4-异丁基苯乙酮加氢-羰基化合成布洛芬

采用CuO-ZnO/Al2O3纳米铜基催化剂催化4-异丁基苯乙酮(IBAP)加氢制备1-(4-异丁基苯基)乙醇(IBPE);然后以PdCl2/PPh3/CuCl2为催化体系,将IBPE经羰基化反应合成2-(4-异丁基苯基)丙酸(布洛芬)。研究结果表明:在反应温度80℃,氢气压力1.5MPa,n(H2)∶n(IBAP)=40∶1,液空速0.30h-1的条件下,IBAP的加氢转化率为100%,IBPE收率达到93.6%。以盐酸为酸性介质、丁酮为溶剂,在温度100℃,CO压力5.5 MPa,反应时间24h的条件下,IBPE羰基化合成布洛芬,IBPE的转化率为100%,布洛芬收率达到72.9%。     

Ultrasound-assisted preparation of novel ibuprofen-loaded excipient with improved compression and dissolution properties

Context: Most of the active pharmaceutical ingredients (APIs) suffer from a drawback of poor aqueous solubility. In addition to the same, some APIs show poor tabletting behavior creating problems in formulation development. Crystal engineering can be an efficient tool in rectification of such problems associated with the APIs. Thus present work deals with crystallization of ibuprofen (a model drug) onto the surface of dicalcium phosphate (DCP) particles using different techniques.

Objective: The objective of the present work was to prepare ibuprofen-loaded DCP particles and further to analyze them for compressibility and dissolution behavior.

Materials and methods: Various crystallization techniques such as solvent evaporation (SE), melt crystallization (MC), melt sonocrystallization (MSC), antisolvent crystallization (AC), and antisolvent sonocrystallization (ASC) were screened for the preparation of ibuprofen-loaded DCP. Products obtained from different techniques were analyzed for physicochemical, micromeritic and compression properties.

Results and discussion: ASC technique was found to be suitable for preparing directly compressible ibuprofen-loaded DCP particles. The change in the crystal habit (needle to plate shape) of ibuprofen and its crystallization in miniscular form onto the surface of DCP particles showed significant improvement in the dissolution rate and compression properties of ibuprofen due to an increase in specific surface area when compared with ibuprofen crystallized by other techniques. Additionally, the tablets prepared from ASC powder did not require binder since ibuprofen acted as melt binder during compression.

Conclusion: Directly compressible ibuprofen-loaded DCP particles can serve as an alternative for conventional ibuprofen tablets prepared by wet granulation technique.     

热熔挤出过程药物在聚己内酯中的分散形态及对药物释放行为的影响

以聚己内酯(PCL)为基体、2种难溶性药物布洛芬(BF)和双氯芬酸钠(DS)为模型药物,采用热熔挤出(HME)技术制备了2种载药体系;通过差示扫描量热法、X射线衍射和扫描电镜等表征了药物在PCL基体中的分散形态,探讨了药物分散形态对其释放行为的影响。结果表明,低熔点的药物BF以无定形态均匀分散于PCL中;而高熔点的药物DS仍以结晶形态分散于PCL中(药物颗粒直径约0.5μm)。在原药溶解度相差不大的情况下,由于在挤出过程2种药物的分散形态不同,挤出产物中BF的释放速率明显快于DS。     

β-TCP porous pellets as an orthopaedic drug delivery system: ibuprofen/carrier physicochemical interactions

Abstract

Calcium phosphate bone substitute materials can be loaded with active substances for in situ, targeted drug administration. In this study, porous β-TCP pellets were investigated as an anti-inflammatory drug carrier. Porous β-TCP pellets were impregnated with an ethanolic solution of ibuprofen. The effects of contact time and concentration of ibuprofen solution on drug adsorption were studied. The ibuprofen adsorption equilibrium time was found to be one hour. The adsorption isotherms fitted to the Freundlich model, suggesting that the interaction between ibuprofen and β-TCP is weak. The physicochemical characterizations of loaded pellets confirmed that the reversible physisorption of ibuprofen on β-TCP pellets is due to Van der Waals forces, and this property was associated with the 100% ibuprofen release.     

Synthesis and Evaluation of Novel Polyester-Ibuprofen Conjugates for Modified Drug Release

Ibuprofen was conjugated at different levels to a novel polyester, poly(glycerol-adipate-co-ω-pentadecalactone) (PGA-co-PL), via an ester linkage to form a prodrug. The conjugates were characterized by differential scanning calorimetry (DSC), nuclear magnetic resonance (NMR), infrared (IR), gel permeation chromatography (GPC), ultraviolet (UV), and high-performance liquid chromatography (HPLC). The conjugates had a molecular weight between 18 and 24 kDa, and there was a suppression of the free hydroxyl groups within the conjugated polymer. DSC scans showed a lowering of the melting point (T_m) when compared with the polyester alone and a difference in the number and area of T_m peaks. Drug release studies showed an initial burst release (13–18%) followed thereafter by very slow release (maximum 35% after 18 days). Continuous work may produce ester-linked conjugates that are sufficiently labile to allow for complete release of ibuprofen over the time period studied.     

