Experimental and Computational Screening Models for Prediction of Aqueous Drug Solubility

Purpose. To devise experimental and computational models to predict aqueous drug solubility. Methods. A simple and reliable modification of the shake flask method to a small-scale format was devised, and the intrinsic solubilities of 17 structurally diverse drugs were determined. The experimental solubility data were used to investigate the accuracy of commonly used theoretical and semiexperimental models for prediction of aqueous drug solubility. Computational models for prediction of intrinsic solubility, based on lipophilicity and molecular surface areas, were developed. Results. The intrinsic solubilities ranged from 0.7 ng/mL to 6.0 mg/mL, covering a range of almost seven log₁₀ units, and the values determined with the new small-scale shake flask method agreed well with published solubility data. Solubility data computed with established theoretical models agreed poorly with the experimentally determined solubilities, but the correlations improved when experimentally determined melting points were included in the models. A new, fast computational model based on lipophilicity and partitioned molecular surface areas, which predicted intrinsic drug solubility with a good accuracy (R ²of 0.91 and RMSE_tr of 0.61) was devised. Conclusions. A small-scale shake flask method for determination of intrinsic drug solubility was developed, and a promising alternative computational model for the theoretical prediction of aqueous drug solubility was proposed.     

Predicting the Solubility of the Anti-Cancer Agent Docetaxel in Small Molecule Excipients using Computational Methods

Purpose To develop an in silico model that provides an accurate prediction of the relative solubility of the lipophilic anticancer agent docetaxel in various excipients. Materials and Methods The in silico solubility of docetaxel in the excipients was estimated by means of the solubility (δ) and Flory-Huggins interaction (χ _FH) parameters. The δ values of docetaxel and excipients were calculated using semi-empirical methods and molecular dynamics (MD) simulations. Cerius² software and COMPASS force-field were employed for the MD simulations. The χ _FH values for the binary mixtures of docetaxel and excipient were also estimated by MD simulations. Results The values obtained from the MD simulations for the solubility of docetaxel in the various excipients were in good agreement with the experimentally determined values. The simulated values for solubility of docetaxel in tributyrin, tricaproin and vitamin E were within 2 to 6% of the experimental values. MD simulations predicted docetaxel to be insoluble in β-caryophyllene and this result correlated well with experimental studies. Conclusions The MD model proved to be a reliable tool for selecting suitable excipients for the solubilization of docetaxel. Electronic supplementary material The online version of this article (doi: ) contains supplementary material, which is available to authorized users.     

A Relative Permittivity Approach for Fast Drug Solubility Screening of Solvents and Excipients in Lipid-Based Delivery

Drug solubility screening in solvents and lipids is central for the development of lipid-based formulations (LBFs), and any guidance to reduce the experimental workload would be highly desirable. Solubility parameters are interesting as they can be predicted in silico for a drug but they are hardly predictable for complex lipids. This paper uses a new approach to convert an in silico drug solubility parameter to an estimated relative permittivity, ε_r. Diverse solvents and lipid-based excipients were then experimentally tested for ε_r and solubility using fenofibrate as model. The typical excipients and solvents used in LBFs showed an ε_r range of about 2-24, and good solubility of fenofibrate was indeed evidenced in vicinity of its estimated relative permittivity 13.2 ± 2.7. Mixtures of promising excipients were studied subsequently, and the obtained ε_r was predictable based on the known values of the individual components. The novel permittivity approach has demonstrated its usefulness, it has much potential in early development for ranking of suitable excipients, and it gives an initial orientation to design formulations. Future research may clarify further opportunities and limits of the novel approach for LBFs.     

Product-Specific Impact of Viscosity Modulating Formulation Excipients During Ultra-High Concentration Biotherapeutics Drug Product Development

Developing ultra-high concentration biotherapeutics drug products can be challenging due to increased viscosity, processing, and stability issues. Excipients used to alleviate these concerns are traditionally evaluated at lower protein concentrations. This study investigates whether classically known modulators of stability and viscosity at low (<50 mg/mL) to high (>50 – 150 mg/mL) protein concentrations are beneficial in ultra-high (>150 mg/mL) concentration protein formulations and drug products. This study evaluates the effect of arginine monohydrochloride, proline, and lysine monohydrochloride on viscosity and concentratability at different high and ultra-high protein concentrations using a monoclonal antibody, mAbN, formulation as a candidate protein system. The effect of excipients on the viscosity and concentratability (rate and extent) was different at high versus ultra-high protein concentrations. These results highlight that classical excipients in literature known to modulate protein interactions at low protein concentrations and reduce viscosity at high protein concentrations may need to be evaluated at target protein concentrations in a product-specific manner while developing ultra-high concentration biologics drug products.     

