Phase Solubility Diagrams Research Articles

Preparation, Solid-State Characterization, Phase Solubility and Dissolution Studies of Azithromycin/Hydroxypropyl-β- Cyclodextrin Host-Guest System

Objectives: Azithromycin has poor aqueous solubility and its dissolution is the rate-limiting step. Therefore the objective of this work to increase the solubility and dissolution of azithromycin. Hence aim of the study was to develop, characterize and evaluate dissolution properties of inclusion complexes of Azithromycin with hydroxypropyl-β-cyclodextrin (HP-β-CD). Methods: Phase solubility was performed by Higuchi and Connors’s method for determination of stoichiometry of AZM/ β-CD and AZM/ HP-β-CD inclusion complex. It again confirmed by Jobs plot. Inclusion complex of Azithromycin with hydroxypropyl-β-cyclodextrin (HP-β-CD) was prepared by kneading method and solvent evaporation method in molar ratio of 1:1. The inclusion complex in solid state was characterized by FT-IR, DSC, HNMR, SEM. Results: AL type was found in the phase solubility diagram which indicated the development of the inclusion complex in 1:1 stoichiometry with HP-β-CD. The stability constant decrease with increasing temperature. All thermodynamic parameters for the inclusion complex were calculated from Van’t Hoff plots. The highest enhancement in dissolution and solubility were observed in the inclusion complex developed with HPβ-CD using the kneading method. FT-IR spectra exhibited that the hydroxyl group of azithromycin was participate in inclusion process. DSC study supportedamorphization of drug molecule and entrapment of drug in the HP-β-CD cavity. It further confirmed with nuclear magnetic resonance and scanning electron microscopy studies. Conclusion: The solubility was significantly improved by the inclusion complex with HP-β-CD (9 fold). The dissolution of azithromycin was improved with inclusion phenomena using kneading method. The result of studies showed the inclusion of Azithromycin molecule inside HP-β-CD cavities.

Encapsulating curcumin in ethylene diamine-β-cyclodextrin nanoparticle improves topical cornea delivery

Curcumin is a powerful scavenger of reactive oxygen species and could prevent the corneal cells from oxidative damage. However, the clinical efficacy of curcumin is limited by its low aqueous solubility and stability, leading to poor bioavailability. β-cyclodextrin, with a hydrophilic surface and a hydrophobic cavity and self-assembling properties, can form inclusion complexes with lipophilic drugs such as curcumin for ocular delivery. We synthesized ethylene diamine (EDA)-modified β-cyclodextrin and prepared the curcumin complexation using the solvent evaporation method. The EDA-β-cyclodextrin provided a better thermodynamic stability and higher complex yield for curcumin complexes, compared to β-cyclodextrin, which were demonstrated on the analysis of their van’t Hoff plots and phase solubility diagrams. We characterized EDA-β-cyclodextrin curcumin nanoparticles and determined that the EDA modified β-cyclodextrin is a more suitable carrier than parental β-cyclodextrin, using FT-IR, XRD, TEM, and analyses of solubility and storage stability. In addition, the curcumin-EDA-β-cyclodextrin nanoparticles had better in vitro corneal penetration and 3 -h cumulative flux in a porcine cornea experiment, and displayed an improved biocompatibility, confirmed by the histological examination of porcine corneas and cell viability of bovine corneal epithelial cells. These results together revealed a role of EDA modification in the β-cyclodextrin carrier, including the improvement of curcumin complex formation, thermodynamic properties, cytotoxicity, and the in vitro corneal penetration. The EDA-β-cyclodextrin inclusion can provide curcumin a higher degree of aqueous solubility and corneal permeability.

