Thermodynamic and kinetic evaluation of the impact of polymer excipients on storage stability of amorphous itraconazole.

Two pharmaceutical polymers with high glass transition temperatures (Tg > 100 °C), polyvinylpyrrolidone-vinyl acetate copolymer (PVPVA) and hydroxypropyl methylcellulose acetate succinate (HPMCAS), have been assessed for their impact on the storage stability of itraconazole (ITZ) amorphous solid dispersions (ASDs). The results showed that the inhibitory effect of PVPVA on the recrystallization of amorphous ITZ was highly sensitive to surrounding relative humidity (RH), especially at RH above 60%. In contrast, amorphous ITZ in HPMCAS matrix exhibited much stronger resistance to recrystallization even under high RH conditions, reflecting the superior crystallization-inhibitory effect of HPMCAS. While the ITZ loads in the two polymers far exceeded the respective thermodynamic solubility limits, both ASD systems remained physically stable over an extended storage period at RH ≤ 60%. Kinetics rather than thermodynamics dictate the physical stability of ITZ ASDs. Crystallization of ITZ in ASDs appears to involve a complex interplay of multiple factors, including polymer type, glass transition temperatures (Tgs) of drug and polymer, crystallization tendency of amorphous drug, and storage conditions. Specifically, with respect to the impact of polymer type, HPMCAS is particularly effective for maintaining the storage stability of ITZ ASDs, which can be attributed to its higher Tg and lower hydrophilicity.

Particle size tailoring of ursolic acid nanosuspensions for improved anticancer activity by controlled antisolvent precipitation.

The present study was aimed at tailoring the particle size of ursolic acid (UA) nanosuspension for improved anticancer activity. UA nanosuspensions were prepared by antisolvent precipitation using a four-stream multi-inlet vortex mixer (MIVM) under defined conditions of varying solvent composition, drug feeding concentration or stream flow rate. The resulting products were characterized for particle size and polydispersity. Two of the UA nanosuspensions with mean particle sizes of 100 and 300 nm were further assessed for their in-vitro activity against MCF-7 breast cancer cells using fluorescence microscopy with 4',6-diamidino-2-phenylindole (DAPI) staining, as well as flow cytometry with propidium (PI) staining and with double staining by fluorescein isothiocyanate. It was revealed that the solvent composition, drug feeding concentration and stream flow rate were critical parameters for particle size control of the UA nanosuspensions generated with the MIVM. Specifically, decreasing the UA feeding concentration or increasing the stream flow rate or ethanol content resulted in a reduction of particle size. Excellent reproducibility for nanosuspension production was demonstrated for the 100 and 300 nm UA preparations with a deviation of not more than 5% in particle size from the mean value of three independent batches. Fluorescence microscopy and flow cytometry revealed that these two different sized UA nanosuspensions, particularly the 300 nm sample, exhibited a higher anti-proliferation activity against the MCF-7 cells and afforded a larger population of these cells in both early and late apoptotic phases. In conclusion, MIVM is a robust and pragmatic tool for tailoring the particle size of the UA nanosuspension. Particle size appears to be a critical determinant of the anticancer activity of the UA nanoparticles.

Delivery of poorly soluble compounds by amorphous solid dispersions.

Solid state manipulation by amorphous solid dispersion has been the subject of intensive research for decades due to their excellent potential for dissolution and bioavailability enhancement. The present review aims to highlight the latest advancement in this area, with focus on the fundamentals, characterization, formulation development and manufacturing of amorphous solid dispersions as well as the new generation amorphization technologies. Additionally, specific applications of amorphous solid dispersion in the formulation of herbal drugs or bioactive natural products are reviewed to reflect the growing interest in this relatively neglected area.

Highly stabilized curcumin nanoparticles tested in an in vitro blood-brain barrier model and in Alzheimer's disease Tg2576 mice.

