Monitoring of High-shear Granulation using Acoustic Emission: Predicting Granule Properties

Sound in the ultrasonic (20 to 1,000 kHz) range emitted during high-shear granulation was recorded and analyzed using multivariate techniques in order to assess the relationship between variations in the physical properties of the obtained granules and the evolution of acoustic emissions taking place during their formation. The acoustic signal analysis was preformed on two different granulators. A four-component model was obtained from the analysis and was capable of predicting the particle size distribution of the granules based on a 13 sieve cut measurement covering the range of 53–1,180 μm. The average error of prediction was less than 2%. Acoustic emission also proved useful as a predictor of granule moisture content. The final granule moisture content could be predicted with a root-mean-square error of prediction of 5.76% and 1.9% in the two different granulators evaluated in this investigation. The acoustic signals emitted during wet granulation contain the information necessary to make quantitative assessments of the changes in water content, particle size, and the particle size distribution of the granules produced by the process.     

慢性疮面之“去腐生肌”的再认识

“去腐生肌”具有独特临床疗效和鲜明中医特色,是慢性疮面治疗过程中的一种重要手段,但目前对“去腐生肌”的认识存在一定局限性且不全面。结合文献及临床实践,将“去腐生肌”重新定义为“去除一切阻碍疮面愈合的增多或新生病理产物,创造有利于或促进疮面愈合的疮面状态或新生产物的过程”。该定义全面考虑了去腐生肌所涉及的有形之腐和无形之腐、有形之肌和无形之肌之间的相互关系,并认为去腐与生肌之间存在“去腐生肌-肌生腐去-腐去肌生”这一动态过程,即去腐是生肌的必然条件,生肌是去腐的最终结果,临床中可依据具体情况选择不同的内治、外治手段来实现去腐和生肌。通过重新认识去腐生肌,以期为慢性疮面治疗提供新的思路。     

Initial moisture content in raw material can profoundly influence high shear wet granulation process

The aim of this work is to demonstrate that uncontrolled initial moisture content in microcrystalline cellulose (MCC) can profoundly affect high shear wet granulation (HSWG) process. We show that granule tabletability is reduced by approximately 50% when initial moisture content in MCC increases from 0.9% to 10.5% while all other processing parameters remain unchanged. An important observation is that granule tableting performance deteriorates significantly when initial moisture content increases from 2.6% to 4.9%, which is considered normal variation in moisture content for typical MCC (3-5%). The deteriorated tabletability is largely caused by increased granule size. On the other hand, granule flowability improves continuously with increasing initial moisture content in MCC. The improved flowability is mainly a result of granule size enlargement. Clearly, moisture content of raw materials for a HSWG process must be carefully monitored and controlled to ensure a robust manufacturing process as required by the quality-by-design principle.     

紫外分光光度法测定烟酸微丸中烟酸的含量

目的：测定烟酸微丸中烟酸的含量。方法：采用离心造粒法制备烟酸含药微丸,利用紫外分光光度法建立烟酸的含量测定方法。结果：在2.0-20.0μg.m l^-1范围内,线性关系良好,平均回收率为98.5%,RSD%小于2.5%,烟酸微丸的含药量为70.6%。结论：采用紫外分光光度法测定烟酸含量方法准确、操作简便,快速,重现性好。     

生、煅石膏与赛霉安散促进创伤愈合作用研究

目的比较研究生、煅石膏及赛霉安散对大鼠创伤愈合的作用。方法制作大鼠外伤动物模型,用生石膏、煅石膏及赛霉安对创口进行给药,肉眼观察创伤愈合情况,并对6天、12d的创口处新生肉芽组织作组织切片,观察创口新生组织生长情况。结果给药12d后,生石膏组创口愈合速度较慢,与对照组没有显著差别,而煅石膏组与赛霉安散组创口恢复速度较快,基本完全愈合。结论石膏经高温煅制后生肌功效明显增强。     

Batch statistical process control of a fluid bed granulation process using in-line spatial filter velocimetry and product temperature measurements

