Inclusion Complexation of Anti-HIV Drug with β-Cyclodextrin

The purpose of present investigation was to investigate the effect of complexation of Nelfinavir Mesylate (NM) – an Anti-HIV drug with Beta-cyclodextrin (β-CD) on its dissolution characteristics and subsequent effect on its absorption properties and bioavailability. Phase solubility studies were conducted to find the interaction of NM with β-CD. Physical mixing and milling method were used for complexation. The inclusion complexes were characterized by X-ray diffractometry, FT-IR and NMR studies and further studied by in-vitro dissolution testing. The plain NM and complex was subjected to intestinal absorption studies by using Everted intestinal sac model. Data was treated statistically by Mann–Whitney U test. Pharmacokinetic studies were carried out in rabbits using cross over design and data was treated by Student’s t test. Phase solubility studies confirmed 1:1 complex formation of NM with β-CD with stability constant of 204.84 M⁻¹. In-vitro dissolution studies of inclusion complexes of NM with β-CD prepared by milling method (T ₉₀=60.89 min) showed better dissolution rate kinetics in distilled water in comparison with plain NM (T ₉₀=374.31). The increased solubility with decreased crystallinity is attributed by inclusion of NM in the cavity of β-CD, which was further confirmed by instrumental studies. Intestinal absorption studies further supports these findings by showing 2.13 times enhancement in the absorption rate of complex as compared to plain NM. The percent relative bioavailability of complex in rabbits was 185.37 as compared to the plain NM.     

Emodin–phospholipid complex

Developing the drugs as amphiphilic lipid complexes is a potential approach for improving therapeutic efficacy of the drugs by increasing solubility, reducing drug crystallinity, modifying dissolution behavior (sustained or controlled release), and improving bioavailability. Emodin (1,3,8-trihydroxy-6-methylanthraquinone), an anthranoid derivative, shows several biological effects like antimicrobial, antidiuretic, anti-cancerous, and potent antioxidant but due to poor solubility, the dissolution restrains its valuable importance. To overcome this limitation, the emodin–phospholipid complex was developed and investigated by thermal analysis (differential scanning calorimetry), crystallographic (X-ray diffractography), surface morphology (scanning electron microscopy), spectroscopic methods (FT-IR, ¹H-NMR), solubility, and the dissolution (in vitro drug release) study. The phospholipid complex of emodin was found, fluffy and porous with rough surface morphology in the SEM. FT-IR, ¹H-NMR, DSC, and X-RPD data confirmed the formation of the complex. The water and n-octanol solubility of emodin was improved from 2.25 to 9.97 and 53.45 to 77.62 μg/ml, respectively, in the prepared complex. The improved dissolution was shown by the phospholipid complex. Based on the results of the study, it can be concluded that the phospholipid complex may be considered as promising drug delivery system for improving the overall absorption and bioavailability of the emodin molecule.     

In vitro and in vivo evaluation of β-cyclodextrin-based nanosponges of telmisartan

Telmisartan (TEL) is a BCS Class II drug having dissolution rate limited bioavailability. The aim of work was to enhance the solubility of TEL so that bioavailability problems are solved. β-Cyclodextrin (β-CD) based nanosponges (NSs) were formed by cross-linking β-CD with carbonate bonds, which were porous as well as nanosized. Drug was incorporated by solvent evaporation method. The effect of ternary component alkalizer (NaHCO₃) on solubility of TEL was studied. In order to find out the solubilization efficiency of NS, phase solubility study was carried out. Saturation solubility and in vitro dissolution study of β-CD complex of TEL was compared with plain TEL and NS complexes of TEL. The NS and NS complexes of TEL were characterized by differential scanning calorimetry, powder X-ray diffraction, Fourier transform infrared spectroscopy, nuclear magnetic resonance and scanning electron microscope. It was found that solubility of TEL was increased by 8.53-fold in distilled water; 3.35-fold in 0.1 N HCl and 4.66-fold in phosphate buffer pH 6.8 by incorporating NaHCO₃ in drug–NS complex than TEL. It was found that the NaHCO₃ in NS based complex synergistically enhanced dissolution of TEL by modulating microenvironmental pH and by changing amorphization of the drug. The highest solubility and in vitro drug release was observed in inclusion complex prepared from NS and NaHCO₃. An increase of 54.4 % in AUC was seen in case the ternary NS complex whereas β-CD ternary complex exhibited an increase of 79.65 %.     

