Solid Dispersion Technique Research Articles

The Enhancement of solubility and dissolution rate of saxagliptine hydrochloride by solid dispersion technique

The Enhancement of solubility and dissolution rate of saxagliptine hydrochloride by solid dispersion technique

Heat and pH stable curcumin-based hydrophilic colorants obtained by the solid dispersion technology assisted by spray-drying

Natural food colorants are on demand due to food safety concerns related with some synthetic counterparts. Health-friendly alternatives can be available from plant sources, which include curcumin extracted from Curcuma longa L. However, its industrial use is difficult to achieve due to the low water affinity, pH and thermal instability, which is particularly challenging, e.g. for baked foods. In this work, the solid dispersion technique followed by spray-drying, an emergent approach in the context of colorants, was applied to curcumin using k-carrageenan, poly(vinyl alcohol) and polyvinylpyrrolidone, as the encapsulant materials. An orthogonal central composite design with dummy-variables was applied, and principal component analysis (PCA) and hierarchical cluster analysis (HCA) carried out to identify the experimental conditions leading to the most effective formulations. In general, particles with a wide range of pH and heat stability have been produced depending on the chosen encapsulant material, used formulation (curcumin, surfactant and polymer contents), and synthesis conditions (pH). Moreover, the used mathematical approach showed to be a valuable tool to support the development of tailor-made formulations directed to specific applications where pH and temperature are relevant processing parameters.

Preparation, characterization and ex vivo–in vivo assessment of candesartan cilexetil nanocrystals via solid dispersion technique using an alkaline esterase activator carrier

The objective of this study was to improve candesartan cilexetil (CC) efficacy by formulating nanocrystals via solid dispersion (SD) technique using tromethamine (Tris). SD was prepared by solvent evaporation at different drug carrier ratios, evaluated for particle size, vitro dissolution studies, TEM, FTIR, and X-ray powder diffraction. Ex vivo, in vivo pharmacokinetic parameters were conducted on selected formulae compared to drug suspension and marketed product. Size analysis demonstrated formation of particles in the nanorange lower than 300 nm. A burst drug release followed by an improved dissolution was observed indicating instant formation of nanocrystals along with amorphization as confirmed by X-ray diffraction. FTIR studies suggested the absence of chemical interaction between Tris and CC. TEM revealed formation of irregular oval nanoparticles. SD-1:5 has higher apparent permeability coefficient compared to CC suspension. Furthermore, the pharmacokinetic results proved the ability of the formed nanoparticles to enhance the efficacy of CC compared to drug suspension and marketed product. In conclusion, using of Tris as alkaline esterase activator carrier could be a promising tool to bypass the controversial effect of esterase enzymes that may be a source for inter-individual variations affecting ester prodrug candidates’ efficacy.

Improvement of the dissolution rate and bioavailability of fenofibrate by the supercritical anti-solvent process

The purpose of this study was to improve solubility and oral bioavailability of fenofibrate via solid dispersion (SD) using a supercritical anti-solvent (SAS) process with amphipathic polymers P407 and TPGS. Solid dispersion techniques have been widely used to enhance the solubility and dissolution profiles of poorly soluble drugs. Fenofibrate is classified as a Biopharmaceutics Classification System class II compound because of its low solubility and high gastrointestinal permeability. Two copolymers were selected based on solubility and dissolution tests. Their physicochemical properties were compared with those prepared by conventional solvent evaporation (CSE). The SD formulations containing fenofibrate were successfully prepared using the SAS and CSE methods. The dissolution rate (%) of fenofibrate at 60 min was significantly improved compared with the solution of raw fenofibrate (19.5% ± 3.7%) by 95.1% ± 2.5% and 93.7% ± 4.1% using the SAS and the CSE process, respectively. This approximately four-fold increase in dissolution rate indicates that oral bioavailability can be enhanced. In addition, pharmacokinetic study was analyzed using the area under the curve (AUC) and Cmax values of SAS-SD and CSE-SD in rats. The AUC was 2.1 times higher and Cmax was 1.9 times higher in SAS-SD, indicating higher concentrations of fenofibrate in the blood. In a pharmacodynamic study to evaluate the efficacy of the drug in hyperlipidemic rat models, SAS-SD showed strong lipid-lowering effects including cholesterol (1.9-fold) and triglycerides (3.3-fold), than CSE-SD. Taken together, these results suggested that SAS-SD has excellent potential as a formulation for the poorly soluble drug fenofibrate.

