Three-dimensional aspects of formulation excipients in drug discovery:a critical assessment on orphan excipients,matrix effects and drug interactions

Formulation/pharmaceutical excipients play a major role in formulating drug candidates,with the objectives of ease of administration,targeted delivery and complete availability.Many excipients used in pharmaceutical formulations are orphanized in preclinical drug discovery.These orphan excipients could enhance formulatability of highly lipophilic compounds.Additionally,they are safe in preclinical species when used below the LD50 values.However,when the excipients are used in formulating compounds with diverse physico-chemical properties,they pose challenges by modulating study results through their bioanalytical matrix effects.Excipients invariably present in study samples and not in the calibration curve standards cause over-/under-estimation of exposures.Thus,the mechanism by which excipients cause matrix effects and strategies to nullify these effects needs to be revisited.Furthermore,formulation excipients cause drug interactions by moderating the pathways of drug metabolizing enzymes and drug transport proteins.Although it is not possible to get rid of excipient driven interactions,it is always advised to be aware of these interactions and apply the knowledge to draw meaningful conclusions from study results.In this review,we will comprehensively discuss a)orphan excipients that have wider applications in preclinical formulations,b)bioanalytical matrix effects and possible approaches to mitigating these effects,and c)excipient driven drug interactions and strategies to alleviate the impacts of drug interactions.

Characterisation of a novel, multifunctional, co-processed excipient and its effect on release profile of paracetamol from tablets prepared by direct compression

Objective: To characterise a novel multifunctional pharmaceutical excipient and investigate its ef ect on paracetamol release from tablets prepared by direct compression.Methods: The excipient was prepared by co-processing gelatinized maize starch with sodium carboxymethyl cellulose and microcrystalline cellulose in a ratio of 2:1:1, dried and pulverized into powder. The excipient formulated was characterized using Fourier transform infrared spectroscopy and dif erential scanning calorimetry. The excipient was used to prepare batches of tablets by direct compression with drug-excipient ratios of 1:1, 1:2, 1:3 and 1:4. Parameters evaluated on tablets include crushing strength, friability and in vitro dissolution studies. Results: Differential scanning calorimetry analysis revealed a crystalline excipient while Fourier transform infrared spectroscopy showed no interaction between the excipient and paracetamol. Tablets from all the batches gave average crushing strength values between 3.47 and 4.88 kp. The 1:1 and 1:2 tablet batches were comparable to each other while 1:3 and 1:4 were also comparable to one another in their dissolution proi les. The dissolution parameters of the 1:4 batch was faster with- m∞(90.5%), t50%(3.5 min), t70%(11.6 min) while that of ratio 1:1 was the least with- m∞(48.6%), m5min(23.8%). Their release kinetics followed a KorsmeyerPeppas model with a super case-II transport mechanism.Conclusions: The drug-excipient ratios of 1:3 and 1:4 gave pharmaceutically acceptable tablets that met the British Pharmacopoeia specii cations. The t50% value of the 1:4 batch of tablets may i nd its usefulness in formulating drugs for which a fast onset of action is desired.

Risk evaluation of impurities in topical excipients:The acetol case

Pharmaceutical excipients for topical use may contain impurities, which are often neglected from a toxicity qualification viewpoint. The possible impurities in the most frequently used topical excipients were evaluated in-silico for their toxicity hazard. Acetol, an impurity likely present in different topical pharmaceutical excipients such as propylene glycol and glycerol, was withheld for the evaluation of its health risk after dermal exposure. 〈br〉 An ex-vivo in-vitro permeation study using human skin in a Franz Diffusion Cell set-up and GC as quantification methodology showed a significant skin penetration with an overall Kp value of 1.82 ？ 10 ？ 3 cm/h. Using these data, limit specifications after application of a dermal pharmaceutical product were estimated. Based on the TTC approach of Cramer class I substances, i.e. 1800 mg/（day？person）, the toxicity-qualified specification limits of acetol in topical excipients were calculated to be 90 mg/mL and 180 mg/mL for propylene glycol and glycerol, respectively.

