Ternary Solid Dispersions Research Articles

Development and optimization of osmotically controlled drug delivery system for poorly aqueous soluble diacerein to improve its bioavailability

In an attempt to improve the low oral bioavailability of Diacerein (DCN), the combination of a ternary solid dispersion and an asymmetric osmotic pump system had been designed to enhance solubility and to control DCN delivery. Ternary DCN solid dispersion was prepared by melting fusion method using surfactant polymers, and carrier (Pluronic® PF127, Solutol® HS15, and PEG 35 K) and this DCN solid dispersion powder with the proper amount of excipients were compressed and coated with Opadry®CA to develop a Semi-Permeable and Asymmetric Osmotic Pump tablets. The ternary DCN solid dispersion by using surfactant polymers (Pluronic® F127 and Solutol® HS 15) with a ratio of 1:1 was displayed market significant improvement in saturated solubility (70.2 ± 4.14 µg/ml) and fast dissolution rate (Q60min = 79.28 ± 3.1% and IDR5 min = 5.25 ± 0.19 ml/min) in comparison to pure DCN. Moreover, the optimized asymmetric osmotic pump tablet with following parameters; 3% w/v Opadry® CA coat concentration, 1% w/w HPMC E15 gelling polymer and 35.8%w/w NaCl Osmogen concentration, was displayed control release of DCN at zero-order kinetic (R2 = 0.977) for up to 24 h(s). The in-vivo study conducted on rabbits was revealed a significant enhancement in the bioavailability of the optimized osmotic pump (28.84 ± 3.32 ng.hr/ml) compared to DCN dispersion (10.39 ± 1.45 ng.hr/ml). In conclusion, the approach of enhancing solubility and wet-ability in accompany with optimized asymmetric osmotic pump system could serve as a promising delivery system and a way to improve the bioavailability of poorly aqueous soluble drugs.

Thermodynamic aspects of the preparation of amorphous solid dispersions of Naringenin with enhanced dissolution rate.

Amorphous ternary solid dispersions of poorly water-soluble Naringenin (NRG) in Poloxamer 188 (POX) and Neusilin US2 (NSL) were prepared in a Hot- Melt Extruder (HME) using the principle of Low-Temperature Solubilization (LTS). Before HME, the NRG-POX solid-state interaction was investigated using Flory Huggins (F-H) theory. Construction of the composition-phase diagram showed Gibbs free energy to be negative close to the melting temperature of NRG, indicating a miscible system. The temperature-composition phase diagram provided insights on the phase behavior of the active-polymer solid dispersion system. The interactions and phase behavior predicted within the framework of the F-H theory were further investigated using Differential Scanning Calorimetry (DSC), X-Ray Diffraction (XRD), Hot Stage Microscopy (HSM) and Fourier-transform infrared spectroscopy (FT-IR). Based on the findings, amorphous solid dispersions of NRG were prepared via HME, which demonstrated a significant increase in the dissolution rate (p≤0.05). The enhancement of the dissolution rate is due to conversion from crystalline to amorphous form, as confirmed by DSC and XRD. The amorphous NRG prepared in the current study exhibited a release of 77% at the end of 2h, which is an increment of 250% from that of pure crystals.

Effect of the third component on the aging and crystallization of cinnarizine-soluplus® binary solid dispersion.

Multiple carriers may be used to prepare solid dispersions (SDs) for different purposes. The aim of this work is to investigate the effect of the third component on the physical stability and physical aging behavior of cinnarizine-soluplus SDs. HPMC, PVP, sorbitol and citric acid were used as the third component to prepare cinnarizine ternary SDs using hot melt extrusion method. The resultant samples were stored at 25°C or under stress conditions. Differential scanning calorimetry, powder X-ray diffraction and dissolution tests were performed to investigate the changes of samples during the storage. Infrared spectroscopy was used to evaluate the interactions between drug and carriers. Results showed that the addition of HPMC or PVP enhanced the physical stability of ternary SDs stored at 25°C rather than those stored under stress conditions. Sorbitol did not show any improvements in physical stability of samples stored at 25°C or under stress conditions. Surprisingly, the physical stability of samples stored at 25°C or under stress conditions was enhanced significantly by citric acid due to the ionic and hydrogen bonding interactions. The miscibility between drug and carriers as well as between different carriers should be considered when using multiple carriers. The third component can act as a "linker" by interacting with drug and polymer to enhance the physical stability of SDs effectively.