Solubility and stability enhancement of curcumin in Soluplus® polymeric micelles: a spectroscopic study

Polymer micelles are considered to be efficient carriers for solubilizing and stabilizing various hydrophobic drugs. In order to address the problem of poor bioavailability of curcumin, a different approach known as solid dispersion technique has been utilized to develop a formulation of curcumin with a novel amphiphilic polymer – Soluplus®. The mechanism of interaction of curcumin with Soluplus® has been elucidated using UV–vis absorption and steady-state fluorescence spectroscopy. At a molecular level, the reduced interaction of water molecules with curcumin, in the optimized system led to an enhancement of both absorption and emission intensities of curcumin accompanied by a hypsochromic shift in the fluorescence spectra. Furthermore, stability analysis indicated a much better environment for the drug with less than 3% degradation of curcumin in 3 days. The steady state anisotropy studies confirms the presence of a rigid environment for curcumin upon encapsulation by the polymer. The extra stability of this system can be ascribed to the formation of multiple intermolecular H-bonding interactions between curcumin and Soluplus® which is proved by IR spectroscopy. Finally, in vitro cell viability assays indicated that it is a highly safe and effective system that could be further screened for a plethora of biological applications.

Amphiphilic Copolymer of Polyhedral Oligomeric Silsesquioxane (POSS) Methacrylate for Solid Dispersion of Paclitaxel

Suitable polymers for the homogeneous formulation of drug/polymer mixtures should be selected to correct the structural and physicochemical nature with a rapid dissolution rate. This study aimed to evaluate a copolymer prepared by the radical polymerization of 2-methacryloyloxyethyl phosphorylcholine (MPC) and a polyhedral oligomeric silsesquioxane (POSS) methacrylate bearing an ethyl (C2H5) group (MPC-ran-C2H5-POSS) as a carrier for the solid formulation of paclitaxel (PTX). A single-phase homogeneous formulation of PTX with the mixture of the MPC-ran-C2H5-POSS and polyvinylpyrrolidone (PVP) was prepared by a solvent method. The formulation of MPC-ran-C2H5-POSS/PVP/PTX enhanced the dissolution rate and the dissolved amount (approximately 90% within 40 min) without precipitation. The X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR) and differential scanning calorimetry (DSC) analysis confirmed the presence of PTX as an amorphous state. The amphiphilic nature of the MPC-ran-C2H5-POSS contributed to enhancing the aqueous solubility of PTX. The new formulation is applicable for solid dispersion technique via the supersaturation of PTX in an aqueous media.

The preparation and physicochemical characterization of eprosartan mesylate-laden polymeric ternary solid dispersions for enhanced solubility and dissolution rate of the drug.

Eprosartan mesylate is a poorly water-soluble drug. It does not dissolve well in the aqueous gastrointestinal fluid, which means it is not absorbed well via the oral route, because a drug can cross cell membranes when it is dissolved in the gastrointestinal fluid. The purpose of this research was to enhance the aqueous solubility and dissolution rate of eprosartan mesylate using the solid dispersion technique. Enhancing the solubility and dissolution leads to better absorption via the oral route. A number of eprosartan mesylate-laden polymeric solid dispersions were prepared with hydroxypropyl methylcellulose (HPMC) and polysorbate 80 by means of the solvent evaporation technique. The impact of the weight ratios of the constituents on the solubility and dissolution rate was studied in comparison with the plain drug. The formulation presenting the optimal solubility and dissolution underwent the solid-state characterization using X-ray diffraction (XRD), differential scanning calorimetry (DSC), scanning electron microscopy (SEM), and Fourier-transform infrared spectroscopy (FTIR). Both polysorbate 80 and HPMC positively affected the solubility and dissolution of eprosartan mesylate. In particular, a ternary solid dispersion consisting of eprosartan mesylate, HPMC and polysorbate 80 at a weight ratio of 1:4.2:0.3 showed the highest solubility (36.39 ± 3.95 mg/mL) and dissolution (86.19 ±4.09% in 10 min). Moreover, the drug was present in the amorphous form in the solid dispersion with no covalent drug-excipient interactions.

