杨梅素-咖啡因共晶在不同有机溶剂中的形成热力学特征

目的考察了杨梅素-咖啡因共晶在甲醇、乙醇、丙酮中的形成热力学特征。方法通过测定杨梅素、咖啡因、杨梅素-咖啡因共晶在甲醇、乙醇、丙酮中的溶解度,探讨杨梅素-咖啡因共晶的溶液络合模型,计算相关热力学参数,并绘制3种溶剂的共晶三元相图。结果杨梅素-咖啡因共晶在3种溶剂中均符合1∶1溶液络合模型;共晶形成反应为热力学自发反应(ΔG°<0),随着温度升高,溶度积(Ksp)逐渐增大,络合常数(K11)逐渐减小,反应自发程度减弱,低温有利于共晶的形成;共晶的溶解为吸热过程(Δ_(sol)H_m>0),升高温度有利于共晶的溶解。杨梅素-咖啡因-溶剂(甲醇、乙醇和丙酮)三元体系的三相图为对称相图,共晶形成区域在乙醇和丙酮中较甲醇中大,共晶更易形成。结论利用热力学研究方法为选择共晶制备用溶剂及优化共晶制备条件奠定了理论和应用基础。     

针毛蕨治疗慢性非细菌性前列腺炎的活性部位研究

摘 要 目的： 探讨针毛蕨甲醇提取物对慢性非细菌性前列腺炎（CNP）模型大鼠的治疗效果,初步确定其活性部位。方法: 粉碎的针毛蕨根茎用甲醇提取,所得浸膏依次用氯仿和乙酸乙酯萃取后得到氯仿部位、乙酸乙酯部位和水部位;建立角叉菜胶诱导的CNP模型,将实验大鼠随机分成正常对照组、模型组、阳性对照组、甲醇提取物组、乙酸乙酯组、氯仿组和水部位组,测定各组的前列腺指数,利用ELISA试剂盒测定各组大鼠血清中白细胞介素-10（IL-10）、肿瘤坏死因子-α（TNF-α）、环氧合酶-2（COX-2）和前列腺素E₂（PGE₂）的含量,前列腺组织HE染色后进行病理学观察。结果: 与模型组相比较,黄酮含量较高的乙酸乙酯组和甲醇提取物组大鼠的前列腺指数明显减小（P<0.01）,前列腺组织病理学改善显著,细胞因子IL-10、TNF-α、COX-2和PGE₂的含量显著降低（P<0.05或P<0.01）,尤其是乙酸乙酯组。结论:针毛蕨对CNP具有较好的治疗效果,初步确定乙酸乙酯部位为其活性部位。     

姜黄素下调NF-κB信号通路抑制化学缺氧诱导的U87细胞炎症反应

目的 研究姜黄素对化学缺氧所致人源性神经星形胶质瘤细胞系U87炎症反应的影响,并探讨相关分子机制。方法 100 μmol/L CoCl₂处理U87细胞不同时间（1、3、6、12、24 h）,实时荧光定量PCR（qRT-PCR）法检测炎症因子白细胞介素-1β（IL-1β）、白细胞介素-6（IL-6）、肿瘤坏死因子-α（TNF-α） mRNA表达变化。100 μmol/L CoCl₂处理U87细胞12 h制备化学缺氧模型,同时给予1、5和10 μmol/L姜黄素处理,对照组（不添加CoCl₂）和模型组给予等体积DMSO;qRTPCR法检测IL-1β、IL-6、TNF-α mRNA表达变化;Western Blotting法检测NF-κB/P65蛋白磷酸化水平及核转位。结果 CoCl₂上调U87细胞IL-1β、IL-6、TNF-α mRNA水平并呈时间相关性,炎症反应在约12 h达到高峰。与模型组比较,姜黄素显著下调炎症因子IL-1β、IL-6和TNF-α的mRNA水平,5和10 μmol/L浓度组差异显著（P<0.05）;显著下调p65的磷酸化水平（P<0.05）;导致细胞核内NF-κB/p65蛋白显著减少、细胞质中NF-κB/p65蛋白显著增加（P<0.05）。结论 姜黄素通过下调NF-κB信号通路抑制化学缺氧诱导的U87细胞炎症反应。     

