干法压片密度一致性调控机制与准则模拟研究

目的 针对干法压片溶解特性与一致性难以调控的共性问题，模拟研究干法压片密度一致性的调控机制与准则。方法 基于Edinburgh Elastic-Plastic Adhesion接触模型，构建干法压片的集粉体螺杆输送与滚压压片于一体的协同耦合模拟仿真方法，提出通过体积流量压缩比调控干法压片相对密度及其一致性的技术，诠释其调控机理。结果 模拟建立了平均相对密度与体积流量压缩比的协同耦合线性关联控制模型，满足压片溶解特性和强度所需的临界体积流量压缩比为0.91，揭示了压片均匀性与稳定性RSD与体积流量压缩比协同耦合演化规律，调控压片均匀性与稳定性RSD<5%的体积流量压缩比取值空间为0.58~1.31。结论 同时保证溶解特性与一致性技术要求的调控准则是干法滚压制粒机的体积流量压缩比应设置在0.91~1.31的取值空间内。     

Impact of fillers on dissolution kinetic of fenofibrate dry foams

Abstract

Dry foam technology reveals the opportunity to improve the dissolution behavior of poorly soluble drugs tending to agglomeration due to micronization. In this study, the impact of fillers on the manufacturability, the properties of dry foams and granules as well as the dissolution kinetics of dry foam tablets was investigated using fenofibrate as a model compound. Different maltodextrins and dried glucose syrups, a maltodextrin–phosphatidylcholine complex, isomalt and a 1:1 mixture of mannitol/glucose syrup were used as filler. Within the group of maltodextrins and glucose syrups, the influences of dextrose equivalent (DE), particle morphology and botanical source of starch were investigated. Comparable macroscopic foam structures were obtained with maltodextrins and glucose syrups whereas different foam morphologies were obtained for the other fillers tested. Regarding the maltodextrins and glucose syrups, different physicochemical and particle properties had a minor impact on granule characteristics and tablet dissolution. Using the maltodextrin–phosphatidylcholine complex resulted in a low specific surface area of the granules and a slow tablet dissolution caused by a slow disintegration. In contrast, a high specific surface area and a fast release were obtained with isomalt and glucose syrup/mannitol mixture indicating that high soluble low molecular weight fillers enable the development of fast dissolving dry foam tablets.     

Influence of formulation composition and processing on the content uniformity of low-dose tablets manufactured at kilogram scale

The purpose of this study was to investigate the impact of processing, API loading, and formulation composition on the content uniformity of low-dose tablets made using direct compression (DC) and roller compaction (RC) methods at 1?kg scale. Blends of 1:1 microcrystalline cellulose/lactose or 1:1 microcrystalline cellulose/dicalcium phosphate anhydrous with active pharmaceutical ingredient (API) at loadings of 0.2, 1 and 5% were processed either by DC or RC. A statistical analysis showed that DC produced comparable content uniformity results to RC. Microcrystalline cellulose/lactose formulations had improved average potency compared to microcrystalline cellulose/dicalcium phosphate anhydrous formulations for both DC and RC. The impact of segregation in the DC blends and adhesion to equipment surfaces was assessed to aid in understanding potency trends. DC may be as suitable as RC for low-dose regime (e.g. <?1?mg) when manufacturing clinical supplies at small scale provided the API has a suitable particle size and potency loss to equipment is negligible.     

Normative comparisons for large neuropsychological test batteries: User-friendly and sensitive solutions to minimize familywise false positives

Introduction. In neuropsychological research and clinical practice, a large battery of tests is often administered to determine whether an individual deviates from the norm. We formulate three criteria for such large battery normative comparisons. First, familywise false-positive error rate (i.e., the complement of specificity) should be controlled at, or below, a prespecified level. Second, sensitivity to detect genuine deviations from the norm should be high. Third, the comparisons should be easy enough for routine application, not only in research, but also in clinical practice. Here we show that these criteria are satisfied for current procedures used to assess an overall deviation from the norm—that is, a deviation given all test results. However, we also show that these criteria are not satisfied for current procedures used to assess test-specific deviations, which are required, for example, to investigate dissociations in a test profile. We therefore propose several new procedures to assess such test-specific deviations. These new procedures are expected to satisfy all three criteria. Method. In Monte Carlo simulations and in an applied example pertaining to Parkinson disease, we compare current procedures to assess test-specific deviations (uncorrected and Bonferroni normative comparisons) to new procedures (Holm, one-step resampling, and step-down resampling normative comparisons). Results. The new procedures are shown to: (a) control familywise false-positive error rate, whereas uncorrected comparisons do not; (b) have higher sensitivity than Bonferroni corrected comparisons, where especially step-down resampling is favorable in this respect; (c) be user-friendly as they are implemented in a user-friendly normative comparisons website, and as the required normative data are provided by a database. Conclusion. These new normative comparisons procedures, especially step-down resampling, are valuable additional tools to assess test-specific deviations from the norm in large test batteries.     

