Naproxen Microparticulate Systems Prepared Using <Emphasis Type="Italic">In Situ</Emphasis> Crystallisation and Freeze-Drying Techniques

Poor drug solubility and dissolution rate remain to be one of the major problems facing pharmaceutical scientists, with approximately 40% of drugs in the industry categorised as practically insoluble or poorly water soluble. This in turn can lead to serious delivery challenges and poor bioavailability. The aim of this research was to investigate the effects of the surfactants, poloxamer 407 (P407) and caprol® PGE 860 (CAP), at various concentrations (0.1, 0.5, 1 and 3% w/v) on the enhancement of the dissolution properties of poorly water-soluble drug, naproxen, using in situ micronisation by solvent change method and freeze-drying. The extent at which freeze-drying influences the dissolution rate of naproxen microcrystals is investigated in this study by comparison with desiccant-drying. All formulations were evaluated and characterised using particle size analysis and morphology, in vitro dissolution studies, differential scanning calorimetry (DSC), and Fourier transform infra-red (FT-IR) spectroscopy. An increase in poloxamer 407 concentration in freeze-dried formulations led to enhancement of drug dissolution compared to desiccator-dried formulations, naproxen/caprol® PGE 860 formulations and untreated drug. DSC and FT-IR results show no significant chemical interactions between drug and poloxamer 407, with only very small changes to drug crystallinity. On the other hand, caprol® PGE 860 showed some interactions with drug components, alterations to the crystal lattice of naproxen, and poor dissolution profiles using both drying methods, making it a poor choice of excipient.     

Amorphization Alone Does Not Account for the Enhancement of Solubility of Drug Co-ground with Silicate: The Case of Indomethacin

The solubility advantage of indomethacin amorphized by co-grinding with Neusilin US2 in various media was investigated. Physical mixtures of γ-indomethacin and Neusilin US2 (in the ratios 1:1, 1:4 and 1:5) were amorphized at room temperature employing 75% RH in a porcelain jar mill using zirconia balls. The crystallinity of the samples was determined using ATR-FTIR and PXRD. The solubility and dissolution profiles of co-ground powders and crystalline counterparts were evaluated in 0.1 N HCl, water and phosphate buffer (pH 6.8) in a USP type II dissolution apparatus at 250 rpm and 37 °C. Very high concentrations of dissolved indomethacin as compared to the solubility of γ-indomethacin (~500 times in water and ~ 3.7 times in phosphate buffer) were attained. However, the presence of other polymorphs detected by PXRD and a change in the pH of the medium made interpretation of the results difficult. In 0.1 N HCl the solubility (i.e., the peak in a concentration versus time plot) of the amorphized drug in a 1:5 ratio with Neusilin increased to 109 times the solubility of crystalline γ-indomethacin alone. An increase in amount of drug and Neusilin in the same ratio added to the dissolution medium also increased peak and plateau dissolution concentrations. The presence of silicic acid and ions (Mg²⁺ and Al³⁺) in the dissolution media were found to cause the increase in the plateau concentration of indomethacin. Amorphization alone does not account for all of the dissolution enhancement; acidity, ions, and silicic acid are major contributors to dissolution enhancement.     

Evaporation Behavior and Characterization of Eutectic Solvent and Ibuprofen Eutectic Solution

Liquid eutectic system of menthol and camphor has been reported as solvent and co-solvent for some drug delivery systems. However, surprisingly, the phase diagram of menthol-camphor eutectic has not been reported previously. The evaporation behavior, physicochemical, and thermal properties of this liquid eutectic and ibuprofen eutectic solution were characterized in this study. Differential scanning calorimetry (DSC) analysis indicated that a eutectic point of this system was near to 1:1 menthol/camphor and its eutectic temperature was ?1°C. The solubility of ibuprofen in this eutectic was 282.11?±?6.67 mg mL^?1 and increased the drug aqueous solubility fourfold. The shift of wave number from Fourier transform infrared spectroscopy (FTIR) indicated the hydrogen bonding of each compound in eutectic mixture. The weight loss from thermogravimetric analysis of menthol and camphor related to the evaporation and sublimation, respectively. Menthol demonstrated a lower apparent sublimation rate than camphor, and the evaporation rate of eutectic solvent was lower than the sublimation rate of camphor but higher than the evaporation of menthol. The evaporation rate of the ibuprofen eutectic solution was lower than that of the eutectic solvent because ibuprofen did not sublimate. This eutectic solvent prolonged the ibuprofen release with diffusion control. Thus, the beneficial information for thermal behavior and related properties of eutectic solvent comprising menthol-camphor and ibuprofen eutectic solution was attained successfully. The rather low evaporation of eutectic mixture will be beneficial for investigation and tracking the mechanism of transformation from nanoemulsion into nanosuspension in the further study using eutectic as oil phase.     

