Polymorphism of Fostedil: Chracterization and Polymophic Change by Mechanical Treatments

Abstract

Two crystal forms of fostedil were characterized using X-ray diffraction patterns and infrared spectra. The melting points of polymorph I and II were 95.3 °C and 96.4 °C, respectively.

Solubility studies demonstrated that, of the two fostedil polymorphs, form II was slightly more soluble than form I. The free energy difference between two polymorphs was small (71.8 cal/mol at 37 °C). Both crystals melted at about 60 °C in water considerably below the melting points.

Compression of form II at a compression force of 500 - 1000 kg/cm² induced polymorphic changes in the crystal. Similar changes also were produced through grinding. The effects of some diluents on the polymorphic transformation from form II into form I by grinding were also studied. Microcrystalline cellulose and corn starch showed a polymorphic transfomation-accelerating effects.

Form I is more suitable for the pharmaceutical preparation.     

Phase Transformations in Sulfathiazole During Mechanical Activation

The effect of mechanical treatment in a planetary ball mill on the transformations of polymorphs of sulfathiazole were studied by means of X-ray diffraction analysis, infrared spectroscopy and differential scanning calorimetry. It has been shown that mechanical treatment initiates transitions of sulfathiazole polymorphs III ⇆ I. In an initial period of mechanical treatment a part of the sulfathiazole was converted into a noncrystalline solid. Preliminary mechanical treatment of form III resulted in the reduction of III—I phase transition temperature by 20-30°C in the samples without form I and by 40-50°C in the samples where the part of the substance were transformed into form I during mechanical treatment.

Single crystal thermomicroscopy studies showed that III → I phase transition proceeds via nucleation and a rapid advance of an interface through the crystal.

It seems that deformation of crystals during mechanical treatment and formation of noncrystallirie solid with high extent of disordering make probable the initiation of phase transition of sulfathiazole during mechanical treatment.     

Studies on spironolactone polymorphic forms

The phenomenon of polymorphism of spironolactone was studied using melting point and aqueous solubility determinations, infrared spectroscopy, differential thermal analysis, X-ray powder diffraction and powder dissolution. The results showed that spironolactone crystals obtained from ethyl acetate had the lowest melting range, while those obtained from acetonitrile had the highest range. The aqueous solubility data indicated the presence of different forms of spironolactone, each with a specific solubility, although practically all of these forms could be considered to be water-insoluble. The infrared spectra were not useful in clearly distinguishing between the different forms. Differential thermal analysis curves indicated that some of the forms obtained by treating spironolactone with different solvents were somewhat similar, others were variable, but all of them were different from the original form of the drug. Moreover, the thermal study proved the absence of any solvates. X-ray patterns were different in spacing (d) values and intensities of radiation absorption, confirming the presence of four different forms of spironolactone. The form obtained from ethyl acetate had the highest dissolution rate, while that obtained from acetonitrile had the lowest rate.

Spironolactone is known to crystallize out from different solvents in different polymorphic forms and to undergo structural rearrangements on heating.^{1, 2} The study was mainly concerned with the infrared identification of steroids, and the results showed that sample preparation techniques have a profound effect on the spectra of these steroids.

Florence and Salole³ undertook a brief investigation into the effects of grinding on the crystalline properties of spironolactone. The results showed no major changes in infrared spectrum after grinding, apart from a decrease in resolution of the absorption peaks. The premelting behavior of the drug was altered, which would indicate that grinding significantly affected the spironolactone crystallinity.

El-dalsh et al.⁴ showed that spironolactone co-precipitate with povidone using different solvents such as absolute ethyl alcohol, acetonitrile and chloroform had a different X-ray diffraction pattern which may be explained on the basis of various polymorphic forms.

The purpose of the present work is to carry out studies to specify the number of polymorphs of spironolactone under the crystallization conditions.     

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.     

Polymorphic Transitions of Carbamazepine During Grinding and Compression

Carbamazepine is a potent anticonvulsivant, but, irregular plasma levels are noticed. The variability of therapeutic efficiency can be attributed to interindividual sensibility, chronobiologic effect, but also to rates of dissolution which can differ when polymorphs are induced by technologic operations.

