Antisolvent precipitation technique: a very promising approach to crystallize curcumin in presence of polyvinyl pyrrolidon for solubility and dissolution enhancement

Curcumin with a vast number of pharmacological activities is a poorly water soluble drug which its oral bioavailability is profoundly limited by its dissolution or solubility in GI tract. Curcumin could be a good anticancer drug if its solubility could be increased. Therefore, the aim of the present study was to increase the dissolution rate of curcumin by employing antisolvent crystallization technique and to investigate the effect of polyvinyl pyrrolidone K30 (PVP) as colloidal particles in crystallization medium on resultant particles. Curcumin was crystalized in the presence of different amounts of PVP by antisolvent crystallization method and their physical mixtures were prepared for comparison purposes. The samples were characterized by scanning electron microscopy (SEM), differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD) and Fourier transform infrared spectroscopy (FT-IR). The solubility and dissolution of the treated and untreated curcumin were also determined. Antisolvent crystallization of curcumin led to the formation of particles with no definite geometric shape. It was interesting to note that the DSC and XRPD studies indicated the formation of a new polymorph and less crystallinity for particles crystallized in the absence of PVP. However, the crystallized curcumin in the presence of PVP was completely amorphous. All crystalized curcumin samples showed much higher dissolution rate compared to untreated curcumin. The amount of curcumin dissolved within 10 for treated curcumin in the presence of PVP (1:1 curcumin:PVP) was 7 times higher than untreated curcumin and this enhancement in the dissolution for curcumin samples crystallized in the absence of PVP was around 5 times. Overall‚ the results of this study showed that antisolvent crystallization method in the absence or presence of small amounts of PVP is very efficient in increasing the dissolution rate of curcumin to achieve better efficiency for curcumin

Curcumin nanoparticles containing poloxamer or soluplus tailored by high pressure homogenization using antisolvent crystallization

Curcumin is a natural active constituent of Curcuma longa from Zingiberaceae family that shows many different pharmacological effects such as anticancer, antioxidant, anti-inflammatory, antimicrobial and antiviral effect. However, its bioavailability is profoundly limited by its poor water solubility. In this study antisolvent crystallization followed by freeze drying was used for the preparation of curcumin nanoparticles. The presence of different ratios of hydrophilic polymers (poloxamer 188 & soluplus) on physicochemical properties of curcumin nanoparticles was also investigated. In addition, the effect of high pressure homogenization (HPH) on solubility and dissolution properties of curcumin was investigated. All nanoparticle formulations were examined to determine their particle size distribution, saturation solubility, morphology (SEM), solid state (DSC, XRPD and FT-IR) and dissolution behavior. It was observed that curcumin crystallized in the presence of polymers exhibited better solubility and dissolution rate in comparison with original curcumin. The results showed that the concentration of the stabilizer and the method used to prepare nanoparticles can control the dissolution of curcumin. The crystallized nanoparticles showed polymorph 2 curcumin with lower crystallinity and higher dissolution rate. Curcumin nanoparticles containing 50% soluplus prepared via HPH method presented 16-fold higher solubility than its original form. In conclusion, samples crystalized and proceed with HPH technique showed smaller particle size, better redispersibility, higher solubility and dissolution rate in water compared with a sample prepared using a simple antisolvent crystallization process

Investigation of the particle growth of fenofibrate following antisolvent precipitation and freeze-drying

peer-reviewedSubmicron to small-micron-sized particles of the hydrophobic drug, fenofibrate, were prepared by controlled crystallization in order to influence its dissolution behavior. An antisolvent precipitation process successfully generated particles (200-300 nm) which matched the size and dissolution behavior of a commercial wet-milled formulation of the drug. Although the preparation of submicron-sized particles was straightforward, retaining their size in suspension and during isolation was a challenge. Additives were employed to temporarily stabilize the suspension, and extend the time window for isolation of the submicron particles. Precipitated particles were isolated primarily by immediate freeze-drying, but drying stresses were found to destabilize the fragile submicron system. The growth pathway of particles in suspension and during oven and freeze-drying were compared. Although the growth pathways appeared considerably different from a visual morphological perspective, an investigation of the electron diffraction patterns and the inner-particle surfaces showed that the growth pathways were the same: molecular addition by Ostwald ripening. The observed differences in the time-resolved particle morphologies were found to be a result of the freeze-drying process.ACCEPTEDpeer-reviewe