Comparative analysis of experimental methods for determining thermodynamic parameters of formation of multi-component molecular crystals: Benefits and limitations

In this work, we have studied the processes of dissolution of 4-aminobenzoic acid (PABA) two-component crystals with 6-methyluracil (6-MeUr), pyrazinamide (PyrAm) and emoxypine (EMX) in the pH 7.4 phosphate buffer. The thermodynamic functions of cocrystal/salt formation have been estimated from the cocrystal/salt solubility and the corresponding solubility of the pure compounds at various temperatures. By analysing the investigated binary systems, we have compared the accuracy of different experimental methods in evaluating the thermodynamic stability of two PABA cocrystals and one salt: the method of phase solubility diagrams and the cocrystal solubility method. A qualitative evaluation of the comparative stability of the cocrystals and salt has been conducted by the competitive reactions method. The lowest value of the Gibbs energy of formation has been found in the PABA cocrystal with 6-MeUr. The fact that the PABA salt with EMX has the highest absolute value of the Gibbs energy of formation is associated with proton transfer.

Use of Terahertz-Raman Spectroscopy to Determine Solubility of the Crystalline Active Pharmaceutical Ingredient in Polymeric Matrices during Hot Melt Extrusion

Polymer-based amorphous solid dispersions (ASDs) comprise one of the most promising formulation strategies devised to improve the oral bioavailability of poorly water-soluble drugs. Exploitation of such systems in marketed products has been limited because of poor understanding of physical stability. The internal disordered structure and increased free energy provide a thermodynamic driving force for phase separation and recrystallization, which can compromise therapeutic efficacy and limit product shelf life. A primary concern in the development of stable ASDs is the solubility of the drug in the polymeric carrier, but there is a scarcity of reliable analytical techniques for its determination. In this work, terahertz (THz) Raman spectroscopy was introduced as a novel empirical approach to determine the saturated solubility of crystalline active pharmaceutical ingredient (API) in polymeric matrices directly during hot melt extrusion. The solubility of a model compound, paracetamol, in two polymer systems, Affinisol 15LV (HPMC) and Plasdone S630 (copovidone), was determined by monitoring the API structural phase transitions from crystalline to amorphous as an excess of crystalline drug dissolved in the polymeric matrix. THz-Raman results enabled construction of solubility phase diagrams and highlighted significant differences in the solubilization capacity of the two polymer systems. The maximum stable API-load was 20 wt % for Affinisol 15LV and 40 wt % for Plasdone S630. Differential scanning calorimetry and XRPD studies corroborated these results. This approach has demonstrated a novel capability to provide real-time API–polymer phase equilibria data in a manufacturing relevant environment and promising potential to predict solid-state solubility and physical stability of ASDs.

Intranasal Tadalafil nanoemulsions: formulation, characterization and pharmacodynamic evaluation

This study aims at improving the bioavailability of a poorly soluble phosphodiesterase-5 inhibitor; tadalafil (TD) via developing intranasal (IN) nanoemulsions (NEs). Optimum NE ingredients were selected based on solubility studies, emulsification tests, and phase diagram construction. Both o/w and w/o NEs were selected based on their drug loading capacity. Optimum formulations were subjected to physicochemical characterization and were assessed for nasal toxicity through biochemical analysis of tumor necrosis factor-α (TNF-α) and caspase-3 in rat nasal tissues. Pharmacodynamic study was performed via biochemical analysis of cyclic guanosine monophosphate (cGMP) in rat penis 2-h post-treatment and compared with oral suspension of Cialis® tablets. Optimum o/w and w/o NEs were successfully prepared using different ratios of Capmul-MCM-EP, Labrasol:Transcutol-HP (1:1) and water. Optimized formulations exhibited more than 4000-fold increase in TD solubility compared with its aqueous solubility. Both formulations were optically isotropic with the majority of globules in the nanometric-size range. Nasal toxicity study revealed no significant difference in values of TNF-α and caspase-3 between the NE-treated groups and the control group. Both TD-NEs succeeded to achieve a significant enhancement in cGMP levels. Our findings suggested that IN administration of the developed TD-NEs could provide a safe and effective alternative to TD oral delivery.

