Characterization of ternary solid dispersions of itraconazole, PEG 6000, and HPMC 2910 E5

In order to reduce the crystallinity of PEG 6000, blends were prepared by spray drying and extrusion with the following polymers; PVP K25, PVPVA 64, and HPMC 2910 E5. The maximal reduction of crystallinity in PEG 6000 was obtained by co-spray drying with HPMC 2910 E5. In the next step the model drug Itraconazole was added to the blend and the resulting ternary solid dispersions were characterized. The results of this study show that the addition of PEG 6000 to the Itraconazole/HPMC 2910 E5 system leads to phase separation that in most cases gives rise to recrystallization of either PEG 6000 or Itraconazole. For all ternary dispersions containing 20% of Itraconazole the drug was highly amorphous and the dissolution was improved compared to the binary 20/80 w/w Itraconazole/HPMC 2910 E5 solid dispersion. For all ternary dispersions containing 40% of Itraconazole, the drug was partially crystalline and the dissolution was lower than the dissolution of the binary 40/60 w/w Itraconazole/HPMC 2910 E5 dispersion. These results show that provided Itraconazole is highly amorphous the addition of PEG 6000 to HPMC 2910 E5 leads to an increase in drug release.     

Formulation and characterization of ternary solid dispersions made up of Itraconazole and two excipients, TPGS 1000 and PVPVA 64, that were selected based on a supersaturation screening study

Both d--tocopheryl polyethylene glycol 1000 (TPGS 1000) and polyvidone-vinylacetate 64 (PVPVA 64) provided an increase in the degree of supersaturation and stability of supersaturated Itraconazole solutions, compared to a blanc without excipient. Therefore, both components were combined as carrier in order to make ternary solid dispersions of Itraconazole by spray drying. This way, TPGS 1000 could be incorporated into a powder. Dissolution experiments on the ternary solid dispersions revealed that during the first hour the release was much higher than for the binary Itraconazole/PVPVA 64 solid dispersions. For some compositions a release of more than 80% was reached after 10 min. However, after the first hour the drug started to precipitate. The ternary solid dispersions were all XRD amorphous, but MDSC revealed the coexistence of multiple amorphous phases and a crystalline Itraconazole phase, depending on the composition. Therefore the burst effect during the first hour can be ascribed to an accelerated dissolution of the amorphous Itraconazole fraction in the presence of TPGS 1000. The precipitation after 1 h, however, is probably due to the combination of the surfactant properties of TPGS and the small crystalline Itraconazole fraction.     

Increased physical stability and improved dissolution properties of itraconazole, a class II drug, by solid dispersions that combine fast- and slow-dissolving polymers

Solid dispersions were prepared of itraconazole-Eudragit E100, itraconazole-PVPVA64, and itraconazole-Eudragit E100/PVPVA64 using a corotating twin-screw hot-stage extruder. Modulated temperature differential scanning calorimetry (MTDSC) was used to evaluate the miscibility of the extrudates, and dissolution experiments were performed in simulated gastric fluid without pepsin (SGF(sp)). Itraconazole and Eudragit E100 are miscible up to 13% w/w drug loading. From that concentration on, phase separation is observed. Pharmaceutical performance of this dispersion was satisfactory because 80% of the drug dissolved after 30 min. Extrudates of itraconazole and PVPVA64 were completely miscible but the pharmaceutical performance was low, with 45% of drug dissolved after 3 h. Combination of both polymers in different ratios, with a fixed drug loading of 40% w/w, was evaluated. MTDSC results clearly indicated a two-phase system consisting of itraconazole-Eudragit E100 and itraconazole-PVPVA64 phases. In these extrudates, no free crystalline or glassy clusters of itraconazole were observed; all itraconazole was mixed with one of both polymers. The pharmaceutical performance was tested in SGF(sp) for different polymer ratios, and Eudragit E100/PVPVA64 ratios of 50/50 and 60/40 showed significant increases in dissolution rate and level. Polymer ratios of 70/30 and 80/20, on the other hand, had a release of 85% after 30 min. Precipitation of the drug was never observed. The combination of the two polymers provides a solid dispersion with good dissolution properties and improved physical stability compared with the binary solid dispersions of itraconazole.     

