Preparation Of Solid Dispersions Research Articles

Sustained-Release Solid Dispersion of High-Melting-Point and Insoluble Resveratrol Prepared through Hot Melt Extrusion to Improve Its Solubility and Bioavailability.

This study aimed to prepare a sustained-release solid dispersion of poorly water-soluble resveratrol (RES) with high melting point in a single hot melt extrusion step. A hydrophobic–hydrophilic polymeric blend (Eudragit RS and PEG6000) was used to control the release of RES. With the dispersive mixing and high shear forces of hot melt extrusion, the thermodynamic properties and dispersion of RES were changed to improve its solubility. The effects of the formulation were investigated through univariate analysis to optimize the preparation of the sustained-release solid dispersion. In vitro and in vivo studies were performed to evaluate the prepared RES/RS/PEG6000 sustained-release solid dispersion. The physical state of the solid dispersion was characterized using differential scanning calorimetry and X-ray diffraction. Surface properties of the dispersion were visualized using scanning electron microscopy, and the chemical interaction between RES and excipients was detected through Fourier-transform infrared spectroscopy. Results suggested that the optimized sustained-release solid dispersion was obtained when the mass ratio of RES-polymeric blend was 1:5, the ratio of PEG6000 was 35%, the barrel temperature was 170 °C, and the screw speed was 80 rpm. In vitro studies demonstrated that the solid dispersion showed a good sustained release effect. The cumulative release of RES reached 82.42% until 12 h and was fit by the Weibull model. In addition, the saturated solubility was 2.28 times higher than that of the bulk RES. In vitro studies demonstrated that the half-life increased from 3.78 to 7.09 h, and the bioavailability improved to 140.38%. The crystalline RES was transformed into the amorphous one, and RES was highly dispersed in the polymeric blend matrix.

Preparation of Solid Dispersion and Its Application in Functional Food

Solid dispersion is considered to be one of the most successful ways to solve the poor water-solubility and dissolution rate of raw materials and drugs in the pharmaceutical field. Due to its unique advantages in solving the problems of water-solubility, poor stability and low bioavailability of functional active ingredients, solid dispersion has been gradually applied to the research and development of functional food. This paper reviews and summarizes the research status and development trend of solid dispersion from four aspects: classification, preparation technology, stability and its application in functional food. Combined with the background of the current post epidemic era, new requirements are put forward for the further application of solid dispersion in the food field in the future, and it is also hoped to provide new reference and research ideas for the further application of solid dispersion in the food field.

Recent and Relevant Methodology in the Advancement of Solid Dispersion

Most of the promising drugs in development channels are poorly water-soluble drugs which limit formulation approaches, clinical application because of their low dissolution and bioavailability. And the major current challenges of the pharmaceutical industry are apropos strategies that improve the water solubility of drugs. Solid dispersion has been considered one of the major evolutions in overcoming these issues with several successfully marketed products. Though solid dispersion has been outlined as an efficient drug delivery system, the design of specific dosage forms for pharmaceutical therapy is necessary to improve the solubility and bioavailability of poorly water-soluble drugs. Solid dispersion can be prepared by several methods such as solvent evaporation, melting, and supercritical fluid technology. This review intends to provide an updated overview of the recent trends over the past few years in solid dispersion preparation techniques and polymer used. Along with the various pharmaceutical strategies and future visions for the solubilization of poorly water-soluble drugs
 Keywords: Solid dispersion, Bioavailability, Solubility, Dissolution parameters, Polymeric carrier

Solid Dispersion Characteristics of Whiteleg Shrimp (Litopenaeus vannamei) Extracted Chitosan with HPMC and PVP K-30 as Anti-cholesterol Agents

