Influence of partition parameter on release of drug from adjuvant-containing charged film microcapsules

Abstract

Rates of release of a series of p-substituted acetanilides from piperazine arabate microcapsules containing the co-encapsulated lipophilic adjuvant acetyl triethyl citrate are inversely proportional to the partition parameter of the substituted acetanilide.     

Controlled release captopril microcapsules: effect of non-ionic surfactants on release from ethyl cellulose microcapsules

Captopril microcapsules were prepared with different viscosity grades of ethyl cellulose by temperature induced coacervation from cyclohexane. Both non-ionic surfactants or their combinations and 2 per cent absolute alcohol as cosolvent were added to the coacervation system to ensure complete solvation of the ethyl cellulose and efficient microencapsulation of the drug. The in vitro dissolution was studied in 0.1 N hydrochloric acid. Microcapsules prepared using 2 per cent Tween 80 with ethyl cellulose of 41 c.p. viscosity grade exhibited the most prolonged release with a t70 per cent of 55 min in comparison to 7.75 min for control microcapsules prepared without surfactant. Different kinetic models have been used to explain the release. The best fit with the highest correlation coefficients was the first-order kinetics plot with two straight lines having two different slopes. The initial slope presents the faster release rate than the terminal slope. This fast release would be useful for the initial dose of the prolonged release formulation.     

Controlled release captopril microcapsules: effect of ethyl cellulose viscosity grade on the in vitro dissolution from microcapsules and tableted microcapsules

Captopril microcapsules were prepared using four different viscosity grades of ethyl cellulose (core: wall ratios 1:1, 1:2 and 1:3) by temperature induced coacervation from cyclohexane. In vitro dissolution studies in 0.1 M hydrochloric acid showed that the drug release was dependent on the core to wall ratio, the viscosity grade of the ethyl cellulose and thus the total viscosity of the coacervation system. Viscosity grade of greater than 100 c.p. was unsuitable for microencapsulation by coacervation method at the concentration used. The surface characteristics of a 1:2 core to wall ratio were studied by scanning electron microscopy. The surface of the microcapsules prepared with 10 c.p. viscosity grade was comparatively more porous with larger size pores than 50 c.p. viscosity grade of ethyl cellulose. However, 300 c.p. viscosity grade showed incomplete wall formation. The microcapsules did not fragment during dissolution, alter in shape or size, or show evidence of enlargement of the surface pores. The tensile strength of tablets prepared at constant pressure from each batch of microcapsules (mean diameter 675 microns) increased as both the core to wall ratios and the viscosity of ethyl cellulose increased. The dissolution rate of the drug from tableted microcapsules was significantly delayed. The in vitro release gave best correlation with first order release kinetics when compared to zero-order and square-root-of-time equations.     

The in vitro dissolution of phenobarbitone sodium from ethyl cellulose microcapsules.

Microcapsules of sodium phenobarbitone, with a wall of ethyl cellulose, have been prepared. The size distribution was determined by use of standard sieves and the effect of coreWALL ratio noted. Release of the drug into an aqueous medium was studied. The release pattern was found to have similar characteristics to the release of a drug from an insoluble porous matrix.     

盐酸苯环壬酯油水分配系数的测定及pH值对其的影响

目的： 测定盐酸苯环壬酯油水分配系数,研究不同pH值对药物脂水分配系数的影响,为盐酸苯环壬酯新剂型的处方设计提供理论参考。方法： 本实验采用摇瓶-高效液相色谱法测定盐酸苯环壬酯在不同pH值条件下正辛醇-水/缓冲液体系中的表观脂水分配系数。结果： 盐酸苯环壬酯的脂水分配系数lgP值为1.29±0.16;在pH为1.2,3.0,4.5,5.0,5.5,6.0,6.8,7.0,8.0,9.0的环境中,脂水分配系数lgP值分别为0.31,0.72,1.16,1.34,1.99,2.26,2.22,1.61,2.34,3.24。结论： 盐酸苯环壬酯的脂水分配系数与介质的pH值有关,在pH 4.5~8.0生理条件下,盐酸苯环壬酯的脂溶性较好,水溶性差。     

Zero order drug delivery from double-layered porous films: release rate profiles from ethyl cellulose,hydroxypropyl cellulose and polyethylene glycol mixtures

