Improvement of solubility and dissolution rate of indomethacin by solid dispersions in Gelucire 50/13 and PEG4000

The aim of this study was to prepare and characterize solid dispersions of water insoluble non-steroidal anti-inflammatory drug, indomethacin (IND), with polyethylene glycol 4000 (PEG4000) and Gelucire 50/13 (Gelu.) for enhancing the dissolution rate of the drug. The solid dispersions (SDs) were prepared by hot melting method at 1:1, 1:2 and 1:4 drug to polymer ratios. Scanning electron microscopy (SEM), X-ray powder diffractometry (XRD) and differential scanning calorimetry (DSC) were used to examine the physical state of the drug. Furthermore, the solubility and the dissolution rate of the drug in its different systems were explored. The data from the XRD showed that the drug was still detectable in its solid state in all SDs of IND–Gelu. and disappeared in case of higher ratio of IND–PEG4000. DSC thermograms showed the significant change in melting peak of the IND when prepared as SDs suggesting the change in crystallinity of IND. The highest ratio of the polymer (1:4) enhanced the drug solubility about 4-folds or 3.5-folds in case of SDs of IND–PEG or IND–Gelu., respectively. An increased dissolution rate of IND at pH 1.2 and 7.4 was observed when the drug was dispersed in these carriers in form of physical mixtures (PMs) or SDs. IND released faster from the SDs than from the pure crystalline drug or the PMs. The dissolution rate of IND from its PMs or SDs increased with an increasing amount of polymer.     

杨梅素固体分散体的制备以及体外溶出试验

目的运用固体分散技术制备杨梅素固体分散体并提高其体外溶出速率。方法选用PEG6000和PVPK30为载体,采用溶剂法和溶剂-熔融法制备杨梅素固体分散体,采用紫外分光光度法进行含量测定,并进行溶解度、体外溶出试验。结果两种载体的固体分散体均能增加药物的溶解度和溶出速率,杨梅素在载体中以高度分散状态存在。结论以PVPK30为载体的杨梅素固体分散体体外溶解度和溶出速率明显提高。杨梅素固体分散体能显著提高杨梅素的溶出速率。     

Development of ternary solid dispersions with hydrophilic polymer and surface adsorbent for improving dissolution rate of carbamazepine

In this study solid dispersions of carbamazepine in the hydrophilic Kollidon® VA64 polymer, adsorbed onto Neusilin® UFL2 adsorption carrier have been employed to improve carbamazepine dissolution rate. In order to evaluate effects of changing in the proportions of all solid dispersion components on carbamazepine dissolution rate, D-optimal mixture experimental design was used in the formulation development. From all prepared solid dispersion formulations, significantly faster carbamazepine dissolution was observed compared to pure drug. Ternary solid dispersions containing carbamazepine, Kollidon® VA64 and Neusilin® UFL2 showed superior dissolution performances over binary ones, containing only carbamazepine and Neusilin® UFL2. Proportion of Kollidon® VA64 showed the most profound effect on the amount of carbamazepine dissolved after 10 and 30?min, whereby these parameters increase upon increasing in Kollidon® VA64 concentrations up to the middle values in the studied range of Kollidon® VA64 concentrations. Physicochemical characterization of the selected samples using differential scanning calorimetry, FT-IR spectroscopy, powder X-ray diffraction and polarizing light microscopy showed polymorphic transition of carbamazepine from more thermodynamically stable monoclinic form (form III) to less thermodynamically stable triclinic form (form I) in the case of ternary, but not of binary solid dispersion formulations. This polymorphic transition can be one of the factors responsible for improving of carbamazepine dissolution rate from studied solid dispersions. Ternary solid dispersions prepared with Kollidon® VA64 hydrophilic polymer and Neusilin® UFL2 adsorption carrier resulted in significantly improvement of carbamazepine dissolution rate, but formation of metastable polymorphic form of carbamazepine requires particular care to be taken in ensuring product long term stability.     

Melt extrusion with poorly soluble drugs

Melt extrusion (ME) over recent years has found widespread application as a viable drug delivery option in the drug development process. ME applications include taste masking, solid-state stability enhancement, sustained drug release and solubility enhancement. While ME can result in amorphous or crystalline solid dispersions depending upon several factors, solubility enhancement applications are centered around generating amorphous dispersions, primarily because of the free energy benefits they offer. In line with the purview of the current issue, this review assesses the utility of ME as a means of enhancing solubility of poorly soluble drugs/chemicals. The review describes major processing aspects of ME technology, definition and understanding of the amorphous state, manufacturability, analytical characterization and biopharmaceutical performance testing to better understand the strength and weakness of this formulation strategy for poorly soluble drugs. In addition, this paper highlights the potential advantages of employing a fusion of techniques, including pharmaceutical co-crystals and spray drying/solvent evaporation, facilitating the design of formulations of API exhibiting specific physico-chemical characteristics. Finally, the review presents some successful case studies of commercialized ME based products.     

