Formulation of immediate release pellets containing famotidine solid dispersions

Famotidine (FM) is a potent H2-receptor antagonist used for the treatment of peptic ulcer. It has a low and variable bioavailability which is attributed to its low water solubility. In this study, the dissolution of the drug was enhanced by a preparation of solid dispersion using two hydrophilic carriers, namely Gelucire 50/13 and Pluronic F-127. The prepared solid dispersions were characterized by differential scanning calorimetry (DSC), which indicated that there were no signs of interaction of the drug with the carriers used in the case of solid dispersions containing higher polymeric contents (1:3 and 1:5). FM solid dispersions in the matrices of Gelucire 50/13 and Pluronic F-127 (1:3) were used to prepare pellets. The scanning electron microscope (SEM) images of pellets showed that the pellets have spherical shape and their size depends on the carrier used. The dissolution of the drug from either solid dispersion or pellets was performed. The dissolution study depicted that, the presence of the drug in solid dispersion enhanced its dissolution in comparison with the drug itself. Also, the drug release from the manufactured pellets was found to be improved in the case of solid dispersions (drug:carrier 1:3). A complete drug release occurred after 30 min from pellets containing solid dispersions, while only about 30% of the loaded FM was released from pellets containing untreated drug after 2 h.     

Enhancing the bioavailability of ABT-963 using solid dispersion containing Pluronic F-68

Solid dispersions using Pluronic F-68 as a carrier were studied for improving the dissolution and bioavailability of ABT-963, a poorly water-soluble compound. The solid dispersions were prepared either by evaporation of the ethanol solutions containing ABT-963 and Pluronic, or by cooling the hot melt of the drug in the carrier. The dispersions were characterized using differential scanning calorimetry, powder X-ray diffractometry, scanning electron microscopy, elemental mapping, and by constructing the melting point phase diagram. In vitro dissolution and in vivo oral bioavailability in fasted dogs were compared for the solid dispersion and a conventional IR capsule formulation. Results showed that, at a composition of approximately 7.5%, ABT-963 formed a eutectic mixture with Pluronic F-68. Both the drug and the polymer were crystalline in the solid dispersion with a wide range of composition of each component. The solid dispersion substantially increased the in vitro dissolution rate of ABT-963. Dosing of the dispersion to fasted dogs resulted in a significant increase of oral bioavailability compared with the conventional IR capsule formulation. These results show that solid dispersion is a promising approach for developing ABT-963 drug products.     

Preparation, Characterization, and In Vitro Evaluation of Ezetimibe Binary Solid Dispersions with Poloxamer 407 and PVP K30

Ezetimibe (EZE), a water insoluble drug, depicts variable bioavailability. The objective of the present investigation was to improve dissolution characteristics of EZE, which might offer improved bioavailability. The solid dispersions were prepared using poloxamer 407 (L 127) and polyvinyl pyrrolidone by melt and solvent method, respectively. Phase solubility studies indicated linear relationship between drug solubility and carrier concentration. In vitro release studies revealed improvement in the dissolution characteristics of EZE in solid dispersions. Solid dispersion with L 127 gave better rate and extent of dissolution. The best fit model indicating the probable mechanism of drug release from solid dispersions was found to be Korsemeyer–Peppas. The results of characterization of solid dispersions by Fourier transform infrared spectroscopy, differential scanning calorimetry, and powder X-ray diffraction revealed reduction in drug crystallinity which might be responsible for improved dissolution properties. The tablets of solid dispersion, containing L 127 prepared by direct compression, exhibited better drug release as compared to marketed formulation.     

Studies on dissolution enhancement and mathematical modeling of drug release of a poorly water-soluble drug using water-soluble carriers.

