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Curcuma comosa (C. comosa) is a Thai medicinal herb that provides numerous pharmacologic activities due to its estrogen-like action. This study aimed to investigate the use of liquisolid technique to prepare tablets containing oleoresin-like crude extract of C. comosa, and to improve the dissolution profiles of its major compounds, diarylheptanoids (DAs). Free flowing powders of C. comosa extract were obtained by adsorption onto solid carriers, microcrystalline cellulose, with colloidal silica as coating material. FTIR results ruled out possible interactions between C. comosa extract and excipients. The results indicated that all of liquisolid tablets met the USP requirements. The release of DAs were significantly increased through liquisolid formulations, compared to crude extract. By decreasing the ratio of carrier to coating from 20 to 10, an improvement in dissolution rate was observed. Addition of additives - namely polymer (polyvinyl pyrrolidone) and/or nonvolatile liquid (propylene glycol) affected tablet properties which involved longer disintegration time and lower DA dissolution. Optimized C. comosa liquisolid formulation was prepared in a carrier to coating ratio of 10 without additives. Stability studies showed that physical properties of liquisolid tablet were not affected by aging, but percent remaining and dissolution profiles of DAs were influenced by storage temperature. In vivo pharmacokinetic behavior of the optimized C. comosa liquisolid tablets was investigated following a single oral administration to rabbits. The results proved that the method used for preparation of liquisolid led to C. comosa tablets with low variation in content uniformity and tablet properties, as well as enhanced dissolution behavior.

Granular materials are part of the design, production and final products of different industrial sectors. Powder flowability is a major topic in manufacturing and transport as it is closely related to process feasibility. Nonetheless, the flows of granular materials are not easy to describe or quantify, even in the simple case of dry monodisperse cohesionless particles. Flowability assessment is not a standard or normalized issue; still, no test is able predict powder flow behavior in all the different mechanical situations encountered during processing. This study aims (1) to evaluate flowability, as device-related, through the force or the energy supplied to the powder bed and (2) to study the effect of glidants and moisture content on flowability. To illustrate these aims, the flowability of two well-known pharmaceutical excipients, Avicel® PH-102 and Retalac® mixed with four different types of precipitated nano-silica (SIPERNAT® D10, D17, 50 S and 500 LS), was assessed using two granular compaction devices: Densitap® and FT4® compaction cell. Our results show that the hydrophilicity of colloidal silica affects surface coverage, ranging from 6% to over 80%. Binary mixtures with hydrophobic additives, D10 and D17, generated smaller silica aggregates with a wider spread on the surface of host particles. For Retalac® conditioned at 20% RH, HR values changed from 1.30 (acceptable flow) to 1.17 (good flow). For Avicel® PH-102, conditioned at 60% RH, HR values changed from 1.22 (fair flow) to less than 1.10 (excellent flow).

Interactions occurring between components in the quaternary powder mixtures consisting of perindopril tert-butylamine, indapamide (active pharmaceutical ingredients), carrier substance and hydrophobic colloidal silica were examined. Two grades of lactose monohydrate: Spherolac(®) 100 and Granulac(®) 200 and two types of microcrystalline cellulose: M101D+ and Vivapur(®) 102 were used as carriers. We determined the size distribution (laser diffraction method), morphology (scanning electron microscopy) and a specific surface area of the powder particles (by nitrogen adsorption-desorption). For the determination of the surface energy of powder mixtures the method of inverse gas chromatography was applied. Investigated mixtures were characterized by surface parameters (dispersive component of surface energy, specific interactions parameters, specific surface area), work of adhesion and cohesion as well as Flory-Huggins parameter χ23('). Results obtained for all quaternary powder mixtures indicate existence of interactions between components. The strongest interactions occur for both blends with different types of microcrystalline cellulose (PM-1 and PM-4) while much weaker ones for powder mixtures with various types of lactose (PM-2 and PM-3).

The mechanism of colloidal silica action to improve flow properties of pharmaceutical powders is known to be based on inter-particle force disruption by silica particles adhered to the particle surface. In the present article, the kinetic aspects of this action are investigated, focusing on non-spherical particles of different size. Blends comprising microcrystalline cellulose or calcium hydrogen phosphate dihydrate and colloidal silica were examined using powder rheometer. The blends were formulated to represent effects of particle size, surface texture, colloidal silica loading, and mixing time. Pre-conditioning, shear testing, compressibility, and flow energy measurements were used to monitor flow properties. Components and blends were analyzed using particle size analysis and scanning electron microscopy (SEM), using energy dispersive spectroscopy (EDS) and back-scattered electron (BSE) detection to determine surface particle arrangement. All studied parameters were found to have substantial effects on flow properties of powder blends. Those effects were explained by identifying key steps of colloidal silica action, which were found to proceed at substantially different rates, causing the flow properties change over time being dependent on the blend formulation and the component properties.

