Solid-state solubility influences encapsulation and release of hydrophobic drugs from PLGA/PLA nanoparticles

Biodegradable nanoparticles formulated from poly(D,L-lactide-co-glycolide) (PLGA) and polylactide (PLA) polymers are being extensively investigated for various drug delivery applications. In this study, we hypothesize that the solid-state solubility of hydrophobic drugs in polymers could influence their encapsulation and release from nanoparticles. Dexamethasone and flutamide were used as model hydrophobic drugs. A simple, semiquantitative method based on drug-polymer phase separation was developed to determine the solid-state drug-polymer solubility. Nanoparticles using PLGA/PLA polymers were formulated using an emulsion-solvent evaporation technique, and were characterized for size, drug loading, and in vitro release. X-ray powder diffraction (XRD) and differential scanning calorimetry (DSC) were used to determine the physical state of the encapsulated drug. Results demonstrated that the solid-state drug-polymer solubility depends on the polymer composition, molecular weight, and end-functional groups (ester or carboxyl) in polymer chains. Higher solid-state drug-polymer solubility resulted in higher drug encapsulation in nanoparticles, but followed an inverse correlation with the percent cumulative drug released. The XRD and DSC analyses demonstrated that the drug encapsulated in nanoparticles was present in the form of a molecular dispersion (dissolved state) in the polymer, whereas in microparticles, the drug was present in both molecular dispersion and crystalline forms. In conclusion, the solid-state drug-polymer solubility affects the nanoparticle characteristics, and thus could be used as an important preformulation parameter.     

Preparation of multi-phase microspheres of poly(D,L-lactic acid) and poly(D,L-lactic-co-glycolic acid) containing a W/O emulsion by a multiple emulsion solvent evaporation technique.

Multi-phase microspheres of poly(D,L-lactic acid) (PLA) or poly(D,L-lactic-co-glycolic acid) (PLGA) containing a water-in-oil (W/O) emulsion were prepared by a multiple emulsion solvent evaporation technique. Acetonitrile was used as the solvent for the polymers and light mineral oil as the dispersion medium for the encapsulation procedure. Process and formulation parameters to optimize the microencapsulation of a W/O emulsion containing water-soluble drugs were investigated. Drug loading efficiencies of 80-100 per cent were obtained under specific preparative conditions. The drug loading efficiency in the microspheres was dependent upon the ratio of the W/O emulsion to polymer and the concentration of surfactant in the mineral oil. Compared to conventional microspheres, in which fine drug particles are homogeneously dispersed in the polymer beads, the multi-phase microspheres permit the higher encapsulation efficiency of water-soluble drugs and eliminate partitioning into the polymer-acetonitrile phase which results in low encapsulation efficiency with conventional solvent evaporation techniques.     

Encapsulation of dexamethasone into biodegradable polymeric nanoparticles

The present paper concerns both the optimization of dexamethasone (DXM) entrapment and its release from biodegradable poly(D,L-lactide-co-glycolide) (PLGA) nanoparticles prepared by the solvent evaporation process. Since the addition of DXM induced the formation of drug crystals beside the nanoparticle suspension, the influence of several parameters on DXM encapsulation was investigated such as the type of organic solvent and polymer, the DXM initial mass, the evaporation rate of the solvent, the continuous phase saturation and the incorporation of a lipid in the polymer. Nanoparticle size and zeta potential were not modified in the presence of DXM and were respectively around 230 nm and -4 mV. The highest drug loading was obtained using 100 mg PLGA 75:25 in a mixture of acetone-dichloromethane 1:1 (v:v) and 10 mg of DXM. The drug was completely released from this optimized formulation after 4 h of incubation at 37 degrees C. Neither the evaporation rate of the organic solvent, nor the aqueous phase saturation with salt or the incorporation of 1mg 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) within the nanoparticles modified the encapsulation efficiency. Differential scanning calorimetry (DSC) and X-ray diffraction (XRD) demonstrated that the drug was molecularly dispersed within the nanoparticles whereas the non-encapsulated DXM crystallized. These results demonstrate the feasibility of encapsulating dexamethasone and its subsequent delivery.     

