Dispersion Formulation Research Articles

The Impact of Water-Soluble Chitosan on the Inhibition of Crystal Nucleation of Alpha-Mangostin from Supersaturated Solutions.

The use of an amorphous drugs system to generate supersaturated solutions is generally developed to improve the solubility and dissolution of poorly soluble drugs. This is because the drug in the supersaturation system has a high energy state with a tendency to precipitate. In the amorphous solid dispersion (ASD) formulation, it was discovered that polymer plays a critical role in inhibiting nucleation or crystal growth of the drugs. Therefore, this study aimed to evaluate the crystallization inhibition of water-soluble chitosan (WSC) on nucleation as well as crystal growth from alpha-mangostin (AM) and elucidate its inhibition mechanism in the supersaturated solutions. During the experiment, WSC was used as a polymer to evaluate its ability to inhibit AM nucleation. The interaction between WSC and AM was also estimated using FT-IR, NMR, and in silico study. The result showed that in the absence of polymer, the concentration of AM rapidly decreased due to the precipitation in one minute. Meanwhile, the addition of WSC effectively inhibited AM crystallization and maintained a supersaturated state for the long term. FT-IR measurement also revealed that the shift in the amine primer of WSC occurred because of the interaction between WSC and AM. In the 1H NMR spectra, the proton peaks of WSC showed an upfield shift with the presence of AM, indicating the intermolecular interactions between AM and WSC. Moreover, in silico study revealed the hydrogen bond interaction between the carbonyl group of AM with hydrocarbon groups of WSC. This indicated that WSC interacted with AM in the supersaturated solution and suppressed their molecular mobility, thereby inhibiting the formation of the crystal nucleus. Based on these results, it can be concluded that the interaction between drug polymers contributed to the maintenance of the drug supersaturation by inhibiting both nucleation and growth.

Characterization and performance of silicone modified Polylactic acid (PLA)-graphene nanoplatelet ink coatings for flexible elastomeric substrates

A polylactic acid (PLA)-graphene nanoplatelets (GnPs) based ink dispersion in an eco-friendly solvent (ethyl acetate/benzyl alcohol) was developed to prepare conductive coatings for porous and non-porous elastomeric surfaces. The ink dispersion remained highly stable over time and to induce conformability to the elastomeric substrates, the dispersion formulations were modified with glycerol triacetate and silicone (PDMS) for plasticisation and ductility. The ink was spray coated on nitrile rubber (non-porous) and a commercial stretchable fabric (porous). To help adhesion, the nitrile rubber surface was pre-treated with acetic acid and the fabric surface was coated with a thin polychloroprene primer adhesive layer. Coating conductivity was tested under several stretch-release cycles at 25 %. The coatings functioned and remained conductive during and after 150 cycles. Gradually, the coatings electrical resistance doubled over the cycles, but decreased to almost initial levels and stabilized before the full 150 cycles were completed. The mechanical behaviour of the uncoated and coated substrates was described by the Mullins effect (stress softening in rubbers). Upon termination of the cyclic stretch-release tests, the coating resistance recovered to its original value. This is attributed to the mechanical energy dissipated through the cycles within the coatings that triggered microstructural rearrangements establishing original physical connections among GnPs.

Towards Shorter, Child-Friendly Regimens for Treatment of Tuberculosis Disease and Infection in Children.

Towards Shorter, Child-Friendly Regimens for Treatment of Tuberculosis Disease and Infection in Children.

Effects of Ingested Water Volume on Oral Absorption of Fenofibrate, a BCS Class II Drug, from Micronized and Amorphous Solid Dispersion Formulations in Rats.

In this study, we investigated the effects of ingested water volume on the oral absorption of fenofibrate (FEN) with several formulations to confirm the applicability of rats for oral formulation screening. Oral absorption of suspended crystalline FEN was significantly improved by increasing ingested water volume (from 0.5 to 2 mL). FEN absorption improvement by particle size reduction and the linearity in oral absorption by dose escalation suggested that the rate-limiting step of FEN absorption in rats was the dissolution rate, consistent with that in humans. When FEN, as an amorphous solid dispersion (ASD) formulation, was suspended in water followed by immediate administration, oral FEN absorption was significantly higher than when administered in crystalline form and was not influenced by the differences in ingested water volume. Oral absorption of FEN from encapsulated ASD formulation in 1 or 2 mL of water was comparable with that of the suspension form. However, 0.5 mL of water significantly reduced the oral absorption of the solid ASD FEN formulation. These results indicate that to improve the oral absorption of poorly water-soluble drugs when performing a preclinical study with rats, 1 mL of water is the minimum preferable ingested volume to evaluate in vivo formulation performance.