Laminated double-layered films comprising a drug-containing and drug-free layer were prepared using tripelennamine, barbitone, salicylic acid and caffeine dispersed in hydroxypropylcellulose (HPC) attached to ethyl cellulose (EC) films containing various proportions of polyethylene glycol (PEG) or HPC to enhance permeability. Drug release in vitro followed zero-order kinetics, rate constants being dependent on the thickness of the drug-free membrane, which was rate-controlling. Thickness-corrected zero order constants were independent of drug-loading, which did, however, control the duration of release. Permeability coefficient measurements on the same rate-controlling films used as single barrier membranes enabled the effective drug concentration (C_o) at the interface between the laminated membranes to be estimated; C_o was independent of drug loading and was of the order expected from the aqueous solubilities of the drugs. Release rates were enhanced by addition of hydrophilic polymer to the rate-controlling membranes, either linearly with fraction of additive for PEG to 0·6 or HPC to 0·4, or logarithmically for HPC from 0·4 to 0·8. Enhancement coefficients, which were different for each system, reflected the different mechanisms of hydrophilic polymer action. PEG was leached out rapidly, pores being formed in the matrix. In contrast, HPC was largely retained, so that the enhancement was less. The logarithmic enhancement stemmed from formation of swollen hydrated channels, which, unlike the low HPC fractions or the PEG systems, allowed entry of buffer ions, so that only in these channel systems were the release rates altered by change of the external pH.     

Release kinetic studies of aspirin microcapsules from ethyl cellulose, cellulose acetate phthalate and their mixtures by emulsion solvent evaporation method

The present study was oriented towards microencapsulation of aspirin and the study of its release kinetics. The desired encapsulation was achieved by emulsion solvent evaporation method using ethyl cellulose (EC), cellulose acetate phthalate (CAP) and their mixture (1:1) of polymeric constituents. Characterization of the formulations was performed by size, shape, drug loading efficiency and in-vitro drug release analysis. The in-vitro release profiles from different polymeric microcapsules were applied on different kinetic models. The prepared microcapsules were found free flowing and almost spherical in shape with particle sizes ranging from 300–700μm, having a loading efficiency of 75–85%. The best fit model with the highest correlation coefficient was observed in Higuchi model, indicating diffusion controlled principle. The n value obtained from Korsemeyer-Peppas model varied between 0.5–0.7, confirming that the mechanism of drug release was diffusion controlled. Comparative studies revealed that the release of aspirin from EC microcapsules was slower as compared to that of CAP and their binary mixture.     

Effect of a second solubilizate on the partition coefficient of drugs in micellar solution and their permeation rate across an artificial membrane

The distribution of a solubilizate between micelles and the aqueous phase does not obey a simple partition law when a second solubilizate species is present. Alterations of the apparent partition coefficient cannot be explained in terms of a simple displacement mechanism, following the interaction of both solubilizates with the same site of the micelle. A non linear increase in solubilizate association to micelles following an increase in surfactant concentration is observed in the presence of a second solubilizate. A depression in the cloud point temperature follows the addition of a second species and is such that cannot be interpreted as a simple additive effect. Alteration of the apparent partition coefficient in a micellar solution has an effect on the permeation rate of the solubilizate across an artificial membrane. Bio-pharmaceutical implications are discussed.     

Influence of pH adjustment on microcapsules obtained from complex coacervation of gelatin and acacia

Abstract

The coacervation behaviour of commercial grade gelatin and acacia mixtures was studied with five different acids to adjust the coacervation pH, i.e. HCI, HNO₃, H₂SO₄, acetic acid, and citric acid. The electrical equivalence pH value (EEP) of the polymer mixture was determined by means of a streaming current detector (SCD). With all acids-except H₂SO₄-maximum coacervate yield was observed at the EEP. Using H₂SO₄ the EEP was found at a lower pH value than compared with the point of maximum coacervate yield. The quantity of coacervate at the EEP was significantly reduced in the presence of H₂SO₄ whereas with all other acids, almost no differences were found. The dependence of the coacervate volume on the added amount of acid did not change in parallel to the dry coacervate yield and there was no coincidence of the maximum coacervate volume and the EEP. The barrier properties of the capsule shells of corresponding microcapsules using indomethacin as a model drug were examined by dissolution studies. Indomethacin microcapsules showed the slowest release rate when the coacervation pH was adjusted to the EEP and not to the pH of maximum coacervate yield. As expected from the coacervation behaviour, dissolution profiles of the microcapsules were quite similar even when different acids were used for pH adjustment.     

Effect of a second solubilizate on the partition coefficient of drugs in micellar solution and their permeation rate across an artificial membrane.

The distribution of a solubilizate between micelles and the aqueous phase does not obey a simple partition law when a second solubilizate species is present. Alterations of the apparent partition coefficient cannot be explained in terms of a simple displacement mechanism, following the interaction of both solubilizates with the same site of the micelle. A non linear increase in solubilizate association to micelles following an increase in surfactant concentration is observed in the presence of a second solubilizate. A depression in the cloud point temperature follows the addition of a second species and is such that cannot be interpreted as a simple additive effect. Alteration of the apparent partition coefficient in a miscellar solution has an effect on the permeation rate of the solubilizate across an artificial membrane. Biopharmaceutical implications are discussed.     

