氟氯西林钠多晶型药物稳定性考察

目的:研究氟氯西林钠多晶型在光照、湿度和高温下的药物稳定性。方法:采用UV法研究了光照、湿度、温度对各晶型药物稳定性的影响。结果:获得了氟氯西林钠各晶型在强光、高温和高湿环境中的稳定性性能。结论:氟氯西林钠3种晶型和无定形均对光稳定,相应顺序为Ⅰ>Ⅲ>Ⅱ>无定形。湿度对各晶型影响较大,高湿环境促进结晶型向无定形转化。温度对3种晶型和无定形药物稳定性影响较小,高温有利于药物分解。氟氯西林钠各晶型在保存和使用中应该避开高湿和高温环境。     

三七总皂苷中代表性皂苷含量测定方法学的建立及稳定性研究

目的 建立同时测定三七总皂苷中三七皂苷R1、人参皂苷Rg1 和人参皂苷Rb1 三种成分的含量测定方法,并对其各种状态下的稳定性进行研究.方法：以乙腈-水系统作为流动相,采用高效液相-梯度洗脱法,同时测定三七总皂苷中三种成分的含量,并考察方法的专属性、线性、精密度和回收率;测定四种pH值溶液中三种皂苷成分的稳定性以及在高温、高湿和强光照射条件下,三七总皂苷粉末中三种皂苷成分的稳定性.结果：方法学验证结果显示,在选定的梯度洗脱条件下,方法专属性良好,三种皂苷可有效分离和定量;在各自的线性范围内线性良好;精密度RSD 值均小于2%;三种皂苷的平均回收率分别为（98.98 ± 0.60）%、（98.86 ± 0.34）%和（100.19 ± 0.64）%,方法准确性良好.稳定性研究结果显示,在溶液状态下,三种皂苷的稳定性趋势基本-致,稳定性与pH值密切相关,在pH 1.2 溶液中药物迅速降解,24 h 含量即降低了约80%;而在pH 4.5 溶液、pH 6.8 溶液以及水中,三种成分的稳定性均良好,24 h 内含量未发生明显变化;而在三七总皂苷粉末中,三种代表性皂苷对湿、热和光照均不敏感,10 d 内含量基本保持稳定;但是在高湿条件下,粉末有-定的吸湿性.结论：所建立的液相方法准确、可靠,溶液状态下三七皂苷R1、人参皂苷Rg1 和人参皂苷Rb1 的稳定性与pH密切相关,随pH的降低稳定性变差,而在固体状态下则稳定性良好.     

氟康唑的多晶型及转化研究

目的对氟康唑的多晶型及其相互转化进行分析研究。方法采用红外光谱仪(IR)、近红外光谱仪(NIR)、拉曼光谱仪(RM)、X-射线粉末衍射仪(XRD)、差示扫描量热仪(DSC)和热重分析仪(TGA)对氟康唑的晶型进行了研究,并考察了温度、湿度、溶剂和研磨对其晶型转化的影响。结果 X-射线粉末衍射法作为晶型判定方法,10个厂家18批氟康唑的晶型有Ⅱ型、Ⅲ型和一水合物晶型;在不同的温度、湿度和结晶溶剂中Ⅱ型和一水合物晶型可相互转化,在氯仿中结晶和高温熔融可得到I型结晶。结论氟康唑不同晶型谱学特征显著,可对氟康唑晶型进行质量控制,各晶型间可以相互转化并确定了转化条件。     

泊沙康唑晶型制备及甲醇-水体系中相图测定

目的 制备泊沙康唑工艺相关的Form I、Form III、Form IV、Form S 4种晶型，研究上述晶型在甲醇-水体系中相互稳定性关系，并绘制相图。方法 采用溶液结晶法控制结晶溶剂、温度等析晶条件进行制备，并采用XRPD、DSC、TGA等方法表征4种晶型，采用晶型竞争试验的方法研究晶型在甲醇-水体系中的相对稳定性。结果 在甲醇-水体系中，泊沙康唑的晶型与水活度及温度密切相关。高水活度和低温更易于形成Form IV；高浓度甲醇和低温更易于形成Form III；高水活度和高温更易于形成Form S；低水活度和高温更易于形成Form I。结论 泊沙康唑在原料药结晶工艺及制剂处方工艺过程中存在转晶风险，制剂处方工艺中采用湿法造粒风险较高，因此在结晶工艺过程中确定析晶和洗涤时的甲醇优选范围对原料药和制剂生产过程中的晶型控制具有较强的指导意义。     