Enhanced bioavailability and hepatoprotective effect of silymarin by preparing silymarin-loaded solid dispersion formulation using freeze-drying method.

This study aimed to develop a solid dispersion formulation of silymarin (Silymarin-SD) using freeze-drying method to enhance its oral bioavailability (BA) by inhibiting the intestinal first-pass effect and increasing its solubility and permeability. Silymarin-SD formulation (i.e., silymarin:tween 80:hydroxypropyl cellulose (HPC) = 1:1:3 (w/w/w) significantly increased silymarin permeability in the duodenum, jejunum, and ileum by decreasing the efflux ratio of silymarin and by inhibiting silymarin-glucuronidation activity, in which tween 80 played a crucial role. As a result, orally administered Silymarin-SD formulation increased plasma silymarin concentrations and decreased silymarin-glucuronide in rats compared with silymarin alone and silymmarin:D-α-tocopherol polyethylene glycol 1000 succinate (1:1, w/w) formulation. In addition to modulating intestinal first-pass effect, Silymarin-SD formulation showed a significantly higher cumulative dissolution for 120min compared with that of silymarin from the physical mixture (PM) of the same composition as Silymarin-SD and silymarin alone; the relative BA of silymarin-SD increased to 215% and 589% compared with silymarin-PM and silymarin alone, respectively. This could be attributed to the amorphous status of the Silymarin-SD formulation without chemical interaction with excipients, such as tween 80 and HPC. Moreover, the hepatoprotective effect of Silymarin-SD in acetaminophen-induced acute hepatotoxicity, as estimated from the alanine aminotransferase and aspartate aminotransferase values, was superior to that of silymarin. In conclusion, the increase in the dissolution rate and intestinal permeability of silymarin, and the inhibition of silymarin-glucuronidation by the Silymarin-SD formulation, prepared using tween 80 and HPC, increased its plasma concentration and resulted in a superior hepatoprotective effect compared to silymarin.

Formulation of a glycolipid:lipopeptide mixture as biosurfactant-based dispersant and development of a low-cost glycolipid production process

Biosurfactant-based dispersants were formulated by mixing glycolipids from Weissella cibaria PN3 and lipopeptides from Bacillus subtilis GY19 to enhance the synergistic effect and thereby achieve hydrophilic-lipophilic balance. The proportions of each biosurfactant and dispersant-to-oil ratios (DORs) were varied to obtain the appropriated formulations. The most efficient glycolipid:lipopeptide mixtures (F1 and F2) had oil displacement activities of 81–88% for fuel and crude oils. The baffled flask test of these formulations showed 77–79% dispersion effectiveness at a DOR of 1:25. To reduce the cost of the dispersant, this study optimized the glycolipid production process by using immobilized cells in a stirred tank fermenter. Semicontinuous glycolipid production was carried out conveniently for 3 cycles. Moreover, food wastes, including waste coconut water and waste frying oil, were found to promote glycolipid production. Glycolipids from the optimized process and substrates had similar characteristics but 20–50% lower cost than those produced from basal medium with soybean oil in shaking flasks. The lowest cost dispersant formulation (F2*) contained 10 g/L waste-derived cell-bound glycolipid and 10 g/L lipopeptide and showed high dispersion efficiency with various oils. Therefore, this biosurfactant-based dispersant could be produced on a larger scale for further application.