Formulation of fast disintegrating tablets of ternary solid dispersions consisting of TPGS 1000 and HPMC 2910 or PVPVA 64 to improve the dissolution of the anti-HIV drug UC 781

Solid dispersion formulations made up of d-alpha-tocopheryl polyethylene glycol succinate 1000 (TPGS 1000) and polyvinyl pyrrolidone co-vinyl acetate 64 (PVPVA 64) or hydroxy propyl methyl cellulose 2910 (HPMC 2910) were developed in order to improve the dissolution of UC 781. UC 781 dissolution rate was markedly improved as compared to the physical mixtures and the pure drug, attaining maximum drug releases of up to 100% after only 5 min in the case of TPGS 1000-UC 781-PVPVA 64 solid dispersions and 30 min in TPGS 1000-UC 781-HPMC 2910. The increased UC 781 dissolution rate could be maintained when formulating UC 781 in PVPVA 64 tablets. The latter disintegrated in only 4 min, reaching drug releases of up to 90% (w/w). In addition, as opposed to the corresponding solid dispersions, no decrease in drug release occurred upon dissolution of PVPVA 64 tablets when the pH was increased to 6.8. Contrary to the PVPVA 64 tablet formulations, HPMC 2910 tablets showed a slow dissolution process due to the gelling nature of the polymer. The drug was slowly released as HPMC 2910 dissolved in the medium, however also in this case 90% (w/w) of the drug was dissolved after 4 h. Both polymers formed compatible blends in combination with the drug. Thermal analysis of the ternary mixtures revealed eutectic behavior exhibiting an extremely fine dispersion of the drug in the carrier. This was confirmed by the fact that no drug crystals could be detected using X-ray diffraction (XRD). As opposed to the physical mixtures, PVPVA 64 and HPMC 2910 solid dispersions did not contain any isolated polymer-rich phases, hence showed improved homogeneity. Amorphous TPGS 1000 clusters occurred in PVPVA 64 and HPMC 2910 formulations upon addition of at least 10% (w/w) UC 781, showing extremely low glass transition temperatures depending of the thermal history of the samples.     

Improvement of the dissolution kinetics of SR 33557 by means of solid dispersions containing PEG 6000

Solid dispersions of SR 33557 in preparations containing from 30 to 80% w/w polyethylene glycol 6000 (PEG 6000) were prepared by the fusion method. The solubility of the drug substance either alone or in solid dispersions was determined in pH 1.2 and 4.5 media (extraction fluid NFXII, without enzyme). A large increase in the solubility was noted from the 80% w/w PEG preparation. A wettability study performed by measuring the contact angle on tablets of either drug substance or PEG 6000, or solid dispersions, revealed a minimal contact angle for the 80% w/w PEG 6000 solid dispersion (eutectic composition of SR 33557/PEG 6000 phase diagram). Dissolution kinetic analysis performed at pH 1.2 on all solid dispersions, on the physical mixtures containing 70 and 80% w/w PEG 6000, and on SR 33557 alone, showed a maximum release rate (100%) for the solid dispersions containing 70 and 80% w/w PEG 6000. The dissolution rate of the physical mixtures was faster than that of the drug substance alone but remained, however, lower than that of the solid dispersions, at the same composition. It was also observed that the dissolution rate, at pH 1.2 and 4.5, of the 70% w/w PEG 6000 solid dispersion was practically pH independent, which was not the case for the drug substance alone. The latter solid dispersion showed a slowing down of the dissolution kinetics after 3 months storage at 50°C whereas no change in the dissolution rate was observed following storage for 12 months at 25°C.     

