D-最优混料设计优化三叶片处方及因子作用分析

目的:采用D-最优混料设计优化三叶片处方,并对各因子的作用进行分析。方法:以磷酸氢钙、微晶纤维素、交联聚维酮和微粉硅胶的用量为考察因素,分别以流化床制粒所得颗粒的颗粒量、松密度以及片剂的崩解时限、抗张强度为指标。选用合适的数学模型预测最优处方,并对最优处方进行验证。结果:磷酸氢钙、微晶纤维素、交联聚维酮和微粉硅胶最优处方配比为23.1%∶0.8%∶3.1%∶2.5%,且可知各项辅料因子所发挥的不同作用。结论:D-最优混料设计可用于三叶片的处方优化,建立的数学模型可以分析出多因素对多指标不同程度的影响,且具有较准确的预测性。     

制备工艺对格列美脲片溶出行为的影响

目的 探索不同制备工艺对格列美脲片溶出行为的影响。方法 以溶出度及在pH （7.20±0.05）缓冲液中溶出曲线为检测指标,并结合流动性和可压性,考察粉末直接压片、干法制粒压片、湿法制粒压片对格列美脲片溶出行为的影响。结果 采用粉末直接压片、干法制粒压片、湿法制粒压片工艺制备的格列美脲片溶出行为存在一定差异。结论 采用空白辅料湿法制粒,外加原料药混合压片制得格列美脲片与参比制剂溶出行为一致,且产品质量稳定,为格列美脲片一致性评价工作奠定了基础。     

中心复合设计-效应面法优化盐酸米诺环素缓释片处方

摘 要 目的：制备盐酸米诺环素缓释片并优化处方。方法: 采用干法制粒压片工艺制备盐酸米诺环素缓释片,以羟丙甲纤维素E50（HPMC E50）和羟丙甲纤维素K100LV（HPMC K100LV）的用量为考察因素,1,2,4,8 h的累积释放度为评价指标,采用中心复合设计 效应面法优化盐酸米诺环素缓释片的处方,并通过体外释放度比较自研片剂和原研片剂在4种释放介质中的溶出相似性。结果: 盐酸米诺环素缓释片处方中HPMC E50和HPMC K100LV的用量分别为35 mg和70 mg,制得的缓释片在各时间点的释放度与原研片剂相似,4种释放介质中自研片剂和原研片剂的溶出相似因子f₂分别为79.06、84.62、75.46和72.95。结论:采用中心复合设计 效应面法优化的盐酸米诺环素缓释片处方制得的片剂体外释放度符合要求,为下一步的工业化生产提供依据。     

汉防己甲素固体分散片的制备及处方优化

目的:优选汉防己甲素固体分散片的制备处方。方法:采用直接压片法制备汉防己甲素固体分散片。采用单因素试验筛选常用辅料,以崩解时间为指标,以交联聚乙烯吡咯烷酮(PVPP)用量、乳糖-微晶纤维素比例、微粉硅胶用量为因素,采用正交试验对处方进行优化,并进行验证。比较所制片剂与汉防己甲素普通片的溶出度,测定最优处方所制片剂的含量。结果:最优处方为以9.5%PVPP为崩解剂、乳糖-微晶纤维素(1∶2)为填充剂,混匀,加入1%的微粉硅胶为润滑剂,粉末直接压片。所制3批片剂的崩解时间分别为79、81、78 s,占标示量百分含量分别为98.66%、99.24%、99.85%,RSD分别为0.72%、1.16%、1.33%。与汉防己甲素普通片比较,所制片剂的溶出度明显提高。结论:成功制得汉防己甲素固体分散片,且处方合理、重复性好。     

确定性筛选设计优化奥氮平片的处方和工艺

目的 研究奥氮平片处方和制备工艺。方法 用HPLC测定奥氮平片的奥氮平和有关物质含量,用光纤药物溶出度实时测定仪测定溶出曲线,用确定性筛选设计优化奥氮平片的处方和工艺。结果 微晶纤维素加入方式（内加或外加）和羟丙基纤维素用量对颗粒大小分布有显著影响,羟丙基纤维素用量和制粒搅拌速率对溶出曲线相似因子f₂有显著影响。经过优化得到的奥氮平片处方为奥氮平2.5%、乳糖78%、微晶纤维素10%（内加）、羟丙基纤维素4%、交联聚维酮5%、硬脂酸镁0.5%;制粒工艺参数：切割速度30 rps、搅拌速度3 rps、制粒时间5 min。结论 确定性筛选设计适用于奥氮平片处方和制备工艺的筛选和优化,根据确定性筛选设计确定的处方和制备工艺所制的奥氮平片,其溶出曲线与参比制剂相似,其含量均匀度和有关物质均符合中国药典2015年版标准。     