HPLC-UV method validation for quantification of β-carotene in the development of sustained release supplement formulation containing solid dispersion-floating gel in situ

Despite the health benefits of β-carotene, its activity has been hampered by poor aqueous solubility and low oral bioavailability. Therefore, it is crucial to develop a new approach to overcome these problems. In this study, we developed a dry powder supplement comprising a combination approach of solid dispersion and floating gel in situ of β-carotene to enhance the solubility and achieve sustained release behavior. Here, we validated an HPLC method to quantify β-carotene as per the guidelines from ICH. The analytical method was validated in methanol and Fasted-State Simulated Gastric Fluid (FaSSGF) to determine β-carotene in recovery and in vitro release studies, respectively. A simple HPLC method using Xselect CSH™ C18 column (Waters, 3.0 × 150 mm) with the particle size of 3.5 µm was validated with 100% acetonitrile as the mobile phase. The calibration curves were found to be linear with LLOQ values < 3 ng/mL. Importantly, the method was accurate and precise without a carry over effect and successfully applied to determine the β-carotene concentration in the content analysis of the compound and in vitro drug release from floating gel in situ laden with solid dispersion formulations. The sensitivity of the method obtained here offers a wide potential use in various applications in drug delivery systems.

Formulation and Evaluation of Aripiprazole Oral Disintegrating Tablets

Aim: This work aims to develop oral disintegrating tablets from solid dispersion of aripiprazole that are capable of enhancing solubility.&#x0D; Methodology: Aripiprazole an antipsychotic is a BCS class IV drug with Oral bioavailability of 87%. To enhance the solubility of this drug the solid dispersions were prepared by using a combination of β-Cyclodextrin and PVP K30 in 1:1, 1:2 by using a physical mixture and solvent evaporation method. The prepared solid dispersions were analyzed for all the physical parameters and drug excipient interactions. The solid dispersion was optimized for the preparation of oral disintegrating tablets by direct compression technique using different concentrations of various natural super disintegrants namely Tapioca starch, Amorphophallus campanulactus, and synthetic super disintegrants namely Sodium starch glycolate, crospovidone.&#x0D; Results: FTIR showed that the drug and excipients are compatible with each other. Among all the solid dispersion formulations SCD6 (Drug: β-cyclodextrin) shows a high percentage of drug release i.e., 98.58±0.28% for 45 min, and solubility was found to be 0.954±0.32mg/ml. Percentage practical yield was found to be 98.36±0.14% and drug content was found to be 97.31±0.04%. SCD6 formulation was optimized for the preparation of oral disintegrating tablets. The post-compression parameters of all the prepared tablets were within the limits. Among all, F3 formulations containing tapioca starch, 7.5% were found to possess a better disintegration time (28±1.52sec) and in-vitro dissolution (98.64±0.29% for 45min).&#x0D; Conclusion: It can be concluded that solid dispersions of Aripiprazole incorporated in oral disintegrating tablets are a very useful approach for better release of Aripiprazole in an efficient manner.

FORMULATION DEVELOPMENT AND IN VITRO CHARACTERIZATION OF TERNARY HYDROTROPIC SOLID DISPERSIONS OF ACECLOFENAC

Objective: Among the various strategies employed to enhance solubility, dissolution, and bioavailability of poorly soluble drugs in vivo, formulation of solid dispersion (SD) using hydrophilic and/or water-soluble carriers with varying physicochemical characteristics seems to be a developable, economically viable and easy option. The goal of the present study was to explore the possibilities of skimmed milk (SKM)-urea (U)-crospovidone (CP) as a novel ternary mixture of carrier-hydrotrope-superdisintegrant in SD of poorly water-soluble aceclofenac (ACF). Methods: Compatibility of ACF and ternary mixture of SKM-U-CP was confirmed by FTIR spectroscopic analysis. SDs of ACF-SKM, ACF-SKM-U and ternary hydrotropic SD, and ACF-SKM-U-CP were prepared in varying ratios of 1:1–1: 5 for ACF-SKM; 1:5:0.5, 1:5:0.75, and 1:5:1 for ACF-SKM-U and 1:5:0.75:0.25–1:5:0.75:1 for ACF-SKM-U-CP by solvent evaporation technique and were characterized by their solubility enhancement (compared to pure drug) at 25°C and drug dissolution profiles in double-distilled water and phosphate buffer (pH 6.8). Results: Based on solubility enhancement data (82.10% and 44.06%) and maximum cumulative percentage drug release data (88.45% in 9 min and 76.18% in 60 s) in double-distilled water and phosphate buffer, respectively, ACF-SKM-U(1:5:0.75) was found to the best among ACF-SKM and ACF-SKM-U SDs which were used for studying the effect of adding CP as superdisintigrant. ACF: SKM: U: CP (1: 5: 0.75: 0.50) exhibited maximum solubility enhancement of 83.92% and 49.69% and cumulative percentage release of 98.55 % in 9 min and 85.67 % in 60 s in double-distilled water and buffer, respectively. Conclusion: Therefore, the novel ternary mixture of SKM-U-CP has demonstrated marginal superiority over SKM as carrier for from hydrotropic SDs of ACF.

