Characterization of azithromycin tablets formulated as inclusion complex and stability studies

Celecoxib is a non-steroidal anti-inflammatory drug (NSAID) used for the treatment of pain and inflammation. Celecoxib is included in class II in the Biopharmaceutis ClassificationAsystem drug (BCS) which has low solubility and high permeability. This study aims to increase the solubility and dissolution rate of celecoxib by characterizing the inclusion complex of celecoxib β-cyclodextrin. Inclusion complexes were prepared by the solvent evaporation method using a water-soluble polymer, β-cyclodextrin. The inclusion complexes were prepared in a 1: 1 ratio between celecoxib and β-cyclodextrins. As a comparison, a physical mixture with the same composition was made. Powder mixtures of physics and inclusion complexes characterized by physicochemical properties include: FT-IR spectroscopy analysis, DSC analysis, assay and dissolution test. The dissolution test was determined by the paddle method. The results of characterization of the inclusion complex using FT-IR spectrophotometry showed a shift in the wave number as well as the physical interaction between celecoxib and β-cyclodextrin. The results of the DSC (Differential Scanning Calorimetry) decreased the enthalpy and melting point between celecoxib, the physical mixture and the inclusion complex. The dissolution test showed an increase in dissolution rate at 60 minutes, namely Celecoxib 55.03%, physical mixture 61.58% and inclusion complex 67.53%.

Determination of glafenine in dosage forms and serum by thin layer densitometry and high performance liquid chromatography

The study was designed to investigate the effect of cyclodextrins (CDs) on the solubility, dissolution rate, and bioavailability of cilostazol by forming inclusion complexes. Natural CDs like beta-CD, gamma-CD, and the hydrophilic beta-CD derivatives, DM-beta-CD and HP-beta-CD, were used to prepare inclusion complexes with cilostazol. Phase solubility study was carried out and the stability constants were calculated assuming a 1:1 stoichiometry. Solid cilostazol complexes were prepared by coprecipitation and kneading methods and compared with physical mixtures of cilostazol and cyclodextrins. Prepared inclusion complexes were characterized by Fourier transform infrared spectroscopy, differential scanning calorimetry (DSC), and X-ray diffraction (XRD) studies. In vitro dissolution study was performed using phosphate buffer pH 6.4, distilled water, and HCl buffer pH 1.2 as dissolution medium. The optimized inclusion complex was studied for its bioavailability in rabbit and the results were compared with those of pure cilostazol and Pletoz-50. Phase solubility study showed dramatic improvement in the solubility of drug by formation of complexes, which was further increased by pH adjustment. The dissolution rate of cilostazol was markedly augmented by the complexation with DM-beta-CD. DSC and XRD curves showed sharp endothermic peaks indicating the reduction in the microcrystallinity of cilostazol. Selected inclusion complex was also stable at ambient temperature up to 6 months. The in vivo study revealed that DM-beta-CD increased the bioavailability of cilostazol with low variability in the absorption. Among all cilostazol-cyclodextrins complexes, cilostazol-DM-beta-CD inclusion complex (1:3) prepared by coprecipitation method showed 1.53-fold and 4.11-fold increase in absorption along with 2.1-fold and 2.97-fold increase in dissolution rate in comparison with Pletoz-50 and pure cilostazol, respectively.

Inclusion complexes using β-cyclodextrin were manufactured by solvent evaporation method. Then, sustained release (SR) hydroxypropylmethylcellulose (HPMC) matrix tablets containing inclusion complex were prepared via direct compression. Isradipine was chosen as a model drug due to its low solubility, photo-instability and short elimination half-life. The physicochemical properties of the inclusion complexes were examined using differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FT-IR). The solubility test and dissolution behaviours were also investigated. Based on the solubility experiments, a 1:2 molar ratio (isradipine:β-Cyclodextrin) was best and chosen to prepare inclusion complexes. In addition, the crystal structure of isradipine was converted to an amorphous structure, as confirmed by Fourier transform infrared spectroscopy (FT-IR) and DSC. The photostability of isradipine in the inclusion complex was more stable than pure isradipine after 4 days radiation. By using hypromellose as the hydrophilic sustained release material, the dissolution rate was retarded during 24 h. A combined method of inclusion complex and SR technology showed increased and sustained release profile above that of Dynacirc® SR Cap. 5 mg.

