Influence of the Solid Form of Siramesine Hydrochloride on its Behavior in Aqueous Environments

Purpose  To study the influence of solid form on the behavior of the salt siramesine hydrochloride in aqueous environments. Methods  The solubilities and dissolution rates of siramesine hydrochloride anhydrate and monohydrate were determined at pH 3.4 and 6.4, and precipitates were examined by X-ray powder diffraction. The mechanism of anhydrate–hydrate conversion was investigated by optical microscopy, and wet massing of the anhydrate was carried out using water and 60% (v/v) ethanol separately as granulation liquids. The wet masses were analyzed using Raman microscopy. Results  At pH 3.4 the anhydrate and monohydrate salts exhibited similar dissolution profiles. At pH 6.4 both the anhydrate and monohydrate salts formed supersaturated solutions of high apparent solubility. From the anhydrate solution, precipitation of the free base occurred, while the solution of the monohydrate salt remained in the supersaturated state. This resulted in a superior dissolution profile of the monohydrate salt. Microscopy and wet massing experiments showed that the anhydrate–hydrate conversion of siramesine hydrochloride was solution-mediated and dissolution-controlled. Conclusion  During development of a formulation based on the anhydrate salt, the risk of processing-induced transformation to the monohydrate form as well as precipitation of the free base should be considered.     

Nonisothermal Kinetics Analysis of the Dehydration of Ziprasidone Hydrochloride Monohydrate by Thermogravimetry

In the current work the kinetics of dehydration of ziprasidone hydrochloride monohydrate was studied by nonisothermal thermogravimetry. Ziprasidone hydrochloride monohydrate was heated from 30 to 150° with a heating rate of 5° per min under nitrogen gas atmosphere and weight loss data were collected. Powder X-ray difraction was used to characterize the solid before and after dehydration. The well accepted Coats-Redfern model fitting approach was applied to the thermogravimetry data for the kinetic analysis. Thirteen solid state reaction models were studied; among them one-dimensional diffusion model was found to be the best fit model for this reaction with an excellent correlation 0.9994. The Arrhenius parameters, activation energy, and pre-exponential factor were determined, the values were found to be 28 k.cal/mol and 9.53×10¹³ sec⁻¹, respectively.     

盐酸瑞芬太尼的波谱学数据和结构分析

[目的]通过波谱学数据对盐酸瑞芬太尼的化学结构进行分析。[方法]测定盐酸瑞芬太尼的红外吸收光谱(IR)、核磁共振氢谱(^1HNMR)、氢-氢相关谱(^1H-^1HCOSY)、核磁共振碳谱(^13CNMR)、DEPT谱、碳-氢相关谱(^13C-^1 HCOSY)、质谱(MS)及单晶X-衍射图谱，进行结构分析和讨论。[结果]该化合物的^1HNMR和^13CNMR谱的所有谱峰均有合理的归属，其IR吸收峰所对应的官能团振动形式、MS的分子离子峰和主要碎片峰以及单晶X-衍射的结构均能得到合理的解释。[结论]上述各种图谱分析数据均能与盐酸瑞芬太尼的结构式相吻合。     

盐酸米那普仑反式异构体的合成及结构确证

(±)-(1S,2S)-2-羟甲基-1-苯基环丙羧酸经溴化、酰氯化、酰胺化、Gabriel反应,最后成盐制得盐酸米那普仑(1)的反式异构体(2),总收率19%。比较了1和2的1HNMR及NOSEY谱学特征。2可作为1质量控制的对照物。     

Preparation and Characterisation of Mucoadhesive Nasal Gel of Venlafaxine Hydrochloride for Treatment of Anxiety Disorders

The aim of the present study is to prepare and evaluate mucoadhesive nasal gels of venlafaxine hydrochloride. Mucoadhesive nasal gels were prepared using polymers like carbopol 934 and sodium alginate and characterized in terms of viscosity, texture profile analysis, ex vivo drug permeation profiles and histopathological studies. The results show that values of viscosity, hardness and adhesiveness increase while those of cohesiveness decrease with corresponding increase in concentration of the polymers. Ex vivo drug permeation profiles showed that formulation containing 5% sodium alginate provided a better controlled release of the drug than the other formulations over a period of 12 h. Histopathological studies assured that gels containing different polymers did not produce any significant change in the nasal mucosae of goat even after 12 h permeation study. Mucoadhesive nasal gel of venlafaxine hydrochloride is a novel dosage form which delivers the drug directly into systemic circulation and provides controlled release of the drug.     