小檗碱与大黄酸沉淀作用的毛细管电泳法

目的研究大黄酸和小檗碱沉淀反应的热力学和动力学性质，为深入研究中药复方泻心汤和芍药汤提供依据。方法用毛细管电泳法测定在不同条件下沉淀反应溶液中两组分的平衡浓度，研究沉淀反应的热力学和动力学。结果沉淀中两组分摩尔比1∶1，20 ℃时溶度积常数k_sp=［B］［R］=(3.29±0.19)×10^-9mol²·L^-2。沉淀反应为吸热过程，k_sp受温度的影响不大。沉淀反应在混合时很快发生，然后是沉淀的陈化过程。结论中药复方泻心汤和芍药汤在煎煮过程中产生的来自于大黄蒽醌和生物碱的沉淀有一定的溶解度。毛细管电泳采用加大进样量后用峰高定量的方法有助于提高简单样品测定结果的重现性。     

基于淫羊藿次苷Ⅱ代谢行为的体外药物相互作用研究

目的 应用体外实验方法筛选淫羊藿次苷Ⅱ在肝微粒体中的尿苷二磷酸葡萄糖醛酸转移酶（UGT）抑制剂,为改善淫羊藿次苷Ⅱ生物利用度提供新思路。方法 首先选择槲皮素、山柰酚、桔皮素、柚皮素、水飞蓟素、草质素、胡椒碱、甘草查尔酮A以及异银杏双黄酮作为抑制剂筛选对象,对以上9种化合物在人肝微粒体、人肠微粒体、大鼠肝微粒体、猴肝微粒体及小型猪肝微粒体中对淫羊藿次苷Ⅱ葡萄糖醛酸化反应的抑制作用进行初步研究。抑制剂分别选择低、中、高3个浓度（1、10、100 μmol/L）,采用超快速高效液相色谱（UFLC）法测定代谢产物生成速率,以UGT代谢酶残余活性评价抑制能力。从中筛选出抑制能力较强的化合物（半数抑制浓度IC₅₀≤10 μmol/L）,对其在人肝微粒体中的抑制机制进行系统研究并计算IC₅₀及抑制常数（K_i）值。IC₅₀值的测定采用单一底物浓度法,在不同浓度代谢酶抑制剂的孵育体系中,代谢产物的生成速率不同,应用非线性回归分析计算而得。K_i的测定需在孵育体系中设计3～4个底物浓度以及4～5个包括0点在内的抑制剂浓度,抑制动力学类型通过Dixon作图法和Lineweaver-Burk作图法确定,采用二次作图法计算K_i。结果 山柰酚、槲皮素及甘草查尔酮A对淫羊藿次苷Ⅱ在不同种属肝微粒体及人肠微粒体中的葡萄糖醛酸化反应均具有较强的抑制作用;对在人肝微粒体中的葡萄糖醛酸化反应抑制作用的IC₅₀值分别为（1.01±0.26）、（4.65±0.51）、（5.34±1.00） μmol/L;Dixon作图法及Lineweaver-Burk作图法表明,甘草查尔酮A能够竞争性抑制淫羊藿次苷Ⅱ在人肝微粒体中的葡萄糖醛酸化反应,K_i值为0.18 μmol/L;槲皮素遵循混合型抑制动力学模型,K_i值为0.23 μmol/L;山柰酚符合非竞争型抑制动力学模型,K_i值为0.36 μmol/L。结论 山柰酚、槲皮素及甘草查尔酮A能够降低淫羊藿次苷Ⅱ在不同种属肝微粒体中的葡萄糖醛酸化反应速率,使代谢产物生成减少,清除减慢。     

