Dissolution of ibuprofen enantiomers from coprecipitates and suspensions containing chiral excipients

The purpose of this research was to evaluate the stereospecific interaction of ibuprofen with chiral excipients such as hydroxypropyl-beta-cyclodextrin (HPCD), tartaric acid, sucrose, hydroxypropylmethylcellulose (HPMC), methylcellulose (MC), and a nonchiral excipient, citric acid. Coprecipitates of ibuprofen were prepared in molar ratios ranging between 1:0.5 and 1:10 by a solvent evaporation method and characterized using x-ray diffraction, Fourier-transform infrared (FTIR) spectroscopy, and dissolution testing. Phase solubility studies of ibuprofen were carried out by adding excess amount of ibuprofen to aqueous excipient solutions of varying concentrations. Interaction was studied in suspensions of ibuprofen with HPMC, MC, and sucrose stored at room temperature and 60 degrees C for 12 weeks. Solubility of ibuprofen in HPCD solutions increased 10-fold, whereas solubility decreased in the tartaric and citric acid solutions, a result of decreased pH with increased amount of the acids in which ibuprofen (pKa 4.8) is less soluble. Phase solubility diagrams of ibuprofen in aqueous HPCD, citric acid, and tartaric acid solutions showed no stereospecific differences in solubility of the two enantiomers. X-ray diffraction studies showed that ibuprofen exists in a crystalline form at low ibuprofen-to-excipient ratios, whereas at the higher ratios, it exists in an amorphous form. FTIR spectroscopy for HPCD coprecipitates showed a shift of the carbonyl stretching band of ibuprofen to a higher wavelength with a markedly decreased intensity, probably because of a breakdown in the intermolecular hydrogen bonding with ibuprofen and restriction of the drug molecule in the HPCD cavity, respectively. Dissolution profiles of the coprecipitates demonstrated higher dissolution rates than those of pure ibuprofen. The presence of chiral excipients did not appear to cause stereoselective release of the drug from the coprecipitates and the suspensions.     

Solubility and dissolution rate of ibuprofen in ionic and non-ionic micellar systems

Equilibrium solubility, the profile and the rate of ibuprofen dissolution in solutions of sodium dodecyl sulfate, Tween 60 and Brij 35 were studied. It was found that the solubility of ibuprofen was enhanced by the formed micellar system. The size and shape of formed micelles depended on the used particular surfactant. The mechanism of ibuprofen dissolution in micellar system was discussed.     

Adsorption of pharmaceutical excipients onto microcrystals of siramesine hydrochloride: Effects on physicochemical properties

A common challenge in the development of new drug substances is poor dissolution characteristics caused by low aqueous solubility. In this study, microcrystals with optimized physicochemical properties were prepared by precipitation in the presence of excipients, which adsorbed to the particle surface and altered particle size, morphology, and dissolution rate. The poorly water-soluble drug siramesine hydrochloride was precipitated by the antisolvent method in the presence of each of various polymeric and surface active excipients. Powder dissolution studies of six of the resulting particle systems showed a significant increase in percent dissolved after 15 min compared to the starting material.A quantitative determination of the amount of excipient adsorbed to the surface of the drug particles proved that only a very small amount of excipient was needed to exert a marked effect on particle properties. The adsorbed amount of excipient constituted less than 1.4% (w/w) of the total particle weight, and thus powders of very high drug loads were obtained. Sodium lauryl sulphate (SLS), hydroxypropyl methylcellulose (HPMC), and hydroxypropyl cellulose (HPC), which exhibited the greatest degree of adsorption, also had the greatest effect on the physicochemical properties of the particles. X-ray Photoelectron Spectroscopy (XPS) analysis of the surface composition and scanning electron microscopy studies on particle morphology suggested that the excipients adsorbed to specific faces of the crystals.     