Cefuroxime Axetil Loaded Dispersed Formulation for Enhanced Drug Release and Antibacterial Activity

Cefuroxime Axetil Loaded Dispersed Formulation for Enhanced Drug Release and Antibacterial Activity

Formulation and Characterization of Carvedilol In situ Gels for Oral Delivery-In vitro and In vivo Pharmacokinetic Studies

The purpose of the study is to develop floating in situ gelling oral delivery system of carvedilol. Before formulating into in situ gels, carvedilol was first made into solid dispersions to enhance its solubility. The solvent evaporation method was employed for making solid dispersions. Drug content, solubility, dissolution, SEM, DSC, and XRD studies were done for solid dispersions. In situ gel formulations were prepared using the optimized solid dispersion formulation. Sodium alginate and HPMC K100M were used as gelling agent and viscosity enhancing agent respectively. In vitro characterizations like gelling capacity, floating time, drug content, viscosity, and % cumulative drug release studies were done. In vivo pharmacokinetic parameters like Cmax, Tmax, half-life, AUC, AUMC, and MRT were studied. FTIR studies ruled out any drug-excipient interactions. The drug release pattern showed a burst effect in the first 30 minutes then followed by a steady release for 12 hours. Stability data indicated that the formulation remained stable with no significant changes in drug content, viscosity, and percent cumulative drug release upon storage. In vivo pharmacokinetic study results were found to be satisfactory. A stable, sustained release, liquid oral floating in-situ gelling systems of carvedilol were successfully formulated and evaluated.

Optimization of Meloxicam Solid Dispersion Formulations for Dissolution Enhancement and Storage Stability Using 33 Full Factorial Design Based on Response Surface Methodology

This study aimed to formulate and optimize solid-dispersion of meloxicam (MX) employing response-surface-methodology (RSM). RSM allowed identification of the main effects and interactions between studied factors on MX dissolution and acceleration of the optimization process. 33 full factorial design with 27 different formulations was proposed. Effects of drug loading percentage (A), carriers’ ratio (B), method of preparation (C), and their interactions on percent MX dissolved after 10 and 30 min (Q10min & Q30min) from fresh and stored samples were studied in distilled water. The considered levels were 2.5%, 5.0%, and 7.5% (factor A), three ratios of Soluplus®/Poloxamer-407 (factor B). Physical mixture (PM), fusion method (FM), and hot-melt-extrusion (HME) were considered factor (C). Stability studies were carried out for 3 months under stress conditions. The proposed optimization design was validated by 3-extra checkpoints formulations. The optimized formulation was selected via numerical optimization and investigated by DSC, XRD, PLM, and in vitro dissolution study. Results showed that HME technique gave the highest MX dissolution rate compared to other techniques (FM & PM). At constant level of factor (C), the amount of MX dissolved increased by decreasing MX loading and increasing Soluplus in carriers’ ratio. Actual responses of the optimized formulation were in close consistency with predicted data. Amorphous form of MX in the optimized formulation was proved by DSC, XRD, and PLM. Selected factors and their levels of the optimization design were significantly valuable for demonstrating and adapting the expected formulation characteristics for rapid dissolution of MX (Q10min= 89.09%) from fresh and stored samples.Graphical abstract

Solid Dispersion of Dolutegravir: Formulation Development, Characterization, and Pharmacokinetic Assessment