Formulation and Evaluation of Carbamazepine Tablets using Biosurfactant in Ternary Solid Dispersion System

Abstract: Objectives: The present study is aimed to develop and evaluate Carbamazepine tablets using ternary solid dispersed product. Carbamazepine belongs to BCS class II having low solubility. Ternary system was formulated with biosurfactant and water-soluble polymers to enhance dissolution rate and bioavailability. Methods: Binary and ternary solid dispersion was prepared using hydroxyl propyl methyl cellulose (HPMC) K-100, Polyvinyl pyrolidine (PVP) K-30 and Poly ethylene glycol (PEG) 6000 as a polymer and biosurfactant respectively by solvent evaporation method and evaluated for drug content uniformity and in-vitro dissolution study. Carbamazepine tablet were prepared by incorporation of ternary solid dispersed product along with other excipients by direct compression technique. Prepared formulations were evaluated for pre-compression and post-compression parameters. Oral toxicity study of biosurfactant was performed using female wistar rats. Results: In-vitro dissolution profile of optimized tablet formulation OF1 and OF2 showed 75.14% and 71.26% release in 1.2 pH respectively and similarly at 6.8 pH buffer 64.33% and 58.96% respectively. Pre-compression and postcompression values of formulated tablets were within the specified acceptable limits. In-vivo dissolution study of optimized formulation OF1 showed an increase in dissolution rate in accordance with pure drug. Oral toxicity study of biosurfactant was safe at 2000 mg per kg body weight of rat. Short term stability of the optimized formulation was stable without deviations at room temperature. Conclusion: Addition of biosurfactant in ternary solid dispersion system proved to be promising excipient in formulation of carbamazepine tablet for enhanced dissolution rate, dose reduction and bioavailability. Key words: Carbamazepine, Solid dispersion, Ternary system, Biosurfactant, in-vivo oral toxicity.

Preparation, characterization, in vitro and in vivo studies of olmesartan medoxomil in a ternary solid dispersion with N-methyl-D-glucamine and hydroxypropyl-β-cyclodextrin

Olmesartan medoxomil (OM) has been used in treatment of hypertension disease, as a prodrug of olmesartan. However, its clinical application is limited by the low oral bioavailability (~28%). Ternary solid dispersion of OM was prepared with hydroxypropyl-β-cyclodextrin and N-methyl-d-glucamine to improve its oral bioavailability using roll mill ML 007. Its physicochemical characterization was measured by scanning electron microscope, differential scanning calorimetry, powder X-ray diffraction and transform infrared spectroscopy. The solutions properties of OM in ternary solid dispersion were investigated involving the solubility, dissolution profiles, 1H NMR analysis, phase solubility study and PAMPA study. Instrument analysis results revealed an amorphous solid dispersion had been synthesized without any side-products. It also showed enhanced solubility and dissolution rate in vitro. Pharmacokinetic study demonstrated an improved oral bioavailability in vivo. The rapid storage assay showed that the chemical stability of inclusion complexes had no change. The synthesized OM ternary solid dispersion is promising to be a better alternative to its pure formation in the market with improved oral bioavailability.

Mechanism and Improved Dissolution of Glycyrrhetinic Acid Solid Dispersion by Alkalizers.

The purpose of this study was to increase the dissolution of glycyrrhetinic acid (GA) by preparing ternary solid dispersion (TSD) systems containing alkalizers, and to explore the modulating mechanism of alkalizers in solid dispersion systems. GA TSDs were prepared by hot melt extrusion (HME) with Kollidon® VA64 as the carrier and L-arginine/meglumine as the alkalizers. The in vitro release of the TSD was investigated with a dissolution test, and the dissociation constant (pKa) was used to describe the ionization degree of the drug in different pH buffers. Scanning electron microscopy (SEM), differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), Fourier Transform Infrared Spectroscopy (FTIR), Raman spectra, X-ray photoelectron spectroscopy (XPS), and a molecular model were used for solid-state characterizations and to study the dissolution mechanism of the TSDs. It was evident that the dissolution of GA significantly increased as a result of the TSD compared to the pure drug and binary solid dispersion. SEM, DSC, and XPRD data showed that GA transformed into an amorphous form in TSD. As illustrated by FTIR, Raman, XPS, and molecular docking, high binding energy ion-pair complexes formed between GA and the alkalizers during the process of HME. These can destroy the H-bond between GA molecules. Further, intermolecular H-bonds formed between the alkalizers and Kollidon® VA64, which can increase the wettability of the drug. Our results will significantly improve the solubility and dissolution of GA. In addition, the lower pKa value of TSD indicates that higher ionization is beneficial to the dissolution of the drug. This study should facilitate further developments of TSDs containing alkalizers to improve the dissolution of weakly acidic drugs and gain a richer understanding of the mechanism of dissolution.