Inclusion complexes of lamotrigine and hydroxy propyl β-cyclodextrin: solid state characterization and dissolution studies

Lamotrigine (LMN) is an antiepileptic drug, with poor aqueous solubility, which might lead to erratic bioavailability. The objective of the present work was to improve the dissolution characteristics of the LMN using Hydroxy propyl β-cyclodextrin (HP β-CD), which might offer reliable bioavailability. The phase solubility profile was classified as A _L -type, revealing 1:1 stoichiometric complexation, with a stability constant (Ks) of 573 M^?1. Binary systems of LMN and HP β-CD were prepared in different molar ratios (1:1, 1:2, 1:3 and 1:4) by kneading method. The binary systems were characterized by Fourier Transform Infrared (FT-IR) Spectroscopy, Differential Scanning Calorimetry (DSC) and Powder X-ray Diffraction Analysis (PXRD). Results revealed that in the kneaded products the entire drug was entrapped inside the HP β-CD cavity and reduction in drug crystallinity also took place, which may be responsible for improved dissolution characteristics as compared to that of the pure drug as depicted from the dissolution studies.     

Doi-Edwards theory evaluation in double-step strain flows

It is widely accepted that for reversing double-step strain deformations, predictions based on the Doi-Edwards (DE) molecular theory without the independent alignment approximation (IAA) are superior to predictions obtained with the IAA, or equivalently, the Kaye-Bernstein-Kearsley-Zapas (K-BKZ) theory. This summation, however, is based on data obtained over limited ranges of strain and time: the time both between the step strains (t₁) and following the second step strain (t–t₁). In this study, a thorough evaluation of the DE theory is carried out using a comprehensive double-step strain flow data set. The results of this study indicate that the DE theory is an improvement over the K-BKZ theory in flows with strain reversal but only for cases when the criteria t₁, t–t₁ ? τ_k is satisfied. The constant τ_k, defined as the time beyond which the stress relaxation modulus is factorable: G(γ, t) = h(γ)G(t), is believed to represent the end of the chain retraction process in the DE theory. It appears that the dynamics of chain retraction have an important influence on double-step strain behavior and, therefore, should be accounted for in molecular-based theories devised to have general validity in this important deformation history. © 1994 John Wiley & Sons, Inc.     

Thermal analysis study of flavonoid solid dispersions having enhanced solubility

Purposes of this paper were to prepare and study new drug delivery systems for both flavanone glycosides and their aglycones based on solid-dispersion systems. These compounds are poor water soluble drugs, so an enhancement of their dissolution is a high priority. Solid-dispersion systems were prepared using PVP, PEG and mannitol as drug carrier matrices. Characterizations of these dispersions were done by differential scanning calorimeter (DSC) and X-ray diffraction (XRD). The glass transition (T_g) temperature of PVP was only recorded in the DSC thermograms of PVP solid-dispersions of both flavanone glycosides and their aglycones, while in case of PEG and mannitol solid-dispersions endotherms of both glycosides and aglycones were noticed with low peak intensity, indicating that high percent of drug is in amorphous state. The XRD patterns of all PVP solid-dispersions of aglycones show typical amorphous materials, but XRD patterns of their glycosides reveal the presence of crystalline material. However, in all solid dispersions shifts in T_g of PVP as well as T_m of PEG were observed, indicating the existence of some interactions between drugs and matrices. SEM and TEM microscopy revealed that PVP/aglycone flavanone compounds are nanodispersed systems while all the other solid dispersions are microcrystalline dispersions. The solubility of both flavanone glycosides and their aglycones was directly affected by the new physical state of solid dispersions. Due to the amorphous drug state or nano-dispersions in PVP matrices, the solubility was enhanced and found to be 100% at pH 6.8 in the nano-dispersion containing 20 mass% of aglycones. Also solubility enhancement was occurred in solid dispersions of PEG and mannitol, but it was lower than that of PVP nano-dispersions due to the presence of the drug compounds in crystalline state in both matrices.     