双去甲氧基姜黄素对四氯化碳致小鼠急性肝损伤的保护作用及机制

目的 研究双去甲氧基姜黄素（BDMC）对四氯化碳（CCl₄）致小鼠肝损伤模型的保护作用及机制。方法 雄性KM小鼠随机分为对照组、模型组、联苯双酯100 mg·kg^-1剂量（BDD100）组、双去甲氧基姜黄素12.5、25及50 mg·kg^-1剂量组,每组12只。联苯双酯及双去甲氧基姜黄素灌胃给药,每天1次,连续给药7 d。末次给药1 h后,除对照组外,其余小鼠均采用腹腔注射2％四氯化碳橄榄油溶液制备小鼠肝损伤模型。造模24 h后,检测血清谷氨酸转氨酶（ALT）及天冬氨酸转氨酶（AST）水平;ELISA法检测血清肿瘤坏死因子α（TNF-α）及白细胞介素1β（IL-1β）水平;Western blot检测肝组织bax、bcl-2及cleaved caspase-3蛋白表达。结果 与对照组相比,模型组小鼠血清谷氨酸转氨酶、天冬氨酸转氨酶活力及肿瘤坏死因子α、白细胞介素1β水平均明显升高（P<0.01）;肝组织bax/bcl-2及cleaved caspase-3表达明显升高（P<0.05,P<0.01）。与模型组相比,双去甲氧基姜黄素12.5、25 mg·kg^-1剂量组小鼠血清谷氨酸转氨酶、天冬氨酸转氨酶活力及肿瘤坏死因子α、白细胞介素1β水平均明显降低（P<0.05,P<0.01）;肝组织bax/bcl-2及cleaved caspase-3表达明显降低（P<0.05, P<0.01）。结论 双去甲氧基姜黄素对四氯化碳致小鼠肝损伤具有保护作用,其机制可能与抗炎及抗凋亡有关。     

脑心通胶囊对缬沙坦在大鼠体内药动学的影响

目的 研究脑心通胶囊对缬沙坦在大鼠体内药动学的影响。方法 建立液相色谱-串联质谱（LC-MS/MS）法检测缬沙坦血药浓度,并进行专属性考察、回收率试验、基质效应、稳定性试验等方法学验证;24只SD雄性大鼠,随机均分为3组,每组8只,分别为缬沙坦组（A组）,缬沙坦和脑心通胶囊单次给药组（B组）,脑心通胶囊给药7 d后,第8天ig给予缬沙坦和脑心通胶囊组（C组）,于给药前及给药后不同时间点由大鼠眼眶静脉丛采血,采用液相色谱-串联质谱（LC-MS/MS）法测定血浆中缬沙坦的质量浓度,DAS2.0软件统计分析,得到缬沙坦的药动学参数。结果 成功建立LC-MS/MS法检测缬沙坦血药浓度方法,方法学验证符合药动学相关规范要求。口服缬沙坦在大鼠体内的药动学属于一室模型。B组C_max明显低于A组,但差异无统计学差异;B组t_1/2显著高于A组（P<0.05）;C组t_max、t_1/2、AUC_0-tn、AUC_0-∞均显著高于A组（P<0.05、0.01）,K_e显著低于A组（P<0.05）;C组AUC_0-tn、AUC_0-∞显著高于B组（P<0.05）。结论 大鼠经连续ig给药脑心通胶囊后,可显著延缓缬沙坦在大鼠体内的达峰时间,并使缬沙坦在大鼠体内的生物利用度升高。     

衢枳壳不同组分体外降糖活性研究及4种黄酮组分含量分析

目的 研究衢枳壳不同极性组分体外降糖活性,并明确各组分中4种黄酮类化合物的含量。方法 采用系统溶剂法提取与分离衢枳壳中不同极性的黄酮组分,通过体外试验明确各组分对α-葡萄糖苷酶活性和HepG2细胞葡萄糖消耗的影响。采用Agilent Zorbax SB C₁₈色谱柱（250 mm×4.6 mm,5 μm）,以乙腈-0.02%磷酸水溶液（20︰80）为流动相,流速1.0 mL·min^-1,检测波长280 nm,柱温35℃,外标法测定衢枳壳各组分中芸香柚皮苷、柚皮苷、橙皮苷和新橙皮苷的含量。结果 衢枳壳各组分均具有α-葡萄糖苷酶抑制作用,抑制强弱顺序为正丁醇组分[IC₅₀：（0.033±0.010） mg·mL^-1] > 甲醇组分[IC₅₀：（0.092±0.006） mg·mL^-1] > 乙酸乙酯组分[IC₅₀：（0.170±0.014） mg·mL^-1] > 氯仿组分[IC₅₀：（0.509±0.070） mg·mL^-1];衢枳壳甲醇组分和正丁醇组分能够显著促进HepG2细胞葡萄糖的消耗,差异具有统计学意义（P<0.05）。含量测定方法经方法学认证,各项参数均符合要求。经分析发现：衢枳壳各组分中均含有芸香柚皮苷、柚皮苷、橙皮苷和新橙皮苷等黄酮类化合物,且正丁醇组分中各黄酮成分含量最高。结论 衢枳壳各组分均具有α-葡萄糖苷酶抑制作用,且随着各组分中黄酮类化合物含量增高作用增强。同时,含有较高黄酮类组分含量的衢枳壳组分具有促进HepG2细胞葡萄糖消耗的作用,如甲醇、正丁醇和乙酸乙酯组分。     