Study on solubility improvement of lidocaine by ternary solid dispersion

Study on solubility improvement of lidocaine by ternary solid dispersion

Effects of Different Formulation Methods on Drug Crystallinity, Drug-Carrier Interaction, and Ex Vivo Permeation of a Ternary Solid Dispersion Containing Nisoldipine

Solid dispersion (SD) is an established approach to increase the solubility and dissolution of BCS class II drugs. The selection of a suitable method of preparation and the suitable polymeric carrier are the two most important parameters for a successful SD. The present research is aimed to evaluate the effect of preparation method on drug crystallinity, drug-polymer interaction, ex vivo permeability, and SD stability. A ternary SD containing nisoldipine as drug and PVP K30, poloxamer 188 as the carrier was prepared by hot melt mixing, solvent evaporation by rotary vacuum evaporator, and lyophilization. The prepared samples were analyzed in comparison in order to meet the objectives. All three methods yielded a mixed system of the crystalline and amorphous phase with a significant increase in saturation solubility compared to the raw drug. Infra-red spectroscopy study showed the highest degree of H bonding between drug and carrier in the freeze-dried formulation. X-ray diffraction study showed maximum loss of drug crystallinity from the rotary vacuum evaporated SD (3.70% at 11.3, 2θ angle). Ex vivo permeability study showed the maximum drug permeation by freeze-dried product. But freeze-dried product was shown to be the least stable in stability analysis. In terms of product stability, melt mixing is the best out of the three methods tested. Different methods of preparation have different impacts on functional group interaction, loss of crystallinity, ex vivo permeation, and stability of ternary SD.

Ternary solid dispersion to improve solubility and dissolution of meloxicam

Background Meloxicam (MLX) is a potent non-steroidal anti-inflammatory drug with poor solubility. Solid dispersion (SD) is an effective formulation strategy to improve the dissolution rate of poorly water-soluble compounds. Hydroxy propyl methyl cellulose (HPMC) as an inert polymer carrier and nicotinic acid (NA) as disturbance can be used as a matrix of SD. The aim of this study was to determine the effect of MLX-HPMC-NA SD on the solubility and dissolution of MLX. Methods SD was prepared by the solvent evaporation technique with methanol being used as a solvent. Methanol was evaporated at room temperature. SD of MLX was prepared involving various matrix compositions at MLX:HPMC:NA ratios of 1:1:1 (SD1), 1:1:2 (SD2), 1:2:1 (SD3), and 1:2:2 (SD4). Results The solubility profile of MLX in SD3 (64.34 ppm) showed a higher improvement than the physical mixture (15.99 ppm) and pure MLX (6.89 ppm). This increase might be due to the formation of molecular dispersion of MLX in the polymer as hydrophilic matrix and NA have both donor-acceptor sites for hydrogen bonding interactions. The dissolution profile of SD3 also showed the highest improvement. The melting endotherm of SD3 was detected at 219.5 °C, in which case it originated from NA rather than from MLX, showing that MLX was molecularly dispersed and amorphous. Conclusions MLX solubility and dissolution profile could be improved by the SD technique with a matrix of HPMC and NA. The best result was given by SD3 with an MLX:HPMC:NA ratio of 1:2:1. Based on the characterization study, it is predicted that hydrophilic polymer and hydrogen bonding interactions play important roles in MLX solubility or dissolution rate improvement.

Critical Excipient Properties for the Dissolution Enhancement of Phenytoin.

