PARTICLE DEPOSITION CONTROL FOR VARIOUS WAFER SURFACES IN ACIDIC SOLUTION WITH SURFACTANT

Particle deposition control for various substrate surfaces was studied using acidic solution with surfactant. It has been demonstrated that particle deposition onto the various substrate surfaces in the chemicals depends on the zeta potential of particle and of the substrate surface. An anionic surfactant addition is found to make both particles and the substrate surface negatively charged, while a cationic surfactant addition is found to make both of them positively charged. The surfactant addition, therefore, can suppress particle deposition onto the substrate surface even when some particles remain in the chemicals.

When some chemical is carried over to the subsequent ultrapure water rinsing bath, this chemical carry-over triggers particle deposition in the ultrapure water rinsing stage when a cationic surfactant is used or when a hydrophilic surface is used. However, this phenomena is not observed when an anionic surfactant is used.

These results suggest that an anionic surfactant is effective in suppressing particle deposition onto the various wafer surfaces in acidic solutions.     

MASS TRANSFER OF SULFUR DIOXIDE TO CONDENSING AQUEOUS AEROSOLS

Sodium chloride aerosols were generated from a 1.0 percent solution and passed through a tubular furnace, then recondensed at 29°C in a cooling section in the presence of SO₂. The dry particles ranged from 0.711 to 0.843 µm and the condensed droplets were in the 1.66 to 2.88 µm range. Final droplet size was varied by controlling the temperature of the nebulizer solution between 17 and 50°C. The SO₂ concentration in the gas phase of the condensing cloud was varied between 0.5x10 - ³ and 2.5 xl0 - ³ atm.

Cloud droplets were separated from the gas stream in a point-to-plane electrostatic precipitator and the droplets analyzed colorimetrically for total sulfur content.

Concentrations of SO₂ in the aqueous phase were about one order of magnitude greater than values obtained from equilibrium constants. The collection rate of SO₂ at 29°C appeared to be first order in SO₂ gas phase concentrations.

A model for this process was constructed, based on the hydrate formation in the gas-water interface[SO₂]_g + n[H₂O]ℓ ⇋ [SO₂ · n(H₂O)]ℓ

The order of the hydrate n was estimated to be 4.0.     

Some Formulation Properties of Lapachol, A Potential Oncolytic Agent of Natural Origin

Lapachol is a naphthaquinone of natural origin with reported oncolytic activity. However, earlier antitumor studies were inhibited by inadequate blood levels, allegedly due to formulation difficulties.

This present study shows that water solubility is markedly influenced by pH, varying from 1.5 μg/mL at pH 4.0 to 5 mg/mL at pH 10.0.

Evaluation of mixed solvent systems demonstrated that up to 30 mg/mL could be dissolved in polyethylene glycol (PEG) 400. Aqueous PEG 400 solutions of lapachol were stable at refrigerator temperatures but deteriorated when exposed to light or autoclaving. Aqueous ethanol or propylene glycol are realistic alternative solvent systems for injectable lapachol solutions that may be sterilized by autoclaving.

Phosphatide stabilized triglyceride emulsions are broken down by lapachol, suggesting an interfacial interaction between the phosphatide and the lapachol in the aqueous phase.     

Preparation and Biological Evaluation of Ethylcellulose Microspheres Containing Tolmetin

Tolmetin microspheres were prepared by the coacervation process from the ethylcellulose. Microspheres were obtained both in presence and without protecting colloids, such as polyisobutilene (PIB) or ethyl-vinylacetate copolimers (EVA). The effect of these agents on the preparation, drug content, wall thickness, surface morphology, drug dissolution arid release from microspheres, were evaluated. The dissolution rate analysis was carried out also in the presence of a surfactant (Tween 80) at different pH values.

In addition, microspheres containing Tolmetin as a core material were submitted to biological tests, in comparison with the free drug, to evaluate upon experimental models the antipyretic activity and the gastric tolerability.     

