Microencapsulation using poly (L-lactic acid) III: Effect of polymer molecular weight on the microcapsule properties

Poly (L-lactic acid) microcapsules were prepared using an emulsification and organic solvent evaporation technique (w/o system) with phenobarbitone as a reference core. Three polymers of different molecular weight (61,300; 43,200, 2400), were used to prepare different core loaded microcapsules. Microcapsule size increased with increase in polymer molecular weight. Microcapsule size was also found to increase with increase in core loading with the two high molecular weight polymers, whilst the low molecular weight polymer tended to aggregate to form larger microcapsules than expected. The calculated microcapsule density was found to decrease with an increase in the polymer molecular weight and core loading. 'Encapsulation efficiency' was reduced with the decrease in initial theoretical core loading. However, the phenobarbitone content of the microcapsules was not affected by the difference in polymer molecular weight. Significant morphological differences were observed due to variations in the polymer molecular weight. The two high molecular weight polymers were found to produce non-uniform, porous microcapsules, whilst low molecular weight polymer formed a uniform non-porous surface when core loading was low. With increasing core loading, an increasing number of phenobarbitone crystals were observed on the surface and microcapsules became increasingly porous. This was more evident after release of the drug. Differential scanning calorimetry of the microcapsules showed thermal events for both the polymer and phenobarbitone.     

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

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 t1/2 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.     

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.     

Microencapsulation using poly(L-lactic acid) IV: Release properties of microcapsules containing phenobarbitone

Microcapsules containing phenobarbitone were prepared from poly(L-lactic acid), using a water/oil emulsification and evaporation process. Polymers of three different molecular weights were used. Particle size was found to increase with an increase in core loading and polymer molecular weight. Release studies were carried out at buffer pHs of 2 and 9 at 37 degrees C. The release mechanism was found to follow a square root of time relationship. Almost 90 per cent of the phenobarbitone was released within 2 h. The release rate was not a direct relationship with the phenobarbitone content of the microcapsules because of the differing size and surface area of the microcapsules. However, normalized release rates (release rate/specific surface area) were found to increase linearly with the increase in phenobarbitone content. First order release plots of the data were not found consistent with the core loading. The release at a buffer pH of 9 was very rapid and with some microcapsules was faster than solution of the uncoated crystalline phenobarbitone. At pH 2 release was also very rapid, due to the presence of large pores in the microcapsules of high molecular weight polymers. Release from the microcapsules prepared from low molecular weight polymer was slower than those from high molecular weight polymers. Microcapsules from the low molecular weight polymer were found to swell in the dissolution medium and finally disintegrated into smaller fragments.     

Microencapsulation using poly (L-lactic acid) II: Preparative variables affecting microcapsule properties

Poly (L-lactic acid) [L-PLA] microcapsules containing phenobarbitone were prepared from a w/o emulsion system, using light liquid paraffin as the continuum and a solution of phenobarbitone and L-PLA in acetonitrile as the disperse phase. Increasing stirring rate and emulsifying agent concentration were found to reduce microcapsule size. Spans (sorbitan esters of fatty acids) and Brijs (polyoxy ethylene ethers of fatty acids) with different physicochemical properties have been found to produce microcapsules of differing size. An attempt has been made to correlate emulsifier properties and the corresponding microcapsule size. It was found that the emulsifiers had little or no effect on the interfacial tension between light liquid paraffin and acetonitrile and there was no correlation between HLB of the emulsifiers and the resulting microcapsule size. It was postulated that microcapsule size would be affected by the packing of the emulsifier at the interface which would depend on the structure of the emulsifier. Closer, more uniform packing by the straight chain saturated fatty acid containing emulsifiers produced smaller microcapsules than when lose packing, which existed when emulsifiers containing either three fatty acid chains or a 'V' shaped cis-double bond containing fatty acid chain, were used. Microcapsule size was found to increase rapidly with an increase in polymer concentration, if this polymer concentration was increased in conjunction with an increase in the total solid content of the dispersed phase. Increases in polymer concentration by reducing the quantity of solvent for the dispersed phase caused little increase in mean microcapsule size. The phenobarbitone content in the microcapsules was not affected significantly by variations in the preparative parameters.     