Host–guest systems based on pH-sensitive acyclic cucurbit[n]urils for controlled release of camptothecin

Stimuli-responsive drug delivery systems may provide an effective way to treat cancer as they can release cargoes regularly according to changes in the human microenvironment. In this work, we design and prepare acid-controlled release complexes of camptothecin with three pH-sensitive acyclic cucurbit[n]urils. The inclusion complexes have been characterized by 1H and 2D nuclear magnetic resonance, X-ray powder diffraction, and phase solubility diagram. Cells incubated with complexes have been analyzed by high-content analysis, and cytotoxicity tests have been completed by MTT assay. The results showed that complexes with different binding constants can release the drug substance in the physiological pH environment of cancer cells, maintain good anticancer activity, and have low cytotoxicity. This provides a strategy about targeted and responsive systems of CPT for clinical application.

Formulation Development, Statistical Optimization and Characterization of the Self-Microemulsifying Drug Delivery System (SMEDDS) of Irbesartan

Background: Irbesartan is an anti-hypertensive BCS class II drug exhibiting poor aqueous solubility, which makes it highly challenging for delivery through the oral route. Based on this fact, a self-microemulsifying drug delivery system (SMEDDS) was designed and characterized for augmenting the aqueous solubility and dissolution rate of irbesartan. Methods: Several blends of oil (Capmul MCM EP), surfactant (Tween 80) and co-surfactant (PEG 600) were screened from the preliminary solubility and pseudo-ternary phase diagram studies. Systematic optimization of the SMEDDS was carried out using 3-factor 3-level Box-Behnken design. Results: The optimized formulation was identified by numerical optimization technique, which revealed faster emulsification time, high percent transmittance and drug content, lower globule size < 100 nm, zeta potential and excellent thermodynamic stability. The optimal formulation unveiled more than 93.3% drug release in vitro within 60 minutes, while the pure drug exhibited only 20% drug release, respectively. Conclusion: Ex vivo permeability and in situ intestinal absorption of drugs was improved nearly 2 to 3- fold by the optimal SMEDDS formulation against the pure drug alone (p < 0.001). Overall, the proposed SMEDDS formulation of irbesartan exhibited a superior biopharmaceutical performance.

Application of the modified BET model to concentrated salt solutions with relatively high water activities: Predicting solubility phase diagrams of NaCl + H2O, NaCl + LiCl + H2O, and NaCl + CaCl2 + H2O

Solubility phase diagrams of mixtures of salts and water are of interest in various application fields and can be calculated using the modified BET model. In comparison with other thermodynamic models, the modified BET model requires only two salt-specific model parameters and has shown to possess a predictive capability. In this work, the modified BET equations are extended in order to calculate solubility phase diagrams of concentrated salt solutions with relatively high water activities within the range of undersaturation. As an example, BET parameters of NaCl are determined and applied to calculate solubility phase diagrams of NaCl + H2O, NaCl + LiCl + H2O, and NaCl + CaCl2 + H2O within the temperature range of around 250–500 K. In the ternary systems, the best agreement with solubility data from literature is obtained using constant BET parameters of NaCl and an additional temperature-dependent regular solution parameter to account for salt-salt interaction.

Holistic QbD approach for hot-melt extrusion process design space evaluation: Linking materials science, experimentation and process modeling

The aim of this work was to investigate the relationship between formulation material properties, process parameters and process performance for the manufacturing of amorphous solid dispersions via hot-melt extrusion (HME) using experimentation coupled with process modeling. Specifically, we evaluated the impact of the matrix copovidone melt rheology with and without the addition of a plasticizing surfactant, polysorbate 80, while also varying the process parameters, barrel temperature and screw speed, and keeping fill volume constant. To correlate the process performance to a critical quality attribute, we used telmisartan as an indicator substance by processing at temperatures below its solubility temperature in the polymeric matrix. We observed a broader design space of HME processes for the plasticized formulation with respect to screw speed than for the copovidone-only matrix formulation. This observation was determined by the range of observed melt temperatures in the extruder, both measured and simulated. The reason was not primarily linked to a reduced shear-thinning behavior, characterized by the power law index, n, but instead more to an overall reduced melt viscosity during extrusion and zero-shear rate viscosity, η0, accordingly. We also found that the amount of residual crystallinity of telmisartan correlated with the simulated maximum melt temperature in the extruder barrel. This finding confirmed the applicability of the temperature-dependent API-matrix solubility phase diagram for HME to process development. Given the complex inter-dependent relationships between material properties, process and performance, process modeling combined with reduced laboratory experimentation was established as a holistic approach for the evaluation of Quality-by-Design-based HME process design spaces.