Mechanism of signal suppression by anionic surfactants in capillary electrophoresis-electrospray ionization mass spectrometry

Micellar-mediated capillary electrophoresis (CE) is used for a wide variety of applications, including the separation of pharmaceuticals, environmental contaminants, illicit drugs, DNA fragments, and many other biological samples. The electrospray ionization interface is one of the most common CE-MS interfaces. Coupling micellar-mediated CE separations with MS detection combines two very powerful, widely applicable analytical techniques. Some types of surfactants strongly interfere with electrospray ionization mass spectrometric (ESI-MS) detection of analytes, and in many cases the ESI-MS analyte signals are completely quenched. Only a few reports have appeared that describe the ESI-MS detection of analytes in the presence of surfactants; however, the exact mechanism of ionization suppression has not yet been addressed. In this work, a modified aerosol ionic redistribution (AIR) model is presented that qualitatively explains the results of previous studies, including those using "polymeric surfactants". Analyte ionization suppression by surfactants appears to be caused by Coulombic interaction between oppositely charged solute and surfactant ions in the ESI-produced offspring droplets. It appears that the ability of surfactants to quench electrospray ionization is directly related to the surface activity and the charge of the surfactant. Also, highly surface active components tend to be enriched in ESI-produced offspring droplets. Analyte ion signals can be detected under conditions that lower the surface concentration of oppositely charged surfactant ions in aerosol droplets. The mechanistic information outlined here may be used to design micellar-mediated CE separations that allow detection of analyte ions by ESI-MS.     

Three Generations of Cyclosporine A Formulations: An In Vitro Comparison

When the microemulsion formulation of the critical dose drug cyclosporine A (CsA) (Sandimmun Optoral®) was introduced in the mid-1990s, it became clear that this new formulation improves the oral bioavailability of CsA and has a positive influence on its pharmacokinetic variability. Previous studies with the original CsA formulation (Sandimmun®) showed that the size of the emulsion droplets and concomitant food intake has an effect on the absorption of CsA from the small intestine when orally administered. It was suggested that these effects might have an influence on the drugs' pharmacokinetic parameters.

In this study, we focused on the two above-mentioned aspects and compared the first and second generations of CsA products (Sandimmun, Sandimmun Optoral) to generic CsA formulations by analyzing the contents of cyclosporine A gel capsules with respect to their emulsion droplet and micelle sizes using photon correlation spectroscopy (PCS). We tried to discern any differences in droplet size between different generations of CsA formulations, primarily the second and third generation, through simple physical tests. Because a high fat content food may influence the absorption of CsA, we also determined the distribution of CsA between hydrophilic and lipophilic phases using high-performance liquid chromatography analysis.

It became clear that when compared under simple physical conditions, established cyclosporine formulations and new generic products show significant differences in droplet size and distribution between an aqueous phase and a high fat content food. Whether these differences are of clinical relevance remains to be investigated.     

Some Properties of an Ethoxylated Castor Oil and Ethoxylated Oleyl Alcohol

Ethoxylated derivates have been used as surfactants for some years. In this work, ethoxylated castor oil and ethoxylated oleyl alcohol alone and/or their I:I mixtures were used as surfactants in oil/water type of emulsion systems.

The physicochemical properties of ethoxylated castor oil (Simulsol OL 50) and ethoxylated oleyl alcohol (Simulsol 98) have been investigated.

Both of these materials have properties associated with non-ionic surfactants, although considerably soluble in water, the compounds have slight solubility in nonpolar solvents.

Surface tensions of aqueous solutions were measured over a temperature range of 20°C to 40°C. CMC were determined by surface tension measurements. pH, refractive index, conductivity and density of the two surfactants were also determined.     

Profiling pH changes in the electrospray plume

Laser-induced fluorescence spectrometry is used to profile pH changes as droplets evaporate in an electrospray plume by measuring emission spectra of 2(or 4)-[10-(dimethylamino)-3-oxo-3H-benzo[c]xanthene-7-yl]-benzenedicarboxylic acid (carboxy SNARF-1), a pH-sensitive fluorescent dye. The observed pH changes depend on initial droplet pH and polarity. In some instances, small or negligible changes of pH are observed, consistent with expected buffering. The pH of initially acidic droplets decreases along the spray axis in both positive and negative ion modes, to an extent larger than expected from solvent evaporation. This phenomenon may be a manifestation of droplet cooling, droplet subdivision, or heterogeneous charge distribution within the spray plume or within individual ES droplets.     

Disintegration Mechanisms of Tablets Containing Starches. Hypothesis About the Particle-Particle Repulsive Force

The disintegration of a tablet immersed in a liquid appears to be essentially a mechanical phenomenon: penetration of liquid then destruction of compressed structure

For a number of authors, the starch granule swelling is the mechanical force which destroys the tablet.

