Haste Makes Waste: The Interplay Between Dissolution and Precipitation of Supersaturating Formulations

Contrary to the early philosophy of supersaturating formulation design for oral solid dosage forms, current evidence shows that an exceedingly high rate of supersaturation generation could result in a suboptimal in vitro dissolution profile and subsequently could reduce the in vivo oral bioavailability of amorphous solid dispersions. In this commentary, we outline recent research efforts on the specific effects of the rate and extent of supersaturation generation on the overall kinetic solubility profiles of supersaturating formulations. Additional insights into an appropriate definition of sink versus nonsink dissolution conditions and the solubility advantage of amorphous pharmaceuticals are also highlighted. The interplay between dissolution and precipitation kinetics should be carefully considered in designing a suitable supersaturating formulation to best improve the dissolution behavior and oral bioavailability of poorly water-soluble drugs.KEY WORDS: amorphous formulation, kinetic solubility, nonsink dissolution testing, poorly water-soluble drug, supersaturation rate     

Solid dispersions: a strategy for poorly aqueous soluble drugs and technology updates

Introduction: Present article reviews solid dispersion (SD) technologies and other patented inventions in the area of pharmaceutical SDs, which provide stable amorphous SDs.

Areas covered: The review briefly compiles different techniques for preparing SDs, their applications, characterization of SDs, types of SDs and also elaborates the carriers used to prepare SDs. The advantages of recently introduced SD technologies such as RightSize^?, closed-cycle spray drying (CSD), Lidose® are summarized. Stability-related issues like phase separation, re-crystallization and methods to curb these problems are also discussed. A patented carrier-screening tool for predicting physical stability of SDs on the basis of drug–carrier interaction is explained. Applications of SD technique in controlled drug delivery systems and cosmetics are explored. Review also summarizes the carriers such as Soluplus®, Neusilin®, Solumer^TM used to prepare stable amorphous SD.

Expert opinion: Binary and ternary SDs are found to be more stable and provide better enhancement of solubility or dissolution of poorly water-soluble drugs. The use of surfactants in the carrier system of SD is a recent trend. Surfactants and polymers provide stability against re-crystallization of SDs, surfactants also improve solubility and dissolution of drug.     

Study on solubility improvement of lidocaine by ternary solid dispersion

In the present study, we aimed to probe the possibility of using mixed poloxamers as carriers to prepare ternary solid dispersion (SD) that facilitated solubility and dissolution rate of the poorly water soluble drug and compare with binary SD with single poloxamer. Lidocaine (LIC) was selected as a model drug, and poloxamer 188 (P188) and poloxamer 407 (P407) were utilized as single and mixed carriers. Depending on DSC and the dissolution testing, the appropriate ratio of SD prepared by melting method was optimized. Ternary and binary SD was characterized by DSC, XRD, SEM and FTIR. In vitro dissolution study, phase solubility study and saturated solubility study were performed to clarify solubilization from apparent phenomena and inherent reason. Moreover, stability study under different relative humidity (RH) was investigated. Physical characterizations of binary and ternary SD exhibited the formation of eutectic mixture and the presence of molecular interaction. Compared with the pure LIC, the dissolution rate and solubility of LIC in binary and ternary SDs were enhanced. The phase solubility study revealed an AL-type curve. Furthermore, the stability test indicated that ternary and binary SD was stable. The results of this study demonstrated that SD with mixed poloxamers could improve dissolution rate and solubility of poorly water-soluble drug.     

Solid dispersions, part I: recent evolutions and future opportunities in manufacturing methods for dissolution rate enhancement of poorly water-soluble drugs

INTRODUCTION: In recent years, the number of active pharmaceutical ingredients with high therapeutic impact, but very low water solubility, has increased significantly. Thus, a great challenge for pharmaceutical technology is to create new formulations and efficient drug-delivery systems to overcome these dissolution problems. AREAS COVERED: Drug formulation in solid dispersions (SDs) is one of the most commonly used techniques for the dissolution rate enhancement of poorly water-soluble drugs. Generally, SDs can be defined as a dispersion of active ingredients in molecular, amorphous and/or microcrystalline forms into an inert carrier. This review covers literature which states that the dissolution enhancement of SDs is based on the fact that drugs in the nanoscale range, or in amorphous phase, dissolve faster and to a greater extent than micronized drug particles. This is in accordance to the Noyes-Whitney equation, while the wetting properties of the used polymer may also play an important role. EXPERT OPINION: The main factors why SD-based pharmaceutical products on the market are steadily increasing over the last few years are: the recent progress in various methods used for the preparation of SDs, the effect of evolved interactions in physical state of the drug and formulation stability during storage, the characterization of the physical state of the drug and the mechanism of dissolution rate enhancement.     