Solubility-enhancing amorphous solid dispersions can aid in the oral delivery of hydrophobic, poorly soluble drugs. Effective solid dispersion excipients enable high supersaturation drug concentrations over biologically relevant time scales. The critical characteristics of an excipient that allow it to work well in a solid dispersion system are not well understood. We prepared poly(N-isopropylacrylamide), poly(N,N-dimethylacrylamide), and poly(N-hydroxyethylacrylamide) excipients of varying molar mass and examined their ability to improve the aqueous solubility of phenytoin, a Biopharmaceutical Class System Class II drug. Binary and ternary solid dispersions of phenytoin and these excipients, along with hydroxypropyl methylcellulose acetate succinate and hydroxypropyl methylcellulose, were prepared at 10 wt % drug loading. Dissolution behavior was studied at early time points (<1 min) and over the course of 6 h. Performance of the ternary solid dispersions was largely a function of the concentration of poly(N-isopropylacrylamide) present in micellar structures and the concentration of PNiPAm micelles in the dissolution media. We present several systems that achieved significant improvement of phenytoin solubility over a wide composition range at enhancement factors among the highest seen to date for phenytoin.

IN VITRO DISSOLUTION STUDY OF GLIMEPIRIDE FROM BINARY AND TERNARY SOLID DISPERSION FORMULATION

Glimepiride (GMP) is poorly water soluble drug, so solubility is the main constraint for its oral bioavailability. Because, poor aqueous solubility and slow dissolution rate of the glimepiride lead to irreproducible clinical response or therapeutic failure in some cases due to sub therapeutic plasma drug levels. In this study, binary and ternary solid dispersion of glimepiride were prepared with polyethylene glycol 6000 (PEG 6000) and polyethylene glycol 4000 (PEG 4000) at different weight ratios using the solvent evaporation and melting method. It was found the drug was released 0.46% after 5 minutes and only 15.83% within 60 minutes from active glimepiride on the other hand the release pattern of glimepiride from the binary formulation containing PEG 4000 in 1:5 (Formulation coding: G5) showed the best result. It was found that the ternary different SD formulation containing(PEG4000:Glimepiride:Povidone) In ratio 1:1:0.25 (Formulation coding were : G13) showed the best result. The drug was changed to amorphous form after solid dispersion. Itwas also evident that solid dispersions improve solubility of drug particles thus enhancing dissolution characteristics of drugs they increase the oral bioavailability.&#x0D; Peer Review History: &#x0D; UJPR follows the most transparent and toughest ‘Advanced OPEN peer review’ system. The identity of the authors and, reviewers will be known to each other. This transparent process will help to eradicate any possible malicious/purposeful interference by any person (publishing staff, reviewer, editor, author, etc) during peer review. As a result of this unique system, all reviewers will get their due recognition and respect, once their names are published in the papers. We expect that, by publishing peer review reports with published papers, will be helpful to many authors for drafting their article according to the specifications. Auhors will remove any error of their article and they will improve their article(s) according to the previous reports displayed with published article(s). The main purpose of it is ‘to improve the quality of a candidate manuscript’. Our reviewers check the ‘strength and weakness of a manuscript honestly’. There will increase in the perfection, and transparency.&#x0D; Received file &#x0D; &#x0D; Average Peer review marks at initial stage: 4.5/10&#x0D; Average Peer review marks at publication stage: 7.5/10&#x0D; Reviewer(s) detail:&#x0D; Name: Dr. Mohammed Abdel-Wahab Sayed Abourehab &#x0D; Affiliation: Umm Al-Qura University; Makkah Al-Mukarramah, Saudi Arabia&#x0D; E-mail: maabourehab@uqu.edu.sa&#x0D; &#x0D; Name: Dr. Evren Alğin Yapar&#x0D; Affiliation: Turkish Medicines and Medical Devices Agency, Turkiye&#x0D; E-mail: evren.yapar@yahoo.com&#x0D; Comments of reviewer(s): &#x0D;

Binary and ternary solid dispersions of an anticancer preclinical lead, IIIM-290: In vitro and in vivo studies

The objective of this study was to formulate an anticancer preclinical lead, IIIM-290, loaded in solid dispersions to enhance its solubility, dissolution, and oral pharmacokinetics. IIIM-290 is an in-house preclinical anticancer lead prepared by semisynthetic modification of the natural product rohitukine. It is an orally bioavailable Cdk inhibitor showing efficacy in xenograft models of pancreatic, colon and leukemia cancer. It demonstrated in vivo efficacy at a relatively higher dose owing to its poor aqueous solubility (~8.6 µg/mL). Binary and ternary solid dispersions containing PVP K-30, xanthan gum, and PEG-PPG-PEG were selected after solubility screening of various hydrophilic polymers. Several formulations with varying ratios of polymers, alone and in combination, were prepared and investigated for their effects on the solubility enhancement of IIIM-290. The binary solid dispersion VKB-SD75, prepared with PVP K-30 at the ratio of 1:4 w/w, was identified as the optimized composition that displayed 17-fold improvement in the aqueous solubility of IIIM-290. VKB-SD75 was scaled up to a 100-g scale. IIIM-290 and VKB-SD75 were evaluated for DSC, p-XRD, FTIR, 1H NMR, SEM, in vitro dissolution, and oral pharmacokinetics, as well as for in vivo anticancer activity in the Ehrlich solid tumor model. The oral administration of VKB-SD75 in BALB/c mice resulted in a 1.9-fold improvement in plasma exposure. These findings also correlated well when the formulation was administered to mice in the Ehrlich solid tumor model. The newly developed solid dispersion is expected to reduce the dose of IIIM-290 by ~40-50% in preclinical and clinical studies.