This study aims at evaluating the characteristics of chitosan solid dispersion from whiteleg shrimp (Litopenaeus vannamei). As anti-cholesterol agent, chitosan requires solubility enhancement which can be facilitated in solid dispersion. Here, chitosan solid dispersion was made by solvent evaporation technique used HPMC and PVP K-30 as the carriers, in which the chitosan was prepared from whitleg shrimp shell Chitosan solid dispersion was varied into six formulation, i.e. chitosan: HPMC = FH1 (1:0.25), FH2 (1:0,5), FH3 (1:2), and chitosan: PVP K-30 = FP1 (1:1), FP2 (1:2), and FP3 (1:3), and pristine chitosan, HPMC, and PVP K-30 were utilized as reference compound. Characteristics of chitosan solid dispersion were assessed from the solubility test, SEM, XRD, and FTIR. The result indicates that solubility of chitosan solid dispersion was better than the pristine chitosan. The recommended formula from this study was FP3, because obtained smaller particle size than the other, that could increase the solubility of chitosan. The crystallinity of chitosan remained unchanged upon solid dispersion preparation.

Miscibility and thermal properties of poly(vinylpyrrolidone-vinyl acetate)/lamivudine and tenofovir binary blends prepared by hot melt extrusion

Preparation of amorphous solid dispersions (ASD) by hot melt extrusion (HME) of poly(vinylpyrrolidone-vinyl acetate) (Kollidon) and the active pharmaceutical ingredients (API) Lamivudine (3TC) and Tenofovir Disoproxyl Fumarate (TDF) was investigated aiming to study their miscibility and thermal behavior. These two drugs are currently used as drugs in first line treatment of patients with Acquired Immunodeficiency Syndrome (AIDS). In order to predetermine parameters for extrusion and the maximum concentration of API to be used without any recrystallization, binary blends were first processed in the mixing chamber at 130°C using a roller type rotor at 10, 20 and 30 rpm for 7 min, giving rise to ASD of both API, at least up to 20 wt% of the drug. Both 3TC and TDF were then extruded individually with Kollidon in a single screw extruder. HME produced ASD with high concentration of both Kollidon/API combinations, being part of the API soluble in the polymer matrix. From HME, Kollidon/3TC forms ASD in concentration up to 50 wt%, but from 30 wt% 3TC, the ASD has no time stability, showing recrystallization in less than 5 months, while the Kollidon/TDF system forms ASD up to 30 wt% of TDF, but it has aging stability inferior to 4 months.

Acoustic levitation and high-resolution synchrotron X-ray powder diffraction: A fast screening approach of niclosamide amorphous solid dispersions

The levitation of samples in an acoustic field has been of interest in the preparation and study of amorphous solid dispersions (ASD). Here, niclosamide-polymer solutions were levitated in a multi-emitter single-axis acoustic levitator and analyzed for 10 min at a High-resolution synchrotron X-ray powder diffraction beamline. This assembly enabled high-quality and fast time-resolved measurements with microliter sample size and measurement of solvent evaporation and recrystallization of niclosamide (NCL). Polymers HPMCP-55S, HPMCP-50, HPMCP-55, Klucel®, and poloxamers were not able to form amorphous dispersions with NCL. Plasdone® and Soluplus® demonstrated excellent properties to form NCL amorphous dispersions, with the last showing superior solubility enhancement. Furthermore, this fast levitation polymer screening showed good agreement with results obtained by conventional solvent evaporation screening evaluated for five days in a stability study, carried out at 40 °C/75% RH. The study showed that acoustic levitation and high-resolution synchrotron combination opens up a new horizon with great potential for accelerating ASD formulation screening and analysis.

Preparation of olmesartan medoxomil solid dispersion with sustained release performance by mechanochemical technology.

Hypertension is a common disease for human with high morbidity and mortality, and olmesartan medoxomil (OM) is widely used in the therapy of hypertension. However, poor water solubility and low bioavailability limit its widespread use. To improve the effect of OM, a ternary OM solid dispersion consisting of hydroxypropyl-β-cyclodextrin (HP-β-CD) and hydroxypropyl methylcellulose (HPMC) was prepared by mechanochemical method. The best preparation parameters were OM/HP-β-CD/HPMC-E5 with mass ratio of 1:2.6:1 and milling time of 4h. Under the optimal preparation conditions, the solubility of the ternary solid dispersion could be increased by 12 times as compared with pure OM. Due to the addition of HPMC-E5, the solid dispersion had sustained release performance with prolonged release time of 12h. Furthermore, in vivo study demonstrated that the prepared solid dispersion could afford significantly improved bioavailability of ~ 3-fold in comparison with pure drug. Hence, the prepared ternary solid dispersion of OM may be a promise delivery system for clinical application.