Crosslinked hydrogels—a promising class of insoluble solid molecular dispersion carriers for enhancing the delivery of poorly soluble drugs

Water-insoluble materials containing amorphous solid dispersions (ASD) are an emerging category of drug carriers which can effectively improve dissolution kinetics and kinetic solubility of poorly soluble drugs. ASDs based on water-insoluble crosslinked hydrogels have unique features in contrast to those based on conventional water-soluble and water-insoluble carriers. For example, solid molecular dispersions of poorly soluble drugs in poly(2-hydroxyethyl methacrylate) (PHEMA) can maintain a high level of supersaturation over a prolonged period of time via a feedback-controlled diffusion mechanism thus avoiding the initial surge of supersaturation followed by a sharp decline in drug concentration typically encountered with ASDs based on water-soluble polymers. The creation of both immediate- and controlled-release ASD dosage forms is also achievable with the PHEMA based hydrogels. So far, ASD systems based on glassy PHEMA have been shown to be very effective in retarding precipitation of amorphous drugs in the solid state to achieve a robust physical stability. This review summarizes recent research efforts in investigating the potential of developing crosslinked PHEMA hydrogels as a promising alternative to conventional water-soluble ASD carriers, and a related finding that the rate of supersaturation generation does affect the kinetic solubility profiles implications to hydrogel based ASDs.KEY WORDS: Amorphous solid dispersions, Crosslinked hydrogels, Poly(2-hydroxyethylmethacrylate), Supersaturation, Kinetic solubility     

Overcoming formulation challenges for the next generation of vaccines

Introduction: In recent years, the number of active pharmaceutical ingredients with high therapeutic impact, but very low water solubility, has increased significantly. Thus, a great challenge for pharmaceutical technology is to create new formulations and efficient drug-delivery systems to overcome these dissolution problems.

Areas covered: Drug formulation in solid dispersions (SDs) is one of the most commonly used techniques for the dissolution rate enhancement of poorly water-soluble drugs. Generally, SDs can be defined as a dispersion of active ingredients in molecular, amorphous and/or microcrystalline forms into an inert carrier. This review covers literature which states that the dissolution enhancement of SDs is based on the fact that drugs in the nanoscale range, or in amorphous phase, dissolve faster and to a greater extent than micronized drug particles. This is in accordance to the Noyes–Whitney equation, while the wetting properties of the used polymer may also play an important role.

Expert opinion: The main factors why SD-based pharmaceutical products on the market are steadily increasing over the last few years are: the recent progress in various methods used for the preparation of SDs, the effect of evolved interactions in physical state of the drug and formulation stability during storage, the characterization of the physical state of the drug and the mechanism of dissolution rate enhancement.     

Characterisation of the thermal,spectroscopic and drug dissolution properties of mefenamic acid and polyoxyethylene–polyoxypropylene solid dispersions

The aim of this study was to investigate the solubility of mefenamic acid (MA), a highly cohesive, poorly water-soluble drug in a copolymer of polyoxyethylene–polyoxypropylene (Lutrol F68®), and to understand the effect drug polymer solubility has on in vitro dissolution of MA. Solid dispersions (SD) of MA were prepared by a hot melt method, using Lutrol F68® as a thermoplastic polymeric platform. High-speed differential scanning calorimetry (Hyper-DSC), Raman spectroscopy, powder X-ray diffractometry (PXRD) and hot-stage/fluorescence microscopy were used to assess the solubility of the drug in molten and solid polymer. Drug dissolution studies were subsequently conducted on single-phase solid solutions and biphasic SD using phosphate buffer pH 6.8 as dissolution media. Solubility investigations using Hyper-DSC, Raman spectroscopy and hot-stage microscopy suggested MA was soluble in molten Lutrol F68® up to a concentration of 35% (w/w). Conversely, the solubility in the solid-state matrix was limited to <15% (w/w); determined by Raman spectroscopy, PXRD and fluorescence microscopy. As expected the dissolution properties of MA were significantly influenced by the solubility of the drug in the polymer matrix. At a concentration of 10% (w/w) MA (a single phase solid solution) dissolution of MA in phosphate buffer 6.8 was rapid, whereas at a concentration of 50% (w/w) MA (biphasic SD) dissolution was significantly slower. This study has clearly demonstrated the complexity of drug–polymer binary blends and in particular defining the solubility of a drug within a polymeric platform. Moreover, this investigation has demonstrated the significant effect drug solubility within a polymeric matrix has upon the in vitro dissolution properties of solid polymer/drug binary blends. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:4545–4556, 2009     

