Emulsion Solvent Evaporation Process Research Articles

Effect of Amount of Water in Dispersed Phase on Drug Release Characteristics of Dextran Microspheres Prepared by Emulsion-Solvent Evaporation Process

Microspheres containing theophylline (TH) were prepared from a hydrophobic dextran derivative by emulsion solvent evaporation method. The objective of this study was to evaluate the effects of poor solvent in dispersed phase on the particle properties and drug release characteristics of the microspheres. Mixtures of acetone and water were used as the dispersed phase and liquid paraffin as the continuous phase. The amount of water (poor solvent for polymer) was varied from 0.5 to 2 ml in 15 ml of dispersed phase. Drug release from the microspheres was examined using JPXIV 1st Fluid (pH 1.2) containing 0.02% Tween 20, and their structure was analyzed by scanning electron microscopy (SEM). The drug release behaviors were greatly affected by the amount of water. The percentage released until 8 h were 89% and 23% for 0.5 and 2.0 ml of water, respectively. The release mechanism shifted from Fickian diffusion to zero-order transport as the amount of water increased. According to SEM observations, TH was uniformly distributed over the entire microsphere prepared using 0.5 ml of water, and existed in the center of the microsphere, having a core-shell structure, when prepared using 2 ml of water. The amount of poor solvent in the dispersed phase was found to be a crucial factor determining the internal structure of microspheres and drug release characteristics.

Effect of temperature-increase rate on drug release characteristics of dextran microspheres prepared by emulsion solvent evaporation process

Microspheres containing theophylline (TH) were prepared from a hydrophobic dextran derivative by an emulsion solvent evaporation process using an acetone/liquid paraffin system. The effects of solvent evaporation rate on particle properties and drug release characteristic of the microspheres were evaluated. The solvent evaporation rate was controlled by the rate of increase in temperature of the water bath, ranging 7.5–30 °C/h. Drug release from the microspheres was examined using JPXIV 2nd fluid (pH 6.8) containing 0.1% Tween 80, and was found to be greatly affected by the solvent evaporation rate. The percentage of drug released until 8 h varied; from 28% to 84% for 30 and 7.5 °C, respectively. Differential scanning calorimetry and powder X-ray diffraction studies revealed that TH partially interacted with the polymer and drug crystallinity was maintained intact in the microspheres. According to scanning electron microscopy observations, all microspheres showed a well-formed spherical particle with a solid interior. The appearances of the microspheres were, however, extremely different. Microspheres prepared at 30 °C/h had a very smooth surface, while those prepared at 7.5–15 °C/h had a rough surface with large craters. These findings demonstrated that the surface morphology and drug release characteristic were controlled by the rate of increase of temperature.

Effect of Viscosity and Concentration of Wall Former, Emulsifier and Pore-Inducer on the Properties of Amoxicillin Microcapsules Prepared by Emulsion Solvent Evaporation

This study reports the laboratory optimization for the preparation of sustained release amoxicillin (AMX) ethylcellulose microcapsules by an emulsion solvent evaporation process by adjusting the viscosity and concentration of ethylcellulose, ratio of amoxicillin to ethylcellulose, and concentration of emulsifier and pore inducer. When ethylcellulose with a viscosity of 45 mPa·s was used, almost no material stuck to the inside wall of the beaker and uniform microcapsules were prepared. The average diameter of microcapsules increased and yield and release rate decreased as the concentration of ethylcellulose increased from 1% to 8%. The release of amoxicillin from microcapsules was influenced by the ratio of the weight of drug to that of ethylcellulose and ratios of 2:1 and 4:1 were most suited for optimum amoxicillin release. The average diameter of microcapsules decreased and the release rate increased as the concentration of the emulsifier increased from 1.5% to 6.0%, however, the size distribution became significantly wider with the increase in the concentration of sorbitan monooleate. Addition of small amounts of a water-soluble agent sucrose improved the release of active ingredient from the microcapsule matrix without influencing the morphology and particulate properties of the microcapsules.

