Stability of Extruded 17β-Estradiol Solid Dispersions

Recrystallization is one of the main problems concerning the stability of solid dispersions. Different analytical methods were applied showing that no recrystallization occurred after treating melt extruded solid dispersions with 17β-Estradiol as the model drug with heat or water vapor. A skillful choice of excipients—a combination of polymers and additives—could be the reason for improving the stability. The requirements of the USP 23 for Estradiol tablets of 75% dissolved drug after 60 min were fulfilled after storing the tablets for 6 months at 40°C/75% RH. By observing the change in glass transition temperature, DSC analysis showed that the solid dispersions were stable against thermal stress. Isothermal microcalorimetry as well as moisture absorption gravimetry were methods to prove the stability of the solid dispersions against water vapor.     

Melt extrusion--an alternative method for enhancing the dissolution rate of 17beta-estradiol hemihydrate.

17Beta-estradiol hemihydrate (17beta-E2) is a poorly water-soluble drug. Physical methods for improving the solubility and dissolution rate, e.g. micronization, have certain inherent disadvantages. The method of choice in this study, melt extrusion, proved to overcome many of the shortcomings of conventional methods. Different compositions of excipients such as PEG 6000, PVP (Kollidon 30) or a vinylpyrrolidone-vinylacetate-copolymer (Kollidon VA64) were used as polymers and Sucroester WE15 or Gelucire 44/14 as additives during melt extrusion. The solid dispersions resulted in a significant increase in dissolution rate when compared to the pure drug or to the physical mixtures. For example, a 30-fold increase in dissolution rate was obtained for a formulation containing 10% 17beta-E2, 50% PVP and 40% Gelucire 44/14. The solid dispersions were then processed into tablets. The improvement in the dissolution behavior was also maintained with the tablets. The USP XXIII requirement for estradiol tablets reaching greater than 75% drug dissolved after 60 min was obtained in this investigation.     

Characteristics of rofecoxib-polyethylene glycol 4000 solid dispersions and tablets based on solid dispersions

The aim of this work was to report the properties of rofecoxib-PEG 4000 solid dispersions and tablets prepared using rofecoxib solid dispersions. Rofecoxib is a poorly water soluble nonsteroidal anti-inflammatory drug with a poor dissolution profile. This work investigated the possibility of developing rofecoxib tablets, allowing fast, reproducible, and complete rofecoxib dissolution, by using rofecoxib solid dispersion in polyethylene glycol (PEG) 4000. Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), X-ray diffraction (XRD) and scanning electron microscopy (SEM) were used to characterize the solid state of solid dispersions. The effect of PEG 4000 concentration on the dissolution rate of rofecoxib from its solid dispersions was investigated. The dissolution rate of rofecoxib from its solid dispersions increased with an increasing amount of PEG 4000. The extent of dissolution rate enhancement was estimated by calculating the mean dissolution time (MDT) values. The MDT of rofecoxib decreased significantly after preparing its solid dispersions with PEG 4000. The FTIR spectroscopic studies showed the stability of rofecoxib and absence of well-defined rofecoxib-PEG 4000 interaction. The DSC and XRD studies indicated the amorphous state of rofecoxib in solid dispersions of rofecoxib with PEG 4000. SEM pictures showed the formation of effective solid dispersions of rofecoxib with PEG 4000 since well-defined change in the surface nature of rofecoxib and solid dispersions were observed. Solid dispersions formulation with highest drug dissolution rate (rofecoxib: PEG 4000 1:10 ratio) was used for the preparation of solid dispersion-based rofecoxib tablets by the direct compression method. Solid dispersion-based rofecoxib tablets obtained by direct compression, with a hardness of 8.1 Kp exhibited rapid drug dissolution and produced quick anti-inflammatory activity when compared to conventional tablets containing pure rofecoxib at the same drug dosage. This indicated that the improved dissolution rate and quick anti-inflammatory activity of rofecoxib can be obtained from its solid dispersion-based oral tablets.     