Ditosylate Salt of Itraconazole and Dissolution Enhancement Using Cyclodextrins

Salt formation has been a promising approach for improving the solubility of poorly soluble acidic and basic drugs. The aim of the present study was to prepare the salt form of itraconazole (ITZ), a hydrophobic drug to improve the solubility and hence dissolution performance. Itraconazolium ditolenesulfonate salt (ITZDITOS) was synthesized from ITZ using acid addition reaction with p-toluenesulfonic acid. Salt characterization was performed using ¹H NMR, mass spectrometry, Fourier transform infrared spectroscopy, differential scanning calorimetry, and X-ray diffraction. The particle size and morphology was studied using dynamic light scattering technique and scanning electron microscopy, respectively. The solubility of the salt in water and various pharmaceutical solvents was found multifold than ITZ. The dissolution study exhibited 5.5-fold greater percentage release value in 3 h of ITZDITOS (44.53%) as compared with ITZ (8.54%). Results of in vitro antifungal studies using broth microdilution technique indicate that ITZDITOS possessed similar antifungal profile as that of ITZ when tested against four fungal pathogens. Furthermore, the physical mixtures of ITZDITOS with two cyclodextrins, β-cyclodextrin (β-CD), and 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) were prepared in different molar ratios and were evaluated for in vitro release. It was observed that in only 30 min of dissolution study, about 74 and 81% of drug was released from 1:3 molar ratios of ITZDITOS with β-CD and ITZDITOS with HP-β-CD, respectively, which was distinctly higher than the drug released from ITZ commercial capsules (70%). The findings warrant further preclinical and clinical studies on ITZDITOS so that it can be established as an alternative to ITZ for developing oral formulations.KEY WORDS: antifungal, BCS class II, dissolution rate, insoluble, itraconazole     

Solid Dispersion of Ursolic Acid in Gelucire 50/13: a Strategy to Enhance Drug Release and Trypanocidal Activity

Solid dispersions (SDs) are an approach to increasing the water solubility and bioavailability of lipophilic drugs such as ursolic acid (UA), a triterpenoid with trypanocidal activity. In this work, Gelucire 50/13, a surfactant compound with permeability-enhancing properties, and silicon dioxide, a drying adjuvant, were employed to produce SDs with UA. SDs and physical mixtures (PMs) in different drug/carrier ratios were characterized and compared using differential scanning calorimetry, hot stage microscopy, Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), particle size, water solubility values, and dissolution profiles. Moreover, LLC-MK2 fibroblast cytotoxicity and trypanocidal activity evaluation were performed to determine the potential of SD as a strategy to improve UA efficacy against Chagas disease. The results demonstrated the conversion of UA from the crystalline to the amorphous state through XRD. FTIR experiments provided evidence of intermolecular interactions among the drug and carriers through carbonyl peak broadening in the SDs. These findings helped explain the enhancement of water solubility from 75.98 μg/mL in PMs to 293.43 μg/mL in SDs and the faster drug release into aqueous media compared with pure UA or PMs, which was maintained after 6 months at room temperature. Importantly, improved SD dissolution was accompanied by higher UA activity against trypomastigote forms of Trypanosoma cruzi, but not against mammalian fibroblasts, enhancing the potential of UA for Chagas disease treatment.Key words: Chagas disease, Gelucire 50/13, solid dispersions, solvent evaporation method, ursolic acid     

Improvement of Dissolution and Hypoglycemic Efficacy of Glimepiride by Different Carriers