Evaluation of Solubility Characteristics of a Hybrid Complex of Components of Soy.

The purpose of this study was to evaluate the solubilities and physicochemical properties of solid dispersions of daidzein (DDZ) and genistein (GST) (the major isoflavones in soybeans) in γ-cyclodextrin (γCD). Dispersions were prepared in distilled water using a three-dimensional ball mill (3DGMw). Phase solubility diagrams confirmed that DDZ/γCD and GST/γCD formed AL type inclusion complexes with a molar ratio of 1:1. A new peak due to inclusion complexes was observed in the results of powder X-ray diffraction (3DGMw(DDZ/γCD = 1:1) and 3DGMw(GST/γCD = 1:1)). Dissolution tests using distilled water found that solubilities of 3DGMw(DDZ/γCD = 1:1) and 3DGMw(GST/γCD = 1:1) were approximately 37- and 51-fold higher, respectively, than the solubilities of pure DDZ and GST. These observations are expected to expand the usefulness of cogrinding of DDZ or GST with γCD using a three-dimensional ball mill.

MELOXICAM-PECTIN-β-CYCLODEXTRIN TERNARY COMPLEX BY KNEADING FOR ENHANCEMENT OF SOLUBILITY AND DISSOLUTION RATE

Objective: The objective of the present investigation was to improve the solubility and dissolution rate of poorly soluble drug meloxicam by its ternary inclusion complexation with natural polymers and beta-cyclodextrin (β-CD) by kneading.
 Methods: Equimolar physical mixture (1:1) was prepared by homogeneously kneading drug and β-CD using a solution of agar and pectin in water to get a paste, then paste was dried overnight to get inclusion complex. Inclusion complex was evaluated for drug content, the yield of the adsorption process, Fourier-transform infrared (FTIR), differential scanning calorimeter (DSC), powder X-ray diffractometry (PXRD), scanning electron microscopy (SEM), dissolution, and stability studies.
 Results: The phase solubility diagrams exhibit AL showing a linear increase of drug solubility and indicating the formation of soluble complexes. The FTIR and DSC show compatibility between meloxicam and β-CD, while slight broadening in the peak with a reduction in intensity and early onset indicates the reduction in drug crystallinity which confirms in PXRD pattern. The SEM of binary, as well as ternary, showed no aggregation, and there was a gap between the particles also indicating good redispersibility. The dissolution rate of the drug from the kneaded ternary complex with pectin was significantly rapid compared with the pure drug. The maximum drug release was observed at 85.21±1.84% at the end of 60 min. The ternary complex was found stable after 3 months stability studies.
 Conclusion: The results indicated that ternary inclusion complexation with natural polymers and β-CD was most useful for enhancement of solubility and dissolution rate of a poorly soluble drug like meloxicam.

Fast-dissolving electrospun gelatin nanofibers encapsulating ciprofloxacin/cyclodextrin inclusion complex.

Electrospun gelatin nanofibrous matrix encapsulating ciprofloxacin (CIP)/hydroxypropyl-beta-cyclodextrin (HPβCD)-inclusion complex (IC) was produced via electrospinning method. Computational modeling indicated that van der Waals forces are the most significant driving forces for the complexation and hydrophobic moiety (piperazinyl) of CIP, which was included in the cavity of HPβCD. The FTIR and XRD studies indicated the formation of CIP/HPβCD host/guest complexation, FTIR also suggested that hydrophobic moiety of CIP is in the HPβCD cavity in parallel with the computational modeling results. The phase solubility diagram demonstrated that the solubility of CIP was enhanced after complexation with HPβCD. SEM images showed that electrospun gelatin nanofibers encapsulating CIP/HPβCD-IC have bead-free morphology with a diameter of ˜90 nm. The gelatin nanofibrous mat loaded with CIP/HPβCD-IC has exhibited fast-dissolving character in water compared to gelatin/CIP nanofibrous mat due to the enhanced wettability of the nanofibrous mat by HPβCD and improvement achieved in the solubility of CIP.