Characteristics of Rofecoxib-Polyethylene Glycol 4000 Solid Dispersions and Tablets Based on Solid Dispersions

The aim of this work was to report the properties of rofecoxib-PEG 4000 solid dispersions and tablets prepared using rofecoxib solid dispersions. Rofecoxib is a poorly water soluble nonsteroidal anti-inflammatory drug with a poor dissolution profile. This work investigated the possibility of developing rofecoxib tablets, allowing fast, reproducible, and complete rofecoxib dissolution, by using rofecoxib solid dispersion in polyethylene glycol (PEG) 4000. Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), X-ray diffraction (XRD) and scanning electron microscopy (SEM) were used to characterize the solid state of solid dispersions. The effect of PEG 4000 concentration on the dissolution rate of rofecoxib from its solid dispersions was investigated. The dissolution rate of rofecoxib from its solid dispersions increased with an increasing amount of PEG 4000. The extent of dissolution rate enhancement was estimated by calculating the mean dissolution time (MDT) values. The MDT of rofecoxib decreased significantly after preparing its solid dispersions with PEG 4000. The FTIR spectroscopic studies showed the stability of rofecoxib and absence of well-defined rofecoxib-PEG 4000 interaction. The DSC and XRD studies indicated the amorphous state of rofecoxib in solid dispersions of rofecoxib with PEG 4000. SEM pictures showed the formation of effective solid dispersions of rofecoxib with PEG 4000 since well-defined change in the surface nature of rofecoxib and solid dispersions were observed. Solid dispersions formulation with highest drug dissolution rate (rofecoxib: PEG 4000 1:10 ratio) was used for the preparation of solid dispersion–based rofecoxib tablets by the direct compression method. Solid dispersion–based rofecoxib tablets obtained by direct compression, with a hardness of 8.1 Kp exhibited rapid drug dissolution and produced quick anti-inflammatory activity when compared to conventional tablets containing pure rofecoxib at the same drug dosage. This indicated that the improved dissolution rate and quick anti-inflammatory activity of rofecoxib can be obtained from its solid dispersion–based oral tablets.     

Dissolution, stability, and absorption characteristics of dicumarol in polyethylene glycol 4000 solid dispersions

The dissolution characteristics of dicumarol were markedly enhanced by preparing dispersions of drug in polyethylene glycol 4000. Solid dispersions of varying weight fractions were formed by a melt method without measurable drug degradation or evaporation. There were no significant differences in dissolution rates among weight fractions, with dynamic solubilities being approximately 2.5 times greater than dicumarol's equilibrium solubility. No indications of drug polymer complexation were noted from equilibrium or in situ absorption experiments. Incorporation of solid dispersions into direct compression tablets provided dosage forms with fast-release properties relative to test tablets of physical mixtures and a commercially available product. Percentages dissolved in 30 min were 370% greater for 1:3 and 1:5 (w/w) solid dispersion tablets compared to a commercial tablet at 37 degrees with a pH 7.5 dissolution buffer. X-ray diffraction of test powder revealed that the crystalline nature of the drug had altered during fusion preparation. Dissolution traits and drug stability for solid dispersions were maintained over 1 year of storage.     

Characterization of a cyclosporine solid dispersion for inhalation

For lung transplant patients, a respirable, inulin-based solid dispersion containing cyclosporine A (CsA) has been developed. The solid dispersions were prepared by spray freeze-drying. The solid dispersion was characterized by water vapor uptake, specific surface area analysis, and particle size analysis. Furthermore, the mode of inclusion of CsA in the dispersion was investigated with Fourier transform infrared spectroscopy. Finally, the dissolution behavior was determined and the aerosol that was formed by the powder was characterized. The powder had large specific surface areas (~ 160 m(2)). The water vapor uptake was dependant linearly on the drug load. The type of solid dispersion was a combination of a solid solution and solid suspension. At a 10% drug load, 55% of the CsA in the powder was in the form of a solid solution and 45% as solid suspension. At 50% drug load, the powder contained 90% of CsA as solid suspension. The powder showed excellent dispersion characteristics as shown by the high emitted fraction (95%), respirable fraction (75%), and fine-particle fraction (50%). The solid dispersions consisted of relatively large (x(50) approximately 7 mum), but low-density particles (rho approximately 0.2 g/cm(3)). The solid dispersions dissolved faster than the physical mixture, and inulin dissolved faster than CsA. The spray freeze-drying with inulin increased the specific surface area and wettability of CsA. In conclusion, the developed powder seems suitable for inhalation in the local treatment of lung transplant patients.     

