Preparation and physicochemical characterization of binary and ternary ground mixtures of carvedilol with PVP and SLS aimed to improve the drug dissolution

The objective of the present study was to enhance the dissolution rate of carvedilol (CA), a poorly water-soluble antihypertensive drug, using a co-grinding method in the presence of polyvinylpyrrolidone (PVP) and sodium lauryl sulfate (SLS). Various ratios of CA:PVP:SLS were ground by a planetary ball mill. They were studied in terms of dissolution, solubility, and particle size. The solid state and morphology of the intact drug and prepared samples were also characterized using differential scanning calorimetry (DSC), infrared spectroscopy (IR), X-ray diffraction (XRD), and scanning electron microscope (SEM). According to the results, co-grinding in the presence of PVP and SLS significantly increased CA dissolution rate. DE₆₀ (dissolution efficiency) obtained for the best ternary ground mixture (89.31%) was 3.4 and 4.5 times higher than that of the related physical mixture (PM) and the intact drug, respectively. Further, the solubility of this formulation was about 10 times higher compared to that of the intact CA. A direct correlation was also observed between the chamber rotation speed of the planetary mill within the range of 100–400?rpm and CA dissolution rate. Finally, DSC, IR, and XRD analysis ruled out any polymorphic changes and chemical interactions during the grinding process.     

Formation and characterization of porous indomethacin-PVP coprecipitates prepared using solvent-free supercritical fluid processing

Supercritical carbon dioxide (sc-CO2) was used to prepare coprecipitates of indomethacin (IM) and poly(vinylpyrrolidone) (PVP) with the aim to improve the dissolution rate of IM. The coprecipitates of IM and PVP at various proportions were prepared using a stirred batch reactor containing sc-CO2 as a gas saturated solution (i.e., the compressible CO2 is dissolved in the molten compound). Temperatures between 40 and 90 degrees C and pressure of 150 or 200 bar were employed. The coprecipitates prepared at 75 degrees C and 150 bar were characterized using differential scanning calorimetry (DSC), powder X-ray diffraction (PXD), scanning electron microscopy (SEM), and dissolution testing. The results suggested that IM was totally amorphous at PVP weight fraction of 0.80 and above (indeed, as a molecular composite in which the drug molecules interact with the polymer backbone). As the PVP weight fraction decreased, IM displayed an increasing amount of crystalline material. The SEM photographs of coprecipitates showed a foamed and porous structure. The dissolution rate of IM was increased by incorporation of PVP. IM and PVP at various weight fractions exhibited comparatively higher dissolution rates than that of crystalline IM alone. The sc-CO2 based process produced a solvent free, completely amorphous porous IM solid dispersion with a rapid dissolution rate.     

Development of amorphous dispersions of artemether with hydrophilic polymers via spray drying: Physicochemical and in silico studies

Artemether (ARM) is a poorly water soluble and poorly permeable drug effective against acute and severe falciparum malaria, hence there is a strong need to improve its solubility. The objective of the study was to enhance the solubility and dissolution rate of ARM by preparation of solid dispersions using spray-drying technique. Solid dispersions of ARM were prepared with Soluplus, Kollidon VA 64, HPMC and Eudragit EPO at weight ratios of 1:1, 1:2, 1:3 using spray drying technology, and characterized by Fourier transform infrared spectroscopy, differential scanning calorimetry (DSC), and X-ray powder diffraction (XRD) to identify the physicochemical interaction between drug and carrier, as well as effect on dissolution. The prepared solid dispersion of ARM with polymers showed reduced crystallinity as compared to neat ARM, which was confirmed by DSC and XRD. Drug/polymer interactions were studied in-silico by docking and molecular dynamics which indicated formation of van der Waals type of interactions of ARM with the polymers. Based on solubility studies, the optimum drug/Soluplus ratio was found to be 1:3. The dissolution studies of formulation SD3 showed highest drug release up to 82% compared to neat ARM giving only 20% at 60 minutes. The spray-dried products were free of crystalline ARM; possessed higher dissolution rates, and were stable over a period according to ICH guidelines. These findings suggest that an amorphous solid dispersion of ARM could be a viable option for enhancing the dissolution rate of ARM.     

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.     