The influence of agitation intensity, particle size and pH of dissolution fluid on the in-vitro release of drug from hard gelatin capsules

The influence of agitation intensity on the in-vitro release of controlled particle size fractions of acetylsalicylic acid from hard gelatin capsules into buffered dissolution fluids has been investigated employing a dissolution technique. The value of T50 decreased as the stirring rate increased from 120 to 320 rev min-1 for all particle size fractions and pH values. A further increase in the stirring rate had a limited effect on the value of T50 and the changes were particle size dependent. The influence of the drug solubility, induced by changing the pH of the dissolution fluid, was decreased by increased agitation. When the capsules were filled at bulk densities above the maximum tapped bulk density, the value of T50 was increased, the extent of increase being greater the smaller the particle size of the drug. The kinetics of the solution process were influenced by agitation intensity and particle packing.     

Effect of particle size on the dissolution behaviors of poorly water-soluble drugs

This study examined the effects of the particle size of various poorly water-soluble drugs on their dissolution behavior through physicochemical and mathematical analysis. As model drugs, hydrochlorothiazide, aceclofenac, ibuprofen and a discovery candidate were selected. The materials were crystallized using an evaporation method and milled without transformation behavior of crystal forms. The particles were sieved and divided into four size groups (< 45 μm, 45～150 μm, 150～250 μm, and 250～600 μm). The specific surface area with regard to the particle size was measured using a BET surface area measurement. The specific surface area increased with decreasing particle size of the drug, resulting in an increase in dissolution rate. During the initial period of the dissolution study, significant differences in dissolution rate were observed according to the particle size and specific surface areas. On the other hand, in the later stages, the surface-specific dissolution rate was almost consistent regardless of the particle size. These observations were evaluated mathematically and the results suggested that the dissolution rate of poorly soluble drugs is strongly related to the particle size distribution. Moreover, physicochemical analysis helped explain the effect of particle size on the dissolution profiles.     

Rationale for ibuprofen co-administration with antacids: Potential interaction mechanisms affecting drug absorption

Ibuprofen is a widely used NSAID which is often co-administered with antacids because of its gastro-irritant effects. Literature data suggest that antacid interactions may increase or decrease the drug's absorption rate and onset of action and that the interaction may be formulation specific. In the present study, literature data on ibuprofen absorption were evaluated in order to gain insight into the nature of the in vivo effect. Solubility determinations in reactive media containing magnesium or aluminium and dissolution studies in the presence of antacid suspension were performed in an attempt to simulate in vitro the effects observed in vivo. The results obtained indicate that magnesium hydroxide enhances ibuprofen solubility, dissolution and bioavailability, while aluminium hydroxide has a retarding effect. Solubility studies indicated formation of a soluble solid ibuprofen phase in the presence of Mg2+, in contrast, an insoluble ibuprofen salt was formed with Al3+. The introduction of magnesium based antacid suspension into the dissolution media resulted in a formulation specific increase in drug dissolution rate with the most pronounced effect observed for the slowest release tablet formulation. The results obtained indicate the potential for in vitro studies to predict physicochemical interactions that are likely to influence drug absorption rate in vivo.     

Physicochemical characterization of meloxicam-mannitol binary systems

The dissolution behaviour of drugs remains one of the most challenging aspects in formulation development. The anti-inflammatory drug, meloxicam (ME) has poor water solubility. The object of this experiment was to improve the rate of dissolution of meloxicam in capsule form. In order to achieve this, mannitol was used as a carrier in different ratios, in physical mixtures and melted forms. Mannitol, a sugar alcohol, is a cheap and readily available excipient. Differential scanning calorimetry (DSC) and X-ray diffractometry were used to investigate the characteristics of meloxicam-mannitol binary systems. Multivariate curve resolution (MCR) as a chemometric method was applied to interpret the X-ray diffractograms. This is believed to be the first published use of this reasoning for this interpretation. According to the results, the amount of mannitol and the particle size of ME were important factors in the rate of dissolution. To the perfect dissolution of ME, the melt technology was used which resulted in mixed crystals. This technology was made by 10 parts of mannitol and 1 part of ME2 with about 6 microm in average particle size. The interaction (adhesion) between mannitol and ME for physical mixtures was not enough to the perfect dissolution.     