In vitro dissolution study of acetylsalicylic acid solid dispersions. Tunable drug release allowed by the choice of polymer matrix

Abstract

Due to their high versatility and diverse excipient options, solid dispersions (SDs) are an elegant choice for the formulation of active pharmaceutical ingredients with inconvenient solubility. Four distinct types of polymers with different physicochemical properties [polyvinylpyrrolidone, poly[N-(2-hydroxypropyl)-metacrylamide], poly(2-ethyl-2-oxazoline), and polyethylene glycol] and variable molecular weights were compared to investigate the influence of the polymer matrix on drug release. To probe the extent of intercomponent interactions, acetylsalicylic acid (ASA) was used as a model active substance. Controlled drug release was demonstrated for all four types of polymer-ASA SDs created by the freeze-drying method. While the polyethylene glycol-ASA SD exhibited an increased dissolution rate, the other polymer-ASA systems exhibited significantly reduced drug dissolution kinetics compared to free ASA. Furthermore, in contrast to physical mixtures, the prepared SDs all exhibited zero-order dissolution kinetics for ASA. The dissolution rate was strongly dependent on the molecular weight of the polymer. These results demonstrate that the type of SD may be controlled by the chemical constitutions of the polymers and that appropriate selection of the molecular weight of the polymer matrix enables finely tuned drug release over a wide range of dissolution rates.     

Formulation and in vivo hypoglycemic effect of glipizide solid dispersion

The present study was carried out with a view to enhance dissolution rate of poorly water-soluble drug glipizide (GZ) (BCS class II) using polyethylene glycol (PEG) 6000, PEG 8000 and poloxamer (PXM) 188 as carriers. Solid dispersions (SDs) were prepared by melting method using different ratios of glipizide to carriers. Phase solubility study was conducted to evaluate the effect of carrier on aqueous solubility of glipizide. SD was optimized by drug content estimation and in vitro dissolution study and optimised SD was subjected to bulk characterization, Scanning electron microscopy (SEM), Fourier transformation infrared spectroscopy (FTIR), Differential scanning calorimetry (DSC) and X-ray diffraction study (XRD). Preclinical study was performed in mice to study the decrease in blood glucose level from prepared SD compared with pure drug. Due to high solubility and drug release, PXM 188 in weight ratio of 1:2 was optimized. Decrease in blood glucose level in mice from SD was significantly higher (p < 0.05) compared to pure glipizide. Thus, solid dispersion technique can be successfully used for the improvement of the dissolution profile of GZ.     

Effect of poloxamer on physicochemical properties of tacrolimus solid dispersion improving water solubility and dissolution rate

Tacrolimus (TCR; also FK-506 and trade name prograf^?), an antibiotic of macrolide family and a novel immunosuppressive agent, is a natural product of actinomycete Streptomyces tskubaensis. But TCR is poorly soluble in water (0.012?mg/mL), so its bioavailability is low and irregular. The aim of this study is to characterize physicochemical properties of TCR and investigate the improvement of solubility and dissolution rate of TCR solid dispersion (SD) with poloxamer. TCR SDs, consisting of various grades and ratios of poloxamer were prepared by hot-melting method and were characterized by DSC, PXRD, and FT-IR. The dissolution profile and solubility of TCR from the SDs were evaluated. SD of TCR prepared with poloxamer 188 at the ratio of 1:1 by the hot-melting method resulted in a significant increase in TCR solubility and enhanced dissolution profile over the TCR crystalline powder.     