Submission of Rifaximin to Different Techniques: Characterization, Solubility Study, and Microbiological Evaluation.

Rifaximin, an oral antimicrobial drug, is marketed as 200-mg tablets. The daily dose ranges from 600mg (1 tablet 3 times a day) to 800mg (2 tablets twice a day). It is used for a wide range of ages, from adults to children, since it is indicated for the treatment of hepatic encephalopathy, travelers' diarrhea, irritable bowel syndrome, Clostridium difficile, ulcerative colitis, and acute diarrhea. The success of pharmacotherapy will depend on correct fulfillment of drug administration; however, it becomes difficult when the tablets are large and the doses are frequent. Rifaximin belongs to class IV according to the Biopharmaceutic Classification System (BCS), meaning that it is both poorly soluble and poorly permeable. Thus, in this study, solubility of rifaximin was improved by its complexation to β-cyclodextrin by (i) phase solubility diagram, (ii) malaxation, and (iii) decreasing particle size by wet milling. Improved solubility provides lower doses and facilitates compliance with pharmacotherapy. The products formed were analyzed by spectrophotometry in the infrared region (FT-IR), differential scanning calorimetry (DSC), and X-ray diffraction (XRD). Also, their solubility and microbiological activity were determined. The products obtained in all techniques were more soluble than the free drug; they presented higher thermal stability and antimicrobial potency was approximately 100% with all the formulations. It is important to highlight that the treatment failure not only affects the quality of life of the patients, but also contributes significantly to the economic burden of the health system. Therefore, these findings are extremely interesting, both from a technological and financial point of view.

Thermodynamic phase diagram of amyloid-β (16–22) peptide

The aggregation of monomeric amyloid β protein (Aβ) peptide into oligomers and amyloid fibrils in the mammalian brain is associated with Alzheimer's disease. Insight into the thermodynamic stability of the Aβ peptide in different polymeric states is fundamental to defining and predicting the aggregation process. Experimental determination of Aβ thermodynamic behavior is challenging due to the transient nature of Aβ oligomers and the low peptide solubility. Furthermore, quantitative calculation of a thermodynamic phase diagram for a specific peptide requires extremely long computational times. Here, using a coarse-grained protein model, molecular dynamics (MD) simulations are performed to determine an equilibrium concentration and temperature phase diagram for the amyloidogenic peptide fragment Aβ16-22 Our results reveal that the only thermodynamically stable phases are the solution phase and the macroscopic fibrillar phase, and that there also exists a hierarchy of metastable phases. The boundary line between the solution phase and fibril phase is found by calculating the temperature-dependent solubility of a macroscopic Aβ16-22 fibril consisting of an infinite number of β-sheet layers. This in silico determination of an equilibrium (solubility) phase diagram for a real amyloid-forming peptide, Aβ16-22, over the temperature range of 277-330 K agrees well with fibrillation experiments and transmission electron microscopy (TEM) measurements of the fibril morphologies formed. This in silico approach of predicting peptide solubility is also potentially useful for optimizing biopharmaceutical production and manufacturing nanofiber scaffolds for tissue engineering.

Interaction of native CDs and their hydroxypropyl derivatives with parabens in aqueous solutions. Part 2: evaluation of paraben/cyclodextrin complex aggregation