Several crystalline forms of Carbamazepine have been characterized. As for us, we have studied three crystalline modifications which can be found in commercialized galenic forms: the most usual beta form, the alpha form and the dihydrate.

The aim of this work was to investigate:

- the behaviour of these three crystalline forms during compression

- the possibility of crystalline structural changes under grinding and tabletting conditions. Indeed, polymorphous transformations may occur during technologic operations such as grinding or compression owing to the increase of internal energy.

Grinding was performed in a ball mill for 15 and 60 minutes. Compression was carried out using an instrumented single punch machine. The different parameters of compression, and hardness of resulting tablets were investigated.

X Ray diffraction and Differential scanning calorimetry were carried out on the different samples of ground powders and on carefully crushed samples of each batch of tablets.

The results point out at the best compressibility of dihydrate, and the most effective stability of the alpha form. However, the usual beta form remains stable in normal conditions of fabrication and storage.     

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.     

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.     

Physicochemical characterization of glybuzole polymorphs and their pharmaceutical properties

Systematic polymorphic screening tests were performed using 11 kinds of solvents and 6 kinds of preparation methods, and the three specific modifications of glybuzole (forms I and II and amorphous form) were identified by X-ray diffractometry and differential thermal analysis (DTA). The physicochemical properties of forms I and II and amorphous forms were measured using X-ray diffractometry, differential scanning calorimetry (DSC), thermogravimetry (TG), scanning electron microscopy (SEM), solubility tests, and others. The solubilities of all modifications in JP XII, first and second fluid (pH 1.2 and 6.8, respectively) were evaluated at 37°C. Forms I and II and the amorphous form showed almost equivalent solubilities. Forms I and II were stable polymorphic forms at 0% and 75% relative humidity (RH), respectively, at 40°C for 2 months, but the amorphous form was not stable. The crystallization rates of the amorphous form at 0% and 75% RH at 40°C were estimated by X-ray diffraction analysis based on the Jander equation, and the rate at 0% RH was 364 times slower than that at 75% RH.     

Elaboration and Physical Study of an Oxodipine Solid Dispersion in Order to formulate Tablets

When drugs particles are very hydrophobic, the carrying out of solid dispersion is a good process in order to obtain a faster drugh dissolution due to the particle the particle size reduction and due to the wettability improvement of the particle surfaces.

The behaviour of these products may differ according to their physical structure, more particularly the dissolution rate of the drug and the stability of the solid dispersion obtained.

The aim of this work is

— to study a product supplied by industry, that is to say a Coprecipitate obtained by evaporation of an ethanolic Oxodipin/Povydone solution. The high melting point of Oxodipin has conduct us to choose coprecipitation. The oxodipin amount in the coprecipitate (20%), is a good compromise between efficiency and technological properties.

— to demonstrate that the product obtained is a solid dispersion.

— to test its stability during compression and during the stockage ether in ambient condition, or at 40° C, or in controled humidity conditions.

Results seem to demostrate that a solid disperision which is a solid solution is obtained. This solid dispersion presents a very good stability of its physical structure and of dissolution properties.     

Solid State Characterization of Stanozolol

A study was undertaken to illustrate the ability to characterize various crystal forms of Stanozolol by by thermal analysis (differential scanning calorimetry-DSC), X-ray powder diffraction (XRPD), and Fourier transform infrared spectroscopy (FTIR). Mixtures of forms I and II were prepared and analyzed by each technique to investigate the strengths and weaknesses of the three methods. The detection of a contaminant polymorph in mixtures of forms I and II was possible by both FTIR and XRPD but not possible by DSC.

Various solvated forms were prepared by recrystallization from methanol, ethanol, 2-propanol, and were shown by thermal gravimetric analysis to exist in a 1:1 stoichiometry with Stanozolol. XRPD analysis of solvates indicated that each solvated form (monohydrate, ethanol solvate, methanol solvate, 2-propanol solvate) exists in a crystal unique with respect to forms I and II.