替格瑞洛川芎嗪分散片的处方前研究

目的 通过开展相关处方前研究,考察原料药理化性质及原辅料配伍稳定性等,为制备复方分散片提供参考。方法 通过恒温平衡法,测定溶解度及稳定性;通过溶出度测定法,考察粒度与替格瑞洛溶解速率的相关性;通过影响因素试验,考察原辅料配伍稳定性及晶型稳定性。结果 替格瑞洛几乎不溶于水,磷酸川芎嗪易溶于水;粒度与替格瑞洛溶解速率相关;原辅料样品与原料药的有关物质变化趋势相似;原辅料样品在高温、光照、受压条件下的替格瑞洛晶型较稳定,在高湿条件下晶型略有变化。结论 两种药物及原辅料的相容性良好,替格瑞洛川芎嗪分散片小试样品稳定性良好。     

人参皂苷Rg1的溶解特性与脂质体包封率关系的研究

目的:研究人参皂苷Rg1油-水分配系数与脂质体包封率的关系。方法:测定人参皂苷Rg1的正辛醇-水分配系数、氯仿-水分配系数,人参皂苷Rg1在水、甲醇、乙醇中的溶解度;采用不同的方法制备脂质体并测定包封率。结果:人参皂苷Rg1油-水分配系数低于0.5,在3种溶剂中微溶;几种制备方法所得人参皂苷Rg1脂质体包封率均较低。结论:人参皂苷Rg1油-水分配系数小,不适合制成脂质体。     

HPMC修饰的氟苯尼考微晶体的制备及表征

目的制备氟苯尼考微晶体,提高氟苯尼考的溶解度,以促进吸收并增加其生物利用度。方法使用改良溶剂反溶剂法制备羟丙甲纤维素(HPMC)修饰的氟苯尼考微晶体,通过正交优化得到最佳制备工艺。考察其形态学、体外溶解性质、稳定性,并通过差示扫描量热法(DSC)和X射线衍射法研究其晶型变化。结果反溶剂为水、溶剂为丙酮、温度为4℃、HPMC为4 mg·m L-1时,制备的微晶体最大饱和溶解度为3.13 mg·m L-1,溶解速度明显增加;原药和微晶体在形态学上差异较大且微晶体粒的径明显小于原药,二者对高温、高湿、强光均稳定;DSC和X射线衍射实验表明药物晶型从两种转变成了一种。结论该制备工艺简单,HPMC修饰的氟苯尼考微晶体明显增加了氟苯尼考的溶解度和溶解速度,性质稳定,有较好的应用前景。     

盐酸阿替卡因的多晶型研究

目的:建立盐酸阿替卡因多晶型的测定方法并研究其理化性质.方法:研究了不同晶型的盐酸阿替卡因的制备方法,采用熔点测定、差示扫描量热法(DSC)、红外吸收光谱法(IR)及粉末X-衍射法(Powder X-ray)研究了不同晶型的特征,并考察了2种晶型在高湿、高温和光照条件下的稳定性.结果:盐酸阿替卡因存在2种不同的晶型,晶型Ⅰ和晶型Ⅱ.通过熔点测定、DSC和IR分析及粉末X-衍射法可区分2种晶型.晶型Ⅰ有较强的吸湿性,而晶型Ⅱ不易吸湿,2种晶型对光照和高温均较稳定.结论:盐酸阿替卡的晶型Ⅱ适合作为药物应用.     

盐酸普拉克索B晶型的制备和表征

目的 制备盐酸普拉克索的B晶型并优化制备工艺,同时进行结构表征和稳定性研究。方法 制备盐酸普拉克索的B晶型,采用热重法(TGA)、差示扫描量热法(DSC)、X射线粉末衍射(PXRD)、X射线单晶衍射(SXRD)等分析手段,对盐酸普拉克索B晶型进行表征研究。结果 制备得到了盐酸普拉克索B晶型,其晶型属正交晶系,空间群P2₁2₁2₁,结构中不含溶剂(包括水)。盐酸普拉克索B晶型热处理后晶型不发生转变。结论 盐酸普拉克索B晶型为无水晶型,热稳定性优于一水合物晶型,具有高温稳定性。     