Cyclodextrins (CDs) and their inclusion complexes are known to self-assemble in aqueous solutions to form aggregates and the physicochemical characteristics of guest molecules have been linked to the aggregate formation. A series of parabens was selected as model compounds due to their small size (aromatic ring fits in the cavity) and different side chain length. In Part 1 it was demonstrated that CDs and parabens form a range of soluble and insoluble complexes dependent on the type of CD (native or hydroxypropylated αCD, βCD or γCD) and the length of the alkyl residue of the parabens. Furthermore, phase-solubility studies suggested that higher order complexes (e.g., aggregates) were formed. Here we apply osmometry and permeation studies to evaluate if and how the alkyl chain length of the parabens influences the process of aggregate formation. Furthermore, the possible effect of CD aggregates on permeation profile of parabens is also elucidated. Changes in osmometry correlate with the type pf phase-solubility profile. For AL-types total osmolality remained unchanged throughout experiment, while for B-types the osmolality of systems displayed significant changes mainly due to precipitation of poorly-soluble complexes. The permeation method is an effective and useful method to detect and evaluate self-assembly of CDs and to detect aggregate formation in aqueous γCD and HPβCD solutions containing parabens. Generally, all parabens modified the natural aggregation behavior of HPβCD and γCD as the apparent critical aggregation concentration (cac) values for paraben/CD systems decreased compared to those of pure aqueous CD solutions. The longer the alkyl side chain, the greater was the promotion of aggregates formation (methyl < ethyl < propyl < butyl) and, consequently, more and larger aggregates are formed. These superstructures are responsible for the observed changes in apparent cac and flux values, as well as, for the observed slopes greater than unity for the phase-solubility diagrams.

Interaction of native cyclodextrins and their hydroxypropylated derivatives with parabens in aqueous solutions. Part 1: evaluation of inclusion complexes

Due to their antimicrobial activity, parabens (i.e. alkyl esters of p-hydroxybenzoic acid) are widely used as preservatives in several industries (pharmaceutical, food, cosmetic). Although being extremely effective, their usage is hampered by their low aqueous solubility. Several formulation strategies can be applied to enhance their solubility, one of which is formation of water-soluble cyclodextrin (CD) complexes. Formation of inclusion complexes has been proved to be a good approach to increase solubility of lipophilic drugs and other active ingredients. Some research has been done in this field. However, a complete and comprehensive study on how the alkyl chain length of parabens influences the complex formation, aggregation and formation of insoluble complexes is still lacking. Phase-solubility studies showed that all the very water-soluble hydroxypropylated CDs form linear (AL) type phase-solubility profiles with all tested parabens. The poorly soluble βCD did also form AL-type profiles with methyl and ethyl paraben while the βCD complexes of propyl and butyl paraben have limited solubility in water and, thus displayed B-type profiles. The paraben complexes of αCD and γCD all had limited solubility in water and, thus, displayed B-type phase-solubility profiles. Fourier-transformed infrared spectroscopy, Differential scanning calorimetry and X-ray powder diffraction were applied to elucidate the nature of the solid phases from the phase-solubility studies. They consistently showed the presence of solid pure paraben over the CD concentration range studied when AL-type profiles were observed, and precipitation of poorly soluble paraben/CD complexes when B-type were observed (i.e. during and after the B-type plateau region). These studies demonstrate that the composition of solid phases is related to the type of phase-solubility profile. It was also shown that in aqueous CD solutions, paraben solubilization increase with increasing side chain length (i.e. methyl < ethyl < propyl < butyl), as well as, with increasing size of the CD cavity (i.e. αCD < βCD < γCD). This statement is valid for linear region of phase-solubility diagrams (i.e. A- and B-type).

Drug Solubilization by Mixtures of Cyclodextrins: Additive and Synergistic Effects.

Cyclodextrins are popular drug solubilizers, but the use of the natural cyclodextrins is hampered by their tendency to coprecipitate with the drug. To understand and overcome such problems, we have studied the solubility of dexamethasone in the presence of natural β-cyclodextrin and γ-cyclodextrin, individually and in various combinations. Equilibrium models of the phase-solubility diagrams with individual cyclodextrins revealed that dexamethasone was solubilized as 1:1 complexes, but formation of insoluble higher-order complexes set an upper limit to the concentration of solubilized dexamethasone. This limit could be raised from 8 to 17 mM by using combinations of the two cyclodextrins, as their solubilizing properties were additive in some regions of the phase-solubility diagram and synergistic in other regions. The additive effects arise from the additivity of solubilities-the same phenomenon contributes to the good solubilizing properties of many modified cyclodextrins. The synergistic effects, however, could not be explained. The results open up for an increased use of the natural cyclodextrins as an improved alternative to modified cyclodextrins.