Microencapsulation using poly(DL-lactic acid). IV: Effect of storage on the microcapsule characteristics

Poly (DL-lactic acid) [DL-PLA] microcapsules containing phenobarbitone were prepared using a W/O emulsion method. Microcapsules of nominal C : P ratio, 1 : 2 and 1 : 3 using three different molecular weight polymers, 20,500, 13,300 and 5,200 were investigated to study the effect of storage conditions on the microcapsule properties. All microcapsules were stored under desiccated condition at temperatures of 4 degrees, 20 degrees and 37 degrees C for six months. Storage temperatures of 4 degrees and 20 degrees C did not cause appreciable changes in the release rate after storage. Microcapsules stored at 37 degrees C showed an annealing effect, causing shrinkage of microcapsules, and lowering of the release rate after storage for six months. The microcapsules prepared from low molecular weight DL-PLA fused completely whilst stored at 37 degrees C and the other two high molecular DL-PLA also showed some aggregation. There were insignificant variations in the mean microcapsule diameter during storage. The phenobarbitone content of the microcapsules was also unchanged.     

Microencapsulation using poly(DL-lactic acid). III: Effect of polymer molecular weight on the release kinetics

Poly(DL-lactic acid) [DL-PLA] microcapsules containing phenobarbitone (PB) were prepared using a w/o emulsion-evaporation method. DL-PLA of three different molecular weights, 20,200, 13,300 and 5,200 were used to prepare microcapsules of nominal core: polymer (C:P) ratios of 1 : 2, 1 : 2.5, 1 : 3 and 1 : 4. The release of PB was investigated in aqueous buffer of pH 2, pH 7 and pH 9 at 37 degrees C and found to follow a square root of time dependent release mechanism. The first order and zero order release mechanisms were disproved by the lower correlation coefficient of the release data as compared to that of the t1/2 mechanism. These microcapsules showed an initial burst phase release followed by a lag phase, during which time little PB was released. This lag time was affected by the polymer molecular weight and pH of the buffer. The polymer matrix was hydrated during the lag phase and a steady state release occurred. The steady state release rate per unit specific surface area (Kh2/SSA) was found to increase exponentially with the increase in core loading of the microcapsules. However the extent of normalized release rate reduced linearly with the increase in polymer molecular weight at any particular core loading (e.g. 20 per cent or 30 per cent). Increases in the normalized steady state release rate with an increase in buffer pH could be correlated to PB solubility in the dissolution medium. PB release from these microcapsules was diffusion controlled. However, swelling and erosion also contributed to the release process.     

Dissolution from tablets prepared using ethyl cellulose microcapsules

Microcapsules containing sodium phenobarbitone cores in ethyl cellulose have been used to prepare tablets at from 3·9 to 358·9 MPa compression pressures. The tensile strength of these tablets is related linearly to the core: wall ratio and to the microcapsule size. Dissolution of the drug from the microcapsules is also related to the core: wall ratio and microcapsule size, but except at low compression pressures is almost independent of the pressure used during preparation. The tablet matrix remains intact during the dissolution and the equations developed by Schwartz, Simonelli & Higuchi (1968) are followed. Large microcapsules of 1:2 core:wall ratio produce friable tablets with rapid release of contents.     

Microenvironment-Controlled Encapsulation (MiCE) Process: Effects of PLGA Concentration,Flow Rate,and Collection Method on Microcapsule Size and Morphology

Purpose To evaluate the real-time effects of formulation and instrumental variables on microcapsule formation via natural jet segmentation, a new microencapsulation system termed the microenvironment-controlled encapsulation (MiCE) process was developed. Methods A modified flow cytometer nozzle hydrodynamically focuses an inner drug and outer polymer solution emanating from a coaxial needle assembly into a two-layer compound jet. Poly(lactic-co-glycolic acid) (PLGA) dissolved in a water-miscible organic solvent resulted in formation of reservoir-type microcapsules by interfacial phase separation induced at the boundary between the PLGA solution and aqueous sheath. Results The MiCE process produced microcapsules with mean diameters ranging from 15–25 μm. The resultant microcapsule size distribution and number of drug cores existing within each microcapsule was largely influenced by the PLGA concentration and microcapsule collection method. Higher PLGA concentrations yielded higher mean diameters of single-core microcapsules. Higher drug solution flow rates increased the core size, while higher PLGA solution flow rates increased the PLGA film thickness. Conclusion The MiCE microencapsulation process allows effective monitoring and control of the instrumental parameters affecting microcapsule production. However, the microcapsule collection method in this process needs to be further optimized to obtain microcapsules with desired morphologies, precise membrane thicknesses, high encapsulation efficiencies, and tight size distributions.     