The effect of some processing conditions on the characteristics of biodegradable microspheres obtained by an emulsion solvent evaporation process

Unloaded microspheres were prepared from polyhydroxybutyrate (PHB) and polyhydroxybutyrate-co-valerate (PHB-HV) polymers using an oil-in-water emulsion solvent evaporation method. The study was conducted to evaluate how the polymer and some process parameters affect properties of the final microspheres such as particle size, superficial area, zeta potential, surface morphology and microsphere degradation. The variables included surfactant concentration in the emulsion water phase and solvent composition. From the results, it was found that the parameters affecting microsphere size the most were surfactant concentration in the emulsion water phase and solvent composition. Properties such as zeta potential, surface area and surface morphology remained pratically unchanged over the range of the processing conditions studied here.

Preparation and characterization of temperature-sensitive poly(N-isopropylacrylamide)-b-poly(D,L-lactide) microspheres for protein delivery.

Temperature-sensitive diblock copolymers, poly(N-isopropylacrylamide)-b-poly(D,L-lactide) (PNIPAAm-b-PLA) with different PNIPAAm contents were synthesized and utilized to fabricate microspheres containing bovine serum albumin (BSA, as a model protein) by a water-in-oil-in-water double emulsion solvent evaporation process. XPS analysis showed that PNIPAAm was a dominant component of the microspheres surface. BSA was well entrapped within the microspheres, and more than 90% encapsulation efficiency was achieved. The in vitro degradation behavior of microspheres was investigated using SEM, NMR, FTIR, and GPC. It was found that the microspheres were erodible, and polymer degradation occurred in the PLA block. Degradation of PLA was completed after 5 months incubation in PBS (pH 7.4) at 37 degrees C. A PVA concentration of 0.2% (w/v) in the internal aqueous phase yielded the microspheres with an interconnected porous structure, resulting in fast matrix erosion and sustained BSA release. However, 0.05% PVA produced the microspheres with a multivesicular internal structure wrapped with a dense skin layer, resulting in lower erosion rate and a biphasic release pattern of BSA that was characterized with an initial burst followed by a nonrelease phase. The microspheres made from PNIPAAm-b-PLA with a higher portion of PNIPAAm provided faster BSA release. In addition, BSA release from the microspheres responded to the external temperature changes. BSA release was slower at 37 degrees C (above the LCST) than at a temperature below the LCST. The microspheres fabricated with PNIPAAm-b-PLA having a 1:5 molar ratio of PNIPAAm to PLA and 0.2% (w/v) PVA in the internal aqueous phase provided a sustained release of BSA over 3 weeks in PBS (pH 7.4) at 37 degrees C.

Potential Applications of Polymeric Microsphere Suspension as Subcutaneous Depot for Insulin

The objective of this investigation was to develop an injectable, depot-forming drug delivery system for insulin based on microparticle technology to maintain constant plasma drug concentrations over prolonged period of time for the effective control blood sugar levels. Formulations were optimized with two well-characterized biodegradable polymers namely, poly(dl-lactide-co-glycolide) and poly-ε-caprolactone and evaluated in vitro for physicochemical characteristics, drug release in phosphate buffered saline (pH 7.4), and evaluated in vivo in streptozotocin-induced hypoglycemic rats. With a large volume of internal aqueous phase during w/o/w double emulsion solvent evaporation process and high molecular weight of the polymers used, we could not achieve high drug capture and precise control over subsequent release within the study period of 60 days. However, this investigation revealed that upon subcutaneous injection, the biodegradable depot-forming polymeric microspheres controlled the drug release and plasma sugar levels more efficiently than plain insulin injection. Preliminary pharmacokinetic evaluation exhibited steady plasma insulin concentration during the study period. These formulations, with their reduced frequency of administration and better control over drug disposition, may provide an economic benefit to the user compared with products currently available for diabetes control.

Effects of solvent evaporation rate on the properties of protein-loaded PLLA and PDLLA microspheres fabricated by emulsion-solvent evaporation process

This paper investigated the effects of the rate of solvent removal by varying the ambient pressure at a fixed temperature on the morphology, particle size, encapsulation efficiency and release pattern of albumin-loaded PLLA and PDLLA microspheres, prepared by the W/O/W emulsion-solvent evaporation process. For PLLA microspheres prepared either with a fast rate of solvent evaporation (FRSE) or a normal rate of solvent evaporation (NRSE) process, the difference in morphology was minor. In contrast, the different processes did affect the morphology of PDLLA microspheres. Large (surface) pores were observed for PDLLA microspheres fabricated with a FRSE process, while a smooth surface was seen in those with a NRSE process. With the FRSE process, both PLLA and PDLLA microspheres showed smaller particle sizes and lower albumin encapsulation efficiencies than those prepared in the NRSE process. PLLA microspheres prepared with the NRSE process had higher drug encapsulation efficiencies than PDLLA ones, but this was not the case for the FRSE process. An initial burst release of albumin was observed for both PLLA and PDLLA microspheres prepared with the NRSE process, while a lesser burst release was seen for those prepared with the FRSE process. In subsequent stages of drug release, PLLA microspheres prepared with the two different processes showed differences, but this was not the case for PDLLA ones.