Solid Dispersion: A Review

Solid dispersion is an effective way of improving the dissolution rate of poorly water soluble drugs and hence its bioavailability. The water soluble carriers used in preparation of solid dispersion enhance the dissolution rate of the poorly water soluble drug. The review article focuses on the methods of preparation, advantages, disadvantages and characterization of the solid dispersions.

Anti-inflammatory and cytoprotective potentials of Meloxicam solid dispersions prepared by different techniques on lipopolysaccharide-stimulated RAW 264.7 macrophages

The present study investigates the anti-inflammatory and cytoprotective potentials of a selective COX-II inhibitor, Meloxicam (MELOX) from solid-dispersions (SDs), using lipopolysaccharide (LPS)–stimulated RAW 264.7 macrophages cell line. MELOX/SDs were prepared by fusion (FM) & hot-melt-extrusion (HME) techniques using Soluplus/Lutrol F127 as mixed-polymers. SDs were physicochemically evaluated by SEM, XRD and solubility-testing. Viability of cell-growth was determined by MTT assay. Evaluation of inflammation was based on production of nitric oxide (NO), tumor necrosis factor-α (TNF-α) and prostaglandin E2 (PGE2). MELOX Solubility increased by 3- and 4- folds from SDs prepared by FM and HME, respectively, compared to pure drug. XRD/SEM analyses confirmed drug-dispersion within mixed-polymers. Exposure of normal-cells to different MELOX-treatments maintained the integrity of cell-growth. LPS-stimulated cells treated with MELOX/SDs exhibited higher viabilities compared to cells treated with pure MELOX. The prepared MELOX/SDs showed statistically stronger inhibition of inflammatory-mediators with respect to pure drug. Only, MELOX/SDs prepared by HME, successfully restored LPS-induced TNF-α level to that of normal-cells. SDs prepared by HME provided superior reduction of NO, TNF-α and PGE2, while maintaining normal cell-growth. The present study highlights the effect of SDs preparation techniques, on MELOX treatment performance.

Facile preparation of solid dispersions by dissolving drugs in N-vinyl-2-pyrrolidone and photopolymerization

Drug solid dispersions improve the dissolution of drugs in aqueous media for enhancement of oral bioavailability. The current preparation methods of drug solid dispersions mainly involve the evaporation of solvents or the melting of drugs and matrix. Here, we create a new and simple method for the preparation of drug solid dispersions by dissolving drugs in N-vinyl-2-pyrrolidone (NVP) and then NVP photopolymerization. A variety of drugs were explored to find whether they were suitable for this method and only some of them were soluble in NVP and formed transparent and hard solid dispersions, including fluconazole, ketoconazole, bifonazole, miconazole nitrate, sulfamethoxazole, aspirin, ibuprofen and artesunate. The formation of photocuring solid dispersions was highly related to the free radical scavenging function of drugs. Those drugs with strong free radical scavenging capability, including curcumin, resveratrol, quercetin, genistein, puerarin, nicergoline, olanzapine, indomethacin, did not form solid dispersions. They scavenged 2,2-diphenyl-1-picrylhydrazyl free radicals, which was demonstrated by ultraviolet spectrometry and electron spin resonance. The scavenging of free radicals stopped the chain polymerization of NVP. The Fourier transform infrared spectra, X-ray diffraction and differential scanning calorimetry of ibuprofen solid dispersions and artesunate solid dispersions showed the molecularly miscible state of the drugs and the hydrogen bonding between the drugs and polyvinyl pyrrolidone. The NVP-based solid dispersions of the two drugs had faster and more complete dissolution than their traditional solid dispersions. The NVP photopolymerization-based solid dispersion method provides a new choice for the production of solid dispersions in the research and industrial fields.

Improved Dissolution Rate and Intestinal Absorption of Fexofenadine Hydrochloride by the Preparation of Solid Dispersions: In Vitro and In Situ Evaluation.

