In Vitro Dissolution Profile of Water-Insoluble Drug Dosage Forms in the Presence of Surfactants

The determination of the in vitro release profile of water-insoluble drug products requires dissolution media different from those used for water-soluble drug products. Since the relevance of drug dissolution in organic solvents is questionable, we investigated the use of surfactants to determine the dissolution profiles of water-insoluble drug products. In most cases, the drug dissolution rate and extent increased as the surfactant concentration in the aqueous dissolution medium increased. Suitable dissolution profiles were obtained in the presence of sodium lauryl sulfate (SLS) for water-insoluble drug products, such as griseofulvin, carbamazepine, clofibrate, medroxyprogesterone, and cortisone acetate. These findings recommend the use of surfactants for determining the aqueous dissolution of water-insoluble drug products rather than adding organic solvents to the dissolution medium.     

不同厂家洛索洛芬钠片溶出度比较

目的 比较5个厂家洛索洛芬钠片在4种溶出介质中的溶出曲线,以评价该药品的质量。方法 采用桨法、转速50 r·min^-1、溶出介质900 mL进行体外溶出试验,分别考察不同厂家洛索洛芬钠片在盐酸溶液、pH 4.5醋酸盐缓冲液、水和pH 6.8磷酸盐缓冲液4种溶出介质中的体外溶出行为,测定溶出曲线并采用相似因子法与原研药进行比较分析。结果 5个厂家洛索洛芬钠片在盐酸溶液中的溶出曲线基本一致,4个厂家的样品与原研药在水中的溶出曲线差异较大,2个厂家样品批间差异明显。结论 仿制药厂家生产的药品与原研药存在质量差异,建议结合生物等效性试验改进处方及生产工艺,提高该药品质量。     

Development and Validation of a Discriminatory Dissolution Method for Rifaximin Products

The commercial product of rifaximin (RFX) contains α form. The α form can change to β form on exposure to high humidity that can occur during manufacturing, stability, and in-use period. It is critical to maintain α form of the drug in a drug product to avoid variability in clinical response. U.S. Food and Drug Administration dissolution method was found to be nondiscriminatory for RFX formulations containing either 100% α or β form. The objective of this study was to develop a discriminatory dissolution method that can detect low levels of α to β transformation in RFX products. Formulations containing a variable fraction of α and β forms were prepared by using direct compression method. Dissolution parameters investigated were type of dissolution medium (water and phosphate buffer), volume (500, 900, and 1000 mL), and paddle speed (50, 75, and 150 rpm). Dissolution in water with 0.2% sodium lauryl sulfate was less than 80% and nondiscriminatory. However, dissolution tested in a phosphate buffer pH 7.4 with 0.2% sodium lauryl sulfate at 50 rpm was discriminatory with more than 17.5% difference in dissolution profile between formulations containing α and β forms. The developed method can detect polymorphic transformation if there is 25% or more β form conversion.     

Dissolution Testing as a Prognostic Tool for Oral Drug Absorption: Dissolution Behavior of Glibenclamide

Purpose. The dissolution behavior of two commercially availableglibenclamide formulations was tested in various media. The aim of thestudy was to investigate whether the use of biorelevant dissolutionmedia (BDM) would be advantageous over the use of standard mediafor predicting the in vivo performance of the two formulations.Methods. The dissolution tests were performed using USP 23 apparatus2. Conventional buffers and USP media were compared with two BDMcontaining different amounts of lecithin and sodium taurocholate.Results. The dissolution of two drug powders was highly dependenton wetting, particle size, pH, and the composition of the mediumused. In addition, the dissolution behavior of the two glibenclamideformulations showed differences in all media tested. The dissolutionresults of the two formulations were compared with those from anin vivo bioequivalence study undertaken by the central quality controllaboratory of the German pharmacists (ZL). The bioequivalencecriterion set by the ZL requires more than 80;pc drug release within 10minutes. Results in FaSSIF, one of the BDMs, met the ZL criterionand this medium was also able to discriminate between the twoformulations. This was not the case for the other media tested.Conclusions. The study indicates that BDM are better able to discriminatebetween glibenclamide formulations than standard dissolutionmedia.     