Preparation, dissolution and characterization of albendazole solid dispersions

In this study, solid dispersion systems of the sparingly water soluble drug, albendazole (ABZ), were mixed with varying concentrations of polyvinylpyrrolidone (PVP K 12) in an attempt to improve the solubility and dissolution rate of ABZ. Physical characteristics were investigated by Powder X-ray diffraction. As expected, the albendazole dissolution rate, expressed as the dissolution efficiency, and also the solubility coefficient were increased when albendazole was mixed with PVP. An increase in the concentration of the polymer in the solid dispersion produced an increase in both parameters. The powder X-ray diffraction patterns showed that the solid dispersion presented an amorphous form of albendazole in this coprecipitate system.     

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.     

固体分散体在提高难溶性药物口服生物利用度中的应用

固体分散体在提高难溶性药物溶出度和口服生物利用度中的应用引起了药学工作者的关注,本文综述了固体分散体常用载体、常用的溶剂、提高难溶性药物溶出速率的机制和制备方法以及其他替代的方法,以期将难溶性药物制备为固体分散体提供参考。     

Manufacturing of solid dispersions of poorly water soluble drugs by spray drying: Formulation and process considerations

Spray drying is an efficient technology for solid dispersion manufacturing since it allows extreme rapid solvent evaporation leading to fast transformation of an API-carrier solution to solid API-carrier particles. Solvent evaporation kinetics certainly contribute to formation of amorphous solid dispersions, but also other factors like the interplay between the API, carrier and solvent, the solution state of the API, formulation parameters (e.g. feed concentration or solvent type) and process parameters (e.g. drying gas flow rate or solution spray rate) will influence the final physical structure of the obtained solid dispersion particles. This review presents an overview of the interplay between manufacturing process, formulation parameters, physical structure, and performance of the solid dispersions with respect to stability and drug release characteristics.     

Solubility enhancement of some poorly soluble drugs by solid dispersion using Ziziphus spina-christi gum polymer

A high percentage of marketed drugs suffer from poor water solubility and require an appropriate technique to increase their solubility. This study aims to compare physically modified and unmodified gum polymers extracted from Ziziphus spina-christi fruits as solid dispersion carriers for some drugs. Taguchi Orthogonal Design (L9) was chosen for the screening and optimization of the solid dispersions. The design has four factors: type of drug, type of polymer, type of solid dispersion process, and drug to polymer ratio. Each factor was varied in three stages and the total number of runs was 9 in triplicate. The polymer was physically modified by heating (M1ZG) or freeze-drying (M2ZG). The drugs were selected according to the biopharmaceutical classification system, namely loratadine and glimepiride (class II) and furosemide (class IV). Drugs were dispersed in the polymer in three different ratios 1: 1, 1: 2, and 1: 3. Solid dispersions were made by co-grinding, solvent evaporation, and kneading methods. Modified and unmodified polymers were characterized in terms of their organoleptic properties, solubility, powder flowability, density, viscosity, swelling index, and water retention capacity. Solid dispersions were characterized in terms of percentage practical yield, solubility improvement, and drug compatibility. The results showed that the organoleptic properties of polymers were not changed by the gum modification. The swelling index of the polymer was doubled in M1ZG. The viscosity and water retention capacity of the polymer was increased in both modified polymers. All solid dispersions showed a high practical percentage yield of more than 93%, the higher values ​​being more associated with loratadine and furosemide than with glimepiride. The improvement in solubility was observed in all solid dispersions prepared, the values ​​varying with the pH of the medium and the method of modification. The FTIR results indicated that there was no chemical interaction between these drugs and the polymer used. Analysis of the results according to the Taguchi orthogonal design indicated 51 folds aqueous solubility enhancement for loratadine using M2ZG polymer at a ratio of 1: 3 of Drug: polymer. This study showed the possibility of improving the solubility of other poorly soluble drugs.     

Preparation,characterization, and in vitro/vivo evaluation of polymer-assisting formulation of atorvastatin calcium based on solid dispersion technique

 Due to low solubility and bioavailability, atorvastatin calcium is confronted with challenge in conceiving appropriate formulation. Solid dispersion of atorvastatin calcium was prepared through the solvent evaporation method, with Poloxamer 188 as hydrophilic carriers. This formulation was then characterized by scanning electron microscopy, differential scanning calorimetry,powder X-ray diffraction and fourier transform infrared spectroscopy. Moreover, all these studies suggested the conversion of crystalline atorvastatin calcium. In addition, the drug solubility studies as well as dissolution rates compared with bulk drug and market tablets Lipitor were also examined. Furthermore, the study investigated the pharmacokinetics after oral administration of Lipitor and solid dispersion. And the AUC0–8 h and Cmax increased after taking ATC-P188 solid dispersion orally compared with that of Lipitor. All these could be demonstrated that ATC-P188 solid dispersions would be prospective means for enhancing higher oral bioavailability of ATC.     