姜黄素对四氯化碳诱导大鼠急性肝损害的保护作用

目的 研究姜黄素对四氯化碳诱导的大鼠急性肝损伤的保护作用及其机制。方法 60只健康♂SD大鼠随机分成6组,即正常对照组,肝损伤模型组,阳性药物对照水飞蓟素组（100 mg·kg^-1）,姜黄素低剂量组（25 mg·kg^-1）,姜黄素中剂量组（50 mg·kg^-1）和姜黄素高剂量组（100 mg·kg^-1）。隔天灌胃给药,共30 d;末次给药1 h后,腹腔注射20 mg·kg^-1 CCl₄玉米油溶液（2 mL·kg^-1）造模,禁食不禁水,12 h后乌拉坦麻醉。取下腔静脉血和肝脏后,分别检测大鼠血清中丙氨酸氨基转移酶（AST）及天门冬氨酸氨基转移酶（ASL）的活性,大鼠肝脏组织中血红素加氧酶Ⅰ（HO-1）及静脉血中HbCO的水平,在体外测定姜黄素清除DPPH自由基及ABTS自由基的能力。结果 与正常对照组相比,模型组血清中ALT、AST活性显著升高,肝组织中HO-1活性及静脉血中HbCO的含量显著降低,组织病理检查显示肝组织损伤明显增加。与模型组相比,姜黄素各剂量组可不同程度的降低血清AST及ASL的活性,增加肝脏组织中HO-1的活性及HbCO的水平,组织病理检查显示肝损伤有不同程度减轻。并且姜黄素具有清除DPPH自由基及ABTS自由基的能力。结论 姜黄素对CCl₄诱导的大鼠急性肝损伤具有一定保护作用,其机制可能与其自身抗氧化能力及诱导HO-1及HbCO有关。     

在体单向灌流法研究阿哌沙班肾衰大鼠肠吸收特性

目的 研究阿哌沙班在肾衰大鼠体内的肠吸收特性,并考察P糖蛋白(P-glycoprotein,P-gp)抑制剂对阿哌沙班吸收行为的影响。方法 选择肾衰大鼠在体单向灌流法进行肠吸收实验,建立大鼠阿哌沙班肠灌流液HPLC分析方法,以考察大鼠在体肠吸收影响因素。结果 阿哌沙班在各肠段的吸收速率常数（K_a）存在显著性差异（P<0.05）,但表观吸收系数（P_app）未见明显差异（P>0.05）;大鼠回肠段的K_a和P_app值随药物浓度的增加而降低;加入 P-gp抑制剂盐酸维拉帕米（0.1 mmol/L）后,阿哌沙班在空肠和回肠段的K_a和P_app值均明显增加。结论 阿哌沙班在各肠段均有吸收;P-gp抑制剂对阿哌沙班在空肠和回肠段的吸收均有明显的促进作用,表明阿哌沙班为P-gp底物,推测其吸收机制为主动转运。     

Characteristics of indomethacin–saccharin (IMC–SAC) co-crystals prepared by an anti-solvent crystallization process

The creation of co-crystals of various insoluble drug substances has been extensively investigated as a promising approach to improve their pharmaceutical performance. In this study, co-crystal powders of indomethacin and saccharin (IMC–SAC) were prepared by an anti-solvent (water) addition and compared with co-crystals by evaporation method. No successful synthesis of a pharmaceutical co-crystal powder via an anti-solvent approach has been reported.Among solvents examined, methanol was practically the only one that resulted in the formation of highly pure IMC–SAC co-crystal powders by anti-solvent approach. The mechanism of a preferential formation of IMC–SAC co-crystal to IMC was explained with two aspects: phase solubility diagram and solution complexation concept. Accordingly, the anti-solvent approach can be considered as a competitive route for producing pharmaceutical co-crystal powders with acceptable properties.     

