Effect of formulation variables on in vitro drug release and micromeritic properties of modified release ibuprofen microspheres

Modified release microspheres of the non-steroidal anti-inflammatory drug, ibuprofen, were formulated and prepared using the emulsion solvent diffusion technique. The contribution of various dispersed phase and continuous phase formulation factors on in vitro drug release and micromeritic characteristics of microspheres was examined. The results demonstrated that the use of Eudragit RS 100 and Eudragit RL 100 as embedding polymers modified the drug release properties as a function of polymer type and concentration. Eudragit RS 100 retarded ibuprofen release from the microspheres to a greater extent than Eudragit RL 100. The drug/polymer concentration of the dispersed phase influenced the particle size and drug release properties of the formed microspheres. It was found that the presence of emulsifier was essential for microsphere formation. Increasing the concentration of emulsifier, sucrose fatty acid ester F-70, decreased the particle size which contributed to increased drug release properties. Scanning electron microscopy revealed profound distortion in both the shape and surface morphology of the microspheres with the use of magnesium stearate as added emulsifier. The application of an additional Eudragit RS 100 coat onto formed microspheres using fluid bed technology was successful and modulated the drug release properties of the coated microspheres.     

Lappaconitine-loaded microspheres for parenteral sustained release: effects of formulation variables and in vitro characterization

Lappaconitine instead of its hydrobromide salts has been encapsulated in poly (lactide-co-glycolide) acid (PLGA) microspheres by the simple o/w emulsion solvent evaporation technique. The effects of several variables including emulsifier (polyvinyl alcohol, PVA) concentration, stirring speed, PLGA concentration and drug/polymer mass ratios on quality of microspheres have been investigated. The particle size and size distribution can be controlled by PVA concentration, stirring speed and PLGA concentration. The entrapment efficiency and the burst release of lappaconitine from drug-loaded microspheres were dominantly affected by the drug/polymer mass ratio and PVA concentration. The best parameters of formulation were 1.5% PVA, the PLGA concentration of 50 g/L, and the stirring speed of 800 rpm and drug/polymer of 1:5. The optimized formulation has a mean particle size of 19.3 +/- 0.93 microm, mean entrapment efficiency of 70.77 +/- 3.23% and mean drug loading of 11.45 +/- 0.47%. Based on the optimized parameters of formulation, the effects of oil/aqueous solubility partition ratio of drug on entrapment efficiency of drug-loaded microspheres prepared by o/w emulsion solvent evaporation were further studied. A good linear relation existed between the partition ratio and entrapment efficiency. The optimized microspheres were characterized by SEM, FT-IR, DSC and XRD. SEM shows spherical and smooth surface and uniform size distribution. The results of DSC, FT-IR study reveal no interaction between drug and polymer. The results of the XRD study indicate lappaconitine trapped in microsphere exists in form of an amorphous or disordered crystalline status in polymer matrix. The in vitro release models were evaluated with two different groups of drug-loaded microspheres including microspheres washed with distilled water and 0.01N HCL, respectively. The drug release profile of lappaconitine-loaded microspheres washed with distilled water agreed with zero order equation and that of the latter better agreed with first order equation.     

Relations between crystallisation conditions and micromeritic properties of ibuprofen

The effects of solvent, cooling rate and type of methacrylic polymer (Eudragit(R)) on the micromeritic properties (size, elongation ratio, roundness and fullness ratio), the temperature change in the crystallisation liquid, the crystal yield and the extent of agglomeration of ibuprofen crystals have been compared. Twenty batches of crystals were prepared and Latin square experimental design was applied with four levels for each factor. It was found that crystal yield (Y) is related to the extrapolated point of maximum rate of temperature-deviation (T(d)) with a logarithmic-type equation [Y=34.45lnT(d)-28.00] and to the area under the curve of temperature-deviation versus time (AUC) with a polynomial equation including cooling rate [Y=19.95AUC-1.57AUC/CR+63.00]. Crystal size is affected by the cooling rate and analysis of variance (ANOVA) showed that elongation ratio and fullness ratio of single crystals (P=0.05 and 0.05), as well as roundness and fullness ratio of agglomerates (P=0.05 and 0.1), are affected by the solvent. Post hoc statistical analysis of the solvent effects on the shape of crystals and agglomerates (Tukey's HSD multiple pairwise comparison test of means) indicated that their significance lies in the different polarity and may be attributed to interactions of solvent (acetone) with the growing crystal faces. Extent of crystal agglomeration was found to be inversely proportional to the ratio of elongation ratio/circle equivalent diameter of the single crystals.     