G多糖提取物胶囊的成型工艺

目的:探讨不同辅料对G多糖提取物流动性和吸湿性的影响,考察G多糖提取物硬胶囊成型工艺。方法:在温度25℃、相对湿度为75%的条件下,以不同辅料(微晶纤维素、微粉硅胶)分别与G多糖提取物均匀混合制粒后,进行休止角、吸湿百分率比较,以确定辅料种类和辅料最佳用量。结果:以10%微粉硅胶为辅料制得的颗粒最佳,其临界相对湿度为58%,可满足胶囊剂装填要求。结论:制剂制备符合胶囊剂质量要求。     

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。     

正交试验优化银翘败毒片的干法制粒工艺

目的:优化银翘败毒片干法制粒的工艺条件。方法:以制粒难易程度和崩解时限等为考察指标,对银翘败毒片中辅料微晶纤维素和可压性淀粉的配比、用量及喷干粉的含水量进行筛选;以颗粒得率和休止角为指标,采用L9(34)正交试验对干法制粒工艺中压轮压力、转速及送料速度等条件进行优化并进行验证试验。结果:微晶纤维素与可压性淀粉的比例为7∶3(m/m),二者与(喷干粉+包合物)的混合比例为1∶5;控制喷干粉含水量在1%~2%之间。干法制粒最优工艺参数为压轮压力3.5 MPa、压轮转速4 r/min、送料速度10 r/min。验证试验中颗粒平均得率为69.2%,平均休止角为31.5°,绿原酸转移率达92%以上,且各指标RSD均在2.53%以下(n=3)。结论:按优化辅料处方和工艺制备的颗粒各项指标均具有较好的重现性和可行性,且工艺稳定,适合工业生产。     

盐酸头孢替安酯片的研制及质量研究

目的 研究盐酸头孢替安酯片的制备工艺及质量。方法 以药物的崩解时限和溶出度为主要指标,采用原研片参比单因素考察法对盐酸头孢替安酯片的处方工艺进行优化,并对其质量进行研究。结果 实验确定最优处方：以无水枸橼酸、α-环糊精、微晶纤维素、羟丙纤维素、二氧化硅、硬脂酸镁、薄膜包衣预混剂（胃溶型）为辅料,采用干法制粒制备盐酸头孢替安酯片。盐酸头孢替安酯片各项指标符合日本药局方（JPXV）标准。结论 盐酸头孢替安酯片的制备工艺可行,产品质量具有良好的稳定性。     

不同型号微晶纤维素的性能与应用的比较

目的：比较山河药辅三种型号微晶纤维素（ microcrystalline cellulose ,MCC）作为片剂辅料的各项性能。方法测定并比较三种型号微晶纤维素的粒径、白度、流动性、松密度、振实密度等性能,并对各型号微晶纤维素做处方设计,考察在片剂中的特点。结果 MCC-CG适合湿法制粒;MCC-101做黏合剂使用,特别适合湿法制粒;MCC-102流动性好,适合直接压片。结论不同型号微晶纤维素可针对性的解决片剂处方问题。     

Potential of Raman Spectroscopy for Evaluating Crushing Strength of Tablets

Introduction  

This study evaluates the sensitivity of Raman spectroscopy to changes in physical attributes of the compacted pharmaceutical formulations prepared with lactose monohydrate (49 wt.%), microcrystalline cellulose (49 wt.%), silicone dioxide (1 wt.%), and magnesium stearate (1 wt.%). The tablets made with raw powder were subjected to two iterative dry granulation cycles, i.e., tablet crushing, sieving, and re-tableting. Different compaction forces were applied during tableting. Small- and wide-angle X-ray scattering was used to study physical changes of the granulates and their respective compacts.     