Overcoming the Challenges of Low Drug Solubility in the Intravenous Formulation of Solithromycin

Solithromycin is a fluoro-ketolide (a fourth-generation macrolide) antibiotic that has been undergoing clinical trials for the treatment of community-acquired bacterial pneumonia. In this study, development of the tri-amino acid–buffered solithromycin intravenous (IV) formulation was performed to minimize the occurrence of infusion-associated local adverse events (infusion-site pain or phlebitis) observed in patients who received the tartaric acid–buffered IV formulation with a lower buffered capacity during phase I clinical trials. Development of the tri-amino acids–buffered solithromycin IV formulation was achieved using a dynamic in vitro precipitation model. Computational modeling also supports the superiority of the amino acid-buffered formulation over the tartaric aid–buffered formulation.     

Prediction of Intestinal Drug Absorption Properties by Three-Dimensional Solubility Parameters

Purpose. The purpose of this study was to investigate the use of solubility parameters for the prediction of gastrointestinal absorption sites and absorption durations of drugs. Methods. Three-dimensional solubility parameters of drug substances were calculated using an advanced parameter set based on the group contribution methods of Fedors and Van Krevelen/Hoftyzer. The results of the calculations were illustrated via Bagley diagram and related to absorption data reported in the literature. Results. Solubility parameters of drugs which are known to be absorbed over a long period in human's digestive tract were found in a limited area within the Bagley diagram. From the three-dimensional solubility parameters of these substances, a region for optimal absorption with the centre coordinates _v = 20.3 (J cm^–3)^0.5 and _h = 11.3 (J cm^–3)^0.5 could be derived. Drugs with absorption sites along the whole gastrointestinal tract were found in this area. Drugs which are preferably absorbed from upper parts of the intestine are located in another typical region with partial solubility parameters _h of more than 17 (J cm^–3)^0.5. Conclusions. The method which is presented in this paper appears as a simple but effective method to estimate the absorption behaviour of new substances in drug research and development.     

几种新型辅料在速释片剂中的应用

考察颗粒质量、片剂硬度、崩解时限和溶出度等质量指标,研究了高效崩解剂粘合剂ＰＶＰ、填充剂微晶纤维素等新型辅助料在速释片剂中的作用。结果表明,盐酸二甲胍片中加入微量纤维素、ＰＶＰ胶剂中加入微晶纤维素、ＰＶＰ胶浆、以及高效崩解剂交联ＰＶＰ、Ｌ－ＨＰＣ、ＣＭＳ－Ｎａ后,可在１ｍｉｎ内崩解,２ｍｉｎ内药物溶出达９５％以上。     

含油片剂处方的辅料优化

目的筛选复方中药含油片剂的制剂处方。方法以湿法制粒难易情况、片剂成型情况、片剂硬度和崩解时间等作为评价指标，比较考察复方妇炎宁片处方中吸收剂、黏合剂、崩解剂和稀释剂的类型。结果处方中可选用适量的微粉硅胶为吸收剂、20％淀粉浆为黏合剂制粒，交联羧甲基纤维素钠作为崩解剂，微晶纤维素作为稀释剂。结论新型辅料性能优良，所优选的片剂处方合理、质量稳定。     

Study and Computational Modeling of Fatty Acid Effects on Drug Solubility in Lipid-Based Systems

Lipid-based systems have many advantages in formulation of poorly water-soluble drugs but issues of a limited solvent capacity are often encountered in development. One of the possible solubilization approaches of especially basic drugs could be the addition of fatty acids to oils but currently, a systematic study is lacking. Therefore, the present work investigated apparently neutral and basic drugs in medium chain triglycerides (MCT) alone and with added either caproic acid (C6), caprylic acid (C8), capric acid (C10) or oleic acid (C18:1) at different levels (5 – 20%, w/w). A miniaturized solubility assay was used together with X-ray diffraction to analyze the residual solid and finally, solubility data were modeled using the conductor-like screening model for real solvents (COSMO-RS). Some drug bases had an MCT solubility of only a few mg/ml or less but addition of fatty acids provided in some formulations exceptional drug loading of up to about 20% (w/w). The solubility changes were in general more pronounced the shorter the chain length was and the longest oleic acid even displayed a negative effect in mixtures of celecoxib and fenofibrate. The COSMO-RS prediction accuracy was highly specific for the given compounds with root mean square errors (RMSE) ranging from an excellent 0.07 to a highest value of 1.12. The latter was obtained with the strongest model base pimozide for which a new solid form was found in some samples. In conclusion, targeting specific molecular interactions with the solute combined with mechanistic modeling provides new tools to advance lipid-based drug delivery.     