The concentration of drug in solution for the different crystal forms was determined at room temperature in 2% SLS at 5 and 24 hours. A significantly higher concentration was observed for the form II sample at 5 hours versus the form I and the monohydrate samples. It is likely that the form I sample had converted to the monohydrate form after 5 hours and a maximum concentration would be observed at an earlier time. At 24 hours, both the form I and II samples had converted to the monohydrate form and concentrations of 0.5-0.6 mg/mL were observed for each form. Due to the transformations to the hydrate during solubility studies, meaningful comparisons were difficult.     

Thermal Aging of Combustion Chemical Vapor Deposited Oxide Coatings

Zirconia coatings containing yttria were deposited onto sapphire substrates using liquid fuel combustion chemical vapor deposition (CCVD^sm ) and subsequently aged in air at 1,200°C. Toluene solutions, containing 2.5 and 7.5 mole percent Y 2-ethylhexanoate (Y 2-EH) (balance Zr 2-EH( and total metal concentrations (Zr + Y) of 0.005 M and 0.02 M, were used. All coatings were polycrystalline with those produced from the higher Y 2-EH solutions displaying complex microstructures, including dendrites at the higher molarity. Gas temperatures measured with a thermocouple during deposition near the substrate surfaces were between 1,200 and 1,400°C

Thermal aging produced significant effects on the coatings' morphologies and x-ray diffraction-patterns. Diffusional processes during annealing caused particle coalescence, and smoothed and densified the coatings. The x-ray diffraction data indicate that substantial micro structural! changes occur in these coatings at 1,200° C.     

The effect of ultrasonic vibration on the compaction characteristics of ibuprofen

An ultrasonic (US) compaction rig has been developed, capable of providing compaction pressure together with high-power ultrasonic vibrations of 20 kHz to a powder or granular material in a die. The rig has been used to investigate the effect of ultrasound on the compaction properties of ibuprofen, a drug with poor compaction properties which produces tablets that are weak and frequently exhibit capping. It was found that coherent ibuprofen tablets could be prepared by ultrasound-assisted compaction at pressures as low as 20-30 MPa. Application of ultrasound before and after compaction was found not to be as effective as ultrasound applied during compaction. The breaking forces of the tablets produced with ultrasound applied during compaction were found to be consistently significantly higher than when compaction was performed conventionally, or with ultrasound applied before or after compaction. Application of ultrasound during compaction made it possible to increase tablet mechanical strength, typically by a factor of 2-5. It was concluded that pressure should be applied together with ultrasound in order to achieve a better acoustical contact, which is required to transmit vibrations from the horn to the material, and also to bond the surfaces of the particles.

Ultrasound application during ibuprofen compaction also resulted in an increase in the apparent density, in relation to the apparent density of conventionally prepared tablets, of up to 14.4%. Ultrasound appears to improve particle rearrangement and provides energy for partial melting of particle asperities and subsequent fusion of particle surfaces, so as to increase interparticulate bonding. Solid bridge formation was thought to result in a reduction of void space, which in turn reduced the rate of water penetration into the compacts and consequently increased disintegration and dissolution times.

It was found that the results of ultrasound-assisted compaction are influenced by formulation and US time. When ibuprofen was mixed with a second material, such as dibasic calcium phosphate dihydrate (DCP) or microcrystalline cellulose (MCC), stronger tablets were prepared by ultrasound-assisted compaction compared to the compacts containing no filler. Positive interactions were considered to have occurred due to ultrasound-induced bonding between the two materials. With an increase in DCP and MCC concentration in ibuprofen formulations, disintegration and drug dissolution rates of the tablets produced with ultrasound significantly increased.

Using temperature-sensitive labels it was found that thermal changes occurred in powdered solids undergoing ultrasound-assisted compaction. Increases in the temperature of tablets were related to US amplitude and US time. With an increase in US amplitude from 5 to 13 µm, the temperature of the DCP tablet surface increased from 40 to 99°C. With an increase in US time from 1 to 5 sec, the temperature of the surface of ibuprofen tablets increased from 43 to 60°C. Increased tablet temperature was thought to be due to ultrasonic energy dissipation turned into heat.