Stability Orders of Acetaminophen and Theophylline Co-crystals Determined by Co-crystal Former Exchange Reactions and Their Correlation With In Silico and Thermal Parameters

The aim of this study was to determine the thermodynamic stability order of co-crystals using co-crystal former exchange reactions and to validate 2 in silico parameters for predicting co-crystal formation. Co-crystal former exchange reactions were performed using acetaminophen (AC) co-crystals of oxalic acid (OX), maleic acid (MA), and theophylline (TH). The addition of TH to an AC-MA co-crystal (AC-MA) afforded AC-TH, suggesting that AC-TH was more stable than AC-MA. The stability order among the other co-crystals was determined in the same manner. The stability order of the AC co-crystals was determined to be AC-TH > AC-MA ≈ AC-OX. Interestingly, the addition of TH to AC-OX afforded TH-OX. The stability order of the TH co-crystals was also determined (OX-TH > AC-TH ≈ MA-TH). Although the stability order of the AC co-crystals was consistent with the differences in their hydrogen bond energy (ΔE), an in silico parameter for predicting co-crystal formation, it showed no relationship to the excess enthalpy (H_ex). These results suggest that co-crystal formation can be predicted with greater accuracy using ΔE rather than H_ex for AC co-crystals. The stability orders of the AC and TH co-crystals also correlated well with their melting points and disintegration temperatures.     

Enthalpy and Entropy Contributions to the Solubility of Sulphamethoxypyridazine in Solvent Mixtures Showing Two Solubility Maxima

The solubility of sulphamethoxypyridazine was measured at several temperatures in mixtures of water: ethanol and ethanol: ethyl acetate. Sulphamethoxypyridazine was chosen as a model drug to compare the solvation effects of proton donor-proton acceptor (water and ethanol) and proton acceptor (ethyl acetate) solvents and mixtures of these solvents because this drug contains functional groups capable of Lewis acid-base interaction. A plot of the mole fraction solubility against the solubility parameter (δ₁) of these solvent mixtures showed two solubility maxima, one at δ₁ = 30·87 MPa^1/2 (20:80 v/v water: ethanol) and another at δ₁ = 20·88 MPa^1/2 (30:70 v/v ethanol: ethyl acetate) at all the temperatures under study. The enthalpies and entropies of mixing as well as the enthalpies and entropies of transfer of sulphamethoxypyridazine from ethanol to water:ethanol and ethanol:ethyl acetate mixtures were calculated to compare solvation characteristics of the solvent mixtures toward the drug. As ethanol is added to water, the entropy increases and the structure of the solvent mixture became less ordered, favouring the interaction of the drug with the solvent mixture. On the other hand, in the case of the ethanol: ethyl acetate mixture, solubility is favoured by the more negative enthalpy values. This way, the same result, i.e. a solubility maximum, is obtained by different routes. In the ethanol: water mixtures, the dissolution process is entropy-controlled while enthalpy is the driving force in the case of ethanol: ethyl acetate mixtures. The two solvent systems show enthalpy-entropy compensation. Water deviates from the linear relationship due possibly to its hydrophobic effect.     

Analysis of a Diffusion Dryer for the Respiratory Delivery of Poorly Water Soluble Drugs

Purpose. The purpose of this study was to analyze a diffusion dryer as a means to remove organic solvents from aerosol particles of poorly water soluble drugs. Methods. Aerosols of methanol, ethanol, and ethyl acetate were generated with an ultrasonic nebulizer, and inflow to outflow concentration ratio of vapor in a annular charcoal column was determined as a function of time by gas chromotography at two to four different airflow rates. In addition, the particle transmission efficiency was determined with an ethanol solution of the test compound, budesonide. The results were analyzed with equations originally developed for assessing the loss of drug from intravenous tubing along with independent measures of the adsorption isotherm of the vapors onto charcoal. Results. Aerosol production was relatively constant with time, and the transmission of solid particles through the column occurred with efficiency nearing 100%. The inlet to outlet vapor concentration ratio was adequately described by a model of three resistances in series composed of the inner tube, the screen mesh, and the charcoal bed. Conclusions. The diffusion dryer was found to be satisfactory for the removal of methanol, ethanol, and ethyl acetate and the efficiency may be assessed from the adsorption isotherms on charcoal and the geometry of the dryer.     

Phytochemical screening and evaluation of in vitro antioxidant and antimicrobial activities of the indigenous medicinal plant Albizia odoratissima

Context: Albizia odoratissima (L. f.) Benth has been used in Indian folk medicine to treat numerous inflammatory pathologies, such as leprosy, ulcers, burns and asthma.