Preparation of double-encapsulated microcapsules for mitigating drug loss and extending release

The double-encapsulated microcapsules were prepared by the non-solvent addition, phase-separation method to form core material and, encapsulated with the O/W emulsion non-solvent addition method to increase drug loading and regulate drug release rate. The drug used was theophylline, which is watersoluble. Dichloromethane and n-hexane were used as the solvent and non-solvent, respectively. This study investigated how various core material and microcapsule EC/TH ratios affect the drug loss, particle size, surface morphology and release rate. The drug loss of the double-encapsulated microcapsules was 12.8% less than that of microcapsules prepared by the O/W emulsion non-solvent addition method alone. The particle size of these double-encapsulated microcapsules decreased as the concentration of EC polymer was increased in the second encapsulation process. The roughness of their surface was also in proportion to the concentration of polymer solution used in the second encapsulation process. The dissolution study showed that the T 20 of the double-encapsulated microcapsules ranged from 2-35.4 h, while that of the O/W emulsion non-solvent addition method microcapsules was from 2.7-7.7 h. The greater the level of EC in the polymer solution, the slower the release rate of the drug from the microcapsules when the EC was not over the critical amount.     

Preparation of double-encapsulated microcapsules for mitigating drug loss and extending release.

The double-encapsulated microcapsules were prepared by the non-solvent addition, phase-separation method to form core material and, encapsulated with the O/W emulsion non-solvent addition method to increase drug loading and regulate drug release rate. The drug used was theophylline, which is water-soluble. Dichloromethane and n-hexane were used as the solvent and non-solvent, respectively. This study investigated how various core material and microcapsule EC/TH ratios affect the drug loss, particle size, surface morphology and release rate. The drug loss of the double-encapsuLated microcapsules was 12.8% less than that of microcapsules prepared by the O/W emulsion non-solvent addition method alone. The particle size of these double-encapsulated microcapsules decreased as the concentration of EC polymer was increased in the second encapsulation process. The roughness of their surface was also in proportion to the concentration of polymer solution used in the second encapsulation process. The dissolution study showed that the T20 of the double-encapsulated microcapsules ranged from 2-35.4 h, while that of the O/W emulsion non-solvent addition method microcapsules was from 2.7-7.7 h. The greater the level of EC in the polymer solution, the slower the release rate of the drug from the microcapsules when the EC was not over the critical amount.     

An enhanced process for encapsulating aspirin in ethyl cellulose microcapsules by solvent evaporation in an O/W emulsion

An enhanced process for microencapsulating aspirin in ethylcellulose was demonstrated using an oil-in-water emulsification/solvent evaporation technique. Methylene chloride (CH2Cl2) was used as the dispersed medium and water as the dispersing medium. The recovered weight, particle size distribution, aspirin loading efficiency, and the aspirin release rate of microcapsules were analysed. The addition of appropriate amounts of non-solvent (n-heptane) prior to the emulsification increases the recovered weight, but decreases the size of the formed microcapsules. The addition of non-solvent also changes the microcapsule characteristics, resulting in a coarser surface and an increased release rate. Increasing the polymer (ethylcellulose) concentration in the dispersed phase increases the size of the microcapsules, the recovered weight, and loading efficiency, but decreases the release rate. The release rate follows first-order kinetics during the first 12 h, suggesting a monolithic system with aspirin uniformly distributed in the microcapsule.     

An enhanced process for encapsulating aspirin in ethyl cellulose microcapsules by solvent evaporation in an O/W emulsion

An enhanced process for microencapsulating aspirin in ethylcellulose was demonstrated using an oil-in-water emulsification/solvent evaporation technique. Methylene chloride (CH2Cl2) was used as the dispersed medium and water as the dispersing medium. The recovered weight, particle size distribution, aspirin loading efficiency, and the aspirin release rate of microcapsules were analysed. The addition of appropriate amounts of non-solvent (n-heptane) prior to the emulsification increases the recovered weight, but decreases the size of the formed microcapsules. The addition of non-solvent also changes the microcapsule characteristics, resulting in a coarser surface and an increased release rate. Increasing the polymer (ethylcellulose) concentration in the dispersed phase increases the size of the microcapsules, the recovered weight, and loading efficiency, but decreases the release rate. The release rate follows first-order kinetics during the first 12h, suggesting a monolithic system with aspirin uniformly distributed in the microcapsule.     