The Effect of Carrier-Drug Ratios on Dissolution Performances of Poorly Soluble Drug in Crystalline Solid Dispersion System

The choice of carrier and drug ratio are critical factors as far as the type of solid dispersion is concerned. Amorphous solid dispersion has been cited as the most desirable type among the different types of solid dispersion due to the benefit of amorphicity in increasing the drug solubility of a poorly soluble drug. Recent reports delineated that a partially crystalline solid dispersion system may perform better due to the inherent issue of solution mediated recrystallisation of a completely amorphous system. In oppose to the conventional choice of using amorphous polymer, this study aimed to investigate the use of a crystalline carrier, polyethylene glycol (PEG) for dissolution enhancement of a model poorly soluble drug, Flurbiprofen (FBP), a BCS Class II candidate. Solid dispersions of different FBP to PEG 6000 molar ratios via solvent evaporation were prepared. Physical characterisation of preparations was performed using differential scanning calorimetry (DSC), attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR) and optical microscope. DSC and ATR-FTIR analyses suggest the obtained solid dispersion exhibits crystalline FBP. This is then supported by the optical microscope analysis as the birefringence of crystals was noted. Further increasing the drug-carrier molar ratio to one-to-three and one-to-six showed that there was an amorphous FBP constituent in the system. DSC analysis revealed the melting point depression of FBP by the carrier which signifies interaction between the drug and polymer. Dissolution study showed the solid dispersion of FBP improves the drug solubility and drug release compared to the pure drug. A higher carrier ratio in the formulation results in a higher drug release.     

Novel lectin-modified poly(ethylene-co-vinyl acetate) mucoadhesive nanoparticles of carvedilol: preparation and in vitro optimization using a two-level factorial design

Abstract

Carvedilol used in cardiovascular diseases has systemic bioavailability of 25–35%. The objective of this study was production of lectin-modified poly(ethylene-co-vinyl acetate) (PEVA) as mucoadhesive nanoparticles to enhance low oral bioavailability of carvedilol. Nanoparticles were prepared by the emulsification-solvent evaporation method using a two-level factorial design. The studied variables included the vinyl acetate content of the polymer, drug and polymer content. Surface modification of PEVA nanoparticles with lectin was carried out by the adsorption method and coupling efficiency was determined using the Bradford assay. Mucoadhesion of nanoparticles was studied on mucin. The particle size, polydispersity index, zeta potential, drug loading and drug release from nanoparticles were studied. The morphology of nanoparticles and crystalline status of the entrapped drug were studied by SEM, DSC and XRD tests, respectively. Results showed the most effective factor on particle size and zeta potential was the interaction of polymer and drug content while, drug loading efficiency and mucoadhesion were more affected by the interaction of polymer type and drug content. Drug concentration was the most effective variable on the drug release rate. The drug was in amorphous state in nanoparticles. The optimum nanoparticles obtained by 45?mg of copolymer contained 12% vinyl acetate/4.3?ml of organic phase and drug concentration of 37.5?wt% of polymer.     

Copolymers of pharmaceutical grade lactic acid and sebacic acid: drug release behavior and biocompatibility.

Pharmaceutical grade D,L-lactic acid, which is rather an economic source in comparison to lactide monomer, was utilized for synthesis of a series of copolymers with sebacic acid. Polymers were characterized by GPC, FTIR, NMR and DSC techniques, and formulated into blank and methotrexate (MTX) loaded microspheres by emulsion-solvent evaporation method. In vitro degradation of blank microspheres was studied by FTIR, GPC and SEM analysis. MTX loaded microspheres showed the encapsulation efficiency of 44-64% and were in the size range of 40-60 microm. These were used to study the release profile of the encapsulated drug. The release was found to be affected by the pH and buffer concentration of the release medium which was in turn revealed by solubility studies of MTX. The overall study demonstrates significance of drug as well as polymer properties on release. Biocompatibility of polymer was evaluated by injecting microspheres subcutaneously into Sprague-Dawley (SD) rat and no local histopathological abnormalities were found.     