Effect of formulation variables on drug and polymer release from HPMC-based matrix tablets

The objective of this work was to assess the effect of two formulation variables, hydroxypropylmethylcellulose (HPMC)/lactose ratio and HPMC viscosity grade, on the release of a model drug and HPMC, as well as the mechanism of drug release from HPMC-based matrix tablets. A water-soluble compound, adinazolam mesylate, was used as the model drug. Both drug and HPMC release were found to be a function of the formulation variables, with higher drug and HPMC release rates for formulations with lower HPMC/lactose ratios and lower HPMC viscosity grades. However, the K15M and K100M formulations had identical drug release profiles. All the drug release data fit well to the Higuchi expression. By comparing the drug and HPMC release data, it was concluded that diffusion of drug through the hydrated gel layer was the predominant drug release mechanism for most of the formulations studied.     

Calcium pectinate gel beads for controlled release drug delivery: II. Effect of formulation and processing variables on drug release.

The effect of four formulation and processing variables, calcium concentration, drying condition, concentration of hardening agent and hardening time on the bead properties and the release characteristics of a model drug from calcium pectinate gel (CPG) beads were studied. A poorly soluble compound, indomethacin, was used as the model drug. The investigated variables affected the bead size, the entrapment efficiency and the release of indomethacin from CPG beads. Drug release was found to be a function of the formulation and processing variables. The slower drug release was achieved from the formulations with higher calcium concentration, higher concentration of hardening agent and longer hardening time. The drying condition, however, did not influence the drug release. The mechanism of indomethacin release from CPG beads followed the diffusion controlled model for an inert porous matrix. All drug release data fitted well to the Higuchi square root time expression.     

Effect of morphological properties on drug release from biodegradable microspheres]

The morphological properties of poly(beta-hydroxybutyric acid) (PHB) or poly(L-lactic acid) microspheres loading flomoxef sodium (FMOX) were investigated with regard to FMOX release. The release profiles of FMOX from the microspheres could be divided into two types, a sustained release type and a burst one. Two representative PHB microspheres, the release profiles of which were quite different from those of FMOX, were compared in detail from a morphological point of view. The shapes of their surfaces and sections were observed by using scanning electron microscopy (SEM), and FMOX distribution was analyzed by using electron probe microanalysis. The crystallinity of polymers was further measured by powder X-ray diffratometry. There was little difference in the FMOX distribution and their microscopic properties such as sphere size, specific surface area, shape of surface and section. In contrast, water penetration into the inside of the microspheres was found to be clearly different by use of cryogenic SEM. A significant difference was also observed in the crystallinity of polymers forming the microspheres. The release of FMOX from the microspheres was affected by the crystallinity of polymers forming the microspheres, and burst phenomena occurred in case the polymer was highly crystallized. It was speculated that the crystallization of polymer induced micro voids in the microspheres which functioned as channels for water penetration.     

Oral controlled release formulations of rifampicin. Part II: Effect of formulation variables and process parameters on in vitro release

Hydrophilic controlled release matrix tablets of rifampicin, a poorly soluble drug, have been formulated using hydroxypropyl methylcellulose (HPMC) polymer (low, medium, and high viscosity) by direct compression method. Influence of formulation variables and process parameters such as drug:HPMC ratio, viscosity grade of HPMC, drug particle size, and compression force on the formulation characters and drug release has been studied. Our results indicated that the release rate of the drug and the mechanism of release from the HPMC matrices are mainly controlled by the drug:HPMC ratio and viscosity grade of the HPMC. In general, decrease in the drug particle size decreased the drug release. Lower viscosity HPMC polymer was found to be more sensitive to the effect of compression force than the higher viscosity. The formulations were found to be stable and reproducible.     