Solid dispersion systems engineered from hydroxypropyl‐β‐cyclodextrin and water‐soluble polymers for enhanced oral bioavailability of nimodipine

Nimodipine (NMD) is a calcium channel blocker that is used in the treatment of cerebrovascular disorders, such as stroke indicated for biological rhythm and neurological disorders. According to biopharmaceutical classification, NMD is categorized as a class ΙΙ drug, meaning it has a poor solubility profile. The objective of this experiment is to prepare multicomponent systems to enhance the solubility, dissolution, and bioavailability of NMD. Inclusion complex and solvent evaporation techniques have been exploited to overcome this challenge. in vitro dissolution studies and solubility, the profile was performed in three pH media (pH 7.5, 1.2, and 6.8). The drug release at (Q_60min) for SD‐PVP3 was 33‐fold higher than pure NMD in double‐distilled water. The solubility of SD PVP3 was about 30 times higher than plain NMD in double‐distilled water. A pharmacokinetic study in rats indicated that the AUC_0‐720 value of the inclusion complex (NMD‐KD) was 1.63‐fold higher than pure NMD. At the same time, the solid dispersion (NMD‐SD PVP3) was 3.94‐fold higher than that of plain NMD, indicating a significant increase in the bioavailability of NMD. The combination of the inclusion complex and solvent evaporation method led to the formation of new solid dispersions (SD PLX and SD PVP), which significantly increased the solubility, dissolution, and the oral bioavailability of NMD.     

Anti-inflammatory activity of saponins from roots of Impatiens parviflora DC.

Abstract

Two triterpene saponins (IPS-1, IPS-2) for the first time were isolated from the roots of Impatiens parviflora DC. (Balsaminaceae). Their anti-inflammatory activity was evaluated by means of two in vitro models: anti-hyaluronidase and anti-denaturation assays. Both saponins were shown to be potent hyaluronidase inhibitors that affect the enzyme in a dose-dependent manner. The anti-hyaluronidase effect of IPS-2 (IC₅₀?=?286.7?µg/mL) was higher than that of the reference drug: escin (IC₅₀?=?303.93?µg/mL). Both saponins protected bovine serum albumin from heat-induced denaturation in a dose-dependent manner. IPS-1 demonstrated higher anti-denaturation effect (IC₅₀?=?86.7?µg/ml) than IPS-2 (IC₅₀?=?109.76?µg/mL) or the standard drug: acetylsalicylic acid (IC₅₀?=?262.22?µg/mL). In conclusion, potent activity of IPS-1, IPS-2 in both in vitro assays shows that saponins from I. parviflora have anti-inflammatory activity. The obtained results allow to suggest that such compounds may be beneficial in inflammatory conditions, especially associated with excessive degradation of hyaluronic acid.     

Formulation optimization and in situ absorption in rat intestinal tract of quercetin-loaded microemulsion

A new microemulsion system has been developed to increase the solubility and oral absorption of quercetin, a poorly water-soluble drug. The formulation of quercetin-loaded microemulsion was optimized by a simplex lattice experiment design. The optimized microemulsion formulation consisted of oil (7%, w/w), surfactant (48%, w/w), and cosurfactant (45%, w/w). Under this condition, the mean droplet diameter of microemulsion was 38.9 nm and solubility of quercetin in the microemulsion was 4.138 mg/ml. The in situ absorption property of quercetin-loaded microemulsion in rat intestine was studied and the results showed there was significant difference in absorption parameters such as K_a, t_1/2 and uptake percentages between microemulsion and micelle solution containing quercetin. The study on absorption percentage in different regions of rat intestine attested that the colon had the best permeability, followed by ileum, duodenum in order. It can be concluded that microemulsion can improve the solubility and oral absorption of quercetin, a poorly water-soluble drug.     

Hepatoprotective Effects of Bioflavonoid Luteolin Using Self-Nanoemulsifying Drug Delivery System

Luteolin (LUT) is a natural pharmaceutical compound that is weakly water soluble and has low bioavailability when taken orally. As a result, the goal of this research was to create self-nanoemulsifying drug delivery systems (SNEDDS) for LUT in an attempt to improve its in vitro dissolution and hepatoprotective effects, resulting in increased oral bioavailability. Using the aqueous phase titration approach and the creation of pseudo-ternary phase diagrams with Capryol-PGMC (oil phase), Tween-80 (surfactant), and Transcutol-HP (co-emulsifier), various SNEDDS of LUT were generated. SNEDDS were assessed for droplet size, polydispersity index (PDI), zeta potential (ZP), refractive index (RI), and percent of transmittance (percent T) after undergoing several thermodynamic stability and self-nanoemulsification experiments. When compared to LUT suspension, the developed SNEDDS revealed considerable LUT release from all SNEDDS. Droplet size was 40 nm, PDI was <0.3, ZP was −30.58 mV, RI was 1.40, percent T was >98 percent, and drug release profile was >96 percent in optimized SNEDDS of LUT. For in vivo hepatoprotective testing in rats, optimized SNEDDS was chosen. When compared to LUT suspension, hepatoprotective tests showed that optimized LUT SNEDDS had a substantial hepatoprotective impact. The findings of this investigation suggested that SNEDDS could improve bioflavonoid LUT dissolution rate and therapeutic efficacy.     