Evaluation of Dissolution Enhancement of Aprepitant Drug in Ternary Pharmaceutical Solid Dispersions with Soluplus® and Poloxamer 188 Prepared by Melt Mixing

In the present study Aprepitant (APT) ternary solid dispersions (SDs) were developed and evaluated for the first time. Specifically, ternary SDs of APT with Poloxamer 188 and Soluplus® (SOL) were prepared via melt mixing and compared to binary APT/Poloxamer 188 and APT/SOL SDs. Initially, combined thermo-gravimetric and hot-stage polarized light microscopy studies indicated that all tested compounds were thermally stable up to 280 °C, while Poloxamer 188 acted as a plasticizer to SOL by significantly reducing the temperature required to fully solubilize the API during SD preparation. Differential scanning calorimetry combined with wide angle X-ray diffraction studies showed that crystalline API was dispersed in both binary and ternary SDs, while Fourier transformation-infrared spectroscopy studies revealed no molecular interactions among the components. Scanning electron microscopy combined with EDAX element analysis showed that the API was dispersed in nano-scale within the polymer matrices, while increasing APT content led to increasing API nano-crystals within the SDs. Finally, dissolution studies showed that the prepared formulations enhanced dissolution of Aprepitant and its mechanism analysis was further studied. A mathematical model was also investigated to evaluate the drug release mechanism.

A comprehensive understanding of lowly-hydrolyzed polyvinyl alcohol-based ternary solid dispersions with the use of a combined mixture-process design

We recently reported lowly hydrolyzed polyvinyl alcohol (L-PVA, 70–74% hydrolyzed, about 580 polymerized, JR-05) as a promising matrix for hot-melt extrusion (HME) due to its unique micelle formation ability compared to the most commonly used PVA (87–89% hydrolyzed, about 580 polymerized). In the present study, we focused on the effect of composition [indomethacin (IND), L-PVA, sorbitol] and process parameters (temperature and screw speed) on each response, i.e. processing torque, and physicochemical properties such as residual crystallinity, residual ratio, and area under the dissolution curve (AUDC) in supersaturated solution using a HME by applying the design of experiment (DoE) approach. To overcome the poor processability of L-PVA, given its semicrystalline nature, we applied sorbitol as a plasticizer and systematically and simultaneously evaluated its influence on the outputs based on the mixture design combined with process factors. Few studies have focused on comprehensive evaluation of the composition and HME process conditions because obtaining a design space requires numerous experiments. We found that incorporating sorbitol into the L-PVA greatly improved the processing torque. However, sorbitol negatively influenced the degree of residual crystallinity and the AUDC of IND. Lastly, we established a laboratory-scale design space that could achieve high supersaturation and ensure adequate miscibility between each component, using an acceptable processing torque for HME, by applying the minimum amount of sorbitol. These fundamental results suggest that sorbitol maximizes the potency of L-PVA as a carrier in HME.

Exploration of supersaturable lacidipine ternary amorphous solid dispersion for enhanced dissolution and in vivo absorption