A novel surface-attached carvedilol solid dispersion with enhanced solubility and dissolution

A novel surface-attached, spray-dried solid dispersion containing poorly water-soluble carvedilol (CV) without any change in the crystallinity was prepared using water, polyvinylpyrrolidone (PVP K30) and Tween 80. The solid dispersion was optimized by investigating the effects of the weight ratios of Tween 80/PVP K30 and carrier/drug on the aqueous solubility of CV. The optimum solid dispersion consisted of a relatively low carrier to drug weight ratio: the weight ratio of CV/PVP K30/Tween 80 was 12/4/2. Unlike conventional methods of solid dispersion preparation, this method yielded CV-loaded solid dispersion with no change in the crystallinity of the drug as was evident from SEM, DSC and XRD. It was demonstrated that the solid dispersions prepared had hydrophilic carriers attached to the surface of the drug, thus changing it from a hydrophobic to a hydrophilic form without changing the crystalline form. The optimized solid dispersion improved the drug solubility and dissolution rate by about 11,500-fold and twofold, respectively. It was further suggested that this method of solid dispersion preparation is better than conventional methods in terms of environmental and industrial standpoints. Thus, it was concluded that CV-loaded solid dispersion prepared using this method would be of use for delivering poorly water-soluble CV with enhanced solubility and dissolution, but without crystalline changes.     

Solubility of Small-Molecule Crystals in Polymers: <Emphasis Type="SmallCaps">d</Emphasis>-Mannitol in PVP,Indomethacin in PVP/VA,and Nifedipine in PVP/VA

Objective  Amorphous pharmaceuticals, a viable approach to enhancing bioavailability, must be stable against crystallization. An amorphous drug can be stabilized by dispersing it in a polymer matrix. To implement this approach, it is desirable to know the drug’s solubility in the chosen polymer, which defines the maximal drug loading without risk of crystallization. Measuring the solubility of a crystalline drug in a polymer is difficult because the high viscosity of polymers makes achieving solubility equilibrium difficult. Method  Differential Scanning Calorimetry (DSC) was used to detect dissolution endpoints of solute/polymer mixtures prepared by cryomilling. This method was validated against other solubility-indicating methods. Results  The solubilities of several small-molecule crystals in polymers were measured for the first time near the glass transition temperature, including d-mannitol (β polymorph) in PVP, indomethacin (γ polymorph) in PVP/VA, and nifedipine (α polymorph) in PVP/VA. Conclusion  A DSC method was developed for measuring the solubility of crystalline drugs in polymers. Cryomilling the components prior to DSC analysis improved the uniformity of the mixtures and facilitated the determination of dissolution endpoints. This method has the potential of providing useful data for designing physically stable formulations of amorphous drugs.     

不同载体木犀草素固体分散体的制备及溶出度测定

目的:制备不同载体的木犀草素(LUT)固体分散体(SD),提高LUT的溶解度和溶出度,并探讨不同载体对药物溶解度和溶出度的影响。方法:应用平衡溶解度和超饱和溶液抑晶试验,筛选合适的载体材料并采用溶剂法制备SD;在单因素试验基础上,以药载比、温度和乙醇用量为影响因素,溶出度为指标,采用Box-Behnken设计优化处方和工艺;用差式扫描量热法(DSC)、扫描电镜(SEM)、X-射线衍射(XRD)以及傅里叶红外光谱(FTIR)对SD进行表征。结果:选择聚乙烯己内酰胺-聚醋酸乙烯酯-聚乙二醇接枝共聚物(Soluplus^?)和共聚维酮(PVP/VA)为载体材料;最优条件为药载比1∶11,温度60℃,乙醇用量50 mL(Soluplus^?)或35 mL(PVP/VA);与原料药相比,2种SD溶解度分别提高42倍(Soluplus^?)和102倍(PVP/VA);120 min时2种SD的累积溶出度均达到95%;SEM、DSC和XRD表征结果显示,药物在SD中均以无定形态存在;IR结果显示,药物与载体之间存在氢键作用。结论:2种载体制...     

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.     

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.     

Electrospun Formulations Containing Crystalline Active Pharmaceutical Ingredients

Purpose

To investigate the use of electrospinning for forming solid dispersions containing crystalline active pharmaceutical ingredients (API) and understand the relevant properties of the resulting materials.

Method

Free surface electrospinning was used to prepare nanofiber mats of poly(vinyl pyrrolidone) (PVP) and crystalline albendazole (ABZ) or famotidine (FAM) from a suspension of the drug crystals in a polymer solution. SEM and DSC were used to characterize the dispersion, XRD was used to determine the crystalline polymorph, and dissolution studies were performed to determine the influence of the preparation method on the dissolution rate.