Herbal Excipients in Novel Drug Delivery Systems

The use of natural excipients to deliver the bioactive agents has been hampered by the synthetic materials. However advantages offered by these natural excipients are their being non-toxic, less expensive and freely available. The performance of the excipients partly determines the quality of the medicines. The traditional concept of the excipients as any component other than the active substance has undergone a substantial evolution from an inert and cheap vehicle to an essential constituent of the formulation. Excipients are any component other than the active substance(s) intentionally added to formulation of a dosage form. This article gives an overview of herbal excipients which are used in conventional dosage forms as well as novel drug delivery systems.     

遗传算法结合人工神经网络模拟药物在超临界流体中溶解度

为更精确地关联预测药物在超临界流体中的溶解度,提出了遗传算法(GA)与LM-反向传播人工神经网络相结合(GA-LM-BP ANN)的模型,并设计了该模型的计算过程,讨论了模型参数的设置.用该模型计算了温度(308～348 K)和压力(122～355 bar)条件下药物(非那吡啶)在超临界CO2中溶解度.结果表明,计算值与实测值的甲均相对误差(AARD)为1.53%,测试集的AARD为3.32%.用Bartle半经验方程得到的计算值与实测值的AARD为14.6%.可见,与Bartle半经验方程相比,GA-LM-BPANN模型的关联和预测精度高,关联范围广.     

Determination of Paclitaxel Solubility and Stability in the Presence of Injectable Excipients

Pharmaceutical Chemistry Journal - Due to poor aqueous solubility of paclitaxel, cremophor is one of the excipients used to improve solubility in Taxol while it is responsible for a number of...     

Solid Lipid Nanoparticles and Nanostructured Lipid Carriers: Emerging Lipid Based Drug Delivery Systems

Pharmaceutical Chemistry Journal - In the past decade, research in the area of nanodrug delivery has reached a new height with the advent of lipid based nanodrug delivery systems. Lipids being...     

Drug Binding and Solubility in Milk

The binding and solubility of nitrofurantoin, piroxicam, indomethacin, prednisolone, diazepam, dicumarol, and griseofulvin in milk were determined at 15, 25, and 37°C in bovine milk samples with fat contents of 0.75 and 3.50%. Drug binding to milk components was independent of drug concentration over the drug concentration studied, and the fat content of milk strongly affected binding values of most of the listed drugs. Further, drug binding increased with decreasing temperatures for most of the drugs examined. The solubility of all drugs is greatly enhanced in milk compared to their aqueous solubility (pH 6.5 phosphate buffer). The high solubility cannot be accounted for solely on the basis of drug binding to milk components. An attempt is made to correlate the binding and solubility data with physicochemical properties of the drugs (logP, pK _a, aqueous solubility). The potential significance of these findings is discussed with regard to preparation and in vivo delivery of drugs from drug–milk formulations.     

合并用药含醇辅料导致双硫仑样不良反应12例分析

通过对12例合并用药患者出现双硫仑样不良反应的分析,探讨合并用药时除了要注意药物之间的作用外,还要关注药物与辅料间的相互作用,最大程度的保障患者安全。     

Determination of Drug Solubility in Aerosol Propellants

Pharmaceutical Research -     

含辅料注射剂的临床合理用药

目的 掌握含辅料注射剂药品说明书中辅料的标明情况,为临床合理用药提供依据。方法 查阅本院注射剂药品说明书,对药品中所含辅料的标明情况进行统计分析。结果 注射用药品共278种,64.75%标明了所含辅料成分;标明辅料品种的共有61种,55.74%被中国药典2015年版所收载;标明辅料的注射剂药品说明书中,分别有2.78%,21.11%,3.89%及0.56%的药品标示了与辅料相关不良反应、禁忌症、注意事项及药物相互作用。结论 临床用药时不仅要关注药品的疗效和不良反应,还要考虑药用辅料的不良反应及其与药物之间的相互作用,以确保临床合理用药。