Investigating the phase-solubility and compatibility study of anticancer drug complexed with β-cyclodextrin and HP–β-cyclodextrin

Poor aqueous solubility and dissolution rates are critical problems that hinders the formulation, development and delivery of most of BCS class II and class IV drugs. Gefitinib is a cytotoxic chemotherapeutic drug used in treatment of cancer. The objective of the present study was to investigate the drug-cyclodextrin compatibility study by FTIR and DSC study. The phase solubility study revealed formation of 1:1 stoichiometry binary inclusion complex. The complex was prepared by kneading method. FT-IR spectra provided the data indicating that the HP-β-CD was more effective than β-CD. Differential scanning calorimetry thermograms indicated stronger amorphization and entrapment of gefitinib with HP-β-CD.

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Inclusion Complex of Fexofenadine Hydrochloride with Cyclodextrins

Mediterranean Journal of Chemistry ◽

10.13171/mjc02112181597huremovic ◽

2021 ◽

Vol 11 (3) ◽

pp. 282

Author(s):

Melita Huremovic ◽

Majda Srabovic ◽

Mirsada Salihovic ◽

Ekrem Pehlic

Keyword(s):

Bathochromic Shift ◽

Aqueous Solubility ◽

Taste Masking ◽

Solid Inclusion ◽

Phase Solubility ◽

Covalent Bonds ◽

Molar Ratios ◽

Solubility Study ◽

Phase Solubility Study ◽

Vis Spectroscopy

Fexofenadine hydrochloride (FFN), (±)-4-[1-hydroxy-4[4-(hydroxydiphenylmethyl)-1-piperidinyl]-butyl] α,α-dimethylbenzeneacetic acid hydrochloride, is a second-generation antihistamine that is used to treat allergies. The drug is highly hydrophobic and slightly soluble in water. Cyclodextrins are widely used to improve the physicochemical and pharmaceutical properties such as solubility, stability, and bioavailability of poorly soluble drug molecules.Cyclodextrins can molecularly encapsulate various drugs into their hydrophobic cavity without forming any covalent bonds. Cyclodextrin (CDs), especially ß-Cyclodextrin (ß-CD), are widely used in the pharmaceutical field due to its ability to stabilize drug molecules and taste masking purposes. The phase solubility study was performed according to the method of Higuchi and Connors by adding the fexofenadine hydrochloride in excess to different concentrations of cyclodextrin solutions. Phase solubility study records show that the stability constant and complex stoichiometry of FFN-CD complexes increases linearly with CD concentration. Also, an increase in the concentration of β-cyclodextrin leads to an increase in the aqueous solubility of FFN. Complexes were analyzed by UV-VIS spectroscopy using the calibration curve of FFN. Also, UV-VIS spectra indicate a bathochromic shift which proves that complex formation has occurred.Solid inclusion complexes of fexofenadine/β-cyclodextrin and its derivatives were prepared at the molar ratios of 1:1 by the physical mixing method. Characterization of the complexes was performed by using infrared spectroscopy.

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Dissolution Enhancement of Flurbiprofen by Solid Dispersion Adsorbate Technique

International Journal of Pharmaceutical Sciences Review and Research ◽

10.47583/ijpsrr.2021.v69i02.014 ◽

2021 ◽

Vol 69 (2) ◽

Author(s):

Sohansinh S. Vaghela ◽

Samkit M. Shah ◽

Sanjesh G. Rathi ◽

Shrenik K. Shah

Keyword(s):