三七二醇皂苷含量测定方法建立及其固有稳定性研究

目的:采用HPLC建立同时测定三七二醇皂苷提取物(PDS)中人参皂苷Rb_1和Rd两种主要药效成分的含量测定方法,并对影响PDS固有稳定性的因素进行初步探索。方法:以乙腈-水系统作为流动相,采用梯度洗脱法,同时测定PDS主要成分的含量,并进行方法学考察;考察PDS主要药效成分在不同pH值溶液中以及在高温、高湿和强光照射条件下的固有稳定性。结果:方法学考察结果显示,人参皂苷Rb_1和Rd分别在0.1502~1.5020mg·mL~(-1)、0.0202~0.2022 mg·mL~(-1)范围内呈良好线性;平均回收率分别为99.35%、98.94%。稳定性研究结果显示,PDS主要药效成分人参皂Rb_1和Rd在pH 1.2的溶液中均迅速降解,24h内含量降低了90%以上;在高温、高湿和强光条件下含量降低幅度不大。结论:建立的含量测定方法准确可靠,可用于PDS含量测定及过程质量控制;溶液pH值会影响PDS的稳定性。高温、高湿和强光对PDS的稳定性有一定影响。该研究可为三七二醇皂苷新制剂的辅料与剂型的选择、处方设计及工艺优化等提供科学依据。     

Changes in the solid state of anhydrous and hydrated forms of sodium naproxen under different grinding and environmental conditions: Evidence of the formation of new hydrated forms

The aim of the present work was to investigate the solid state change of the anhydrous and hydrate solid forms of sodium naproxen under different grinding and environmental conditions. Grinding was carried out manually in a mortar under the following conditions: at room temperature under air atmosphere (Method A), in the presence of liquid nitrogen under air atmosphere (Method B), at room temperature under nitrogen atmosphere (Method C), and in the presence of liquid nitrogen under nitrogen atmosphere (Method D). Among the hydrates, the following forms were used: a dihydrate form (DSN) obtained by exposing the anhydrous form at 55% RH; a dihydrate form (CSN) obtained by crystallizing sodium naproxen from water; the tetrahydrate form (TSN) obtained by exposing the anhydrous form at 75% RH. The metastable monohydrate form (MSN), previously described in the literature, was not used because of its high physical instability.The chemical stability during grinding was firstly assessed and proven by HPLC. Modification of the particle size and shape, and changes in the solid state under different grinding methods were evaluated by scanning electron microscopy, and X-ray powder diffractometry and thermogravimetry, respectively. The study demonstrated the strong influence of starting form, grinding and environmental conditions on particle size, shape and solid state of recovered sodium naproxen forms. In particular, it was demonstrated that in the absence of liquid nitrogen (Methods A and C), either at air or at nitrogen atmosphere, the monohydrate form (MSN) was obtained from any hydrates, meaning that these grinding conditions favored the dehydration of superior hydrates. The grinding process carried out in the presence of liquid nitrogen (Method B) led to further hydration of the starting materials: new hydrate forms were identified as one pentahydrate form and one hexahydrate form. The hydration was caused by the condensation of the atmospheric water on sodium naproxen particles by liquid nitrogen and by the grinding forces that created a close contact between water and drug. The simultaneous disruption of the crystals, occurring during grinding, and their close contact with water molecules promoted the conversion in higher hydrates. Under the Method D, it was possible to highlight a certain tendency to hydration probably due to a rearrangement of water already present into the hydrates, but results were substantially different from Method B. Thus, summarizing, the different SN forms behave differently under different grinding and environmental conditions.     

New Sodium Mefenamate – Nicotinamide Multicomponent Crystal Development to Modulate Solubility and Dissolution: Preparation,Structural, and Performance Study

A cocrystal of mefenamic acid (MA) - nicotinamide (NA) has been reported to increase the solubility of MA, but it still does not exceed the solubility of sodium mefenamate (SM). Accordingly, this research dealt with a new salt cocrystal arrangement of SM – NA. Cocrystal screening was performed, followed by powder and single-crystal preparation. Solvent drop grinding and slow evaporation at cold and ambient temperatures were employed to produce the multicomponent crystal. Two new salt cocrystals were found as hemihydrates and monohydrates, named SMN-HH and SMN-MH, respectively. SMN-MH single crystals were successfully isolated and structurally analyzed using a single crystal X-ray diffractometer. Pharmaceutical properties were investigated, including hydrate stability, solubility, and intrinsic dissolution. The experiments showed that the hemihydrate was stable under ambient humidity and temperature, and that the monohydrate rapidly changed to hemihydrate. Both hydrates improved the solubility and intrinsic dissolution of SM, but SMN-HH was superior. The data showed that SMN salt cocrystals combine the advantages of salt and cocrystals and show potential for dosage form development.     