Cyclodextrin complexation improves aqueous solubility of the antiepileptic drug,rufinamide: solution and solid state characterization of compound-cyclodextrin binary systems

Rufinamide (RUF) was characterized in terms of cyclodextrin (CD) complexation in order to improve its aqueous solubility. Binary systems of RUF with three CDs—β-cyclodextrin (β-CD), randomly methylated-β-cyclodextrin (RAMEB) and sulfobutylether-β-cyclodextrin (SBE-β-CD)—were characterized with a wide variety of analytical techniques. Liquid state characterization was carried out by complementary techniques such as nuclear magnetic resonance spectroscopy (NMR), capillary electrophoresis (CE), mass spectrometry (MS) and phase solubility studies. The latter revealed that the stability of the complexes decreased in the order of RAMEB?>?β-CD?>?SBE-β-CD. A_L-type diagrams were obtained in all cases, characteristic of 1:1 stoichiometry, with a maximum of over 15-fold increase in RUF solubility, when complexed with RAMEB. NMR Job plot and MS studies confirmed phase solubility results, regarding the binding stoichiometry. ¹H NMR and 2D ROESY investigations revealed the inclusion of the triazole moiety of RUF, confirmed by molecular modeling. Solid state complexation in 1:1 molar ratio was carried out by kneading method and investigated by differential scanning calorimetry (DSC) and infrared spectroscopy (IR). Comparative dissolution studies indicated an over two-fold improvement in dissolution efficacy of the kneaded products, when compared to the pure drug. Results of the present study might pave the way for a drug formulation with improved bioavailability.     

Solubility and dissolution enhancement of saquinavir mesylate by inclusion complexation technique

The objective of the present study was to formulate inclusion complex of saquinavir mesylate to improve the aqueous solubility and dissolution rate. Saquinavir mesylate is a BCS class II drug having low aqueous solubility and therefore low oral bioavailability. In the present study, inclusion complex of saquinavir mesylate with hydroxypropyl-β-cyclodextrin were prepared by kneading method. Inclusion complex were characterized by differential scanning calorimetry (DSC), X-ray diffractometry (XRD), ¹H NMR studies, and Fourier transform infrared spectroscopy and evaluated for in vitro dissolution, and phase solubility studies. DSC and XRD study demonstrated that there was a significant decrease in crystallinity of pure drug present in inclusion complex, which resulted in an increased dissolution rate of saquinavir mesylate and ¹H NMR studies strongly, confirmed that the inclusion complex has formed. Inclusion complexation results in improvement in solubility and dissolution rate. The inclusion complexation would be suitable method for dissolution and bioavailability enhancement of saquinavir mesylate.     

Self-Nanoemulsifying Drug Delivery System (SNEDDS) of Apremilast: In Vitro Evaluation and Pharmacokinetics Studies

Psoriatic arthritis is an autoimmune disease of the joints that can lead to persistent inflammation, irreversible joint damage and disability. The current treatments are of limited efficacy and inconvenient. Apremilast (APR) immediate release tablets Otezla^® have 20–33% bioavailability compared to the APR absolute bioavailability of 73%. As a result, self-nanoemulsifying drug delivery systems (SNEDDS) of APR were formulated to enhance APR’s solubility, dissolution, and oral bioavailability. The drug assay was carried out using a developed and validated HPLC method. Various thermodynamic tests were carried out on APR-SNEDDS. Stable SNEDDS were characterized then subjected to in vitro drug release studies via dialysis membrane. The optimum formulation was F9, which showed the maximum in vitro drug release (94.9%) over 24 h, and this was further investigated in in vivo studies. F9 was composed of 15% oil, 60% S_mix, and 25% water and had the lowest droplet size (17.505 ± 0.247 nm), low PDI (0.147 ± 0.014), low ZP (−13.35 mV), highest %T (99.15 ± 0.131) and optimum increases in the relative bioavailability (703.66%) compared to APR suspension (100%) over 24 h. These findings showed that APR-SNEDDS is a possible alternative delivery system for APR. Further studies are warranted to evaluate the major factors that influence the encapsulation efficiency and stability of APR-containing SNEDDS.     