Solid Dispersion ◽

Aqueous Solubility ◽

Dissolution Enhancement ◽

Phase Solubility ◽

Fusion Method ◽

Poloxamer 188 ◽

X Ray ◽

Solubility Study ◽

Phase Solubility Study

Flurbiprofen solid dispersion Adsorbate (SDA) has been prepared using PEG 4000 and Poloxamer 188 as carrier and Neusilin as adsorbent material. The SDA of Flurbiprofen was prepared by using Fusion method in various drugs to carrier ratios. The phase solubility study concludes that both polymers have ability to improve the aqueous solubility of flurbiprofen. Pure API Flurbiprofen and final formulation samples of SDA are characterized by FTIR, DSC and X-ray diffraction spectroscopy. X-ray powder diffraction and DSC study indicated that the drug was present in amorphous form. FTIR study revealed that the characteristic peaks in spectra of pure Flurbiprofen are also present in spectra of SDA’s. Drug found compatible with the excipients. The highest improvement in solubility and in-vitro drug release were observed in solid dispersion prepared with Poloxamer 188 (F14) by fusion method. The increased dissolution rate of drug from solid dispersion adsorbates may be due to surface tension lowering effect of polymer to the medium and increased wettability and dispersibility of drug. Hence, F14 Solid dispersion adsorbates with the Poloxamer carrier in 1:2 ratio considered as most satisfactory among all solid dispersion adsorbates.

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Solubility Enhancement of Myricetin by Inclusion Complexation with Heptakis-O-(2-Hydroxypropyl)-β-Cyclodextrin: A Joint Experimental and Theoretical Study

International Journal of Molecular Sciences ◽

10.3390/ijms21030766 ◽

2020 ◽

Vol 21 (3) ◽

pp. 766 ◽

Cited By ~ 3

Author(s):

Dongxu Han ◽

Zhongbao Han ◽

Liyan Liu ◽

Ying Wang ◽

Shigang Xin ◽

...

Keyword(s):

Inclusion Complexation ◽

Aqueous Solubility ◽

Solubility Enhancement ◽

Dynamics Simulation ◽

Structural Deformation ◽

Phase Solubility ◽

Position Change ◽

Oh Groups ◽

Solubility Study ◽

Phase Solubility Study

Four cyclodextrins (CD) including β-cyclodextrin (β-CD), γ-cyclodextrin (γ-CD), heptakis-O-(2-hydroxypropyl)-β-cyclodextrin (HP-β-CD), and heptakis-O-(2, 6-di-O-methyl)-β-cyclodextrin (DM-β-CD) were used as solubilizer to study the solubility enhancement of myricetin. The results of the phase solubility study showed that the presence of CDs could enhance the solubility of myricetin by forming 1:1 complexes. Among all CDs, HP-β-CD had the highest solubilization effect to myricetin. The concentration of myricetin could be 1.60 × 10−4 moL/L when the presence of HP-β-CD reached 1.00 × 10−2 moL/L, which was 31.45 times higher than myricetin’s aqueous solubility. Subsequently, the HP-β-CD:myricetin complex was characterized by Fourier transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD), and thermogravimetric analysis (TGA). In order to get an insight of the plausible structure of the complex, molecular docking was used to study the complexation process of HP-β-CD and myricetin. In the complex, the A ring and C ring of myricetin were complexed into the hydrophobic cavity of HP-β-CD, while the ring B was located at the wide rim of HP-β-CD. Four hydrogen bonding interactions were found between HP-β-CD and -OH groups of the guest in the HP-β-CD: myricetin complex. The complexation energy (△E) for the host-guest interactions was calculated with a negative sign, indicating the formation of the complex was an exergonic process. A 30-ns molecular dynamics simulation was conducted to the HP-β-CD: myricetin complex. Calculation results showed that no large structural deformation or position change were observed during the whole simulation time span. The average root-mean-square deviation (RMSD) changes of the host and guest were 2.444 and 1.145 Å, respectively, indicating the complex had excellent stability.