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-modulating mechanism of alkalizers and polymers in a nanoemulsifying solid dispersion containing ionizable and poorly water-soluble drug

We investigated the dissolution-modulating mechanism of alkalizers and polymers in nanoemulsifying Gelucire 44/14 (GUC)-based solid dispersions (SDs) for controlled release. Aceclofenac (AFC), an ionizable and poorly water-soluble drug, was chosen because of its extremely low solubility at low pH. Nanoemulsifying SD systems containing alkalizers and/or polymers were prepared by the melting method. Drug crystallinity, microenvironmental pH (pH_M), dissolution rate, and droplet size in the media from nanoemulsifying SD were then characterized. Ternary SD containing alkalizers, mainly Na₂CO₃ and NaHCO₃, enhanced the initial release rate of AFC in simulated gastric fluid (pH 1.2), but resulted in spring-like precipitation. However, adding a secondary polymer, Poloxamer 407, prevented precipitation in the quaternary SD system. Poloxamer 407 and alkalizer (Na₂CO₃) facilitated nanoemulsion formation (80-140 nm) with a smaller droplet size in a medium of pH 1.2 as visualized by TEM. The surface and inner pH_M were also modulated by the alkalizers, but not by the polymers. The drug’s crystalline structure was further changed to partially or almost amorphous form by the alkalizers and polymers in SD as characterized by instrumental analysis. The synergistic effects of alkalizers and secondary polymers in SD on reduction of drug crystallinity and modulation of pH_M via molecular interactions could modulate dissolution rates of ionizable and poorly water-soluble model drug without spring-like precipitation by providing more favorable nanoemulsion-forming environment.     

Maintenance of supersaturation I: indomethacin crystal growth kinetic modeling using an online second-derivative ultraviolet spectroscopic method

Formulations that produce supersaturated solutions after their oral administration have received increased attention as a means to improve bioavailability of poorly water-soluble drugs. Although it is widely recognized that excipients can prolong supersaturation, the mechanisms by which these beneficial effects are realized are generally unknown. Difficulties in separately measuring the kinetics of nucleation and crystal growth have limited progress in understanding the mechanisms by which excipients contribute to the supersaturation maintenance. This paper describes the crystal growth kinetic modeling of indomethacin, a poorly water-soluble drug, from supersaturated aqueous suspensions using a newly developed, online second-derivative ultraviolet spectroscopic method. The apparent indomethacin equilibrium solubility after crystal growth at a high degree of supersaturation (S=6) was approximately 55% higher than the indomethacin equilibrium solubility determined prior to growth, which was attributed to the deposition of a higher energy indomethacin form on the seed crystals. The indomethacin crystal growth kinetics (S=6) was of first order. By comparing the mass transfer coefficients from indomethacin dissolution and crystal growth, it was shown that the indomethacin crystal growth kinetics at S=6 was bulk diffusion controlled. The change in indomethacin seed crystal size distribution before and after crystal growth was determined and modeled using a mass-balance relationship.     

Solid dispersions, part II: new strategies in manufacturing methods for dissolution rate enhancement of poorly water-soluble drugs

INTRODUCTION: The absorption of poorly water-soluble drugs, when presented in the crystalline state to the gastrointestinal tract, is typically dissolution rate-limited, and according to BCS these drugs belong mainly to class II. Both dissolution kinetics and solubility are particle size dependent. Nowadays, various techniques are available to the pharmaceutical industry for dissolution rate enhancement of such drugs. Among such techniques, nanosuspensions and drug formulation in solid dispersions are those with the highest interest. AREAS COVERED: This review discusses strategies undertaken over the last 10 years, which have been applied for the dissolution enhancement of poorly water-soluble drugs; such processes include melt mixing, electrospinning, microwave irradiation and the use of inorganic nanoparticles. EXPERT OPINION: Many problems in this field still need to be solved, mainly the use of toxic solvents, and for this reason the use of innovative new procedures and materials will increase over the coming years. Melt mixing remains extremely promising for the preparation of SDs and will probably become the most used method in the future for the preparation of solid drug dispersions.     