Indeed, a study on a series of experimental carboxymethylstraches indicates that those that do not swell, show the same disintegration time to those that do swell.

We can also notice that the carboxymethylstarches wich swell much less in a gastric medium, produce even shorter disintegration times in this medium.

The destruction of the cohesion forces between the constitutive elements of the tablet under the action of water may be ascribed to the creation of a repulsive force when the elements of the tablet enter into contact with water, or to a simple annihilation of the hydrogen bonds or of the capillary cohesion forces.

The hydrophilic nature of starch seems to be determinant: water penetrates into the tablet owing to hydrophilic porosity under the action of an important hydrostatic pressure.     

The field-induced ion evaporation effect in the bipartition of charged droplets

A physical mechanism explaining the formation of a cluster phase during the electrostatic bipartition of droplets unstable with respect to their own charge is suggested. The mechanism assumes the possibility of the field-induced evaporation of ions from the surface of droplets of a micron size formed in the final stage of a droplet decay cascade.     

Optimal Massing Liquid Volume Determination by Energy Consumption Measurement: Study of the Influence of Some Physical Properties of Solvents and Products Used

This study tried to investigate, by the power comsumption technique, the influence of the powder's and solvent's properties on wet granulation.

It could be shown that the required amount of granulation liquid decreases when the particle size of the powder to be granulated increases. This relationship is however only true when the particle size distribution of the powder to be granulated is rather narrow.

Powders having the same solubility in different solvents require the same optimal liquid quantity for granulation, but the properties of resulting granules depend on surface tension and wetting properties of the solvent.

When the powder to be granulated contains crystallisation water, the temperature rising in the mixer can be sufficient to liberate this water, which must be taken into account in the optimal granulation liquid requirement.

The effect of a macromolecular binder (PVP, HPMC) has also been studied: the optimal liquid quantity required changes with the kind of binder used and the manufacturing process (binder used in solution or added as dry powder).

It was also shown that in the case of lactose, the optimal quantity of PVP or HPMC can be determined from the power consumption records and from the granules friability studies     

Disintegrants in Solid Dosage Forms

The dynamic approach to tablet disintegration, which is based on the measurement of the force that develops inside the compact upon water entrance, is basically taken up.

The combined measurements of force development and water uptake, simultaneously effected on the same compact, provide a novel parameter that is proposed to quantify and compare the efficiency of disintegrants.

The new parameter, which is based on the “force-equivalent” concept, expresses the capability of a disintegrant of transforming water uptaken into swelling (or disintegrating) force. A few examples, that illustrate the usefulness of this parameter for disintegrant characterization, are given.

In parallel to the quantification of swelling (or disintegrating) efficiency inside compacts, attention is also being paid to the characterization of swelling disintegrants as pure materials.

In particular the case of the so-called limited swelling materials, for which the quantification of intrinsic swelling (particle volume increase in swelling media) is critical, is considered.

The applicability of an instrumental method, which is based on the employment of a Coulter Counter, is discussed alternatively to microscopic methods.

Disintegrant characterization may also be considered in view of new possible exploitations of the swelling properties of polymers in controlling drug release.     

ULTRA-PRECISION DIAMOND MACHINING OF ADVANCED TECHNOLOGY COMPONENTS

The design, development, and application of ultra-precision CNC machines for

the single point diamond turning of non-conventional metal optical components (Al, Ge, etc. )

the diamond grinding of ferrite and, other ceramic components for magnetic disc flying heads, etc.

is described. In both cases, tolerances on workpieces in the order of ± 0·1 μm were specified and achieved, together with the overriding need to minimize degenerated surface layers, i.e. surface damage.

The effects of chip formation at low depths of cut are discussed. The factors affecting the depths of “damaged layers” formed in turning and grinding are mentioned. Typical advanced technology components for which ultra-precision diamond turning or grinding are widely used are:

Convex mirrors for high output C0₂ laser resonators

X-ray mirrors

infrared lenses in germanium for thermal imaging systems

scanners for laser printers. and drums for copiers

elliptical mirrors for YAG laser beam collectors

spherical bearing surfaces in beryllium, copper, and other materials

ceramics for magnetic read/write heads for computer memory discs

ceramics for cams, cam followers, valve seat inserts, cylinder liners, bearings, cylinder heads, turbo impell ers, etc.

