Improving drug solubility for oral delivery using solid dispersions.

The solubility behaviour of drugs remains one of the most challenging aspects in formulation development. With the advent of combinatorial chemistry and high throughput screening, the number of poorly water soluble compounds has dramatically increased. Although solid solutions have tremendous potential for improving drug solubility, 40 years of research have resulted in only a few marketed products using this approach. With the introduction of new manufacturing technologies such as hot melt extrusion, it should be possible to overcome problems in scale-up and for this reason solid solutions are enjoying a renaissance. This article begins with an overview of the historical background and definitions of the various systems including eutectic mixtures, solid dispersions and solid solutions. The remainder of the article is devoted to the production, the different carriers and the methods used for the characterization of solid dispersions.     

Dissolution and bioavailability improvement of bioactive apigenin using solid dispersions prepared by different techniques

Apigenin (APG) is a poorly soluble bioactive compound/nutraceutical which shows poor bioavailability upon oral administration. Hence, the objective of this research work was to develop APG solid dispersions (SDs) using different techniques with the expectation to obtain improvement in its in vitro dissolution rate and in vivo bioavailability upon oral administration. Different SDs of APG were prepared by microwave, melted and kneaded technology using pluronic-F127 (PL) as a carrier. Prepared SDs were characterized using “thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), Fourier transform infra-red (FTIR) spectrometer, powder X-ray diffraction (PXRD) and scanning electron microscopy (SEM)”. After characterization, prepared SDs of APG were studied for in vitro drug release/dissolution profile and in vivo pharmacokinetic studies. The results of TGA, DSC, FTIR, PXRD and SEM indicated successful formation of APG SDs. In vitro dissolution experiments suggested significant release of APG from all SDs (67.39–84.13%) in comparison with control (32.74%). Optimized SD of APG from each technology was subjected to in vivo pharmacokinetic study in rats. The results indicated significant improvement in oral absorption of APG from SD prepared using microwave and melted technology in comparison with pure drug and commercial capsule. The enhancement in oral bioavailability of APG from microwave SD (319.19%) was 3.19 fold as compared with marketed capsule (100.00%). Significant enhancement in the dissolution rate and oral absorption of APG from SD suggested that developed SD systems can be successfully used for oral drug delivery system of APG.     

Improving the solubility and bioavailability of dihydroartemisinin by solid dispersions and inclusion complexes

Dihydroartemisinin (DHA) is a poorly water-soluble drug that displays low bioavailability after oral administration. Attempts have been made to improve the solubility of DHA. Yet, no information is available concerning improved bioavailability. This study aimed to improve the water solubility of DHA by two systems: solid dispersions with polyvinylpyrrolidone (PVPK30, PVPK25, PVPK15) and inclusion complexes with hydroxypropyl-β-cyclodextrin (HPβCD), as well as improving the bioavailability of both systems. The phase transition of DHA with hydrophilic polymers was evaluated by X-ray diffraction (XRD) and differential scanning calorimetery (DSC). DHA became amorphous in DHA-HPβCD complexes and showed more amorphous behavior in XRD analyses with rise in molecular weight of PVP. Melting onset temperature of DHA decreased, while DSC thermograms revealed the peak area and enhanced enthalpy change (DH) in solid dispersions as well as inclusion complexes. DHA solubility was enhanced 84-fold in DHA-HPβCD complexes and 50-times in DHA-PVPK30. The improved solubility using the four polymers was in the following order: HPβCD > PVPK30 > PVPK25 > PVPK15. Values of area under curve (AUC) and half life (t_1/2) of DHA-PVPK30 were highest followed by DHA-HPβCD, DHA-PVPK15 and DHA-PVPK25. V_d/f of DHA-PVPK30 was 7-fold. DHA-HPβCD, DHA-PVPK15 and DHA-PVPK25 showed significantly different pharmacokinetic parameters compared with DHA solutions. The 95% confidence interval was meaningful in AUC and t_1/2. Pharmacokinetic parameters revealed that all four-test preparations were significantly more bioavailable than DHA alone.     