Encapsulation of chlorothiazide in whey proteins: effects of wall-to-core ratio and cross-linking conditions on microcapsule properties and drug release

A model drug with limited water-solubility, chlorothiazide, was successfully encapsulated in whey protein-based wall systems cross-linked by glutaraldehyde-saturated toluene via an organic phase. The effects of drug content of the core-in-wall suspension and of cross-linking conditions on core retention and on microcapsule size, structure and core release properties were investigated. Spherical, surface cracks-free microcapsules ranging in diameter from approximately 200-1300 microm were obtained. Particle size distribution of microcapsules was affected by core content and cross-linking conditions. Core retention in microcapsules prepared at different cross-linking conditions and different wall-to-core ratios ranged from 48.9-81%, from 42.2-76.1% and from 37.3-67.2% in large (L), medium-size (M) and small (S) microcapsules, respectively. In all cases, drug crystals were physically entrapped and embedded throughout the cross-linked protein matrix. Core release from the microcapsules into enzyme-free simulated gastric fluid was governed by a diffusion-controlled mechanism and did not involve erosion or softening of the wall matrix. Rate of core release was significantly affected by a combined influence of core content, microcapsule size and cross-linking density. Complete core release from L, M and S microcapsule prepared at different wall-to-core ratios and cross-linking conditions ranged from 28.6-81.2 h, from 16.8-28.6 h and from 7.2-15.9 h, respectively. Results suggested that whey protein-based wall matrix cross-linked by GAST may provide significant opportunities in modulating the release of an encapsulated core with a limited water solubility.     

Solvent Exchange Method: A Novel Microencapsulation Technique Using Dual Microdispensers

PURPOSE: A new microencapsulation method called the "solvent exchange method" was developed using a dual microdispenser system. The objective of this research is to demonstrate the new method and understand how the microcapsule size is controlled by different instrumental parameters. METHOD: The solvent exchange method was carried out using a dual microdispenser system consisting of two ink-jet nozzles. Reservoir-type microcapsules were generated by collision of microdrops of an aqueous and a polymer solution and subsequent formation of polymer films at the interface between the two solutions. The prepared microcapsules were characterized by microscopic methods. RESULTS: The ink-jet nozzles produced drops of different sizes with high accuracy according to orifice size of a nozzle, flow rate of the jetted solutions, and forcing frequency of the piezoelectric transducers. In an individual microcapsule, an aqueous core was surrounded by a thin polymer membrane; thus, the size of the collected microcapsules was equivalent to that of single drops. CONCLUSIONS: The solvent exchange method based on a dual microdispenser system produces reservoir-type microcapsules in a homogeneous and predictable manner. Given the unique geometry of the microcapsules and mildness of the encapsulation process, this method is expected to provide a useful alternative to existing techniques in protein microencapsulation.     

Use of ion-exchange resins to prepare 100 microm-sized microcapsules with prolonged drug-release by the Wurster process

Ion-exchange resin (IER)--drug complexes were used as core materials to explore their capability to prepare a 100 microm-sized, highly drug-incorporated microcapsule with a prolonged drug release by the Wurster process. Diclofenac sodium was loaded into Dowex 1-X2 fractionated into 200--400 mesh and subsequently microencapsulated with two types of aqueous colloidal polymer dispersion, Aquacoator Eudragit RS30D. The mass median diameter and drug content of the microcapsules thus obtained were 98 microm and 46% with Aquacoat, and 95 microm and 50% with Eudragit RS30D, respectively. Each microcapsule was obtained at a product yield of 94%. The rate of drug release from the microcapsules was highly dependent on the encapsulating materials. For the microcapsules coated with Aquacoat, diclofenac sodium was found to be rapidly released over 4 h, even at a 25 wt% coating level because of cracks on the microcapsule surfaces resulting from the swelling stress of the drug-loaded IER cores. In contrast, significantly prolonged drug-release was achieved in the microcapsules prepared with Eudragit RS30D: even such a very low coating level as 3 wt% provided an exceptionally prolonged drug-release over 24 h. The results indicated that the use of IER along with a flexible coating material would be a feasible way to prepare a prolonged release type of microcapsules with a diameter of 100 microm and a drug content of more than 50% by the Wurster process.     