DEVELOPMENT AND IN VITRO DISSOLUTION STUDY OF BINARY AND TERNARY SOLID DISPERSIONS OF ACECLOFENAC

The poor aqueous solubility of the drug exhibits in variable dissolution rate and hence poor bioavailability. Aceclofenac is poorly water soluble drug. The aim of the present study was to improve the water solubility and the dissolution rate of Aceclofenac by solid dispersion technique using different water soluble polymers. The term solid dispersions refer to the dispersions of one or more active ingredients in an inert carrier or matrix at solid state. In this study, binary solid dispersion of Aceclofenac were prepared by fusion method using Polyethylene glycol 6000 (PEG 6000), Polyethylene glycol 4000 (PEG 4000), Poloxamer as carrier. Different drug-carrier weight ratio was used for this study. The effect of the carrier on the solubility and in-vitro dissolution were studied. It was found the drug was released 26.86% after 5 minutes and only 40.19% within 60 mins from active Aceclofenac on the other hand the release pattern of Aceclofenac from the binary SD formulation containing PEG 6000 in 1:5 ratio (Formulation coding: A5) showed the best result in comparison of other binary and ternary SD formulations which was 62.29% after 5 min and 83.03% within 60 mins. The hydrophilic polymers used for the preparation of solid dispersion are showed significant increase in the solubility of Aceclofenac.

Design expert assisted mathematical optimization of solubility and study of fast disintegrating tablets of Lercanidipine Hydrochloride

90% of drugs being researched today, posses poor solubility setback which inturn renders the drug with slower rate of absorption from the buccal route; hence dissolution is the rate limiting step for such lipophilic drugs. So, there is a need to keep a check on the dissolution profile of these drugs to ensure maximum therapeutic utilization. The dissolution rate therefore becomes a primary factor which governs the rate and extent of its absorption. Enormous work is being performed in the field of enhancement of solubility and dissolution behaviour of such drugs. Advancements and innovations have developed solid dispersion (SD) technique as the novel method for the solubility enhancement. Precision of dosing and patient's compliance is a crucial prerequisite for the management of chronic Antihypertensive treatment, So there arised a need to formulate a system which should resolve the difficulties associated with conventional tablets. This issue can be better tackled with the formulation of orally fast disintegrating tablets. The aim of the present study was to improve the solubility and dissolution rate of Lercanidipine hydrochloride (LRH) by formulating a solid dispersion with Polyvinyl pyrollidine (PVP-K30) and Guargum. Full Factorial designs are exploited to learn and research the effects of different variables on the quality determinant parameters. An appropriate statistical model was selected for the scrutiny of the enhanced dissolution pattern. Finally, these solid dispersions were incorporated into fast disintegrating tablets.
 Keywords: Lercanidipine Hydrochloride, Solid dispersion, Statistical design approach, Melt fusion method, Fast disintegrating tablet, In vivo studies

A Comparative Study of Solubility Enhancement of Aceclofenac by Solid Dispersion Technique Using Several Polymers

The attempt has been made to compare the aqueous solubility and dissolution characteristics of Aceclofenac (ACE) enhanced by solid dispersion technique using several water soluble carriers PEG 6000, β-Cyclodextrin (β –CD) and Sodium Carboxy methyl cellulose (Na-CMC). Solid dispersions of ACE were prepared with solvent evaporation method. Solid dispersions with carriers were prepared in drug: carrier (1:1, 1:2, 1:3 and 1:4) ratios. The prepared dispersions were evaluated by solubility, in vitro dissolution studies and X-Ray diffraction studies (XRD). The results from XRD analysis showed that ACE might exist in an amorphous state in the solid dispersion. Considerably improved dissolution profile was obtained by PEG ratios (1:2), whereas there was no significant improvement in dissolution of ACE along with β-CD at higher carrier ratios. Na- CMC showed least dissolution improvement among all carriers. The solid dispersion prepared as AC: PEG 6000 (1:2), exhibited the fastest dissolution among all solid dispersions, was formulated into tablets using direct compression method and further compared with immediate release marketed brands of ACE. The results indicated that formulated tablets displayed better dissolution profiles as compared to existing commercial tablets.