Effects of tromethamine (Tris), polyvinylpyrrolidone (PVP-K25), and low molecular weight chitosan (LM-CH) on dissolution and therapeutic efficacy of glimepiride (Gmp) were investigated using physical mixtures (PMs), coground mixtures, coprecipitates (Coppts) or kneaded mixtures (KMs), and compared with drug alone. Fourier transform infrared spectroscopy, differential scanning colorimetry, and X-ray diffractometry were performed to identify any physicochemical interaction with Gmp. Surface morphology was examined via scanning electron microscopy. The results of Gmp in vitro dissolution revealed that it was greatly enhanced by Coppt with Tris or PVP-K25 and KM with LM-CH at a drug to carrier ratio of 1:8. Gmp amorphization by PVP-K25 and LM-CH was a major factor in increasing Gmp dissolution. Being basic, Tris might increase the pH of the microdiffusion layer around Gmp particles improving its dissolution. Formation of water-soluble complexes suggested by solubility study may also explain the enhanced dissolution. Capsules were prepared from Coppts and KM 1:8 drug to carrier binary systems and also with Tris PMs. In vivo, the hypoglycemic efficacy of Gmp capsules in rabbits increased by 1.63-, 1.50-, and 1.46-fold for 1:8 Coppts with Tris or PVP-K25 and KM with LM-CH respectively, compared with Gmp alone. Surprisingly, the response to Tris PM 1:20 capsules was 1.52-fold revealing statistically insignificant difference to that of Tris Coppt 1:8 (1.63 fold). As a conclusion, dissolution enhancement and hypoglycemic potentiation by 1:20 PM of Gmp/Tris, being simple and easy to prepare, may enable development of a reduced-dose and fast-release oral dosage form of Gmp.     

Tablet formulation studies on nimesulide and meloxicam-cyclodextrin binary systems

The objective of this work was to develop tablet formulations of nimesulide-β-cyclodextrin (NI-β-CD) and meloxicam-γ-cyclodextrin (ME-γ-CD) binary systems. In the case of nimesulide, 3 types of binary systems—physical mixtures, kneaded systems, and coevaporated systems—were studied. In the case of meloxicam, 2 types of binary systems—physical mixtures and kneaded systems—were investigated. Both drug-CD binary systems were prepared at 1∶1 and 1∶2 molar ratio (1∶1M and 1∶2M) and used in formulation studies. The tablet formulations containing drug-CD binary systems prepared by the wet granulation and direct compression methods showed superior dissolution properties when compared with the formulations of the corresponding pure drug formulations. Overall, the dissolution properties of tablet formulations prepared by the direct compression method were superior to those of tablets prepared by the wet granulation method. Selected tablet formulations showed good stability with regard to drug content, disintegration time, hardness, and in vitro dissolution properties over 6 months at 40°C±2°C and 75% relative humidity. Published: May 11, 2007     

Comparison of the effect of tromethamine and polyvinylpyrrolidone on dissolution properties and analgesic effect of nimesulide

The solubilizing and absorption enhancer properties towards nimesulide (ND) of tromethamine (Tris) and polyvinylpyrrolidone (PVP) have been investigated. Solid binary systems were prepared at various drug-polymer ratios by mixing or coprecipitation, characterized by differential scanning calorimetry, X-ray diffractometry, and Fourier transform infrared spectroscopy, and tested for dissolution behavior. Both carriers improved drug dissolution and their performance depended on concentration of the hydrophilic carrier in coprecipitates. Tris was more effective than PVP, despite the amorphizing power of PVP as revealed by solid state analyses. Complete drug amorphiztion was attained at 1∶3 (wt/wt) drug: PVP, 25% (wt/wt) ND in PVP. According to thermal behavior of ND and Tris, ND-Tris systems present a eutectic behavior. The eutectic composition was 30% ND-70% Tris at ∼129°C. Amorphous ND-PVP and eutectic ND-Tris mixtures showed an improvement of 5.55 and 6.6 times of drug dissolution efficiency, respectively. In vivo experiments in mice demonstrated that administration of 60 mg/kg of drug coprecipitated with PVP or Tris resulted, respectively, in a 50% and 94% reduction of acetic acid-induced writhings in comparison with pure drug, which, instead, was statistically ineffective as compared with the control group. Moreover, the eutectic mixture of ND-Tris demonstrated antiwrithing potency 1.88 times higher than amorphous ND-PVP coprecipitate. Thus, the solubilizing power, dissolution-enhancing effect, and analgesic effect enhancer ability toward the drug make Tris particularly suitable for developing a reduced-dose, fast-release solid oral dosage form of nimesulide. Published: August 10, 2007     

In vivo evaluation of modified gum karaya as a carrier for improving the oral bioavailability of a poorly water-soluble drug,nimodipine