盐酸胺碘酮固体分散体的制备及溶出度测定

目的制备盐酸胺碘酮固体分散体,测定其体外溶出度,同时与普通胶囊剂的体外溶出度比较。方法以聚乙二醇6000(PEG6000)为载体,溶剂熔融法制备盐酸胺碘酮固体分散体,用紫外分光光度法测定体外溶出度。结果盐酸胺碘酮固体分散体的体外溶出度比普通胶囊剂显著提高。结论成功制备了盐酸胺碘酮固体分散体。     

尼群地平固体分散片的制备及其体外溶出度的测定

目的 制备尼群地平(NT)固体分散体片，提高其溶出度：方法 以聚乙烯吡咯烷酮(PVPk30)为载体，用溶剂法制备NT固体分散体；显微镜观察和差示热分析(DTA)鉴别药物在载体中的状态；制备普通片和固体分散体片，测定溶出度，并与市售国产片相比。结果 DTA曲线表明药物在固体分散体中以非晶体状态存在，其体外溶出速率明显提高，20min的累计释放率为73．2％，而普通片及市售国产片分别为22．5％和21．7％。结论 NT制成固体分散体片能明显增加NT的体外溶出度。     

Fundamental aspects of solid dispersion technology for poorly soluble drugs

The solid dispersion has become an established solubilization technology for poorly water soluble drugs. Since a solid dispersion is basically a drug–polymer two-component system, the drug–polymer interaction is the determining factor in its design and performance. In this review, we summarize our current understanding of solid dispersions both in the solid state and in dissolution, emphasizing the fundamental aspects of this important technology.KEY WORDS: Solid dispersion, Poorly soluble drug, Phase separation, Drug–polymer interaction     

聚合物载体对固体分散体稳定性影响的研究进展

固体分散体是改善难溶性药物溶解度最行之有效的策略之一,其中活性药物成分以分子形态、无定形态或微晶形态分散于载体材料中,由于载体是配方最大的组成部分,其特性将在很大程度上影响着固体分散体的稳定性,聚合物是最常用的固体分散体载体,基于此,本文将从聚合物的理化性质及药物与载体的混溶性等方面,讨论聚合物对固体分散体稳定性的影响,有助于载体的合理选择,及固体分散技术研究设计与制备水平的提高。     

伊曲康唑固体分散体制备及体外溶出实验

目的:运用固体分散体技术提高难溶性药物伊曲康唑的溶解度及体外溶出速率.方法:选用聚乙烯吡咯烷酮(PVPK30)为载体,采用喷雾干燥法制备伊曲康唑固体分散体,通过差热分析及X射线衍射对固体分散体进行鉴定,比较考察伊曲康唑及其物理混合物和固体分散体的溶出特性.结果:差热分析、X射线衍射图谱表明药物以无定形状态分散于载体中;体外溶出结果表明固体分散体能显著增加药物在水及人工胃液中的溶出度(45 min时1:4固体分散体体外溶出度为伊曲康唑的11.5倍.1:4固体分散体在0.1 mo1·L-1盐酸中溶解度是伊曲康唑的67倍).结论:伊曲康唑固体分散体能明显提高伊曲康唑的溶解度及体外溶出速率.     

马尼地平栓的制备及质量评价

目的:制备马尼地平(MNDP)栓,并对其进行质量评价。方法:以成型性等指标筛选甘油明胶等栓剂基质;将MNDP制成固体分散体后再制成栓剂;加入表面活性剂以提高栓剂溶出并采用正交试验筛选表面活性剂的最佳处方;测定并比较3种栓剂(甘油明胶、固体分散体、加入表面活性剂)的累积溶出度。结果:筛选出以甘油明胶为栓剂的基质,表面活性剂的最佳处方为吐温801%,泊洛沙姆2.50%,十二烷基磺酸钠0.125%,聚乙二醇400010%。3种栓剂8h时MNDP的累积溶出度分别为25%、44%、60%;优化后栓剂24h时MNDP的累积溶出度达到90%以上。结论:MNDP固体分散体能明显增加主药的体外溶出,加入表面活性剂可进一步增加药物的溶出,优选出最佳处方后制得的3批栓剂质量均符合要求。     

Physicochemical characterization and in vitro dissolution studies of solid dispersions of ketoprofen with PVP K30 and d-mannitol