非诺贝特体外溶出度考察及其微粉化制剂的研究

目的考察不同厂家非诺贝特固体制剂体外溶出度以及微粉化对非诺贝特溶出度的影响。方法分别以 40 % (φ)乙醇溶液、5 0 % (φ)乙醇溶液、5g/L十二烷基硫酸钠溶液、1 0g/L十二烷基硫酸钠溶液为溶出介质 ,对 4种市售非诺贝特固体制剂的体外溶出度进行考察。采用球磨机制备微粉化非诺贝特 ,对其溶出度进行测定。结果 1 0 g/L十二烷基硫酸钠溶液中微粉化制剂的溶出速率明显快于其余 3种非微粉化制剂 ,初步探讨了非诺贝特固体制剂体外溶出度标准。用相似因子法对自制微粉化胶囊和法国生产的微粉化胶囊的溶出实验数据进行统计分析 ,结果表明两者溶出行为相似 ,相似因子f2 =72 4(5 0≤f2 ≤ 1 0 0 )。结论不同厂家非诺贝特固体制剂的溶出度差异较大 ,微粉化工艺能显著提高非诺贝特的溶出度     

长春西汀海藻酸钠骨架片体外释药影响因素研究

目的以海藻酸钠为骨架材料 ,制备长春西汀控释骨架片 ,对影响其体外释放的多种因素进行了考察。方法以海藻酸钠为亲水骨架材料 ,粉末直接压片制备长春西汀控释片 ,采用《中华人民共和国药典》2 0 0 0年版二部收载的溶出度测定方法Ⅱ法 (桨法 ) ,测定药物在不同条件下的体外释放度 ,考察海藻酸钠用量及黏度 ,枸橼酸用量 ,释放介质离子强度和pH值对药物体外释放行为的影响。结果与结论海藻酸钠用量及黏度 ,枸橼酸用量 ,释放介质离子强度和pH值均对药物体外释放行为有显著影响。值得注意的是 ,通过调节处方中枸橼酸用量可以使释药行为达零级 ,这为制备长春西汀控释片提供指导 ,有进一步开发的价值。     

苯溴马隆片溶出度测定方法的研究

目的:建立苯溴马隆片的溶出度测定方法。方法:通过对溶出介质、溶出方法、转速和取样时间的选择,确定苯溴马隆片的溶出度方法。并对方法的回收率、线性、稳定性进行考察。结果:采用桨法,以含0.25%十二烷基硫酸钠的磷酸盐缓冲液为溶出介质,转速100 r.min-1,45 min取样,以紫外分光光度法测定。苯溴马隆在2.085～16.678μg.mL-1范围内溶液浓度与吸收值呈良好线性关系(r=0.999 5);平均回收率为98.9%,(RSD为0.84%,n=9)。结论:该方法稳定、简便易行,可用于苯溴马隆片的溶出度检查。     

阿魏酸钠滴丸的制备及溶出度测定

目的：通过固体分散技术制备滴丸，以提高阿魏酸钠的溶出度。方法：以聚乙二醇（PEG）6000、泊洛沙姆188为载体基质制备滴丸，HPLC法测定含量，转篮法考察溶出度。结果：滴丸中PEG6000／药物比值越大．阿魏酸钠溶出越快；所制得滴丸外观圆整，质地均匀；分别以0．1mol／L盐酸溶液、水、pH6,8磷酸盐缓冲液为溶出介质，阿魏酸钠滴丸均较市售片显著增加溶出度。结论：阿魏酸钠滴丸具有良好的速释效果。     