This work examines the influence of modified gum karaya (MGK) on the oral bioavailability of a poorly water-soluble drug, nimodipine (NM), in comparison with that of gum karaya (GK). A cogrinding method was selected to prepare mixtures of NM and GK or MGK in a 1:9 ratio (NM:GK/MGK). Differential scanning calorimetry (DSC), Fourier transmission infrared (FT-IR) spectroscopy, X-ray diffraction (XRD), solubility studies, and in vitro release studies were performed to characterize the properties of the cogrinding mixtures. No drug-carrier interactions were found, as confirmed by DSC and FT-IR studies. The XRD study revealed that the crystallinity of NM was identical in both the cogrinding mixtures and was decreased when compared to that of physical mixtures or pure NM. The in vitro release rate of NM from both cogrinding mixtures was significantly higher than that of physical mixtures or pure NM. The in vivo study revealed that the bioavailability of NM from pure drug was significantly lower when compared to the cogrinding mixtures. The oral bioavailability was found to be NM powder < cogrinding mixtures of NM and GK < cogrinding mixtures of NM and MGK < NM solution. It can be inferred from the above results that MGK, an economical carrier, could be used for the dissolution enhancement of NM.     

Novel Self-Nanoemulsifying Drug Delivery Systems (SNEDDS) for Oral Delivery of Cinnarizine: Design, Optimization, and In-Vitro Assessment

Due to its extreme lipophilicity, the oral delivery of cinnarizine (CN) encounters several problems such as poor aqueous solubility and pH-dependent dissolution, which result in low and erratic bioavailability. The current study aims to design self-nanoemulsifying drug delivery systems (SNEDDS) of CN that circumvent such obstacles. Equilibrium solubility of CN was determined in a range of anhydrous and diluted lipid-based formulations. Dynamic dispersion tests were carried out to investigate the efficiency of drug release and magnitude of precipitation that could occur upon aqueous dilution. Droplet sizes of selected formulations, upon (1:1,000) aqueous dilution, were presented. The optimal formulations were enrolled in subsequent dissolution studies. The results showed that increasing lipid chain length and surfactant lipophilicity raised the formulation solvent capacity, while adding co-solvents provoked a negative influence. The inclusion of mixed glycerides and/or hydrophilic surfactants improved the drug release efficiency. Generally, no significant precipitation was observed upon aqueous dilution of the formulations. Five formulations were optimal in terms of their superior self-emulsifying efficiency, drug solubility, dispersion characteristics, and lower droplet size. Furthermore, the optimal formulations showed superior dissolution profile compared to the marketed (Stugeron®) tablet. Most importantly, they could resist the intensive precipitation observed with the marketed tablet upon shifting from acidic to alkaline media. However, SNEDDS containing medium-chain mixed glycerides showed the highest drug release rate and provide great potential to enhance the oral CN delivery. Accordingly, the lipid portion seems to be the most vital component in designing CN self-nanoemulsifying systems.     

Preformulation Studies on Solid Self-Emulsifying Systems in Powder Form Containing Magnesium Aluminometasilicate as Porous Carrier

The influence of alkaline and the neutral grade of magnesium aluminometasilicate as a porous solid carrier for the liquid self-emulsifying formulation with ibuprofen is investigated. Ibuprofen is dissolved in Labrasol, then this solution is adsorbed on the silicates. The drug to the silicate ratio is 1:2, 1:4, and 1:6, respectively. The properties of formulations obtained are analyzed, using morphological, porosity, crystallinity, and dissolution studies. Three solid self-emulsifying (S-SE) formulations containing Neusilin SG2 and six consisting of Neusilin US2 are in the form of powder without agglomerates. The nitrogen adsorption method shows that the solid carriers are mesoporous but they differ in a specific surface area, pore area, and the volume of pores. The adsorption of liquid SE formulation on solid silicate particles results in a decrease in their porosity. If the neutral grade of magnesium aluminometasilicate is used, the smallest pores, below 10 nm, are completely filled with liquid formulation, but there is still a certain number of pores of 40–100 nm. Dissolution studies of liquid SEDDS carried out in pH = 1.2 show that Labrasol improves the dissolution of ibuprofen as compared to the pure drug. Ibuprofen dissolution from liquid SE formulations examined in pH of 7.2 is immediate. The adsorption of the liquid onto the particles of the silicate causes a decrease in the amount of the drug released. Finally, more ibuprofen is dissolved from S-SE that consist of the neutral grade of magnesium aluminometasilicate than from the formulations containing the alkaline silicate.KEY WORDS: dissolution, ibuprofen, labrasol, magnesium aluminometasilicate, self-emulsifying powder     