Effect of high pressure homogenization on physicochemical properties of curcumin nanoparticles prepared by antisolvent crystallization using HPMC or PVP

Dissolution enhancement of poorly water soluble drugs is a major challenge in pharmaceutical industry. The aim of this study is to fabricate curcumin nanoparticles by antisolvent crystallization in the presence of PVP-K30 or HPMC with various concentrations as a stabilizer. The effect of high pressure homogenization on properties of curcumin particles is also investigated in this study. The antisolvent crystallization method followed by freeze drying (CRS-FD) and also antisolvent crystallization and high pressure homogenization followed by freeze drying (HPH-FD) were employed to modify curcumin particles. Physical mixtures of the drug and additives were also prepared for comparison purposes. The solid state analysis (DSC, XRPD and FT-IR studies), particle size measurement, morphological analysis, saturation solubility and dissolution behavior of the samples were investigated. The curcumin crystallized without using stabilizer produced polymorph 2 curcumin with lower crystallinity and higher solubility. The samples obtained in the presence of stabilizers showed higher solubility compared to its physical mixtures counterpart. It was found that the stabilizers used in the current study were capable of inhibiting the crystal growth of particles during crystallization. High pressure homogenizer method generated smaller particles compared to those samples that were not subjected to high pressure homogenizer (for example, 2748 nm for 5% PVP CRS-FD sample and 706 nm for 5% PVP HPH-FD sample). Particles obtained via HPH showed better solubility and dissolution rate compared to those samples that HPH was not employed (for example, the saturated solubility of 25% PVP CRS-FD sample was near 2 μg/ml while this amount was approximately 4.3 μg/ml for 25% HPH-FD sample. The effect of high pressure homogenization on dissolution rate is more pronounced for samples with lower stabilizer ratio. The samples prepared with high pressure homogenizer using 50% PVP showed 25-fold higher solubility compared to untreated curcumin. Generally, it can be concluded that the method of preparation, selection of suitable stabilizer and concentration of stabilizer play a critical role on particle size and dissolution rate of curcumin

Polymorphs of Curcumin and Its Cocrystals With Cinnamic Acid

YesWe report formation of polymorphs and new eutectics and cocrystals of curcumin, a sparingly water-soluble active component in turmeric, structurally similar to cinnamic acid. The curcumin polymorphs were formed using liquid antisolvent precipitation, where acetone acted as a solvent and water was used as the antisolvent. The metastable form 2 of curcumin was successfully prepared in varied morphology over a wide range of solvent-to-antisolvent ratio and under acidic pH conditions. We also report formation of new eutectics and cocrystals of curcumin with cinnamic acid acting as a coformer. The binary phase diagrams were studied using differential scanning calorimetry and predicted formation of the eutectics at the curcumin mole fraction of 0.15 and 0.33, whereas a cocrystal was formed at 0.3 mole fraction of curcumin in the curcumin–cinnamic acid mixture. The formation of the cocrystal was supported with X-ray powder diffraction, the enthalpy of fusion values, Fourier-transform infrared spectroscopy, and scanning electron microscopy. The hydrogen bond interaction between curcumin and cinnamic acid was predicted from Fourier-transform infrared spectra, individually optimized curcumin and cinnamic acid structures by quantum mechanical calculations using Gaussian-09 and their respective unit cell packing structures

Development of a Dry Powder Inhaler and Nebulised Nanoparticle-Based Formulations of Curcuminoids for the Potential Treatment of Lung Cancer. Development of Drug Delivery Formulations of Curcuminoids to the Lungs using Air Jet Milling and Sonocrystallisation Techniques for Dry Powder Inhaler Preparations; and Nanoemulsion and Microsuspension for Nebuliser Formulations