SOLID DISPERSION - A NOVEL APPROACH FOR BIOAVAILABILITY ENHANCEMENT OF POORLY WATER-SOLUBLE DRUGS IN SOLID ORAL DOSAGE FORMS

Enhancement of the bioavailability of poorly water-soluble drugs is a challenging task in drug development. Currently 40% of new chemical entities are discovered as poorly water-soluble drugs. Solid dispersion is one of the best technology for improving solubility, dissolution rate, and bioavailability. Solid dispersion techniques are more useful for enhancing drug solubility for a combination of drug and inert carrier to improve wettability, reduced particle size, and converting amorphous particles. This article reviews various advantages, methods of solid dispersions, carriers used in solid dispersion, characterization, and marketed products.

Preparation, characterization and in vitro evaluation of tablets containing microwave-assisted solid dispersions of apremilast

Solid dispersions are among the techniques successfully employed to enhance the dissolution of poorly water-soluble drugs. Microwave (MW)-assisted evaporative crystallization has been used to prepare solid dispersions of drugs and polymers. The aim of the study was to investigate the solubility of apremilast (APM) in water by exploring the effect of MW-assisted solid dispersion technology. In the present study, solid dispersions of APM, a poorly water-soluble drug, were prepared. The solid dispersions were prepared using the conventional method (CM) and the MW-based solvent evaporation technique. Microwave energy was used to enhance the solubility and dissolution rate of APM. The physical mixture and solid dispersions were characterized using Fourier-transform infrared spectroscopy (FTIR), X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), and scanning electron microscopy (SEM). Apremilast tablets containing MW-assisted solid dispersions were prepared by the direct compression technique and compared with the marketed formulation (Aprezo tablets). The results obtained confirmed the conversion of crystalline APM to an amorphous form. The XRPD pattern of the MW-assisted formulation at a 2:1 ratio suggests the amorphous structure of APM within the formulation. Based on solubility studies results, Syloid® 244FP was selected as the best carrier. The dissolution study results suggested that the APM tablet prepared using MW-assisted solid dispersions at a 2:1 carrier/drug ratio improved the APM dissolution rate compared to the marketed formulation. Based on the results, it can be concluded that the MW-assisted solid dispersion technique may be an effective approach to enhancing the dissolution profile of other poorly water-soluble drugs.

Formulation and Evaluation of Ramipril Fast Dissolving Tablet using Solid Dispersion

Solubility is a key parameter for oral bioavailability of poorly water soluble drugs. Ramipril is sparingly soluble in water which affects the absorption of drug via GIT, and ultimately makes the drug with low bioavailability. In the present study is solubility enhancement of Ramipril by solid dispersion technique. Solid dispersion of Ramipril is prepared by using two polymers ie: Polyvinyl Pyrrolidone (PVP K30) and Polyethylene Glycol 4000 (PEG 4000) in different ratios (1:1, 1:2, 1:3) using solvent evaporation method. On the basis of % drug content and solubility study S.D.2 and S.D.5 solid dispersion were selected an taken for formulation of fast dissolving tablet of Ramipril. On evaluating various FDTs of Ramipril the best formulation was found to be F6 (1:2 PEG 4000) showed disintegration time was 28 sec. and cumulative percentage drug release 97.68 % in 40 min.

Formulation Development and Evaluation of Poorly Water Soluble Gliclazide Tablet Containing Aerosil 380 as Carrier

The core objective of the current work was to improve dissolution rate of poorly water-soluble anti-diabetic drug gliclazide by solid dispersions (SDs) technique using fumed silica particles Aerosil 380 as carrier into compressed tablets. Different FGA-1, FGA-2, FGA-3 (Formulated Gliclazide Aerosil; weight ratio, 1:1) and FPG-1, FPG-2 (Formulated Plain Gliclazide) tablet batches were formulated, prepared, evaluated and characterized. All the findings of pre-compression factors were found to be satisfactory and post-com- pression parameters revealed good mechanical integrity and good uniformity in all formulations. All the formulated tablets satisfied the compendia limits of weight variation, friability and the disintegration time. Among all formulations, FGA-3 was optimized based on in vitro drug release findings, disintegration time, hardness and other quality attributes. The percent of drug release from the formulated FGA tablets containing gliclazide loaded aerosil is about 3 fold higher when compared with the tablets formulated and prepared with plain gliclazide (FPG) and the tested commercial brands in first 60 minutes. There was no significant change noted in the drug content and drug release pattern in the FGA tablets batches when stored in 40℃ and 75% RH for three months. It was thus concluded that SDs formulations of gliclazide could be successfully used to design and develop a solid dosage form of the drug, which would have significant benefits over the existing commercial brands.