Amorphous solid dispersion stands out among different formulation strategies for the improvement of dissolution rate and bioavailability via generating supersaturated drug solution, which provides a higher solubility than the crystalline counterpart, leading to a promoted intestinal absorption. Soluplus (SOL), termed as the fourth generation of solid dispersion carrier, presented a preferable effect on supersaturation maintaining and bioavailability enhancement for poorly water soluble drugs. However, some binary drug/SOL systems still suffer from insufficient dissolution and unsatisfied in vivo absorption. Thus, taking Lacidipine (LCDP) as a model drug, the aim of this study was to explore a ternary amorphous solid dispersion consisted of SOL and a surfactant to further increasing the dissolution rate and in vivo absorption. First of all, various surfactants were screened via equilibrium solubility enhancement and sodium dodecyl sulfate (SDS) was selected as the most effective candidate. Thereafter, the influence of SOL/SDS and drug/carrier weight ratio on the supersaturation maintaining was investigated. The supersaturated drug solutions were spray dried and the in vitro release, pharmacokinetic behavior as well as physical stability were investigated. It was found that although combination use of SOL and SDS did not present remarkable advantage in supersaturation maintenance in liquid state, 6–7 times higher dissolution rate under non-sink condition was noticed at SOL/SDS ratio 3:1 after spray drying, for LCDP/SOL/SDS based formulation compared to that of the binary LCDP/SOL system, which was maintained even after 92.5% humidity and 60 °C accelerated stability test. Moreover, compared to the LCDP/SOL formulation, approximately 3.3 and 3.7-fold increase in C max and AUC0–∞ was achieved with LCDP/SOL/SDS based formulation. In conclusion, the presented SDS could not only be regarded as solubility enhancer but also dissolution or bioavailability promoter, highlighting its potential application in ternary supersaturable amorphous solid dispersion for further increasing the dissolution and in vivo absorption of poorly water soluble drugs.

Insight into the Dissolution Molecular Mechanism of Ternary Solid Dispersions by Combined Experiments and Molecular Simulations.

With the increase concern of solubilization for insoluble drug, ternary solid dispersion (SD) formulations developed more rapidly than binary systems. However, rational formulation design of ternary systems and their dissolution molecular mechanism were still under development. Current research aimed to develop the effective ternary formulations and investigate their molecular mechanism by integrated experimental and modeling techniques. Glipizide (GLI) was selected as the model drug and PEG was used as the solubilizing polymer, while surfactants (e.g., SDS or Tween80) were the third components. SD samples were prepared at different weight ratio by melting method. In the dissolution tests, the solubilization effect of ternary system with very small amount of surfactant (drug/PEG/surfactant 1/1/0.02) was similar with that of binary systems with high polymer ratios (drug/PEG 1/3 and 1/9). The molecular structure of ternary systems was characterized by differential scanning calorimetry (DSC), infrared absorption spectroscopy (IR), X-ray diffraction (XRD), and scanning electron microscope (SEM). Moreover, molecular dynamic (MD) simulations mimicked the preparation process of SDs, and molecular motion in solvent revealed the dissolution mechanism of SD. As the Gordon-Taylor equation described, the experimental and calculated values of Tg were compared for ternary and binary systems, which confirmed good miscibility of GLI with other components. In summary, ternary SD systems could significantly decrease the usage of polymers than binary system. Molecular mechanism of dissolution for both binary and ternary solid dispersions was revealed by combined experiments and molecular modeling techniques. Our research provides a novel pathway for the further research of ternary solid dispersion formulations.

Aprepitant Drug in Ternary Pharmaceutical Solid Dispersions with Soluplus® and Poloxamer 188 Prepared by Melt Mixing

In the present study Aprepitant (APT) ternary solid dispersions (SDs) were developed and evaluated for the first time. Specifically, ternary SDs of APT with Poloxamer 188 and Soluplus® (SOL) were prepared via melt mixing and compared to binary APT/Poloxamer 188 and APT/SOL SDs. Initially, combined thermo-gravimetric and hot-stage polarized light microscopy studies indicated that all tested compounds were thermally stable up to 280 °C, while Poloxamer 188 acted as a plasticizer to SOL by significantly reducing the temperature required to fully solubilize the API during SD preparation. Differential scanning calorimetry combined with wide angle X-ray diffraction studies showed that crystalline API was dispersed in both binary and ternary SDs, while Fourier transformation-infrared spectroscopy studies revealed no molecular interactions among the components. Scanning electron microscopy combined with EDAX element analysis showed that the API was dispersed in nano-scale within the polymer matrices, while increasing APT content led to increasing API nano-crystals within the SDs. Finally, dissolution studies showed that the prepared formulations enhanced dissolution of Aprepitant and its mechanism analysis was further studied. A mathematical model was also investigated to evaluate the drug release mechanism

How can we improve the physical stability of co-amorphous system containing flutamide and bicalutamide? The case of ternary amorphous solid dispersions