The therapeutic effects of curcumin in treating Alzheimer's disease (AD) depend on the ability to penetrate the blood-brain barrier. The latest nanoparticle technology can help to improve the bioavailability of curcumin, which is affected by the final particle size and stability. We developed a stable curcumin nanoparticle formulation to test in vitro and in AD model Tg2576 mice. Flash nanoprecipitation of curcumin, polyethylene glycol-polylactic acid co-block polymer, and polyvinylpyrrolidone in a multi-inlet vortex mixer, followed by freeze drying with ß-cyclodextrin, produced dry nanocurcumin with mean particle size <80 nm. Nanocurcumin powder, unformulated curcumin, or placebo was orally administered to Tg2576 mice for 3 months. Before and after treatment, memory was measured by radial arm maze and contextual fear conditioning tests. Nanocurcumin produced significantly (p=0.04) better cue memory in the contextual fear conditioning test than placebo and tendencies toward better working memory in the radial arm maze test than ordinary curcumin (p=0.14) or placebo (p=0.12). Amyloid plaque density, pharmacokinetics, and Madin-Darby canine kidney cell monolayer penetration were measured to further understand in vivo and in vitro mechanisms. Nanocurcumin produced significantly higher curcumin concentration in plasma and six times higher area under the curve and mean residence time in brain than ordinary curcumin. The P(app) of curcumin and tetrahydrocurcumin were 1.8×10(-6) and 1.6×10(-5)cm/s, respectively, for nanocurcumin. Our novel nanocurcumin formulation produced highly stabilized nanoparticles with positive treatment effects in Tg2576 mice.

Simultaneously improving the mechanical properties, dissolution performance, and hygroscopicity of ibuprofen and flurbiprofen by cocrystallization with nicotinamide.

PURPOSE: To be fully exploitable in both formulation and manufacturing, a drug cocrystal needs to demonstrate simultaneous improvement of multiple key pharmaceutical properties over the pure drug crystal. The present work was aimed at investigating such feasibility with two model profen-nicotinamide cocrystals. METHODS: Phase pure 1:1 ibuprofen-nicotinamide and flurbiprofen-nicotinamide cocrystals were prepared from solutions through rapid solvent removal using rotary evaporation,and characterized by DSC, PXRD, FTIR, phase solubility measurements, equilibrium moisture sorption analysis, dissolution testing and tabletability analysis. RESULTS: Temperature-composition phase diagrams constructed from DSC data for each profen and nicotinamide crystal revealed the characteristic melting point of the 1:1 cocrystal as well as the eutectic temperatures and compositions. Both cocrystals exhibited higher intrinsic dissolution rates than the corresponding profens. The cocrystals also sorbed less moisture and displayed considerably better tabletability than the individual profens and nicotinamide. CONCLUSIONS: Phase behaviors of 1:1 profen-nicotinamide cocrystal systems were delineated by constructing their temperature-composition phase diagrams. Cocrystallization with nicotinamide can simultaneously improve tableting behavior, hygroscopicity, and dissolution performance of ibuprofen and flurbiprofen. This could pave the way for further development of such cocrystal systems into consistent, stable, efficacious and readily manufacturable drug products.

Formulation of sustained-release microspheres of granulocyte macrophage colony stimulating factor by freezing-induced phase separation with dextran and encapsulation with blended polymers.

This study aimed to assess the potential merits of formulating sustained-release microspheres of recombinant human granulocyte macrophage colony stimulating factor (rhGM-CSF) via freezing-induced phase separation (FIPS) of the protein with dextran followed by encapsulation with binary mixture of poly(lactic-co-glycolic acid) (PLGA) 2A (MW∼12K) and 3A (MW∼47K) or of PLGA2A and polylactic acid (PLA; MW∼83K). The formulated dextran particles and microspheres were characterized in vitro for loading, aggregation, bioactivity and release behavior of the protein where appropriate. rhGM-CSF retained about 60% of bioactivity with no significant aggregation after each formulation step. Encapsulation of protein-loaded dextran particles attained only 80% with the PLGA2A and PLGA3A blend, but 100% with the PLGA2A and PLA mixture. The former formulation exhibited a triphasic in-vitro release profile typical of PLGA microspheres while the latter revealed a much lower initial burst followed by a steady and complete release of rhGM-CSF with preserved bioactivity over a 15-day period.

Spray freeze drying with polyvinylpyrrolidone and sodium caprate for improved dissolution and oral bioavailability of oleanolic acid, a BCS Class IV compound.

Spray-freeze-drying (SFD) of oleanolic acid (OA), a BCS Class IV compound, with polyvinylpyrrolidone-40 (PVP-40) as stabilizer and sodium caprate (SC) as wetting agent and penetration enhancer produced kinetically stable, amorphous solid dispersion systems with superior in vitro dissolution performance, and better and more uniform absorption in comparison with commercial OA tablet. Relative to the SC-free formulation, the presence of SC in the formulation resulted in a significant increase in the in vivo absorption rate of OA while exerting no apparent impact on the extent of OA absorption. The SFD-processed OA formulations and commercial OA tablet generally exhibited large inter-animal variability in oral bioavailability, consistent with the absorption characteristics of BCS Class IV compounds. Inclusion of SC coupled with the replacement of OA with its sodium salt (OA-Na) in the formulation was shown to substantially decrease the observed absorption variability. Above results suggested that increases in both dissolution rate and intestinal permeability of BCS Class IV compounds, as exemplified by the SFD-processed dispersion system containing both OA-Na and SC, are critical to reducing the large inter-individual absorption variability commonly observed with this class of drugs.