藤黄酸自微乳化释药系统的制备与质量评价

目的构建藤黄酸自微乳化释药系统(GA-SMEDDSs),并对其质量进行评价。方法通过溶解度实验确定GA-SMEDDSs使用的油相、乳化剂和助乳化剂种类,根据伪三元相图法绘制出影响其微乳液形成的辅料用量范围,采用中心复合设计-效应面法优化并确定GA-SMEDDSs的最佳处方组成,在透射电镜下观察GA-SMEDDSs形成微乳的微观结构,用马尔文激光粒度仪测定粒径分布,考察GA-SMEDDSs经模拟人体生理体液稀释后的稳定性,比较GA-SMEDDSs与原料药的体外药物溶出速率。结果通过实验优化得到GA-SMEDDSs的最优处方组成:肉豆蔻酸异丙酯(IPM)质量分数为20.0%,辛酸癸酸聚乙二醇甘油酯(labrasol)质量分数为35.0%,二乙二醇单乙基醚(transcutol P)质量分数为45.0%,GA-SMEDDSs经水分散可形成黄色透明状微乳液,透射电镜下可观察到微乳呈类球状,大小均匀,平均粒径为168.4±5.9 nm;经模拟人体生理体液稀释后微乳物理稳定性良好;GA-SMEDDSs在人工胃液和人工肠液中药物溶出速率均显著提高。结论藤黄酸制备成自微乳化释药系统可提高药物溶出速度,...     

Jet milling industrialization of sticky active pharmaceutical ingredient using quality-by-design approach

Jet milling is frequently used in pharmaceutical industry to achieve different objectives. It can be used as enabling technology to overcome poor water solubility linked to hydrophobic active of pharmaceutical ingredient (API) by reducing the particle size and therefore increasing the dissolution rate. Alternatively, jet milling can be used either to enhance blending efficiency of API with excipient in case of formulation at low dosage strength or to achieve the required particle size for inhalation therapy. In this study, development of commercial manufacturing process of sticky API and its industrialization are described. The methodology used is based on quality-by-design approach to deliver safe, effective and robust manufacturing process. The study showed that the specific energy is a key factor that drives particle size during jet milling and the scale-up from lab to industrial scale. After understanding the process, a design space was built where different zones such as operating point, operating space (where the product is compliant to specification despite variability of process parameters), and the knowledge space were outlined. Finally, an industrial installation was proposed to deliver product with high productivity yield, compliant with safety regulation, and cleanable in place.     

Effect of Excipients on the Particle Size of Precipitated Pioglitazone in the Gastrointestinal Tract: Impact on Bioequivalence

This study sought to understand the reasons for the bioinequivalence of a newly developed generic product of pioglitazone hydrochloride and to improve its formulation so that it is equivalent to that of the reference listed drug (RLD). In this clinical study, despite a similar in vitro dissolution profile, the new oral product exhibited a lower plasma concentration of pioglitazone compared to the RLD. The strong pH-dependency of pioglitazone solubility as a weak base indicates that pioglitazone would precipitate in the small intestine after being dissolved in the stomach. Thus, in vitro experiments were performed to investigate the effect of excipients on the particle size distribution of precipitated pioglitazone. Then, the impact of particle size on in vivo absorption was discussed. The precipitated pioglitazone from the RLD showed a peak for small particles (less than 1 μm), which was not observed in the precipitate from the new product. As an excipient, hydroxypropyl cellulose (HPC) influenced the particle size of precipitated pioglitazone, and the amount of HPC in the formulation was increased to the same level as that in the RLD. The precipitate from this improved product showed approximately the same particle size distribution as that of the RLD and successfully demonstrated bioequivalence in the clinical study. In conclusion, for drugs with low solubility, this type of analysis of the particle size distribution of precipitated drugs, in addition to the dissolution test, may help to obtain a better in vitro-in vivo correlation for oral absorption and to develop a bioequivalent product.     

