Investigation of Solid Dosage Form Components Interaction Using Orthogonal Techniques- Discovery of New Forms of Sodium Stearyl Fumarate

Physical or chemical interactions between drug product (DP) components can occur during manufacturing and/or upon storage; and may alter DP shelf life and performance. In this work a new Powder X-ray Diffraction (PXRD) peak was observed in DP under accelerated storage conditions. Due to the complex drug product matrix (including API, polymer, fillers, super disintegrant and lubricant), it was challenging to pinpoint the component(s) responsible for the new peak. In addition to PXRD, other orthogonal techniques including Differential Scanning Calorimetry (DSC), thermogravimetric analysis (TGA), dynamic vapor sorption (DVS), Solid State Nuclear Magnetic Resonance (SSNMR) and Infrared (IR) spectroscopy were employed in this investigation to understand the root cause mechanistically. Specifically, multi nuclei SSNMR (¹H, ²³Na, ¹³C) was instrumental in delineating the components of the matrix. We identified the root cause to be an acid base reaction occurring in the DP, whereby sodium ion in sodium stearyl fumarate (SSF) is replaced by proton leading to SSF form conversion. We also identified commercially available SSF to be a hydrate that can dehydrate to an anhydrous form upon heating. In general, the same techniques can be used to investigate interactions of any multi component solid dosage forms.     

经宁颗粒成型工艺的改进

摘 要 目的：针对经宁颗粒制备过程中收率低、易吸潮,服用过程中溶化性差进而影响临床疗效等问题,进行成型工艺的改进。方法: 采取浸膏直接与乳糖、糊精混匀后干燥、制粒的新工艺,与原工艺所得颗粒从外观、溶化性、吸湿性、颗粒成型率（即粒度）等方面进行比较,并考察临界相对湿度的差异。结果: 新工艺制得颗粒外观、溶化性、颗粒成型率等均较原工艺为优,吸湿率降低,临界相对湿度提升至70%（25℃）,增强了颗粒稳定性。结论:采取新的成型工艺后,颗粒剂成型率、得到改善,有效解决了易吸潮、溶化性差的问题,提高了该颗粒剂质量。     

头孢菌素类抗生素的吸湿性研究

目的 对头孢菌素类抗生素进行吸湿性研究,测定药物的临界相对湿度.方法 将试药置于具有不同相对湿度干燥器内,测定不同时间的吸湿率,绘制吸湿平衡曲线图.结果 测得头孢硫脒、头孢唑啉钠、头孢哌酮钠、头孢呋辛钠的吸湿平衡时间为72 h,临界相对湿度分别为31%、32%、75%、73%.结论 吸湿性研究为工业化生产控制合理的相对湿度环境提供科学依据.     

复方杨桃颗粒的成型工艺研究

目的 优选复方杨桃颗粒的成型工艺.方法 以吸湿率、成型率、溶化性因素为考察指标,筛选最佳辅料与配比,确定复方杨桃颗粒的成型工艺.结果 最佳成型工艺条件为:干浸膏:可溶性淀粉:糊精=1:1:0.2,90％乙醇为润湿剂,按照该成型工艺制备3批颗粒并作评价.颗粒的成型率可达80％以上,粒度检查、水分测定和溶化性均符合规定,颗...     

甲壳素的理化研究 Ⅱ.初步稳定性研究

本文对甲壳素进行了影响因素试验、加速试验和室温留样观察试验,结果表明甲壳素除有一定的吸湿性外性质相当稳定。     

乳糖微粉改性技术改善金银花浸膏粉吸湿性的研究＊

目的 借助乳糖微粉改性技术，降低金银花浸膏粉的吸湿性，解决生产过程中金银花浸膏粉易吸潮、不易存放的问题。方法 以吸湿率为评价指标，优选乳糖种类、药辅比、研磨时间等工艺参数，通过中试放大验证改性技术对金银花膏粉吸湿性的改善作用。结果 乳糖微粉改性最佳工艺条件为金银花浸膏粉与乳糖超微粉碎（粉碎2 min）等比例研磨3 min，改性物的粒径d 0.1，d 0.5，d 0.9分别为3.412、20.146、76.145 μ6，乳糖颗粒包覆在金银花浸膏粉表面。结论 乳糖适度微粉化能明显降低金银花浸膏粉的吸湿初速度和吸湿加速度的绝对值，能显著降低金银花浸膏粉的吸湿性，有效解决生产过程中金银花浸膏粉吸湿性严重的实际问题。     