替莫唑胺壳聚糖缓释微球的制备及体外释药特性

目的:制备替莫唑胺壳聚糖缓释微球,并对其体外释药模式进行研究.方法:以替莫唑胺为模型药物,采用乳化交联法制备壳聚糖微球,两步优化法优化处方和制备工艺.通过测定微球的粒径及其分布、载药量、包封率和体外释放速度对微球进行质量评价.结果:优化工艺制得的微球平均粒径为(3.9±1.6)μm,载药量为(7.1±0.5)%(n=3),包封率为(25.0±0.8)%(n=3),体外释药特性研究具有良好的缓释特性,在0～8 h符合Higuchi方程,Q=11.717 26.951t1/2(r=0.980),8～24 h符合一级释放曲线,lnQ=4.37 0.007 5t(r=0.983).结论:通过优化处方和制备工艺,采用乳化交联法可制备出以壳聚糖为载体、替莫唑胺为模型药物的缓释微球,其体外释药具有明显的缓释作用.     

Effects of formulation variables and characterization of guaifenesin wax microspheres for controlled release

Sustained-release wax microspheres of guaifenesin, a highly water-soluble drug, were prepared by the hydrophobic congealable disperse method using a salting-out procedure. The effects of formulation variables on the loading efficiency, particle properties, and in-vitro drug release from the microspheres were determined. The type of dispersant, the amount of wetting agent, and initial stirring time used affected the loading efficiency, while the volume of external phase and emulsification speed affected the particle size of the microspheres to a greater extent. The crystal properties of the drug in the wax matrix and the morphology of the microspheres were studied by differential scanning calorimetry (DSC), powder x-ray diffraction (XRD), and scanning electron microscopy (SEM). The DSC thermograms of the microspheres showed that the drug lost its crystallinity during the microencapsulation process, which was further confirmed by the XRD data. The electron micrographs of the drug-loaded microspheres showed well-formed spherical particles with a rough exterior.     

Extended release lipophilic indomethacin microspheres: formulation factors and mathematical equations fitted drug release rates.

Extended release liphophilic microspheres of indomethacin were prepared using cetostearyl alcohol (CsA), stearyl alcohol (SA) and cetyl alcohol (CA) in the various drug-lipid ratios. The release of indometacin was studied on the basis of USP criteria and the effects of drug-lipid ratio, the size of microspheres and carboxymethylcellulose sodium (CMC-Na) added as a hydrophilic polymer on the drug release were investigated. In vitro dissolution studies were performed using USP XXIII apparatus I at pH 6.2. Release profiles were evaluated according to first order, Higuchi square root of time and Hixson-Crowell cube root models. The best fit was found with the square root of time model (r2=0.991) for the microspheres (125-250 microm) prepared in 1:4:1 drug-lipid-copolymer ratio using stearyl alcohol. With a further regression analysis, an excellent equation (Release%=-10.721+42.549*square root of (t)-4.027*t) was developed for empirical drug estimation (r2=0.998).     

Preparation, characterization and in vitro drug release of isosorbide dinitrate microspheres.

Microspheres of isosorbide dinitrate (ISDN) were prepared using the emulsification/solvent evaporation method. The impacts of different factors such as stirring rate, concentration of ethyl cellulose (EC) as matrix polymer, poly vinyl chloride (PVA) as stabiliser and ISDN on the characteristics of the microspheres were investigated. The morphology of microspheres was studied using optical and scanning electron microscopy and it was shown that microspheres had a spherical shape and smooth surface. The particle size distribution of microspheres, analysed by a sieving method, was affected by stirring rate and concentrations of EC, PVA and ISDN. Larger microspheres showed greater drug loading and smaller microspheres showed a faster drug release. The in vitro drug release from microspheres was predictable and reproducible, conforming to the Higuchi model of release kinetics.     

Preparation and evaluation of modified release ibuprofen microspheres with acrylic polymers (Eudragit) by quasi-emulsion solvent diffusion method: effect of variables

The aim of this study was to prepare and evaluate microspheres containing ibuprofen. Microspheres were prepared by modified quasi-emulsion solvent diffusion method. The influence of formulation factors (drug-polymer ratio, volumes of solvent, polyvinyl alcohol concentration and type of polymer) on the morphology, particle size distribution, drug loading capacity, micromeritical properties and the in vitro release characteristics of the microspheres were investigated. Physical characterizations of ibuprofen microspheres were also carried out using scanning electron microscopy, X-ray diffractometry and IR spectrophotometry. It was found that the yield of preparation was dependent on the initial temperature gradient between the emulsion phases. When there was an initial difference of temperature between the aqueous phase and dispersed emulsion phases, yield of preparation was increased distinctly. The drug loading capacities were very high for all formulations of the microspheres which were obtained. Mean particle size changed by changing the drug-polymer ratio, volumes of solvent or polyvinyl alcohol concentration. The flow properties were much improved over those of the original crystals. In vitro dissolution results showed that the release rate of ibuprofen was modified in all formulations. Although ibuprofen release rates from Eudragit RS microspheres were very slow, they were fast from Eudragit RL microspheres. These results observed that if Eudragit RS and Eudragit RL are used in combination, optimum release profiles may be obtained.     

