Development and evaluation of orally disintegrating tablets of cilostazol-β-cyclodextrin inclusion complexes

Context: The clinical applications of cilostazol (CLZ) are limited by its low aqueous solubility (<5?µg/ml) and high biovariability.

Objective: The aim of this study was to enhance the solubility of CLZ by forming inclusion complexes (ICs) with beta cyclodextrin (β-CD) and formulating them into oral disintegrating tablets.

Methods: Phase solubility study of CLZ with β-CD was performed in water. Job’s plot was constructed to determine the stoichiometry of ICs. ICs, prepared by spray-drying technique, were characterized using Fourier transform infrared spectroscopy, differential scanning calorimetry, hot stage microscopy, powder X-ray diffraction and nuclear magnetic resonance. Molecular modeling studies were performed to understand the mode of interaction of CLZ with β-CD. The formulation process was undertaken using a reproducible design of experiment generated model, attained by variation of diluents and disintegrants at three levels. Tablets were evaluated for drug content, hardness, friability, disintegration time (DT), wetting time (WT) and dissolution profiles.

Results and discussion: Phase solubility studies suggested an A_L type curve with stability constant (K_s) of 922.52?M^?1. Job’s plot revealed 1:2 stoichiometry. All analytical techniques confirmed inclusion complexation. Molecular modeling revealed dispersive van der Waals interaction energy as a major contributor for stabilization of complex. The spray-dried complexes showed higher solubility and faster dissolution compared to plain CLZ. The optimized formulation showed DT of 11.1?±?0.8?s, WT of 8.7?±?0.9?s and almost complete dissolution of CLZ in 15?min.

Conclusion: The prepared tablets with low DT and fast dissolution will prove to be a promising drug delivery system with improved bioavailability and better patient compliance.     

Prediction of in vivo drug performance using in vitro dissolution coupled with STELLA: a study with selected drug products

Prediction of the in vivo performance of the drug product from the in vitro studies is the major challenging job for the pharmaceutical industries. From the current regulatory perspective, biorelevant dissolution media should now be considered as quality control media in order to avoid the risk associated. Physiological based pharmacokinetic models (PBPK) coupled with biorelevant dissolution medium is widely used in simulation and prediction of the plasma drug concentration and in vivo drug performance. The present investigation deals with the evaluation of biorelevant dissolution media as well as in vivo drug performance by PBPK modelling using STELLA® simulation software. The PBPK model was developed using STELLA® using dissolution kinetics, solubility, standard gastrointestinal parameters and post-absorptive disposition parameters. The drug product selected for the present study includes Linezolid film-coated immediate-release tablets (Zyvox), Tacrolimus prolonged-release capsules (Advagraf), Valganciclovir tablets (Valcyte) and Mesalamine controlled-release capsules (Pentasa) each belonging to different biopharmaceutics classification system (BCS). The simulated plasma drug concentration was analyzed and pharmacokinetic parameters were calculated and compared with the reported values. The result from the present investigation indicates that STELLA® when coupled with biorelevant dissolution media can predict the in vivo performance of the drug product with prediction error less than 20% irrespective of the dosage form (immediate release versus modified release) and BCS Classification. Thus, STELLA® can be used for in vivo drug prediction which will be helpful in generic drug development.     

Solubility and dissolution enhancement strategies: current understanding and recent trends

Identification of lead compounds with higher molecular weight and lower aqueous solubility has become increasingly prevalent with the advent of high throughput screening. Poor aqueous solubility of these lipophilic compounds can drastically affect the dissolution rate and subsequently the drug absorbed in the systemic circulation, imposing a significant burden of time and money during drug development process. Various pre-formulation and formulation strategies have been applied in the past that can improve the aqueous solubility of lipophilic compounds by manipulating either the crystal lattice properties or the activity coefficient of a solute in solution or both, if possible. However, despite various strategies available in the armor of formulation scientist, solubility issue still remains an overriding problem in the drug development process. It is perhaps due to the insufficient conceptual understanding of solubility and dissolution phenomenon that hinders the judgment in selecting suitable strategy for improving aqueous solubility and/or dissolution rate. This article, therefore, focuses on (i) revisiting the theoretical and mathematical concepts associated with solubility and dissolution, (ii) their application in making rationale decision for selecting suitable pre-formulation and formulation strategies and (iii) the relevant research performed in this field in past decade.     

棉纤维在NMMO溶液中的溶胀与溶解

用不同质量分数的N-甲基吗啉-N-氧化物(NMMO)溶液,在不同的温度和时间条件下,探究棉纤维的溶胀和溶解情况,并利用X射线衍射和红外光谱对纤维素溶胀前后的结构变化进行表征。结果表明:NMMO质量分数低于80%时,棉纤维只溶胀不溶解;在质量分数分别为83%、85%、87%的NMMO溶液中,棉纤维出现溶解现象;随着NMMO质量分数的增大、温度的升高、时间的延长,棉纤维的溶胀程度不断增加。在质量分数为83%的NMMO溶液中,棉纤维先溶胀后溶解;在质量分数为87%的NMMO溶液中,棉纤维不溶胀直接溶解;在质量分数为85%的NMMO溶液中,棉纤维的溶解存在先溶胀后溶解和直接溶解两种形式。质量分数为80%以下的NMMO水溶液处理后的棉纤维,结晶结构和化学结构均没有变化。     

Improving dissolution kinetics of pharmaceuticals by fluidized bed impregnation of active pharmaceutical ingredients