Role of various water-soluble carriers was studied for dissolution enhancement of a poorly soluble model drug, rofecoxib, using solid dispersion approach. Diverse carriers viz. polyethylene glycols (PEG 4000 and 6000), polyglycolized fatty acid ester (Gelucire 44/14), polyvinylpyrollidone K25 (PVP), poloxamers (Lutrol F127 and F68), polyols (mannitol, sorbitol), organic acid (citric acid) and hydrotropes (urea, nicotinamide) were investigated for the purpose. Phase-solubility studies revealed AL type of curves for each carrier, indicating linear increase in drug solubility with carrier concentration. The sign and magnitude of the thermodynamic parameter, Gibbs free energy of transfer, indicated spontaneity of solubilization process. All the solid dispersions showed dissolution improvement vis-à-vis pure drug to varying degrees, with citric acid, PVP and poloxamers as the most promising carriers. Mathematical modeling of in vitro dissolution data indicated the best fitting with Korsemeyer-Peppas model and the drug release kinetics primarily as Fickian diffusion. Solid state characterization of the drug-poloxamer binary system using XRD, FTIR, DSC and SEM techniques revealed distinct loss of drug crystallinity in the formulation, ostensibly accounting for enhancement in dissolution rate.     

Preparation and physicochemical characterizations of tanshinone IIA solid dispersion

This investigation describes a novel approach to prepare solid dispersions of tanshinone IIA using a laboratory-scale planetary ball mill. Poloxamer 188 was employed as the surfactant carrier to improve the solubility and dissolution of the poorly soluble drug, tanshinone IIA. Solubility and dissolution were evaluated compared to the corresponding physical mixtures and pure drug. Furthermore, the physicochemical properties of the solid dispersions were investigated using scanning electron microscopy, powder X-ray diffraction, differential scanning calorimetry, Fourier transform infrared spectroscopy and ultraviolet spectrophotometry. The solid dispersion significantly enhanced drug solubility and dissolution compared with pure drug and the physical mixtures. Scanning electron microscopy, powder X-ray diffraction, differential scanning calorimetry and Fourier transform infrared spectroscopy analyses of tanshinone IIA/poloxamer 188 system confirmed that there were intermolecular interactions between tanshinone IIA and poloxamer 188 and no conversion to crystalline material. Tanshinone IIA existed in a microcrystalline form in the system. These results suggested that improvement of the dissolution rate could be correlated to the formation of a eutectic mixture between the drug and the carrier. After 60 days the solid dispersion samples were chemically and physically stable. The present studies indicated that the planetary ball mill technique could be considered as a novel and efficient method to prepare solid dispersion formulations.     

Physicochemical characterization of tacrolimus-loaded solid dispersion with sodium carboxylmethyl cellulose and sodium lauryl sulfate

To develop a novel tacrolimus-loaded solid dispersion with improved solubility, various solid dispersions were prepared with various ratios of water, sodium lauryl sulfate, citric acid and carboxylmethylcellulose-Na using spray drying technique. The physicochemical properties of solid dispersions were investigated using scanning electron microscopy, differential scanning calorimetery and powder X-ray diffraction. Furthermore, their solubility and dissolution were evaluated compared to drug powder. The solid dispersion at the tacrolimus/CMC-Na/sodium lauryl sulfate/citric acid ratio of 3/24/3/0.2 significantly improved the drug solubility and dissolution compared to powder. The scanning electron microscopy result suggested that carriers might be attached to the surface of drug in this solid dispersion. Unlike traditional solid dispersion systems, the crystal form of drug in this solid dispersion could not be converted to amorphous form, which was confirmed by the analysis of DSC and powder X-ray diffraction. Thus, the solid dispersion system with water, sodium lauryl sulfate, citric acid and CMC-Na should be a potential candidate for delivering a poorly water-soluble tacrolimus with enhanced solubility and no convertible crystalline.     