基于2D电阻抗成像的位置误差和相对数量指数的后处理方法

本文提出了一种基于2D电阻抗成像的位置误差和相对数量指数的后处理方法,用于多种电导率分布的确定、组织成分的识别以及位置信息的确定。此外,还介绍了一种基于现有两种重建算法的混合正则化算法,并将三种重建算法重建的结果进行了比较。结果证明,这种后处理方法可以提高2D电阻抗成像的位置精度和空间分辨率,使得电阻抗成像适用于临床检查和过程监测。     

亲水凝胶骨架材料制备盐酸多奈哌齐缓释片的可行性研究

目的 采用亲水凝胶骨架材料制备盐酸多奈哌齐缓释片,并对其质量进行评价。方法 采用亲水凝胶骨架材料HPMC K100LV和K4M联用通过干法制粒工艺制备盐酸多奈哌齐缓释片,以溶出曲线相似性f2值作为评价指标,通过正交设计进行处方优化,用高效液相色谱法进行含量和杂质检测,通过加速和长期试验考察片剂稳定性。结果 以该方法制备的盐酸多奈哌齐缓释片质量稳定,具有与原研制剂一致的溶出特征。结论 以该方法制备盐酸多奈哌齐缓释片具有可行性。     

着色氧化锆材料喷雾造粒浆料的制备

目的：研究氧化锆材料浆料流变特性,浆料中固含量、聚乙烯醇（PVA）含量和球磨时问对氧化锆喷雾造粒浆料的影响。方法：选取浆料固含量（30wt％、40wt％、50wt％）,PVA加入量（1wt％、2wt％、3wt％）,球磨时间（8h、16h、24h）作为氧化锆材料制备浆料的生产条件,以浆料的平均粘度和沉降度为评价指标。采用三因素三水平正交实验设计,优选出制备氧化锆浆料的最佳工艺组合。结果：优选出的最佳工艺组合结果为浆料固含量为50wt％,PVA加入量为3wt％,球磨时间为24h。结论：通过最佳工艺得到了高固含量、低粘度、稳定性好、着色剂分散均匀的氧化锆喷雾造粒浆料。     

离心造粒法制备裸花紫珠微丸的工艺研究

目的：考察裸花紫珠微丸制备工艺。方法采用离心造粒法,以微丸粉体学性质如粒径、圆整度、堆密度、脆碎度等及微丸收率为指标,考察影响微丸成型的处方因素和工艺因素。结果微丸的制备工艺为：微晶纤维素与药粉(1：1),以5%PVP-k3060%乙醇溶液为黏合剂,主机转速为200 r/min,以5~25 r/min速度喷5%PVP k-3060%乙醇溶液。结论在优化条件下采用离心造粒法可制得表面光滑,圆整度较好的裸花紫珠微丸,微丸的收率达到85%以上。     

Assessment of Intragranular and Extragranular Fracture in the Development of Tablet Tensile Strength

When a tablet is compacted from deformable granules and then broken, the fracture plane may cleave granules in 2 (intragranular fracture) or separate neighboring granules (extragranular fracture). In this study, a novel method was developed to quantify the extent of intragranular versus extragranular fracture by compacting tablets from multicolored ideal granules and evaluating fracture surfaces. The proportions of intragranular and extragranular fracture were quantified and modeled in light of a new metric; the deformation potential, Δ, reflecting the solid fraction increase as an initial granule bed is compressed into a final tablet. Results show that a measurable tablet strength is achieved at Δ > 0.18, but intragranular fracture is not observed until Δ > 0.21. At very large Δ, tablets experience almost exclusively intragranular fracture, yet the tablet tensile strength is considerably lower than that of a tablet compacted from raw powders versus precompacted granules. Thus, secondary compaction of granules appears to weaken the granule matrix, leading to reduced tablet tensile strength even in the presence of strong extragranular bonding.     

Enhancing tablet disintegration characteristics of a highly water-soluble high-drug-loading formulation by granulation process

Abstract

The objective of this study was to improve the disintegration and dissolution characteristics of a highly water-soluble tablet matrix by altering the manufacturing process. A high disintegration time along with high dependence of the disintegration time on tablet hardness was observed for a high drug loading (70% w/w) API when formulated using a high-shear wet granulation (HSWG) process. Keeping the formulation composition mostly constant, a fluid-bed granulation (FBG) process was explored as an alternate granulation method using a 2^(4?1) fractional factorial design with two center points. FBG batches (10 batches) were manufactured using varying disingtegrant amount, spray rate, inlet temperature (T) and atomization air pressure. The resultant final blend particle size was affected significantly by spray rate (p?=?.0009), inlet T (p?=?.0062), atomization air pressure (p?=?.0134) and the interaction effect between inlet T*spray rate (p?=?.0241). The compactibility of the final blend was affected significantly by disintegrant amount (p?<?.0001), atomization air pressure (p?=?.0013) and spray rate (p?=?.05). It was observed that the fluid-bed batches gave significantly lower disintegration times than the HSWG batches, and mercury intrusion porosimetry data revealed that this was caused by the higher internal pore structure of tablets manufactured using the FBG batches.