Extruded Soluplus/SIM as an oral delivery system: characterization,interactions, in vitro and in vivo evaluations

Abstract

The aim of this study was to obtain a stable, amorphous solid dispersion (SD) with Soluplus, prepared by hot-melt extrusion (HME) as an effective and stable oral delivery system to improve the physical stability and bioavailability of the poorly water-soluble simvastatin (SIM), a drug with relatively low Tg. The drug was proved to be miscible with Soluplus by calculation and measurements. The solubility, dissolution, thermal characteristics, interactions and physical stability of the SIM/Soluplus SDs were investigated. The crystal state of simvastatin in the SD was found to change from crystalline to amorphous form during the HME process and also hydrogen bonds were observed between SIM and the extruded Soluplus. The phase solubility showed the solubilization effect of Soluplus was strong and spontaneous. The equilibrium solubility illustrated that Soluplus/SIM SDs gained much higher solubility than its corresponding physical mixtures (PMs). Both of the dissolution profiles and in-vivo performance showed that the SIM/Soluplus SD obtained a marked enhancement, compared with the PM. There was a little change in the SIM/Soluplus SD during a 3-month storage period (40?°C, 75%), indicating the good physicochemical stability. The extruded Soluplus system prepared by HME is a good alternative for the water-insoluble SIM to improve the stability and bioavailability.     

Dissolution enhancement of felodipine by amorphous nanodispersions using an amphiphilic polymer: insight into the role of drug–polymer interactions on drug dissolution

Context: Felodipine, a poorly soluble drug, is widely used in the treatment of angina pectoris and hypertension.

Objective: This study aimed at the preparation of amorphous solid dispersion (SD) of felodipine using an amphiphilic polymer, soluplus, for the potential enhancement in solubility of the drug.

Materials and methods: Solid dispersions with varying proportions of drug and soluplus were prepared and the rate and extent of dissolution from SDs was compared with that of the pure drug. FT-IR and ¹H NMR spectroscopic analysis were carried out to examine the formation mechanism of SDs. Various techniques were used for solid state characterization of designed SDs.

Results: Formation of amorphous solid dispersions with particle size in nanometer range indicated suitability of polymer and method used in the preparation. FT-IR and ¹H NMR spectroscopy revealed that soluplus was involved in strong hydrogen bonding with felodipine molecules which resulted in the conversion of crystalline felodipine into amorphous form. Solid dispersion with 1:10 drug/polymer ratio showed more than 90% drug dissolution in 30?min whereas pure felodipine showed less than 19% drug dissolution in 1?h.

Discussion and conclusion: Amorphous SDs of felodipine were prepared using soluplus resulting in substantial enhancement in the rate and extent of dissolution of felodipine.     

Preparation and characterization of emulsified solid dispersions containing docetaxel

An emulsified solid dispersion of docetaxel was prepared and characterized in vitro. In contrast to conventional solid dispersions, emulsifying pharmaceutical excipients and hydroxypropyl methylcellulose (HPMC) as a supersaturation promoter were introduced into the PEG6000-based solid dispersion to further improve its solubilizing capability. The solubility, dissolution in vitro and stability of the prepared emulsified solid dispersions were studied taking into consideration of the effects of different emulsifying excipients, preparation methods and the media. Results of the emulsified solid dispersion of docetaxel showed that the solubility and dissolution at 2 h were 34.2- and 12.7-fold higher than the crude powder. The type of emulsifying excipient used had a significant influence on the dissolution of the emulsified solid dispersion. The dissolution of the emulsified solid dispersion prepared by the solvent-melting method or the solvent method was higher than the melting method. There were no apparent differences among the dissolution media utilized. The status of the drug in the emulsified solid dispersion was observed in an amorphous or a molecular dispersion state by differential thermal analysis and powder Xray diffraction. In conclusion, the incorporation of emulsifying pharmaceutical excipients and HPMC with polymers into a solid dispersion could be a new and useful tool to greatly increase the solubility and dissolution of poorly water-soluble drugs.     