Experimental design and desirability function approach for development of novel anticancer nanocarrier delivery systems

The therapeutic effects of anticancer drugs would highly improve if problems with low water solubility and toxic adverse reactions could be solved. In this work, a full factorial experimental design was used to develop a polymeric nanoparticulate delivery system as an alternative technique for anticancer drug delivery. Nanoparticles containing tamoxifen citrate were prepared and characterized using an O/W emulsification-solvent evaporation technique and different analytical methods. Scanning Electron Microscopy (SEM), particle size analysis and High Pressure Liquid Chromatography (HPLC) were used for characterization of nanoparticles. Nanoparticles' characteristics including size, size distribution, drug loading and the efficiency of encapsulation were optimized by means of a full factorial experimental design over the influence of four different independent variables and desirability function using Design-Expert software. The resulting tamoxifen loaded nanoparticles showed the best response with particle sizes less than 200 nm, improved encapsulation efficiency of more than 80% and the optimum loading of above 30%. The overall results demonstrate the implication of desirability functionin experimental design as a beneficial approach in nanoparticle drug delivery design.     

Influence of microencapsulation method and peptide loading on formulation of poly(lactide-co-glycolide) insulin nanoparticles

Insulin stability during microencapsulation and subsequent release is essential for retaining its biological activity. Therefore we investigated a novel solid/oil/water anhydrous encapsulation method with a combination of stabilizers for maintaining the integrity of insulin during formulation and delivery. Two methods were used for preparation of nanoparticles, namely water/oil/water solvent evaporation and s/o/w anhydrous encapsulation to study the influence of the microencapsulation method on nanoparticle characteristics such as size and morphology, drug content, encapsulation efficiency, and in vitro and in vivo release profile. Poly (lactic-co-glycolic) acid (PLGA) with co-polymer ratio 50:50 was selected to prepare drug-loaded nanoparticles. When nanoparticles were prepared by solvent evaporation higher encapsulation efficiencies could be obtained, e.g. 74 +/- 13 with 5% target loading, whereas with 12% target loading, encapsulation efficiency was 27 +/- 8.6. The s/o/w method has a direct influence on the evaluation parameters where very poor encapsulation efficiencies 11 +/- 6.8 (max) were observed. The presence of stabilizers in the nanoparticles resulted in an increase in particle size but a reduction of encapsulation efficiency. Insulin release rate was comparatively higher for the batches prepared by the w/o/w method containing stabilizers than the s/o/w method. Also the presence of stabilizers resulted in sustained release of insulin resulting in prolonged reduction of blood glucose levels in streptozotocin induced diabetic rats. From the in vitro and in vivo studies, it can be concluded that careful selection of processing conditions and combination of stabilizers also result in beneficial effects without compromising the advantages of these delivery systems.     

Effect of processing temperature on Eudragit RS PO microsphere characteristics in the solvent evaporation process

Eudragit RS PO microspheres containing stavudine as a model drug were prepared by the solvent evaporation method using acetone liquid paraffin system. The influence of processing temperature: 10, 30 and 40 degrees C on various parameters like particle shape, size distribution, drug loading, drug polymer interaction and release kinetic were studied. It was found that at lower temperature (10 degrees C) small particles of irregular size, rough and wrinkled surface were formed, whereas higher temperature gradually increases the particle size as well as improves the shape and smoothness of microspheres. It was found that temperature had no effect on encapsulation efficiency and drug polymer compatibility. Drug release rate from microspheres were found to be a function of mean particle size distribution.     

Copolymers of pharmaceutical grade lactic acid and sebacic acid: Drug release behavior and biocompatibility

Pharmaceutical grade d,l-lactic acid, which is rather an economic source in comparison to lactide monomer, was utilized for synthesis of a series of copolymers with sebacic acid. Polymers were characterized by GPC, FTIR, NMR and DSC techniques, and formulated into blank and methotrexate (MTX) loaded microspheres by emulsion-solvent evaporation method. In vitro degradation of blank microspheres was studied by FTIR, GPC and SEM analysis. MTX loaded microspheres showed the encapsulation efficiency of 44–64% and were in the size range of 40–60 μm. These were used to study the release profile of the encapsulated drug. The release was found to be affected by the pH and buffer concentration of the release medium which was in turn revealed by solubility studies of MTX. The overall study demonstrates significance of drug as well as polymer properties on release. Biocompatibility of polymer was evaluated by injecting microspheres subcutaneously into Sprague–Dawley (SD) rat and no local histopathological abnormalities were found.     