Comparison of HPMC based polymers performance as carriers for manufacture of solid dispersions using the melt extruder

Preparation of amorphous solid dispersions using hot-melt extrusion process for poorly water soluble compounds which degrade on melting remains a challenge due to exposure to high temperatures. The aim of this study was to develop a physically and chemically stable amorphous solid dispersion of a poorly water-soluble compound, NVS981, which is highly thermal sensitive and degrades upon melting at 165 °C. Hydroxypropyl Methyl Cellulose (HPMC) based polymers; HPMC 3cps, HPMC phthalate (HPMCP) and HPMC acetyl succinate (HPMCAS) were selected as carriers to prepare solid dispersions using hot melt extrusion because of their relatively low glass transition temperatures. The solid dispersions were compared for their ease of manufacturing, physical stability such as recrystallization potential, phase separation, molecular mobility and enhancement of drug dissolution. Two different drug loads of 20 and 50% (w/w) were studied in each polymer system. It was interesting to note that solid dispersions with 50% (w/w) drug load were easier to process in the melt extruder compared to 20% (w/w) drug load in all three carriers, which was attributed to the plasticizing behavior of the drug substance. Upon storage at accelerated stability conditions, no phase separation was observed in HPMC 3cps and HPMCAS solid dispersions at the lower and higher drug load, whereas for HPMCP, phase separation was observed at higher drug load after 3 months. The pharmaceutical performance of these solid dispersions was evaluated by studying drug dissolution in pH 6.8 phosphate buffer. Drug release from solid dispersion prepared from polymers used for enteric coating, i.e. HPMCP and HPMCAS was faster compared with the water soluble polymer HPMC 3cps. In conclusion, of the 3 polymers studied for preparing solid dispersions of thermally sensitive compound using hot melt extrusion, HPMCAS was found to be the most promising as it was easily processible and provided stable solid dispersions with enhanced dissolution.     

Physical stability of solid dispersions of the antiviral agent UC-781 with PEG 6000, Gelucire 44/14 and PVP K30

This paper describes the physical stability of solid dispersions of UC-781 with PEG 6000, Gelucire 44/14 and PVP K30 prepared by the solvent and melting methods. The concentration of the drug in the solid dispersions ranged from 5 to 80% w/w. The solid dispersions were stored at 4-8 and 25 degrees C (25% RH), then their physicochemical properties were analysed by differential scanning calorimetry (DSC), X-ray powder diffraction and dissolution studies as a function of storage time. The DSC curves of solid dispersions of UC-781 with PVP K30 did not show any melting peaks corresponding to UC-781 after storage, indicating no recrystallization of the drug. The DSC data obtained from PEG 6000 and Gelucire 44/14 showed some variations in melting peak temperatures and enthalpy of fusion of the carriers. It was shown that the enthalpy of fusion of PEG 6000 in the dispersions increased after storage; it was more pronounced for samples stored at 25 degrees C compared to those at 4-8 degrees C indicating the reorganization of the crystalline domains of the polymer. Similarly, the enthalpy of fusion of Gelucire 44/14 in the solid dispersions increased as a function of time. Dissolution of UC-781 from all solid dispersions decreased as a function of storage time. While these observations concurred with the DSC data for all solid dispersions, they were not reflected by X-ray powder diffraction data. It was concluded that it is the change of the physical state of the carriers and not that of the drug, which is responsible for the decreased dissolution properties of the solid dispersions investigated.     