A recently authorized antiviral drug called dolutegravir has solubility problems and could be a Biopharmaceutical Classification System (BCS) class II candidate. The current study aimed to improve dolutegravir’s solubility and efficiency by employing the solid dispersion method. Different ratios of hydrophilic polymeric carriers, including polyethylene glycol (PEG) 6000, polyvinyl pyrrolidone (PVP) (30K), and hydroxypropyl methylcellulose (HPMC), were used. Dolutegravir (DTG) and soluplus were produced as a solid dispersion at 1:5 ratio using the solvent evaporation method. A variety of techniques were utilized to describe the solid state, including powder X-ray diffraction (XRD), differential scanning calorimetry (DSC), and fourier transform infrared spectroscopy (FTIR). Produced solid dispersion did not reveal any physicochemical interactions between the DTG and soluplus, but the X-ray diffractogram clearly showed that the drug’s crystalline state had transformed to an amorphous state. DTG was released quickly from solid dispersion (92%) compared to pure drug (10.12%), physical mixture (22.06%), and commercially available DTG (62.90%). The formed solid dispersion’s drug release kinetics was in line with the Higuchi Model. Finally, the rapid drug release from the solid dispersion formulation showed higher Cmax (15.25 ± 0.40 μg/mL) compared to the physical mixture (5.11 ± 0.20 μg/mL) and pure drug (4.91 ± 0.73 μg/mL). DTG’s enhanced bioavailability in experimental wistar rats (AUC: 147.99 ± 23.86 μg/h/mL) further supported this when compared to the AUC of animals administered with physical mixture (52.35 ± 4.32 μg/h/mL) and pure drug (43.32 ± 3.13 μg/h/mL). Thus, it could be inferred that by employing the solid dispersion delivery system and the hydrophilic carrier, soluplus, the bioavailability and dissolution profile of DTG could both be improved, which could be expected to improve the drug’s effectiveness in treating Human immunodeficiency virus/Acquired immunodeficiency syndrome (HIV/AIDS).

Formulation and Physicochemical Characterization of Glibenclamide Solid Dispersion Using Various Carriers

Aims: Glibenclamide is an oral hypoglycemic agent exhibits inadequate aqueous solubility resulting in poor and unpredictable bioavailability. The study was designed to enhance the solubility and dissolution of glibenclamide by solid dispersion.&#x0D; Place and Duration of Study: Department of Pharmacy, University of Rajshahi, Bangladesh between June 2017 and July 2018.&#x0D; Methodology: Solid dispersions of glibenclamide were prepared by solvent evaporation technique using mixture of PEG-8000, sodium citrate, HPMC as additives in different ratios and subsequently, in-vitro dissolution studies were performed. The characterization of solid dispersions was done by Differential Scanning Calorimetry, Powder X-ray Diffractometer, Fourier Transform Infrared Spectroscopy and Scanning Electron Microscope.&#x0D; Results: Out of twelve formulations, the GCHP-4 composed of glibenclamide: HPMC: Na-citrate: PEG-8000 1:1:1:1) demonstrated highest percentage of yield (87.76%) and encapsulation efficiency (95.68%). The maximum dissolution of glibenclamide obtained from GCHP-4 (3.34 µg/ml), which was 5.2-fold higher than that of pure glibenclamide (0.64 µg/ml) at 120 min. The mechanism of increased solubility of glibenclamide from solid dispersion might be resulted due to the conversion of its crystalline form into amorphous state and no interaction between drug and carriers which was confirmed by differential scanning calorimetry and fourier transform infrared spectroscopy respectively.&#x0D; Conclusion: The dissolution rate of glibenclamide was greatly increased when loaded in solid dispersions which might be responsible for the improvement of its bioavailability in aqueous medium.

Effects of Polymers on the Drug Solubility and Dissolution Enhancement of Poorly Water-Soluble Rivaroxaban.