Solubility of Small-Molecule Crystals in Polymers: <Emphasis Type="SmallCaps">d</Emphasis>-Mannitol in PVP,Indomethacin in PVP/VA,and Nifedipine in PVP/VA

Objective  Amorphous pharmaceuticals, a viable approach to enhancing bioavailability, must be stable against crystallization. An amorphous drug can be stabilized by dispersing it in a polymer matrix. To implement this approach, it is desirable to know the drug’s solubility in the chosen polymer, which defines the maximal drug loading without risk of crystallization. Measuring the solubility of a crystalline drug in a polymer is difficult because the high viscosity of polymers makes achieving solubility equilibrium difficult. Method  Differential Scanning Calorimetry (DSC) was used to detect dissolution endpoints of solute/polymer mixtures prepared by cryomilling. This method was validated against other solubility-indicating methods. Results  The solubilities of several small-molecule crystals in polymers were measured for the first time near the glass transition temperature, including d-mannitol (β polymorph) in PVP, indomethacin (γ polymorph) in PVP/VA, and nifedipine (α polymorph) in PVP/VA. Conclusion  A DSC method was developed for measuring the solubility of crystalline drugs in polymers. Cryomilling the components prior to DSC analysis improved the uniformity of the mixtures and facilitated the determination of dissolution endpoints. This method has the potential of providing useful data for designing physically stable formulations of amorphous drugs.     

Microencapsulation using poly(DL-lactic acid) I: Effect of preparative variables on the microcapsule characteristics and release kinetics

Abstract

Poly(DL-lactic acid) (DL-PLA, molecular weight 20 500) microcapsules containing phenobarbitone (PB) as a reference core were prepared using a water/oil (W/O) emulsion system. Surface morphology, particle size and ‘encapsulation efficiency’ of the microcapsules prepared using different preparative variables have been investigated. Buffer pH 9 was used as a dissolution medium to determine the affect of preparative variables on the release rate from these microcapsules.

With an increase in temperature of evaporation the microcapsule surface became increasingly irregular and porous, due to deposition of phenobarbitone crystals near the vicinity of the microcapsule surface leading to rapid release of the core. The normalized release rate was found to increase exponentially with an increase in the temperature of evaporation. Microcapsule morphology was also severely affected due to differences in polymer concentration in the disperse phase solvent. With the increase in polymer concentration, the microcapsule surface was found to be increasingly irregular and non-continuous, due to rapid precipitation of the polymer. Increased polymer concentrations also increased mean microcapsule diameter. The release rate increased with the increase in polymer concentration due to surface defects and did not exhibit a straight line correlation. When core loading was very high (e.g. C:P, 2:1 and 1:1), crystals of phenobarbitone appeared at the surface and these caused a very rapid burst effect. However, microcapsules containing a lower phenobarbitone content were found to follow t^1/2 dependent release. The encapsulation efficiency was not seriously affected due to variations in temperature of preparation and polymer concentration. However, with the decrease in initial core loading the encapsulation efficiency of microcapsules was found to be reduced.     

Spherical crystals of celecoxib to improve solubility, dissolution rate and micromeritic properties

Celecoxib spherical agglomerates were prepared with polyvinylpyrrolidone (PVP) using acetone, water and chloroform as solvent, non-solvent and bridging liquid, respectively. The agglomerates were characterized by differential scanning calorimetry (DSC), X-ray diffraction (XRD), IR spectroscopic studies and scanning electron microscopy (SEM). The IR spectroscopy and DSC results indicated the absence of any interactions between drug and additives. XRD studies showed a decrease in crystallinity in agglomerates. The crystals exhibited significantly improved micromeritic properties compared to pure drug. The loading efficiency (% or mg drug per 100 mg crystals) was in the range of 93.9 +/- 2.3 and 97.3 +/- 1.3% (n = 3) with all formulations. The aqueous solubility and dissolution rate of the drug from crystals was significantly (p < 0.05) increased (nearly two times). The solubility and in vitro drug release rates increased with an increase in PVP concentration (from 2.5 to 10%). The SEM studies showed that the crystal posseses a good spherical shape with smooth and regular surface.     