Neuroprotective effect of honokiol and magnolol, compounds from Magnolia officinalis, on beta-amyloid-induced toxicity in PC12 cells.

Amyloid ß peptide (Aß) induced toxicity is a well-established pathway of neuronal cell death which might play a role in Alzheimer's disease. In this regard, the toxic effect of Aß on a cultured Aß-sensitive neuronal cell line was used as a primary screening tool for potential anti-Alzheimer's therapeutic agents. The effects of nine pure compounds (vitamin E, α-asarone, salidroside, baicolin, magnolol, gastrodin, bilobalide, honokiol and ß-asarone) from selected Chinese herbs on neuronal cell death induced by Aß in NGF-differentiated PC12 cells were examined. Only two of the studied compounds, honokiol and magnolol, significantly decreased Aß-induced cell death. Further experiments indicated that their neuroprotective effects are possibly mediated through reduced ROS production as well as suppression of intracellular calcium elevation and inhibition of caspase-3 activity. The results provide for the first time a scientific rationale for the clinical use of honokiol and magnolol in the treatment of Alzheimer's disease.

Process-induced phase transformation of berberine chloride hydrates.

Berberine is a natural quaternary ammonium alkaloid used clinically in the chloride salt form for the treatment of diarrhea in many Asian countries. Although the hydrate formation of berberine chloride (BCl) is well documented, the associated mechanism and implications in pharmaceutical formulation have not been studied in detail. In this study, pure BCl dihydrate and BCl tetrahydrate were recrystallized from water and their phase transformation behaviors under defined conditions were investigated. Additionally, pharmacopoeial grade BCl material consisting predominantly of the dihydrate form was examined for potential phase changes when being subjected to a conventional wet granulation procedure for tablet production. Results from solubility measurements, thermal analysis, variable temperature-powder X-ray diffraction (VT-PXRD), and variable temperature-Fourier transform infrared spectroscopy (VT-FTIR) confirmed the solid-state interconversions between the tetrahydrate and dihydrate at 30-49 degrees C and between the dihydrate and anhydrate at 70-87 degrees C. Consistent with the observed phase changes of the two pure hydrates, wet massing of the pharmacopoeial grade BCl sample led to a thermodynamics-driven transition to the tetrahydrate form at room temperature while subsequent tray drying at 50 degrees C caused a reversion back to the dihydrate form. The rate and extent of such hydrate conversion depended largely on the water activity of the granulated powder matrix, which in turn was governed by the particular excipients employed. The present findings have important implications in the regulation of the hydrate forms of BCl in the finished products using specific excipients.

Self-nanoemulsifying drug delivery system (SNEDDS) for oral delivery of Zedoary essential oil: formulation and bioavailability studies.

The aim of the present study was to develop a self-nanoemulsifying drug delivery system (SNEDDS) for the oral delivery of Zedoary turmeric oil (ZTO), an essential oil extracted from the dry rhizome of Curcuma zedoaria. Pseudo-ternary phase diagrams were constructed to identify the efficient self-emulsification regions. ZTO could serve as a partial oil phase with the aid of the second oil phase to enhance drug loading. Increasing the surfactant concentration reduced the droplet size but increased the emulsification time, while the reverse effect was observed by increasing the co-surfactant concentration. Based on the emulsification time, droplet size and zeta potential after dispersion into aqueous phase, an optimized formulation consisting of ZTO, ethyl oleate, Tween 80, transcutol P (30.8:7.7:40.5:21, w/w) and loaded with 30% drug was prepared. Upon mixing with water, the formulation was rapidly dispersed into fine droplets with a mean size of 68.3+/-1.6 nm and xi-potential of -41.2+/-1.3 mV. The active components remained stable in the optimized SNEDDS stored at 25 degrees C for at least 12 months. Following oral administration of ZTO-SNEDDS in rats, both AUC and C(max) of germacrone (GM), a representative bioactive marker of ZTO, increased by 1.7-fold and 2.5-fold respectively compared with the unformulated ZTO.