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The Preservation and Enantiomeric Selection of Linalool by Nanoencapsulation Using Cyclodextrins

Scientia Pharmaceutica ◽

10.3390/scipharm89030042 ◽

2021 ◽

Vol 89 (3) ◽

pp. 42

Author(s):

Tanaporn Poonphatanapricha ◽

Sasimas Katanyutanon ◽

Kulpavee Jitapunkul ◽

Luckhana Lawtrakul ◽

Pisanu Toochinda

Keyword(s):

Inclusion Complexes ◽

Computational Simulation ◽

Aqueous Solubility ◽

Free Form ◽

Study Phase ◽

Phase Solubility ◽

Solubility Study ◽

Beta Cyclodextrin ◽

Phase Solubility Study ◽

Enantiomeric Selectivity

Linalool, a volatile terpene alcohol, is responsible for a characteristic aroma in food, beverages, and cosmetics. However, linalool’s low aqueous solubility and high volatility limit the applications and shelf life of linalool-containing products. Nanoencapsulation using beta-cyclodextrin (BCD), methyl-beta-cyclodextrin (MBCD) and hydroxypropyl-beta-cyclodextrin (HPBCD) was studied to improve the aqueous solubility and stability of linalool. Linalool has two enantiomers with distinct flavors and odors which affect product quality. The enantiomeric selectivity of the cyclodextrins (CDs) toward racemic linalool standard was evaluated. A computational simulation was performed to predict the conformations and interactions of the inclusion complexes. The 1:1 host-guest ratio from the computer simulation was implemented in the experimental study. Phase solubility study shows an improvement in linalool aqueous solubility after being encapsulated by CDs. The encapsulation efficiencies of linalool/BCD, linalool/MBCD, and linalool/HPBCD inclusion complexes are 66.30%, 51.38% and 32.31%, respectively. Nanoencapsulation by CDs can preserve linalool in the form of inclusion complexes compared to its free form. The amount of remaining linalool in linalool/BCD, linalool/MBCD, and linalool/HPBCD inclusion complexes are 89.57%, 87.07%, and 74.86%, respectively which are considerably larger than that of pure linalool (42.30%). CDs also show the enantiomeric selectivity toward (R)-linalool as evident from (R)-linalool percentage of 54.53% in the inclusion complex.

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Effect of inclusion of citric acid and Lutrol® F-68 on ziprasidone and β-cyclodextrin complexation: Characterization, solubility and dissolution studies

European Journal of Chemistry ◽

10.5155/eurjchem.11.4.280-284.2010 ◽

2020 ◽

Vol 11 (4) ◽

pp. 280-284

Author(s):

Vaishali Yogesh Londhe ◽

Sreevidya Ramesh Krishnan

Keyword(s):

Citric Acid ◽

Antipsychotic Agent ◽

Aqueous Solubility ◽

In Vitro Dissolution ◽

Scanning Calorimetry ◽

Solubility Study ◽

Dissolution Studies ◽

Enhanced Solubility ◽

Ft Ir

Ziprasidone (ZPR) is an antipsychotic agent having less solubility. It is used for the treatment of schizophrenia. Complexation of hydrophobic drugs with cyclodextrins leads to enhanced solubility and dissolution. In this study, inclusion complexes were prepared by different methods, using ZPR, β-cyclodextrin (β-CD), and different auxiliary agents like hydrophilic polymer and hydroxy acid (1:1:0.5) to improve the aqueous solubility. The characterization of the ternary complexes was carried out using solubility study, Differential scanning calorimetry (DSC), Powder X-ray diffraction (PXRD), Fourier transformation infrared spectroscopy (FT-IR) and in vitro dissolution studies. DSC, XRD, and FT-IR studies showed interaction in drug, cyclodextrin, and auxiliary agents which are confirmed by enhancement of solubility and dissolution. Spray-dried dispersion showed less crystallinity and higher solubility as compared to the kneading method for both citric acid and Lutrol® F-68. Thus, the investigation concludes that the presence of the auxiliary agent has a synergistic action on complexation with cyclodextrin, which helps to modify the physicochemical properties of the drug.

