Presence Of Hydroxypropyl Methylcellulose Research Articles

Controlled Crystallization of Acetazolamide from Aqueous Polymeric Solutions for Enhancing Dissolution Rate: Application of Statistical Moment Theory and Molecular Docking

Presence of additives in crystallization process in a controlled manner can lead to different crystal morphologies which could have a favourable impact on drug dissolution rate. Four different hydrophilic polymers (methylcellulose, hydroxypropyl methylcellulose, polyvinyl alcohol, and carboxymethyl cellulose) were used for the controlled crystallization of acetazolamide (ACZ) by solvent evaporation technique. Crystal imperfections of ACZ occurred in the lattice of growing crystal when crystallized from aqueous polymeric solution and evaluated using both the traditional Full Width at Half Maximum (FWHM) (b) and statistical mean value of the XRD peak width (b¢). Crystal imperfection has brought about significant improvement in the dissolution of newly produced acetazolamide crystals. ACZ crystal produced in presence of Hydroxypropyl methylcellulose (AHPMC) showed crystal imperfection to the maximum extent and also the greatest dissolution of the drug was noticed from AHPMC compared to other crystals. Statistical mean value of the peak width of XRD data as the error-free technique has been utilized successfully for estimating crystallite properties of acetazolamide crystallized from ethanol as solvent and aqueous polymeric solution as anti-solvent. Crystallite properties using traditional Full Width Half Maxima method and the error-free Statistical Moment Analysis were compared. This controlled crystallization technique could be utilized in the design and development of formulation for improved solubility and bioavailability of the drug.

Study on the Role of Polymers in Preventing the Crystallization of Roxadustat in an Aqueous Environment

The use of polymers is an increasingly common approach to prevent crystallization from the supersaturated solutions for enhanced bioavailability of poorly water-soluble drugs. In this study, roxadustat (RST), a water-insoluble drug, was selected as a model substance. We quantified the effectiveness of three polymers with different types of hydrogen bonding moieties, polyvinylpyrrolidone (PVP), poly(1-vinylpyrrolidone-co-vinyl acetate) (PVPVA), and hydroxypropyl methylcellulose (HPMC), on nuclear inhibition of RST and found that the inhibitory effect was HPMC > PVPVA > PVP. In the absence of polymers, the induction time of RST in the RST supersaturated solution was 1.5 min, while in the presence of HPMC, the induction time of RST was as long as 84.5 min. Simulation by Material Studio suggested that the compatibility and bonding energy between the polymers and RST showed a strongly positive correlation with the effectiveness of polymers. The combined inhibitory effect of hydrogen bonding and hydrophobic interaction between RST and polymers were revealed by FTIR, 1H NMR spectroscopy, and nuclear Overhauser effect spectroscopy. Moreover, the obtained amorphous-state RST in RST–polymer amorphous solid dispersions achieved improved solubility than that of crystalline RST, and the dissolved amorphous RST maintained the supersaturation for 6 h in the dissolution test without the decrease in concentration due to nucleation and crystal growth.

Ternary Inclusion Complex of Sinapic Acid with Hydroxypropyl-β-cyclodextrin and Hydrophilic Polymer Prepared by Microwave Technology

Sinapic acid (SA) is a poorly water-soluble substance which could result in poor bioavailability. The aim of this study was to determine the “hydroxypropyl β-cyclodextrin (HPβCD)” solubilization of SA in the presence of the auxiliary substance hydroxypropyl methylcellulose (HPMC) and to evaluate the ternary inclusion complex prepared by microwave technology. Phase-solubility profiles showed that HPβCD exhibited the greatest solubilizing effect on SA in the presence of HPMC. The enhanced rate of SA dissolution was exhibited by a ternary complex. Outcomes of analyses such as “DSC, FTIR, NMR, and SEM” confirmed the embedding of SA into the cavity of the HPβCD and the formation of a ternary inclusion complex. The outcomes of antioxidant activity (ABTS and nitric oxide scavenging activity) demonstrated that SA ternary inclusion complex (TIC) presented strong antioxidant activity, which might be a result of the enhanced solubility of SA in the TIC prepared by microwave technology. Hence, SA-TIC formulation could be a better dosage form which may protect the body from free radical damage and oxidative stress. Microwave technology greatly boosted the interaction of SA with HPβCD and HPMC, and such findings are expected to contribute to raising the solubility of SA, thereby improving the bioavailability of SA.