X-ray powder diffraction (XRD) studies of ibuprofen tablets prepared by ultrasound-assisted compaction at 32 MPa revealed that no changes in chemical or/and crystalline structure of the material occurred when ultrasound was applied for up to 5 sec (US amplitude 7 µm). An XRD study of DCP tablets produced by ultrasound-assisted compaction at 32 MPa with ultrasound of different amplitudes (5, 7, 13 µm) applied for 2 sec indicated that no material deterioration occurred in all the tested samples.     

ELECTROCHEMICAL METALLIZING OF ADVANCED MATERIALS

Electrochemical metallizing provides sound metallurgical coatings for maintenance and production applications. The technique involves tankless electroplating, using a brush-on procedure.

Maintenance applications involve resizing, restoring, rebuilding or resurfacing worn, damaged, corroded, eroded or overmachined metal components. This paper deals with special production applications. The title may be a misnomer, since the paper deals with advanced materials, but also covers special unique applications and infrequently used metals and alloys.

For experimenting with new advanced materials, electrochemical metallizing is invaluable. Manually operated, not requiring large or expensive equipment, enabling rapid controlled deposition of numerous metals, alloys and composites, the system provides a low-cost experimental start-up procedure.

Advanced materials covered are primarily metal composites--nickel with a codeposited fluorinated carbon and a nickel-silicon deposit. The first has a decomposition temperature of 850° to 1000°F (460° to 535°C) and a very low friction coefficient. This makes it useful for high temperatures, low sticking and high wear applications, sometimes replacing Teflon or chromium. The second has a Vickers hardness of HV725 (at 100 grams load) and interesting high hardness applications. Also noted are nickel-silicon carbide, nickel-alumina-silicon dioxide and cobalt composites.

Special application deposits exist for preventing galling; improving brazeability; improved bonding of rubber or plastic to aluminum alloys; aluminum hard coatings; repairing electroless nickel; and light-absorbent surfaces.

Finally, the paper deals with electrochemical metallizing materials infrequently used, e.g. antimony, arsenic, bismuth, gallium, indium, palladium, rhenium, ruthenium, nickel-zinc, nickel-phosphorous, nickel-tungsten and tin-indium.     

Dissolution Rate of Polymorphs and Two New Pseudopolymorphs of Sulindac

This study reports the enhancement of sulindac dissolution rate by using the acetone and chloroform solvated forms. me intrinsic dissolution rates of potymorphs I and II and the influence of crystal habit on the drug dissolution process have also been studied. The dissolution properties were studied by calculating the intrinsic dissolution rate (k) by linear regression analysis from the amount dissolved versus time. The results indicated that the intrinsic dissolution rates of solvates in acetone and chloroform were much higher (k = 0.076 mg min^-1cm-², respectively) than those of polymorphs I and II (k = 0.036 mg min^-1cm^-2). However, the dissolution rates of the two solvates were found to be essentially the same and independent of the solvent nature. The intrinsic dissolution rates of form II recrystal-lized in methanol and ethanol differed (k = 0.031 and 0.036 mg min^-1cm^-2, respectively), which confirms the influence of crystal habit on sulindac dissolution rate. No significant difference in dissolution profiles were observed between forms I and II, in agreement with the similar values of fusion cemperature (1187 and 183°C respectively.     

Solubility Studia of Certain 2.3 Quinolino - Phthalidea

The solubilities of feve derivatives of 2.3 quinolino-phthalides in distilled water and in potassiem chloride solatioas of varying ionic atrength was detarained at 25°. 37°. and 51°C. The solubilities were lower in potassium chloride solutions: the over-all “aslting- out” comfficients were caleulated. for the effects of potaasium chloride using the empirical Setschenow equation logSo/S=KC

The differential beats of aolutions ranged from 2kcal/mole to 7.5 kcal/wole and were determined from the slopers of the semi-logaritimumic plots. of the solubilitiea verus the reciprocal temperaturas. The affect of the functional groups on this water solubilities of these compounds will be dlscussed.     

Study of the Relationship Between the Initial Rate of Moisture Sorption/Desorption of Norfloxacin Tablets to the Total Moisture and Temperature of Surrounding Environment

The relationship between absolute moisture content of air (expressed as pounds of water per pound of dry air) at 25°C and 40°C to the initial rate of moisture sorption/desorption of NORFLOXACIN tablets was studied. At the temperatures and relative humidities in the study, linear relationships were observed.