Solubility improvement of Lapatinib by Novel Techniques of Solid Dispersion

Objective: Tyrosine kinase inhibitor, Lapatinib (LAP) is highly lipophilic in nature and presents challenges with regard to its low and variable oral bioavailability. Polymer-based solid dispersion technology has been considered as the major advancement in overcoming limited aqueous solubility and oral absorption issues. In the present research work, approaches were taken to improve the dissolution characteristics of LAP by developing suitable systems of solid dispersion. Methods: Solid dispersions of lapatinib were prepared utilizing techniques like solvent controlled coprecipitation, fusion, nanoprecipitation and spray drying. Polymers with different ionic characteristics like Eudragit® EPO (cationic), Eudragit® L 100 55 (anionic), HPMCP HP 55 (anionic), HPMC AS (anionic) and Povidone K 30 (non-ionic) were employed at three different ratios of 1:1, 1:2 and 1:3 to prepare the solid dispersions of weakly basic lapatinib. Dissolution study in media corresponding to different physiologically relevant pH was performed to understand the effectiveness of the technique and effect of the polymer. Additionally, samples were also subjected for X-ray powder diffraction study to understand the nature of the drug in the solid dispersion systems. Results: It was observed that irrespective of the pH of the dissolution media, the dissolution rate of solid dispersions of LAP prepared with anionic polymers in particular HPMCP HP 55 is more which is attributed to the weakly basic nature of lapatinib. The diffractograms show substantial decrease in the crystallinity of lapatinib in the solid dispersions. Conclusion: The combination of solid dispersion technique with supersaturable systems appears to hold promise for improving dissolution and bioavailability of poorly soluble drugs. Solid dispersions significantly increase dissolution of LAP, which can be a starting point of a new LAP formulation with improved bioavailability. The selection of polymers that can inhibit crystallization of LAP in a supersaturated state becomes the key factor for an effective formulation. The present work is an attempt in this direction.

Solid Dispersion Technique for Solubility Improvement of Ketoconazole for Vaginal Delivery

The activity of any drug depends on bioavailability of drug. As biological barriers permit only dissolved molecules, it is essential to have sufficient solubility in biological fluid. Vaginitis is a very common gynecological problem in women of all age groups and mostly indicated as mixed vaginal infection. Ketoconazole is a topical antifungal drug used to treat vaginitis and has poor solubility (BCS class- II). In the present study, an attempt has been made to improve the solubility of ketoconazole by solid dispersions (SD) prepared by kneading and spray drying techniques using hydrophilic carrier; Soluplus, Poloxamer 188 and s-cyclodextrin. The SD prepared by soluplus with spray drying method exhibited higher solubility than those prepared by kneading method. SD was further characterized by FTIR, DSC, and XRD analysis. Fourier transform infrared spectroscopy study confirmed the formation of SD complex of ketoconazole and soluplus. Polymer entrapped the drug and formed amorphous state which was confirmed by DSC studies. The surface morphology of the SD by X-ray diffraction confirmed conversion of drug from crystalline form to amorphous. Conclusively, Soluplus looks to be a promising carrier to improve the solubility of poorly soluble drugs.

Challenges to improve the biopharmaceutical properties of poorly water-soluble drugs and the application of the solid dispersion technology

The oral solid dosage forms are extremely relevant to drug therapy and responsible for much of the pharmaceutical industry turnover worldwide. However, the development of medicines in solid form involves significant challenges, including obtaining formulations with appropriate bioavailability for low aqueous solubility drugs (classes II and IV of the Biopharmaceutics Classification System). One of the most effective strategies to overcome poor dissolution rate and low absorption of drugs is the solid dispersion technique, however, although it has been the focus of much research in recent decades, there are relatively few commercially available products based on such technology. This is mainly due to problems related to production scale-up and physicochemical instability and creates opportunities for new studies to explore the full potential of the technology. This review presents an overall approach to the factors affecting the dissolution rate and oral bioavailability of BCS-classes II and IV drugs and a brief review of the state-of-the-art of solid dispersion technology. Keywords: oral delivery, drug solubility, drug dissolution, solid dispersion.