The objective of this study was to enhance dissolution and permeation of a low soluble, absorbable fexofenadine hydrochloride (FFH) by preparing solid dispersions using polyethylene glycol 20,000 (PEG 20,000) and poloxamer 188 as carriers. The phase solubility measurement for the supplied FFH revealed a linear increase in the solubility of fexofenadine with increasing carrier concentration in water (1.45 mg/mL to 11.78 mg/mL with 0% w/v to 30% w/v PEG 20,000; 1.45 mg/mL to 12.27 mg/mL with 0% w/v to 30% w/v poloxamer 188). To select the appropriate drug carrier concentration, a series of solid dispersions were prepared in the drug carrier weight ratios of 1:1, 1:2 and 1:4 by fusion method. The solid dispersions composed of drug carrier at 1:4 weight ratio showed highest dissolution with the time required for the release of 50% of the drug <15 min compared to the supplied FFH (>120 min). The intestinal absorption study presented a significant improvement in the absorption of drug from the solid dispersions composed of poloxamer 188 than PEG 20,000. In summary, the solid dispersions of FFH prepared using PEG 20,000 and poloxamer 188 demonstrated improved dissolution and absorption than supplied FFH and could be used to improve the oral bioavailability of fexofenadine.

Effect of carrier type and Tween® 80 concentration on the release of silymarin from amorphous solid dispersions

Silymarin is a mixture of flavonolignans obtained from the seeds of milk thistle (Silybum marianum L. Gaertner). Silymarin behaves as a weak acid and is categorised as a class IV drug substance in accordance with biopharmaceutics drug disposition classification system, possessing low solubility, as well as low bioavailability. The scope of this study was to identify possible formulation strategies of silymarin. Then, the main aim was to manufacture silymarin solid dispersions using a solvent evaporation approach and to characterise the physicochemical and drug release properties of the two formulations containing two different porous carriers, namely Avicel® PH-102 and Syloid® XDP 3150, and different concentrations of Tween® 80. Silymarin Log P was determined to be 1.6 (±0.14) negating the possibility of bypassing first pass metabolism via lymphatic transport. Utilising alkaline titration, the apparent pKa of silymarin was found to be similar to that of the silybin pKa (5.68). The crystallinity of raw silymarin was confirmed using powder X-ray diffraction and differential scanning calorimetry, and its thermal degradation was observed at a temperature higher than 220 °C (thermogravimetric analysis). Avicel® PH-102 and Syloid® XDP 3150 were characterised in terms of morphology using scanning electron microscopy, particle size distribution (laser diffraction spectroscopy), pore size distribution and intra-particle porosity using mercury intrusion porosimetry. Solid dispersions were manufactured using an organic solvent method incorporating silymarin, the carrier and optionally Tween® 80. The amorphous state of silymarin in all prepared formulations was confirmed using differential scanning calorimetry and powder X-ray diffraction. Silymarin dissolution kinetics were faster for Syloid® XDP 3150 versus Avicel® PH-102 and explained through carrier properties. The addition of Tween® 80 and increasing the concentration from 0.3 to 1.6% (w/w) significantly increased the drug release kinetics of Avicel® PH-102 formulations but had no effect on Syloid® XDP 3150 formulations. Drug release from prepared formulations was compared with Legalon® 70 using the similarity factor (F2). Syloid® XDP 3150-based formulations showed F2>50%. Tween® 80 had a negligible effect on the silymarin release from Syloid® XDP 3150-based formulations. Interestingly, the ability of Tween® 80 to inhibit gut wall efflux is well known. Thus, the inclusion of this excipient offers an opportunity to modulate the silymarin bioavailability without changing the drug release profile. A six-month stability study (at room temperature and 40% RH) confirmed that solid dispersions were still powder X-ray diffraction and differential scanning calorimetry amorphous. Acetone was used for both silymarin extraction and preparation of solid dispersions. Thus, there is an opportunity to use a single step to both load silymarin and form solid dispersions within a single-step.