Enhanced dissolution of sildenafil citrate as dry foam tablets

Dry foam formulation technology is alternative approach to enhance dissolution of the drug. Sildenafil citrate was suspended in sodium dodecyl sulfate solution and adding a mixture of maltodextrin and mannitol as diluent to form a paste. Sildenafil citrate paste was passed through a nozzle spray bottle to obtain smooth foam. The homogeneous foam was dried in a vacuum oven and sieved to obtain dry foam granules. The granules were mixed with croscarmellose sodium, magnesium stearate and compressed into tablet. All formulations were evaluated for their physicochemical properties and dissolution profiles. All the tested excipients were compatible with sildenafil citrate by both differential scanning calorimetry (DSC) and infrared (IR) analysis. There are no X-ray diffraction (XRD) peaks representing crystals of sildenafil citrate observed form dry foam formulations. The hardness of tablets was about 5?kg, friability test <1% with a disintegration time <5?min. The sildenafil citrate dry foam tablet had higher dissolution rate in 0.1 N HCl in comparison with commercial sildenafil citrate tablet, sildenafil citrate prepared by direct compression and wet granulation method. Sildenafil citrate dry foam tablet with the high-level composition of surfactant, water and diluent showed enhanced dissolution rate than that of the lower-level composition of these excipients. This formulation was stable under accelerated conditions for at least 6 months.     

A biorelevant dissolution stress test device – background and experiences

Importance of the field: The prediction of the in vivo drug release characteristics of modified release (MR) oral dosage forms by in vitro dissolution tests is a prerequisite for successful product development.

Areas covered in this review: To improve the predictive power of dissolution testing, the authors recently developed a new dissolution test apparatus that simulates physical conditions of the gastrointestinal (GI) passage of MR dosage forms. The simulation includes pressure force exerted by GI motility, shear stress force generated during phases of GI transport and intermittent contact with intestinal fluids while the dosage form is located in an intestinal air pocket.

What the reader will gain: The article briefly describes selected aspects of GI tract physiology, evolution and goals of dissolution testing as well as the development and use of test devices that are intended to simulate GI tract conditions. The data are discussed in the light of the test results obtained with the new dissolution stress test device developed by the authors' group. Achievements reported from 1986 to 2010 are referred to.

Take home message: The new apparatus was evaluated using extended release (ER) tablets of nifedipine and diclofenac. The dissolution characteristics of some of the tested products were strongly dependent on the test conditions and could be distinctly influenced by the mechanical stress events of biorelevant intensity. Results of these experiments thus indicated that a high sensitivity of dosage forms to GI-specific physical conditions has to be regarded as a major cause of irregularities in the drug release profiles, which may result in fluctuations of the individual drug plasma concentration profiles, as, for example, caused by dose dumping.     

Development of Fast Dispersible Aceclofenac Tablets: Effect of Functionality of Superdisintegrants

Aceclofenac, a non-steroidal antiinflammatory drug, is used for posttraumatic pain and rheumatoid arthritis. Aceclofenac fast-dispersible tablets have been prepared by direct compression method. Effect of superdisintegrants (such as, croscarmellose sodium, sodium starch glycolate and crospovidone) on wetting time, disintegration time, drug content, in vitro release and stability parameters has been studied. Disintegration time and dissolution parameters (t_50% and t_80%) decreased with increase in the level of croscarmellose sodium. Where as, disintegration time and dissolution parameters increased with increase in the level of sodium starch glycolate in tablets. However, the disintegration time values did not reflect in the dissolution parameter values of crospovidone tablets and release was dependent on the aggregate size in the dissolution medium. Stability studies indicated that tablets containing superdisintegrants were sensitive to high humidity conditions. It is concluded that fast-dispersible aceclofenac tablets could be prepared by direct compression using superdisintegrants.     

光纤药物溶出仪实时测定孟鲁司特钠片溶出度

目的对孟鲁司特钠片进行全程的实时、原位在线溶出度测定,并与该品种现有标准溶出度测定结果进行比较。方法采用FODT-601光纤药物溶出仪,选择284/500 nm双波长法,消除辅料的干扰,按该品种现有标准溶出度检查项溶出条件,测试该药物溶出曲线,并将二者测得的溶出曲线进行比较。结果在1.0¹2μg·mL-1范围内,浓度对应的溶出量(Q)%与吸光度(A)呈良好的线性关系,相关系数为0.9993;3个浓度的平均回收率为99.3%、98.9%、98.5%;对应的RSD分别为0.86%、1.02%、0.91%(n=18)。结论与现有标准方法相比,光纤药物溶出仪能连续提供药品溶出过程的信息,可更好的为药品生产工艺和内在质量提供有效的评价依据。     