Aim of the present study was to improve the solubility and dissolution rate of poorly water soluble, BCS class-II drug Ketoprofen (KETO) by solid-dispersion approach. Solid dispersions were prepared by using polyvinylpyrrolidone K30 (PVP K30) and d-mannitol in different drugs to carrier ratios. Dispersions with PVP K30 were prepared by kneading and solvent evaporation techniques, whereas solid dispersions containing d-mannitol were prepared by kneading and melting techniques. These formulations were characterized in the liquid state by phase-solubility studies and in the solid state by Differential Scanning Calorimetry (DSC), Fourier Transform Infrared (FTIR) spectroscopy, X-ray diffraction (XRD) and Scanning Electron Microscopy (SEM). The aqueous solubility of KETO was favored by the presence of both carriers. The negative values of Gibbs free energy illustrate the spontaneous transfer from pure water to the aqueous polymer environment. Solid state characterization indicated KETO was present as fine particles in d-mannitol solid dispersions and entrapped in carrier matrix of PVP K30 solid dispersions. In contrast to the very slow dissolution rate of pure KETO, dispersions of drug in carriers considerably improved the dissolution rate. This can be attributed to increased wettability and dispersibility, as well as decreased crystallinity and increase in amorphous fraction of drug. Solid dispersions prepared with PVP K30 showed the highest improvement in dissolution rate of KETO. Even physical mixtures of KETO prepared with both carriers also showed better dissolution profiles than those of pure KETO.     

Preparation of esomeprazole zinc solid dispersion and study on its pharmacokinetics

Esomeprazole zinc (EZ) is a poorly water-soluble substance. In order to increase its dissolution rate and bioavailability, solid dispersions of esomeprazole zinc (SDEZ) in polyethylene glycol 4000 (PEG4000) with different EZ to PEG4000 ratios were prepared by solvent method. Our studies showed that dissolution rate of EZ were distinctively increased in the solid dispersion system compared to that in pure EZ or physical mixtures. The increase of dissolution rate was obviously related to the ratio of EZ to PEG4000. The solid dispersion system (EZ/PEG4000=1/8, w/w) gave the highest dissolution rate: about 14.7-fold higher than that of the pure EZ. EZ was proved to be in amorphous state in this solid dispersion by using differential scanning calorimetry (DSC) and scanning electron microscopy (SEM) techniques. In vivo administration studies, SDEZ in enteric capsule (SDEZ-EC) has a lower Cmax and a longer Tmax than that of esomeprazole magnesium enteric-coated tablet (Nexium), and the differences of Cmax and Tmax between SDEZ-EC and Nexium are significant. This result suggests SDEZ-EC has a lower absorption rate than Nexium and corresponds with the in vitro dissolution.     

Transformation of acidic poorly water soluble drugs into ionic liquids

Poor water solubility of active pharmaceutical ingredients (API) is a major challenge in drug development impairing bioavailability and therapeutic benefit. This study is addressing the possibility to tailor pharmaceutical and physical properties of APIs by transforming these into tetrabutylphosphonium (TBP) salts, including the generation of ionic liquids (IL). Therefore, poorly water soluble acidic APIs (Diclofenac, Ibuprofen, Ketoprofen, Naproxen, Sulfadiazine, Sulfamethoxazole, and Tolbutamide) were converted into TBP ILs or low melting salts and compared to the corresponding sodium salts. Free acids and TBP salts were characterized by NMR and IR spectroscopy, DSC and XRPD, DVS and dissolution rate measurements, release profiles, and saturation concentration measurements. TBP salts had lower melting points and glass transition temperatures and dissolution rates were improved up to a factor of 1000 as compared to the corresponding free acid. An increase in dissolution rates was at the expense of increased hygroscopicity. In conclusion, the creation of TBP ionic liquids or solid salts from APIs is a valuable concept addressing dissolution and solubility challenges of poorly water soluble acidic compounds. The data suggested that tailor-made counterions may substantially expand the formulation scientist’s armamentarium to meet challenges of poorly water soluble drugs.     

Characterization of the distribution, polymorphism, and stability of nimodipine in its solid dispersions in polyethylene glycol by micro-Raman spectroscopy and powder x-ray diffraction

In the present study, a series of solid dispersions of the drug nimodipine using polyethylene glycol as carrier were prepared following the hot-melt method. Micro-Raman spectroscopy in conjunction with X-ray powder diffractometry was used for the characterization of the solid structure, including spatial distribution, physical state, and presence of polymorphs, as well as storage stability of nimodipine in its solid formulations. The effect of storage time on drug stability was investigated by examination of the samples 6 months and 18 months after preparation. Confocal micro-Raman mapping performed on the samples showed that the drug was not uniformly distributed on a microscopic level. The presence of crystals of nimodipine with sizes varying between one and several micrometers was detected, and the crystal size seemed to increase with overall drug content. In samples examined 6 months after preparation it was found that the crystals existed mainly as the racemic compound, whereas after 18 months of storage mainly crystal conglomerates were observed.