Volume of water-filled pores in the ethyl cellulose membrane and the permeability of microcapsules

The volume fraction of the water-filled pores in the microcapsule membranes was calculated and the values from 0.55 to 2.5% were obtained. Differential scanning calorimetry of aqueous suspensions of microcapsules showed no structured water present in the ethyl cellulose membranes. The temperature effect on the apparent diffusion coefficient of a drug was investigated and the apparent activation energy of diffusion was calculated.     

pH值对富马酸比索洛尔化学稳定性及油水分配系数的影响

目的:研究pH值对富马酸比索洛尔(bisoprolol fumarate,BF)的化学稳定性及油水分配系数(P)的影响,为研制BF的粘膜给药液体制剂奠定基础。方法:采用HPLC法测定BF的浓度;在不同pH值下,分别测定BF在80℃下的降解百分率以及在25℃下正辛醇-水/缓冲液系统中的P值。结果:在所考察pH值范围内,随着pH的增加,BF的降解百分率逐渐减小,在pH大于4.0时,BF的降解速率趋于零。BF在正辛醇-水系统中的P值为0.23;在正辛醇-缓冲液系统中,pH为2.0～7.0范围时,药物的P值均小于1,在pH大于7.0时,P值显著增大。结论:pH值对BF的化学稳定性以及P值均有明显影响。选择适宜的pH值,对研制BF的粘膜给药液体制剂极其重要。     

The effect of the molecular weight of ethyl cellulose on the drug release properties of mixed films of ethyl cellulose and hydroxypropylmethylcellulose

The effect of the molecular weight of ethyl cellulose on the drug release properties of mixed films of ethyl cellulose and hydroxypropyl methylcellulose has been studied by coating spherical granules with a film and measuring the release of a water-soluble model drug substance. Drug release was found to decrease with increasing molecular weight and on the addition of plasticizer. diethyl phthalate, to the films prepared from the low molecular weight grades. At molecular weights in excess of 35.000 (equivalent to a grade with a nominal viscosity of 20 mPas) the addition of a plasticizer had no effect on drug release. The results have been correlated with the mechanical properties of films prepared from the various molecular weight grades of ethyl cellulose, the rapid release with the low molecular weight grades being caused by the presence of cracks and flaws in the film.     

pH值对盐酸小檗碱表观油水分配系数的影响

目的测定盐酸小檗碱在正辛醇-水和正辛醇-缓冲液体系中的表观油水分配系数,为其体内吸收研究提供参考。方法采用HPLC法测定盐酸小檗碱的浓度,采用经典摇瓶法测定盐酸小檗碱在正辛醇-水/缓冲液中的表观油水分配系数。结果在37.0℃时,盐酸小檗碱在水中的表观油水分配系数为0.084(lgPapp=-1.08);在pH值为1.0、2.0、11.0、12.0的缓冲液中,其油水分配系数分别为1.74、1.22、1.91、15.17;在pH值为3.0～10.0时,其油水分配系数极小,变化不大,lgPapp均<0。结论在水及pH值1.0～8.0的缓冲液中,盐酸小檗碱的lgPapp均<1.0,预测其在机体胃肠道并不易被吸收。pH值对盐酸小檗碱的表观油水分配系数有一定影响,在一定范围内,pH增加可使其分配系数增大,在pH 12.0的磷酸盐缓冲液中达到最大(Papp=15.17,lgPapp=1.18)。     

pH值依赖的利培酮化学稳定性、溶解度及油水分配系数研究

目的研究pH值对利培酮(RIS)的化学稳定性、溶解度及油水分配系数(P)的影响,为研制RIS的黏膜给药制剂奠定基础。方法采用HPLC法测定RIS的浓度;在不同pH值下,分别测定RIS在80℃条件下的降解百分率,在25℃条件下的溶解度以及在37℃正辛醇-水/缓冲液系统中的P值。结果在pH<10.0时,随着pH值的增大,RIS的降解百分率逐渐增加,溶解度明显降低;当pH≥8.0时,RIS几乎不溶;RIS在正辛醇-水系统中的P值为1.46。在正辛醇-缓冲液系统中,当pH<5.0时,RIS的P值远<1;当pH>5.0时,随着pH值增加,药物的P值显著增加。结论pH值对RIS的化学稳定性、溶解度以及P值均有明显影响。选择适宜的pH值对研制RIS的黏膜给药制剂非常重要。