Both single point and diamond grinding for ultraprecision low stress surfaces demand high precision machines that provide

high stiffness of structures and high band-width servo drives;

low rumble, high averaging bearings such as hydrostatic air or oil;

high internal damping of stuctures and drive systems;

multi closed loop control of many parameters, including temperature of coolant and temperature gradients across structures and sub-systems;

coolant delivery to the abrasive/workpiece interface is of critical importance for controlling high surface finish and minimizing surface tresses.

The paper gives examples of how these problems are satisfied in today's state of the art ultra-precision CNC machine tools.     

The Release Rate of Indomethacin from Solid Dispersions with Eudragite

The coprecipitates were prepared by a solvent technique using Eudragit E as carrier and indomethacin as a model drug.

X-Ray diffractometry, differential scanning calorimetry (DSC) and wettability tests were employed to investigate the physical state of the studied formulations. Up to 50% of indomethacin can be dispersed in an amorphous state in Eudragit E.

The influence of the pH on the in vitro release of solid dispersions has been evaluated. Because of the good solubility of Eudragit E at pH 1.2 a fast dissolution rate of the drug was observed while a marked delay was noticed at pH 7.5 where the polymer is only permeable to water. At pH 5.8 the kinetics of drug release can be modulated by the drug/polymer ratio. The dissolution rate of the drug can be increased by decreasing its amount in the coevaporate.     

Carbamazepine Modified Release Dosage Forms

The preparation of sustained release dosage forms of Carbamazepine (anti-epileptic drug characterized by a very low water solubility and by a short half life on chronique dosing) was carried out.

These formulations were obtained in two different steps:

a) modified release granules were prepared by the loading of cross-linked sodium carboxymethylcellulose (swellable polymer), with the drug and an enteric polymer. Cellulose acetate phthalate, methacrylic acid - methacrylic acid methyl ester copolymer (usually employed as enteric coating agents) and cellulose acetate trimellitate (a new enteric polymer) were used in different weight ratios.

b) some sustained release dosage forms were prepared tabletting physical mixtures of the modified release granules with different weight ratios of hydroxypropylmethylcellulose.

In vitro dissolution tests of modified release granules in gastric fluid (USP XXI) showed a modulation of the drug release, while in intestinal fluid (USP XXI) a quick drug dissolution was observed.

In vitro dissolution tests of sustained release dosage forms, performed varying during the test, the pH of the dissolution medium, (hydrochloric acid pH 1 from 0 to 2 hours and phosphate buffer pH 6.8 from 2 to 18 hours) showed that the determining factors in the controlling release of the drug are: the type and amount of enteric polymer constituting the granules and the amount of hydroxy-propylmethylcellulose mixed with them.     

Study of chemistry in droplets with net charge before and after Coulomb explosion: ion-induced nucleation in solution and implications for ion production in an electrospray

Droplets with net charge are essential intermediaries in the production of gaseous ions in the electrospray (ES) ion source. There could be a wealth of knowledge regarding the chemistry that occurs in such droplets as a result of their violation of electroneutrality. Such information could lead to improved understanding of the ion generation process in an ES along with factors that affect it. The experiments performed involved the levitation of individually charged droplets that were, and were not, allowed to undergo Coulomb explosion while they remained levitated in an electrodynamic balance (EDB). Through examination of precipitates formed within the levitated droplets, it was observed that onset of NaCl precipitation was promoted in droplets (glycerol:water 9:1 v/v) that had mass-to-net-charge (m/z) ratio <-4.8 x 10(9) amu/e. This threshold m/z value is exceeded in essentially all droplets generated in an ES because it is above the calculated threshold for Coulomb explosion. This finding suggests that cluster formation in droplets having net charge could occur at solute concentrations lower than would be anticipated on the basis of homogeneous nucleation. The effect of large entities such as precipitates existing in the droplet on the dynamics of droplet Coulomb explosion was also examined. Using droplets whose initial size and magnitude of net charge were equivalent within experimental error but having different concentration of solutes, we showed that the m/z of their main residues following Coulomb explosion were different. Micrometer-size droplets containing 20 nm fluorescent beads that underwent Coulomb explosion resulted in main residues that had higher m/z for higher initial bead concentration in the starting solution (320 nM) when compared to main residues resultant from starting solutions having lower initial bead concentration (21 nM).     