Characterization and stability of solid dispersions based on PEG/polymer blends

Solid dispersions were prepared by a melting method from the water-insoluble model drugs carbamazepine and nifedipine and polyethylene glycol 1500 (PEG 1500) or 1:1 mixtures of PEG 1500 and the polymers polyvinylpyrrolidone (PVP 30, PVP 12), polyvinylpyrrolidone-co-vinylacetate (PVPVA) and Eudragit EPO (Eudragit) in order to combine advantages of the different carrier polymers (recrystallization inhibition, processability and stability). The solid dispersions were characterized by dissolution, powder X-ray diffractometry and microscopy directly after preparation and after storage for 3 and 6 months at 25 °C/0% relative humidity (RH) or 3 months at 40 °C/75% RH. More than 80% drugs were released from all solid dispersions within 20 min. The dissolution rate of carbamazepine decreased in the order of PEG 1500 > PEG 1500/Eudragit > PEG 1500/PVP 30 > PEG 1500/PVPVA > PEG 1500/PVP 12. The dissolution rank order was not directly correlated to the amorphous/crystalline state of the drugs, but rather to the properties of the PEG 1500/polymer compositions. Nifedipine was released in the order of PEG 1500 > PEG 1500/PVPVA > PEG 1500/PVP 30 > PEG 1500/PVP 12 > PEG 1500/Eudragit. Amorphous nifedipine was present in all PEG 1500/polymer dispersions except in pure PEG 1500 solid dispersion. The significant increase in dissolution rate of PEG 1500 solid dispersions was due to the reduced crystallinity of the drug and the excellent solubilisation properties of PEG 1500. After 6 months storage at 25 °C/0% RH, the solid dispersions released both drugs in the order PEG 1500/PVPVA > PEG 1500/PVP 30 > PEG 1500/PVP 12 > PEG 1500/Eudragit > PEG 1500. The stabilized amorphous state of the drug resulted in stable dissolution profiles of PEG 1500/PVPVA, PEG 1500/PVP 30 and PEG 1500/PVP 12 when compared to the PEG 1500 solid dispersions, which contained a higher amount of crystalline drug. The solid dispersions with PEG 1500/PVPVA or PEG 1500/PVP stored for 3 months at 40 °C/75% RH showed phase separation due to the hygroscopic properties of the polymers. The influence of 10% (w/w) of the solubilisers polyoxyl 40 hydrogenated castor oil (Cremophor), macrogol-15-hydroxystearate (Solutol) and fatty alcohol alkoxylate (Pluronic) on the dissolution rate and the physical state of the drug was significant.     

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.     

Physicochemical characterization of solid dispersions of the antiviral agent UC-781 with polyethylene glycol 6000 and Gelucire 44/14

The purpose of this study was to prepare and characterize solid dispersions of the antiviral thiocarboxanilide UC-781 with PEG 6000 and Gelucire 44/14 with the intention of improving its dissolution properties. The solid dispersions were prepared by the fusion method. Evaluation of the properties of the dispersions was performed using dissolution studies, differential scanning calorimetry, Fourier-transform infrared spectroscopy and X-ray powder diffraction. To investigate the possible formation of solid solutions of the drug in the carriers, the lattice spacings [d] of PEG 6000 and Gelucire 44/14 were determined in different concentrations of UC-781. The results obtained showed that the rate of dissolution of UC-781 was considerably improved when formulated in solid dispersions with PEG 6000 and Gelucire 44/14 as compared to pure UC-781. From the phase diagrams of PEG 6000 and Gelucire 44/14 it could be noted that up to approximately 25% w/w of the drug was dissolved in the liquid phase in the case of PEG 6000 and Gelucire 44/14. The data from the X-ray diffraction showed that the drug was still detectable in the solid state below a concentration of 5% w/w in the presence of PEG 6000 and Gelucire 44/14, while no significant changes in the lattice spacings of PEG 6000 or Gelucire 44/14 were observed. Therefore, the possibility of UC-781 to form solid solutions with the carriers under investigation was ruled out. The results from infrared spectroscopy together with those from X-ray diffraction and differential scanning calorimetry showed the absence of well-defined drug–polymer interactions.     

Influence of polyethylene glycol chain length on compatibility and release characteristics of ternary solid dispersions of itraconazole in polyethylene glycol/hydroxypropylmethylcellulose 2910 E5 blends

The present study aims to elucidate the influence of the polyethylene glycol chain length on the miscibility of PEG/HPMC 2910 E5 polymer blends, the influence of polymer compatibility on the degree of molecular dispersion of itraconazole, and in vitro dissolution. PEG 2000, 6000, 10,000 and 20,000 were included in the study. Solid dispersions were prepared by spray drying and characterized with MDSC, XRPD and in vitro dissolution testing. The polymer miscibility increased with decreasing chain length due to a decrease in the Gibbs free energy of mixing. Recrystallization of itraconazole occurred as soon as a critical temperature of ca. 75 degrees C was reached for the glass transition that represents the ternary amorphous phase. Due to the lower miscibility degree between the longer PEG types and HPMC 2910 E5, the ternary amorphous phase was further separated, leading to a more rapid decrease of the ternary amorphous phase glass transition as a function of PEG and itraconazole weight percentage and hence, itraconazole recrystallization. In terms of release, an advantage of the shorter chain length PEG types (2000, 6000) over the longer chain length PEG types (10,000, 20,000) was observed for the polymer blends with 5% of PEG with respect to the binary itraconazole/HPMC 2910 E5 solid dispersion. Among the formulations with a 15/85 (w/w) PEG/HPMC 2910 E5 ratio on the other hand, there was no difference in the release profile.     