Investigational drugs are increasingly becoming less soluble in aqueous media, thus, presenting real challenges during development. Previous work has successfully demonstrated the manufacturing of pharmaceuticals using fluidized bed (FB) impregnation of APIs onto porous carriers. This study demonstrates the usefulness of FB impregnation in formulating poorly soluble drugs. We show that dissolution of Fenofibrate is greatly improved by FB impregnation onto Neusilin^® (Fuji Health Science Inc, Burlington, NJ USA), a synthetic amorphous form of magnesium alumino‐metasilicate. We impregnate Neusilin^® for range of loadings and examine Fenofibrate's physical state. Dissolution of impregnated formulations is drug loading dependent and loadings below 40% show great improvement (decrease) in release time compared to physical blend. Release times are further improved by milling. We also examine feasibility of coimpregnating Fenofibrate with additives and observe stability (1.5 years) of the amorphous form of Fenofibrate inside Neusilin^®. This stabilization significantly improves Fenofibrate's dissolution kinetics, making our formulation comparable to one of the current market formulations, TriCor^® tablets (AbbVie Inc, North Chicago, IL USA). © 2016 American Institute of Chemical Engineers AIChE J, 62: 4201–4214, 2016     

Localized dissolution initiated at single and clustered intermetallic particles during immersion of Al–Cu–Mg alloy in sodium chloride solution

Aiming at understanding how intermetallic phases response when AA2024-T3 aluminium alloy is exposed to chloride-containing aqueous medium, scanning electron microscopy was employed to provide morphological information on alloy surface before and after corrosion testing. Energy dispersive X-ray spectroscopy was carried out to determine compositional change in intermetallic particles. Atomic force microscopy was used to examine topographical variation introduced by the reactions of intermetallic phases. Transmission electron microscopy combined with ultramicrotomy was carried out on dealloyed Al₂CuMg particles and their periphery region. It is found that dealloyed Al₂CuMg particles exhibited porous, polycrystalline structure comprised of body-centred cubic copper particles with sizes of 5 to 20 nm. Aluminium matrix started to trench in the periphery of Al₂CuMg particles at the early stage of dealloying. Development of trenching in Al–Cu–Fe–Mn–(Si) particle's periphery was not uniform and took longer time to initiate than Al₂CuMg dealloying. Localized corrosion at a cluster of Al₂CuMg and Al₂Cu particles was mainly associated with Al₂CuMg particles.     

聚丙烯腈/离子液体体系研究进展

综述了丙烯腈(AN)在离子液体中的均聚共聚、聚丙烯腈(PAN)在离子液体中的溶解机理、溶液特性以及纺丝成形的研究进展。指出以离子液体为溶剂的AN均聚和共聚反应具有反应快,聚合物相对分子质量分布窄的特点,离子液体是PAN溶解的良好溶剂;PAN/离子液体体系随温度降低呈现出可逆物理凝胶特征,PAN/离子液体具有良好的可纺性,采用干喷湿纺、静电纺丝和增塑纺丝,已制备出各种纤维;建议应进一步加强对离子液体在PAN的聚合、溶解及纺丝成形方面的研究。     

石墨粉对低锌含量水性环氧富锌漆阴极保护性能的影响

配制了颜料体积浓度(PVC)与临界颜料体积浓度(CPVC)之比为0.9的低锌含量水性环氧富锌漆,加入占锌粉质量1%、2%和3%的石墨粉,研究了石墨粉对水性环氧富锌涂层阴极保护性能的影响。涂层的阴极保护性能评价采用传统的开路电位(OCP)测试法与自行开发设计的恒电流溶解法。OCP测试结果表明,添加石墨后的涂层有更长的阴极保护时间,石墨粉添加量越大,阴极保护时间越长。恒电流溶解法测试结果表明,加入石墨粉之后涂层的活性溶解时间变长,石墨粉添加量越高,活性溶解时间越长。导电胶和涂层电极在3.5%NaCl溶液中的电化学阻抗谱测试结果表明,随着石墨粉含量的增加,涂层阻抗降低,阴极保护作用增强。     

Determination and correlation of temperature and pH value dependent solubility of dl-methionine

In order to provide basic data for the crystallization of dl -methionine and understand the thermodynamic properties of dissolution, the solubility of dl -methionine in water was measured by gravimetric method from 294.05 to 347.05 K and the solubility at different pH values under temperature 302.95 to 342.05 K was determined by elemental analysis in this work. The experimental data show that the solubility of dl -methionine increases with increasing temperature as well as more acidic or basic pH values. The van't Hoff equation, modified Apelblat equation, λh equation, Wilson model, NRTL model, and UNIQUAC model were used to correlate the solubility data versus temperature. The melting temperature, enthalpy of fusion, enthalpy and entropy of dissolution were estimated from solubility data and it shows that the expression of solubility by enthalpy and entropy of dissolution gives more reasonable estimation and Wilson model gives a better correlation for these thermodynamic properties.     

基于萤石溶解/表面转化的含钙矿物表面定向调控浮选技术及机理研究

研究了萤石在白钨矿和方解石表面溶解和转化的可能性, 发现萤石可以在特定的捕收剂体系下作为抑制剂实现含钙矿物的浮选分离。浮选实验结果表明, 萤石作为抑制剂, 在白钨矿和方解石的浮选中, 用量小、作用效果明显; 动电位检测结果证实了萤石能明显降低方解石的动电位, 但对白钨矿基本没有影响; XPS检测结果证明了萤石对方解石的作用主要在于对Ca-O键能的减弱和Ca-F基团的生成, 即在方解石表面生成CaF2膜; AFM检测则可直观观察到方解石表面经过萤石处理之后出现明显的起伏, 印证了离子的侵蚀与CaF₂膜的生成。