Results

The electrospun fibers contained 31 wt% ABZ and 26 wt% FAM for the 1:2 ABZ:PVP and 1:2 FAM:PVP formulations, respectively, and both APIs retained their crystalline polymorphs throughout processing. The crystals had an average size of about 10 μm and were well-dispersed throughout the fibers, resulting in a higher dissolution rate for electrospun tablets than for powder tablets.

Conclusions

Previously used to produce amorphous formulations, electrospinning has now been demonstrated to be a viable option for producing fibers containing crystalline API. Due to the dispersion of the crystals in the polymer, tablets made from the fiber mats may also exhibit improved dissolution properties over traditional powder compression.     

Improved physicochemical characteristics of felodipine solid dispersion particles by supercritical anti-solvent precipitation process

Solid dispersions of felodipine were formulated with HPMC and surfactants by the conventional solvent evaporation (CSE) and supercritical anti-solvent precipitation (SAS) methods. The solid dispersion particles were characterized by particle size, zeta potential, scanning electron microscopy (SEM), differential scanning calorimetry (DSC), powder X-ray diffraction (XRD), solubility and dissolution studies. The effects of the drug/polymer ratio and surfactants on the solubility of felodipine were also studied. The mean particle size of the solid dispersions was 200-250 nm; these had a relatively regular spherical shape with a narrow size distribution. The particle size of the solid dispersions from the CSE method increased at 1 h after dispersed in distilled water. However, the particle sizes of solid dispersions from the SAS process were maintained for 6 h due to the increased solubility of felodipine. The physical state of felodipine changed from crystalline to amorphous during the CSE and SAS processes, confirmed by DSC/XRD data. The equilibrium solubility of the felodipine solid dispersion prepared by the SAS process was 1.5-20 microg/ml, while the maximum solubility was 35-110 microg/ml. Moreover, the solubility of felodipine increased with decreasing drug/polymer ratio or increasing HCO-60 content. The solid dispersions from the SAS process showed a high dissolution rate of over 90% within 2 h. The SAS process system may be used to enhance solubility or to produce oral dosage forms with high dissolution rate.     

Effect of physiochemical variables on phase solubility and dissolution behavior of indomethacin solid dispersion system

To study the influence of temperature and pH on solubility and dissolution behavior of indomethacin solid dispersions were prepared using several classes of hydrophilic carriers. Investigations on dissolution of indomethacin in binary system are reported earlier. However the phase solubility and dissolution behavior at different pH and temperature left void. The present investigation includes: phase solubility study at various pH; preparation of solid dispersion by solvent evaporation, melting and kneading method; characterization of various blends by dissolution study, and solid state studies to ensure interaction of drug with carrier. The binding between drug and carriers (PVP K30, βCD and PEG) was explained by thermodynamic parameters as calculated from phase solubility study. Indomethacin in association with PVP K30 showed very high apparent binding constant (Ka) and Gibb’s free energy change (?G) in comparison to other blends. The ternary system (drug:βCD:PVP K30, 1:5:1) showed better dissolution of about 80.97 and 99 % at pH 7.2 after 5 and 30 min respectively. At higher proportion of carrier (1:9) in binary solid dispersion of drug and PVP K30, drug dissolution was 96.23 and 97.85 % after 5 and 30 min respectively. This raised solubility of indomethacin would be helpful in designing a dosage form.     

Enhanced kinetic solubility profiles of indomethacin amorphous solid dispersions in poly(2-hydroxyethyl methacrylate) hydrogels