Supercritical CO2 versus water as an antisolvent in the crystallization process to enhance dissolution rate of curcumin

Antisolvent crystallization approach using either water (in conventional crystallization process (WAS)), or supercritical CO2 (in supercritical anti-solvent crystallization (SCAS)), was employed in presence of hydroxypropyl methylcellulose (HPMC) to enhance the dissolution of curcumin. The impact of pressure, temperature and depressurization time on the SCAS process was studied using the Box-Behnken design to achieve the highest saturation solubility. A physical mixture of curcumin-HPMC was prepared for comparison purposes. Saturation solubility, scanning electron microscopy, differential scanning calorimetry, X-ray diffraction analysis and Fourier transform infrared spectroscopy were conducted to characterize the solid-state characteristics of the crystallized samples. Dissolution studies helped in ascertaining the effects of the crystallization techniques on the performance of the formulation. Curcumin crystalized by different antisolvent displayed varied shapes, sizes, saturation solubility’s and dissolution properties. In SCAS process, the maximum saturation solubility (2.83 µg/mL) was obtained when the pressure, temperature and depressurization time were 275 bars, 55 °C, and 22 min respectively. The SCAS samples showed the highest dissolution (70%) in 30 min compared to WAS (27%), physical mixture (18%) and unprocessed curcumin (16%). The improved dissolution rate of SCAS sample originates from the development of sponge-like particles with augmented porosity, decreased crystallinity as well as increased solubility of curcumin.

Characterization, Stability, and Antibrowning Effects of Oxyresveratrol Cyclodextrin Complexes Combined Use of Hydroxypropyl Methylcellulose.

Oxyresveratrol (Oxy) has attracted much attention by employing it as an antibrowning agent in fruits and vegetables. In this study, the formation of cyclodextrin (CD) inclusion exhibited a certain protective effect on Oxy oxidative degradation, while hydroxypropyl-β-cyclodextrin (HP–β-CD) inclusion complex showed stronger stabilizing effects than those of β-cyclodextrin (β-CD). The combined use of CD and hydroxypropyl methylcellulose (HPMC) greatly improved the stability of Oxy–CD inclusion complexes, with approximately 70% of the trans-Oxy retained after 30 days of storage under light conditions at 25 °C. The results of the interaction between CD and Oxy determined by phase solubility studies and fluorescence spectroscopic analysis showed that the binding strength of CD and Oxy increased in the presence of HPMC. Moreover, Oxy combined with ascorbic acid and HPMC showed an excellent antibrowning effect on fresh-cut apple slices during the 48 h test period, indicating that adding HPMC as the third component will not influence the antibrowning activity of Oxy.

Effect of solvent and additives on the electrospinnability of BSA solutions

Electrospun nanofibrous membranes have attracted the interest of the scientific community over the past decades due to their unique properties (e.g., high surface area, enzyme encapsulation high efficiency in filtering). Among the most promising membranes are those derived from natural polymers, which are not based on fossil fuels and most of them are highly biocompatible. In this regard, this study is focused on the development and characterization of electrospun nanofibrous membranes of bovine serum albumin (BSA) with potential applications in several fields, from tissue engineering to advanced filtering. Although the globular structure of BSA hinders the generation of nanofibers, some previous studies have succeeded in its electrospinning. However, they made use of either toxic reagents or co-electrospinning with synthetic polymers, which resulted in poorer biocompatibility. To prevent this, the present study explores the impact of non-hazardous reagents on the formation of BSA nanofibers. As a result, it was observed that the addition of ethanol (EtOH) in the solvent mixture and the thermal denaturation of BSA favored the electrospraying of nanoparticles (∼ 300 nm). It was also noticed that the presence of hydroxypropyl methylcellulose (HPMC) favors the formation of nanofibers (∼ 60 nm). However, bead formation was found in these membranes. This work contributes to clarifying the influence of solvents and surfactants when proteins are electrospun, enabling the manufacture of bio-based nanofibrous mats with applications in different fields (e.g., filtering, biomaterials, active packaging).