Preparation and optimization of a resveratrol solid dispersion to improve the physicochemical properties and oral bioavailability of resveratrol

Although resveratrol (RES) possesses potentially attractive activities, it has poor oral bioavailability due to its poor solubility. Solid dispersion (SD) is an efficient strategy to address the restricted dissolution rate and poor bioavailability of compounds that have poor water solubility. In this study, resveratrol solid dispersion (RES-SD) was prepared with mixture carriers through the melt method and optimized by an orthogonal array experimental design. The physicochemical properties and oral absorption of RES-SD formulations in vivo were measured. Analyses indicated that RES was dispersed in the optimal RES-SD formulation in the form of amorphous molecularly dispersed particles; as a result, the optimal SD exhibited a more than 80-fold increase in solubility and the dissolution rate was significantly improved relative to RES. Furthermore, pharmacokinetic studies in mice indicated that the optimal RES-SD formulation exhibited significantly improved RES oral bioavailability. Based on these findings, RES–SD developed through melt method was suitable for industrial production and avoid solvent remained. Moreover, the RES-SD with PEG6000 and F68 appears to be a promising approach to enhance the dissolution, bioavailability of RES.

Design preparation and formulation of piroxicam solid dispersion

Design preparation and formulation of piroxicam solid dispersion

Preparation and characterization of lapatinib-loaded PVP nanofiber amorphous solid dispersion by electrospinning

Preparation and characterization of lapatinib-loaded PVP nanofiber amorphous solid dispersion by electrospinning

Influence of Particle Size and Drug Load on Amorphous Solid Dispersions Containing pH-Dependent Soluble Polymers and the Weak Base Ketoconazole

Among the great number of poorly soluble drugs in pharmaceutical development, most of them are weak bases. Typically, they readily dissolve in an acidic environment but are prone to precipitation at elevated pH. This was aimed to be counteracted by the preparation of amorphous solid dispersions (ASDs) using the pH-dependent soluble polymers methacrylic acid ethylacrylate copolymer (Eudragit L100–55) and hydroxypropylmethylcellulose acetate succinate (HPMCAS) via hot-melt extrusion. The hot-melt extruded ASDs were of amorphous nature and single phased with the presence of specific interactions between drug and polymer as revealed by X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), and Fourier-transform infrared spectroscopy (FT-IR). The ASDs were milled and classified into six particle size fractions. We investigated the influence of particle size, drug load, and polymer type on the dissolution performance. The best dissolution performance was achieved for the ASD made from Eudragit L100–55 at a drug load of 10%, whereby the dissolution rate was inversely proportional to the particle size. Within a pH-shift dissolution experiment (from pH 1 to pH 6.8), amorphous-amorphous phase separation occurred as a result of exposure to acidic medium which caused markedly reduced dissolution rates at subsequent higher pH values. Phase separation could be prevented by using enteric capsules (Vcaps Enteric®), which provided optimal dissolution profiles for the Eudragit L100–55 ASD at a drug load of 10%.

Comparison of Amorphous Solid Dispersions of Spironolactone Prepared by Spray Drying and Electrospinning: The Influence of the Preparation Method on the Dissolution Properties.

This research aimed to compare two solvent-based methods for the preparation of amorphous solid dispersions (ASDs) made up of poorly soluble spironolactone and poly(vinylpyrrolidone-co-vinyl acetate). The same apparatus was used to produce, in continuous mode, drug-loaded electrospun (ES) and spray-dried (SD) materials from dichloromethane and ethanol-containing solutions. The main differences between the two preparation methods were the concentration of the solution and application of high voltage. During electrospinning, a solution with a higher concentration and high voltage was used to form a fibrous product. In contrast, a dilute solution and no electrostatic force were applied during spray drying. Both ASD products showed an amorphous structure according to differential scanning calorimetry and X-ray powder diffraction results. However, the dissolution of the SD sample was not complete, while the ES sample exhibited close to 100% dissolution. The polarized microscopy images and Raman microscopy mapping of the samples highlighted that the SD particles contained crystalline traces, which can initiate precipitation during dissolution. Investigation of the dissolution media with a borescope made the precipitated particles visible while Raman spectroscopy measurements confirmed the appearance of the crystalline active pharmaceutical ingredient. To explain the micro-morphological differences, the shape and size of the prepared samples, the evaporation rate of residual solvents, and the influence of the electrostatic field during the preparation of ASDs had to be considered. This study demonstrated that the investigated factors have a great influence on the dissolution of the ASDs. Consequently, it is worth focusing on the selection of the appropriate ASD preparation method to avoid the deterioration of dissolution properties due to the presence of crystalline traces.