The purpose of this study was to investigate the efficacy of hydrophilic polymers in a solid dispersion formulation in improving the solubility and dissolution rate of rivaroxaban (RXB), a poorly soluble drug. The developed solid dispersion consisted of two components, a drug and a polymer, and the drug was dispersed as amorphous particles in a polymer matrix using the spray drying method. Polymeric solid dispersions were evaluated using solubility tests, in vitro dissolution tests, powder X-ray diffraction, differential scanning calorimetry, scanning electron microscopy, and particle size distribution analysis. To maximize physical stability against crystallization and improve the solubility and dissolution of RXB, it is important to select the appropriate polymer type and the optimal ratio of the polymer to the drug. The optimized polyvinyl alcohol (PVA)-based (1/0.5, w/w) and gelatin-based (1/5, w/w) solid dispersion formulations showed 6.3 and 3.6 times higher drug solubilities than pure RXB powder, respectively, and the final dissolution rate was improved by approximately 1.5 times. Scanning electron microscopy and particle size distribution analyses confirmed that the gelatin-based solid dispersion was smaller and more spherical than the PVA-based solid dispersion, suggesting that the gelatin-based solid dispersion had a faster initial dissolution rate. Differential scanning calorimetry and powder X-ray diffraction analyses confirmed that RXB had successfully changed from a crystalline form to an amorphous form, contributing to the improvement in its solubility and dissolution rate. This study provides a strategy for selecting suitable polymers for the development of amorphous polymer solid dispersions that can overcome precipitation during dissolution and stabilization of the amorphous state. In addition, the selected polymer solid dispersion improved the drug solubility and dissolution rate of RXB, a poorly soluble drug, and may be used as a promising drug delivery system.

Role of surfactants in improving release from higher drug loading amorphous solid dispersions

Amorphous solid dispersion formulations (ASD) are increasingly being used as a formulation strategy to improve bioavailability of poorly soluble drugs. One of the limitations of ASDs, in particular for high glass transition temperature (Tg) compounds, is the drug loading threshold (termed the limit of congruency, LoC) below which rapid, complete and congruent release of drug and polymer is achieved. In this study, several ionic and non-ionic surfactants were added to atazanavir-copovidone ASDs with the main goal of increasing the limit of congruency. Atazanavir (ATZ) is a relatively high Tg compound with a LoC of 5 % drug loading (DL). Surface normalized dissolution studies revealed that addition of 5 % w/w of surfactant, sodium dodecyl sulfate (SDS) or cetrimonium bromide (CTAB), to the binary copovidone-based ASD doubled the LoC (from 5 to 10 % DL), resulting in a more than 30-fold increase in total release compared to the corresponding binary ASD. Moreover, addition of 5 % of Span®80 increased the LoC to 15 % DL. ASD Tg was found to decrease upon addition of surfactants and water sorption extent was found to increase. We speculate that surfactants act as plasticizers, which may facilitate polymer release from ASDs containing a high Tg drug, providing a possible explanation for the observed enhancement in drug release from ternary ASDs and the increase in LoC.

Theoretical evaluation of supersaturation of amorphous solid dispersion formulations with different drug/polymer combinations using mathematical modeling

Amorphous solid dispersion (ASD) is a preparation widely used for improving the solubility and low oral absorbability of poorly water-soluble drugs, but the quantitative analysis of its dissolution profiles and its supersaturation status remains an important issue. We previously reported a new mathematical model for analyzing the dissolution characteristics of ASD preparations that enabled evaluation of theoretical solubility of ASDs and crystal precipitation rate constants of ASD preparations. In this study, to analyze the relationship between the mathematical parameters of the model and the dissolution behavior in detail, we simulated the dissolution behaviors upon changing parameters. We quantitatively evaluated the supersaturation of ASD preparations composed of various combinations of two drugs (ibuprofen or indomethacin) and three polymers (polyvinylpyrrolidone (PVP), copovidone or hydroxypropylmethylcellulose (HPMC)). Based on parameter comparison, the difference in the peak of drug concentration between IB/PVP and IB/HPMC ASDs was found to be derived from precipitation rate constant, not the theoretical solubility. In addition, although IMC/PVP ASD had higher solubility than IMC/HPMC ASDs, HPMC could suppress crystal precipitation and maintain supersaturation at higher concentrations than IMC/PVP ASD by comparing parameters derived from model fitting. Thus, our results show that the use of mathematical parameters can illuminate theoretical mechanical information regarding dissolution behaviors of various ASDs and permit a visualization of the character of the dissolution process.

In Vitro-In Vivo Relationship in Mini-Scale-Enabling Formulations of Corallopyronin A.