The Investigation of Thymol Formulations Containing Poloxamer 407 and Hydroxypropyl Methylcellulose to Inhibit Candida Biofilm Formation and Demonstrate Improved Bio-Compatibility.

The aim of this study was to investigate the potential of thymol to inhibit Candida biofilm formation and improve thymol biocompatibility in the presence of hydroxypropyl methylcellulose (HPMC) and poloxamer 407 (P407), as possible drug carriers. Thymol with and without polymers were tested for its ability to inhibit biofilm formation, its effect on the viability of biofilm and biocompatibility studies were performed on HEK 293 (human embryonic kidney) cells. Thymol showed a concentration dependent biofilm inhibition; this effect was slightly improved when it was combined with HPMC. The Thymol-P407 combination completely inhibited the formation of biofilm and the antibiofilm effect of thymol decreased as the maturation of Candida biofilms increased. The effect of thymol on HEK 293 cells was a loss of nearly 100% in their viability at a concentration of 250 mg/L. However, in the presence of P407, the viability was 25% and 85% using neutral red uptake and sulforhodamine B assays, respectively. While, HPMC had less effect on thymol activity the thymol-P407 combination showed a superior inhibitory effect on biofilm formation and better biocompatibility with human cell lines. The combination demonstrates a potential medical use for the prevention of Candida biofilm formation.

Integrated Treatment of Mining Dam Wastewater with Quaternized Chitosan and PAN/HPMC/AgNo3 Nanostructured Hydrophylic Membranes

This study was developed a novel nanostructured membrane by electrospinning process, from polyacrylonitrile (PAN) modify by hydroxypropyl methylcellulose (HPMC) polymers containing silver nitrite (AgNO3), to be used as a filter in an integrated wastewater dam treatment process to reuse it as drinking water. Different formulations (108 samples) were electrospun from PAN and (0, 5, 10 w%) HPMC and (0, 0.5, 1 w%) solutions to selected a more efficient formulation in water disinfection and higher hydrophilic character of the membrane to flow performance in the wastewater treatment. The PAN and HPMC phases in membranes were characterize by infrared spectroscopy and thermogravimetric analysis. The nanostructured membranes were characterized by Scanning electron microscopy and the fibers had a diameter between 251 ± 58 and 306 ± 49 nm. The presence of HPMC and AgNO3 in membrane formulation endows superhydrophilicity and permeability increase which up to 21,151 ± 445 L⋅m−2 Permeability h−1. After filtration process with PAN/HPMC/AgNO3, all the tested water potability indexes were achieved. The primary treatment, using quaternized chitosan reduced the turbidity parameter from 19,000 Nephelometric turbidity units (NTU) to 14 NTU, and after filtration with nanostructured membrane, to levels was below 1 NTU and pathogenic potential removed (Total Coliform and Escherichia coli). The results of this study indicated that the hydrophilic nanostructured membranes PAN/10% HPMC/1% AgNO3 have adequate properties to potential wastewater treatment mining for reuse. It’s give a sustainable strategy for managing wastewater which should be reduce the volume of water in the tailing’s dams and contributes to increasing the stability of dams and reducing risks with catastrophic environmental impact.

Laser diffraction as a powerful tool for amorphous solid dispersion screening and dissolution understanding

