The miniwid-coater: I. design and evaluation of a temperature-controlled miniature fluid-bed pan coater

Abstract

A novel miniature laboratory-scale pan coater has been developed. Small batches of 50 to 100 g of pellets, granules, large crystalls and small tablets allow the formulation development with minimal quantities of valuable drugs and new active ingredients. Although originally it is a pan coater, the core bed will be slightly fluidized by the inlet air flow due to the small dimensions of the coating pan. This allows a rapid drying and the loss of coating materials will be negligible.

A computer was used to control the core bed temperature during the coating process by varying the spraying rate of an analytical dosing pump. Additionally, the drying air temperature can be adopted. It was possible to change the parameters during the process to optimize the operation conditions within one run. The computer program described in this article provides a constant bed temperature with a precision of ± 0.3 °C.

In the MiniWiD-Coater, neutral pellets have been loaded with bisacodyl and then enteric-coated with aqueous dispersions of Eudragit L 30 D. Batch homogeneity and reproducibility were excellent. Friability of the cores and abrasion of the coat remained low. The loss of coating material during operation was always below 5 %.     

The MiniWiD-Coater. III. Effect of Application Temperature on the Dissolution Profile of Sustained-Release Theophylline Pellets Coated with Eudragit Rs 30 D

Theophylline pellets were coated with Eudragit RS 30 D in a miniature fluid-bed pan coater called MiniWiD developed recently. The dispersions were plasticized with varying amounts of triethyl citrate (TEC), dibutyl phthalate (DBP), and polyethylene glycol 6000 (PEG) and applied at different temperatures ranging from 25 to 45 °C. Theophylline release was tested by dissolution using the USP Apparatus 2 (paddle) in 0.1 N hydrochloric acid under sink conditions over 6 hours.

At a coating level of 4 % (0.7 mg/cm²) sustained-release profiles were obtained from dispersions plasticized with TEC or DBP. By reducing the amount of plasticizer from 20 to 10%, films with higher permeabilities were obtained. This effect was compensated by tempering the pellets at 50 deg;C for 24 hours. The coating temperature had little effect on the dissolution profiles of TEC-plasticized films and no effect on films with DBP.

Coatings plasticized with 20% PEG were applied at temperatures ranging from 25 to 45 °C. These films required a coating level of about 18 % (3.3 mg/cm²) to provide comparable sustained-release properties. In contrast to DBP and TEC, a strong influence of the coating temperature on the release rates was observed in which higher temperatures led to slower release rates. This behavior can be explained by the minimum film-forming temperature (MFT). Since PEG does not lower the MFT of Eudragit RS 30 D, the application of these films below the MFT of 45 °C is associated with a lower degree of film formation.     

The MiniWiD-COATER: II. Comparison of acid resistance of enteric-coated bisacodyl pellets coated with different polymers

Neutral pellets were loaded with bisacodyl and enteric-coated with hydroxypropyl methylcellulose acetate succinate (HPMCAS), carboxymethyl ethylcellulose (CMEC), cellulose acetate trimellitate (CAT), and poly(ethylacrylate, methacrylic acid) (Eudragit L 30 D) in a miniature fluid-bed pan coater called MiniWiD. Gastric juice resistance was tested by dissolution using USP Apparatus 2 (paddle) in 0.1 N hydrochloric acid under sink conditions over 6 hours. As a measure of enteric coating quality the USP specifications were used meaning that no more than 10 % of the drug should be released within 2 hours.

Organic-solvent based films of HPMCAS, CMEC and CAT at a coating level of 18 to 25 % provided gastroresistance for more than 6 hours. Aqueous suspensions of HPMCAS and CMEC as well as the ammonium salt aqueous solutions of CAT produced films with a short gastroresistance of below 0.6 hours. By doubling the coating level of water-based HPMCSD films the protection was prolonged to 3.4 h.