In the present study, a novel hierarchical porous carbon monolith (HPCM) with three-dimensionally (3D) ordered macropores (∼400 nm) and uniform accessible mesopores (∼5.2 nm) was synthesized via a facile dual-templating technique using colloidal silica nanospheres and Poloxamer 407 as templates. The feasibility of the prepared HPCM for oral drug delivery was studied. Valsartan (VAL) was chosen as a poorly water-soluble model drug and loaded into the HPCM matrix using the solvent evaporation method. Scanning electron microscopy (SEM) and specific surface area analysis were employed to characterize the drug-loaded HPCM-based formulation, confirming the successful inclusion of VAL into the nanopores of HPCM. Powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC) demonstrated that the incorporated drug in the HPCM matrix was in an amorphous state and the VAL formulation exhibited good physical stability for up to 6 months. In vitro tests showed that the dissolution rate of HPCM-based formulation was increased significantly compared with that of crystalline VAL or VAL-loaded 3D ordered macroporous carbon monoliths (OMCMs). Furthermore, a pharmacokinetic study in rats demonstrated about 2.4-fold increase in oral bioavailability of VAL in the case of HPCM-based formulation compared with the commercially available VAL preparation (Valzaar ® ). These results therefore suggest that HPCM is a promising carrier able to improve the dissolution rate and oral bioavailability of the poorly water-soluble drug VAL.

Nateglinide is a non-sulphonylurea insulinotropic oral antidiabetic agent. The main problem in formulating an oral dosage form is its low solubility in aqueous media. This problem is particularly critical for an anti-diabetic drug because it should be administered just before the meals and be quickly bioavailable to cover the post-prandial glycemic peak. In this work, some technological approaches have been studied to improve the dissolution rate of nateglinide. Furthermore, two different polymorphs of nateglinide (H and B) have been tested to evaluate the influence of the crystal habitus on the dissolution behavior of the drug. The results have clearly demonstrated that wettability plays a key role in the dissolution behavior of nateglinide. As a matter of fact the physical dispersion of the drug with colloidal silica or hydrophilic swellable polymers strongly enhances the dissolution rate of nateglinide. The two polymorphs tested did not show significant differences in terms of dissolution behavior.

In order to compare the effects of hydrophilic and hydrophobic solid carrier on the formation of solid self-microemulsifying drug delivery system (SMEDDS), two solid SMEDDS formulations were prepared by spray-drying the solutions containing liquid SMEDDS and solid carriers. Colloidal silica and dextran were used as a hydrophobic and a hydrophilic carrier, respectively. The liquid SMEDDS, composed of Labrafil M 1944 CS/Labrasol/Trasncutol HP (12.5/80/7.5%) with 2% w/v flurbiprofen, gave a z-average diameter of about 100 nm. Colloidal silica produced an excellent conventional solid SMEDDS in which the liquid SMEDDS was absorbed onto its surfaces. It gave a microemulsion droplet size similar to that of the liquid SMEDDS (about 100 nm) which was smaller than the other solid SMEDDS formulation. In the solid SMEDDS prepared with dextran, liquid SMEDDS was not absorbed onto the surfaces of carrier but formed a kind of nano-sized microcapsule with carrier. However, the drug was in an amorphous state in two solid SMEDDS formulations. Similarly, they greatly improved the dissolution rate and oral bioavailability of flurbiprofen in rats due to the fast spontaneous emulsion formation and the decreased droplet size. Thus, except appearance, hydrophilic carrier (dextran) and hydrophobic carrier (colloidal silica) hardly affected the formation of solid SMEDDS such as crystalline properties, dissolution and oral bioavailability.