Improvement of solubility,dissolution and stability profile of artemether solid dispersions and self emulsified solid dispersions by solvent evaporation method

Abstract

The purpose of this study was to investigate changes in the water solubility of artemether; a poorly soluble drug used for the treatment of malaria. Different solid dispersions (SDs) of artemether were prepared using artemether and polyethylene glycol 6000 at ratio 12:88 (Group 1), self-emulsified solid dispersions (SESDs) containing artemether, polyethylene glycol 6000, cremophor-A-25, olive oil, hydroxypropylmethylcellulose and transcutol in the ratio 12:75:5:4:2:2, respectively (Group 2). SESDs were also prepared by substituting cremophor-A-25 in Group 2 with poloxamer 188 (noted as Group 3). Each of these preparations was formulated using physical mixing and the solvent evaporation method. Aqueous solubility of artemether improved 11-, 95- and 102-fold, while dissolution (in simulated gastric fluid) increased 3-, 13- and 14-fold, for formulation groups 1, 2 and 3, respectively. X-ray diffraction patterns of SDs indicated a decrease in peak intensities at 10° implying reduced artemether crystallinity. Scanning electron micrographs invariably revealed embedment of artemether by various excipients and a glassy appearance for solvent evaporated mixtures for all three formulation Groups. Our findings indicate improved hydrophilic interactions for drug particles yield greater solubility and dissolution in the following order for artemether formulating methods: solvent evaporation mixtures?>?physical mixtures?>?pure artemether.     

Preparation, characterization and evaluation of coenzyme Q10 binary solid dispersions for enhanced solubility and dissolution

Phase solubility behavior of coenzyme Q10 (CoQ10) at 25 degrees C in various molar solutions of poloxamer 188 (P188) in water was observed and their binary solid dispersions (BSD) at different weight ratios were prepared by a simple, rapid, cost effective, uncomplicated and potentially scalable low temperature melting method. BSDs were characterized by scanning electron microscopy (SEM) and differential scanning calorimetry (DSC), and evaluated for improved solubility at 25 degrees C and 37 degrees C and in-vitro release of CoQ10 at 37 degrees C in distilled water. Solubility of CoQ10 increased with increasing concentrations of P188 in water. Gibbs free energy (deltaG(o)tr) values were all negative indicating the spontaneous nature of CoQ10 solubilization and decreased with increasing concentration of P188 demonstrating that the reaction conditions became more favorable as the concentration of P188 increased. DSC and SEM analysis indicated that the homogeneity of dispersion was not at the molecular level. However, BSDs exhibited a remarkably improved aqueous solubility and dissolution of CoQ10.     

提高原人参二醇口服生物利用度的固体分散体及其片剂的制备与评价

目的 本文拟研究一种加水复溶后可转化为纳米混悬液的新型固体分散体片剂,提高原人参二醇(PPD)口服给药的溶解度和生物利用度。方法 通过将药物、聚合物载体和表面活性剂按10∶14∶6的比例溶解于乙醇后,减压真空干燥制备固体分散体,然后将固体分散体、乳糖、交联聚乙烯吡咯烷酮和硬脂酸镁按300∶16∶60∶4的比例混合后,直接压成片重400 mg的片剂。结果 发现含泊洛沙姆188和维生素E聚乙二醇琥珀酸酯(TPGS)的原人参二醇固体分散体加水复溶后可转变为纳米混悬液。以乙烯基吡咯烷酮/醋酸乙烯共聚物64(PVP-VA)为载体,维生素E聚乙二醇琥珀酸酯为表面活性剂的固体分散体加水复溶后可转变为平均粒径小于120 nm的纳米混悬液,该混悬液放置8 h后粒径基本稳定。固体分散体经压制成片剂后可在15 min内溶出超过90%的药物,且其溶出的药物可稳定维持至少8 h。固体分散体经大鼠灌胃给药后,其最高血药浓度和生物利用度是原型药物及辅料物理混合物的6.59倍和2.54倍。结论 该研究表明可转化为纳米混悬液的固体分散体片剂是一种可提高原人参二醇口服生物利用度的新制剂方法。     

Prednisolone multicomponent nanoparticle preparation by aerosol solvent extraction system