A novel in vitro delivery system for assessing the biological integrity of protein upon release from PLGA microspheres.

The development of a novel in vitro system is required to assess the stability and release kinetics of a protein microsphere formulation used for drug delivery to the brain. Microspheres containing lysozyme as model protein were prepared using a (w/o/w) emulsion-solvent evaporation process. Both the active and total (active + inactive) encapsulation efficiencies and release profiles were determined. The biologic activity of lysozyme was measured using bacterial cell lysis; total protein content was measured using a 125I-radiolabel. A novel in vitro apparatus was developed to determine kinetics over a sustained time period (>30 days). The microencapsulation technique allowed an entrapment of active lysozyme at 80 +/- 4% and a sustained (>42 days) in vitro release. The kinetics study showed that the novel in vitro system was able to detect the release of low amounts (ng) of protein. To improve the stability of the protein within microspheres and allow the release of biologically active lysozyme, a basic additive ( Mg(OH)2 ) was successfully encapsulated. This novel in vitro system was appropriate to study protein microsphere release kinetics. In addition, the model is cost-effective and mimes brain physiological conditions more closely than previous models.

Polymers for biodegradable medical devices XI. Microencapsulation studies: characterization of hydrocortisone-loaded poly-hydroxybutyrate-hydroxyvalerate microspheres

Hydrocortisone-loaded monolithic microspheres were prepared, using a single emulsion solvent evaporation process, from a range of poly- #103 -hydroxybutyrate-hydroxyvalerate copolymers in which both molecular weight and hydroxyvalerate content were varied. Many similarities were observed in the effects of process parameters and co-polymer composition on the morphologies of the microspheres, and the morphologies of microcapsules prepared (and previously reported) by a double emulsion process. The yields of the single emulsion process were generally superior to those of the double emulsion process, although these were adversely affected by hydrocortisone incorporation as the molecular weight of the copolymer was reduced. The predominant effect of hydrocortisone incorporation was on polymer morphology, characterized by the appearance of small surface pores; an effect which increased with increasing drug loading. Changes in polymer molecular weight, copolymer composition and process temperature, together with the incorporation of polycaprolactone in the form of a solvent blend, enabled microspheres with a range of morphologies to be produced providing the potential for control of drug release.

Effects of the rate of solvent evaporation on the characteristics of drug loaded PLLA and PDLLA microspheres

We investigated the effects of the rate of solvent removal by varying ambient pressure at a fixed temperature on the morphology, particle sizes, drug encapsulation efficiency and releases pattern of lidocaine loaded poly- l-lactatide (PLLA) and poly- d,l-lactatide (PDLLA) microspheres, prepared with O/W emulsion–solvent evaporation process. Prepared in the fast rate of solvent evaporation (FRSE) process by reducing ambient pressure, smoothly morphological surface of drug loaded PLLA and PDLLA microspheres was observed. While in the normal rate of solvent evaporation (NRSE) process, roughness or pinhole surface was only found at drug loaded PLLA microspheres. Fabricated in the FRSE process, both PLLA and PDLLA microspheres showed smaller particle sizes and lower drug encapsulation efficiencies than those prepared in NRSE process. In regard to two materials, PLLA microspheres had higher drug encapsulation efficiencies than PDLLA ones for both processes. Although initial burst releases of drug were observed for both PLLA and PDLLA microspheres prepared in whatever solvent removal process, drug release for PLLA microspheres was slightly less than that for PDLLA ones in the earlier stage of drug release. However, in the subsequent stage of drug release, there was no difference between two materials. In corporation with different crystalline characteristics of PLA polymer and its derivatives, FRSE process by reducing ambient pressure could be further applied to produce different characteristics of microspheres for drug delivery.