Study of the physicochemical properties and stability of solid dispersions of loperamide and PEG6000 prepared by spray drying.

Solid dispersions of PEG6000 and loperamide-a poorly water-soluble agent-were prepared by spray drying. Their physicochemical properties were evaluated immediately after preparation. The dissolution was higher than that of pure crystalline loperamide. DSC- and XRD-measurements revealed that in the dispersions, loperamide is partially present in the crystalline state. A eutectic state diagram was obtained. The samples containing 20% loperamide were stored under different conditions (40 degrees C and 0% RH, 25 degrees C and 52% RH, 4 degrees C and 0% RH) to investigate their stability as a function of time. The dissolution properties deteriorate upon storage at high temperature (40 degrees C and 0% RH) and in conditions of higher relative humidity (25 degrees C and 52% RH). The DSC-curves clearly indicate an increase in the amount of crystalline compound under these conditions. From these observations it could be concluded that loperamide, which is partially crystalline and partially amorphous in the freshly prepared samples, continues to crystallize under these conditions, resulting in progressively poorer dissolution properties.     

Effect of particle size on the available surface area of nifedipine from nifedipine-polyethylene glycol 6000 solid dispersions

Solid dispersions containing 5%, 10%, 20%, 30% and 50% of nifedipine were prepared with polyethylene glycol (PEG) 6000 as carrier, respectively, by the fusion method. Drug release from four different size fractions of nifedipine-polyethylene glycol 6000 solid dispersions were examined. The probability parameters of Weibull distribution or log-normal distribution could be obtained from linear regression of the dissolution data. The effects of particle size on the dissolution rate of nifedipine were evaluated in terms of the time course of the available surface area (S(t)). The X-ray diffraction patterns showed that nifedipine was dispersed homogeneously in an amorphous state in the solid dispersions with nifedipine concentration up to 10%. The initial values and faster rate of decrease of S(t) during the dissolution process were markedly enhanced in the solid dispersions with lower contents of nifedipine (5% and 10%) due to the formation of high energy metastable (amorphous) states of the drug and differences in the particle sizes had little effect on the values of the available surface area and the dissolution of the drug. Values of available surface area were particle size dependent for the solid dispersions with higher contents of nifedipine (20%, 30% and 50%) and the rate of decrease of S(t) was enhanced as the particle size reduced.     

Evaluation of Polycaprolactone Matrices for Sustained Vaginal Delivery of Nevirapine in the Prevention of Heterosexual HIV Transmission

Nevirapine (NVP) was loaded in polycaprolactone (PCL) matrices to produce vaginal inserts with the aim of preventing HIV transmission. NVP dispersions in PCL were prepared, at 10% (w/w) theoretical loading, measured with respect to the PCL content of the matrices, in the form of (1) NVP only, (2) a physical mixture of NVP with polyethylene glycol (PEG) 6000 or (c) a solid dispersion (SD) with PEG produced by co-dissolution in ethanol. Characterisation of SD by differential scanning calorimetry and attenuated total reflectance–Fourier transform infrared spectroscopy suggested transformation of the crystalline structure of NVP to an amorphous form which consequently increased the dissolution rate of drug. A low-loading efficiency of 13% was obtained for NVP-loaded matrices and less than 20% for matrices prepared using physical mixtures of drug and PEG. The loading efficiency was improved significantly to around 40% when a 1:4 NVP–PEG SD was used for matrix production. After 30 days, 40% of the drug content was released from NVP-loaded matrices, 55% from matrices containing 1:4 NVP–PEG physical mixtures and 60% from matrices loaded with 1:4 NVP–PEG SDs. The in vitro anti-viral activity of released NVP was assessed using a luciferase reporter gene assay following the infection of HeLa cells with pseudo-typed HIV-1. NVP released from PCL matrices in simulated vaginal fluid retained over 75% anti-HIV activity compared with the non-formulated NVP control. In conclusion, 1:4 NVP–PEG SDs when loaded in PCL matrices increase drug loading efficiency and improve release behaviour.     