盐酸锥双净异构物的分离纯化与结构鉴定

抗锥虫新药盐酸锥双净的水溶液加热产生的新化合物经分离纯化,由^1HNMR、MS和元素分析进行结构鉴定,确证为异构体2,2可能通过异构体3形成。化合物2无明显的体外抗锥虫作用。     

Insights Into the Dehydration Behavior of Thiamine Hydrochloride (vitamin B1) Hydrates: Part II

Thiamine hydrochloride (THCl) can exist as an anhydrate (AH) and as a hemihydrate (HH). AH sorbs water as a function of environmental water vapor pressure to form a nonstoichiometric hydrate (NSH). NSH dehydration is initiated at ～40°C to yield AH, an isomorphic desolvate (ID) of NSH (Chakravaty et al., 2009, J Pharm Sci). Upon heating, dehydration of HH occurs only at elevated temperatures (>120°C) and is accompanied by chemical decomposition. When heated at reduced temperature (60–90°C) and pressure (20–760 mTorr), HH was incompletely dehydrated with partial loss of long‐range lattice order. Complete dehydration of HH to AH was achieved through a solvent‐mediated transformation in ethanol. The crystal structures of NSH and HH exhibit pronounced differences in the hydrogen bonding of water. The dehydration mechanism of NSH and HH can be explained by the “continuous and unified” dehydration model.¹⁰. © 2009 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 1882–1895, 2010     

Biophysical and Structural Characterisation of Nucleic Acid Complexes with Modified Cyclodextrins Using Circular Dichroism

Modified cyclodextrins (CDs) have shown great promise as non-viral gene and siRNA delivery vectors in a range of in vitro and in vivo studies. In the current study, structural and biophysical characterisation of selected CDs was carried out to enhance our understanding of their interaction with nucleic acids. The methods used for such characterisation were dynamic light scattering, zeta potential measurements and circular dichroism. Variations in the chemistries of individual CDs and in the type of formulation were shown to affect key properties of complexes such as size, surface charge and nucleic acid conformation. Furthermore, the effects of temperature and pH on the conformation of nucleic acids were investigated. pH studies were intended to mimic the conditions encountered by cationic complexes during endocytosis. Circular dichroism studies revealed that changes occurred in DNA and siRNA conformation upon complexation with CDs and when exposed to increasing temperature and decreasing pH. Overall, siRNA appeared to be more susceptible to conformational changes although complexation of siRNA with CDs tended to have a stabilising effect. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.     

HPLC法同时测定林可霉素利多卡因凝胶中林可霉素和盐酸利多卡因的含量

目的:完善该药品中林可霉素的测定方法,建立盐酸利多卡因的含量测定方法.方法:用ODS柱,以O.05mol/L的硼砂溶液(用85%磷酸调节pH5.0)-甲醇-乙腈(60:35:5)为流动相,流速O.7ml/min,检测波长214nm.结果:林可霉素浓度在0.14～0.28mg/ml,利多卡因浓度在0.10～0.20mg/ml之间,峰面积与进样浓度呈良好的线性关系(r=0.9999和r=0.9998),重现性RSD分别为0.23%和0.25%.结论:该方法能快速简便地同时测定两组分的含量,结果准确可靠.     

A Structural Powder Diffraction Study of Two Polymorphic Forms of Nortriptyline Hydrochloride

Nortriptyline hydrochloride, a tricyclic antidepressant, appears in two different polymorphic forms, only one of which (hereafter, form β) has been previously characterized by single‐crystal analysis. Form β is monoclinic, P2₁/c, with a = 5.070(2), b = 34.088(5), c = 9.976(1) Å, and β = 90.74(2)°. A second crystalline form (the α form) has now been characterized by structural powder diffraction methods (using both laboratory and synchrotron radiation diffraction data). Form α crystallizes in the monoclinic P2/c space group, a = 9.99126(6), b = 5.10021(3), c = 34.1636(1) Å, and β = 98.684(6)°. The thermodynamic relationship between the two forms has been determined by differential scanning calorimetry analysis and variable‐temperature thermodiffractometric experiments, revealing that the two forms are monotropically related and form α is more stable. Both phases are characterized by a sequence of hydrogen‐bonded N‐protonated molecules, which, in the two crystalline environments, adopt the same conformation. The difference between the two crystals can be traced back to the supramolecular arrangement characterized by one‐dimensional chains, built by homochiral molecules (for conformationally driven chirality) in the α form, and by enantiomeric ones in the β form. This observation nicely explains why, upon heating, solid‐solid interconversion between the two forms does not occur.     