Biopharmaceutics Classification System (BCS) class II and IV drugs may be formulated as supersaturating drug delivery systems (e.g., amorphous solid dispersions [ASDs]) that can generate a supersaturated drug solution during gastrointestinal (GI) transit. The mechanisms that contribute to increased bioavailability are generally attributed to the increased solubility of the amorphous form, but another mechanism with significant contributions to the improved bioavailability have been recently identified. This mechanism consists on the formation of colloidal species and may further improve the bioavailability several fold beyond that of the amorphous drug alone. These colloidal species occur when the concentration of drug generated in solution exceeds the amorphous solubility during dissolution, resulting in a liquid-liquid phase separation (LLPS). For the appearance of LLPS, the crystallization kinetics needs to be slow relatively to the dissolution process. This work intended to implement an analytical methodology to understand the ability of a drug to form colloidal species in a biorelevant dissolution media. This screening tool was therefore focused on following the colloidal formation and crystallization kinetics of itraconazole (ITZ; model drug from BSC class II) in the presence of hydroxypropyl methylcellulose (HPMC-AS L and HPMC-AS M, which are HPMC-AS with varying ratios of succinoyl:acetyl groups), using a laser diffraction-based methodology. The ability of ITZ to form colloids by a solvent-shift approach was compared with the actual colloidal formation of ITZ amorphous solid dispersions produced by spray-drying. Results indicate that regardless of the used methodology, colloids of ITZ can be detected and monitored. The extension of colloid generation showed to be correlated with the ASD disintegration/dissolution rate, i.e, polymers with faster wettability kinetics led to faster ASD disintegration and colloidal formation.As conclusion, this study showed that laser diffraction could give complementary information about colloidal formation and ASD dissolution profile, showing to be an excellent screening strategy to be applied in the early stage development of amorphous solid dispersions.

Influence of the liquid phase content and presence of hydroxypropyl methyl cellulose on the properties of a calcium phosphate bone cement

Introduction Calcium phosphate cements (CPCs) have been widely used for bone defect´s filling given their excellent biocompatibility, osteoconduction ability and ease of manipulation [1]. Nevertheless, their mechanical properties and handling performance still need to be improved to satisfy clinical requirements. Indeed, enhancing their injectability can widen its application to minimally invasive surgical procedures [2]. This work aims to investigate the effect of the liquid phase amount and presence of hydroxypropyl methyl cellulose (HPMC) on the basic properties of a commercial CPC containing a polymeric adjuvant, chitosan (Chi). Materials and methods Starting from the original formulation containing Chi, samples with different amounts of liquid phase (LP 30%, 38%, 42%, 50%) were prepared. Additionally, for LP 38% and 42% formulations, Chi was replaced by HPMC polymer. Setting times were measured using the Vicat apparatus. After 6 days of setting, mechanical properties were studied through compression assays and Vickers hardness was measured. Injectability experiments were done and the cytotoxicity of the commercial CPC was assessed using MG63 and NIH/3T3 cell lines following the ISO 10993-5 guidelines. Results As shown in Table 1, increasing the LP content from 30% to 50% increased the initial setting time from 6.5 min to 24 min, and the final setting time from 7.5 min to 32 min. Concerning the resistance to compression, it was lowered from 9.53 ± 1.00 MPa to 0.83 ± 0.20 MPa. Regarding materials’ hardness, it decreased by 77%. Injectability measurements showed that only 38% and 42%LP formulations could be injected. Nonetheless, while 38%LP formulation presented an injectability of 31 ± 2%, 42%LP formulation showed an injectability of 91 ± 1%. As for the addition of HPMC, for 38%LP formulation an initial setting time of 6.5 min and a final setting time of 10.5 min were measured, and for 42%LP formulation 12 min and 14.5 min, respectively. The mechanical properties presented similar values regardless the added polymer. Moreover, the formulations containing HPMC presented 69 ± 6% injectability for 38%LP and 94 ± 1% for 42%LP. Finally, when in contact with extracts of the commercial CPC for 24 h, the studied cell lines presented viability greater than 75% when compared to unexposed cells. Discussion and conclusions: Our study shows that LP content has a significant impact on the CPC studied properties. Effectively, for 38 and 42%LP the setting times, resistance to compression and hardness of the materials assume suitable values for their use as trabecular bone defect fillers. For the Chi CPC, 42%LP formulation is ∼200% more injectable than the 38%LP one. Even though the replacement of Chi by HPMC does not affect the mechanical properties significantly, HPMC itself seems to promote injectability, increasing it by 126%. Finally, the commercial CPC does not show a cytotoxic effect under the conditions of this assay. Table 1. Effect of the LP content on the properties of the Chi containing CPC.