Enhanced dissolution of ibuprofen using solid dispersion with poloxamer 407

To improve its dissolution, ibuprofen solid dispersions (SDs) were prepared, characterized by scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and Fourier transform infrared spectroscopy (FTIR), and evaluated for solubility, and in-vitro ibuprofen release. Loss of individual surface properties during melting and re-solidification as revealed by SEM micrographs indicated the formation of effective SDs. Absence or shifting towards the lower melting temperature of the drug peak in SDs and physical mixtures in DSC study indicated the possibilities of drug-polymer interactions. FTIR spectra showed the presence of drug crystalline in SDs. The effect of improved dissolution on the oral absorption of ibuprofen in rats was also studied. Quicker release of ibuprofen from SDs in rat intestine resulted in a significant increase in AUC and C_max, and a significant decrease in T_max over pure ibuprofen. Comparison of the enhanced solubility, dissolution, AUC, and C_max of ibuprofen from different poloxamers suggested that the preparation of ibuprofen SDs using P 407 as a meltable hydrophilic polymer carrier could be a promising approach to improve its solubility, dissolution and absorption rate.     

The influence of pH of dissolution fluid and particle size of drug on the in-vitro release of drug from hard gelatin capsules

The influence of pH of the dissolution fluid on the in-vitro release of acetylsalicylic acid from hard gelatin capsules has been studied for a series of particle size fractions of the drug. Generally, the time required for 50% of the drug content of the capsule to appear in solution during a dissolution test, T50, increased as the pH increased from 1.2 to 2.0; thereafter the value of T50 decreased as the pH increased from 3 to 7. These changes were found to be related to the apparent solubility of the drug. The extent of the changes was found to be further dependent on the particle size of the drug. For capsules filled with particle size fractions of 2.5 and 5.5 microns median diameter, the changes were small. Larger changes were observed with particles of median diameters of 45, 100, 220 and 330 microns while the largest changes (greater than two-fold) were obtained with particles of median diameter 130 and 430 microns. The type of kinetics that could be used to express the release rates was found to be particle size-dependent. For particles of 45 microns and larger, the release rate followed an apparent zero order process while an apparent first order process represented the release for the two smallest particle size fractions.     

Dissolution rate enhancement of gliclazide by ordered mixing

The poorly water soluble antidiabetic drug gliclazide was selected to study the effect of excipients on dissolution rate enhancement. Ordered mixtures of micronized gliclazide with lactose, mannitol, sorbitol, maltitol and sodium chloride were prepared by manual shaking of glass vials containing the drug and excipient(s). Different water soluble excipients, addition of surfactant and superdisintegrant, drug concentration and carrier particle size influenced the dissolution rate of the drug. Dissolution rate studies of the prepared ordered mixtures revealed an increase in drug dissolution with all water soluble excipients. The order of dissolution rate improvement for gliclazide was mannitol > lactose > maltitol > sorbitol > sodium chloride. Composite granules of the particle size range 355-710 μm were superior in increasing the drug dissolution rate from ordered mixtures. Reducing the carrier particle size decreased the dissolution rate of the drug as well as the increase in drug concentration. Kinetic modeling of drug release data fitted best the Hixson-Crowell model, which indicates that all the ordered mixture formulations followed the cube root law fairly well.     

Dissolution rate studies of pharmaceutical multisized powders — A practical approach using the coulter method

The aim of this work is the study of the influence of particle size and related properties on the dissolution rate of a sparingly soluble drug indomethacin. Different size fractions were fully characterized concerning particle size distribution, specific surface area, density, degree of crystallinity and solubility. A particle size counter the Coulter Multisizer II — was used, not only to characterize the primary particle size distribution of the different fractions, but also to monitor the size and number of the suspended particles during the dissolution process. Although this information was applied to evaluate dissolution profiles (dissolution drug concentration vs. time) it can be further used to thoroughly study the dissolution phenomenon. The accuracy of this instrument to assess dissolution profiles was confirmed by comparing its results with those obtained by HPLC. As expected a strong influence of the fraction size on the dissolution rate was found. A correlation was established between the mean dissolution time (MDT) and the mean particle size of the various indomethacin fractions.     