The article describes the preparation and characterization of binary mixtures of two antiandrogens used in prostate cancer treatment, i.e. flutamide (FL) and bicalutamide (BIC), as well as their ternary mixtures with either poly(methyl methacrylate-co-ethyl acrylate) (MMA/EA) or polyvinylpyrrolidone (PVP). The samples were converted into amorphous form to improve their water solubility and dissolution rate. Broadband dielectric spectroscopy and differential scanning calorimetry revealed that FL-BIC (65%) (w/w) does not tend to crystallize from the supercooled liquid state. We made the assumption that the drug-to-drug weight ratio should be maintained as in the case of monotherapy so we decided to investigate the system containing FL and BIC in 15:1 (w/w) ratio with 30% additive of polymers as stabilizers. Our research has shown that only in the case of the FL-BIC-PVP mixture the crystallization has been completely inhibited, both in glassy and supercooled liquid state, which was confirmed by X-ray diffraction studies. In addition, we performed solubility and dissolution rate tests, which showed a significant improvement in solubility of ternary system as compared to its crystalline counterpart. Enhanced physical stability and water solubility of the amorphous ternary system makes it promising for further studies.

Complex amorphous solid dispersions based on poly(2-hydroxyethyl methacrylate): Study of drug release from a hydrophilic insoluble polymeric carrier in the presence and absence of a porosity increasing agent

Amorphous solid dispersions are nowadays typically made up of a drug compound and a water-soluble polymer. However, recently it has been demonstrated that amorphous solid dispersions based on insoluble polymers have a different and more delayed drug release profile, resulting in a prolonged duration of supersaturation. In this paper, binary and ternary amorphous solid dispersions based on poly(2-hydroxyethyl methacrylate) were prepared through spray drying to further investigate the potential of this type of carrier. As drug release from this matrix system was expected to be dictated by a diffusion-driven process, porosity of the formulation was adjusted by the inclusion of a water-soluble polymer. The solid state of the formulations was characterized with modulated differential scanning calorimetry, X-ray powder diffraction and thermogravimetric analysis. The release of drug and of the porosity increasing agent was measured in acidic and neutral conditions. In addition, the release performance of the spray dried product was compared with the drug release from poly(2-hydroxyethyl methacrylate) beads, which had already been reported in literature. It appeared that in the case of the spray dried poly(2-hydroxyethyl methacrylate), drug and porosity increasing agent could only be released to a certain extent due to entrapment of both compounds in the poly(2-hydroxyethyl methacrylate) network. While the chemical crosslinks of poly(2-hydroxyethyl methacrylate) beads ensured a more rigid structure with sufficient free space for drug diffusion, the spray dried product was susceptible to intense physical crosslinking upon contact with the dissolution medium.

Development of a Ternary Solid Dispersion Formulation of LW6 to Improve the In Vivo Activity as a BCRP Inhibitor: Preparation and In Vitro/In Vivo Characterization

LW6 (3-[2-(4-adamantan-1-yl-phenoxy)-acetylamino]-4-hydroxy-benzoic acid methyl ester) is a potent inhibitor of drug efflux by the breast cancer resistance protein (BCRP). However, its poor aqueous solubility leads to low bioavailability, which currently limits in vivo applications. Therefore, the present study aimed to develop ternary solid dispersion (SD) formulations in order to enhance the aqueous solubility and dissolution rate of LW6. Various SDs of LW6 were prepared using a solvent evaporation method with different drug/excipient ratios. The solubility and dissolution profiles of LW6 in different SDs were examined, and F8-SD which is composed of LW6, poloxamer 407, and povidone K30 at a weight ratio of 1:5:8 was selected as the optimal SD. The structural characteristics of F8-SD were also examined using Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), and scanning electron microscopy (SEM). In the acidic to neutral pH range, F8-SD achieved rapid dissolution with a drug release of 76–81% within 20 min, while the dissolution of pure LW6 was negligible. The XRPD patterns indicated that F8-SD probably enhanced the solubility and dissolution of LW6 by changing the drug crystallinity to an amorphous state, in addition to the solubilizing effect of the hydrophilic carriers. Furthermore, F8-SD significantly improved the oral bioavailability of topotecan, which is a BCRP substrate, in rats. The systemic exposure of topotecan was enhanced approximately 10-fold by the concurrent use of F8-SD. In conclusion, the ternary SD formulation of LW6 with povidone K30 and poloxamer 407 appeared to be effective at improving the dissolution and in vivo effects of LW6 as a BCRP inhibitor.