Prednisolone nanoparticles were prepared in the presence of a hydrophilic polymer and a surfactant by the aerosol solvent extraction system (ASES). A ternary mixture of prednisolone, polyethylene glycol (PEG), and sodium dodecyl sulfate (SDS) dissolved in methanol was sprayed through a nozzle into the reaction vessel filled with supercritical carbon dioxide. After the ASES process was repeated, precipitates of the ternary components were obtained by depressurizing the reaction vessel. When a methanolic solution of prednisolone/PEG 4000/SDS at a weight ratio of 1:6:2 was sprayed under the optimized ASES conditions, the mean particle size of prednisolone obtained after dispersing the precipitates in water was observed to be ca. 230 nm. Prednisolone nanoparticles were not obtained by the binary ASES process for prednisolone, in the presence of either PEG or SDS. Furthermore, ternary cryogenic cogrinding, as well as solvent evaporation, was not effective for the preparation of prednisolone nanoparticles. As the ASES process can be conducted under moderate temperature conditions, the ASES process that was applied to the ternary system appeared to be one of the most promising methods for the preparation of drug nanoparticles using the multicomponent system.     

Preparation and characterization of metoprolol controlled-release solid dispersions

In recent years, great attention has been paid to using solid dispersions to make sustained-release drugs. The objective of this study is to produce sustained-release systems of metoprolol tartrate using solid dispersion techniques and to evaluate their physicochemical characteristics. The solid dispersions were produced by melting and solvent methods, containing 7%, 15%, or 25% of the drug and different ratios of Eudragit RLPO and RSPO in ratios of 0:10, 3:7, 5:5, 7:3, and 10:0. Drug release profiles were determined by USP XXIII rotating paddle method in phosphate buffer solution (pH 6.8). XRD, DSC, IR, and microscopic observations were performed to evaluate the physical characteristics of solid dispersions. Results showed that the drug release from dispersions was at a slower rate than pure drug and physical mixtures. Moreover, the formulations containing greater ratios of Eudragit RSPO showed slower release rates and smaller DE_8% but larger mean dissolution time than those containing greater ratios of Eudragit RLPO. Dispersions with particle size of less than 100 μm containing 7% of metoprolol and Eudragit RL:RS 5:5 (solvent method) and those with the ratio of 3:7 (melting method) had similar release pattern to Lopressor® sustained-release tablets by zero-order and Higuchi kinetics, respectively.     

Preparation and characterization of emulsified solid dispersions containing docetaxel

An emulsified solid dispersion of docetaxel was prepared and characterized in vitro. In contrast to conventional solid dispersions, emulsifying pharmaceutical excipients and hydroxypropyl methylcellulose (HPMC) as a supersaturation promoter were introduced into the PEG6000-based solid dispersion to further improve its solubilizing capability. The solubility, dissolution in vitro and stability of the prepared emulsified solid dispersions were studied taking into consideration of the effects of different emulsifying excipients, preparation methods and the media. Results of the emulsified solid dispersion of docetaxel showed that the solubility and dissolution at 2 h were 34.2- and 12.7-fold higher than the crude powder. The type of emulsifying excipient used had a significant influence on the dissolution of the emulsified solid dispersion. The dissolution of the emulsified solid dispersion prepared by the solvent-melting method or the solvent method was higher than the melting method. There were no apparent differences among the dissolution media utilized. The status of the drug in the emulsified solid dispersion was observed in an amorphous or a molecular dispersion state by differential thermal analysis and powder Xray diffraction. In conclusion, the incorporation of emulsifying pharmaceutical excipients and HPMC with polymers into a solid dispersion could be a new and useful tool to greatly increase the solubility and dissolution of poorly water-soluble drugs.     

Preparation, dissolution and characterization of albendazole solid dispersions

In this study, solid dispersion systems of the sparingly water soluble drug, albendazole (ABZ), were mixed with varying concentrations of polyvinylpyrrolidone (PVP K 12) in an attempt to improve the solubility and dissolution rate of ABZ. Physical characteristics were investigated by Powder X-ray diffraction. As expected, the albendazole dissolution rate, expressed as the dissolution efficiency, and also the solubility coefficient were increased when albendazole was mixed with PVP. An increase in the concentration of the polymer in the solid dispersion produced an increase in both parameters. The powder X-ray diffraction patterns showed that the solid dispersion presented an amorphous form of albendazole in this coprecipitate system.     