Studies on the in vitro release characteristics of ibuprofenloaded polystyrene microparticles

Ibuprofen-loaded polystyrene microparticles were prepared by the emulsionsolvent evaporation process from an aqueous system. The effects of different parameters on the drug content and on the release of the drug from the microparticles were investigated. The drug content, in all the formulations, was less than the theoretical drug loading. The lower drug content was due to drug partitioning to the external aqueous phase during formulation. Statistical analysis revealed that the variation in the concentrations of the emulsion stabilizer and the organic disperse phase volume did not significantly alter the release of the drug. Although an increase in drug loading increased drug release from the microparticles, a biphasic linear relationship was observed between the time required for 50% drug release and the drug loading. The effect of size of the microparticles on drug release was more important for the low drug-loaded microparticles than that for the high drug-loaded microparticles. Such release behaviour from the microparticles was explained on the basis of the morphological structure of the microparticles.

Novel bioresorbable and bioeliminable surfactants for microsphere preparation.

The objective of this work is to prepare microspheres by the emulsion-solvent evaporation process using MPOE-PLA copolymers as the matrix material and/or the surfactant. This preparation was studied in order to avoid the use of PVA as the surfactant in the process. Two series of MPOE-PLA copolymers were synthesised. The first, with a long and constant length PLA chain (45,000 g.mol(-1), was used as the matrix material, the second, with short PLA chains (< or = 2.200 g.mol(-1)), and different HLB as the surfactant. Microspheres were prepared by the "simple" and "double" emulsion methods. The steric stabilization effect of the copolymers was investigated using confocal microscopy and X-ray photoelectron spectroscopy (XPS). Confocal microscopy and XPS analysis showed that the microspheres prepared using MPOE5K-PLA0.5K as the surfactant and MPOE-PLA45K copolymers as the matrix material had an MPOE coating present at the microsphere surface. This hydrophilic layer ensures steric stabilization of the particles. MPOE-PLA copolymers can be used for the preparation of particles instead of PVA and their use can be extended whenever a biocompatible and bioeliminable surfactant is required for biological or medical applications.

Degradation of porous poly(anhydride- co-imide) microspheres and implications for controlled macromolecule delivery

The degradation properties of porous microspheres made using a new family of polyanhydride copolymers, the poly(anhydride- co-imides), were studied. Poly[trimellitylimido- l-tyrosine- co-sebacic acid- co-1,3-bis(carboxyphenoxy)propane] microspheres, with and without entrapped bovine serum albumin (BSA) as a model protein, were made using the double emulsion solvent evaporation process. Water penetration and anhydride bond cleavage (polymer degradation) occurred rapidly (<5 days) compared to the time scale of overall microsphere erosion (weeks to months) with most polymer compositions. Subsequent to bond cleavage, the ultimate erosion of the microsphere and release of entrapped BSA was due mainly to the slow dissolution of the individual hydrophobic monomers (TMA-Tyr, SA and CPP) from the microsphere surface. BSA was released at approximately the same rate as the polymer eroded. Due to the fast degradation of anhydride bonds relative to microsphere erosion, initial polymer molecular weight did not have a significant effect on macromolecule release rates. Instead, monomer solubility correlated well with polymer erosion and BSA release rates. This erosion mechanism leads to predictable drug release rates which may be appropriate for the delivery of many protein therapeutics, including vaccine antigens. The anhydride–imide copolymers were well tolerated in acute toxicity studies in rats and therefore show promise as biomaterials.

Instability of bovine insulin in poly(lactide-co-glycolide) (PLGA) microspheres.

Biodegradable poly(lactide-co-glycolide) (PLGA; 50/50) microspheres containing bovine insulin as a model protein was prepared by an oil-in-oil (o/o) emulsion solvent evaporation process. When aluminum tristearate (0.15% (w/v)) was employed as a dispersing agent, the loading efficiency of insulin was almost 100% and the yield was over 80%. The average diameter of the PLGA microspheres always ranged between 100 and 200 microns. Morphology study using a scanning electron micrograph showed smooth, spherical, fairly monodispersed PLGA microspheres containing insulin. In relation to release profile, the very low release rate of insulin was demonstrated (only 1% of insulin released after 7 d release test in pH 7.4 Tris buffer) for the PLGA microspheres. Nevertheless, the degradation of bovine insulin in PLGA microspheres was confirmed by high performance liquid chromatography. This degradation seemed to be caused by an acidic condition caused by poly(lactide-co-glycolide) polymer.