西洛他唑/介孔碳固体分散体的制备及体外溶出性质的考察

目的为了提高难溶性药物西洛他唑的溶出度,制备西洛他唑/介孔碳固体分散体。方法以表面活性剂F127为胶束模板,以酚醛树脂的乙醇溶液为碳源制备介孔碳,选用西洛他唑作为模型药,采用吸附平衡挥干法和溶液吸附法载药制得西洛他唑固体分散体,采用扫描电镜、氮气吸附-脱附和热分析手段表征介孔碳及西洛他唑/介孔碳固体分散体的性质。结果制得的介孔碳孔径均一,其孔径主要集中在6.3 nm,载体的比表面积为1 255.4 m2.g-1,孔容为1.441 cm3.g-1,载体的载药质量可高达33.1%,溶出数据表明西洛他唑/介孔碳固体分散体的溶出速率与累积溶出度与药物西洛他唑相比均有了显著提高。结论介孔碳有望成为能提高难溶性药物溶出度的优良载体。     

Preparation, characterization and in vitro dissolution studies of solid dispersion of meloxicam with PEG 6000

The poor solubility and wettability of meloxicam leads to poor dissolution and hence showing variations in bioavailability. The present study is aimed to increase solubility and dissolution of the drug using solid dispersion techniques. The solid binary systems were prepared at various drug concentrations (5-40%) with polyethylene glycol 6000 by different techniques (physical mixing, solvent evaporation). The formulations were characterized by solubility studies, differential scanning calorimetry, fourier transform infrared spectroscopy and in vitro dissolution rate studies. The solubility of drug increased linearly with increase in polymer concentration showing A(L) type solubility diagrams. Infrared spectroscopy studies indicated the possibility of hydrogen bonding with polymer. The differential scanning calorimetry and powder X ray diffraction demonstrated the presence of polymer as eutectica or monotectica in solid dispersion along with the physical characteristics of the drug (crystalline, amorphous or a mixture of both). The solid dispersions of the drug demonstrated higher drug dissolution rates than physical mixtures and pure meloxicam, as a result of increased wettability and dispersibility of drug in a solid dispersion system.     

卡维地洛-PVPVA64固体分散体的制备与表征

目地：制备卡维地洛的固体分散体,提高其在水中的溶解度和溶出度。方法：以乙烯基吡咯烷酮／醋酸乙烯共聚物（PVPVA64）为载体,无水乙醇为溶剂,制备卡维地洛固体分散体,并通过差示扫描量热法、x-射线粉末衍射法、红外分光光度法、原子力显微镜扫描、溶解度测定、溶出度实验及稳定性试验对固体分散体进行表征。结果：差示扫描量热法、x-射线粉末衍射法以及原子力显微镜扫描的谱图和图像分析表明卡维地洛以无定形状态存在于制得的固体分散体中,而傅里叶变换红外光谱分析则表明在固体分散体中卡维地洛与PVPVA64间可能以氢键结合形式存在。与卡维地洛原料药相比,该固体分散体的溶解度提高了80倍,且1h溶出百分率也从10％以下提高到95．5％。经差示扫描量热法、x-射线粉末衍射法及溶出度实验考察发现,在温度为40℃、相对湿度为75％的环境条件下,于90d内,该固体分散体稳定性良好。结论：卡维地洛与PVPVA64形成固体分散体后可显著提高其溶解度和溶出度,且热力学稳定,可进一步用于制备生物利用度更高的口服固体剂型。     

The Effect of Carrier-Drug Ratios on Dissolution Performances of Poorly Soluble Drug in Crystalline Solid Dispersion System

The choice of carrier and drug ratio are critical factors as far as the type of solid dispersion is concerned. Amorphous solid dispersion has been cited as the most desirable type among the different types of solid dispersion due to the benefit of amorphicity in increasing the drug solubility of a poorly soluble drug. Recent reports delineated that a partially crystalline solid dispersion system may perform better due to the inherent issue of solution mediated recrystallisation of a completely amorphous system. In oppose to the conventional choice of using amorphous polymer, this study aimed to investigate the use of a crystalline carrier, polyethylene glycol (PEG) for dissolution enhancement of a model poorly soluble drug, Flurbiprofen (FBP), a BCS Class II candidate. Solid dispersions of different FBP to PEG 6000 molar ratios via solvent evaporation were prepared. Physical characterisation of preparations was performed using differential scanning calorimetry (DSC), attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR) and optical microscope. DSC and ATR-FTIR analyses suggest the obtained solid dispersion exhibits crystalline FBP. This is then supported by the optical microscope analysis as the birefringence of crystals was noted. Further increasing the drug-carrier molar ratio to one-to-three and one-to-six showed that there was an amorphous FBP constituent in the system. DSC analysis revealed the melting point depression of FBP by the carrier which signifies interaction between the drug and polymer. Dissolution study showed the solid dispersion of FBP improves the drug solubility and drug release compared to the pure drug. A higher carrier ratio in the formulation results in a higher drug release.     

