美托拉宗的合成

目的合成利尿降压药美托拉宗。方法以 2 甲基 5 氯苯胺为起始原料 ,经乙酰化保护、氯磺化、氨解、氧化、脱保护基、成酰胺、缩合制得美托拉宗。结果与结论合成了美托拉宗 ,总收率为1 5 % ,其结构经元素分析、1H NMR、13 C NMR和质谱确证。     

LC-MS／MS法测定美托拉宗血浓度及其药物动力学研究

目的：建立一种快速测定人血浆中关托拉宗浓度的液相色谱一串联质谱色谱法,用以研究美托拉宗在健康人体内的药动学。方法：色谱柱：TC—C18（150mm×4．6mm,5μm）,流动相：甲醇：去离子水（70：30）,质谱离子源为电喷雾离子化（ESI）源,选择性离子检测方式检测;血浆样品在0．05～100ng·ml^-1内线性关系良好,定量下限为0．05ng·ml^-1,精密度和准确度试验均符合生物分析要求。健康受试者口服3个单剂量（0．5,1,2mg）进行药物动力学研究,采用DAS2．0软件计算药动学参数。结果：服用0．5,1,2mg美托拉宗后的药动学参数,t1／2分别为（8．6±2．6）、（7．0±1．2）、（7．6±1．9）h;tmax,分别为（1．7±0．9）、（1．6±0．6）、（1．5±1．3）h;Cmax分别为（9．3±1．9）、（18．4±3．6）、（36．8±7．1）μg·ml^-1;AUC0-48分别为（52．17±14．00）、（96．51±19．15）、（162．4±26．9）ng·h·ml^-1;呈线性动力学特征。结论：该方法灵敏度高、专属性强、准确、简便,适用于美托拉宗的人体药动学研究。     

差示扫描量热法在药物多晶型定量分析中的应用

药物多晶型直接影响药物的安全性和质量可控性。因此仅对药物进行晶型的定性研究已不能满足要求。为了确保药品的疗效及安全性,测定原料药或制剂中有效晶型含量需要采用适当的方法对多晶型进行定量分析。本文具体综述了近年来传统差式扫描量热法、调制式差示扫描量热法及超高效差示扫描量热法在药物多晶型定量分析方面的应用,并对其优缺点进行了总结,展望了其应用前景。     

盐酸美西律多晶型研究

目的：研究盐酸美西律的多晶型特征。方法：采用差示扫描量热法、红外光谱分析法和X—ray法，对盐酸美西律多晶型进行了初步研究。结果：盐酸美西律原料有多晶型现象，样品经过溶剂处理和热处理后均可获得稳定晶型。结论：获得了盐酸美西律多晶型相关的热力学数据、红外光谱和X—ray特征，为盐酸美西律对照品及其原料和制剂的质量标准提供了依据。     

阿戈美拉汀的多晶型研究

目的研究阿戈美拉汀的多晶型特征。方法通过平衡溶解度测定、差示扫描量热分析(DSC)、红外光谱(IR)、粉末X射线衍射(PXRD)谱等鉴定阿戈美拉汀多的晶型,并考察其室温放置的稳定性。结果获得Ⅰ～Ⅳ型阿戈美拉汀。利用DSC或PXRD分析可区分4种晶型。结论不同晶型阿戈美拉汀的理化性质有明显差异。Ⅱ型阿戈美拉汀最稳定,Ⅰ、Ⅲ、Ⅳ型稳定性较差。     

盐酸班布特罗多晶型的鉴别

采用差示扫描显热法和红外光谱分析法,对盐酸班布特罗的多晶作了鉴别,并就其晶型的转换作了讨论。     

盐酸文拉法辛多晶型现象的研究

建立了盐酸文拉法辛晶型分析方法.盐酸文拉法辛产品用各种溶剂重结晶及190℃加热相转变,所得样品用X-射线粉末衍射法和差示扫描量热法分析.溶剂结晶法易制得晶型2,晶型1次之.190℃加热相转变则得晶型6.工业化产品用异丙醇重结晶得到以晶型2为主的混合晶型.加速试验研究结果显示,混合晶型中的晶型6会转变为晶型2.     