The use of a new hydrophilic polymer, Kollicoat IR, in the formulation of solid dispersions of Itraconazole.

Kollicoat IR, a new pharmaceutical excipient developed as a coating polymer for instant release tablets, was evaluated as a carrier in solid dispersions of Itraconazole. The solid dispersions were prepared by hot stage extrusion. Modulated temperature differential scanning calorimetry and X-ray powder diffraction were used to evaluate the miscibility of the drug and the carrier. The pharmaceutical performance was evaluated by dissolution experiments, performed in simulated gastric fluid without pepsin (SGF(sp)). In the X-ray diffractograms no Itraconazole peaks were visible; the polymer on the other hand appeared to be semi-crystalline. Moreover, its crystallinity increased during the extrusion process due to exposure to heat and shear forces. Modulated temperature differential scanning calorimetry analysis showed that the drug and the polymer formed a two phase system. Separate clusters of glassy Itraconazole were present for drug loads of 40% or higher, indicating further phase separation. Dissolution measurements demonstrated a significantly increased dissolution rate for the solid dispersions compared to physical mixtures. Interestingly the physical mixture made up of glassy Itraconazole and Kollicoat IR (20/80, w/w) showed a dissolution rate and maximum that was much higher than that of the physical mixture made up of crystalline Itraconazole and that of pure glassy Itraconazole. The results of this study show that Kollicoat IR is a promising excipient for the formulation of solid dispersions of Itraconazole prepared by hot stage extrusion.     

Amorphous Stabilization and Dissolution Enhancement of Amorphous Ternary Solid Dispersions: Combination of Polymers Showing Drug–Polymer Interaction for Synergistic Effects

The purpose of this study was to understand the combined effect of two polymers showing drug–polymer interactions on amorphous stabilization and dissolution enhancement of indomethacin (IND) in amorphous ternary solid dispersions. The mechanism responsible for the enhanced stability and dissolution of IND in amorphous ternary systems was studied by exploring the miscibility and intermolecular interactions between IND and polymers through thermal and spectroscopic analysis. Eudragit E100 and PVP K90 at low concentrations (2.5%–40%, w/w) were used to prepare amorphous binary and ternary solid dispersions by solvent evaporation. Stability results showed that amorphous ternary solid dispersions have better stability compared with amorphous binary solid dispersions. The dissolution of IND from the ternary dispersion was substantially higher than the binary dispersions as well as amorphous drug. Melting point depression of physical mixtures reveals that the drug was miscible in both the polymers; however, greater miscibility was observed in ternary physical mixtures. The IR analysis confirmed intermolecular interactions between IND and individual polymers. These interactions were found to be intact in ternary systems. These results suggest that the combination of two polymers showing drug–polymer interaction offers synergistic enhancement in amorphous stability and dissolution in ternary solid dispersions. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:3511–3523, 2014     

Influence of Glass Forming Ability on the Physical Stability of Supersaturated Amorphous Solid Dispersions

In this study, the influence of the glass-forming ability (GFA) of a drug on its physical stability in a supersaturated solid dispersion was investigated. Nine drugs were classified according to their GFA using their respective critical cooling rate. Their respective solubility in poly(vinylpyrrolidone-co-vinyl acetate) 6:4 (PVPVA64) was predicted using the melting point depression method based on the Flory-Huggins lattice theory. Supersaturated amorphous solid dispersions at a level of 25% w/w drug above saturation solubility in the polymer were prepared by film-casting, and their respective physical stability at temperatures of 10°C or 20°C above or below their respective T_g (dry conditions) was monitored by the use of polarized light microscopy. This study showed that drugs with good GFA (class 3) on average have higher physical stability in supersaturated amorphous solid dispersion compared to drug with modest GFA (class 2), which in turn have higher physical stability in supersaturated amorphous solid dispersion than drugs with poor GFA (class 1). These results indicate that the GFA of a drug and its physical stability in a supersaturated amorphous solid dispersion stored at a temperature above or below its T_g are correlated.     