The influence of strain deformation on the solubility of ethyl acetate vapor in poly(vinylidene fluoride)

The degree to which a polymer film develops plastic flow depends largely on the total strain ? and the elongation time t_h. The magnitude and the time dependence of the elastic component ?_e of the total deformation are controlling factors, respectively, in the solubility and diffusion processes. The plastic deformation ?_pl seems not to contribute to the transport properties. The nonlinearity in solubility due to ? may be conveniently handled. In this study, the solubility of ethyl acetate vapor in poly(vinylidene fluoride) was determined as a function of pressure and total elongation at 30°C. These results suggest that the strain magnitude and time de pendence of the component deformations play important roles in transport behavior.     

Application of Response Surface Methodology To Formulation Optimization of Rapamycin Loaded Magnetic Fe3O4/Carboxymethylchitosan Nanoparticles

In this paper, a new drug delivery system was designed using magnetic Fe₃O₄/carboxymethylchitosan nanoparticles (Fe₃O₄/CMCS NPs) as carrier and rapamycin (Rapa) as the antitumor drug. The process and formulation variables of Fe₃O₄/CMCS-Rapa NPs were optimized using response surface methodology (RSM) with a three-level, three-factor Box-Behnken design (BBD). The independent variables were the mass ratio of Fe₃O₄/CMCS: Rapa, W/O phase ratio and stirring rate; dependent variables were drug loading content and entrapment efficiency. Mathematical equations and response surface plots were used to relate the dependent and independent variables. The optimized formulation was characterized by TEM, FT-IR, and in vitro drug release. Results for mean particle size, drug loading content, entrapment efficiency and in vitro drug release of Fe₃O₄/CMCS-Rapa were found to be of 30 ± 2 nm, 6.32% ± 3.36%, 62.9% ± 2.30%, and 65.35% ± 2.46% at pH 7.4 after 70 h, respectively; also, they possess magnetism with a saturation magnetization of 67.1 emu/g, negligible coercivity and remanence at room temperature. Also the effect of magnetic targeted nanoparticles on the proliferation of human hepatoma cell line HepG2 in vitro was investigated. The results from MTT assays showed that the Fe₃O₄/CMCS-Rapa nanoparticles could effectively inhibit the proliferation of HepG2 cells, which displayed time or concentration-dependent manner. All these results indicated that the nanoparticles had the potential to be used as a novel drug carrier system.     

Physicochemical characterisation and cyclodextrin complexation of erlotinib

Erlotinib (ERL), the anticancer drug of poor bioavailability, was quantified in terms of bio-relevant physicochemical parameters, such as acid–base properties, lipophilicity and solubility, and a comprehensive study on its inclusion complexation was carried out. The protonation constant of ERL (log K = 5.32) indicates that it exists mainly in deprotonated form at the pH of blood plasma. The high lipophilicity (log p = 2.75) explains its good permeability, while the very low solubility (S₀ = 12.46 μM) causes its low bioavailability and renders injection formulation a difficult job. This problem could be alleviated by enhancing ERL solubility through cyclodextrin (CD) inclusion complexation. Therefore, ERL–CD interactions were studied by a number of analytical techniques. The apparent stability constants of ERL with seven different CDs were determined using affinity capillary electrophoresis. Results indicated that the seven-membered β-CD and its derivatives were the most suitable hosts. Using UV Job plot titration 1:1 stoichiometry was determined, confirmed by electrospray ionisation-mass spectrometry experiments. The geometry of the inclusion complex was investigated by 2D ROESY NMR techniques, revealing that the ethynylphenyl ring enters the β-CD cavity. Phase-solubility analysis shows greatly enhanced solution concentration by CD complexation. The determined equilibrium and structural information offer molecular basis to elaborate improved drug formulation with enhanced bioavailability.     