Preparation, characterization and in vivo evaluation of amorphous atorvastatin calcium nanoparticles using supercritical antisolvent (SAS) process

In this work, amorphous atorvastatin calcium nanoparticles were successfully prepared using the supercritical antisolvent (SAS) process. The effect of process variables on particle size and distribution of atorvastatin calcium during particle formation was investigated. Solid state characterization, solubility, intrinsic dissolution, powder dissolution studies and pharmacokinetic study in rats were performed. Spherical particles with mean particle size ranging between 152 and 863 nm were obtained by varying process parameters such as precipitation vessel pressure and temperature, drug solution concentration and feed rate ratio of CO2/drug solution. XRD, TGA, FT-IR, FT-Raman, NMR and HPLC analysis indicated that atorvastatin calcium existed as anhydrous amorphous form and no degradation occurred after SAS process. When compared with crystalline form (unprocessed drug), amorphous atorvastatin calcium nanoparticles were of better performance in solubility and intrinsic dissolution rate, resulting in higher solubility and faster dissolution rate. In addition, intrinsic dissolution rate showed a good correlation with the solubility. The dissolution rates of amorphous atorvastatin calcium nanoparticles were highly increased in comparison with unprocessed drug by the enhancement of intrinsic dissolution rate and the reduction of particle size resulting in an increased specific surface area. The absorption of atorvastatin calcium after oral administration of amorphous atorvastatin calcium nanoparticles to rats was markedly increased.     

Comminution of ibuprofen to produce nano-particles for rapid dissolution

A critical problem associated with poorly soluble drugs is low and variable bioavailability derived from slow dissolution and erratic absorption. The preparation of nano-formulations has been identified as an approach to enhance the rate and extent of drug absorption for compounds demonstrating limited aqueous solubility. A new technology for the production of nano-particles using high speed, high efficiency processes that can rapidly generate nano-particles with rapid dissolution rate has been developed. Size reduction of a low melting ductile model compound was achieved in periods less than 1h. Particle size reduction of ibuprofen using this methodology resulted in production of crystalline particles with average diameter of approximately 270nm. Physical stability studies showed that the nano-suspension remained homogeneous with slight increases in mean particle size, when stored at room temperature and under refrigerated storage conditions 2-8°C for up to 2 days. Powder containing crystalline drug was prepared by spray-drying ibuprofen nano-suspensions with mannitol dissolved in the aqueous phase. Dissolution studies showed similar release rates for the nano-suspension and powder which were markedly improved compared to a commercially available drug product. Ibuprofen nano-particles could be produced rapidly with smaller sizes achieved at higher suspension concentrations. Particles produced in water with stabilisers demonstrated greatest physical stability, whilst rapid dissolution was observed for the nano-particles isolated in powder form.     

Development and Evaluation of Sustained-Release Ibuprofen–Wax Microspheres. II. In Vitro Dissolution Studies

A modified USP paddle method using minibaskets was used to study the effects of various formulations on in vitro dissolution of ibuprofen microspheres. Formulations containing waxes such as paraffin or ceresine wax without modifiers exhibited very slow dissolution profiles and incomplete release, which did not improve with increased drug loading or the preparation of smaller microspheres. The addition of modifiers such as stearyl alcohol and glyceryl mono-stearate greatly increased the dissolution rate, with 20% (w/w) near the optimum for predictable dissolution. Higher drug loading and decreased microsphere size increased the dissolution rate from microspheres containing modifier. Optimum formulations contained ceresine wax or microcrystalline wax and stearyl alcohol as a modifier, with a drug content of 17%. An increase in the encapsulation dispersant concentration had little effect on the dissolution profiles. The dissolution data from narrow size fractions of microspheres indicated spherical matrix drug release kinetics; the 50% dissolution time decreased with the square of the microsphere diameter. With appropriate modifiers, wax microsphere formulations of drugs with solubility characteristics similar to those of ibuprofen can offer a starting basis for predictable sustained release dosage forms.     