MORPHOLOGICAL TEXTURAL FEATURES

This paper describes the statistical and mathematical models for the gray level surface. Morphological Textural Features (MTFs) derived from the models are invariants. They include:

• Bessel-Fourier Coefficients

• Measurments of Gray Level Distributions

• Rotational Symmetry

• Translational Symmetry

• Coarseness

• Contrast

• Roughness

• Regularity

Potential Applications in Particle Technology are also outlined.     

The Granulation of a Tablet Formulation in a High-Speed Mixer, Diosna P 25

The impeller speed, the loss-on-drying of starch, and the added amount of water significantly influenced these response variables: granule fractions of less than 0.150 mm and more than 2.00 mm; and granule median diameter. The influence of the drug concentration on the response variables was less important. All the response variables showed significant interactions.

At a fixed impeller speed, the fine fraction was reduced when the loss-on-drying of starch increased, and when water was added in increasing amounts. The coarse fraction and granule median diameter increased along with an increasing moisture content in the starch. Increasing amounts of added water had the same effect.

The response surface contours of a fraction less than 0.150 mm, and a fraction exceeding 2.00 mm, were plotted. So was the granule median diameter. Suitable levels for the processing variables involved in obtaining a granulation of the desired proportions - fine or coarse fraction - can be read from the contour plots.

Heat was generated in the mixer during kneading, which caused some evaporation of water.

The change in the rotation rate of the impeller during the addition of the granulating liquid can be used as an indication of the fraction percentages below 0.150 mm and above 2.00 mm, but not of the median diameter     

Development and Validation of Method for Determination of In Vitro Release of Retinoic Acid from Creams

The objective of this study was to develop and validate an in vitro test method that can be used as a tool for accessing batch-to-batch uniformity of finished topical products. The studies were performed by utilizing topical creams containing the 13-cis isomer of retinoic acid. Various physicochemical factors which may affect drug release from topical cream formulations were evaluated including drug concentration, internal phase droplet size distribution, viscosity and the composition of the emulsion internal and external phases. Utilizing a modified Franz diffusion cell with a cellulose membrane, the in vitro drug release profile from various cream formulations was established

The effect of varying the concentrations of various key ingredients by 30% does affect the viscosities and release rates compared to a standard formulation. However, there is no correlation between the viscosities and the release rates. No significant differences in pH and droplet size distribution were observed in these cream formulations compared to a standard formulation. The oil phase volume ratio appears to have the largest influence on the in vitro release of the drug. Intra- and inter-batch comparisons of the finished cream products show reproducible release profiles. Based on the results obtained in this study, when used together, both in vitro release and viscosity measurements may be useful as tools to assess batch-to-batch uniformity and consistent manufacturing of the finished cream product     

Mass spectrometry of acoustically levitated droplets

Containerless sample handling techniques such as acoustic levitation offer potential advantages for mass spectrometry, by eliminating surfaces where undesired adsorption/desorption processes can occur. In addition, they provide a unique opportunity to study fundamental aspects of the ionization process as well as phenomena occurring at the air-droplet interface. Realizing these advantages is contingent, however, upon being able to effectively interface levitated droplets with a mass spectrometer, a challenging task that is addressed in this report. We have employed a newly developed charge and matrix-assisted laser desorption/ionization (CALDI) technique to obtain mass spectra from a 5-microL acoustically levitated droplet containing peptides and an ionic matrix. A four-ring electrostatic lens is used in conjunction with a corona needle to produce bursts of corona ions and to direct those ions toward the droplet, resulting in droplet charging. Analyte ions are produced from the droplet by a 337-nm laser pulse and detected by an atmospheric sampling mass spectrometer. The ion generation and extraction cycle is repeated at 20 Hz, the maximum operating frequency of the laser employed. It is shown in delayed ion extraction experiments that both positive and negative ions are produced, behavior similar to that observed for atmospheric pressure matrix-assisted laser absorption/ionization. No ion signal is observed in the absence of droplet charging. It is likely, although not yet proven, that the role of the droplet charging is to increase the strength of the electric field at the surface of the droplet, reducing charge recombination after ion desorption.