Dissolution behaviour of nalidixic acid solid dispersions using water soluble dispersion carriers

The oral bioavailability of nalidixic acid (NA) is low due to its poor solubility and slow dissolution. Solid dispersions of NA containing varying concentrations of polyvinylpyrrolidone (PVP), beta-cyclodextrin (BCD) and sodium starch glycolate (SSG) were prepared by solvent evaporation technique in an attempt to improve dissolution rate of NA. Physical characterization of NA, physical mixtures (PM) and solid dispersions were investigated by a variety of analytical methods including scanning electron microscopy (SEM), infrared (IR) spectroscopy and powder X-ray diffraction (XRD). SEM was useful in the verification of possible nalidixic acid inclusion in the dispersion system by studying its surface and shape characteristics of different samples. IR analysis demonstrated no strong interaction between the drug and the carrier exists in the solid dispersions. The degree of crystallinity of nalidixic acid decreased and also differed with the dispersion systems of different carriers. Disolution studies indicated that the dissolution rate and percent dissolution efficiency (DE) were significantly increased in the solid dispersions compared with drug alone. The relative potency of the carriers to enhance the dissolution rate of nalidixic acid was in the order: BCD > PVP > SSG. The dissolution rate of the drug in the solid dispersions was faster when the ration of the drug to carrier was smaller. F-test suggests that first order model may be used for explaining the kinetics of drug release from all the solid dispersion systems.     

紫杉醇-PVP固体分散体的制备、物相鉴定及细胞药效

用溶剂法制备紫杉醇-PVP固体分散体，对其溶解度及体外溶出特性进行考察并对物相进行鉴定。采用溶剂法制备紫杉醇-PVP固体分散体，对固体分散体中紫杉醇的溶解度和溶出率进行测定，研究固体分散体的溶出性质。同时，利用差热分析（Differential scanning calorimetry，DSC）、粉末X衍射（X-ray powder diffractometry,PXRD）、扫描电镜（Scanning electron microscopy，SEM）等方法对其进行物相鉴定。采用SRB法对紫杉醇-PVP固体分散体对SKOV-3细胞药效进行测定。紫杉醇-PVP固体分散体中紫杉醇的溶解度和溶出速率相对其原料药和物理混合物均有了明显的提高；热差分析及粉末X衍射结果表明固体分散体中紫杉醇呈非结晶形式；扫描电镜下固体分散体中无紫杉醇晶体。细胞药效结果表明紫杉醇-PVP固体分散体的细胞药效强于紫杉醇纯药。采用溶剂法制备的紫杉醇-PVP固体分散体可显著提高紫杉醇的溶解度和溶出速度。     

Studies on Flash Evaporation for Preparation of Porous Solid Dispersions Using Piroxicam as a Model Drug

An amalgamation of solid dispersion and capillarity has been attempted in present study for enhancement of dissolution rate of poorly soluble drugs. Flash evaporation technique was utilized for enhancement of the dissolution rate of piroxicam. One of the major problems with this drug is its very low solubility in biological fluids, which results in poor bioavailability after oral administration. An attempt was made to enhance the dissolution rate of piroxicam by converting it into porous solid dispersion by flash evaporation method using polyvinylpyrrolidone (PVP) 40,000 as a water-soluble carrier. The resulting solid dispersions were characterized by DSC, FTIR, and X-ray diffraction. In vitro dissolution study revealed significant improvement of dissolution profile of piroxicam. The release of drug from porous solid dispersions containing PVP was superior to those of marketed product, conventional nonporous solid dispersion prepared by solvent evaporation method and drug alone. The steep increase in dissolution rate of porous form is attributable to combined effect of solid dispersion and capillarity.     