Effects of particle size on the triboelectrification phenomenon in pharmaceutical excipients:Experiments and multi-scale modeling

Particle sizes play a major role to mediate charge transfer, both between identical and different material surfaces. The study probes into the probable mechanism that actuates opposite polarities between two different size fractions of the same material by analyzing the charge transfer patterns of two different sizes of microcrystalline cellulose(MCC). Quantum scale calculations confirmed alteration of charge transfer capacities due to variation of moisture content predicted by multiple surface and bulk analytical techniques. Discrete Element Method(DEM) based multi-scale computational models pertinent to predict charge transfer capacities were further implemented, and the results were in accordance to the experimental charge profiles.

Investigation of the potential application of sodium bentonite as an excipient in formulation of sustained release tablets

In this study, the application of sodium bentonite(SB) in formulation of tablets prepared by direct compression for oral administration was tested. Three different model drugs with different solubilities: paracetamol, diclofenac sodium and metformin HCl were tested. Each drug was mixed with SB at ratio of 50% and the mixtures were subsequently compressed.Compatibility studies were conducted using both Deferential Scanning Calorimeter(DSC)and Fourier Transform Infrared Spectroscopy(FTIR). The dissolution profile for each drug was determined in USP-buffers at different time intervals. Diclofenac sodium in pH 6.8 buffer and paracetamol in both pH 6.8 and pH 4.5 buffers showed extended release. However,metformin HCl showed immediate release at the different pH values. The study showed that using SB was possible to prepare tablets with different release profiles. However, these profiles differ depending on dissolution media and drug type.

Effects of polyol excipient stability during storage and use on the quality of biopharmaceutical formulations

Biopharmaceuticals are formulated using a variety of excipients to maintain their storage stability.However,some excipients are prone to degradation during repeated use and/or improper storage,and the impurities generated by their degradation are easily overlooked by end users and are usually not strictly monitored,affecting the stability of biopharmaceuticals.In this study,we evaluated the degradation profile of polyol excipient glycerol during repeated use and improper storage and identified an unprecedented cyclic ketal impurity using gas chromatography with mass spectrometry(GC-MS).The other polyol excipient,mannitol,was much more stable than glycerol.The effects of degraded glycerol and mannitol on the stability of the model biopharmaceutical pentapeptide,thymopentin,were also evaluated.The thymopentin content was only 66.4% in the thymopentin formulations with degraded glycerol,compared to 95.8% in other formulations after the stress test.Most glycerol impurities(i.e.,aldehydes and ketones)reacted with thymopentin,affecting the stability of thymopentin formulations.In conclusion,this work suggests that more attention should be paid to the quality changes of excipients during repeated use and storage.Additional testing of excipient stability under real or accelerated conditions by manufacturers would help avoid unexpected and painful results.

Effect of Excipients on Stability and Structure of rhCuZn-SOD Encapsulated in PLGA Microspheres

When a protein is encapsulated into poly( DL -lactide-co-glycolide)(PLGA) microspheres by means of the double-emulsion method,the harsh microspheres formation process including ultrasonification,exposure to an organic solvent and a polymer may cause the denaturation of the protein. In this study,we investigated the enzymatic activity change and the effect of the excipients on the stability of recombinant human Cu,Zn-superoxide dismutase(rhCu,Zn-SOD) during the emulsification. The specific activity recovery was found to be concentration dependent and the excipients involved such as PEG 600 and Tween 20,and trehalose were shown to increase the stability of rhCu,Zn-SOD. The protein structural integrity within the microspheres was analyzed by FTIR. The structure of rhCu,Zn-SOD within PLGA microspheres containing trehalose was found to be similar to that of the native solid state,whereas the protein encapsulated during the preparation in the absence of any excipient changed due to the possible hydrophobic interaction with the polymer. The results suggest that a rational stability strategy for protein to be encapsulated into microspheres should aim at different processes.