Controlled Microwave Processing Applied to the Pharmaceutical Formulation of Ibuprofen

The first successful development of controlled microwave processing for pharmaceutical formulations is presented and illustrated with a model drug (ibuprofen) and two excipients (stearic acid and polyvinylpyrrolidone). The necessary fine temperature control for formulation with microwave energy has been achieved using a uniquely modified microwave oven with direct temperature measurement and pulse-width modulation power control. In addition to comparing microwave and conventional heating, the effect of the presence of liquid (water) in aiding the mixing of the drug and excipient during formulation was also investigated. Analysis of the prepared formulations using differential scanning calorimetry and dissolution studies suggest that microwave and conventional heating produce similar products when applied to mixtures of ibuprofen and stearic acid. However, the differences were observed for the ibuprofen and polyvinylpyrrolidone formulation in terms of the dissolution kinetics. In all cases, the presence of water did not appear to influence the formulation to any appreciable degree. The application of controllable microwave heating is noteworthy as fine temperature control opens up opportunities for thermally sensitive materials for which microwave methods have not been feasible prior to this work.     

Low-Viscosity Hydroxypropylcellulose (HPC) Grades SL and SSL: Versatile Pharmaceutical Polymers for Dissolution Enhancement, Controlled Release, and Pharmaceutical Processing

Hydroxypropylcellulose (HPC)-SL and -SSL, low-viscosity hydroxypropylcellulose polymers, are versatile pharmaceutical excipients. The utility of HPC polymers was assessed for both dissolution enhancement and sustained release of pharmaceutical drugs using various processing techniques. The BCS class II drugs carbamazepine (CBZ), hydrochlorthiazide, and phenytoin (PHT) were hot melt mixed (HMM) with various polymers. PHT formulations produced by solvent evaporation (SE) and ball milling (BM) were prepared using HPC-SSL. HMM formulations of BCS class I chlorpheniramine maleate (CPM) were prepared using HPC-SL and -SSL. These solid dispersions (SDs) manufactured using different processes were evaluated for amorphous transformation and dissolution characteristics. Drug degradation because of HMM processing was also assessed. Amorphous conversion using HMM could be achieved only for relatively low-melting CBZ and CPM. SE and BM did not produce amorphous SDs of PHT using HPC-SSL. Chemical stability of all the drugs was maintained using HPC during the HMM process. Dissolution enhancement was observed in HPC-based HMMs and compared well to other polymers. The dissolution enhancement of PHT was in the order of SE > BM > HMM > physical mixtures, as compared to the pure drug, perhaps due to more intimate mixing that occurred during SE and BM than in HMM. Dissolution of CPM could be significantly sustained in simulated gastric and intestinal fluids using HPC polymers. These studies revealed that low-viscosity HPC-SL and -SSL can be employed to produce chemically stable SDs of poorly as well as highly water-soluble drugs using various pharmaceutical processes in order to control drug dissolution.KEY WORDS: controlled release formulations, hydroxypropylcellulose, melt extrusion, solid dispersion     

Investigating the Use of Liquisolid Compacts Technique to Minimize the Influence of pH Variations on Loratadine Release

Loratadine is a class II water-insoluble drug and its dissolution rate and, consequently, absorption are dependent on the gastrointestinal pH. The resulting very high variability in bioavailability and related inter- and intra-subject absorption variations present a major challenge that hinders the realization of an effective and uniform therapy. Among the several techniques that have been used to minimize pH dependency of dissolution rate, liquisolid compacts technique can be suggested as a promising solution. In this study, it was hypothesized that the formulation of loratadine using liquisolid compacts technique may reduce the effect of pH variation on the drug dissolution rate. Solubilities of loratadine in propylene glycol, Tween 80, and polyethylene glycol 400 were first measured and propylene glycol was selected as for producing the highest solubility among the tested solvents. Several liquisolid tablet formulations containing various ratios of drug: propylene glycol (5%, 10%, and 20% w/w) were prepared. The ratio of microcrystalline cellulose (carrier) to silica (coating powder material) was kept constant in all formulations. The dissolution behavior of loratadine from liquisolid compacts was investigated in several buffered media with different pH values (pH 1.2, 2.5, and 5). The results showed that the drug release rates produced by liquisolid compacts were significantly higher and less affected by pH variation compared with conventionally made (direct compression) and commercial (Clarityn) tablets. In conclusion, liquisolid compacts technique may be used as a tool to minimize the effects of pH variation on the dissolution rate of drugs with poor water solubility.     