Extraction of metal cations by polyterephthalamide microcapsules containing a poly(acrylic acid) gel

Polyterephthalamide microcapsules containing a poly(acrylic acid) gel as a macromolecular ligand (PAA-CAPS) were prepared using an original two step polymerization process in a water-in-oil inverse emulsion system. A polyamide microcapsule containing acrylic acid, initiator and cross-linking agent, is formed by interfacial polycondensation of terephthaloyl dichloride with hexamethylenediamine. In situ radical polymerization of the microcapsule core acrylic acid is initiated to obtain encapsulated poly(acrylic acid) gel. Reference polyamide microcapsules, i.e. without ligand (CAPS), were also synthesized. The mean diameter of synthesized microcapsules was 210 #181;m, and the microcapsule wall thickness was evaluated by SEM and TEM observations of microcapsule cross-section cuts. The microcapsule water content was determined by thermogravimetric experiments. The extractabilities of Cu(II), Ni(II), Co(II) and Zn(II) into PAA-CAPS were examined. The stripping of the various cations can be promoted in diluted hydrochloric acid solutions.     

Extraction of metal cations by polyterephthalamide microcapsules containing a poly(acrylic acid) gel.

Polyterephthalamide microcapsules containing a poly(acrylic acid) gel as a macromolecular ligand (PAA-CAPS) were prepared using an original two step polymerization process in a water-in-oil inverse emulsion system. A polyamide microcapsule containing acrylic acid, initiator and cross-linking agent, is formed by interfacial polycondensation of terephthaloyl dichloride with hexamethylenediamine. In situ radical polymerization of the microcapsule core acrylic acid is initiated to obtain encapsulated poly(acrylic acid) gel. Reference polyamide microcapsules, i.e. without ligand (CAPS), were also synthesized. The mean diameter of synthesized microcapsules was 210 microm, and the microcapsule wall thickness was evaluated by SEM and TEM observations of microcapsule cross-section cuts. The microcapsule water content was determined by thermogravimetric experiments. The extractabilities of Cu(II), Ni(II), Co(II) and Zn(II) into PAA-CAPS were examined. The stripping of the various cations can be promoted in diluted hydrochloric acid solutions.     

Dissolution from tablets prepared using ethyl cellulose microcapsules.

Microcapsules containing sodium phenobartitone cores in ethyl cellulose have been used to prepare tablets at from 3-9 to 358-9 MPa compression pressures. The tensile strength of these tablets is related linearly to the core: wall ratio and to the microcapsule size. Dissolution of the drug from the microcapsules, is also related to the core:wall ratio and microcapsule size, but except at low compression pressures is almost independent of the pressure used during preparation. The tablet matrix remains intact during the dissolution and the equations developed by Schwartz, Simonelli & Higuchi (1968) are followed. Large microcapsules 1:2 core: wall ratio produce friable tablets with rapid release of contents.     

Trapping of chemical carcinogens with magnetic polyethyleneimine microcapsules: II. Effect of membrane and reactant structures

Effects of the membrane structure and reactant type on the trapping of carcinogens and other reactive species by semipermeable magnetic polyethyleneimine (PEI) microcapsules are investigated. A series of these microcapsules with poly(hexamethyleneterephthalamide) membranes was prepared by interfacial polymerization with an 8-fold variation of hexamethylenediamine concentration in the aqueous emulsion phase. Although little change was found in the encapsulation of PEI (within the microcapsule core) and magnetite, the microcapsule membrane showed a 6-fold alteration in regard to mass and associated PEI. All the microcapsule types tested were capable of trapping N-methyl-N-nitrosourea and fluorescein isothiocyanate as covalent-binding probes, and eosin and tetrasodium copper phthalocyanine tetrasulfonic acid (CPTS) as ionic-binding probes. Very rapid penetration and reaction of eosin and CPTS with the membranes was demonstrated, with apparent saturation of membrane binding affecting the overall trapping. Differences in the site and quantity of binding were ascribed to the following factors: the core:membrane distribution of incorporated PEI; the probe molecular weight; the reaction or adsorption of the probes with the microcapsule membrane; the probe stability in aqueous solution; and the amount of probe used. These probes represent the chemical-physical features of many known carcinogens or metabolites; together with previous data, these results indicate the potential usefulness of this type of microcapsule for trapping carcinogens (and their metabolites) as covalently or ionically bound products.