Influence of Low-Molecular-Weight Excipients on the Phase Behavior of PVPVA64 Amorphous Solid Dispersions

Purpose

The oral bioavailability of poorly water-soluble active pharmaceutical ingredients (APIs) can be improved by the preparation of amorphous solid dispersions (ASDs) where the API is dissolved in polymeric excipients. Desired properties of such ASDs like storage stability, dissolution behavior, and processability can be optimized by additional excipients. In this work, the influence of so-called low-molecular-weight excipients (LMWEs) on the phase behavior of ASDs was investigated.

Method

Binary ASDs of an amorphous API, naproxen (NAP) or acetaminophen (APAP), embedded in poly-(vinylpyrrolidone-co-vinyl acetate) (PVPVA64) were chosen as reference systems. Polyethylene glycol 1500 (PEG1500), D-α-tocopherol polyethylene glycol 1000 succinate (TPGS1000), propylene glycol monocaprylate type II (Capryol? 90), and propylene glycol monolaurate type I (Lauroglycol? FCC) were used as LMWEs. The API solubility in the excipients and the glass-transition temperature of the ASDs were modeled using the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT) and the Kwei equation, respectively, and compared to corresponding experimental data.

Results

The API solubility curves in ternary systems with 90/10 wt%/wt% PVPVA64/LMWE ratios were very close to those in pure PVPVA64. However, the glass-transition temperatures of API/PVPVA64/LMWE ASDs were much lower than those of API/PVPVA64 ASDs. These effects were determined experimentally and agreed with the predictions using the PC-SAFT and Kwei models.

Conclusion

The impact of the LMWEs on the thermodynamic stability of the ASDs is quite small while the kinetic stability is significantly decreased even by small LMWE amounts. PC-SAFT and the Kwei equation are suitable tools for predicting the influence of LMWEs on the ASD phase behavior.

     

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.     

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.     

Implication of inclusion complexation of glimepiride in cyclodextrin-polymer systems on its dissolution, stability and therapeutic efficacy

The effect of complexation of glimepiride, a poorly water-soluble antidiabetic drug, with β-cyclodextrin and its derivatives (HP-β-CyD and SBE-β-CyD) in presence of different concentrations of water-soluble polymers (HPMC, PVP, PEG 4000 and PEG 6000) on the dissolution rate of the drug has been investigated. The results revealed that the dissolution rate of the drug from these ternary systems is highly dependent on polymer type and concentration. The dissolution rate of the drug from ternary systems containing PEG 4000 or PEG 6000 seems to be generally higher than from systems containing HPMC or PVP. An optimum increase in the dissolution rate of the drug was observed at a polymer concentration of 5% for PEG 4000 or PEG 6000 and at 20% concentration of HPMC or PVP. The dissolution rate of the drug from the ternary system glimepiride–HP-β-CyD–5% PEG 4000 was high compared to the other systems. Tablets containing the drug or its equivalent amount of this ternary system were prepared and subjected to accelerated stability testing at 40 °C/75% R.H. to investigate the effect of storage on the chemical stability as well as therapeutic efficacy of the tablets. The results revealed stability of the tablets and consistent therapeutic efficacy on storage.     

水飞蓟素-聚乙二醇6000固体分散体系的制备及其特征考察

目的制备水飞蓟素固体分散体，加快药物的溶出，并进行特征考察。方法以聚乙二醇6000(PEG6000)为材料，采用熔融法将难溶性药物水飞蓟素制成固体分散体，通过体外释药试验考察固体分散技术对水飞蓟素的增溶作用，并以X-射线粉末衍射、傅立叶变换红外光谱(FT-IR)考察水飞蓟素固体分散体的特性。结果与原药比较，固体分散体中药物的释放速率明显增大，PEG6000固体分散体系能显著加快水飞蓟素的溶出。X-射线粉末衍射分析表明，PEG6000及药物在固体分散体中的晶格点阵面间距离、衍射峰位移及其相对强度等均发生了规律性变化，FT-IR分析表明PEG6000与药物间无相互作用。结论PEG6000固体分散体系的对难溶性药物溶出和扩散的加快，与载体材料和药物的晶格参数的改变密切相关。