Microstructural formation of gypsum by setting in the presence of hydroxypropyl methylcellulose (HPMC)

The role of a polymer as a retarder additive is to enhance workability of the gypsum paste by modifying its setting process and to improve its properties. The study focuses on the influence of water-soluble cellulose derivative hydroxypropyl methylcellulose (HPMC) on the setting kinetics as well as on the properties and the microstructure of gypsum. The influence of HPMC (used in mass fractions of up to 1.5%) on the kinetics of crystallization/hydration of hemihydrate calcium sulfate was investigated by heat flow measurements using differential scanning calorimetry (DSC). To describe the experimental results, the Avrami equation was used and its parameters n and K were determined. The hydration/crystallization process was modified by the presence of the polymer. As a result, the K value decreased, but n ≈ 2.5 pointed to the three-dimensional diffusion-controlled mechanism. The morphology studies involved porosity measurements. Mechanical properties of the gypsum plaster composites were examined using the bending strength test and correlated with the sample microstructure.

Effects of redispersible polymer powders on the structural build-up of 3D printing cement paste with and without hydroxypropyl methylcellulose

This paper studies the effects of polyvinyl acetate-ethylene (VAE) based redispersible polymer powder (RPP) and polyvinyl acetate-vinyl versatate-ethylene (VVE) based RPP on the structural build-up of 3D printing cement paste within several hours of hydration. At the same time, two cases of the presence or absence of hydroxypropyl methylcellulose (HPMC) were considered. The build-up performance of cement paste was assessed by the hysteresis area, dynamic yield stress ratio, static yield stress, shear modulus and ultrasonic plus velocity from the dynamic shear test, static shear test and ultrasonic wave transmission test. In addition, the limit layer thickness and printing velocity were calculated by dynamic and static yield stresses to quantitatively characterize shape stability and printing efficiency of cement paste. Results indicate that both VAE with higher ethylene content (VAE1) and VVE decrease the structural build-up rate of cement paste, independent of shear test modes. However, VAE with lower ethylene content (VAE2) increases the structural build-up rate of cement paste under dynamic shear test whereas decreases the growth rate of static yield stress. The dynamic yield stress ratio of cement paste containing 2% VAE2 is 0.57, which is 83.9% higher than that of pure cement paste. In addition, HPMC alters the effects of VAE2 on the structural build-up of cement paste. VAE1 and VVE decrease the shape stability of cement pastes with and without HPMC, while VAE2 is beneficial to the shape stability of cement paste. Limit layer thicknesses of cement pastes with 4% VAE2 are 7.3 mm and 14 mm in the absence and presence of HPMC, which are about 3.0 and 5.8 times that of pure cement paste. In the absence of HPMC, VVE decreases the limit printing velocity of cement paste in the first tens of minutes. VAE1 and VAE2 can improve the printing efficiency due to the increase of limit printing velocity in the first tens of minutes. In the presence of HPMC, only VAE2 significantly improves the limit printing velocity of cement paste.

Ca2+-induced whey protein emulgels for the encapsulation of crystalline nobiletin: Effect of nobiletin crystals on the viscoelasticity

Due to the high crystallization, nobiletin was encapsulated by Ca2+-induced whey protein concentrate (WPC)-stabilized emulgels. Hydroxypropyl methylcellulose (HPMC) was used to regulate the interfacial properties of emulsions and viscoelasticity of emulgels. The formation of nobiletin crystals were monitored in emulgels and after digestion. Micro-rheometer was used to characterize the viscoelasticity of emulgels. Bioaccessibility of nobiletin was determined by an in vitro digestion model. Ca2+ crosslinking increased the particle size of WPC-stabilized emulsion, while HPMC/WPC-stabilized emulsions kept smaller particle size. WPC-stabilized emulgels were more apt to syneresis, which could be prevented in the presence of HPMC. Nobiletin crystallization process in emulgels was delayed by HPMC. In the gelation process, HPMC addition increased the viscosity, but decreased the elasticity of emulgels. HPMC interrupted the crosslinking process of WPC and Ca2+. After destruction, emulgels had lower viscosity and elasticity, which became lower in the presence of HPMC. The fluctuation of mean square displacement profiles could indicate the formation of nobiletin crystals, which reduced the viscosity and elasticity of emulgels. HPMC increased the bioaccessibility of nobiletin. Higher Ca2+ concentration was undesirable to enhance the nobiletin bioaccessibility, depending on the structure of emulgels.