A novel freeze pelletization technique was evaluated for the preparation of wax-based sustained release matrix pellets. Pellets containing water-soluble drugs were successfully prepared using a variety of waxes. The drug release significantly depended on the wax type used and the aqueous drug solubility. The drug release decreased as the hydrophobicity of wax increased and the drug release increased as the aqueous drug solubility increased. In glyceryl monostearate (GMS) pellets, drug release rate decreased as the loading of theophylline increased. On the contrary, the release rate increased as the drug loading of diltiazem HCl increased in Precirol pellets. Theophylline at low drug loads existed in a dissolved state in GMS pellets and the release followed desorption kinetics. At higher loads, theophylline existed in a crystalline state and the release followed dissolution-controlled constant release for all the waxes studied. However, with the addition of increasing amounts of Brij 76, theophylline release rate increased and the release mechanism shifted to diffusion-controlled square root time kinetics. But the release of diltiazem HCl from Precirol pellets at all drug loads, followed diffusion-controlled square root time kinetics. Therefore, pellets capable of providing a variety of release profiles for different drugs can be prepared using this freeze pelletization technique by suitably modifying the pellet forming matrix compositions.

The aim of this study is to use texture analysis as a non-destructive test for hard gelatin capsules filled with liquid formulations to investigate mechanical changes upon storage. A suitable amount of water in the formulations is determined to obtain the best possible compatibility with the gelatin shell. This quantity of water to be added to a formulation is called the balanced amount of water (BAW). Texture profiling was conducted on capsules filled with hydrophilic polymer mixtures and with formulations based on amphiphilic masses with high HLB value. The first model mixture consisted of polyethylene glycol 400 and polyvinylpyrrolidone K17 with water and the second type consisted of caprylocaproyl macrogol glycerides (Labrasol®) with colloidal silica (Aerosil® 200) and water. The liquid-fill capsules were investigated by measuring changes on mass and stiffness after storage under confined conditions in aluminium foils. Capsule stiffness was investigated also as a parameter in a response surface analysis to identify the BAW. Polyvinylpyrrolidone did not show a great influence on the BAW in the range of 10–12% (w/w) for the first model mixture. Capsules with the less hydrophilic Labrasol® formulations, however, kept their initial stiffness after storage best with only half of that amount, i.e. 5–6% (w/w) of water in the compositions. From this study it can be concluded that texture profiling in the framework of an experimental design helps to find hydrophilic or amphiphilic formulations that are compatible with gelatin capsules. Short-term stability tests are meaningful if capsule embrittlement or softening is due to water equilibration or another migration process that takes place rapidly. Long-term stability tests will always be needed for a final statement of compatibility between a formulation and hard gelatin capsules.

A new particle design method was proposed for dry powder inhalation of hydrophobic cohesive drug particles (pranlukast hydrate, D 50 =2.1 μ m) by the surface modification with hydrophilic colloidal silica (AEROSIL, D 50 =16 nm). The surface of drug particle was modified by compounding AEROSIL (2–10%) under shear with a manually operating mortar (PM method) or a high-speed elliptical-rotor-type mixer (Theta-Composer ® , TC method). The surface modifications were also conducted by lyophilizing (FD method) or spray drying (SD method) the aqueous dispersions of the drug and AEROSIL. The surface modified particles were aerosolized through a Spinhaler ® and their inhalation behaviors were evaluated by a twin impinger in vitro. The inhalation behaviors were evaluated by the coefficient of inhalation efficiency (EI) defined as the geometric mean of the drug % emitted from the device and delivered % in respirable fraction of the twin impinger. The EI of modified particles with TC, FD and SD methods were dramatically increased up to 66.9, 52.7 and 47.7%, respectively, with increasing AEROSIL content compared with that of (22.4%) original powder. The surface modification to hydrophilic with AEROSIL reduced the cohesive force between the drug particles, owing to the decrease in van der Waals and electrostatic forces, improving the dispersibilities of emitted particles from the Spinhaler ® .

The in vitro release of physi- and chemiadsorbates of p-hydroxybenzoic acid methyl ester (PHBAME) on a colloidal (Aerosil 0 × 50; BET surface 50 m2 g−1) and a porous silica support (KG 100; mean pore size 10 nm, BET surface 300 m2 g−1) in an acidic dissolution fluid was investigated and the release kinetics described by mathematical modeling with an analog-hybrid computer. The release from physiadsorbates on both the colloidal and the porous silica proved to be a fast process, best described by two release constants. The release from the chemiadsorbates, however, is based on different mechanisms: from the plain surface of colloidal silica (fractal dimension 2.0) the drug release can be best described by two hydrolysis reaction rates while four different reaction rates were evaluated for the release of PHBAME from the porous support. From the reaction rates and the activation energies it is concluded that the hydrolysis of the surface link between the PHBAME and the silica surface, the Si-O-c bond is strongly influenced by the surface character of the supports, described by their different fractal dimensions (porous support fractal dimension 2.56).