差示扫描量热法测定7种药物纯度

目的 用差示扫描量热（DSS）法测定药物纯度及探讨影响测定结果的因素。方法用DSC法测定吲哚美辛等7种不同类别药物的纯度，并与《中国药典》规定方法结果进行对照。结果DSC法测定药物纯度的准确性好；试药的用量、纯度、升温速度对测定结果产生影响。结论本法测定高纯度药物简便、结果准确。     

热分析法对卡托普利晶型的研究

目的建立卡托普利晶型的测定方法,并对进口及国内卡托普利原料的晶型进行考察。方法利用差示扫描量热法(DSC)测定卡托普利的晶型,考察在氮气氛下升温速率对测定结果的影响。结果国内不同生产企业生产的卡托普利原料晶型相同,均为高熔点B晶型。结论该分析方法简便、快捷,可有效地控制卡托普利的晶型。     

阿替洛尔与片剂辅料相容性的热分析考察

目的考察阿替洛尔与片剂辅料的相容性。方法应用差示扫描量热法考察。结果阿替洛尔与微晶纤维素、预胶化淀粉、羧甲基淀粉钠、硬脂酸镁等辅料的相容性好,与微粉硅胶、乳糖、聚乙烯吡咯烷酮、枸橼酸、十二烷基硫酸钠等辅料有配伍反应。结论用热分析技术考察主药与辅料的相容性是一种简便有效的方法。     

长春胺胃滞留缓释片的辅料相容性研究

目的：考察长春胺胃滞留缓释片处方中药物与辅料之间的相容性。方法：应用差示扫描量热技术（DSC）对药物与辅料混合样品进行筛选检测,使用高效液相色谱法（HPLC）对影响因素条件（强光4500Lx＋500LX、高温60℃、高湿90％±5％RH）与稳定性加速实验条件（40℃、75％RH）下放置的样品进行检测,对DSC筛选结果进行验证与补充。结果和结论：在考察的3种助流剂、润滑剂中硬脂酸镁最优,2种稀释剂中优化微晶纤维素较优,2种粘合剂均应尽量避免使用．2种产气剂中碳酸钙较优．2种缓释材料中羟丙甲纤维素较优．     

Evaluation of the Physical Stability of Freeze-Dried Sucrose-Containing Formulations by Differential Scanning Calorimetry

Freeze-dried samples of sucrose with buffer salts, amino acids, or dextran have been analyzed with differential scanning calorimetry (DSC) to evaluate the use of DSC thermograms in predicting the physical storage stability. The glass transition temperature, T _g, of the amorphous cake, crystallization, and melting of sucrose are observed with DSC. T _g appeared to be an important characteristic of the physical stability of the amorphous freeze-dried cake. A storage temperature above T _g results in collapse or shrinkage of the cake, which for a sucrose-based formulation, may be accompanied by crystallization of the sucrose. The T _g of the amorphous sucrose is influenced by other components present in the cake. Dextran-40 raised T _g, while the addition of glycine to the formulation lowered T _g. The residual moisture content strongly influences T _g, since water acts as a plasticizer of the system; the higher the moisture content, the lower the T _g and the less physically stable the freeze-dried cake. Crystallization of amorphous sucrose is shown to be inhibited by high molecular weight components or ionic compounds. DSC analysis of freeze-dried cakes proved to be a powerful tool in formulation studies.     

The Effect of Additives on the Crystallization of Cefazolin Sodium During Freeze-Drying

Purpose. To monitor the phase transitions during freeze-drying of cefazolin sodium (I) as a function of process and formulation variables. Methods. Aqueous solutions of I were frozen under controlled conditions in the sample chamber of a variable temperature X-ray powder diffractometer (XRD). The instrument was modified so that the chamber could be evacuated and the samples dried under reduced pressures. Thus, the entire freeze-drying process was carried out in the XRD holder with real time monitoring of the phase transitions during the different stages of freeze-drying. Results. When aqueous solutions of cefazolin sodium (10% w/w) were cooled to -40°C, the XRD pattern revealed only the crystallization of ice. Annealing the frozen sample led to the crystallization of I as the pentahydrate. Differential scanning calorimetry revealed that the presence of isopropyl alcohol (IPA) (5% w/w) led to a decrease in the Tg, the glass transition temperature of the system, and lowered the temperature of crystallization. The crystallization was studied at -8 and at -15°C in the XRD, and, as expected, more rapid crystallization was observed at the higher temperature. Primary drying at -8°C led to the dehydration of the pentahydrate, resulting in a poorly crystalline product. Again, XRD permitted real time monitoring of the decrease in intensities of some characteristic peaks of the pentahydrate. The in situ XRD technique also enabled us to study the effects of processing conditions (different primary and secondary drying temperatures) and crystalline bulking agents on the solid-state of I in the lyophile. When I was lyophilized using mannitol or glycine as an additive, without an annealing step, the drug was X-ray amorphous although the additive crystallized. When annealed and freeze-dried, I remained crystalline in the presence of glycine but not in the presence of mannitol. Conclusions. The in situ XRD technique has enabled us to characterize the phase transitions during freeze-drying of cefazolin sodium in multicomponent systems.     