The formation of hydrochlorothiazide inclusion complexes has been carried out to improve the physicochemical properties and increase the dissolution rate of hydrochlorothiazide. Inclusion complexes were made by co-grinding using ß cyclodextrin at a ratio of 1:1 mol, with variations in milling time, namely 30 minutes (F1), 1 hour (F2), and 2 hours (F3). The inclusion complexes formed were characterized by X-ray diffraction analysis, differential scanning calorimetry (DSC), Fourier transforms infrared (FT-IR), scanning electron microscopy, and dissolution tests. X-ray diffraction results showed a decrease in hydrochlorothiazide intensity, the DSC thermogram showed a decrease in endothermic peaks and enthalpy values, and FT-IR spectrum analysis showed that there was a chemical interaction between hydrochlorothiazide and ß-cyclodextrin. All characterization checks carried out met the requirements and confirmed an increase in the dissolution rate. The dissolution yield of hydrochlorothiazide was 41.711%, the physical mixture was 57.135%, the F1 inclusion complex was 59.52%, the F2 inclusion complex was 79.17%, and the F3 inclusion complex was 103.62%. This proves that the formation of inclusion complexes with the addition of ß-cyclodextrin can significantly increase the dissolution

Sitagliptin is an inhibitor of the enzyme dipeptidyl peptidase-4, used for the treatment of type 2 diabetes mellitus. The crystal structure of active pharmaceutical solids determines their physical and chemical properties. The polymorphism, solvates and hydrates can influence the free energy, thermodynamic parameters, solubility, solid-state stability, processability and dissolution rate, besides directly affecting the bioavailability. Thus, the physicochemical characterization of an active pharmaceutical ingredient is required to guarantee the rational development of new dosage forms. In this context, we describe herein the solid-state characterization of three crystalline forms of sitagliptin: sitagliptin phosphate monohydrate, sitagliptin phosphate anhydrous and sitagliptin base form. The investigation was carried out using differential scanning calorimetry (DSC), thermogravimetry (TG)/derivative thermogravimetry (DTG), spectroscopic techniques, X-ray powder diffraction (XRPD) and morphological analysis by scanning electron microscopy. The thermal analysis revealed that during the dehydration of sitagliptin phosphate monohydrate (Tpeak = 134.43 °C, ΔH = −1.15 J g−1) there is a characteristic crystalline transition event, which alters the physicochemical parameters of the drug, such as the melting point and solubility. The crystalline behavior of sitagliptin base form differs from that of sitagliptin phosphate monohydrate and sitagliptin phosphate anhydrous, mainly with regard to the lower temperature of the fusion event. The melting point (Tpeak) values obtained were 120.29 °C for sitagliptin base form, 206.37 °C for sitagliptin phosphate monohydrate and 214.92 °C for sitagliptin phosphate anhydrous. In relation to the thermal stability, sitagliptin phosphate monohydrate and sitagliptin phosphate anhydrous showed a slight difference; however, both are more thermostable than the base molecule. Therefore, through this study it was possible to establish the most suitable crystalline form of sitagliptin for the development of a safe, effective and appropriate pharmaceutical dosage form.

Context: Colchicine (CLC) causes cell death by destabilizing the tubulin unit. However, it ionizes at physiological pH resultant low bioavailability and therapeutic efficacy.Objectives: We have attempted to augment the bioavailability of CLC by fabricating the inclusion complex with hydroxypropyl-β-cyclodextrin (HP-β-CD).Materials and methods: CLC-HP-β-CD inclusion complex was prepared and evaluated with Fourier-transform infrared spectroscopy, differential scanning calorimetry, powder X-ray diffractometry, scanning electron microscopy, 1H nuclear magnetic resonance (1H NMR) spectroscopy and rotating frame overhauser enhancement spectroscopy (ROESY). Oral bioavailability of CLC-HP-β-CD inclusion complex was analyzed using high performance liquid chromatography method.Results and discussion: Our phase-solubility data indicated the formation of a stable complex with Kc ~0.31 mM−1 at pH 7.4. 1H NMR ascertains that NHCOCH3 moiety of CLC enters in the HP-β-CD cavity and deshielded the H-3 and H-5 protons. ROESY also correlates the Hf and Hg of CLC with H-3 and H-5 protons of HP-β-CD and indicates that Hf and Hg protons of CLC are present either as cis and/or trans form in CLC-HP-β-CD inclusion complex. Pharmacokinetic studies showed a 1.82-fold increase in absolute bioavailability of CLC upon complexation.Conclusion: CLC-HP-β-CD inclusion complex may potentially be used as a viable formulation of CLC.