Curcuminoids have strong anticancer activities but have low bioavailability. The highest rate of cancer deaths comes from lung tumours; therefore, inhaled curcuminoids could treat lung cancer locally. To date, there are no nebulised formulations of curcuminoids, and there are no inhalable curcuminoids particles without excipients using air jet mill and sonocrystallisation methods for DPI formulations. It is the first time; the aerodynamic parameters of curcumin, demethoxycurcumin and bisdemethoxycurcumin were measured individually using NGI. The size, shape, free surface energy, and the crystal polymorphism of the produced inhalable curcuminoid particles were characterised using laser diffraction, SEM, IGC, DSC and XRPD, respectively. Several DPI formulations with a variable particle size of curcuminoids were prepared in two drug-carrier ratios (1:9 and 1:67.5). The best performance of the DPI formulations of the sonocrystallised particles, which exist in crystal structure form1, were obtained from ethanol- heptane, as illustrated FPF 43.4%, 43.6% and 43.4% with MMAD of 3.6µm, 3.5µm and 3.4µm, whereas the best DPI formulation of the air jet milled particles was presented FPF 38.0%, 38.9%, and 39.5% with MMAD of 3.6µm, 3.4µm and 3.2µm for curcumin, demethoxycurcumin and bisdemethoxycurcumin, respectively. Nebulised curcuminoids using nanoemulsion and microsuspension formulations were prepared. The physical properties, such as osmolality, pH and the viscosity of the aerosolised nanoemulsion and the microsuspension formulations were determined. The FPF% and MMAD of nebulised nanoemulsion ranged from 44% to 50% and from 4.5µm to 5.5µm respectively. In contrast, the FPF% of microsuspension ranged from 26% to 40% and the MMAD from 5.8µm to 7.05µm. A HPLC method was developed and validated in order to be used in the determination of curcuminoids from an aqueous solution

Production of Pure Drug Nanocrystals and Nano Co-crystals by Confinement Methods

The use of drug nanocrystals in the drug formulation is increasing due to the large number of poorly water-soluble drug compounds synthetized and due to the advantages brought by the nanonization process. The downsizing processes are done using a top-down approach (milling and homogenization currently employed at the industrial level), while the crystallization process is performed by bottom-up techniques (e.g., antisolvent precipitation to the use of supercritical fluids or spray and freeze drying). In addition, the production of nanocrystals in confined environment can be achieved within microfluidics channels. This review analyzes the processes for the preparation of nanocrystals and co-crystals, divided by top-down and bottom-up approaches, together with their combinations. The combination of both strategies merges the favorable features of each process and avoids the disadvantages of single processes. Overall, the applicability of drug nanocrystals is highlighted by the widespread research on the production processes at the engineering, pharmaceutical, and nanotechnology level.Peer reviewe

A Cross-Flow Ultrasound-Assisted Extraction of Curcuminoids from Curcuma longa L.: Process Design to Avoid Degradation

Rhizomes of Curcuma longa L. are well known for their content of curcuminoids, which are compounds with interesting biological activity against various inflammatory states and diseases. Curcuminoids can degrade during processing. This piece of work investigates fast, efficient and cost-effective metabolite recovery from turmeric under ultrasound-assisted extraction (UAE). An analytical evaluation of curcuminoid stability under sonication in different solvents is reported for the first time. HPLC and quantitative 1H-NMR were used. Under the applied conditions, EtOAc was found to be the optimal extraction medium, rather than EtOH, due to its lower radical generation, which facilitates better curcuminoid stability. Kinetic characterization, by means of the Peleg equation, was applied for single-step UAE on two different rhizome granulometries. Over a time of 90 min, maximum extraction yields were 25.63% and 47.56% for 6 and 2 mm matrix powders, respectively. However, it was observed that the largest portion of curcuminoid recovery was achieved in the first 30 min. Model outcomes were used as the basis for the design of a suitable multi-step cross-flow approach that supports and emphasizes the disruptive role of cavitation. The maximum curcuminoid yield was achieved over three steps (92.10%) and four steps (80.04%), for lower and higher granulometries, respectively. Finally, the central role of the solvent was further confirmed by turmeric oleoresin purification. The EtOAc extract was purified via crystallization, and a 95% pure curcuminoid product was isolated without any chromatographic procedure. No suitable crystallization was observed for the EtOH extract

Phenolic compounds particle engineering and formulation with dense gas technology.