Effect of Excipients on Recombinant Interleukin-2 Stability in Aqueous Buffers

In order to retain structural and functional integrity, protein medicines are frequently stabilized with excipients in aqueous solutions. The goal of this investigation was to see how stable IL-2 is with excipients that are acceptable for cell therapy. We investigated the time-dependent stability of commercially available recombinant IL-2 in aqueous solutions (CTS, RPMI, PBS, and water) at different temperatures [2°C - 8°C, room temperature (20°C ± 2°C) and 37°C] in the presence of excipients (EDTA, methionine, histidine, and glycine) over a period of up to 30 days. To detect and quantify IL-2, reversed phase high performance liquid chromatography was employed. Electrophoresis on a sodium dodecyl sulfate polyacrylamide gel was used to assess conformational stability. We discovered that IL-2 stability was improved in aqueous solutions including excipients, and that it may have retained its biological activity and sterility in these conditions.

Azocalixarenes: a scaffold of universal excipients with high efficiency

Excipients are important components of pharmaceutical preparations that affect their quality, safety, and efficacy. Macrocyclic receptors are a family of supramolecular excipients with several advantages, including molecular-level protection, small sizes,fast kinetics of host-guest recognition, and modular construction. With the continuous advances in the medical field, personalized and precision medicine requires the development of excipients with low dosages, integrated modifying effects, universality,and controlled release. To meet these requirements, we have developed a new family of macrocyclic excipients based on calixarenes by integrating their covalent(broad chemical design space) and noncovalent(wide range of substrates) advantages.Accordingly, azocalixarenes(Azo CAs) were designed, showing high binding affinities to a broad spectrum of active pharmaceutical ingredients(APIs), selectivity to interferents, and responsiveness to hypoxic microenvironments. Due to their highly efficient and controllable recognition, Azo CAs serve as low-dose excipients for 30 APIs. Molecular encapsulation by Azo CAs results in the integrated modification of the physicochemical properties of APIs, including solubility, stability, bioavailability,and biocompatibility. Moreover, Azo CAs can be reduced by azoreductases overexpressed in hypoxic microenvironments,leading to the controlled release of APIs. Collectively, Azo CA excipients have broad application prospects for a series of diseases such as enteritis, arthritis, stroke, cancer, bacterial infection and kidney injury, with diverse therapeutic modalities,including chemotherapy, photodynamic therapy, photothermal therapy, immunotherapy, boron neutron capture therapy, radiotherapy, fluorescence imaging, and their combinations.

Microcalorimetric Investigation of Toxic Effects of Three Injectable Solubilizing Excipients on Tetrahymena thermophila BF5 Growth

Using microcalorimetry, thermal metabolic curves of Tetrahymena thermophila BF5 （T. thermophila BFs） growth at 28℃ affected by three injectable solubilizing excipients （ISE） including tween 80, hydroxypro- pyl-β-cyclodextrin （HP-β-CD） and poloxamer 188 were measured. Meanwhile, the toxicities of three ISE were evaluated by dynamic parameters of thermal metabolic curves. In addition, the irritative effects of the ISE on myoblast L6cells were investigated to show their cytotoxicities by biochemical method. The results indicated that the effects of the ISE on T. thermophila BF5 varied for different ISE. 5% inhibition concentration values （IC5） of the ISE were 1.33, 1.83 and 1.64 mg/mL for tween 80, HP-β-CD and poloxamer 188, respectively. By the principal component analysis （PCA）, the total quantity of heat （Q）, growth rate constant （k） and second maximum power （P2） were selected as the main characteristic parameters to present their toxicities, there were good linear relationships between Q, k, P2 and concentrations c, suggesting that the toxicities of the ISE on T. thermophila BF5 were closely linked to their concentrations. The results of creatine kinase （CK） bioassay of myoblast L6 cells indicated that the sequence of irritative effects of the ISE was HP-β-CD〈poloxamer 188〈tween 80, which added to the results ob- tained from microcalorimetry.