Dissolution of artemisinin/polymer composite nanoparticles fabricated by evaporative precipitation of nanosuspension

Objectives An evaporative precipitation of nanosuspension (EPN) method was used to fabricate composite particles of a poorly water‐soluble antimalarial drug, artemisinin, with a hydrophilic polymer, polyethylene glycol (PEG), with the aim of enhancing the dissolution rate of artemisinin. We investigated the effect of polymer concentration on the physical, morphological and dissolution properties of the EPN‐prepared artemisinin/PEG composites. Methods The original artemisinin powder, EPN‐prepared artemisinin nanoparticles and artemisinin/PEG composites were characterised by scanning electron microscopy, Fourier‐transform infrared spectroscopy, differential scanning calorimetry (DSC), X‐ray diffraction (XRD), dissolution testing and HPLC. The percentage dissolution efficiency, relative dissolution, time to 75% dissolution and mean dissolution time were calculated. The experimental drug dissolution data were fitted to various mathematical models (Weibull, first‐order, Korsemeyer–Peppas, Hixson–Crowell cube root and Higuchi models) in order to analyse the release mechanism. Key findings The DSC and XRD studies suggest that the crystallinity of the EPN‐prepared artemisinin decreased with increasing polymer concentration. The phase‐solubility studies revealed an A_L‐type curve, indicating a linear increase in drug solubility with PEG concentration. The dissolution rate of the EPN‐prepared artemisinin and artemisinin/PEG composites increased markedly compared with the original artemisinin powder. Conclusions EPN can be used to prepare artemisinin nanoparticles and artemisinin/PEG composite particles that have a significantly enhanced dissolution rate. The mechanism of drug release involved diffusion and erosion.     

Interactions between a poorly soluble cationic drug and sodium dodecyl sulfate in dissolution medium and their impact on in vitro dissolution behavior

In the pharmaceutical industry, in vitro dissolution testing ofsolid oral dosage forms is a very important tool for drug development and quality control. However, ion-pairing interaction between the ionic drugand surfactants in dissolution medium often occurs, resulting in inconsistent and incomplete drug release. The aim of this study is toevaluate the effects ofsodium dodecyl sulfate (SDS) mediated medium onthe dissolution behaviors of a poorly soluble cationic drug (Drug B). The study was carried out by measuring solubility of Drug B substance and dissolution rate of Drug B product in media containing SDS.Desolubilization of Drug B substance was observed at pH 4.5 in the presence of SDS at concentrations below critical micelle concentration (CMC) which is attributed to the formation of an insoluble di-dodecyl sulfate salt between SDS and Drug B. This ion-pairing effect is less significant with increasing medium pH where Drug B is less ionized and CMC of SDS is lower. In medium at pH 4.5, dissolution of Drug B product was found incomplete with SDS concentration below CMC due to the desolubilization of Drug B substance. In media with SDS level above CMC, the dissolution rate is rather slower with higher inter-vessel variations compared to that obtained in pH 4.5 medium without SDS. The dissolution results demonstrate that the presence of SDS in medium generates unexpected irregular dissolution profiles for Drug B which are attributed to incompatible dissolution medium for this particular drug. Therefore, non-ionic surfactant was selected for Drug B product dissolution method and ion-pairing effect in SDS mediated medium should be evaluated when developing a dissolution method for any poorly soluble cationic drugs.     

