Estimation of Melting Points of Organics

Unified physicochemical property estimation relationships is a system of empirical and theoretical relationships that relate 20 physicochemical properties of organic molecules to each other and to chemical structure. Melting point is a key parameter in the unified physicochemical property estimation relationships scheme because it is a determinant of several other properties including vapor pressure, and solubility. This review describes the first-principals calculation of the melting points of organic compounds from structure. The calculation is based on the fact that the melting point, T_m, is equal to the ratio of the heat of melting, ΔH_m, to the entropy of melting, ΔS_m. The heat of melting is shown to be an additive constitutive property. However, the entropy of melting is not entirely group additive. It is primarily dependent on molecular geometry, including parameters which reflect the degree of restriction of molecular motion in the crystal to that of the liquid. Symmetry, eccentricity, chirality, flexibility, and hydrogen bonding, each affect molecular freedom in different ways and thus make different contributions to the total entropy of fusion. The relationships of these entropy determining parameters to chemical structure are used to develop a reasonably accurate means of predicting the melting points over 2000 compounds.     

Predictive Screening Tools Used in High-Concentration Protein Formulation Development

This review examines the use of predictive screening approaches in high-concentration protein formulation development. In addition to the normal challenges associated with protein formulation development, for high-concentration formulations, solubility, viscosity, and physical protein degradation play major roles. To overcome these challenges, multiple formulation conditions need to be evaluated such that it is desirable to have predictive but also low-volume and high-throughput methods in order to identify optimal formulation conditions very early in development without time- and material-consuming setups. Many screening techniques have been reported for use in high-concentration formulation development, but not all fulfill the requirements mentioned previously. This review summarizes the advantages and disadvantages of different screening approaches currently used in formulation development and the correlation of predictive data to protein solubility, viscosity, and stability at high protein concentrations.     

黄芩苷的处方前研究

目的：通过处方前研究,阐明黄芩苷原料药（质量分数为85.5%）的基本理化性质。方法采用HPLC法测定黄芩苷含量,分别进行黄芩苷的平衡溶解度、油水分配系数、破坏性试验、吸湿性考察等处方前研究。结果原料药中黄芩苷在水中的平衡溶解度为0.0326 mg/mL,较甲醇、正丁醇、乙醇等溶剂低;在pH 小于5.0的磷酸盐缓冲液中几乎不溶,其平衡溶解度随着pH值的增大呈增大的趋势;黄芩苷在正辛醇/水中的油水分配系数（P值）为1.19,在正辛醇/磷酸盐缓冲液（pH 2～10）中的P值均比正辛醇/水中的低;黄芩苷不耐碱,且易被氧化;在温度25℃、RH 75%条件下吸湿性较小。结论该研究可为黄芩苷新制剂原料与剂型的选择、处方设计及工艺优化等提供实验依据。     

Light effect on the stability of β-lapachone in solution: pathways and kinetics of degradation

Objectives The purpose of this work was to study the chemical stability of the new antitumoral β‐lapachone (βLAP) to determine the degradation pathway/s of the molecule and the degradation kinetics in addition to identifying several degradation products. Method Samples of βLAP in solution were stored under conditions of darkness and illumination at 40°C at which the pseudo‐first order rate constants for the βLAP degradation were determined. Furthermore, drug degraded solutions were concentrated and purified using Sephadex LH‐20 and preparative thin‐layer chromatography and degradation products were identified by nuclear magnetic resonance spectroscopy. Key findings The results revealed that βLAP shows two different degradation routes: hydrolysis in the dark and photolysis under the light. The βLAP exposure to light accelerated the drug degradation about 140 fold, compared with the samples stored in the absence of light. The hydrolysis produced hydroxylapachol as the main degradation product. The photolysis yielded phthalic acid, 6‐hydroxy‐3methylene‐3H‐isobenzofuran‐1‐one and a benzomacrolactone together with a complex mixture of other phthalate‐derivatives such as 2‐(2‐carboxy‐acetyl)‐benzoic acid. Conclusions This study provides useful information for the development of βLAP dosage forms, their storage, manipulation and quality control.     

左旋多巴咀嚼片的处方前研究

目的对左旋多巴进行处方前研究,为设计优良的处方奠定基础。方法利用HPLC建立测定左旋多巴的体外分析方法学,并进行溶解度、油水分配系数、破坏性实验等处方前研究。结果采用HPLC建立了可靠的左旋多巴体外分析方法,在0.316～63mg·mL-1范围内线性良好(r=0.9999)。处方前研究证实左旋多巴易被氧化,不耐高温,在pH1.2的盐酸溶液中溶解度最大,在pH7.4的磷酸盐缓冲液和pH8.0的氢氧化钠碱性溶液中有降解,油水分配系数都小于0.5。结论建立的分析方法准确可靠。处方前研究表明左旋多巴遇光降解,在碱性溶液中不稳定,易被氧化,不耐高温。     

溶菌酶的处方设计前稳定性研究

目的考察pH值、温度、保护剂、有机溶剂对溶菌酶物理稳定性和生物活性的影响,为其缓释注射剂的处方学研究提供依据。方法以HPLC法测定溶液中溶菌酶的含量,以比浊法测定溶菌酶的生物活性。结果在pH4．0、pH10．0条件下溶菌酶的物理稳定性较好,pH4．0条件下溶菌酶可保持较高的生物活性,pH1．0的条件会完全破坏溶菌酶的溶菌活性;低温条件有利于保持溶菌酶的物理稳定性和生物活性;甘露醇对溶菌酶的稳定性具有先增强后减弱的作用;有机溶剂会严重破坏溶菌酶的物理稳定性,但仍保留着一部分溶菌活性。结论pH值、温度、保护剂、有机溶剂对溶菌酶的物理稳定性和生物活性具有明显影响。     