Enhancement of the Solubility and Dissolution Rate of Rebamipide by Using Solid Dispersion Technique (Part I)

Solid dispersion is an attractive tool of pharmaceutical technology used to improve the physical properties of drugs. Among these properties is to enhance the solubility of the drugs.Rebamipide is a poorly soluble drug of class IV of biopharmaceutical classification system (BCS).Rebamipide is used as potent antiulcer, mucoprotective drug, by stimulating the generation of prostoglandine enhanced mucosal protection.Rebamipide was formulated as a solid dispersion using different polymers such as pluronic F-127, PEG6000, PVP K30, and TPGS by using different preparation methods solvent evaporation, fusion, and kneading methods.It was seen that rebamipide was successfully dispersed in a homogenous solid dispersion matrix by solvent evaporation method using TPGS (1:15) drug carrier ratio.Moreover, the results revealed that the solubility of rebamipide (23.9µg/ml) increased significantly (p?0.05) by 36.4 x fold to obtain 874µg/ml solubility in rebamipide matrix. On the other hand, characterization of rebamipide solid dispersion using FTIR, DSC, SEM and x-ray diffraction demonstrated no drug polymer interaction, and converting the rebamipide from crystal to amorphous state lattice.

A novel composition of ticagrelor by solid dispersion technique for increasing solubility and intestinal permeability

The aim of this study is to improve the bioavailability of ticagrelor, BCS class 4 drug, using solid dispersion technique, and to evaluate the potential of ticagrelor loaded-solid dispersion, as a new formulation. The solid dispersion formulation was prepared via solvent evaporation method using ethanol. TPGS and Neusilin® US2 selected via screening studies were used for preparing formulation. The results of scanning electron microscopy, differential scanning calorimetry and powder X-ray diffraction showed that the crystallinity of the ticagrelor was completely transformed to an amorphous form and maintained in the solid dispersion formulation. The released amount of the optimized solid dispersion significantly increased by 2.2- and 34-fold in comparison with physical mixture (Ticagrelor:TPGS:Neusilin® US2 = 1:2:2, w/w/w) and commercial product (Brilinta®) in distilled water at 90 min, respectively. The absorptive permeability was improved (1.4-fold) and the efflux ratio was decreased (0.45-fold) by formulation containing TPGS acting as a P-gp inhibitor compared to pure drug. The solid dispersion formulation improved the peak plasma concentration (Cmax) and relative bioavailability compared to that of pure drug as 238.09 ± 25.96% and 219.78 ± 36.33%, respectively, after oral administration in rats. Thus, we successfully prepared the solid dispersion formulation for enhancing oral bioavailability of ticagrelor, and then this formulation would be recommended as a practical oral pharmaceutical product.

Enhancement of dissolution rate of Olmesartan medoxomil using urea as carrier by different solid dispersion techniques

The poor solubility of drug substances in water and their low dissolution rate in aqueous G.I.T fluid often leads to insufficient bioavailability. As per Biopharmaceutical Classification System (BCS), Olmesartan belongs to the class-II category having poor solubility and high permeability. Since only dissolved drug can pass the gastrointestinal membrane, the proper solubility of the drug is ultimately desired. Its oral bioavailability is 26%. Hence, an attempt was made to enhance its solubility by formulating solid dispersions using different techniques viz., Melting, Kneading, Co-precipitation, Solvent evaporation and Physical mixing etc., Drug and carrier (Urea) in different ratios like 1: 1, 1: 2, 1: 3 and 1:4 were used for formulating solid dispersions. The compatibility of the drug with the carrier was checked by FTIR studies, these results revealed that there was no interaction between them. The angle of repose, bulk density, tapped density; Carr’s index and Hausner ratio were calculated for the micrometric characterization of all the solid dispersions. The drug content was found to be high and uniform in all formulations. The prepared Solid dispersion SEM4 (1:4) showed minimal wetting time of 13 seconds compared with the other formulations. In vitro dissolution, release studies in Phosphate buffer pH of 6.8 revealed that the prepared solid dispersions showed faster drug release compared with the pure drug. The in vitro dissolution profile showed ascendency on increasing the carrier concentration