Increasing the solubility of phenazepam by forming solid dispersions

The effect of solid dispersion (SD) formation on the solubility of phenazepam has been studied. Phenazepam and its SDs with poly(ethyleneglycol)-1500 (PEG), poly(vinylpyrrolidone)-10000 (PVP), and β-cyclodextrin were studied. The SD with PVP increases both the solubility and the dissolution rate of phenazepam. Results obtained by a complex of physical and chemical methods suggest that the improved release of phenazepam from the SD with PVP is due to solubilization, amorphization, and formation of a colloidal dispersion of the parent drug substance.     

Formulation studies of a poorly water-soluble drug in solid dispersions to improve bioavailability

To improve the bioavailability of a poorly water-soluble drug, RP 69698 (1), solid dispersion formulations were investigated in beagle dogs. The formulations were prepared by a melting method with water-soluble carriers in which 1 is highly soluble. When incorporated into a solid dispersion formulation composed of polyethylene glycol (PEG) 3350, Transcutol and Labrasol, the bioavailability of 1 was determined to be 11.8%. This represented about 2-fold improvement over 6% bioavailability observed previously with an aqueous suspension of the drug in 0.5% methylcellulose. When the formulation contained only Labrasol, in which 1 was completely solubilized, the bioavailability of 1 was 12.9%. Addition of a surfactant, polysorbate 80, at a strength of 10% to the dispersion with PEG 3350 and Labrasol as carriers increased the bioavailability of 1 from 11.8 to 27.6%. This result was attributed to the ability of the surfactant to increase the wettability and spreadability of the drug in a solubilized state once released in the gastrointestinal medium. Increase in the concentration of the surfactant did not further increase the bioavailability of 1. DSC and powder XRD data demonstrated that the major fraction of drug was dissolved in the carrier. A possible explanation for the maximum achievable bioavailability of about 25% with solid dispersion preparation may be that once released, a significant fraction of drug may precipitate in the GI tract. Re-solubilization of the precipitated drug for the absorption is likely to be difficult due to its very low aqueous solubility.     

Processing factors in development of solid solution formulation of itraconazole for enhancement of drug dissolution and bioavailability

This study investigated solid solutions of itraconazole, a water insoluble antifungal, for improved dissolution and improved bioavailability. Influence of processing factors on drug and carrier properties in solid solution and subsequently on drug dissolution behavior was also studied. An optimized solid solution formulation was compared with marketed product in healthy human subjects under fasted and fed conditions for bioequivalency. Polyethylene glycol (PEG) and drug were made into a solid solution at 120 degrees C. The cooled, solid solution was then ground into granules of different sizes. Solid solutions of lower drug concentration dissolved at a faster rate, and drug dissolution improved considerably with increasing molecular weight of PEG. Initial treatment of itraconazole with the wetting agent/cosolvent glycerol prior to making itraconazole into a solid solution improved drug dissolution, and also reduced the PEG amount required to dissolve drug to form solid solution. Addition of a polymer such as HPMC to the solid solution eliminated precipitation of drug following dissolution. As the granule size of the solid solution was reduced, precipitation of drug during dissolution became prominent. Equivalence of two formulations could not be shown for pharmacokinetic parameters C(max) and AUC, under both fasting and fed conditions.     

Physicochemical characterization of solid dispersions of three antiepileptic drugs prepared by solvent evaporation method

We have investigated the solid dispersion and dissolution profiles of three antiepileptic drugs (carbamazepine (CBZ), oxcarbazepine (OXC) and rufinamide (RFN)) with different aqueous solubilities, prepared by the solvent evaporation method. Solid dispersions of the three drugs in hydroxy-propylmethylcellulose (HPMC), with drug:polymer ratios of 1:4, were prepared and characterized by differential scanning calorimetry (DSC), Fourier transformation infrared (FTIR) spectroscopy, X-ray diffraction (XRD) and scanning electron microscopy. The release mechanism was also investigated and the kinetic order of the solid dispersions was evaluated. It appeared that the dissolution behaviour depended on the physicochemical properties of the drug and drug-polymer interactions. DSC thermographs showed amorphous forms for all drugs confirmed by XRD patterns. The FTIR spectra of CBZ and OXC demonstrated drug interactions with HPMC through hydrogen polymer bonds. Thus, solid dispersions of these drugs had an improved dissolution profile. In contrast, solid dispersions of RUF showed modest enhancement of dissolution, suggesting negligible drug-polymer interactions. The different dissolution behaviour is attributed to the extent of interactions between the polymer hydroxyl group and the drug amide groups.     