Solubility enhancement of desloratadine by solid dispersion in poloxamers

The present study investigates the possibility of using poloxamers as solubility and dissolution rate enhancing agents of the poorly water soluble drug substance desloratadine that can be used for the preparation of immediate release tablet formulation. Two commercially available poloxamer grades (poloxamer P 188 and poloxamer P 407) were selected, and solid dispersions (SDs) containing different weight ratio of poloxamers and desloratadine were prepared by a low temperature melting method. All SDs were subjected to basic physicochemical characterization by thermal and vibrational spectroscopy methods in order to evaluate the efficiency of poloxamers as solubility enhancers. Immediate release tablets were prepared by direct compression of powdered solid dispersions according to a General Factorial Design, in order to evaluate the statistical significance of two formulation (X(1) - type of poloxamer in SD and X(2) - poloxamer ratio in SD) and one process variable (X(3) - compression force) on the drug dissolution rate. It was found that desloratadine in SDs existed in the amorphous state, and that can be largely responsible for the enhanced intrinsic solubility, which was more pronounced in SDs containing poloxamer 188. Statistical analysis of the factorial design revealed that both investigated formulation variables exert a significant effect on the drug dissolution rate. Increased poloxamer ratio in SDs resulted in increased drug dissolution rate, with poloxamer 188 contributing to a faster dissolution rate than poloxamer 407, in accordance with the results of intrinsic dissolution tests. Moreover, there is a significant interaction between poloxamer ratio in SD and compression force. Higher poloxamer ratio in SDs and higher compression force results in a significant decrease of the drug dissolution rate, which can be attributed to the lower porosity of the tablets and more pronounced bonding between poloxamer particles.     

Preparation and evaluation of glibenclamide-polyglycolized glycerides solid dispersions with silicon dioxide by spray drying technique.

Solid dispersions (SDs) of glibenclamide (GBM); a poorly water-soluble drug and polyglycolized glycerides (Gelucire with the aid of silicon dioxide (Aerosil 200); as an adsorbent, were prepared by spray drying technique. SDs and spray dried GBM in comparison with pure GBM and corresponding physical mixtures (PMs) were initially characterized and then subjected to ageing study up to 3 months. Initial characterization of SDs and spray dried GBM by DSC and XRPD showed that GBM was present in its amorphous form (AGBM). Improvement in the solubility and dissolution rate was observed for all samples. DRIFT spectroscopy revealed presence of hydrogen bonding in SDs. During ageing study, almost no decrease of in vitro drug dissolution was observed, over the period of 3 months as compare with freshly prepared SDs. Slight crystallinity in SDs was observed in the DSC and XRPD studies during ageing. Moreover in vivo study in Swiss Albino mice also justified the improvement in the therapeutic efficacy of amorphous GBM in SDs over pure GBM. Thus, present study demonstrated the high potential of spray drying technique for obtaining stable free flowing SDs of poorly water-soluble drugs using polyglycolized glycerides carriers with the aid of silicon dioxide as an adsorbent.     

A comparative study on the effects of amphiphilic and hydrophilic polymers on the release profiles of a poorly water-soluble drug

This paper reports the use of two crystalline polymers, an amphiphilic Pluronic® F-127 (PF-127) and a hydrophilic poly(ethylene glycol) (PEG6000) as drug delivery carriers for improving the drug release of a poorly water-soluble drug, fenofibrate (FEN), via micelle formation and formation of a solid dispersion (SD). In 10% PF-127 (aq.), FEN showed an equilibrium solubility of ca. 0.6?mg/mL, due to micelle formation. In contrast, in 10% PEG6000 (aq.), FEN only exhibited an equilibrium solubility of 0.0037?mg/mL. FEN-loaded micelles in PF-127 were prepared by direct dissolution and membrane dialysis. Both methods only yielded a highest drug loading (DL) of 0.5%. SDs of FEN in PF-127 and PEG6000, at DLs of 5–80%, were prepared by solvent evaporation. In-vitro dissolution testing showed that both micelles and SDs significantly improved FEN’s release rate. The SDs of FEN in PF-127 showed significantly faster release than crystalline FEN, when the DL was as high as 50%, whereas SDs of PEG6000 showed similar enhancement in the release rate when the DL was not more than 20%. The DSC thermograms of SDs of PF-127 exhibited a single phase transition peak at ca. 55–57?°C when the DL was not more than 50%, whereas those in PEG6000 exhibited a similar peak at ca. 61–63?°C when the DL was not more than 35%. When the DL exceeded 50% for SDs of PF-127 and 35% for SDs of PEG6000, DSC thermograms showed two melting peaks for the carrier polymer and FEN, respectively. FT-IR studies revealed that PF-127 has a stronger hydrophobic–hydrophobic interaction with FEN than PEG6000. It is likely that both dispersion and micelle formation contributed to the stronger effect of PF-127 on enhancing the release rate of FEN in its SDs.