Investigation of molecular aggregation mechanism of glipizide/cyclodextrin complexation by combined experimental and molecular modeling approaches

Cyclodextrin complexation is a wise strategy to enhance aqueous solubility of water-insoluble drugs. However, the aggregation mechanism of drug-cyclodextrin complexes is still unclear. This research aimed to investigate the molecular aggregation mechanism of glipizide/cyclodextrin complexation by the combination of experimental and modeling methods. Binding free energies between glipizide and cyclodextrins from modeling calculations were higher than those by the phase solubility diagram method. Both experimental and modeling results showed that methylated-β-cyclodextrin exhibited the best solubilizing capability to glipizide. Size-measurement results confirmed the aggregation between glipizide and all four cyclodextrins in high concentrations. Glipizide/γ-cyclodextrin and glipizide/β-cyclodextrin complexes showed stronger aggregation trend than HP-β-cyclodextrin and methylated-β-cyclodextrin. The substituted groups in the rim of HP-β-cyclodextrin and methylated-β-cyclodextrin lead to weak aggregation. This research provided us a clear molecular mechanism of glipizide/cyclodextrin complexation and aggregation. This research will also benefit the formulation development of cyclodextrin solubilization.

Thermal analysis used to guide the production of thymol and Lippia origanoides essential oil inclusion complexes with cyclodextrin

This study aimed to use thermal analysis and other analytical tools to guide the production of thymol (TML) and essential oil of Lippia origanoides (EO) solid inclusion complexes from a screening of different cyclodextrins (CDs) types and production methods (freeze drying, spray drying, rotary evaporation and supercritical CO2). According to the phase solubility diagrams, the best complexation efficiency of TML was achieved using hydroxypropyl-β-cyclodextrin (~ 0.7), comparing to the natives CDs, which showed values below 0.5. Thermogravimetry was effective in evaluating the amount of drug inclusion complexes in each solid sample by measuring the evaporation of TML, which was dependent of its degree of interaction with the CD. Freeze drying was the most effective method in originating true inclusion complexes in solid state producing the encapsulation of nearly 70% of available TML which were stable at temperature ranges from 200 to 280 °C. Indeed, according to the stability assay, the shelf-life increase achieved for the TML standard was 354%, while the EO had a stability increase of around 45%. Finally, the antifungal effect against Candida albicans (ATCC 14053) was increased in complexed forms in about 1.5 times and 5.4 times for EO and TML, respectively, while the antifungal activity for Trichophyton mentagrophytes (ATCC 11481) was increased with TML and EO encapsulated with CD in more than 22 times and 45 times, respectively, compared to their free forms. Thus, the optimized inclusion complexes seem to be promising in pharmaceutical field for a future development of topical preparations containing TML and its natural substrates.

Assessment of the Physical Properties of Inclusion Complexes of Forchlorfenuron and γ-Cyclodextrin Derivatives and Their Promotion of Plant Growth.

The current study prepared solid dispersions of forchlorfenuron (CPPU) and γ-cyclodextrin (γCD) or CPPU and 2-hydroxypropyl-γ-cyclodextrin (HPγCD) via cogrinding and coprecipitation to assess their physicochemical properties and their effect on plant growth. According to phase solubility diagrams, both CPPU/γCD and CPPU/HPγCD formed an inclusion complex at a molar ratio of 1/1. According to differential scanning calorimetry and powder X-ray diffraction, a ground mixture (GM) of CPPU and γCD (molar ratio = 1/1), a GM of CPPU and HPγCD (molar ratio = 1/1), and a coprecipitate (CP) of CPPU and γCD (molar ratio = 1/1) formed an inclusion complex. According to 1H–1H nuclear Overhauser effect spectroscopy NMR spectroscopy of the GMs and CP, the aromatic rings of the CPPU molecule are presumably included in CD from the wider to the narrower rim of its ring. Cultivation of broccoli sprouts with the GMs and CP resulted in no differences in the length of sprouts in comparison to a commercial preparation (Fulmet).