Inhibition of Co-Crystallization of Olmesartan Medoxomil and Hydrochlorothiazide for Enhanced Dissolution Rate in Their Fixed Dose Combination.

Olmesartan medoxomil (Olm) and hydrochlorothiazide (HCTZ) are fixed dose combination (FDC) for treatment of hypertension. They have hydrogen bonding sites and may interact during co-processing. The consequences of such interaction are not clear. This study investigated the possibility of this interaction during co-processing. The research was extended to inhibit deleterious interactions. The drugs were co-evaporated from ethanolic solution to maximize the chance of interaction. This was performed in the absence and presence of hydroxypropyl methylcellulose (HPMC) and/or aerosil. The products were characterized using Fourier transform infrared spectroscopy (FTIR), differential thermal analysis, and powder X-ray diffraction (PXRD) in addition to dissolution studies. Co-evaporation of Olm with HCTZ in the absence of excipients produced crystalline material with FTIR spectrum showing intermolecular hydrogen bonding. This material showed thermal pattern of new crystalline species. This was identified as Olm/HCTZ co-crystal by PXRD. This co-crystallization reduced the dissolution rate of both drugs. This co-crystallization was inhibited in the presence of HPMC, but the dissolution rate was not significantly enhanced accordingly. Co-processing in the presence of both HPMC and aerosil eliminated the co-crystallization and minimized the intermolecular drug-drug interaction with subsequent dissolution enhancement. The study introduced a composition for fixed dose combination of Olm and HCTZ with enhanced dissolution.

Polymer Templated Structural Evolution of a Poorly Water-Soluble Active Pharmaceutical Ingredient from Nanoparticles to Hierarchical Crystals

The hydrate form of a poorly water-soluble active pharmaceutical ingredient (API), spironolactone (SP), was produced using antisolvent precipitation in the presence/absence of polymer templates and stirring. Different crystal habits were observed depending on the polymer added. Superstructures consisting of primary constituent units were obtained in the presence of hydroxypropyl methylcellulose (HPMC), while tubular crystals with highly fused surfaces were observed in the presence of polyvinylpyrrolidone (PVP). In contrast, tubular and dendritic crystals were obtained in the absence of polymer. The structural evolution of the particle formation process was monitored by scanning electron microscopy (SEM), which reveals the growth mechanisms leading to different crystal habits. Superstructures are attributed to self-assembly growth, while tubular and dendritic crystals are formed under diffusion limited growth. The results suggest a potential way to produce crystals with the desired crystal habit by appropr...

Impact of Eudragit EPO and hydroxypropyl methylcellulose on drug release rate, supersaturation, precipitation outcome and redissolution rate of indomethacin amorphous solid dispersions

The purpose of this work was to evaluate the impact of polymer(s) on the dissolution rate, supersaturation and precipitation of indomethacin amorphous solid dispersions (ASD), and to understand the link between precipitate characteristics and redissolution kinetics. The crystalline and amorphous solubilities of indomethacin were determined in the absence and presence of hydroxypropylmethyl cellulose (HPMC) and/or Eudragit ® EPO to establish relevant phase boundaries. At acidic pH, HPMC could maintain supersaturation of the drug by effectively inhibiting solution crystallization while EPO increased both the crystalline and amorphous solubility of the drug, but did not inhibit crystallization. The HPMC dispersion dissolved relatively slowly without undergoing crystallization while the supersaturation generated by rapid dissolution of the EPO ASD was short-lived due to crystallization. The crystals thus generated underwent rapid redissolution upon pH increase, dissolving faster than the reference crystalline material, and at a comparable rate to the amorphous HPMC dispersion. A ternary dispersion containing both EPO and HPMC dissolved rapidly, generating an apparent drug concentration that exceeded the amorphous solubility of indomethacin, leading to the formation of a new nanosized droplet phase. These nanodroplets dissolved virtually immediately when the pH was increased. In conclusion, the concentration-time profiles achieved from indomethacin ASD dissolution are a complex interplay of drug release rate, precipitation kinetics and outcome, and precipitate redissolution rate, whereby each of these processes is highly dependent on the polymer(s) employed in the formulation.