Fluid bed granulation is a batch process, which is characterized by the processing of raw materials for a predefined period of time, consisting of a fixed spraying phase and a subsequent drying period. The present study shows the multivariate statistical modeling and control of a fluid bed granulation process based on in-line particle size distribution (PSD) measurements (using spatial filter velocimetry) combined with continuous product temperature registration using a partial least squares (PLS) approach. Via the continuous in-line monitoring of the PSD and product temperature during granulation of various reference batches, a statistical batch model was developed allowing the real-time evaluation and acceptance or rejection of future batches.Continuously monitored PSD and product temperature process data of 10 reference batches (X-data) were used to develop a reference batch PLS model, regressing the X-data versus the batch process time (Y-data). Two PLS components captured 98.8% of the variation in the X-data block. Score control charts in which the average batch trajectory and upper and lower control limits are displayed were developed. Next, these control charts were used to monitor 4 new test batches in real-time and to immediately detect any deviations from the expected batch trajectory. By real-time evaluation of new batches using the developed control charts and by computation of contribution plots of deviating process behavior at a certain time point, batch losses or reprocessing can be prevented.Immediately after batch completion, all PSD and product temperature information (i.e., a batch progress fingerprint) was used to estimate some granule properties (density and flowability) at an early stage, which can improve batch release time. Individual PLS models relating the computed scores (X) of the reference PLS model (based on the 10 reference batches) and the density, respectively, flowabililty as Y-matrix, were developed. The scores of the 4 test batches were used to examine the predictive ability of the model.     

异丙醇对阿替洛尔片溶出行为的影响

目的考察异丙醇用量对阿替洛尔片溶出行为的影响。方法以不同用量的异丙醇为润湿剂,通过湿法制粒制备阿替洛尔片(规格为每粒50 mg),分别测定其5,10,15,25,45,60 min时的累积溶出度,绘制溶出曲线并与参比制剂比较,计算其f2值。结果异丙醇用量对阿替洛尔片的溶出行为影响显著。结论随着异丙醇用量的增加,阿替洛尔的溶出速率加快;当异丙醇用量为0.080 mL/片时,阿替洛尔的溶出行为与参比制剂相似。     

复方缬沙坦/苯磺酸氨氯地平片的制备和体外溶出测定

目的:研制与上市品具有相似体外溶出的复方缬沙坦/苯磺酸氨氯地平片。方法:采用湿法制粒压片工艺制备自制品,通过单因素试验初步筛选处方,中心复合设计优化处方。比较不同pH溶出介质(pH 1.2盐酸、pH 4.5乙酸缓冲液和0.1%聚山梨酯80-pH 6.8磷酸缓冲液)中自制品与市售复方片的溶出行为,通过相似因子f2计算,评价2种药物体外溶出的相似性。结果:与市售片比较,以优化处方制备的复方片中缬沙坦和苯磺酸氨氯地平在不同pH值溶出介质中的溶出度相似因子f 2均>50。结论:自制的复方片与市售片体外溶出行为相似。     

烟酸缓释微丸的制备及体外释放度考察

目的:制备24 h烟酸缓释微丸,考察其体外释放度。方法:使用离心造粒机,采用空白丸芯粉末上药法制备烟酸载药素丸;使用国产流化床包衣机,以乙基纤维素为包衣材料进行包衣。考察包衣处方因素、热处理条件和释放介质对释放度的影响。结果:烟酸素丸圆整度良好,光滑;16～20目收率约90%。包衣增重、致孔剂类型以及用量是影响药物释放的关键因素。烟酸缓释微丸在pH 1.2的盐酸溶液中释放较快,在水,pH 4.5的醋酸盐缓冲溶液,pH 6.8和pH 7.9的磷酸盐溶液中释放无明显区别。以乙基纤维素包衣增重9%,以PEG 4000为致孔剂用量37%,得到的缓释微丸具备体外24 h缓释特征。结论:该缓释微丸的体外释放符合缓释制剂要求。     

保精片一步制粒法工艺研究

目的:改进保精片制粒工艺,使其适合压片和薄膜包衣.方法:采用一步制粒法制备保精片用颗粒,确定其一步制粒的最佳工艺条件.结果:最佳制粒工艺条件是将一定量的保精片用干膏10 ～0.12 MPa中,开启风机并加热,使物料在流化状态下均匀升温至50℃,以速度25～32 r·min-1喷入黏合剂,雾化压力0.10～0.12 MPa,进风温度75～90℃,物料温度随后控制在43～ 47℃,密切观察物料流化状态,直至黏合剂全部喷入,继续干燥8～10 min,降温出料.结论:一步制粒法颗粒可压性提高,所压片芯硬度好、片重差异幅度缩小、崩解时限符合规定.且一步制粒法比摇摆式制粒法更易控制,生产效率也更高.