Effect of bioadhesive excipients on absorption of total flavonids from Puerariae Lobatae Radix transporting across Caco-2 cell monolayer

Objective: Pueraria total flavonids(PTF) can treat cardiovascular and cerebrovascular diseases, but it has poor membrane permeability and oral bioavailability. Some excipients, such as carbomer, chitosan, and hydroxypropyl methylcellulose, can improve the oral bioavailability. Traditional in vitro evaluation techniques, including the rat intestinal perfusion and cell line models, cannot evaluate PTF absorption and holistic transporters.Methods: This study evaluated excipients' adhesiveness and effect on PTF transport across Caco-2 cell monolayer. cDNA microarrays identified gene expression changes in Caco-2 cells exposed to PTF and PTF with excipients, and revealed the mechanism underlying the effect of excipients on PTF absorption.Results: In vitro adhesion and transport experiments across Caco-2 showed that excipients had higher adhesiveness to gastric mucosa and transport efficiency across Caco-2 cells than PTF alone. The interaction of PTF with excipients significantly changed the expression of some genes, which might influence the absorption rate of PTF.Conclusion: Different bioadhesive polymers can improve intestinal absorption of PTF, which was related to some genes affiliated to the ATP-binding cassette(ABC) and solute carrier transporter(SLC) to some extent.

Drug-Excipient Interactions: Case Studies and Overview of Drug Degradation Pathways

The objective of the current research article is to provide a comprehensive review of excipients impact on the stability of the drug product and their implications during the product development. Recent developments in the understanding of the degradation pathways further impact methodologies used in the pharmaceutical industry for potential stability assessment. The formation of drug excipient adducts was very common based on the sensitive chemical moieties in the drugs and the excipients. The formation of the impurities was not limited to drug related impurities but there were several possibilities of the drug-excipient adduct formations as well as excipient impurities reaction with Active Pharmaceutical Ingredients. Identification of drug degradation in presence of excipients/excipient impurities requires extensive knowledge and adequate analytical characterization data. Systematic literature review and understanding about the drug formulation process, give you a smooth platform in establishing the finished product in the drug market. This paper discusses mechanistic basis of known drug-excipient interactions with case studies and provides an overview of common underlying themes in solid, semisolid and parenteral dosage forms.

The toxic effect of solubilizing excipients on Tetrahymena thermophila BF_5 growth investigated by microcalorimetry

The toxic effect of different solubilizing excipients on the growth and metabolism of Tetrahymena thermophila BF5(T.t.BF5) at various concentrations was investigated by microcalorimetry.The thermogenic curves of T.t.BF5 growth were determined at 28°C,and were evaluated by dynamic parameters.The results indicated that the values of growth rate constant(k),maximum power(P1,P2),peak time(T1,T2) and total quantity of heat(Q) varied for different excipients.There was a good linear relationship between k and concentrations(r>0.95,P<0.01).5% inhibition concentration(IC5) of poloxamer 188,Tween 80,PEG 600,PEG 400 and Tween 20 was 2.18,1.07,1.35,0.58,and 0.045 mg/mL,respectively.After the principal component analysis(PCA),Q,k and P1 could characterize the effect of these excipients on T.t.BF5 growth.Comprehensive evaluation indicated that compared with the control group,poloxamer 188 had the weakest toxicity and Tween 20 had the strongest toxicity.

Drug-Excipient Interaction of Methylphenidate with Glycerin in Methylphenidate Oral Solution and Identification of its Transesterification Products by UPLC-MS/MS

Reactions between active drug substances and excipients are of interest in the drug formulation process should be checked for the interactions during the storage conditions. Some excipients react with certain chemical groups in drug substances which will form new impurities in the finished product formulations. In the present paper transesterification reaction of methylphenidate with glycerin to form different structural isomeric products was described. These impurities identified in forced degradation studies, excipient compatibility studies and stability analysis of the finished product. Stability samples were analyzed and observed that about ~0.6% of the Methylphenidate content was transformed into methylphenidate-glycerin isomers within 3 Months at 40&deg;C/75% RH and 18 Months at 25&deg;C/60% RH conditions. Analysis of two lots of marketed preparations having expiry dates in 2012 and 2013 showed content of the Methylphenidate esters corresponding to ~0.6% of the declared Methylphenidate content. The samples of this impurity were investigated by HPLC, UPLC-MS/MS to generate the mechanism of the impurity formation.