Bupivacaine-loaded biodegradable poly(lactic-co-glycolic) acid microspheres I. Optimization of the drug incorporation into the polymer matrix and modelling of drug release

Bupivacaine has been encapsulated by solvent evaporation method based on O/W emulsion, using poly(DL-lactic-co-glycolic) acid (PLGA) 50:50. The particle size can be controlled by changing stirring rate and polymer concentration. The encapsulation efficiency was affected by polymer concentration and burst effect of bupivacaine released from particles was affected by drug/polymer mass ratio. Orthogonal design was used to optimize the formulation according to drug content, encapsulation efficiency and burst effect. The dissolution profile and release model were evaluated with two different bupivacaine microspheres (bupi-MS) groups including low drug loading (6.41%) and high drug loading (28.92%). It was observed that drug release was affected by drug loading especially the amount of drug crystal attached on surface of bupi-MS. The drug release profile of low drug loaded bupi-MS agreed with Higuchi equation and that of high drug loaded bupi-MS agreed with first order equation.     

盐酸表柔比星-聚乳酸-羟基乙酸共聚物纳米粒的制备

摘要目的制备盐酸表柔比星 聚乳酸 羟基乙酸（PLGA）共聚物纳米粒,对其进行质量评价。方法采用乳化 溶剂挥发法制备盐酸表柔比星纳米粒;对主要处方因素如PLGA用量、外水相中聚山梨酯 80用量、泊洛沙姆188和聚山梨酯 80比例进行正交设计,以药物的包封率、载药量和药物利用率等为考察指标。结果采用优化后处方制得的纳米粒药物包封率为（32.6±1.2）%,载药量为（7.2±0.5）%,药物利用率为（51.6±3.4）%,纳米粒平均粒径166.6 nm,药物可持续160 h释放。结论该方法制备盐酸表柔比星纳米粒工艺简单,无需使用聚乙烯醇,药物释放缓慢。     

Mechanisms of burst release from pH-responsive polymeric microparticles

Objectives Microencapsulation of drugs into preformed polymers is commonly achieved through solvent evaporation techniques or spray drying. We compared these encapsulation methods in terms of controlled drug release properties of prepared microparticles and investigated the underlying mechanisms responsible for the ‘burst release’ effect. Methods Using two different pH‐responsive polymers with a dissolution threshold of pH 6 (Eudragit L100 and AQOAT AS‐MG), hydrocortisone, a model hydrophobic drug, was incorporated into microparticles below and above its solubility within the polymer matrix. Key findings Although, spray drying was an attractive approach due to rapid particle production and relatively low solvent waste, the oil‐in‐oil microencapsulation method was superior in terms of controlled drug release properties from the microparticles. Slow solvent evaporation during the oil‐in‐oil emulsification process allowed adequate time for drug and polymer redistribution in the microparticles and reduced uncontrolled drug burst release. Electron microscopy showed that this slower manufacturing procedure generated nonporous particles whereas thermal analysis and X‐ray diffractometry showed that drug loading above the solubility limit of the drug in the polymer generated excess crystalline drug on the surface of the particles. Raman spectral mapping illustrated that drug was homogeneously distributed as a solid solution in the particles when loaded below saturation in the polymer with consequently minimal burst release. Conclusions Both the manufacturing method (which influenced particle porosity and density) and drug:polymer compatibility and loading (which affected drug form and distribution) were responsible for burst release seen from our particles     

Properties of poly(lactic-co-glycolic acid) nanospheres containing protease inhibitors: camostat mesilate and nafamostat mesilate

Poly(lactic-co-glycolic acid) (PLGA) nanospheres containing protease inhibitors, camostat mesilate (CM) and nafamostat mesilate (NM), were prepared by the emulsion solvent diffusion methods in water or in oil, and the w/o/w emulsion solvent evaporation method. The average diameter of PLGA nanospheres prepared in the water system were about 150-300 nm, whereas those prepared in the oil system were 500-600 nm. Among the three methods, these drugs were the most efficiently encapsulated up to 60-70% in PLGA nanospheres in the oil system. Other factors that may influence drug encapsulation efficiency and in vitro release such as drug load, molecular weight of polymer were also investigated. Both the CM- and NM-loaded nanospheres prepared in the water system immediately released about 85% of the drug upon dispersed in the release medium while the drug initial burst of nanospheres prepared by the emulsion solvent diffusion in oil method reduced to 30% and 60% for CM and NM, respectively. Poly(aspartic acid) (PAA), a complexing agent for cationic water soluble drugs, showed little effect on the encapsulation efficiency and release behavior for CM and NM. The DSC study and AFM pictures of nanospheres demonstrated that temperature-dependent drug release behavior was ascribable to the glass transition temperature of the polymer, which also affected the morphology of nanospheres upon dispersed in the release medium and influenced the drug release consequently.     