盐酸溴己新缓释片的制备及体外释放度研究

目的制备盐酸溴已新（Bromhexine hydrochloride．BH）缓释片。方法以聚乙烯毗咯烷酮（PVP）为载体。将盐酸溴己新制成固体分散体．再以羟丙甲基纤维素（HPMC）为骨架材料,采用湿法制粒压片制备盐酸溴己新缓释片,并进行体外释放度试验。结果所制备的缓释片12h内呈现良好的缓释特性,符合Higuchi方程。结论盐酸澳己新缓释片体外释药缓慢、平稳,符合设计要求。     

Moisture-Induced Amorphous Phase Separation of Amorphous Solid Dispersions: Molecular Mechanism,Microstructure, and Its Impact on Dissolution Performance

Amorphous phase separation (APS) is commonly observed in amorphous solid dispersions (ASD) when exposed to moisture. The objective of this study was to investigate: (1) the phase behavior of amorphous solid dispersions composed of a poorly water-soluble drug with extremely low crystallization propensity, BMS-817399, and PVP, following exposure to different relative humidity (RH), and (2) the impact of phase separation on the intrinsic dissolution rate of amorphous solid dispersion. Drug-polymer interaction was confirmed in ASDs at different drug loading using infrared (IR) spectroscopy and water vapor sorption analysis. It was found that the drug-polymer interaction could persist at low RH (≤75% RH) but was disrupted after exposure to high RH, with the advent of phase separation. Surface morphology and composition of 40/60 ASD at micro-/nano-scale before and after exposure to 95% RH were also compared. It was found that hydrophobic drug enriched on the surface of ASD after APS. However, for the 40/60 ASD system, the intrinsic dissolution rate of amorphous drug was hardly affected by the phase behavior of ASD, which may be partially attributed to the low crystallization tendency of amorphous BMS-817399 and enriched drug amount on the surface of ASD. Intrinsic dissolution rate of PVP decreased resulting from APS, leading to a lower concentration in the dissolution medium, but supersaturation maintenance was not anticipated to be altered after phase separation due to the limited ability of PVP to inhibit drug precipitation and prolong the supersaturation of drug in solution. This study indicated that for compounds with low crystallization propensity and high hydrophobicity, the risk of moisture-induced APS is high but such phase separation may not have profound impact on the drug dissolution performance of ASDs. Therefore, application of ASD technology on slow crystallizers could incur low risks not only in physical stability but also in dissolution performance.     

Incorporation of lipophilic drugs in sugar glasses by lyophilization using a mixture of water and tertiary butyl alcohol as solvent

In this study, a new and robust method was evaluated to prepare physically stable solid dispersions. Trehalose, sucrose, and two inulins having different chain lengths were used as carrier. Diazepam, nifedipine, Delta(9)-tetrahydrocannabinol, and cyclosporine A were used as model drugs. The sugar was dissolved in water and the drug in tertiary butyl alcohol (TBA). The two solutions were mixed in a 4/6 TBA/water volume ratio and subsequently freeze dried. Diazepam could be incorporated at drug loads up to 63% w/w. DSC measurements showed that, except in some sucrose dispersions, 97-100% of the diazepam was amorphous. In sucrose dispersions with high drug loads, about 10% of the diazepam had crystallised. After 60 days of exposure at 20 degrees C and 45% relative humidity (RH), diazepam remained fully amorphous in inulin dispersions, whereas in trehalose and sucrose crystallization of diazepam occurred. The excellent physical stability of inulin containing solid dispersions can be attributed to the high glass transition temperature (T(g)) of inulin. For the other drugs similar results were obtained. The residual amount of the low toxic TBA was only 0.1-0.5% w/w after freeze drying and exposure to 45% RH and 20 degrees C. Therefore, residual TBA will not cause any toxicity problems. This study provides a versatile technique, to produce solid dispersions. Inulin glasses are preferred because they provide an excellent physical stability of the incorporated amorphous lipophilic drugs.     

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.     