The feasibility of forming solid molecular dispersions of poorly water-soluble drugs in crosslinked poly(2-hydroethyl methacrylate) (PHEMA) hydrogel has recently been reported by our group. The purpose of the present study is to investigate the extent of enhancement of kinetic solubility of amorphous solid dispersions (ASDs) of indomethacin (IND) in crosslinked PHEMA hydrogels as compared with those based on conventional water-soluble polymer carriers. Our results show that under non-sink conditions, the initial solubility enhancement is higher for ASDs based on polyvinylpyrrolidone (PVP) and hydroxypropylmethylcellulose acetate succinate (HMPCAS), but the ability to maintain this solubility enhancement at longer times is better for ASDs based on PHEMA over a period of 24h with the extent of solubility enhancement of IND ASDs in PHEMA falling between those in PVP and HPMCAS at 10.0% IND loading after 6h and outperforming those in PVP and HPMCAS at 32.9% IND loading after 8h. The observed kinetic solubility profiles reflect the fact that the amorphous IND is released from PHEMA by a different mechanism than those from water-soluble polymer carriers. In this case, the dissolution of IND ASD from water-soluble PVP and HPMCAS is almost instantaneous, resulting in an initial surge of IND concentration followed by a sharp decline due to the nucleation and crystallization events triggered by the rapid build-up of drug supersaturation. On the other hand, the dissolution of IND ASD from insoluble crosslinked PHEMA hydrogel beads is less rapid as it is regulated by a feedback-controlled diffusion mechanism, thus avoiding a sudden surge of supersaturation in the dissolution medium. The absence of an apparent decline in drug concentration during dissolution from IND-PHEMA ASD further reflects the diminished nucleation and crystallization events during IND dissolution from hydrogel-based solid molecular dispersions. Based on the XRD analyses, a threshold IND loading level of about 34% in PHEMA has been identified, above which amorphous to crystalline transition tends to occur. Also, by selecting the appropriate particle sizes, immediate to controlled release of IND from IND-PHEMA ASD can be readily achieved as the release rate increases with decreasing PHEMA bead size. Furthermore, a robust physical stability has been demonstrated in IND-PHEMA ASD with no drug precipitation for up to 8 months at IND loadings below 16.7% under direct open cup exposure to accelerated stability conditions (40°C/75% RH).     

Dissolution of artemisinin/polymer composite nanoparticles fabricated by evaporative precipitation of nanosuspension

Objectives An evaporative precipitation of nanosuspension (EPN) method was used to fabricate composite particles of a poorly water‐soluble antimalarial drug, artemisinin, with a hydrophilic polymer, polyethylene glycol (PEG), with the aim of enhancing the dissolution rate of artemisinin. We investigated the effect of polymer concentration on the physical, morphological and dissolution properties of the EPN‐prepared artemisinin/PEG composites. Methods The original artemisinin powder, EPN‐prepared artemisinin nanoparticles and artemisinin/PEG composites were characterised by scanning electron microscopy, Fourier‐transform infrared spectroscopy, differential scanning calorimetry (DSC), X‐ray diffraction (XRD), dissolution testing and HPLC. The percentage dissolution efficiency, relative dissolution, time to 75% dissolution and mean dissolution time were calculated. The experimental drug dissolution data were fitted to various mathematical models (Weibull, first‐order, Korsemeyer–Peppas, Hixson–Crowell cube root and Higuchi models) in order to analyse the release mechanism. Key findings The DSC and XRD studies suggest that the crystallinity of the EPN‐prepared artemisinin decreased with increasing polymer concentration. The phase‐solubility studies revealed an A_L‐type curve, indicating a linear increase in drug solubility with PEG concentration. The dissolution rate of the EPN‐prepared artemisinin and artemisinin/PEG composites increased markedly compared with the original artemisinin powder. Conclusions EPN can be used to prepare artemisinin nanoparticles and artemisinin/PEG composite particles that have a significantly enhanced dissolution rate. The mechanism of drug release involved diffusion and erosion.     

Spherical crystals of celecoxib to improve solubility, dissolution rate and micromeritic properties

Celecoxib spherical agglomerates were prepared with polyvinylpyrrolidone (PVP) using acetone, water and chloroform as solvent, non-solvent and bridging liquid, respectively. The agglomerates were characterized by differential scanning calorimetry (DSC), X-ray diffraction (XRD), IR spectroscopic studies and scanning electron microscopy (SEM). The IR spectroscopy and DSC results indicated the absence of any interactions between drug and additives. XRD studies showed a decrease in crystallinity in agglomerates. The crystals exhibited significantly improved micromeritic properties compared to pure drug. The loading efficiency (% or mg drug per 100 mg crystals) was in the range of 93.9 +/- 2.3 and 97.3 +/- 1.3% (n = 3) with all formulations. The aqueous solubility and dissolution rate of the drug from crystals was significantly (p < 0.05) increased (nearly two times). The solubility and in vitro drug release rates increased with an increase in PVP concentration (from 2.5 to 10%). The SEM studies showed that the crystal posseses a good spherical shape with smooth and regular surface.     