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

International Journal of Molecular Sciences ◽

10.3390/ijms21165741 ◽

2020 ◽

Vol 21 (16) ◽

pp. 5741

Author(s):

Verônica Muniz Couto ◽

Laura de Oliveira-Nascimento ◽

Luiz Fernando Cabeça ◽

Danilo Costa Geraldes ◽

Juliana Souza Ribeiro Costa ◽

...

Keyword(s):

Titration Calorimetry ◽

Phase Solubility ◽

Cyclodextrin Complex ◽

Scanning Calorimetry ◽

High Association ◽

Solubility Study ◽

Freeze Dried ◽

Phase Solubility Study ◽

Charged Form

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.

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Native Cyclodextrins as Complexation Agents for Pterostilbene: Complex Preparation and Characterization in Solution and in the Solid State

Pharmaceutics ◽

10.3390/pharmaceutics14010008 ◽

2021 ◽

Vol 14 (1) ◽

pp. 8

Author(s):

Laura Catenacci ◽

Alexios I. Vicatos ◽

Milena Sorrenti ◽

Maria Cristina Bonferoni ◽

Mino R. Caira

Keyword(s):

Solid State ◽

Complex Formation ◽

Aqueous Solubility ◽

Molar Ratio ◽

Phase Solubility ◽

Scanning Calorimetry ◽

Complex Preparation ◽

Ft Ir ◽

Sugar Levels ◽

Co Precipitation

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 1H-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 AL-type profiles for α- and β-CD and a BS profile for γ-CD, with K1:1 values of 1144, 4950, and 133 M−1 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.

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DISSOLUTION ENHANCEMENT OF ATOVAQUONE USING CYCLODEXTRINS AND FORMULATING TO ORODISPERSIBLE TABLETS

INDIAN DRUGS ◽

10.53879/id.53.06.10427 ◽

2016 ◽

Vol 53 (06) ◽

pp. 32-39

Author(s):

A. K Mahapatra ◽

◽

P. N. Murthy

Keyword(s):

Inclusion Complexes ◽

Dissolution Enhancement ◽

Phase Solubility ◽

Scanning Calorimetry ◽

Compression Technique ◽

Sodium Starch Glycolate ◽

Orodispersible Tablets ◽

Kneading Method ◽

Gibb’S Free Energy ◽

Better Than

The aim of the study was to enhance the dissolution rate of atovaquone by preparing inclusion complexes with cyclodextrins (β-CD/ HP β-CD) and formulating their orodispersible tablets. Phase solubility studies were conducted by adding 0.5, 1, 2 and 4% of cyclodextrins in water. The values of Gibb’s free energy were found increased. Inclusion complexes of atovaquone were prepared using β -CD/ HP β -CD by kneading method. Tablets were formulated using superdisintegrants i.e., sodium starch glycolate, crospovidone and Ac-Di sol at concentrations of 4, 8 and 12% of tablet weight by direct compression technique. The interaction studies were made by Fourier transform infrared spectroscopy and differential scanning calorimetry, and no significant interaction was observed. Inclusion complexes showed better dissolution than pure atovaquone and HP-β-CD established better than β-CD. Inclusion complexes of atovaquone at 1:0.25 w/w (drug: HP β -CD) in the tablets with 12% of crospovidone showed satisfactory results.

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FORMULATION DEVELOPMENT AND EVALUATION OF GASTRO-RETENTIVE DOSAGE FORM OF ATAZANAVIR SULPHATE

International Journal of Pharmacy and Pharmaceutical Sciences ◽

10.22159/ijpps.2018v10i1.21179 ◽

2018 ◽

Vol 10 (1) ◽

pp. 60

Author(s):

Hemant Kumar Jain ◽

Madhuri Taware

Keyword(s):