An evaluation of microcrystalline cellulose and lactose excipients using an instrumented single station tablet press

The objective of this study was to evaluate the effects of microcrystalline cellulose of two particle sizes from two suppliers at two concentration levels, in combination with anhydrous lactose or Fast-Flo lactose on various properties of hydrochlorothiazide tablets. The powder blends before compression were evaluated for flow, density and compressibility. Tablets were compressed at three hardnesses and evaluated for friability, disintegration and hydrochlorothiazide dissolution. Powder blends containing Fast-Flo lactose exhibited a flow rate predicted to be sufficient for high-speed tableting whereas only when anhydrous lactose was used with the larger particle size microcrystalline cellulose was the same degree of flowability obtained. Density was affected by the concentration of microcrystalline cellulose. Fast-Flo lactose markedly increased density at the lower level of microcrystalline cellulose concentration. No difference was found in blend compressibility as a result of microcrystalline cellulose particle size or supplier source at medium to high tablet hardness levels, however, anhydrous lactose blends were more compressible than Fast-Flo lactose blends. At all hardness levels, tablets from all blends exhibited excellent friability. In most instances, tablet disintegration seemed to be more rapid when Fast-Flo lactose was present. Hydrochlorothiazide dissolution from all tablets easily met USP specifications. The microcrystalline cellulose from the two sources are interchangeable within particle size classification. Anhydrous lactose is more compressible than Fast-Flo lactose but Fast-Flo lactose is more flowable and its use results in more rapid drug dissolution at the higher microcrystalline cellulose levels.     

Effect of spray-dried mannitol on the performance of microcrystalline cellulose-based wet granulated tablet formulation

The purpose of this study was to evaluate mannitol as filler along with microcrystalline cellulose (MCC) in wet granulated tablet formulation, in situations where lactose cannot be included in the formulation due to chemical incompatibility with the active drug. A two-level full factorial design with two center points was used to study the effect of three variables: mannitol: MCC ratio (mannitol weight fraction of the filler; low 0 (no mannitol) and high 0.5), water to intragranular solids ratio (low 0.25 and high 0.4) and magnesium stearate concentration, w/w (0.6% low and 1.2% high). The response variables evaluated were granulation compactibility, ejection force, normalized granule size, % fines, flowability index, compression speed sensitivity and hardness loss upon storage. Addition of mannitol in the MCC formulation increased compactibility of the final granulation as it decreased the susceptibility of the formulation to compaction loss upon wet granulation. Presence of mannitol in the formulation reduced the compression speed sensitivity and also decreased the susceptibility of the formulation to hardness loss upon storage.     

Thermophysical Properties of Some Pharmaceutical Excipients Compressed in Tablets

Purpose. Thermophysical properties of three tableting excipients; microcrystalline cellulose, lactose and dicalcium phosphate dihydrate were observed to evaluate their ability to resist temperature induced changes in tablet form. Methods. Two thermophysical parameters, thermal diffusivity and specific heat, were measured by a pulse heating method. The materials were also evaluated by differential scanning calorimetry (DSC). Results. Microcrystalline cellulose in tablet form was found to be rather insensitive to heating and cooling treatments, even though the tablets seemed to remain in a stressed state four weeks after tableting. This stress, indicated by low temperature anomalies, was observed by the pulse method, but not by DSC. When magnesium stearate was incorporated as a lubricant within the microcrystalline cellulose powder, the thermophysical parameters indicated that the internal structure of the tablets changed with heating and cooling. Magnesium stearate eliminated the low temperature anomalies as well. The heat treatment changed the thermophysical properties of tablets made of the crystalline excipients lactose and dicalcium phosphate dihydrate, permanently causing irreversible structural changes. Conclusions. The melting of the lubricant together with enhanced stress relaxation in the structure of microcrystalline cellulose most probably caused the improved thermal diffusivity. The observed thermophysical changes with the crystalline excipients were due to changes in tablet's structure and material. The combination of methods used was found to be an accurate and reliable way to obtain useful information on the structural changes and material relaxations of intact tablets during temperature treatment and age-related changes in material properties.     