In VitroRelease of Disopyramide from Cellulose Acetate Butyrate Microspheres

AbstractDisopyramide was microencapsulated with cellulose acetate butyrate (CAB) using an emulsion-solvent evaporation process. Drug dissolution from microcapsules was studied in both simulated gastric (SGF) and intestinal fluids (SIF) under sink conditions using the USP paddle method. There was no significant difference between drug release into SIF and SGF. As the CAB to drug ratio decreased from 3:1 to 2:1 at constant polymer mass, the drug release rate increased and the T50Y0 decreased from 2.3 hr to 0.3 hr for 303 pm particles. Dissolution T50% increased from 0.4 hr to 2 hr when the mean microcapsule size was increased from 153 to 428 μm (26% drug loading). The addition of acetone to the external phase during preparation shifted the size distribution toward larger particles, but resulted in a higher drug dissolution rate for a given particle size range. A shift to smaller particles was obtained upon increasing the concentration of surfactant. The dissolution profiles were described by the Higuchi and...

Polymers for biodegradable medical devices. X. Microencapsulation studies: control of poly-hydroxybutyrate-hydroxyvalerate microcapsules porosity via polycaprolactone blending.

Reservoir-type microcapsules were prepared using a double emulsion solvent evaporation process from a range of different poly-beta-hydroxybutyrate homopolymers and copolymers thereof with 3-hydroxyvalerate (P(HB-HV) polymers) blended with 20 per cent by weight of poly-epsilon-caprolactone (PCL). Microcapsules prepared from these P(HB-HV)/20 per cent PCL blends had very different typical surface morphologies from those prepared from the corresponding unblended P(HB-HV) polymers. At this blend ratio the effects of polymer blending on particle morphology were clearly dependent on the molecular weight of P(HB-HV) polymer and, to a reduced extent, the 3-hydroxyvalerate content. Microcapsules were also prepared from blends of a high molecular weight P(HB-HV) polymer with PCL in which the proportion of the latter was varied from 0 to 100 per cent at 10 per cent intervals. Increasing the proportion of PCL from 0 to 50 per cent produced a systematic and dramatic increase in microcapsule porosity; with only skeletal particles being generated from the even 50-50 blend. When the proportion of PCL in the blends was increased from 50 to 70 per cent the level of particle porosity diminished, and at 80 per cent or above the microcapsules were essentially smooth and non-porous.

Preparation of poly (D,L) lactide microspheres by emulsion-solvent evaporation, and their clinical applications as a convenient embolic material.

The aim of preoperative embolization is to facilitate surgical removal by reducing tumor volume and vascularity, thereby decreasing blood loss during surgery. In a search for a better embolic material, compared to heterogeneous commercial products, we describe here in detail the preparation of poly (D,L) lactide microspheres by an emulsion-solvent evaporation process. The size distribution of the microparticles and their aggregation state--critical parameters in view of such application--have been investigated. Their effectiveness, as an embolic material, has been evaluated by some preliminary experiments undertaken on humans. The results were assessed on clinical and histological grounds.

The influence of temperature upon the reflection of X-rays by calcite

Acrylic enteric microparticles for oral drug delivery were prepared by an oil-in-oil emulsion solvent evaporation process. The novel use of sorbitan sesquioleate as a surfactant produced Eudragit L55, L and S (pH thresholds of 5.5, 6 and 7, respectively) microparticles of good morphology (spherical, smooth surfaced), size (<100 μm) and size uniformity. The process was efficient (yield approximately 90%) and the encapsulated model drug (prednisolone) was in the amorphous form. The Eudragit L and S microparticles showed excellent pH-responsive drug release in dissolution studies (negligible drug release at pH 1.2; rapid drug release above the polymers’ pH thresholds). In contrast, Eudragit L55 particles aggregated in fluid and showed poor control of drug release. In vivo in rats, Eudragit L microparticles released their drug load rapidly (Tmax < 1 h) and the Cmax and AUC were higher than those of a control suspension of prednisolone. Drug absorption from Eudragit S microparticles was low which was attributed to the fact that the threshold pH of Eudragit S was not reached in the rat intestine and drug release was therefore incomplete. It was concluded that although the rat is an inappropriate model for the investigation of Eudragit S microparticles, the positive results seen with the Eudragit L microparticles indicate its potential use in pH-targeted drug delivery.