Improving the solubility of ampelopsin by solid dispersions and inclusion complexes

The aim of this study was to increase the solubility of ampelopsin (AMP) in water by two systems: solid dispersions with polyethylene glycol 6000 (PEG 6000) or polyvinylpyrrolidone K-30 (PVP K30) and inclusion complexes with beta-cyclodextrin (BCD) and hydroxypropyl-beta-cyclodextrin (HPBCD). The interaction of AMP with the hydrophilic polymers was evaluated by differential scanning calorimetry (DSC), Fourier transformation-infrared spectroscopy (FTIR), scanning electron microscopy (SEM). The results from DSC, FTIR and SEC analyses of solid dispersions and inclusion complexes showed that AMP might exist as an amorphous state or as a solid solution. On the other hand, the SEM images of the physical mixtures revealed that to some extent the drug was present in a crystalline form. The influence of various factors (pH, temperature, type of polymer, ration of the drug to polymer) on the solubility and dissolution rate of the drug were also evaluated. The solubility and dissolution rates of AMP were significantly increased by solid dispersions and cyclodextrin complexes as well as their physical mixtures. The improvement of solubility using polymers was in the following order: HPBCD approximately BCD>PVP K30>PEG 6000.     

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.     

芒果苷PVP固体分散体的制备和表征及在体外肠道菌群模型中的代谢

目的：制备芒果苷（MGF）聚乙烯吡咯烷酮（PVP）固体分散体（MGF-SD）,提高MGF的溶解度和溶出速度,并对比考察MGF、MGF-SD在体外肠道菌群模型中的代谢差异。方法：以PVP为载体材料,采用共沉淀法制备MGF固体分散体,通过差示扫描量热法（DSC）、X射线粉末衍射法（XRD）和红外光谱（IR）表征其物相特征。采用摇瓶法测定MGF、MGF-SD溶解度。采集健康志愿者新鲜粪便,制备肠道菌群混悬液,分别与MGF、MGF-SD在厌氧环境下孵育,HPLC法监测MGF含量变化。结果：当MGF与PVP的质量比分别为1∶2,1∶4,1∶9时,MGF溶解度分别提高了432,513,633倍。DSC、XRD和IR均显示,MGF-SD中MGF晶体结构发生破坏,以非晶状态存在。体外释放度测定结果表明,MGF-SD中MGF释放速度快于MGF原料。与MGF原料相比,MGF制备成固体分散体后,离体人肠道菌群对MGF的代谢速度降低。结论：MGF制备成PVP固体分散体后,MGF以非晶型分子状态高度分散在载体材料中,MGF溶出度与溶解度显著提高,同时可减慢肠道菌群对MGF的代谢,有利于提高MGF口服生物利用度。     

Microcrystallization of indomethacin using a pH-shift method

This study developed a microcrystallization process for indomethacin, a nonsteroidal anti-inflammatory drug (NSAID), using a pH-shift method in aqueous solution. The physicochemical properties of the microcrystals produced were similar to those of the standard crystalline powder in X-ray diffraction (XRD), differential scanning calorimetry (DSC), and Fourier transform infrared spectroscopy (FT-IR) analyses, except for a lower XRD peak height and a slightly lower melting temperature (Tm) (1.5 degrees C). Phase contrast microscopy and scanning electron microscopy (SEM) showed that the indomethacin microcrystals were plate-like with a uniform size distribution (mean diameter =10.4+/-0.4 microm). In the initial phase, the dissolution rate of the indomethacin microcrystals was about 2.2 times higher than that of the standard crystalline powder. The biological activity of the indomethacin microcrystals was about 20% higher than that of the standard crystalline powder in their ability to inhibit the proliferation of colon cancer cells (HT-29).     

Intraorally fast-dissolving particles of a poorly soluble drug: Preparation and in vitro characterization

In this study, the dissolution rate of a poorly soluble drug, perphenazine (PPZ) was improved by a solid dispersion technique to permit its usage in intraoral formulations. Dissolution of PPZ (4 mg) in a small liquid volume (3 ml, pH 6.8) within one minute was set as the objective. PVP K30 and PEG 8000 were selected for carriers according to the solubility parameter approach and their 5/1, 1/5 and 1/20 mixtures with PPZ (PPZ/polymer w/w) were prepared by freeze-drying from 0.1 N HCl solutions. The dissolution rate of PPZ was improved with all drug/polymer mixture ratios compared to crystalline or micronized PPZ. A major dissolution rate improvement was seen with 1/5 PPZ/PEG formulation, i.e. PPZ was dissolved completely within one minute. SAXS, DSC and XRPD measurements indicated that solid solutions of amorphous PPZ in amorphous PVP or in partly amorphous PEG were formed. DSC and FTIR studies suggested that PPZ dihydrochloride salt was formed and hydrogen bonding was occurred between PPZ and the polymers. It was concluded that molecular mixing together with salt formation promoted the dissolution of PPZ, especially in the case of the 1/5 PPZ/PEG dispersion, making it a promising candidate for use in intraoral formulations.