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.     

Polymorphic Behavior of Sprayed Lipid Micropellets and Its Evaluation by Differential Scanning Calorimetry and Scanning Electron Microscopy

Considering the importance of polymorphism occurring in solid dosage forms causing instability, the polymorphic behavior of spray-dried and -congealed lipid micropellets was examined by differential scanning calorimetry and scanning electron microscopy. The results showed that both of the spraying processes exert an important effect on their polymorphic and crystallization properties. In spray-drying, due to the rapid solvent evaporation, the obtained lipid micropellets possess an unstable polymorphic form. This unstable form transforms gradually toward a stable form by storage at elevated temperatures. The same modifications were observed with spray-congealed lipid micropellets. The type of glyceride (composition, chain length), solvent and drugs (estradiol cypionate, medroxyprogesterone acetate) and, further, the presence of a stabilizing agent such as lecithin affect the polymorphic transition and its rate.     

Starch Gelatinization Under Thermal Stress

The behavior under thermal stress of starch dispersed in water was studied by differential scanning calorimetry (DSC) to estimate the heat transported through the aqueous medium in gelatinization, and to characterize the range of gelatinization temperatures. In DSC scanning mode, the endotherm of 10% starch in aqueous dispersion showed the tracing of gelatinization at between 67 and 80°C, having an onset at approximately 69°C. In the isothermal mode, characteristically distinct isothermal heat flow profiles were revealed. It was hypothesized that the thermal influx proposed as being analogous to the diffusion process may affect the profiles. The profiles were transformed and nonlinearly fitted according to the square root of time model to characterize a so-called t-parameter, which was related to mean square displacement of molecular distribution. The t-parameter of starch in excess of water decreased compared to that of water only. The plot of difference in these t-parameters, expressed as Δ, against temperature showed a dramatically decreased Δ at the temperature between 66.7 and 75.2°C, which coincided with the findings from scanning mode DSC. It was further hypothesized that the decreased Δ may be due to the gelatinizing process. According to the theory of polymer solution, the critical temperature (Θ) at 75.2°C, where the free energy became theoretically negative, i.e., the starch became spontaneously dissolved, was drawn. This Θ was located within the range of gelatinizing temperatures. It was deduced that starch polymer may have dissolved during gelatinization. The dissolution from acetaminophen tablets prepared by starch paste was lower compared with that of negative controls (without paste). Moreover, the paste prepared at gelatinizing temperature (70°C) seemed to inhibit acetaminophen dissolution from tablet matrices more than that prepared at subgelatinizing temperature (50°C).     

A Systematic Review and Meta-Analysis of Metolazone Compared to Chlorothiazide for Treatment of Acute Decompensated Heart Failure

Treatment of volume overload in the setting of acute decompensated heart failure (ADHF) is typically achieved through the use of loop diuretics. While they are highly effective, some patients may develop loop diuretic resistance. One strategy to overcome this scenario includes sequential nephron blockade with a thiazide-type diuretic; however, it is unknown which thiazide-type diuretic used in this setting is most effective. A systematic review and meta-analysis were performed to compare the efficacy and safety of chlorothiazide with metolazone as add-on therapy in the setting of loop diuretic resistance for the treatment of ADHF. Literature searches were conducted through PubMed, Google Scholar, and Science Direct from inception through February 2020 using the following search terms alone or in combination: metolazone, chlorothiazide, acute decompensated heart failure, loop diuretic, and urine output. All English-language prospective and retrospective trials and abstracts comparing metolazone to chlorothiazide for the treatment of ADHF were evaluated. Studies were included if they analyzed urine output for at least 24 hours in patients with ADHF. Meta-analysis was conducted to evaluate pooled effect size by using a random-effect model. Primary outcomes included net and total urine output. Secondary outcomes included commonly reported safety outcomes. Four studies comparing the use of metolazone to chlorothiazide as an adjunct to loop diuretics to treat ADHF were included in the evaluation. Metolazone was as effective as chlorothiazide to augment loop diuretic therapy in ADHF in most studies with no pooled difference in net or total urine output. However, there were notable differences in baseline loop diuretic dosing, ejection fraction, renal function, race, and endpoint timing across studies. Adverse effects were commonly observed and included electrolyte abnormalities, change in renal function, and hypotension but were comparable between groups. Metolazone is as effective as chlorothiazide as add-on to loop diuretics in treating ADHF without an increase in safety concerns.