Determination of surface-adsorbed excipients of various types on drug particles prepared by antisolvent precipitation using HPLC with evaporative light scattering detection

A common challenge in the development of new drug substances is poor dissolution characteristics related to low aqueous solubility. One approach to overcome this problem is antisolvent precipitation in the presence of polymers or surfactants, which may enhance the dissolution rate through reduced particle size and increased wettability. In this study, a simple method based on size exclusion chromatography (SEC) with evaporative light scattering detection (ELSD) was developed for the determination of polymers and surfactants adsorbed to drug particles prepared by antisolvent precipitation of the poorly water-soluble model drug Lu 28-179. Detection of many polymeric excipients and surfactants is problematic due to the lack of UV-absorbing chromophores, but ELSD proved successful for the direct determination of the investigated compounds. A mixed mode column was used to effectively separate each of the excipient structures from the drug. The mobile phase comprised acetonitrile-ammonium formate (20mM; pH 6.5) (50:50, v/v) at a flow-rate of 0.6 ml/min. Qualification studies showed that the method was adequately sensitive and precise with limits of detection between 0.72 and 4.32 microg/ml. Linearity of the calibration curves was achieved by log-log modelling. The method was applied for determination of nine polymeric excipients and surfactants adsorbed to particles of the model drug. The extent of excipient adsorption varied between 0.07 and 1.39% (w/w) of the total particle weight.     

Improved solubility and in vitro dissolution of Ibuprofen from poloxamer gel using eutectic mixture with menthol

To improve the solubility and in vitro dissolution of poorly water-soluble ibuprofen with poloxamer and menthol, the effects of menthol and poloxamer 188 on the aqueous solubility of ibuprofen were investigated. The dissolution study of ibuprofen delivered by poloxamer gels composed of poloxamer 188 and menthol were performed. In the absence of poloxamer, the solubility of ibuprofen increased until the ratio of menthol to ibuprofen increased from 0:10 to 4:6, followed by an abrupt decrease in solubility above the ratio of 4:6, indicating that 4 parts of ibuprofen formed eutectic mixture with 6 parts of menthol. In the presence of poloxamer 188, the solutions with the same ratio of menthol to ibuprofen showed abrupt increase in the solubility of ibuprofen. Furthermore, the solution with ratio of 4:6 showed more than 2.5- and 6-fold increase in the solubility of ibuprofen compared with that without poloxamer and that without menthol, respectively. The poloxamer gel with menthol/ibuprofen ratio of 1:9 and higher than 15% poloxamer 188 showed the maximum solubility of ibuprofen, 1.2 mg/ml. Menthol improved the dissolution rates of ibuprofen from poloxamer gels. Dissolution mechanism showed that the dissolution rate of ibuprofen from the poloxamer gels without menthol was independent of the time, but the drug might be dissolved from the poloxamer gels with menthol by Fickian diffusion. Thus, the poloxamer gels developed using eutectic mixture with menthol, which gave the improved solubility and dissolution of drug, are potential candidates for ibuprofen-loaded transdermal and rectal delivery system.     

Influence of different sources on the processing and biopharmaceutical properties of high-dose ibuprofen formulations.

It is known that depending on the manufacturing and synthetic processes, drugs may exist as different forms. As a result, physicochemical properties, compression characteristics, intrinsic dissolution and bioavailability may vary substantially. The purpose of this study was to investigate the effect of different sources of ibuprofen on the processing of tablets and on their properties. Another emphasis of this work was to rationalize one or several key characteristics of the raw material as directly related to wet granulation parameters and to the behavior of final tablets. Commercially available ibuprofen was obtained from different manufacturers and a preformulation program, including X-ray crystallography, differential scanning calorimetry, scanning electron microscopy, determination of particle size distribution and flowability, was performed to characterize the raw material. Granules were prepared with a planetary mixer and liquid requirements for the end point were obtained by monitoring power consumption. Tablets were manufactured on Stokes rotary and single punch instrumented presses. Data acquisition interfaces produced compression data for each formulation. Granules and final tablets were analyzed for hardness, dissolution profiles and content uniformity. Statistical evaluations using analysis of variance and multiple comparison procedures were performed on the results to determine the significance of the variability between independent parameters. The ibuprofen tested was found to be a unique polymorphic form with some differences in the external crystallinity. The particle size characteristics of the material also allowed a differentiation between sources and although there was no differences in dissolution patterns or content uniformity, particle size was found to account for 50% of the variability in tablet hardness. Two sources of ibuprofen with lower mean particle size showed significant variations in end point liquid requirements resulting in variable tablet crushing strength.