Production and characterization of a spray-dried hydroxypropyl-beta-cyclodextrin/quercetin complex.

BACKGROUND: Quercetin (QC) is a poorly water-soluble and degradation-prone bioflavonoid. AIM: This study aimed to investigate the formation of a chemically stable and readily water-soluble solid complex of QC with hydroxypropyl-beta-cyclodextrin (HP-beta-CD). METHOD: A solid HP-beta-CD/QC complex was prepared by spray drying and characterized by high-performance liquid chromatography, Fourier-transform infrared spectroscopy, scanning electron microscopy, laser-diffraction particle sizing, powder X-ray diffraction, thermal analysis, Brunauer-Emmett-Teller nitrogen adsorption, and dissolution testing. RESULTS: The complex displayed excellent thermal stability during spray drying, a broad diffuse X-ray diffraction pattern, and a single glass transition temperature (T(g)) characteristic of amorphous HP-beta-CD. Dissolution testing of the complex in simulated gastric fluid revealed an approximately eightfold increase in the rate and extent of dissolution of QC compared with its molar equivalent physical mixture of QC and blank spray-dried HP-beta-CD, although the surface area of QC in the mixture was about seven times that of the complex. CONCLUSIONS: All these observations can be explained by specific interaction between QC and HP-beta-CD in the amorphous solid state, possibly in the form of an inclusion complex.

Anti-hygroscopic effect of dextrans in herbal formulations.

Equilibrium moisture sorptions of two dried aqueous herbal extracts and their mixtures with dextrans of various molecular weights were investigated as a function of relative humidity at ambient temperature, and the data were analyzed by both the Guggenheim-Anderson-deBoer (GAB) and Brunauer-Emmett-Teller (BET) equations. Glass transition temperatures (T(g)) of the samples were measured by differential scanning calorimetry, and their dependence on the moisture contents of the extracts was analyzed by the linear, Fox and expanded Gordon-Taylor mathematical models. All dextran-extract mixtures exhibited single T(g) values, indicating that they existed as single homogeneous phases. The BET equation was found adequate for description of the moisture sorption isotherms for all samples. The dextrans appeared to reduce the hygroscopicity of the herbal extracts solely by a dilution effect. The observed increase in T(g) and accompanying decrease in tackiness of the herbal extracts in the presence of dextrans may be explained by the ability of dextrans to restrict the molecular mobility of simple sugars and to counteract the plasticizing effect of water in the extracts. The expanded Gordon-Taylor equation has proved useful in predicting the T(g) of hygroscopic amorphous herbal mixtures.

Physical characterization of oleanolic acid nonsolvate and solvates prepared by solvent recrystallization.

Oleanolic acid is a naturally occurring compound used clinically in China for the treatment of hepatitis B. The solid-state chemistry of oleanolic acid recrystallized from a variety of solvents was investigated. Glassy materials were prepared from dichloromethane and chloroform solvents. The oleanolic acid non-solvate prepared from acetone (OA-acetone), and the two oleanolic acid solvates prepared from methanol (OA-methanol) and ethanol (OA-ethanol) were physicochemically characterized. Upon desolvation, both the methanol and ethanol solvates were found to undergo phase transformation to a crystalline phase similar to OA-acetone around 190-195 degrees C. The PXRD patterns of commercial pharmaceutical grade OA and the OA-methanol were similar, so the commercial form is probably desolvated oleanolic acid methanol solvate.

Influence of operating temperature and pressure on the polymorphic transition of salmeterol xinafoate in supercritical fluids.

Precipitation of pure polymorphic forms (I and II) of salmeterol xinafoate (SX) in supercritical fluids was investigated as a function of operating pressure and temperature. It has been shown that the formation of each polymorph is governed by both thermodynamic shift and kinetic effects, which are closely associated with the extent of miscibility between the supercritical CO(2) and methanol cosolvent. In addition, the surface energetics of SX exhibit a sharp discontinuity at the transition point in concordance with the particular polymorphic form generated, being essentially independent of the temperature or pressure below and above this point. The conditions of complete miscibility of the two solvent phases involved are critical for the formation of SX Form II.

Engineering of pharmaceutical materials: an industrial perspective.

Crystal engineering provides a rational approach to solving formulation, processing and product performance problems. This review discusses how the concept of crystal engineering can be judiciously utilized to manipulate the solid-state properties of drugs and excipients for successful pharmaceutical formulation and process development. Existing and emerging manufacturing as well as co-processing technologies being applied in the pharmaceutical industry are also presented together with selected examples of crystal form design, crystal form selection and crystal modifications for illustration purposes.