The solubility and dissolution rate of naproxen (NPX) complexed with 2-hydroxypropyl-β-cyclodextrin (2-HPβCD) using coprecipitation, evaporation, freeze-drying and kneading method were investigated. Solubility of NPX linearly increased (correlation coefficient, 0.995) as 2-HP-βCD concentration increased, resulting in AL type phase solubility curve. Inclusion complexes prepared by four different methods were compared by differential scanning calorimetry (DSC). The NPX showed sharp endothermic peak around 156°C but inclusion complexes by evaporation, freeze-drying and kneading method showed very broad peak without distinct phase transition temperature. In contrast, inclusion complex prepared by coprecipitation method resulted in detectable peak around 156°C which is similar to NPX, suggesting incomplete formation of inclusion complex. Dissolution rate of inclusion complexes prepared by evaporation, freeze-drying and kneading except coprecipitation method was largely enhanced in the simulated gastric and intestinal fluid when compared to NPX powder and commercial NAXEN® tablet. However, about 65% of NPX in gastric fluid still remained unreleased but most of NPX dissolved within 5 min in intestinal fluid. In case of inclusion complex prepared by coprecipitation method, formation of inclusion complex appeared to be incomplete, resulting in no marked enhancement of dissolution rate. From these findings, inclusion complexes of poorly water-soluble NPX with 2-HPβCD were useful to increase solubility and dissolution rate, resulting in enhancement of bioavailability and minimization of gastrointestinal toxicity of drug upon oral administration of inclusion complex.

Posaconazole/hydroxypropyl-β-cyclodextrin host–guest system: Improving dissolution while maintaining antifungal activity

An alternative cyclodextrin based formulation for oral anticancer drug exemestane: In vitro and cell culture studies

Background: Allyl isothiocyanate is an excellent antimicrobial compound that has been applied in the development of active food packaging materials in the last years. However, the high volatility of this compound could prevent a lasting effect over time. In order to avoid this problem, cyclodextrin inclusion complexes have been proposed as an alternative, being beta-cyclodextrin (β-CD) as the main candidate. In addition, β-CD could act as a relative humidity-responsive nanoparticle. In this regard, the aim of this study was to develop inclusion complexes based on β-CD and AITC as relative humidity-responsive agents, which can be used in the design of active food packaging materials.Methods: Two different β-CD:AITC inclusion complexes (2:1 and 1:1 molar ratios) were obtained by the co-precipitation method. Entrapment efficiency was determined by gas chromatography, while inclusion complexes were characterized through thermal, structural, and physicochemical techniques. Antifungal capacity of inclusion complexes was determined in a headspace system. Furthermore, the AITC release from inclusion complexes to headspace at different percentages of relative humidity was evaluated by gas chromatography, and this behavior was related with molecular dynamic studies.Key Findings and Conclusions: The entrapment efficiency of inclusion complexes was over to 60%. Two coexisting structures were proposed for inclusion complexes through spectroscopic analyses and molecular dynamic simulation. The water sorption capacity of inclusion complexes depended on relative humidity, and they exhibited a strong fungicide activity against Botrytis cinerea. Furthermore, the AITC release to headspace occurred in three stages, which were related with changes in β-CD conformational structure by water sorption and the presence of the different coexisting structures. In addition, a strong influence of relative humidity on AITC release was evidenced. These findings demonstrate that β-CD:AITC inclusion complexes could be used as potential antifungal agents for the design of food packaging materials, whose activity would be able to respond to relative humidity changes.