Dynamic Dissolution Testing To Establish <Emphasis Type="BoldItalic">In Vitro</Emphasis>/<Emphasis Type="BoldItalic">In Vivo</Emphasis> Correlations for Montelukast Sodium,a Poorly Soluble Drug

Purpose  The objectives of the study was to develop a dissolution test method that can be used to predict the oral absorption of montelukast sodium, and to establish an in vitro/in vivo correlation (IVIVC) using computer simulations. Methods  Drug solubility was measured in different media. The dissolution behaviour of montelukast sodium 10 mg film coated tablets was studied using the flow-through cell dissolution method following a dynamic pH change protocol, as well as in the USP Apparatus 2. Computer simulations were performed using GastroPlus™. Biorelevant dissolution media (BDM) prepared using bile salts and lecithin in buffers was used as the dissolution media, as well as the USP simulated intestinal fluid (SIF) pH 6.8 and blank FaSSIF pH 6.5. Dissolution tests in the USP Apparatus 2 were performed under a constant pH condition, while the pH range used in the flow through cells was pH 2.0 to 7.5. The in vitro data were used as input functions into GastroPlus™ to simulate the in vivo profiles of the drug. Results  The solubility of montelukast sodium was low at low pH, but increased as the pH was increased. There was no significant difference in solubility in the pH range of 5.0 to 7.5 in blank buffers, but the drug solubility was higher in biorelevant media compared with the corresponding blank buffers at the same pH. Using the flow through cells, the dissolution rate was fast in simulated gastric fluid containing 0.1% SLS. The dissolution rate slowed down when the medium was changed to FaSSIF pH 6.5 and increased when the medium was changed to FaSSIF medium at pH 7.5. In the USP Apparatus 2, better dissolution was observed in FaSSIF compared with the USP buffers and blank FaSSIF with similar pH values. Dissolution was incomplete with less than 10% of the drug dissolved in the USP-SIF, and was practically non existent in blank FaSSIF pH 6.5. The in vitro results of the dynamic dissolution test were able to predict the clinical data from a bioavailability study best. Conclusions  Dynamic dissolution testing using the flow through cell seems to be a powerful tool to establish in vitro/in vivo correlations for poorly soluble drugs as input function into GastroPlus.     

用光纤过程监测不同厂家螺内酯片的溶出度

目的：对6个厂家生产的螺内酯片进行溶出度的实时监测,考察并评价其工艺质量。方法：采用光纤药物溶出度实时测定仪进行溶出度测定。采用桨法,以含0.1%十二烷基硫酸钠的0.1 mol/L盐酸溶液1 000 ml为溶出介质,设定水浴温度37℃,转速75 r/min,检测波长242 nm,参比波长550 nm,用3 mm探头监测螺内酯片的溶出曲线,对实时相对溶出百分率与溶出时间进行作图分析。结果：各厂家螺内酯片的溶出度均符合《中华人民共和国药典》规定,但溶出曲线和溶出速率存在差异。结论：利用光纤药物溶出度实时测定仪监测螺内酯片的溶出度,可以实时、连续、动态、定量地监测药物的溶出过程,直观地反映各厂家同种药品溶出过程的差异,为全面评价药品的内在质量提供参考。     

Dissolution of lonizable Drugs in Buffered and Unbuffered Solutions

The dissolution kinetics of ionizable drugs (weak acids or bases) are analyzed with a mathematical model derived from the theory of mass transfer with chemical reaction. The model assumes that the overall process is diffusion limited, that all the reactions are reversible and instantaneous, and that dissolution and reaction are limited to the stagnant fluid film adjacent to the solid phase. Dissolution into buffered and unbuffered aqueous solutions are considered separately, with covenient analytical solutions obtained in both cases. In addition, equations for the time to partial and complete dissolution are derived. The dissolution rate is shown to be dependent on the pK _a and intrinsic solubility and the medium properties, i.e., pH, buffer capacity, and mass transfer coefficient. Equations of a form analogous to the nonionized case are derived to account explicitly for all these factors, with dissolution rates expressed in terms of the product of a driving force (concentration difference) and resistance (inverse of mass transfer coefficient). The solutions are in an accessible analytical form to calculate the surface pH and subsequently the surface concentrations driving the drug dissolution. Numerical examples to illustrate dissolution into unbuffered and buffered media are presented and the results are shown to be in accord with experimental data taken from the literature.     

Evaluation and selection of bio-relevant dissolution media for a poorly water-soluble new chemical entity.