The initial rate of moisture sorption/desorption was found to be dependent upon both the moisture content as well as the temperature of the surrounding environment.     

Effect of Storage on the Properties of Acetylsalicylic acid Tablets Coated with Aqueous Hydroxypropyl Methyl-Cellulose Dispersion

The objective of this study was to investigate whether the properties of acetylsalicylic acid tablets coated with aqueous hydroxypropyl methylcellulose dispersion using glycerol or polyethylene glycol 6000 as plasticizer change during storage at 25° or 40°C. Titanium dioxide was used as pigment. The tablets were coated in a fluid bed apparatus. The disintegration time and the release of acetylsalicylic acid during two hours were determined for both uncoated and coated tablets immediately after their preparation and after different storage periods.

When the tablets were stored at room temperature (25°C) the coat protected the core efficiently against changes in the measured parameters as compared with uncoated tablets. However, at higher temperature (40°C) some unfavorable phenomena occurred in the coat and after storage of 48 months, the disintegration time was longer and the dissolution of acetylsalicylic acid slower than from uncoated tablets. Polyethylene glycol was found to be a better protecting agent than glycerol.     

Solubility of Various Sulfonamides in N-Alkanols I. Effect of Polarity and Temperature

The solubilities of several sulfonamides were studied at three temperatures over a wide spectrum of polarity of normal alcohols. The sulfonamides chosen for study were sulfasoxaeole, sulfadimethoxine, sulfasomidine and sulfadiazine and their solubility behavior in various alcohols such ae methanol through 1-decanol at 25°. 30° and 37°.

Solubility in alcohols was found to increase with temperature and the rank order of solubility at any temperature wae found to be in the general order of sulfasoxizole, sulfadimethoxine, sulfasomidine and sulfadiaeine. Solubility was found to be highest in methanol and diminished with increasing chain length of the alcohol.

The solubility magnitude for several of the sulfonamides gave an interesting reversal in 1-decanol and all the results obtained are discussed further in this communication.     

Gelatine Gels and Polyoxyethylene-Polyoxypropylene Gels: Comparative Study of Their Properties

ABSTRACT

Gelatine gels and polyoxyethylene-polyoxypropylene (Pluroni^R) F-108 and F-127 gels were prepared at concentrations ranging between 5 and 25% (W/V), the former by dispersion at 37°C, the later by dispersion at 4°C. The viscosity, the gel-sol transition temperature and the “in vitro” release kinetics of these gels were compared as a first step for the elaboration of parented controlled release formulations. Phenolsulphonftaleine (PR) was used as a tracer.

In all cases the viscosity increased with the rise in the concentration of gelatin (20 to 264 cps for 5 to 20%) or pluronic (260 and 1,520 cps for 20 and 25% F-108). The gel-sol transition temperature for gelatine gels was directly related to the concentration. On the contrary, for pluronic gels an inverse relation was observed, being the gel-sol transition temperature higher in copolymers with a large percentage of polyoxyethylene groups (30±0.2 °C for 25 % F-108). In both types of gels, a rise in pH and ionic strength decreased the gel-sol transition temperature, whereas PR increase this temperature. The release of the tracer, from the gels to the aqueous medium, showed a zero-order kinetics and the release rates were inversely proportional to the concentration of gelling agent.     

An Economical Heat Treatment Cycle for IMI Ti-230

IMI Ti-230 (Ti + 2.5% Cu) is a commercial age-hardening alloy which is capable of withstanding considerable cold deformation in the solution heat treated condition. Age-hardening is associated with the coherent Ti₂Cu precipitates. IMI recommends a duplex aging treatment comprising of nucleation (first aging) at 400°C for 24 hours followed by growth (second aging) for 8 hours at 475°C.

This investigation was aimed at designing a shorter and economical heat treatment cycle for achieving properties comparable to those obtained by the standard 32 hours duplex aging treatment as recommended by IMI. In addition, the effects of cold deformation at various stages in the aging cycle on the precipitation reaction were assessed by tensile property measurements.