Preformulation Study of Etoposide: Identification of Physicochemical Characteristics Responsible for the Low and Erratic Oral Bioavailability of Etoposide

Preformulation studies of etoposide, including pH–solubility profile, partition coefficient, pH–stability profile, and in vitro dissolution kinetics, were conducted to identify the responsible factor(s) for the low and erratic oral bioavailability of etoposide. A stability-indicating high-performance liquid chromatographic (HPLC) assay was used for drug monitoring. The equilibrium aqueous solubility of etoposide at 37°C was low, 148.5–167.25 µg/ml, and did not vary over the pH range of 2 to 6. The pH–stability profile indicated rapid degradation of etoposide at pH 1.3 and 10, with degradation half-lives of 2.88 and 3.83 hr, respectively, at 25°C. The half-life at pH 7.30 was 27.72 days. Maximum stability at 25°C was reached at pH 5 to 6.15, with half-lives of 63 and 49.5 days, respectively. The intrinsic dissolution rate, determined on a Wood's apparatus, was slow, 0.0094 mg/min/cm², while the etoposide partition coefficient between n-octanol and water was 9.94. Therefore, etoposide absorption appears to be dissolution rate limited rather than permeation rate limited. The low equilibrium aqueous solubility, slow intrinsic dissolution rate, and chemical instability at pH 1.3 could account for the low oral bioavailability.     

The chick chorioallantoic membrane imaging method as a platform to evaluate vasoactivity and assess irritancy of compounds

Objective To determine if the chick chorioallantoic membrane (CAM) is a potential alternative that is capable of screening test substances for vasoactivity in terms of vessel diameter changes. The CAM was also evaluated as a tool for irritancy screening. Methods Visual assessment of the CAM for irritancy after the application of the test substance or solvent to its surface was made. An imaging based‐in‐vivo CAM model was developed by imaging CAM blood vessels in a pre‐defined area using a semi‐automatic image processing and analysis technique to measure blood vessel diameters. Solvents and drugs such as 70% v/v ethanol, normal saline, 5% w/v glucose monohydrate, glycerin, glucagon, N‐methylpyrrolidone, nicotine, glyceryl trinitrate, glucagon, propranolol and caffeine were tested on the CAM. Key findings Propranolol, nicotine and glycerin were irritants on CAM. Changes in the diameters of fine blood vessels were accurately measured by high resolution image analysis. Vasoconstriction was seen with 70% v/v ethanol while vasodilation was displayed with glucagon and caffeine. The results reflected expected trends with evidence of feedback mechanisms ensuring homeostasis. Conclusion The CAM model can be applied to assess pharmaceutical and cosmetic formulations in early development work to gain useful insights to potential irritancy and biological effects of components and formulations.     

盐酸吉西他滨的处方前研究

目的测定盐酸吉西他滨在不同pH缓冲液中的平衡溶解度以及在正辛醇-水和正辛醇-缓冲液体系中的表观油水分配系数,并对其水溶液的稳定性进行研究。方法采用HPLC法测定盐酸吉西他滨的含量,摇床法测定该药物的表观溶解度和油水分配系数。结果 25℃条件下,盐酸吉西他滨在水中的平衡溶解度为58.82 g.L-1,在酸性介质中的平衡溶解度相对增加;盐酸吉西他滨的表观油水分配系数LgP为-1.22;60℃条件下,盐酸吉西他滨水溶液在pH3.84~10.37内较稳定,pH小于2或pH大于11时,降解反应加快,药物含量明显下降。结论盐酸吉西他滨的水溶性较强,其水溶液在强酸和强碱环境下不稳定。     

酮咯酸异丙酯静脉注射脂肪乳剂的处方前研究

目的 对酮咯酸前体药物酮咯酸异丙酯进行处方前研究。方法 合成酮咯酸异丙酯,建立HPLC-UV方法并进行方法学验证。对酮咯酸异丙酯溶解度、油水分配系数和降解规律等理化性质进行研究,考察加速降解实验中的原料稳定性和原辅料相容性。结果 酮咯酸异丙酯在水中难溶（溶解度52.66 μg·mL^-1）,但可以和油相混溶,其LogP值为3.95±0.03。酮咯酸异丙酯的分析方法线性关系良好,仪器精密度良好（RSD<2%）,回收率较高（>99.5%）。在给定条件下,酮咯酸异丙酯的溶液稳定性随pH和温度升高而降低。酮咯酸异丙酯可在大鼠血浆和肝匀浆溶液中迅速降解,例如,在50%大鼠血浆溶液或20%肝匀浆溶液中,酮咯酸异丙酯的降解速率常数（k_obs）分别为0.51 min^-1和0.15 min^-1。酮咯酸异丙酯在高温、高湿环境下较稳定,但对光照敏感;原辅料相容性同样证实了这一点。结论 酮咯酸异丙酯在溶解度、分配系数、降解规律、原料稳定性和原辅料相容性方面,具备了制成静脉注射乳剂的适宜条件,为开发新型酮咯酸注射剂提供了实验依据。