Determining the solubility of synthomycin in solid dispersions

The influence of solid dispersions (SDs) on the solubility of synthomycin (INN chloramphenicol) has been determined. SDs of synthomycin with poly(ethyleneglycol) (PEG-1500), poly(vinylpyrrolidone) (PVP-10000), and β-cyclodextrin have been obtained and studied. The solubility of synthomycin from SDs increases by a factor of 1.5–2.0; the solubility rate, 2.7–3.4, as compared to those for the parent substance. Data obtained by a combination of physicochemical methods indicate that the improved release of synthomycin from SDs is related to a decrease in the degree of crystallinity and to the formation of intermolecular complexes.     

Solid dispersions of itraconazole for inhalation with enhanced dissolution, solubility and dispersion properties

The purpose of this study was to produce a dry powder for inhalation (DPI) of a poorly soluble active ingredient (itraconazole: ITZ) that would present an improved dissolution rate and enhanced solubility with good aerosolization properties. Solid dispersions of amorphous ITZ, mannitol and, when applicable, D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) were produced by spray-drying hydro-alcoholic solutions in which all agents were dissolved. These dry formulations were characterized in terms of their aerosol performances and their dissolution, solubility and physical properties. Modulate differential scanning calorimetry and X-ray powder diffraction analyses showed that ITZ recovered from the different spray-dried solutions was in an amorphous state and that mannitol was crystalline. The inlet drying temperature and, indirectly, the outlet temperature selected during the spray-drying were critical parameters. The outlet temperature should be below the ITZ glass transition temperature to avoid severe particle agglomeration. The formation of a solid dispersion between amorphous ITZ and mannitol allowed the dry powder to be produced with an improved dissolution rate, greater saturation solubility than bulk ITZ and good aerosol properties. The use of a polymeric surfactant (such as TPGS) was beneficial in terms of dissolution rate acceleration and solubility enhancement, but it also reduced aerosol performance. For example, significant dissolution rate acceleration (f(2)<50) and greater saturation solubility were obtained when introducing 1% (w/w) TPGS (mean dissolution time dropped from 50.4 min to 36.9 min and saturation solubility increased from 20 ± 3 ng/ml to 46 ± 2 ng/ml). However, the fine particle fraction dropped from 47 ± 2% to 37.2 ± 0.4%. This study showed that mannitol solid dispersions may provide an effective formulation type for producing DPIs of poorly soluble active ingredients, as exemplified by ITZ.     

Improving the solubility of ampelopsin by solid dispersions and inclusion complexes

The aim of this study was to increase the solubility of ampelopsin (AMP) in water by two systems: solid dispersions with polyethylene glycol 6000 (PEG 6000) or polyvinylpyrrolidone K-30 (PVP K30) and inclusion complexes with beta-cyclodextrin (BCD) and hydroxypropyl-beta-cyclodextrin (HPBCD). The interaction of AMP with the hydrophilic polymers was evaluated by differential scanning calorimetry (DSC), Fourier transformation-infrared spectroscopy (FTIR), scanning electron microscopy (SEM). The results from DSC, FTIR and SEC analyses of solid dispersions and inclusion complexes showed that AMP might exist as an amorphous state or as a solid solution. On the other hand, the SEM images of the physical mixtures revealed that to some extent the drug was present in a crystalline form. The influence of various factors (pH, temperature, type of polymer, ration of the drug to polymer) on the solubility and dissolution rate of the drug were also evaluated. The solubility and dissolution rates of AMP were significantly increased by solid dispersions and cyclodextrin complexes as well as their physical mixtures. The improvement of solubility using polymers was in the following order: HPBCD approximately BCD>PVP K30>PEG 6000.