Enhancement of dissolution rate of hydrochlorothiazide via solid dispersion

Solid dispersions of hydrochlorothiazide (1) in mannitol (2) and in dihydroxypropyltheophylline (3) were prepared by melting and solvent methods. For both systems, phase diagrams of simple eutectic type were obtained. A significant increase in dissolution rate was observed for 1/2 and 1/3 physical mixtures and solid dispersion as compared to pure drug. Solubility of 1 in 2 and in 3 solution at 27 degrees C and 37 degrees C was studied. At 37 degrees C the water solubility of the drug increased 3.7 times using 0.4 mol X 1(-1) 3. The solubilization of the drug by 3 in water was due to the formation 1 : 1 soluble complex. 1 tablets from physical mixtures and solid dispersion were prepared. Effect of ageing on the physical properties of the prepared 1 tablets was investigated.     

Fast-dissolving tablets of glyburide based on ternary solid dispersions with PEG 6000 and surfactants

Marketed glyburide tablets present unsatisfying dissolution profiles that give rise to variable bioavailability. With the purpose of developing a fast-dissolving tablet formulation able to assure a complete drug dissolution, we investigated the effect of the addition to a reference tablet formulation of different types (anionic and nonionic) and amounts of hydrophilic surfactants, as well as the use of a new technique, based on ternary solid dispersions of the drug with an hydrophilic carrier (polyethylene glycol [PEG] 6000) and a surfactant. Tablets were prepared by direct compression or previous wet granulation of suitable formulations containing the drug with each surfactant or drug:PEG:surfactant ternary dispersions at different PEG:surfactant w/w ratios. The presence of surfactants significantly increased (p<0.01) the drug dissolution rate, but complete drug dissolution was never achieved. On the contrary, in all cases tablets containing ternary solid dispersions achieved 100% dissolved drug within 60 min. The best product was the 10:80:10 w/w ternary dispersion with PEG 6000 and sodium laurylsulphate, showing a dissolution efficiency 5.5-fold greater than the reference tablet formulation and 100% drug dissolution after only 20 min.     

Effect of drug-carrier interaction on the dissolution behavior of solid dispersion tablets

The objective of this study was to compare the dissolution behavior of tablets prepared from solid dispersions with and without drug-carrier interactions. Diazepam and nifedipine were used as model drugs. Two types of carriers were used; polyvinylpyrrolidone (PVP K12, K30 and K60) and saccharides (inulin 1.8?kDa, 4?kDa and 6.5?kDa). Solid dispersions with various drug loads were prepared by lyophilization. It was found that the drug solubility in aqueous PVP solutions was significantly increased indicating the presence of drug-carrier interaction while the drug solubility was not affected by the saccharides indicating absence of drug-carrier interaction. X-ray powder diffraction and modulated differential scanning calorimetry revealed that all solid dispersions were fully amorphous. Dissolution behavior of solid dispersion tablets based on either the PVPs or saccharides was governed by both dissolution of the carrier and drug load. It was shown that a fast drug dissolution of solid dispersions with a high drug load could be obtained with carrier that showed interaction with the drug.     

联苯双酯的共沉淀物和固体分散物的制备及其对湿度的稳定性

联苯双酯从它的PVP共沉淀物和它的PEG4000、PEG6000的固体分散物中的体外溶出速率明显高于市售片剂(P<0.01),非离子表面活性剂对联苯双酯的共沉淀物和固体分散物体外溶出速率几乎无影响,联苯双酯的固体分散物对湿度(75%RH,40℃)的稳定性高于其共沉淀物。     

Compaction of lactose drug mixtures: quantification of the extent of incompatibility by FT-Raman spectroscopy.