Synthesis,Characterisation and In Vivo Behaviour of a Norfloxacin-Poly(L-Lysine Citramide Imide) Conjugate Bearing Mannosyl Residues

Abstract

With the aim of promoting the targeting of macrophage mannose receptors and the internalisation of the norfloxacin antibiotic, which is active against some intracellular bacteria, a macromolecular prodrug was synthesised where the antibiotic and mannosyl moieties were coupled to a polymeric carrier, namely poly(L-lysine citramide imide). This carrier, which derived from two metabolites, citric acid and L-lysine, is known to be biocompatible and slowly degradable under slight acidic conditions. Norfloxacin was coupled onto the acid groups present along the polymer chains, and conjugates were characterised by UV, TLC and SEC. The mannosyl groups selected to promote the targeting of the mannose-specific lectin present on the outer membrane of macrophages were incorporated through a biodegradable glycolic spacer arm. Two different strategies were considered to synthe-sise the full conjugates, namely coupling norfloxacin onto mannosylated conjugates, and coupling mannose onto PLCAI/Nflx conjugates. The second pathway led to better results regarding mannosylation. The presence of norfloxacin and mannose caused chain aggregation, especially for conjugates with a high content of mannosyl residues. The targeting ability of the prodrug was investigated using a method based on the competition between the mannosylated macromolecules and glucose oxidase, a mannosyl-bearing non-human protein. This method showed that prodrug macromolecules competed effectively with glucose oxidase and thus should be able to bring the drug up to the mannosyl receptor-bearing membranes of macrophages infected by intracellular bacteria.     

HPLC测定复方盐酸多塞平胶囊中盐酸多塞平与盐酸可乐定的含量

采用高效液相色谱法测定复方盐酸多塞平胶囊中盐酸多塞平与盐酸可乐定的含量。盐酸多塞平在５～３０μｇ／ｍｌ（ｒ＝０９９９８），盐酸可乐定在２～１２μｇ／ｍｌ（ｒ＝０９９９９）范围内，峰面积与其浓度呈良好线性关系；方法平均回收率分别为１００１８％（ＲＳＤ＝１０２％），１００３４％（ＲＳＤ＝１６３％）。结果表明，方法简便、快速、准确。     

高效液相色谱法测定氨酚曲麻片中盐酸曲普利啶的含量

目的改进氨酚曲麻片中盐酸曲普利啶含量的测定方法。方法采用高效液相色谱法,色谱柱为HypersilBDSC18,流动相为甲醇-0.4%醋酸铵溶液-三乙胺(70∶30∶0.1),流速为1ml/min,检测波长为233nm,进样量为10μl。结果盐酸曲普利啶检测浓度在28.8~86.3μg/ml范围内与峰面积积分值线性关系良好(r=0.9998),平均回收率为100.5%(RSD=0.5%)。结论本方法简便、准确度高、重现性好,可用于本品的含量测定与质量控制。     

Forced Degradation Behaviour of Fluphenazine Hydrochloride by LC and Characterization of its Oxidative Degradation Product by LC–MS/MS

A novel, stability-indicating high-performance liquid chromatographic (HPLC) method is delivered for the determination of fluphenazine hydrochloride (FPZ) and its degradation products. The forced degradation testing of FPZ was carried out for hydrolytic, oxidative, photolytic, and thermal degradation. The degradation appeared using a reversed-phase C18 column at ambient temperature with a mobile phase comprised of methanol : acetonitrile : (10 mM) ammonium acetate (70:15:15, v/v/v) pH 6.0, adjusted with acetic acid, having a flow rate of 1 ml min⁻¹ and a detection wavelength at 259 nm. Primarily, the maximum degradation products were formed under oxidative stress conditions. The product was distinguished through LC-MS/MS fragmentation studies. Based on the results, a more complete degradation pathway for the drug could be proposed. The modernized method was found to be precise, accurate, specific, and selective. The method was found to be suitable for the quality control of fluphenazine hydrochloride in the tablet as well as in stability-indicating studies.     