Experimental factorial designs were built to investigate the effects of five parameters on production yields and moisture contents of spray-dried products. These factors concerned both the solution feed (drug concentration, colloidal silica concentration and polymer/drug ratio) and the spray dryer (inlet temperature and feed rate). Three formulations containing cellulose derivatives and acetaminophen were tested. The aim of the study was to optimize the operating conditions to maximize production yields while minimizing moisture contents. First screening experiments consisting of fractional factorial designs revealed the most significant factors to be inlet temperature, feed rate and their interaction for both formulations containing sodium carboxymethylcellulose and feed rate and colloidal silica concentration for the formulation containing microcrystalline cellulose. Then, the optimal operating conditions were estimated by response surface methodology. Central rotational composite designs showed quadratic models were adequate. New assays were carried out using these last conditions to evaluate both the repeatability and reproducibility of the spray-drying technique. Yields above 80% and moisture content of approximately 1% were reached. The characterization of microparticles revealed the poor flowability of the spray-dried products due to significant cohesiveness and very small size (less than 55 microm).

Three crystalline phases of carbamazepine (C), namely (i) the needle-shaped form I (tempered) with high crystalline order, (ii) beam-shaped form I (anhydrate) with lower crystalline order, which was prepared by dehydration of the dihydrate, and (iii) the prismatic form III , which is stable at room temperature, were prepared and their physical properties were determined. Then they were separately mixed with 40% (w/w) colloidal silica and stored open under climatic stress at 4 temperatures (56–72°C) and 3 relative humidities (41–71%). The physial and chemical stability of C was followed for 200 days. Form I (anhydrate) transformed under all conditions to form III , with the highest rate at 51° C, while the other phases were physically stable. C degraded chemically by hydrolysis to iminostilbene (IS); about 10 mol% were formed at the highest stress after 200 days. Small amounts of secondary products were detected. An initial constant degradation rate up to 1 mol% IS was followed by a slower, again linear degradation. The initial rates of formation of IS per unit surface area of the crystals (°k, mol%/day) were highest for form I (anhydrate) and lowest to form I (tempered). The calculated Arrhenius activation energies up to 67° C were of the order form III > form I (anhydrate) > form I (tempered) with 135, 125 and 104 kJ/mol, respectively. The energies of activation for chemical degradation correlate well with the content in free enthalpy of the respective crystalline phases and their correspondent physical stability.

The influence of mixing time and colloidal silica on the lubricating properties of magnesium stearate was studied using an instrumented single-punch machine. The lubricant was mixed with sodium chloride, anhydrous lactose, calcium citrate granulate and sodium chloride-colloidal silica-mixtures. Short mixing time decreased the negative effects of magnesium stearate on tablet strength and disintegration without reducing the lubricating efficiency. Addition of colloidal silica had a positive effect on the strength of lubricated sodium chloride tablets but increased the friction and did not improve the disintegration.

A directly compressible powder of the physical mixture and the complex of theophylline and phenobarbital was prepared directly from droplets using a spray-drying technique. Aqueous or ammonium hydroxide slurries of theophylline and phenobarbital, with colloidal silica or methylcellulose, were atomized by a centrifugal wheel atomizer into a drying chamber held at various temperatures. The products prepared from the aqueous slurry were physical mixtures of theophylline and phenobarbital with a small amount of the molecular complex. From the ammonium hydroxide slurry, the molecular complex containing a small amount of theophylline or phenobarbital was prepared. The parameters affecting the amount of the molecular complex contained in the resultant products were the amounts of excipients, i.e. colloidal silica or methylcellulose, and the composition ratio of theophylline to phenobarbital in the formulation used for spray-drying. Drying temperature also affected the amount of the molecular complex in the products

The intensity of the interactions between the components of the ternary powder system microcrystalline cellulose, magnesium stearate and colloidal silica have been predicted using literature and calculated values for their partial solubility parameters. These show that there is a greater interaction between magnesium stearate and colloidal silica than between magnesium stearate and microcrystalline cellulose, consistent with known literature data. With these results predictions can be made concerning the properties of tablets prepared from these ternary mixtures.