Supersaturation of zafirlukast in fasted and fed state intestinal media with and without precipitation inhibitors

Poor water solubility is a bottle neck in the development of many new drug candidates, and understanding and circumventing this is essential for a more effective drug development. Zafirlukast (ZA) is a leukotriene antagonist marketed for the treatment of asthma (Accolate®). ZA is poorly water soluble, and is formulated in an amorphous form (aZA) to improve its solubility and oral bioavailability. It has been shown that upon dissolution of aZa, the concentration of ZA in solution is supersaturated with respect to its stable crystalline form (ZA monohydrate), and thus, in theory, the bioavailability increases upon amorphization of ZA. The polymers hydroxypropylmethylcellulose (HPMC) and polyvinylpyrrolidone (PVP), often used as stabilizers of the supersaturated state, are in the excipient list of Accolate®. It is not recommended to take Accolate® with food, as this reduces the bioavailability by 40%.The aim of this study was to investigate the effect of simulated fasted and fed state intestinal media as well as the effect of HPMC and PVP on the supersaturation and precipitation of ZA in vitro.Supersaturation of aZA was studied in vitro in a small scale setup using the μDiss Profiler™. Several media were used for this study: One medium simulating the fasted state intestinal fluids and three media simulating different fed state intestinal fluids. Solid state changes of the drug were investigated by small angle x-ray scattering. The duration wherein aZA was maintained at a supersaturated state was prolonged in the presence of HPMC and lasted more than 20h in the presence of PVP in a fasted state intestinal medium. The presence of PVP increased the concentration of drug dissolved in the supersaturated state. The duration of supersaturation was shorter in fed than in a fasted state simulated intestinal media, but the concentration during supersaturation was higher. It was thus not possible to predict any positive or negative food effects from the dissolution/precipitation curves from different media. Lipolysis products in the fed state simulated media seemed to cause both a negative effect on the duration of supersaturation, and an increased drug concentration during supersaturation. In contrast, when testing the effect of a fed state simulated medium compared to the fasted state medium, in the presence of PVP, a clear negative effect was seen on the dissolution/precipitation curved of the fed state medium. The drug concentration during supersaturation was marginally different in the two media, but a precipitation of ZA was seen in the fed state medium, which was not observed in the fasted state medium. Solid state transformation from aZA to ZA monohydrate (mhZA) upon precipitation of the supersaturated solutions was confirmed by small angle x-ray scattering. All of these results can explain the described in vivo behavior of ZA. For ZA simple dissolution experiments in vitro can be used to examine supersaturation, effectiveness of PI and potential food effects on these.

Cost-effective alternative to nano-encapsulation: Amorphous curcumin–chitosan nanoparticle complex exhibiting high payload and supersaturation generation

While the wide-ranging therapeutic activities of curcumin have been well established, its successful delivery to realize its true therapeutic potentials faces a major challenge due to its low oral bioavailability. Even though nano-encapsulation has been widely demonstrated to be effective in enhancing the bioavailability of curcumin, it is not without drawbacks (i.e. low payload and costly preparation). Herein we present a cost-effective bioavailability enhancement strategy of curcumin in the form of amorphous curcumin–chitosan nanoparticle complex (or curcumin nanoplex in short) exhibiting a high payload (>80%). The curcumin nanoplex was prepared by a simple yet highly efficient drug–polysaccharide complexation method that required only mixing of the curcumin and chitosan solutions under ambient condition. The effects of (1) pH and (2) charge ratio of chitosan to curcumin on the (i) physical characteristics of the nanoplex (i.e. size, colloidal stability and payload), (ii) complexation efficiency, and (iii) production yield were investigated from which the optimal preparation condition was determined. The nanoplex formation was found to favor low acidic pH and charge ratio below unity. At the optimal condition (i.e. pH 4.4. and charge ratio=0.8), stable curcumin nanoplex (≈260nm) was prepared at >90% complexation efficiency and ≈50% production yield. The amorphous state stability, colloidal stability, and in vitro non-cytotoxicity of the nanoplex were successfully established. The curcumin nanoplex produced prolonged supersaturation (3h) in the presence of hydroxypropyl methylcellulose (HPMC) at five times of the saturation solubility of curcumin. In addition, curcumin released from the nanoplex exhibited improved chemical stability owed to the presence of chitosan. Both results (i.e. high supersaturation and improved chemical stability) bode well for the ability of the curcumin nanoplex to enhance the bioavailability of curcumin clinically.