The purpose of this work is to develop a bio-relevant dissolution method for formulation screening in order to select an enhanced bioavailable formulation for a poorly water-soluble drug. The methods used included a modified rotating disk apparatus for measuring intrinsic dissolution rate of the new chemical entity (NCE) and the USP dissolution method II for evaluating dissolution profiles of the drug in three different dosage forms. The in vitro dissolution results were compared with the in vivo bioavailability for selecting a bio-relevant medium. The results showed that the solubility of the NCE was proportional to the concentration of sodium lauryl sulfate (SLS) in the media. The apparent intrinsic dissolution rate of the NCE was linear to the rotational speed of the disk, which indicated that the dissolution of the drug is a diffusion-controlled mechanism. The apparent intrinsic dissolution rate was also linear to the surfactant concentration in the media, which was interpreted using the Noyes and Whitney Empirical Theory. Three formulations were studied in three different SLS media using the bulk drug as a reference. The dissolution results were compared with the corresponding bioavailability results in dogs. In the 1% SLS--sink conditions--the drug release from all the formulations was complete and the dissolution results were discriminative for the difference in particle size of the drug in the formulations. However, the data showed poor IVIV correlation. In the 0.5% SLS medium--non-sink conditions--the dissolution results showed the same rank order among the tested formulations as the bioavailability. The best IVIV correlation was obtained from the dissolution in 0.25% SLS medium, an over-saturated condition. The conclusions are: a surfactant medium increases the apparent intrinsic dissolution rate of the NCE linearly due to an increase in solubility. A low concentration of surfactant in the medium (0.25%) is more bio-relevant than higher concentrations of surfactant in the media for the poorly water-soluble drug. Creating sink conditions (based on bulk drug solubilities) by using a high concentration of a surfactant in the dissolution medium may not be a proper approach in developing a bio-relevant dissolution method for a poorly water-soluble drug.     

Use of a Physiologic Bicarbonate Buffer System for Dissolution Characterization of Ionizable Drugs

Purpose. The aim of this study was to examine if sparging with CO₂(g) could be used to establish stable biorelevant bicarbonate buffers, in aqueous medium, for use in dissolution characterization of low-solubility ionizable drugs. Methods. Preparation of the bicarbonate-containing dissolution medium was monitored by use of a commercially available fiberoptic probe to measure the concentration of dissolved CO₂(aq). Intrinsic dissolution measurements at 100 rpm, 37°C for indomethacin and dipyridamole were performed using a rotating disk and UV detection at pH 6.8 and 5.0 in a USP dissolution vessel apparatus. Results. Indomethacin dissolution at pH 6.8 was significantly impacted by the concentration of CO₂(g) in the sparging gas. Dipyridamole flux at pH 6.8 was independent of buffer species or buffer concentrations studied. However, dipyridamole dissolution at pH 5 was also a strong function of the concentration of CO₂(g) in the sparging gas. Conclusions. Stable bicarbonate biorelevant buffers could be established to perform intrinsic dissolution rate determinations for indomethacin and dipyridamole as long a continuous gas sparging of CO₂(g) was used. Depending of the pH of the dissolution medium, the intrinsic dissolution rates of both indomethacin and dipyridamole were affected by the bicarbonate concentration. Sparging with CO₂(g) to create physiologic buffers has a unique advantage over conventional buffers in that gas sparging serves as a continuous source of bicarbonate buffer species. This advantage was demonstrated by performing dissolution experiments at pH values typically associated with the fed state (pH 5) and applying relatively low CO₂(g) pressures, resulting in bicarbonate concentrations less than 0.5 mM. It was demonstrated that CO₂(g) sparging at a pH consistent with the fed state created an in-situ bicarbonate buffer at low concentrations, which had a significant impact on the dissolution of a basic drug such as dipyridamole.     

金荞麦片溶出度测定方法研究

目的 以金荞麦片为模型药,探讨中药固体制剂的溶出度测定方法。方法 采用桨法,75 r/min,以0.25%十二烷基硫酸钠（SDS）1 000 mL为溶出介质,自身对照,采用紫外分光光度法在280 nm波长下测定溶出度。结果 建立的方法分辨率高,重现性好。结论 中药固体制剂溶出度的测定方法的建立,对于提高药品质量和有效性具有重要意义。