In vivo studies in mice provide a valuable model to test novel active pharmaceutical ingredients due to their low material need and the fact that mice are frequently used as a species for early efficacy models. However, preclinical in vitro evaluations of formulation principles in mice are still lacking. The development of novel in vitro and in silico models supported the preclinical formulation evaluation for the anti-infective corallopyronin A (CorA). To this end, CorA and solubility-enhanced amorphous solid dispersion formulations, comprising povidone or copovidone, were evaluated regarding biorelevant solubilities and dissolution in mouse-specific media. As an acidic compound, CorA and CorA-ASD formulations showed decreased solubilities in mice when compared with human-specific media. In biorelevant biphasic dissolution experiments CorA-povidone showed a three-fold higher fraction partitioned into the organic phase of the biphasic dissolution, when compared with CorA-copovidone. Bioavailabilities determined by pharmacokinetic studies in BALB/c mice correlated with the biphasic dissolution prediction and resulted in a Level C in vitro–in vivo correlation. In vitro cell experiments excluded intestinal efflux by P-glycoprotein or breast cancer resistance protein. By incorporating in vitro results into a physiologically based pharmacokinetic model, the plasma concentrations of CorA-ASD formulations were predicted and identified dissolution as the limiting factor for bioavailability.

Process Modelling, Scale-Up and Characterization of Acetaminophen Spray Dried Milk Powder as Novel Pediatric Dosage Form.

Successful drug therapy in children is contingent upon hassle-free administration of pediatric dosage forms. Pediatric patients suffer from difficulty in swallowing due to weak esophagus muscles in their early age. Considering this challenge liquid formulations are preferred over solid dosage form among pediatric patients to avoid the possibility of choking which can be a serious life-threatening condition in children. The main aim of the present research work was to develop a reconstitutable amorphous acetaminophen spray-dried milk powder (ASDM) as novel pediatric formulation. ASDM was prepared by spray drying process and the spray drying process was optimized using Box-Behnken design to study the effect of spray drying process parameters at X1 [inlet temperature], X2 [aspiration rate] and X3 [feed rate] to Y1 [% yield], Y2 [angle of repose], Y3 [Hausner's Ratio] and Y4 [Carr's Index] as dependent variables of ASDM. In addition, each batch was characterized for particle size by polarized light microscopy and drug entrapment. Predicted parameters from optimized spray drying process model were successfully employed to manufacture a scale up cum validation batch of ASDM, which showed notably improved yield and desirable flow properties. The scale-up validation batch was further characterized using thermal analysis, diffraction studies, spectroscopic analysis, dispersion studies, stability APAP in dispersion formulation and formulation stability studies to confirm the physico-chemical stability of ASDM. Thus, ASDM for oral use can serve as a promising pediatric formulation and the developed prototype formulation can be further extended to future newly discovered drugs with similar characteristics.

A Dispersive Formulation of Time-Domain Meshless Method With PML Absorbing Boundary Condition for Analysis of Left-Handed Materials

We have proposed a dispersive formulation of scalar-based meshless method for time-domain analysis of electromagnetic wave propagation through left-handed materials (LHMs). Moreover, we have incorporated Berenger’s perfectly matched layer (PML) absorbing boundary condition (ABC) into the dispersive formulation to truncate open-domain structures. In general, the dispersive formulations of conventional numerical methods are proper tools for analysis of left-handed (LH) media, whenever the LH media can be characterized by considering spatial or frequency dispersion effect for the constitutive parameters. In comparison to the grid-based numerical methods, it is proven that meshless methods not only are strong tools for accurate approximation of derivatives in Maxwell’s equations but also can provide more flexibility in modeling the spatial domain of problems. However, we have not seen any reports on using dispersive forms of meshless methods for simulation of wave propagation in metamaterials and applying any PML ABCs to dispersive formulation of meshless method. The proposed formulation enables us to take advantage of meshless methods in analysis of LH media with frequency-dependent parameters. For modeling the frequency behavior of the medium, we have used auxiliary differential equation (ADE) method based on the relations between electromagnetic fields intensities and current densities. Effectiveness of the proposed formulation is verified by analysis of 2-D and 3-D numerical examples; also, some basic factors which affect the accuracy, stability, and computational cost of the simulations are studied.