复方羟丙茶碱去氯羟嗪胶囊中盐酸克伦特罗的含量测定

目的：建立复方羟丙茶碱去氯羟嗪胶囊（舒喘平胶囊）中盐酸克仑特罗含量测定的方法。方法：采用ZORBAX SB-C18 (4.6 mm×250mm，5μm)色谱柱；以甲醇-0.02mol?L-1磷酸二氢钠溶液（用磷酸调节pH至2.5）为流动相，梯度洗脱；流量1.0mL?min-1；检测波长210nm；柱温35℃；进样量20μL。结果：盐酸克伦特罗的浓度在1.7～6.8μg?mL-1范围内与峰面积呈良好线性关系（r=0.999 9），平均回收率为101.9%，其RSD为3.81%（n=9）。结论：所建方法简便、准确，可作为复方羟丙茶碱去氯羟嗪胶囊中盐酸克伦特罗的定量分析方法。     

Structural Behaviour of 2-Hydroxypropyl-β-Cyclodextrin in Water: Molecular Dynamics Simulation Studies

Purpose To investigate the effect of 2-hydroxypropyl side group substitutions on the structure of β-cyclodextrin (CD) in water. Methods Molecular dynamics simulations were carried out on four HPBCDs that broadly represent a range of degree of substitutions in order to investigate the effect of substitution of β-cyclodextrin with 2-hydroxypropyl groups at various O2 and O6 positions of the glucose units. Results The 2-hydroxypropyl side groups located at the O2 positions widen the cavity entrance at the secondary OH position of the CD molecule. These groups are spatially more spread out but dynamically more restricted, due to the formation of a hydrogen bond network between the hydroxyl groups of the side chains and the glucose units. On the other hand, the 2-hydroxypropyl groups at the O6 positions are dynamically more flexible. Conclusions The extent and the location of the substitution can affect the cavity structure of the CD molecule, and thus possibly the molecular encapsulation capabilities.     

高效液相色谱法测定盐酸普鲁卡因及其注射液的含量

目的采用高效液相色谱（HPLC）法测定盐酸普鲁卡因及其注射液的含量。方法色谱柱为Diamonsail C18（200mmx4．6mm,5μm）,以32：68的甲醇-磷酸盐缓冲液（0．05mol／L磷酸二氢钾,0．1％庚烷磺酸钠,用磷酸调pH至3．0）为流动相,检测波长290nm,流速1．0mL／min。结果盐酸普鲁卡因质量浓度在40～2000μg／mL范围内与峰面积线性关系良好,r=0．9999（n=10）,平均回收率为100．32％,RSD为0．28％（n=9）。结论HPLC法灵敏、专属、快速方便,可以更好地控制产品质量。     

高效液相色谱法测定稳心颗粒中非法添加药物的含量

目的建立检测稳心颗粒中非法添加的盐酸普萘洛尔、盐酸维拉帕米和盐酸普罗帕酮含量的高效液相色谱法。方法采用Inertsil ODS—SP C18色谱柱（250mm×4．6mm,5μm）,流动相为磷酸盐缓冲液（取磷酸二氢钾6．8g,辛烷磺酸钠1．3g,加水溶解并稀释至1000mL,用磷酸调节pH至3．0）-甲醇（40：60）,流速为O．8mL／min,检测波长为223nm,柱温为25℃。结果盐酸普萘洛尔、盐酸维拉帕米和盐酸普罗帕酮进样量的线性范围分别为0．01976～2．47μg（r=1）,0．01～2．5μg（r=1）和0．009948～2．487μg（r=1）;平均回收率分别为97．11％,97．63％和98．88％,RSD分别为1．85％,1．92％和1．46％（n=6）。结论该方法准确、重现性好,可作为稳心颗粒中非法添加盐酸普茶洛尔、盐酸维拉帕米和盐酸普罗帕酮的有效检测方法。     

HPLC法测定盐酸丁卡因麻黄碱溶液中盐酸丁卡因的含量

目的建立高效液相色谱法测定盐酸丁卡因麻黄碱溶液中盐酸丁卡因的含量方法。方法采用Agilent ZORBAX SB-C18色谱柱;以0.05mol/L磷酸二氢钾溶液[用稀磷酸或三乙胺调节pH值至(3.0±0.1)]-乙腈(70∶30);检测波长:310nm;流速:1mL/min;进样量:20μL;柱温:30℃。结果盐酸丁卡因在1.02~50.95μg/mL范围内线性良好(r2=1),平均回收率为100.31%,RSD为0.61%(n=9)。结论该方法可有效的测定样品中盐酸丁卡因的含量,精密度高、方法简便准确可靠。