微管蛋白抑制剂SUD-35固体分散体的制备、鉴定及初步体外药效学研究

目的将难溶性微管蛋白抑制剂SUD-35制备成固体分散体,以增加其溶解度及溶出速率。方法以聚乙二醇6000为载体,溶剂-熔融法制备SUD-35固体分散体。采用差示扫描量热分析与X-射线衍射观察药物在载体中的存在状态,并进行溶解度和体外溶出度研究。采用MTT法对SUD-35固体分散体对小鼠白血病L1210细胞药效进行测定。结果 SUD-35固体分散体中SUD-35的溶解度和溶出速率相对原料药和物理混合物均有明显提高,差示扫描量热分析与X-射线衍射结果显示SUD-35以无定型状态存在于固体分散体中,细胞药效结果显示SUD-35固体分散体对小鼠白血病L1210细胞增殖抑制率强于SUD-35纯药。结论聚乙二醇6000为载体制备SUD-35固体分散体,可显著提高SUD-35的溶解度及溶出速率。     

介孔二氧化硅纳米粒的制备及对载药与药物溶出度的影响

目的为提高水难溶性药物的分散性及溶出度,制备介孔二氧化硅纳米粒作为水难溶性药物的载体。方法探索得到简单有效地制备球状介孔二氧化硅纳米粒的工艺条件,采用扫描电镜及氮气吸附-脱附等手段分析表征载体的外观形貌,比表面积及孔径分布,并选取水难溶性药物西洛他唑作为模型药物,以溶剂浸渍挥干法载药制得药物固体分散体,采用热分析、氮气吸附-脱附曲线以及溶出度实验研究药物固体分散体的基本性质。结果制得的二氧化硅载体的形貌近球状,粒径大小分布在200～250 nm,载体的比表面积最高可达1 101.54 m2.g-1,孔径分布主要集中在3.0～4.0 nm。载药过程对西洛他唑在载体中的存在形式没有影响,固体分散体中西洛他唑的溶出度得到显著提高,当药物与载体的质量比为1∶3时,药物60 min累计溶出达85%。结论介孔二氧化硅纳米粒有望成为水难溶性药物的优良载体。     

Poly(2-Ethyl-2-Oxazoline) as an Alternative to Poly(Vinylpyrrolidone) in Solid Dispersions for Solubility and Dissolution Rate Enhancement of Drugs

Poly(2-ethyl-2-oxazoline) (PEOX), a biocompatible polymer considered as pseudopolypeptide, was introduced as a potential alternative to the commonly used polymer, poly(vinylpyrrolidone) (PVP) for the preparation of solid dispersion with a poorly soluble drug. Glipizide (GPZ), a Biopharmaceutical Classification System class II model drug, was selected for solubility and dissolution rate study. GPZ-polymer solid dispersions and physical mixtures were characterized and investigated by X-ray diffractometry, differential scanning calorimetry, scanning electron microscopy, and FTIR spectroscopy. The impact of polymers on crystal nucleation kinetics was studied, and PEOX exhibited strong inhibitory effect compared with PVP. Solubility and dissolution behavior of the prepared solid dispersions and their physical blends were in vitro examined and evaluated. A significant enhancement in GPZ solubility was obtained with PEOX compared with the pure drug and solid dispersion with PVP. A big improvement in the intrinsic dissolution rate (45 times) and dissolved amount of GPZ (58 times) was achieved with PEOX in fasted state simulated intestinal fluid, against comparable enhancement observed with PEOX and PVP in phosphate buffer at pH 6.8. Lower molecular weight of PEOX-5K (5000 g/mol) was found to be superior to higher molecular weight PEOX-50K (50,000 g/mol) in the improvement of dissolution behavior. The findings of this study with GPZ as a model drug introduce lower molecular weight PEOX as a promising polymeric carrier toward better oral bioavailability of poorly soluble drugs.     