Sustained release spherical agglomerates of polymethacrylates containing mefenamic acid: in vitro release, micromeritic properties and histological studies

Mefenamic acid (MA) spherical agglomerates (SAs) were prepared with various polymethacrylates having different permeability characteristics (Eudragit RS 100, Eudragit RL 100 and Eudragit L 100) and also with combination of Eudragit RS 100 and Eudragit L 100 in different ratios. SAs were prepared by spherical crystallization method using ethanol/dichloromethane solvent (crystallization) system. The influence of various formulation factors on the encapsulation efficiency, as in vitro drug release, and micromeritic properties was investigated. Target release profile of MA was also drawn. The yields of preparation and the encapsulation efficiencies were high for all formulations. The shape and surface characteristics of SAs were observed by a scanning electron microscope. The particle sizes are in the range of 0.219 ± 0.1 to 0.482 ± 0.25 mm (mean ± confidence interval t(95%)). In addition, histological studies showed that the administration of MA in SAs containing Eudragit RS/L provided a distinct tissue protection in the stomach and duodenum. Differential scanning calorimetry and X-ray diffraction of powder studies showed that MA particles crystallized in the presence of polymethacrylates did not undergo structural modifications.     

处方和工艺参数对盐酸昂丹司琼微球体外释放度的影响

目的：考察处方工艺参数对微球体外释放度的影响.方法：采用O/O型乳化溶剂挥发法,以乳酸-羟基乙酸共聚物为载体,制备盐酸昂丹司琼（Ondansetron hydrochloride,OND）微球.采用紫外分光光度法测定微球的体外释放度.结果：选择对OND具有较好溶解能力的混合溶剂为内油相溶剂,可以降低突释;增加理论载药量,延缓正己烷加入的时间和减小粒径可以增加OND微球的释药速度.结论：通过对处方和工艺的调节可使OND微球的体外释药曲线符合Higuchi方程,2周的累积释放量在80%左右.     

beta-Estradiol biodegradable microspheres: effect of formulation parameters on encapsulation efficiency and in vitro release

The purpose of this work was to study the effect of organic solvent and surfactant type on the in vitro release behavior in general and on the burst release in particular of beta-estradiol from PLA/PLGA microspheres. Also the effect of these variables on the encapsulation efficiency was investigated. The microspheres were prepared by solvent evaporation technique using dichloromethane (DCM), ethyl acetate (EtAc), tetrahydrofuran (THF), chloroform (CHCl3) or acetone (AC) as organic solvent and polyvinyl alcohol (PVA), Tween 80, sodium lauryl sulfate (SLS) or benzalkonium chloride (BKCI) as surfactant. The obtained microspheres were tested for encapsulation efficiency and in vitro drug release using 50% methanol/buffer pH 7.4 as dissolution medium. EtAC and PVA formulations showed the highest encapsulation efficiency and the lowest burst release. These microspheres were further characterized for particle size distribution, SEM and zeta potential. The results suggested that these materials could be starting materials to prepare a beta-estradiol biodegradable controlled delivery system.     

替莫唑胺聚乳酸-羟基醋酸微球的制备及体外释药

目的:对替莫唑胺聚乳酸-羟基醋酸微球的制备工艺、含量测定及体外释药特性进行初步研究。方法:以人工合成可生物降解聚合物聚乳酸-羟基醋酸为载体,采用乳化-溶剂挥发法制备替莫唑胺聚乳酸-羟基醋酸微球,用紫外分光光度计测定其药物含量和体外释药量。结果:所制备的替莫唑胺聚乳酸-羟基醋酸微球外形圆整,算术平均球径为62.2μm,载药量为7.47%,包封率为83.53%,体外释放可达1个月。结论:替莫唑胺聚乳酸-羟基醋酸微球具有很好的控释能力,使用前景广阔。     