辐射法制备布洛芬金属分子印迹聚合膜

以消炎镇痛药(S)-布洛芬与Cu2+配合物为模板分子,以甲基丙烯酸为功能单体,乙二醇二甲基丙烯酸酯为交联剂,聚砜膜为多孔支撑层,利用辐射引发聚合制备了Cu2+配位分子印迹复合膜。通过紫外光谱研究发现,(S)-布洛芬、Cu2+和甲基丙烯酸形成了配位比为1∶2∶2的3元配合物。通过扫描电镜及渗透实验发现聚砜基膜固含量为17%时,修饰后印迹膜形态及性能最好。同时,通过选择渗透实验发现,印迹膜对其手性对称物(R)-布洛芬及结构类似物酮洛芬渗透选择性较差。     

水-有机溶剂混合体系脂包衣酶制备S-(+)-布洛芬

用二-十二烷基-N-D-葡萄糖酸-L-谷氨酸酯对来源于Candida cylindrucea的脂肪酶包衣后应用于水-有机溶剂体系中催化选择性水解布洛芬甲酯制备S-(+)-布洛芬。考察了体系的有机溶剂种类和体积分数、温度、pH值等因素对转化率和对映选择性的影响。结果表明,在布洛芬甲酯为100 mmol,脂包衣脂肪酶250 mg/mL,pH值为7.5,温度为40℃,N,N-二甲基甲酰胺(DMF)体积分数在20%时,15 h后催化的转化率可达48.3%,对映选择率达465。动力学研究表明脂包衣脂肪酶在水-DMF混合体系中其酶促反应符合米氏方程,其米氏常数Km是水相中没有包衣酶的1/2,最大反应速度vm ax是它的1.4倍。     

Enhanced Dissolution of Ibuprofen Using Solid Dispersion with Polyethylene Glycol 20000

To improve its dissolution, ibuprofen solid dispersions (SDs) were prepared in a relatively easy and simple manner, characterized by scanning electron microscopy (SEM), differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FTIR), and evaluated for solubility and in vitro drug release. Loss of individual surface properties during melting and re-solidification as revealed by SEM micrographs indicated the formation of effective SDs. Absence or shifting toward the lower melting temperature of the drug peak in SDs in DSC study indicated the possibilities of drug–polymer interactions. FTIR spectra showed the presence of drug crystalline in SDs. The effect of improved dissolution on the oral absorption of ibuprofen in rats was also studied. Quicker release of ibuprofen from SDs in rat intestine resulted in a significant increase in AUC and C_max, and a significant decrease in T_max over pure ibuprofen. Preliminary results from this study suggested that the preparation of fast dissolving ibuprofen SDs by low-temperature melting method using polyethylene glycol 20000 as a meltable hydrophilic polymer carrier could be a promising approach to improve solubility, dissolution, and absorption rate of ibuprofen.     

Simple and Sensitive HPLC Method with Fluorescence Detection for the Measurement of Ibuprofen in Rat Plasma: Application to a Long-Lasting Dosage Form

A simple and sensitive high-performance liquid chromatography (HPLC) assay applied to the measurement of ibuprofen in rat plasma has been developed. Two parameters have been investigated to improve ibuprofen detectability using fluorescence detection: variation of mobile phase pH and the use of β-cyclodextrin (β-CD). Increasing the pH value from 2.5 to 6.5 and adding 5 mM β-CD enhanced the fluorescence signal (λ_exc = 224 nm; λ_em = 290 nm) by 2.5 and 1.3-fold, respectively, when using standards. In the case of plasma samples, only pH variation significantly lowered detection and quantification limits, down to 10 and 35 ng/mL, respectively. Full selectivity was obtained with a single step for plasma treatment, that is, protein precipitation with acidified acetonitrile. The validated method was applied to a pharmacokinetic study of ibuprofen encapsulated in microspheres and subcutaneously administered to rats.     

Enantioselective esterification of ibuprofen with ethanol as reactant and solvent catalyzed by immobilized lipase: experimental and molecular modeling aspects

BACKGROUND: In recent years enantioselective esterification of racemic ibuprofen performed in organic co‐solvent media such as isooctane and cyclohexane and catalyzed by lipases, has been proposed as an effective way to increase the concentration of S‐ibuprofen in the racemic mixture. In this contribution, the enantioselective enzymatic esterification of (R,S)‐ibuprofen with ethanol catalyzed by commercial Novozym 435 without the addition of a co‐solvent is thoroughly investigated. Experimental data are further analyzed considering the results of extensive molecular modeling calculations. RESULTS: The conversion of ibuprofen towards the ethyl esters and the enantiomeric excess towards S‐ibuprofen are greatly affected by the ethanol and water contents of the reaction media. The optimum conditions for the esterification of racemic ibuprofen in a batch‐type reactor were as follows: molar ratio of ethanol to ibuprofen = 7, 4.8% v/v of water, 160 mg of Novozym 435, 45 °C and 200 rpm. Under these conditions an enantiomeric excess of 54% and 63% of ibuprofen conversion were reached. CONCLUSIONS: Results showed that the reaction in excess of the esterifying alcohol in a system free of additional organic solvents is possible if the proper conditions are set. Molecular modeling calculations demonstrated that the formation of dead‐end compounds between the enzyme and ethanol/water may account for lipase inhibition at high concentrations of those compounds. Copyright © 2009 Society of Chemical Industry