水溶性壳聚糖和壳寡糖的吸湿保湿性能及对几种致病菌抑制作用的研究

研究了水溶性壳聚糖、壳寡糖的吸湿性、保湿性能和其对铜绿假单胞菌、粪肠菌和肺炎克伯菌的抑菌作用。     

Bulk,surface properties and water uptake mechanisms of salt/acid amorphous composite systems

Developing amorphous pharmaceuticals can be desirable due to advantageous biopharmaceutical properties. Low glass transition temperature (T_g) amorphous drugs can be protected from crystallisation by mixing with high T_g excipients, such as polymers, or with salt forms. However, both polymers and salts can enhance the water uptake. The aim of this study was to formulate physico-chemically stable amorphous materials, by co-processing different proportions of sulfathiazole and its sodium salt to produce an optimum ratio, characterised by the best physical stability and lowest hygroscopicity. Both sulfathiazole and salt amorphised upon spray drying. At room temperature, sulfathiazole crystallised within 1 h at <5% relative humidity while the salt deliquesced when exposed to ambient humidity conditions. In the case of composite systems, FTIR spectroscopy, thermal and surface analysis suggested interactions with an acid:salt stoichiometry of 1:2. Increasing proportions of salt raised the T_g, enhancing the storage stability, however this was opposed by an enhanced hygroscopicity. The water uptake mechanism within the different amorphous systems, analysed by fitting the water sorption isotherms with the Young and Nelson equation, was dependent on the ratio employed, with the salt and the acid facilitating absorption and adsorption, respectively. Tuning the properties of amorphous salt/acid composites by optimising the ratio appears potentially promising to improve the physical stability of amorphous formulations.     

Selection of Optimal Hydrate/Solvate Forms of a Fibrinogen Receptor Antagonist for Solid Dosage Development

ABSTRACT

The objective of this work was to compare the physicochemical properties of four crystalline forms of the fibrinogen receptor antagonist L-738,167 [2(S)-[p-toluenesulfonyl amino]-3-[[[5,6,7,8-tetrahydro-4-oxo-5-[2-(piperidin-4-yl)ethyl]-4-H-pyrazolo[1,5-a][1,4]diazepin-2-yl]carbonyl]amino]-propionic acid] to determine the best form for use in the development of oral dosage formulations. Four crystalline forms [form A (trihydrate), form B (pentahydrate), form C, and form D] were compared using x-ray powder diffractometry, thermal analysis, and moisture sorption studies. The trihydrate, form A, was demonstrated to hydrate upon exposure to relative humidity (RH) above 50% at room temperature (25°C) with conversion to the pentahydrate. The pentahydrate, form B, converted to the trihydrate at room temperature when exposed to humidity levels below 25% RH. The crystalline pentahydrate was shown to be stable to dehydration upon storage at 30°C/60% RH and 40°C/75% RH for 3 months. The suspension of form A or form D in water resulted in conversion to form B, the stable hydrated form in an aqueous environment. Form C has a unique crystalline structure that is stable in an aqueous environment and not subject to hydration/dehydration with changes in relative humidity and thus may offer some advantages in pharmaceutical development.     

Efficient throughput method for hygroscopicity classification of active and inactive pharmaceutical ingredients by water vapor sorption analysis

The conventional method of hygroscopicity determination proposed by Callahan and co-workers utilizes more sample and time, may not be precise in all the cases, and is a relatively broader classification system. The method of indicating degree of hygroscopicity as per European Pharmacopoeia considers equilibration of sample for 24 hours under single humidity condition and may not necessarily ensure equilibration in all the cases. Additionally, both these methods do not provide information on solid state changes occurring within the sample during the course of experiment. This research work envisages an efficient throughput method for hygroscopicity determination, and validates it with active and inactive pharmaceutical ingredients using sorption analysis. Further, this method has been performed under optimal equilibration conditions, in a throughput manner (consuming less sample and time), with additional information on solid state changes occurring within the experimental conditions. This throughput method would be a valuable tool for hygroscopicity assessment of new chemical entities, during drug development in particular, and across all pharmaceutical materials in general.