Effect of external factors on the curcumin/2-hydroxypropyl-β-cyclodextrin: in vitro and in vivo study

The effect of 2-hydroxypropyl-β-cyclodextrin (HPβCD) on solubility, stability and oral bioavailability of curcumin by external factors adjustment, was investigated with an aim of a simple, stable and effective formulation. The phase solubility studies showed the solubility of curcumin increased slightly with increasing pH. However, the apparent stability constant (K _S) were found to decrease with increasing pH from 1.29?×?10⁴?M^?1 at pH 3.0 to 5.22?×?10³?M^?1 at pH 7.0. The thermodynamic parameters were calculated for inclusion complex formation in aqueous solution. Interestingly, it could be concluded that the degrees of curcumin stability improved by HPβCD grew with increasing drug–cyclodextrin binding ability. Furthermore, in vivo study not only revealed that the bioavailability of curcumin after oral administration to rats was significantly improved by curcumin/HPβCD inclusion complex, but also showed more dramatic changes in the plasma concentration–time curve (1752.76–866.70?ng?mL^?1?h) and the peak plasma concentration (370.10–178.11?ng?mL^?1) of drug by formation of complexes in pH 3–7 solution.     

Physicochemical properties of the binary system glibenclamide and polyethylene glycol 4000

Solid dispersions of the antidiabetic drug glibenclamide and polyethylene glycol 4000 (macrogol 4000) were prepared by the melting method in order to increase the solubility of this poorly water-soluble compound. The temperature/composition phase diagram of the components was analyzed by hot-stage microscopy and differential scanning calorimetry, showing a monotectic. Polarized light hot stage microscopy and X-ray-powder diffraction confirmed, that glibenclamide is mainly present in a non-crystalline state after melting and solidifying of a 10% (w/w) mixture, which results in an enhanced solubility compared to physical mixtures. The solubility and dissolution rate of the drug increases clearly with decreasing drug/polymer ratio. Moreover, it was observed for the first time that a drug could crystallize as whiskers at the surface of aged solid dispersion particles. Besides relaxation phenomena, this crystallization mechanism may be responsible for a deterioration of liberation properties and bioavailability of solid dispersion based drug products with increasing storage time. This revised version was published online in July 2006 with corrections to the Cover Date.     

Controlled Release of Model Drug from Biodegradable Segmented Polyurethane Ureas: Morphological and Structural Features

Segmented polyurethane ureas (SPUUs), which are being used in implant devices, were evaluated as drug delivery matrices using theophylline as a model drug without much sacrificing the mechanical properties of films after drug doping. SPUUs were synthesized from aliphatic diisocyanate (lysine methyl ester diisocyante (LDI)), poly(caprolactone) diol with molecular weights 530, 1250 and 2000 and 1,4-butanediamine. Three series of segmented SPUUs were prepared with various soft segment lengths and were characterized by Fourier transform infrared spectroscopy, dynamic viscoelastic measurements and tensile testing. A single tanδ peak was observed in dynamic viscoelastic measurements, which revealed phase mixing of hard and soft segments. Low elongation at break was observed in case of PCL 2000 based SPUUs, may be due to partial cystallization of PCL segment. The degradation of SPUUs in alkaline solution and in vitro drug release of theophylline in pH 7.4 buffer were also investigated. The drug release behavior from these films were analyzed by the exponent relation M_t/M_∞ = ktⁿ, where k and n are constants and M_t/M_∞ is the fraction of drug released until time, t. The constant n was found to be close to 0.5 in all samples, which suggests the release of drug from these polymers can be explained by the Fickian diffusion model.     

Cyclodextrin based drug delivery system of protease inhibitor—nelfinavir mesylate

The purpose of present investigation was to understand the interactions involved in complexation of Nelfinavir Mesylate (NM)—a protease inhibitor, used in the treatment of HIV/AIDS with Beta-cyclodextrin (β-CD) and its subsequent effect on its absorption properties and bioavailability. Milling method was used for complexation. The inclusion complexes were characterized by 2D NOESY NMR and ITC studies. The feasibility of findings was further confirmed by using Cerius² software of Tripos Inc. using Silicon Graphics O_2. Pharmacokinetic studies were carried out in rabbits and data was treated by Student’s t Test. 2D NOESY NMR studies showed very intricate behavior showing interactions amongst drug and β-CD molecule as well as amongst β-CD–β-CD molecules. This fact of formation of molecular aggregates was further confirmed by ITC studies. Computer simulation studies further supported the finding of forming shallow complex. The percent relative bioavailability of complex at the dose of 400 mg/kg in rabbits was 185.37 as compared to the plain NM at 400 mg/kg dose. The studies were conducted at low dose of 200 mg/kg of drug in the form of complex in rabbit does not show statistically significant difference in AUC, T _1/2 and Kel. as compared to plain drug at 400 mg/kg of rabbit.