron microscopy was also employed to confirm complex formation. In vitro biological evaluation, using a glucose uptake assay, showed that the homogeneous RTC1/HPBCD complex solution showed the same activity to that of RTC1 alone, with no reduction in activity due to the presence of HPBCD.

Aqueous solubility of kinase inhibitors: II the effect of hexadimethrine bromide on the dovitinib/γ-cyclodextrin complexation

Dovitinib is a small molecule kinase inhibitor (KI) that is practically insoluble in water but demonstrates high antitumor activity. The aqueous solubility of dovitinib can be improved through formation of water-soluble γ-cyclodextrin (γCD) complexes. However, the very low intrinsic solubility hammers the complex formation. The aim of the present study was to investigate dovitinib binary and ternary complexes with both γCD and hexadimethrine bromide (HDMBr) in both aqueous solution and the solid state. The phase-solubility diagrams of dovitinib were of Bs-type. Addition of HDMBr to the complexation media, that is formation of ternary dovitinib/γCD/HDMBr complex, resulted in four-fold increase in the complexation efficacy (CE). The enhanced CE can decrease the amount of γCD needed to solubilize given amount of dovitinib. The solid dovitinib complexes were characterized by differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), Fourier transform infrared spectroscopy (FTIR), and in vitro dissolution. The dissolution test showed that γCD did stabilize supersaturated dovitinib solution.