Structure and drug release in a crosslinked poly(ethylene oxide) hydrogel.

Hydrogels are a continuously expanding class of pharmaceutical polymers designed for sustained or controlled drug release. The structure and intermolecular interactions in such systems define their macroscopic properties. The aim of this study was to investigate the mechanism of swelling, drug impregnation, and drug release from poly(ethylene oxide) (PEO) gel crosslinked by urethane bonds. A combination of SAXS/WAXS/SANS techniques enabled us to determine the phase transition between lamellar and extended gel network, and to apply different descriptions of crystallinity, based on lamellar and crystal lattice structures. It is shown that even low (1-7% w/w) loading of model drugs acetaminophen and caffeine, produced significant disorder in the polymer matrix. This effect was particularly pronounced for acetaminophen due to its specific ability to form complexes with PEO. The drug-release profiles were analyzed using a general cubic equation, proposed for this work, which allowed us to determine the gel hydration velocity. The results indicate that the release profiles correlate inversely with the polymer crystallinity.

Particle engineering for pulmonary drug delivery.

With the rapidly growing popularity and sophistication of inhalation therapy, there is an increasing demand for tailor-made inhalable drug particles capable of affording the most efficient delivery to the lungs and the most optimal therapeutic outcomes. To cope with this formulation demand, a wide variety of novel particle technologies have emerged over the past decade. The present review is intended to provide a critical account of the current goals and technologies of particle engineering for the development of pulmonary drug delivery systems. These technologies cover traditional micronization and powder blending, controlled solvent crystallization, spray drying, spray freeze drying, particle formation from liquid dispersion systems, supercritical fluid processing and particle coating. The merits and limitations of these technologies are discussed with reference to their applications to specific drug and/or excipient materials. The regulatory requirements applicable to particulate inhalation products are also reviewed briefly.

Particle size analysis in pharmaceutics: principles, methods and applications.

Physicochemical and biopharmaceutical properties of drug substances and dosage forms can be highly affected by the particle size, a critical process parameter in pharmaceutical production. The fundamental issue with particle size analysis is the variety of equivalent particle diameters generated by different methods, which is largely ascribable to the particle shape and particle dispersion mechanism involved. Thus, to enable selection of the most appropriate or optimal sizing technique, cross-correlation between different techniques may be required. This review offers an in-depth discussion on particle size analysis pertaining to specific pharmaceutical applications and regulatory aspects, fundamental principles and terminology, instrumentation types, data presentation and interpretation, in-line and process analytical technology. For illustration purposes, special consideration is given to the analysis of aerosols using time-of-flight and cascade impactor measurements, which is supported by a computational analysis conducted for this review.

Lack of effect of beta-cyclodextrin and its water-soluble derivatives on in vitro drug transport across rat intestinal epithelium.

The present study aimed to investigate whether beta-cyclodetxrin (beta-CD) and its water-soluble derivatives, hydroxypropyl-beta-cyclodextrin (HP-beta-CD) and sulfobutyl ether beta-cyclodextrin (SBE-beta-CD), exert any effects on the permeation of two drug transport markers (propranolol and lucifer yellow) across rat intestinal epithelium. Rat ileum was stripped of its serosa and mounted inside an Ussing Chamber. Apparent permeability coefficients (P(app)) of the markers from the mucosal to serosal side of the tissue were determined at 37 degrees C in the presence and absence of the beta-cyclodextrins on the mucosal side. Potential difference (PD) was constantly monitored during each experiment to ensure maintenance of the viability and integrity of the tissue. Pre-incubation with 1% beta-CD, 1% HP-beta-CD or 1.48% SBE-beta-CD on the mucosal side for 30 min did not significantly alter the PD and the propranolol permeability (p>0.05). Co-incubation with 1% beta-CD or 1% HP-beta-CD exerted no significant effect on the P(app) of both propranolol and lucifer yellow (p>0.05), but co-incubation with 1.48% SBE-beta-CD lowered the P(app) of propranolol from (1.71+/-0.44)x10(-5) to (0.19+/-0.04)x10(-5)cm/s, which may be ascribed to the molecular complexation of propranolol with SBE-beta-CD. All three beta-cyclodextrins exert no apparent impact on both (passive) transcellar and paracellular drug transports.