Objective: To evaluate the antioxidant and antimicrobial properties of A. odoratissima.

Materials and methods: Dried leaves of A. odoratissima were extracted in organic solvents (hexane, chloroform, ethyl acetate, and methanol). The total phenolic content (TPC) and total flavonoid content (TFC) were determined using the Folin-Ciocalteu and aluminum chloride colorimetric methods, respectively. The antioxidant activity was examined using 2,2-diphenyl-1-picrylhydrazyl (DPPH), hydrogen peroxide (H₂O₂), 2,2′-azino-bis-(3-ethylbenzothiazoline-6-sulphonic acid) diammonium salt (ABTS), and ferric reducing antioxidant power (FRAP) assays. The antibacterial activity was examined using minimum inhibitory concentration (MIC) and the minimum bacterial concentration (MBC), determined by broth microdilution method against Gram-negative bacteria (Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa, and Proteus vulgaris) and Gram-positive bacterium (Staphylococcus aureus).

Results: The TPC ranged from 4.40?±?1.06 to 1166.66?±?31.85?mg GAE/g of dry weight (DW), and the TFC ranged from 48.35?±?3.62 to 109.74?±?1.84?mg QE/g of DW. The IC₅₀ values of the ethyl acetate extract for DPPH, ABTS, and H₂O₂ were 10.96?±?0.40, 4.35?±?0.07, and 163.82?±?1.52?μg/mL, respectively. Both methanol and ethyl acetate extracts demonstrated effective antibacterial activity with MICs and MBCs values ranging 136–546?μg/mL and 273–1093?μg/mL, respectively, against the tested pathogenic species.

Conclusions: The leaves of A. odoratissima showed potent free radical scavenging property and antimicrobial activity.     

Local composition models in pharmaceutical chemistry. I. Liquid-liquid distribution coefficients from COMMON UNIQUAC parameters

A literature compilation of COMMON UNIQUAC parameters has been employed to correlate mutual solubilities in binary and ternary systems on one side and distribution coefficients between water and organic solvent of infinitely diluted liquid solutes, K_d, on the other. The following organic solvents were considered: butan-1-ol, 2-methylpropan-l-ol, ethyl acetate, chloroform, octan-1-ol. benzene, hexane, cyclohexane, heptane, octane and 2,2,4-trimethylpentane. Satisfactory K_d predictions were observed for various solutes in 2-methylpropan-l-ol/water and butan-1-ol/water and ethyl acetate/water. For all other systems, the reliability of predicted K_d values decreased with decreasing mutual saturabilities, outliers being most frequently found among alkane/water distribution coefficients of hydrogen-bonding and acidic solutes. These results are comparable to those of previous empirical correlation studies and much better than those produced by a solubility parameter concept.     

Preparation,Characterization, and Evaluation of Dipfluzine–Benzoic Acid Co-crystals with Improved Physicochemical Properties

Purpose

To prepare and characterize the co-crystal of dipfluzine and benzoic acid. To investigate the feasibility of the co-crystal for improving solubility and a faster dissolution rate in vitro and evaluate the bioavailability and tissue distribution of co-crystal in vivo.

Methods

A novel dipfluzine–benzoic acid co-crystal prepared using the solvent-assisted co-grinding and the solvent ultrasonic methods were identified and characterized by powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA), as well as Raman, solid-state nuclear magnetic resonance (ssNMR), and terahertz (THz) spectroscopy. Pharmacokinetics and tissue distribution were tested in vivo using murine models. Statistics analysis for dissolution data of co-crystal in vitro and animal experiment data in vivo were evaluated using t-test.

Results

Results of PXRD and DSC identified the dipfluzine–benzoic acid co-crystals were formed with a molar ratio of 1:2. The IR, Raman, and ssNMR spectra verified the formation of O-H?·?·?·?O and O-H?·?·?·?F hydrogen bonds. The complex constant, K, was evaluated to be 10⁹ orders of magnitude with Δ _r G?<?0. The co-crystal solubility, the rate of drug dissolution and the relative bioavailability were approximately 500 times, five times and double that of dipfluzine, respectively. Increased solubility of co-crystal did not reduce distribution in the brain; the mean concentrations in the brain increased, but the differences had no statistic significance (p?>?0.05).