Co-solvent Evaporation Method for Enhancement of Solubility and Dissolution Rate of Poorly Aqueous Soluble Drug Simvastatin: In vitro–In vivo Evaluation

A number of synthesized chemical molecules suffer from low aqueous solubility problems. Enhancement of aqueous solubility, dissolution rate, and bioavailability of drug is a very challenging task in drug development. In the present study, solubility and dissolution of poorly aqueous soluble drug simvastatin (SIM) was enhanced using hydrophilic, low viscosity grade polymer hydroxypropyl methylcellulose (HPMC K₃LV). The co-solvent evaporation method was developed for efficient encapsulation of hydrophobic drug in polymer micelles of HPMC K₃LV. Spray drying and rotaevaporation method were applied for solvent evaporation. Co-solvent-evaporated mixture in solid state was determined by differential scanning calorimetry (DSC), X-ray diffraction studies (XRD), scanning electron microscopy, and Fourier-transform infrared spectroscopy. In vitro–in vivo studies were performed on co-solvent-evaporated mixture and compared with SIM. In vivo study was conducted on healthy albino rats (Wister strain), and formulations were administered by oral route. Results of the study show the conversion of crystalline form of SIM into amorphous form. The dissolution rate was remarkably increased in co-solvent-evaporated mixtures compared to SIM. co-solvent-evaporated mixtures showed better reduction in total cholesterol and triglyceride levels than the SIM. The low-viscosity grade HPMC acts as a surfactant, which enhances the wetting of drug and thus improves the solubility of drug. The co-solvent evaporation method provides good encapsulation efficiency and produces amorphous form of SIM, which gave better solubility and dissolution than the crystalline SIM.     

Combined Use of Crystalline Sodium Salt and Polymeric Precipitation Inhibitors to Improve Pharmacokinetic Profile of Ibuprofen through Supersaturation

To maximize the pharmacological effect of a pain reliever such as ibuprofen, early onset of action is critical. Unfortunately, the acidic nature of ibuprofen minimizes the amount of drug that can be solubilized under gastric conditions and would be available for immediate absorption upon entry into the intestine. Although the sodium salt of ibuprofen has higher solubility, rapid conversion from the salt to the poorly soluble free acid phase occurs under gastric conditions. Therefore, the combination of the highly soluble sodium salt form of ibuprofen with polymers was evaluated as an approach to prolong supersaturation of ibuprofen during the disproportionation of the salt. Binary combinations of ibuprofen sodium with polymers resulted in the identification of several formulations that demonstrated high degrees and extended durations of supersaturation during in vitro dissolution experiments. These formulations included HPMC, polyvinyl pyrrolidone-vinyl acetate copolymer (PVP-VA64), methylcellulose (MC), and hydroxypropyl cellulose (HPC). The in vitro supersaturation observed with these ibuprofen-polymer formulations translated to an increase in C_max and an earlier T_max for the PVP-VA64, MC, and HPC formulations relative to ibuprofen only controls when administered orally to rats under fasted conditions. Based on these observations, combining ibuprofen sodium with polymers such as PVP-VA64, MC, or HPC is a viable formulation approach to prolong supersaturation in the stomach and enable an optimized pharmacokinetic profile in vivo where rapid onset of action is desired.     

Solid Dispersion as an Approach for Bioavailability Enhancement of Poorly Water-Soluble Drug Ritonavir

Ritonavir is an antiretroviral drug characterized by low solubility and high permeability which corresponds to BCS class II drug. The purpose of the study was to develop solid dispersion by different methods and investigate them for in vitro and in vivo performance for enhancing dissolution and bioavailability, respectively. Since the drug possesses food-related absorption, the effect of biorelevant media (FaSSIF and FeSSIF state) on dissolution behavior was also studied. The solid dispersion was prepared using Gelucire as carrier in 1:4 ratio by different methods and were characterized for differential scanning calorimetry (DSC), X-ray diffractometry, scanning electron microscopy, and FT-IR. Oral bioavailability of 10 mg of ritonavir in solid dispersion prepared by solvent evaporation (SE1) and melt method (MM1) was compared with pure drug after oral administration of solid dispersion and pure drug to Albino Wistar rats of either sex. The results suggested formation of eutectic solid dispersion. In vitro dissolution studies was performed in 0.1 N HCl and biorelevant media showed enhanced dissolution rate as compared to pure drug in both FeSSIF media and 0.1 N HCl. The apparent rate of absorption of ritonavir from SE1 (C _max 20221.37 ng/ml, t _max 0.5 h) was higher than that of MM1 (C _max 2,462.2, t _max 1 h) and pure drug (C _max 1,354.8 ng/ml, t _max 0.5 h). On the basis of the result obtained, it was concluded that solid dispersion is a good approach to enhance solubility and bioavailability of poorly water-soluble ritonavir.     