Flibanserin (FLB) is a drug used for female hypotensive sexual desire disorder approved by the FDA in August 2015. FLB exhibits extensive hepatic first-pass metabolism and low aqueous solubility, hence poor oral bioavailability. In this study, beta hydroxypropyl cyclodextrin-FLB inclusion complexes were incorporated into orally fast dissolving films. This dosage form was expected to improve FLB aqueous solubility, which would give fast onset of action and decrease presystemic metabolism, hence improving oral bioavailability. The inclusion complex at a ratio of 1:1 was prepared by the kneading method. Differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), and powder X-ray diffractometry (XRD) were used to confirm complex formation. The Box–Behnken design (15 different formulae of FLB fast-dissolving oral films (FLBFDOFs) were utilized for the optimization of the prepared films. The Expert Design 11 program was utilized to examine the effects of three selected factors, polymer concentration (X1), plasticizer concentration (X2), and disintegrant concentration (X3) on four responses: disintegration time (DT), initial dissolution rate (IDR), dissolution efficiency (DE), and film quality (QF). Numerical optimization was performed by minimizing disintegration time (Y1), while maximizing the initial drug dissolution rate (Y2), dissolution efficiency (Y3), and the quality factor (Y4). The statistical analysis showed that X1 has a significant positive effect on the disintegration time and a significant negative effect on IDR. While X2 and X3 produced a nonsignificant negative effect on IDR. Dissolution efficiency was maximized at the middle concentration of both X2 and X3. The best film quality was observed at the middle concentration of both X1 and X2. In addition, increasing X3 leads to an improvement in film quality. The optimized film cast from an aqueous solution contains hydroxypropyl cellulose (2%) as a hydrophilic film-forming agent and propylene glycol (0.8%) as a plasticizer and cross povidone (0.2%) as a disintegrant. The prepared film released 98% of FLB after 10 min and showed good physical and mechanical properties. The optimized formula showed a disintegration time of 30 s, IDR of 16.6% per minute, DE15 of 77.7%, and QF of 90%. This dosage form is expected to partially avoid the pre-systemic metabolism with a fast onset of action, hence improving its bioavailability that favors an advantage over conventional dosage forms.

Purpose: To evaluate the effect of the preparation method on the inclusion complex of curcumin and hydroxypropyl-β-cyclodextrin (HP- β -CD).Methods: HP-β-CD was selected to prepare an inclusion complex with curcumin at a molar ratio of 1:1. The inclusion complexes were prepared using three different methods: common solvent evaporation (CSE), freeze drying (FD), and pH shift. The inclusion complexes were characterized by differential scanning calorimetry (DSC) and fourier transform infrared (FTIR) spectroscopy. The content, solubility, dissolution, and stability of the complexes were evaluated and compared with curcumin and their physical mixture.Results: Formation of inclusion complexes was confirmed by DSC and FTIR results. CSE and FD methods gave a high content of curcumin in the inclusion complexes (> 88.39 %), while pH shift gave a lower content (64.04 %). All three methods significantly (p < 0.05) increased curcumin solubility (> 276.43-fold). However, higher stability complexes were obtained using CSE and FD methods.Conclusion: Among the three preparation methods (CSE, FD and pH shift) used for the inclusion complexes, CSE is the most suitable method for preparation of curcumin-HP-β-CD inclusion complex for increased curcumin solubility and stability.Keywords: Curcumin, Cyclodextrin, Inclusion complex, Solubility, Stability, Common solvent evaporation, Freeze drying, pH shift

Preparation and characterization of inclusion complexes formed by biodegradable poly(ε-caprolactone)–poly(tetrahydrofuran)–poly(ε-caprolactone) triblock copolymer and cyclodextrins

Phenobarbital, a hypnotic and sedative agent, was found to form inclusion complex with hydroxypropyl-β-cyclodextrine at 1:1 molar ratio. The formation of inclusion complex in the solution was detected due to the increased solubility of phenobarbital and in the solid was confirmed by differential scanning calorimetry, X-Ray diffractometry, and infrared spectroscopy. In the solid, inclusion complex was prepared by freezed drying method. The inclusion complex formed was characterized, compared with phenobarbital, hydroxypropyl-β-cyclodextrine, and the physical mixture of phenobarbital and hydroxypropyl-β-cyclodextrine. Analyses using DSC and X-ray diffractometry showed that phenobarbital formed inclusion complex with hydroxypropyl-β-cyclodextrine. Key words : phenobarbital, hydroxypropyl-β-cyclodextrine, inclusion complex