Preparation and Characterization of Solid Dispersions Composed of Curcumin, Hydroxypropyl Cellulose and/or Sodium Dodecyl Sulfate by Grinding with Vibrational Ball Milling.

Solubility is an important physicochemical property affecting drug bioavailability. One approach to improve drug solubility is using amorphous formulations, which can improve solubility by up to a 1000-fold. Herein, amorphous curcumin (CUR) and amorphous solid dispersions (SDs) consisting of CUR, hydroxypropyl cellulose (HPC) and/or sodium dodecyl sulfate (SDS) were developed using vibrational ball milling. The resulting ground mixtures (GMs) were characterized using powder X-ray diffractometry, Fourier transform infrared spectroscopy, differential scanning calorimetry and a dissolution test. The 60-min GM containing 90% HPC significantly increased the drug solubility. Presence of SDS in the GMs containing 90% HPC reduced the grinding duration from 60 min to 30 min in forming a ground SD that significantly increased the CUR dissolution rate. This amorphous state was stable for 30 days when stored at 40 °C/RH 75%.

Characterization and thermal stability study of efavirenz and solid dispersion with PVPVA 64 by means of thermal analysis and pyrolysis coupled with GC/MS

The acquired immunodeficiency syndrome remains a major problem in worldwide public health and its antiretroviral treatment therapy combines at least three high activity classes of drugs. Access to antiretroviral treatment for HIV-infected patients is a global public health priority and efavirenz (EFZ) is one of the first drug choices. However, EFZ is classified as a class II drug, according to the biopharmaceutics classification system due to low solubility and high permeability, which leads it to fail in absorption and hence bioavailability. One of the approaches used to overcome these issues is the preparation of solid dispersions. In this study, thermal analysis and pyrolysis coupled with gas chromatography-mass spectrometry (GC/MS) were employed to determine efavirenz thermal stability and the solid dispersion with poly (vinylpyrrolidone-co-vinylacetate) (PVPVA 64). Thus, it suggests that EFZ was converted to its amorphous state, and there was an increase in EFZ thermal stability when it is dispersed in a polymer matrix compared to the drug alone, since there was an increase in the activation Energy (Ea) and a decrease in frequency factor (A). Furthermore, there was a change in the zero reaction order to one. The thermal stability time of the formulation was estimated at 7 months. In addition, it was possible to observe a good correlation between loss of mass and the technique of Pyrolysis-GC–MS and to posit the formation of new fragments, which clarifies the technique with regard to the identification of thermal decomposition fragments.

Preparation and characterization of curcumin solid dispersion using HPMC.

Curcumin solid dispersions were prepared using hydroxypropyl methylcellulose (HPMC) to enhance water solubility of curcumin. The particle size of curcumin solid dispersions was in range from 371 to 528nm and particles were shaped as spherical with wrinkles. The encapsulation efficiency was over 93% for all samples, and water solubility of curcumin was significantly improved to 238µg/mL when the ratio of curcumin to HPMC was 20:80. The results of X-ray diffraction, differential scanning calorimeter, and Fourier transform infrared spectroscopy showed that crystalline form of curcumin changed to amorphous form. Curcumin solid dispersions showed improved dissolution behavior compared to pure curcumin and the curcumin release kinetic studies were applied to find best-fitting model. This study showed a great potential of solid dispersion using HPMC as curcumin delivery system with improved water solubility and oral absorption. PRACTICAL APPLICATION: Curcumin has limited applications in the food industry because of low water solubility. Dongoh water-soluble curcumin (DW-CURs) were prepared by solid dispersion method with HPMC. Our results indicated that curcumin solid dispersions improved the water solubility of curcumin and showed a sustained release, demonstrating its possibility of body application. Therefore, DW-CURs are a promising formulation for application as a functional ingredient in the food industry.