Phenolic compounds have robust activity against free radicals, thus they possess potential in the treatment of various metabolic disorders such as cancer, diabetes, cardiovascular, osteoporosis and malaria. The application of the compounds, however, has been hindered by their intrinsic physicochemical properties of having poor solubility and stability in the human gastro-intestinal pathway. As a result, phenolic compounds have low oral bioavailability. Addressing the drawbacks such as those exhibited by phenolic compounds usually focuses on the strategy of processing and formulation. The processing can contribute to improvement of the physical properties of the compounds and exploration of alternative administration, while formulation can facilitate the modification of compound interactions with the targeted site of delivery. In this study, particle engineering and formulation were applied to phenolic compound of curcumin for development composite products. Derived compound of cyclodextrins; hydroxypropylated and methylated beta cyclodextrins, and water soluble polymer of polyvinylpyrrolidone (PVP) were used as excipients to investigate synergistic effect of the co-formulations. The method of dense gas anti-solvent technology was used throughout the study, using compressed CO2 as processing medium. Processing and formulation had succeeded to improve curcumin performance in term of dissolution property as 80% of curcumin in 200 min and enhancement of aqueous solubility of 190 times could be obtained. Inhalable powders of curcumin composite having enhanced properties on aerodynamic performance with 61% - compared to 11% of the unprocessed material - of fine particle fraction (FPF) was produced. In addition, inhalable powder exhibited improved aqueous solubility as high as 70 times. Further, the ARISE processed pulmonary products had enhanced activity towards lung cancer cells. Process scale-up to evaluate feasibility of the dense gas method of the atomized rapid injection solvent extraction (ARISE) system was also conducted both technically and economically. The applicability of the ARISE method to produce micrometric particle of phenolic para-coumaric acid was examined in the lab and pilot-lab scale processing. An evaluation on the economics has confirmed scalability of the ARISE method to process micro- or nanoscale materials at larger scale operation

Sonocrystallization and sonofragmentation

Acoustic cavitation occurs when ultrasound is applied to a liquid. Bubbles are generated, oscillate, expand and, when specific criteria are met, implosively collapse. These collapses generate hot spots and shockwaves. Hot spots have intense local temperatures (~5,000 K) and pressures (~1,000 atm), and a rapid heating and cooling rate (> 1010 K s-1). Shockwaves can induce crystallization, i.e., sonocrystallization, or break existing crystals, i.e., sonofragmentation in solid-liquid mixtures. The sonofragmentation of ionic and molecular crystals is discussed in Chapters 2 and 3. When ultrasound was applied to slurries of ionic or molecular crystals, crystal breakage occurred not by interparticle collision but by direct interactions between crystals and shockwaves. Sonofragmentation rates depended strongly on the strength of the crystal material, as described by its Vickers hardness or Young’s modulus. This is a mechanochemical extension of the Bell–Evans–Polanyi Principle or Hammond’s Postulate: i.e., activation energies for solid fracture correlate with the binding energies of solids. In addition, from comparisons of sonofragmentation patterns between ionic and molecular crystals, it was confirmed that the sonofragmentation of ionic crystals was more sensitive to changes in material hardness than that of molecular crystals. Finally, two possible mechanisms of particle breakage via sonofragmentation were suggested: particle breakage from defects formed by shock-induced compression-expansion of the initial crystal and particle breakage from defects created during shock-induced bending or torsion of the initial crystal. In Chapters 4 and 5, the sonocrystallization of pharmaceutical agents having inherently low water solubility is discussed. Chapter 4 describes the development of a spray sonocrystallization system. Spray sonocrystallization produced nano-scale carboxyphenyl salicylate crystals (c.a. 100 nm) with a narrow size distribution. The crystal size was controllable by changing the initial solute concentration. In Chapter 5, carbamazepine crystals were produced via various crystallization methods, including spray sonocrystallization. Crystal sizes, solubility and dissolution rates were compared among carbamazepine crystals generated by five different crystallization methods. Spray sonocrystallization produced the smallest crystals and resulted in the most rapid observed dissolution rate in water