Solid Dispersion ◽

Dosage Form ◽

In Vitro Release ◽

Hplc Method ◽

Phase Solubility ◽

Dissolution Profile ◽

Formulation Development ◽

Peg 6000 ◽

Phase Solubility Study ◽

Gastro Retentive

Objective: To improve dissolution properties of atazanavir sulphate by preparing gastro-retentive granules by solid dispersion method and development of RP-HPLC method for estimation of this drug.Methods: Estimation of atazanavir sulphate was done using high performance liquid chromatography (HPLC) on inertsil column (5 µm, 250x4, 6 mm) with a mobile phase consists of methanol: water (91:9 v/v), at 0.5 ml/min flow rate and 249 nm UV detection. The method was validated as per ICH guidelines. Selection of the carrier for gastro-retentive formulation was based on phase solubility study of the drug. Solid dispersions of gastro-retentive granules of different composition of drug and carrier, were prepared by the kneading, heating and solvent evaporation. A 32factorial design was applied to optimize the gastro-retentive formulation. The amounts of polyethylene glycol 6000 (PEG 6000) (X1) and hydroxypropyl methyl cellulose (HPMC) (X2) were selected as independent variables and in vitro-release at 5, 9 h and total floating time was selected as dependent variables. Results: HPLC method was found to be linear in a concentration range of 10-60 μg/ml of the drug (r2= 0.999). The low value of % RSD in precision study indicates reproducibility of the method. The low value of LOD and LOQ suggests the sensitivity of the method. The solubility enhancement study of drug with various carriers followed descending order of solubility [Gelucire 44/14>PEG 6000>polyvinyl pyrrilidone (PVP)]. Highest % cumulative release was observed for the heating method at drug polymer (PEG 6000) ratio 1:5. Hence, this ratio has been selected for preparation of solid dispersion. From comparison of dissolution profile of formulated batches, formulation F4 [containing PEG6000 (1.6 g) and HPMC (200 mg)] showed promising dissolution parameters with desired floating properties.Conclusion: Results obtained by validation studies suggested that the developed HPLC method is simple, accurate, precise and can be used for routine analysis of atazanavir sulphate formulation. Results of evaluation of prepared batches indicate that batch F4 is a promising formulation for gastro-retentive dosage form of drug.

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Enhanced Solubility, Stability, and Herbicidal Activity of the Herbicide Diuron by Complex Formation with β-Cyclodextrin

Polymers ◽

10.3390/polym11091396 ◽

2019 ◽

Vol 11 (9) ◽

pp. 1396 ◽

Cited By ~ 9

Author(s):

Shuang Gao ◽

Jing-Yu Jiang ◽

Yan-Yan Liu ◽

Ying Fu ◽

Li-Xia Zhao ◽

...

Keyword(s):

Inclusion Complex ◽

1H Nmr ◽

Water Solubility ◽

Herbicidal Activity ◽

Environmental Damage ◽

Phase Solubility ◽

Scanning Calorimetry ◽

Enhanced Solubility ◽

Phase Solubility Study ◽

Herbicide Diuron

The herbicide diuron is hardly soluble in water and most organic solvents and is usually made into a wettable powder or mixed with soil when used, which causes environmental risk and a reduction in herbicidal efficacy. In this study, the physicochemical properties were changed by using β-cyclodextrin (β-CD) to encapsulate diuron to form an inclusion complex. Some key technologies, including X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and nuclear magnetic resonance (1H NMR), were used to characterize the inclusion complex. The stoichiometry of the inclusion complex was determined by recording the 1H NMR spectrum or by using a diagram of inclusion ratios. A phase solubility study proved that the formed inclusion complex exhibited higher water solubility. Thermogravimetric analysis (TGA) demonstrated that the formed inclusion complex exhibited better thermal stability. Biological activity studies indicated that the herbicidal activity, in terms of herbicide removal, of the formed inclusion complex was higher than that of the original diuron. In general, the formation of the inclusion complex could reduce the environmental damage caused by diuron and enhance its herbicidal activity, providing an environmentally friendly method for using diuron.

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