It is well known that lactoses interact with drugs containing amino groups and undergo the Maillard reaction. Lactose monohydrate may also interact with moisture sensitive drugs and affect the stability of the drug. These interactions were analyzed using three model drugs - Thiaminchloride hydrochloride, Nicotinamide and Acetylsalicylic acid - which interact with spray-dried lactose or anhydrous lactose. FT-Raman spectroscopy was used for the first time to qualitatively and quantitatively analyze these excipient drug interactions in powders and tablets. Both lactoses undergo the Maillard reaction with Thiaminchloride hydrochloride. Nicotinamide did not react with the lactoses because the amide group is protected against the reaction with the lactoses. Only a transition from beta- to alpha-lactose was noticed. The moisture sensitive drug Acetylsalicylic acid remained stable even when the tablets were stored under accelerated conditions (40 degrees C and 75% RH). The crystal water of lactose monohydrate (spray-dried lactose) had no influence on the drug stability but a transition from beta- to alpha-lactose was noticed. In conclusion, FT-Raman spectroscopy is a fast and valuable tool for a quantitative determination of the extents of incompatibility in solid dosage forms.     

Improving the dissolution rate of poorly water soluble drug by solid dispersion and solid solution: pros and cons

The solid dispersions with poloxamer 188 (P188) and solid solutions with polyvinylpyrrolidone K30 (PVPK30) were evaluated and compared in an effort to improve aqueous solubility and bioavailability of a model hydrophobic drug. All preparations were characterized by differential scanning calorimetry, powder X-ray diffraction, intrinsic dissolution rates, and contact angle measurements. Accelerated stability studies also were conducted to determine the effects of aging on the stability of various formulations. The selected solid dispersion and solid solution formulations were further evaluated in beagle dogs for in vivo testing. Solid dispersions were characterized to show that the drug retains its crystallinity and forms a two-phase system. Solid solutions were characterized to be an amorphous monophasic system with transition of crystalline drug to amorphous state. The evaluation of the intrinsic dissolution rates of various preparations indicated that the solid solutions have higher initial dissolution rates compared with solid dispersions. However, after storage at accelerated conditions, the dissolution rates of solid solutions were lower due to partial reversion to crystalline form. The drug in solid dispersion showed better bioavailability in comparison to solid solution. Therefore, considering physical stability and in vivo study results, the solid dispersion was the most suitable choice to improve dissolution rates and hence the bioavailability of the poorly water soluble drug.     

Enhanced release of oxazepam from tablets containing solid dispersions

Solid dispersions of different ratios of Gelita collagel as the carrier and lactose were prepared by the spray drying method. Dissolution studies have shown that by preparing solid dispersions the dissolution rate and the solubility of oxazepam increase markedly, independent of the ratio of drug, carrier and lactose. The properties of the solid dispersions were characterized by X-ray diffraction and polarizing microscopic studies. An amorphous form of all prepared solid dispersions were indicated in X-ray studies. Tablets of solid dispersions of oxazepam/Gelita Collagel, physical mixtures and the drug alone were prepared. The best results from the dissolution test were obtained for tablets containing solid dispersions. They remained in good physical properties when stored for one year in normal conditions.     

Characterization of moisture-protective polymer coatings using differential scanning calorimetry and dynamic vapor sorption

The aim of this study was to evaluate the moisture-protective ability of different polymeric coatings. Free films and film-coated tablets (with cores containing freeze-dried garlic powder) were prepared using aqueous solutions/dispersions of hydroxypropyl methylcellulose (HPMC), Opadry AMB [a poly(vinylalcohol)-based formulation] and Eudragit E PO [a poly(methacrylate-methylmethacrylate)]. The water content of the systems upon open storage at 75% relative humidity (RH) and 22 degrees C (room temperature) was followed gravimetrically. Furthermore, polymer powders, free films and coated tablets were analyzed by differential scanning calorimetry (DSC) and dynamic vapor sorption (DVS). The type of polymer strongly affected the resulting water uptake kinetics of the free films and coated tablets. DSC analysis revealed whether or not significant physical changes occurred in the coatings during storage, and whether the water vapor permeability was water concentration dependent. Using DVS analysis the critical glass transition RH of Opadry AMB powder and Opadry AMB-coated tablets at 25 degrees C could be determined: 44.0% and 72.9% RH. Storage below these threshold values significantly reduces water penetration. Thus, DVS and DSC measurements can provide valuable information on the nature of polymers used for moisture protection.