Screening for pharmaceutical cocrystal hydrates via neat and liquid-assisted grinding

The formation of cocrystal hydrates represents a potential route to achieve molecular materials with improved properties, particularly stability under conditions of high relative humidity. We describe the use of neat and liquid-assisted grinding for screening for hydrated forms of pharmaceutical cocrystals. In the case of liquid-assisted grinding, water is present in the reaction mixture as a liquid, whereas in the case of neat grinding, it is introduced by employing crystalline hydrates as reactants. The ability to form a cocrystal hydrate by either of the two methods appears to be variable, depending on the choice of cocrystal components. Theophylline readily forms a cocrystal hydrate with citric acid. This contrasts with the behavior of caffeine, which provides only an anhydrous cocrystal ("caffeine citrate") even when both reactants are crystalline hydrates. The preference of theophylline to form a cocrystal hydrate is qualitatively explained by similarity between crystal structures of the products and reactant hydrates. Overall, liquid-assisted grinding is less sensitive to the form of the reactant (i.e., hydrate or anhydrate) than neat grinding. For that reason liquid-assisted grinding appears to be a more efficient method of screening for cocrystal hydrates, and it is also applicable to screening for hydrates of APIs.     

Effect of Environmental Humidity on the Transformation Pathway of Nitrofurantoin Modifications During Grinding and the Physicochemical Properties of Ground Products

Abstract— The effect of humidity on the physicochemical properties of nitrofurantoin anhydrate and monohydrate during grinding in a humidity-controlled system was investigated using X-ray diffraction analysis, IR spectroscopy, thermal analysis and scanning electron microscopy. Anhydrate and monohydrate were transformed into a noncrystalline solid and a stable monohydrate, respectively, during grinding in a closed system. During grinding in an open system, in which the humidity level of the air was controlled (5, 50 and 75% r.h.), the anhydrate absorbed moisture from the supplied air and water content was increased at 75% r.h.; thereafter the compound was transformed into monohydrate II. The anhydrate did not absorb at 5 or 50% r.h. and was transformed into a noncrystalline solid. Monohydrate I desorbed crystal water during grinding at 5% r.h. and was transformed into a noncrystalline solid. However, monohydrate I was transformed into monohydrate II at 50 and 75% r.h. without desorption of crystal water. These results suggest that the solid-state transformation of nitrofurantoin during grinding depends upon the environmental humidity.     

pH对注射用盐酸地尔硫稳定性的影响

目的：确定注射用盐酸地尔硫[艹卓]的制备工艺并考察稳定性影响因素。方法：采用HPLC测定注射用盐酸地尔硫[艹卓]的含量及有关物质，考察制剂在强光、高热、高湿条件下的稳定性。结果：溶液状态时盐酸地尔硫[艹卓]最适pH为4，pH为5时冻干成品稳定性较好。注射用盐酸地尔硫[艹卓]对强光、高热条件下稳定性较差，在高湿条件下易吸潮塌陷。结论：本工艺条件能有效降低冻干成品有关物质，提高稳定性。     

A Novel Drug-Drug Cocrystal of Levofloxacin and Metacetamol: Reduced Hygroscopicity and Improved Photostability of Levofloxacin

Levofloxacin (LVFX), a broad-spectrum antibacterial agent from the fluoroquinolone family, is universally prescribed with antipyretics, including paracetamol (APAP) analogs. In this study, a new drug-drug cocrystal of LVFX and an APAP analog was developed using a grinding and heating approach. Among 9 APAP analogs, only metacetamol (AMAP) was able to form a cocrystal with LVFX, with a stoichiometric ratio of 1:1. This cocrystal was obtained from a eutectic melt of anhydrous LVFX and AMAP after complete desorption of water from LVFX hemihydrate. The crystal structure of the cocrystal was determined by single-crystal X-ray structural analysis. Unlike LVFX hydrates, the LVFX-AMAP cocrystal did not form a channel structure where water molecules reside in LVFX hydrates. Thus, the LVFX-AMAP cocrystal did not undergo hydration under high relative humidity conditions during vapor sorption-desorption analysis and physical stability tests. LVFX photostability was improved by cocrystallization when compared with that of the hemihydrate because of hydrogen bond formation between the hydroxyl group of AMAP and the N-methylpiperazine group of LVFX, which is possibly involved in LVFX photodegradation. The LVFX-AMAP cocrystal, which is superior to LVFX hydrates in both pharmacological and physicochemical properties, is expected to be a useful solid form.     