微流控制备包覆含能材料模拟物的核壳结构微球

基于简单的生产单重乳液的液滴微流控技术,结合相分离和结晶固化的方法,制备出具有对硝基苯甲醛(p-NBA)核层和聚苯乙烯(PS)壳层的核壳结构微球,一步完成了对高能炸药3,4-二硝基呋咱基氧化呋咱(DNTF)的模拟物p-NBA的包覆;通过调控p-NBA、PS以及赋形剂乙基纤维素(EC)的含量配比,可以得到不同结构和形貌的微球,并研究了上述因素对核壳结构微球的影响;基于高能炸药DNTF的包覆钝化效果和包覆量双重条件,在使用大相对分子质量(M r=300000~350000)PS情况下,得出最佳实验条件为:EC和p-NBA质量比为1∶10,PS质量分数为8%。结果表明,赋形剂的添加有助于促进p-NBA的结晶,使其能够在液滴相分离的时候形成球形颗粒,从而被完整包覆;PS在微液滴中的初始质量分数越大,形成的壳层越厚、球形度越高,但封装DNTF的壳层越厚,爆炸威力会降低。

YY 0793.3-2023《血液透析和相关治疗用液体的制备和质量管理第3部分:血液透析和相关治疗用浓缩物》标准解读

YY 0793.3-2023《血液透析和相关治疗用液体的制备和质量管理第3部分:血液透析和相关治疗用浓缩物》将于2025年07月01日开始实施。本文将YY 0793.3-2023与YY 0598-2015、ISO 23500-4:2019进行对比,并对部分重要条款的差异进行解读,包括标准适用范围、化学原辅料的要求、溶质浓度及试验方法、微生物限度及其试验方法、pH值、在线使用联机B干粉的pH值及溶质浓度,最终帮助相关企业理解运用该标准。

《中国药典》2020年版第一增补本药用辅料标准解读

《中国药典》2020年版第一增补本自2024年3月12日起施行,它起着重要的承上启下的作用,其中药用辅料标准新增11个、修订46个。本次制修订药用辅料标准是基于风险管理理念和全过程管理理念,围绕保障药品临床安全性和有效性,在制定标准过程中突出对药用辅料关键质量属性的评估,增加了功能性相关指标、安全性指标,突出了标准国际协调和绿色环保标准理念,加强了标准规范性和可操作性。本文着重介绍了《中国药典》2020年版第一增补本中药用辅料新增和修订标准的总体思路和主要特点。以期对《中国药典》的使用者正确理解、执行或运用药典标准有所帮助。

药用辅料硅酸镁铝(IB型)黏度测定方法探讨

目的:确定硅酸镁铝(IB型)登记备案标准中黏度测定方法是否可行。方法:采用棒状高速搅拌器及旋转黏度计考察硅酸镁铝(IB型)黏度,采用破壁机及旋转黏度计考察硅酸镁铝(IB型)黏度。结果:采用棒状高速搅拌器及旋转黏度计考察硅酸镁铝(IB型)黏度时,样品均不符合规定,采用破壁机及旋转黏度计考察硅酸镁铝(IB型)黏度时,样品均符合规定。结论:硅酸镁铝(IB型)为触变性非牛顿流体,其黏度测定结果受高速搅拌器类型影响较大,建议药用辅料登记备案标准中明确使用的高速搅拌器类型,细化前处理方法。

基于《药物制剂辅料与包装材料》在线开放课程的隐形分层教学改革研究

目的研究针对《药物制剂辅料与包装材料》课程开展的基于互联网+背景下的隐形分层教学。方法选取2021年3月—2023年3月重庆医药高等专科学校90名学生为研究对象,其中2019级专科药品生产技术专业1班45名在校生作为对照组,2020级专科药品生产技术专业1班45名在校生作为研究组。在中国大学MOOC和智慧职教平台搭建《药物制剂辅料与包装材料》在线开放课程。对照组采用课程教学APP辅助的常规教学,研究组采用课程教学APP辅助的隐形分层教学,对比两组学生期末卷面成绩、平时成绩和满意度。结果研究组期末卷面笔试成绩为(88.06±5.09)分,高于对照组的(80.52±4.66)分,差异有统计学意义(t=3.843,P<0.05);研究组平时成绩(课前课后任务、课中互动、课中实训和半期在线测试成绩)高于对照组,差异有统计学意义(P均<0.05);研究组学生满意度评分高于对照组,差异有统计学意义(P均<0.05)。结论互联网+背景下的隐形分层教学能满足因材施教的教学理念,适应职业教育发展需求。