Encapsulation of water-soluble drugs by a modified solvent evaporation method. I. Effect of process and formulation variables on drug entrapment

Pseudoephedrine HCl, a highly water-soluble drug, was entrapped within poly (methyl methacrylate) microspheres by a water/oil/water emulsification-solvent evaporation method. An aqueous drug solution was emulsified into a solution of the polymer in methylene chloride, followed by emulsification of this primary emulsion into an external aqueous phase to form a water/oil/water emulsion. The middle organic phase separated the internal drug-containing aqueous phase from the continuous phase. Microspheres were formed after solvent evaporation and polymer precipitation. The drug content of the microspheres increased with increasing theoretical drug loading, increasing amounts of organic solvent, polymer and polymeric stabilizer, and decreased with increasing stirring time, increasing pH of the continuous phase and increased volume of the internal and external aqueous phase.     

In vitro modified release of acyclovir from ethyl cellulose microspheres

The aim of this study was to demonstrate a sustained-release microparticulate dosage form for acyclovir via an in vitro study. Ethyl cellulose was selected as a model encapsulation material. All of the microspheres were prepared by an oil-in-water solvent evaporation technique. A 2³ full factorial experiment was applied to study the effects of the viscosity of polymer, polymer/drug ratio, and polymer concentration on the drug encapsulation efficiency and the dissolution characteristics. The encapsulation efficiency of acyclovir in microspheres was in the range of 20.0-56.6%. Increase in the viscosity of ethyl cellulose and the ratio of CH₂Cl₂/ethyl cellulose increased drug encapsulation efficiency. The drug continuously released from microspheres for at least 12 h, and the release rate depended on the pH of the release medium. The sustained release characteristic was more prominent in the simulated intestine fluid than in the simulated gastric fluid. A faster release of drug was observed when a high viscosity polymer was used. The decomposition of acyclovir significantly decreased when encapsulated by ethyl cellulose, especially when stored at 37 and 50 °C.     

In vitro modified release of acyclovir from ethyl cellulose microspheres

The aim of this study was to demonstrate a sustained-release microparticulate dosage form for acyclovir via an in vitro study. Ethyl cellulose was selected as a model encapsulation material. All of the microspheres were prepared by an oil-in-water solvent evaporation technique. A 2(3) full factorial experiment was applied to study the effects of the viscosity of polymer, polymer/drug ratio, and polymer concentration on the drug encapsulation efficiency and the dissolution characteristics. The encapsulation efficiency of acyclovir in microspheres was in the range of 20.0-56.6%. Increase in the viscosity of ethyl cellulose and the ratio of CH2Cl2/ethyl cellulose increased drug encapsulation efficiency. The drug continuously released from microspheres for at least 12 h, and the release rate depended on the pH of the release medium. The sustained release characteristic was more prominent in the simulated intestine fluid than in the simulated gastric fluid. A faster release of drug was observed when a high viscosity polymer was used. The decomposition of acyclovir significantly decreased when encapsulated by ethyl cellulose, especially when stored at 37 and 50 degrees C.     

Sustained release spherical agglomerates of polymethacrylates containing mefenamic acid: in vitro release,micromeritic properties and histological studies

Mefenamic acid (MA) spherical agglomerates (SAs) were prepared with various polymethacrylates having different permeability characteristics (Eudragit RS 100, Eudragit RL 100 and Eudragit L 100) and also with combination of Eudragit RS 100 and Eudragit L 100 in different ratios. SAs were prepared by spherical crystallization method using ethanol/dichloromethane solvent (crystallization) system. The influence of various formulation factors on the encapsulation efficiency, as in vitro drug release, and micromeritic properties was investigated. Target release profile of MA was also drawn. The yields of preparation and the encapsulation efficiencies were high for all formulations. The shape and surface characteristics of SAs were observed by a scanning electron microscope. The particle sizes are in the range of 0.219?±?0.1 to 0.482?±?0.25?mm (mean ± confidence interval t_95%). In addition, histological studies showed that the administration of MA in SAs containing Eudragit RS/L provided a distinct tissue protection in the stomach and duodenum. Differential scanning calorimetry and X-ray diffraction of powder studies showed that MA particles crystallized in the presence of polymethacrylates did not undergo structural modifications.