Preparation and physicochemical properties of niclosamide anhydrate and two monohydrates

The intent of the study was to prepare and characterize three crystal forms of niclosamide namely the anhydrate and the two monohydrates and to investigate the moisture adsorption and desorption behavior of these crystal forms. The crystal forms were prepared by recrystallization and were characterized by differential scanning calorimetry, thermogravimetric analysis, isoperibol solution calorimetry, Karl Fischer titration, and X-ray powder diffractometry. Moisture adsorption by the anhydrate at increased relative humidities and two temperatures, 30 and 40 degrees C, was measured while the desorption from the monohydrates was determined at 45, 55, and 65 degrees C for monohydrate H(A) and 75, 90, and 100 degrees C for monohydrate H(B). Thermal analysis and solution calorimetry showed that monohydrate H(B) is more stable than monohydrate H(A) and solubility measurements showed the solubility of the crystal forms decreased in the order: anhydrate>monohydrate H(A)>monohydrate H(B). With an increase in temperature and relative humidity niclosamide anhydrate adsorbed moisture to form monohydrate H(A) by a random nucleation process. Dehydration of monohydrate H(A) at increased temperatures followed zero order kinetics and resulted in a change to the anhydrate. Monohydrate H(B) was transformed to the anhydrate at higher temperatures by a three-dimensional diffusion mechanism.     

自微乳缓释片中西罗莫司的稳定性提高研究

目的：提高自微乳缓释片中西罗莫司（SRL）的稳定性。方法：考察SRL在不同pH条件下的稳定性,再利用柠檬酸或苹果酸调节自微乳的pH并制备缓释片,利用铝塑材料对自微乳缓释片进行包装,考察在高温、高湿和强光照射条件下SRL的含量变化。结果：SRL原料药在高温、高湿和强光照射条件下稳定,市售片中的SRL含量仅在强光照射下少量降低,而自制自微乳缓释片中的SRL在高温和强光照射试验下均不稳定。自微乳的碱性环境可能是导致SRL高温不稳定的主要原因,测定发现SRL稳定的pH为4.5~5.8。利用苹果酸和柠檬酸均可提高自微乳中药物的高温稳定性,使（40±2）℃条件下,缓释片中药物的含量达到98%以上。苹果酸的吸湿性导致片重增加,表面有湿润感,因此确定选用0.20%的柠檬酸作为pH调节剂。光照对自微乳缓释片中的药物有不利影响,采用铝塑包装（内含暗黑色避光层）,可使SRL含量由94.06%提高至99.37%。综合应用0.20%柠檬酸和铝塑包装所得的SRL自微乳缓释片在高温、高湿和强光照射条件下,10 d时的含量均在99%以上。结论：经铝塑包装的含0.20%柠檬酸的SRL自微乳缓释片,在高温、高湿、强光照射条件下均具有良好的稳定性。     

丹参酮Ⅱ_A-聚乙烯吡咯烷酮K30固体分散体的稳定性考察

目的:考察温度、湿度及光照对丹参酮ⅡA-聚乙烯吡咯烷酮(PVP)K30固体分散体质量的影响。方法:以丹参酮ⅡA为指标成分,选用影响因素稳定性试验,在不同温度、湿度及光照条件下,用高效液相色谱法进行含量测定。结果:高温及强光均能降低丹参酮ⅡA-PVPK30固体分散体中丹参酮ⅡA的含量;而湿度虽未影响丹参酮ⅡA的含量,但由于PVP的引湿性,可引起丹参酮ⅡA-PVPK30固体分散体自身质量的增加。结论:丹参酮ⅡA-PVPK30固体分散体应干燥、常温、避光贮存。     

Physical characterization of the hydrates of urapidil

Three hydrates of urapidil were prepared and characterized by means of differential scanning calorimetry, thermogravimetric analysis, infrared spectroscopy, X-ray powder diffraction, intrinsic dissolution rates, and solution calorimetry. The stoichiometry of the urapidil hydrates was found to be 1:5, 1:3, and 1:1 (urapidil:water). The crystal and molecular structures of urapidil pentahydrate were determined from three-dimensional X-ray data. The stability of the pentahydrate and monohydrate under different storage conditions was also determined.