托伐普坦固体分散体的制备及体外溶出特性考察

目的 采用固体分散技术提高难溶性药物托伐普坦的体外溶出度。方法 选用聚维酮K_29/32为载体材料,以溶剂蒸发法制备托伐普坦固体分散体。采用差示扫描量热法(DSC)、X-射线粉末衍射法(XRPD)对所得固体分散体进行鉴定, 并进行溶解度、体外溶出实验。结果 固体分散体的DSC 图谱及X-射线粉末衍射确定了托伐普坦以无定形态分散在载体中, 体外溶解实验表明其溶出较原料药、物理混合物均有明显提高。结论 将托伐普坦与PVP K_29/32制成固体分散体,其分散状态发生了改变,溶出性能明显提高。     

尼莫地平固体分散体的研究

目的 制备尼莫地平固体分散体,增加其溶出速度.方法 应用聚乙烯吡咯烷酮（PVP）为载体,采用喷雾干燥制备尼莫地平固体分散体,通过差示扫描量热分析（DSC）和X-射线粉末衍射分析鉴别药物在载体中的存在状态,并进行了体外溶出度研究.结果 尼莫地平在载体中以分子状态存在,尼莫地平固体分散体的溶出度与尼莫地平原料药和原料药载体物理混合物相比有显著提高,载体比例越大,药物溶出越快,药物载体比例为1：3时t50仅0.972 6 min,结论聚乙烯吡咯烷酮（PVP）作为尼莫地平固体分散体的载体载药量大;喷雾干燥工艺重现性好,分散体颗粒无需粉碎可满足各类固体制剂的制备要求,是一种较理想的尼莫地平固体分散体的制备方法.     

Solubility enhancement and physicochemical characterization of carvedilol solid dispersion with Gelucire 50/13

The objective of the study was enhancement of dissolution of poorly soluble carvedilol by solid dispersions (SDs) with Gelucire 50/13 using solvent evaporation method. The solubility of carvedilol showed linear increase with increasing concentrations of Gelucire indicating A_L type solubility diagrams. SDs characterized for physicochemical characteristics using differential scanning calorimetry and X-ray diffractometry revealed transformation of crystalline form of drug to amorphous form which was confirmed by scanning electron micrographs. Further fourier transform infrared spectroscopy results suggested there is no drug carrier interaction. From the dissolution parameters such as mean dissolution time, dissolution efficiency and drug release rate, improved dissolution characteristics for SDs were observed compared with physical mixture and pure drug. Thus SDs of carvedilol in Gelucire 50/13 showed enhanced solubility and dissolution rate compared to pure drug.     

Preparation and characterization of spray-dried valsartan-loaded Eudragit® E PO solid dispersion microparticles

The purpose of this study was to develop the immediate release stomach-specific spray-dried formulation of valsartan (VAL) using Eudragit^® E PO (EPO) as the carrier for enhancing dissolution rate in a gastric environment. Enhanced solubility and dissolution in gastric pH was achieved by formulating the solid dispersion using a spray drying technique. Different combinations of drug–polymer–surfactant were dissolved in 10% ethanol solution and spray-dried in order to obtain solid dispersion microparticles. Use of the VAL–EPO solid dispersion microparticles resulted in significant improvement of the dissolution rate of the drug at pH 1.2 and pH 4.0, compared to the free drug powder and the commercial product. A hard gelatin capsule was filled with the VAL–EPO solid dispersion powder prior to the dissolution test. The increased dissolution of VAL from solid dispersion microparticles in gastric pH was attributed to the effect of EPO and most importantly the transformation of crystalline drugs to amorphous solid dispersion powder, which was clearly shown by scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and powder X-ray diffraction (P-XRD) studies. Thus, VAL, a potential antihypertensive drug in the form of a solid dispersion microparticulate powder, can be effectively delivered in the immediate release dosage form for stomach-specific drug delivery.