Conclusions

The co-crystal of dipfluzine–benzoic acid improved the physicochemical properties of dipfluzine, such as solubility and dissolution rate. Furthermore, the increased relative bioavailability of co-crystal indicated the potential use in further clinical study     

Effects of Aphloia theiformis on key enzymes related to diabetes mellitus

Context: Aphloia theiformis (Vahl.) Benn. (Flacourtiaceae) (AT) is traditionally used for the management of diabetes mellitus (DM), but there is no scientific data regarding activity against enzymes linked to this condition.

Objective: To evaluate the kinetics of AT on key enzymes inhibition related to DM, and establish the antioxidant profile of AT.

Materials and methods: Dried powdered AT leaves were used to prepare crude methanol extract (70% v/v) (CME). Kinetics of CME (5000 to 156.25?μg/mL) on α-amylase, α-glucosidase, and lipase inhibition were studied. CME was partitioned using solvents of increasing polarity and kinetics of enzyme inhibition of each fraction (1000–31.25?μg/mL) was evaluated. Potent fractions were combined to assess any synergistic effect. Total phenol, flavonoid, tannin, anthocyanin contents, and antioxidant capacity of AT was evaluated using standard spectrophotometric methods.

Results: CME, ethyl acetate, and n-butanol fractions showed potent inhibitory activities against the enzymes with IC₅₀ ranging from 22.94–939.97?μg/mL. Significant (p?50 (15.72 and 157.03?μg/mL against α-amylase and lipase, respectively) was observed when ethyl acetate and n-butanol fractions were combined; showing synergism. The extracts showed noncompetitive inhibition against α-amylase and α-glucosidase. Ethyl acetate, n-butanol fractions, and CME showed highest antioxidant capacities (0.44–1.41?μg GAE/mg sample), and phenol content (211.74-675.53?μg GAE/mg sample).

Conclusion: This study supports the use of AT in the management of DM and provides the rationale for bioactivity guided isolation and characterization of compounds from the ethyl acetate and n-butanol fractions.     

Albendazole Generics—A Comparative In Vitro Study

Purpose. We sought to determine whether disintegration and dissolution behavior differs among various albendazole generic formulations obtained from third world countries and to compare them with the innovator's product. Methods. Dissolution behavior of various albendazole formulations was studied with USP Apparatus 2 in SGF_sp and in a modified SGF_sp which contained 0.1% of the nonionic surfactant Triton^® × 100. Disintegration was tested according to the European Pharmacopoeia. Results. Dissolution experiments in SGF_sp showed a wide range in rate and extent of albendazole dissolution. The innovator product released 81 percent within two hours, a profile matched by only one other formulation. For other formulations 32 to 64% was released within two hours. Use of a modified SGF_sp, containing 0.1% Triton^® × 100 to simulate the surface tension of gastric juice, resulted in less discrimination between products. The innovator product again showed the fastest and most complete dissolution, with ninety percent released within two hours. The generic formulations released between 67 and 82%, except for one formulation which achieved only 43% release. The results in SGF_sp plus Triton^® × 100 may be more meaningful than in SGF_sp, since the surface tension of the medium is closer to the physiological value. All formulations passed the disintegration test according to the European Pharmacopoeia, with disintegration times ranging from 2.5 to 11 minutes. Conclusions. Generic albendazole products vary widely in their dissolution behavior. Differences among products were greater in SGF_sp than in SGF_sp plus Triton^® × 100. These differences were not reflected in the disintegration behavior of the products.     

Independence of the Product of Solubility and Distribution Coefficient of pH

Purpose. The relationship between the pH, solubility, and partition coefficient was investigated to show that the product of intrinsic values of solubility and partition coefficient is equal to the product of total values of solubility and distribution coefficient at different pH. Methods. The pH distribution profiles were obtained from the literature and the pH solubility profiles were obtained from the literature or calculated from their intrinsic solubility and pK _a. Results. The pH solubility and pH distribution coefficient profiles of 25 compounds were investigated to show that the product of intrinsic solubility (S _w) and intrinsic octanol-water partition coefficient (K _ow) is equal to the product of total solubility of a partially ionized solute (S _T) and its octanol-buffer distribution coefficient (K _D) at any pH where ion pair formation and salt precipitation are not present. Conclusions. The fact that S _w K _ow can be used instead of S _T K _D to model the absorption of partially ionized drugs in the gastrointestinal tract has important biopharmaceutical implications.