Fluconazole encapsulation in PLGA microspheres by spray-drying

Fluconazole-loaded PLGA microspheres were prepared by the spray-drying process. The influence of some process parameters on the physical characteristics of the microspheres was evaluated. Neither type nor polymer concentration influenced significantly the mean diameter of the microspheres, their size distribution and encapsulation efficiency of the drug. However, the drug loading greatly affected their size and the physical state in which fluconazole can exist in the matrix of the carriers, and, thus, affected the release rate of the drug. Results obtained by differential thermal analysis and X-ray powder diffraction revealed that at low nominal drug loading, fluconazole was incorporated in an amorphous state or in a molecular dispersion in the matrix of the microspheres and at high nominal drug loading part of the drug was in a crystalline form. Release profiles of fluconazole from the microspheres displayed a biphasic shape. The duration and extent of each phase were affected mainly by polymer nature, drug loading and physical state in which fluconazole existed in the polymeric matrix.     

色胺酮纳米胶束的制备及其性质研究

目的制备色胺酮纳米胶束,改善色胺酮的水溶性,并进行体外性质考察。方法以二硬脂酰基磷脂酰乙醇胺-聚乙二醇2000(DSPE-PEG2000)为载体,用溶剂挥发法制备色胺酮纳米胶束,通过正交实验筛选制备胶束的最佳条件,核磁共振氢谱(1 HNMR)验证色胺酮包载于纳米胶束,用芘荧光探针法测定其临界胶束浓度(CMC),用紫外分光光度计测定其包封率和载药率,动态光散射法测定胶束的粒径,以粒径、外观形态和包封率为指标考察胶束的稳定性。结果色胺酮纳米胶束的CMC为8.93×10-6mol·L~(-1),色胺酮与聚合物投药比为0.442 9∶1(mol∶mol),真空干燥1h,水化5min时,胶束的包封率为32.24%±1.37%,载药率为5.468%±0.39%。色胺酮纳米胶束平均粒径为112.5nm,平均分散系数为0.208,4℃条件下胶束可稳定15d以上。结论制备色胺酮纳米胶束,将色胺酮的溶解度提高至1.625mmol·L~(-1),为改善色胺酮生物利用度的研究奠定了基础。     

Encapsulation of hydrophobic drugs in polymeric micelles through co-solvent evaporation: the effect of solvent composition on micellar properties and drug loading

This study was designed to develop an optimized co-solvent evaporation procedure for the efficient encapsulation of hydrophobic drugs in polymeric micelles of methoxy poly(ethylene oxide)-block-poly(epsilon-caprolactone) (MePEO-b-PCL). MePEO-b-PCL block copolymers having varied MePEO and PCL molecular weights were synthesized, assembled to polymeric micelles, and used for the encapsulation of cyclosporine A (CyA) by a co-solvent evaporation method. The co-solvent composition was varied by changing the type of organic co-solvent (using acetone, acetonitrile and tetrahydrofuran), the ratio of organic to aqueous phase, and their order of addition. Carrier size, morphology and encapsulated CyA levels were defined by dynamic light scattering (DLS), transmission electron microscopy (TEM) and HPLC, respectively, and the effect of co-solvent composition on micellar properties and loaded CyA levels was evaluated. Application of acetone and acetonitrile as the selective co-solvent for the core-forming block led to a decrease in the average diameter of self-assembled structures. When acetone was added to water, a decrease in the ratio of organic to aqueous phase led to an increase in the loading efficiency of CyA in MePEO-b-PCL micelles. A similar trend in CyA loading was observed for MePEO-b-PCL micelles of varied MePEO and PCL block lengths. The ratio of organic to aqueous phase did not affect CyA loading when water was added to acetone. Irrespective of the order of addition, the decrease in the organic to aqueous phase ratio caused a reduction in the average diameter of the empty and CyA loaded micelles. We conclude that the co-solvent evaporation method may be optimized to improve the efficiency of drug encapsulation in polymeric micelles. For CyA encapsulation in MePEO-b-PCL micelles, addition of acetone to water at lower organic to aqueous phase ratio is shown to be the optimum procedure leading to higher drug encapsulation and smaller average diameter for the self-assembled structures.