Enhanced physical stabilization of fenofibrate nanosuspensions via wet co-milling with a superdisintegrant and an adsorbing polymer

Drug nanoparticles in suspensions can form aggregates leading to physical instability, which is traditionally mitigated using soluble polymers and surfactants. The aim of this paper was to explore common superdisintegrants, i.e., sodium starch glycolate (SSG), croscarmellose sodium (CCS), and crospovidone (CP), as novel class of dispersants for enhanced stabilization of fenofibrate (FNB), a model BCS Class II drug, suspensions. FNB was wet-milled with superdisintegrants along with hydroxypropyl methylcellulose (HPMC), a soluble adsorbing polymer, in a stirred media mill. For comparison, FNB was also milled in the presence of HPMC and/or SDS (sodium dodecyl sulfate) without superdisintegrants. Laser diffraction, scanning electron microscopy, viscometry, differential scanning calorimetry, and powder X-ray diffraction were used to characterize the suspensions. The results show that 2% HPMC along with 1% SSG or 1% CCS mitigated the aggregation of FNB nanoparticles significantly similar to the use of either 5% HPMC or 1% HPMC–0.075% SDS, whereas CP was not effective due to its low swelling capacity. CCS/SSG enhanced steric–kinetic stabilization of the FNB suspensions owing to their high swelling capacity, viscosity enhancement, and physical barrier action. Overall, this study provides a mechanistic basis for a novel method of formulating surfactant-free drug nanosuspensions with co-milled superdisintegrants.

Designing self-nanoemulsifying delivery systems to enhance bioaccessibility of hydrophobic bioactives (nobiletin): Influence of hydroxypropyl methylcellulose and thermal processing

Emulsion-based delivery systems are widely utilized for encapsulation of hydrophobic bioactive compounds. However, they must be carefully designed to retain and stabilize the encapsulated components during storage, and to release them after ingestion. In the present work, the influence of hydroxypropyl methylcellulose (HPMC) addition and heat treatment on the retention and release of a model hydrophobic nutraceutical (nobiletin) in nanoemulsions prepared by self-emulsification was investigated. Physical stability was assessed by measuring nobiletin retention, crystal morphology, and droplet size during storage. Further, the bioaccessibility of nobiletin was evaluated using a simulated gastrointestinal model. The results indicated that the presence of HPMC in the aqueous phase improved the retention of nobiletin in the nanoemulsions, without promoting any physical instability. The saturation concentration of nobiletin in the nanoemulsions increased from 4.5 to 6.0 mg/mL in the presence of HPMC. Heating the nanoemulsions promoted rapid droplet coalescence above a critical temperature. The combination of HPMC addition and heat treatment increased the retention time of nobiletin in nanoemulsions. Neither HPMC addition nor heat treatment affected the bioaccessibility (around 85%) of nobiletin when it was fully dissolved in the nanoemulsions. However, when nobiletin was not fully dissolved in the nanoemulsions, HPMC addition (from 52 to 59% without heat treatment) and heat treatment (from 52% to 82% without HPMC and from 59% to 84% with HPMC) increased the bioaccessibility. These findings are useful for the rational design and fabrication of nanoemulsion-based delivery systems with high loading efficiency and good release characteristics.