Oral Bioavailability Enhancement of Exemestane from Self-Microemulsifying Drug Delivery System (SMEDDS)

Limited aqueous solubility of exemestane leads to high variability in absorption after oral administration. To improve the solubility and bioavailability of exemestane, the self-microemulsifying drug delivery system (SMEDDS) was developed. SMEDDS comprises of isotropic mixture of natural or synthetic oil, surfactant, and cosurfactant, which, upon dilution with aqueous media, spontaneously form fine o/w microemulsion with less than 100 nm in droplet size. Solubility of exemestane were determined in various vehicles. Ternary phase diagrams were plotted to identify the efficient self-emulsification region. Dilution studies, droplet size, and zeta potential of the formulations were investigated. The release of exemestane from SMEDDS capsules was studied using USP dissolution apparatus in different dissolution media and compared the release of exemestane from a conventional tablet. Oral pharmacokinetic study was performed in female Wistar rats (n = 8) at the dose of 30 mg kg⁻¹. The absorption of exemestane from SMEDDS form resulted in about 2.9-fold increase in bioavailability compared with the suspension. Our studies illustrated the potential use of SMEDDS for the delivery of hydrophobic compounds, such as exemestane by the oral route.Key words: bioavailability enhancement, exemestane, microemulsion, SMEDDS     

Polymeric surfactant based etodolac chewable tablets: formulation and in vivo evaluation

Etodolac (ET) is a nonsteroidal anti-inflammatory drug with proved potential antitumor and uric acid lowering effects. It shows dissolution rate-dependent bioavailability. This work was carried out to improve the dissolution rate of etodolac using three carriers of known potential to improve solubility and hence dissolution rate of poorly soluble drugs through coevaporation technique. The polymeric surfactant inutec, 2-hydroxypropyl-β-cyclodextrin, and tromethamine were used at three different drug/carrier ratios. The dissolution rate of ET at pH 1.2 and 6.8 is improved in all of the solid dispersion systems compared to that of the pure drug and physical mixtures. DSC of coevaporates at 1:5 drug/carrier ratio providing the fastest dissolution rate suggested loss of ET crystallinity which was further confirmed by X-ray diffraction. Inutec-based coevaporate was chosen for the formulation of ET chewable tablets. Chewable tablets (F3) that met the USP monograph specifications for ET tablets, with 86% dissolved amount within 15 min, was chosen for in vivo absorption study in comparison with pure ET-filled hard gelatin capsules. The results showed significantly higher mean C _max and shorter mean T _max (about 2 h earlier) and about 1.32-fold higher mean AUC_0–24 values for the F3 chewable tablets compared to ET-filled capsules.     

Spray-dried voriconazole–cyclodextrin complexes: Solubility,dissolution rate and chemical stability

The present work investigates the effect of complexation with hydroxypropyl-beta-cyclodextrin (HPBCD) and 2-O-methyl-beta-cyclodextrin (2-O-MBCD), on voriconazole solubility, dissolution rate and chemical stability. Drug–cyclodextrin complexes were prepared as aqueous solutions, which were spray-dried, and their properties were compared to wet ground samples and physical mixtures. DSC analysis revealed absence of crystalline voriconazole from spray-dried complexes. FTIR spectroscopy indicated changes in the H-bonding network of the hydroxyl groups of cyclodextrin following drug inclusion. Dissolution rate of voriconazole was significantly higher from spray-dried complexes with either cyclodextrin in comparison with free drug, physical mixtures, or wet ground mixtures. However, two degradation impurities were found in aged samples, with slightly higher impurity level with HPBCD. Performed solubility studies suggested that 2-O-MBCD is more efficient solubilizer. Molecular docking simulations showed a difference in the 1:1 binding affinities and sites, with HPBCD surprisingly forming complexes of much lower energy, thus suggesting a multiple rather than a 1:1 complexation.