瑞格列奈二甲双胍片制备工艺研究

目的:设计并制备符合中试产业化生产的瑞格列奈二甲双胍片。方法:以溶出度为指标进行处方筛选和工艺优化。结果:以泊洛沙姆188、葡甲胺、聚维酮(PVP)K30、交联羧甲纤维素钠、微晶纤维素(MCC)PH101、山梨醇、硬脂酸镁及包衣粉为辅料,按照特定的制备工艺制备瑞格列奈二甲双胍片,在4种介质中的溶出行为与参比制剂相似。结论:瑞格列奈二甲双胍片的制备工艺简单可行,质量稳定可控。     

Influence of adjuvants on the dissolution profile of tablets containing high doses of spray-dried extract of Maytenus ilicifolia

A 2(3) factorial design was used in order to evaluate the influence of some adjuvants on the dissolution profile of tablets containing high doses of Maytenus ilicifolia spray-dried extract. Tablets were prepared on a single punch tablet press using 15 mm flat punches by individual direct compression of 650 mg from each formulation containing 375 mg of the spray-dried extract. The factors investigated were disintegrant (croscarmellose sodium or sodium starch glycolate), lubricant (colloidal silicon dioxide or magnesium stearate) and filler/binder (microcrystalline cellulose or lactose). The dissolution profiles were analyzed to determine the dissolution kinetics, the dissolution half-lives (t50%), the similarity factor (f2) and the dissolution efficiency (DE %), which was selected as the response criteria to evaluate the factorial design. The results revealed that in spite of the high content of spray-dried powder in the tablets, the dissolution profiles of the extract did depend on the adjuvant used. The filler/binder had the most important effect on the dissolution efficiency of the tablets.     

粉末直接压片法制备格列本脲片及稳定性考察

采用粉末直接压片工艺制备格列本脲片,以乳糖为助流剂,微晶纤维素为吸附剂,HPLC法检测含量及有关物质.加速稳定性试验表明,制品稳定性优于湿法制粒工艺所得产品.     

Development of Agglomerated Directly Compressible Diluent Consisting of Brittle and Ductile Materials

The objective of this investigation was to develop a novel multifunctional coprocessed adjuvant consisting of three known diluents that show different consolidation mechanisms. The method of wet granulation was adopted for the preparation of coprocessed product. Microcrystalline cellulose (MCC) and colloidal silicon dioxide (X₁), lactose monohydrate (X₂), and dibasic calcium phosphate dihydrate (X_3, DCP) were used as independent variables in a simplex lattice design. Croscarmellose sodium was used at 4% level intragranularly in all the batches. The granules (44/120 #) were characterized for angle of repose, bulk density, tapped density, and Carr's index. The tablets of coprocessed adjuvants were characterized for crushing strength, friability, and disintegration time. Multiple linear regression was adopted for evolving refined mathematical models. A checkpoint batch was prepared and evaluated for particle size distribution, moisture uptake, and dilution potential by using nimesulide as a model drug. Microcrystalline cellulose shows poor flowability due to irregular shape and interlocking. Moreover, it loses a part of its compactibility on wet granulation. To attend these problems, a physical blend of 97% microcrystalline cellulose and 3% colloidal silicon dioxide M5 was prepared and used. The blend of MCC and colloidal silicon dioxide showed better flow than that of the original MCC. Hence, it may be easier to mix with lactose and dibasic calcium phosphate. The loss in compactibility of microcrystalline cellulose on wet granulation was also reduced due to presence of colloidal silicon dioxide. As expected, all the batches exhibited acceptable angle of repose (<35°) and quick disintegration (<1 min). Full and refined models for Carr's index and crushing strength were evaluated. Based on the results of grid analysis, a checkpoint (50% MCC, 40% lactose, and 10% DCP) that satisfies both the conditions of Carr's index and crushing strength was selected. The adjuvants absorb very little moisture in the moisture uptake study. The results of dilution potential study reveal that up to 30% nimesulide, a poorly compressible drug, can be incorporated in the coprocessed product. In vitro drug dissolution from capsules containing pure drug powder and compressed tablets was comparable (f₂=79). The results reveal that the desired product characters can be obtained by varying the quantity of MCC (a ductile material that undergoes plastic deformation), lactose (brittle material with low-fragmentation propensity), and DCP (brittle material with high-fragmentation propensity).