Enteric coatings were obtained from all aqueous latex dispersions of Eudragit L 30 D at a coating level of 24 %. The alteration of coating temperature between 25 and 45 °C had no significant effect on the release rates, whereas the variation of type and amount of plasticizer led to a different release rate after 2 hours. Best protection was obtained using films plasticized with 20 % of dibutyl phthalate (DBP) allowing a release of only 4 % of the drug in 6 hours although the application temperature was 15 °C below the minimum film-forming temperature (MFT). All coatings dissolved in artificial intestinal fluid within 15 minutes.     

Preparation of codeine-resinate and chlorpheniramine-resinate sustained-release suspension and its pharmacokinetic evaluation in beagle dogs

Using ion exchange resins (IERs) as carriers, a dual-drug sustained release suspension containing codeine, and chlorpheniramine had been prepared to elevate drug safety, effectiveness and conformance. The codeine resinate and chlorpheniramine resinate beads were prepared by a batch process and then impregnated with Polyethylene glycol 4000 (PEG 4000), respectively. The PEG impregnated drug resinate beads were coated with ethylcellulose as the coating polymer and di-n-butyl-phthalate as plasticizer in ethanol and methylene chloride mixture by the Wurster process. The coated PEG impregnated drug resinate beads were dispersed in an aqueous suspending vehicle containing 0.5% w/w xanthan gum and 0.5% w/w of hydroxypropylmethylcellulose of nominal viscosity of 4000 cps, obtaining codeine resinate and chlorpheniramine resinate sustained-release suspension (CCSS).

Codeine phosphate and chlorpheniramine maleate were respectively loaded onto AMBERLITE® IRP 69, and PEG 4000 was used to impregnate drug resinate beads to maintain their geometry. Ethylcellulose with di-n-butyl-phthalate in ethanol and methylene chloride mixture for the coating of drug resinate beads was performed in Glatt fluidized bed coater, where the coating solution flow rate was 8-12 g/min, the inlet air temperature was 50-60°C, the outlet air temperature was 32-38°C, the atomizing air pressure was 2.0 bar and the fluidized air pressure was adjusted as required. Few significant agglomeratation of circulating drug resinate beads was observed during the operation. The film weight gained 20% w/w and 15% w/w were suitable for the PEG impregnated codeine resinate and chlorpheniramine resinate beads, respectively. Residual solvent content increased with coating level, but inprocess drying could reduce residual solvent content.

In the present study, the rates of drug release from both drug resinate beads were measured in 0.05M and 0.5M KCl solutions. The increased ionic strength generally accelerated the release rate of both drugs. But the release of codeine from its resinate beads was much more rapid than chloropheneramine released from its resinate beads in the same ionic strength release medium. The drug release specification of the CCSS, where release mediums were 0.05M KCl solution for codeine and 0.5M KCl solution for chlorpheniramine, was established to be in conformance with in vivo performance.

Relative bioavailability and pharmacokinetics evaluation of the CCSS, using commercial immediate-release tablets as the reference preparation, were performed following a randomized two-way crossover design in beagle dogs. The drug concentrations in plasma were measured by a validated LC-MS/MS method to determine the pharmacokinetic parameters of CCSS. This LC-MS/MS method demonstrated high accuracy and precision for bioanalysis, and was proved quick and reliable for the pharmacokinetic studies. The results showed that the CCSS had the longer value of T_max and the lower value of C_max, which meant an obviously sustained release effect, and its relative bioavailability of codeine and chlorpheniramine were (103.6 ± 14.6)% and (98.1 ± 10.3)%, respectively, compared with the reference preparation. These findings indicated that a novel liquid sustained release suspension made by using IERs as carriers and subsequent fluidized bed coating might provide a constant plasma level of the active pharmaceutical ingredient being highly beneficial for various therapeutic reasons.     

Use of Colloidal Silica as a Separating Agent in Film Forming Processes Performed with Aqueous Dispersion of Acrylic Resins

Aqueous dispersion of polymers are going to take the place of the corresponding organic solution in the film forming process of tablets, pellets and granules, because of some definite advantages.

Among the additives used in formulation techniques, talc, that is normally utilized as an antiadherent and polishing agent, presents some problems connected with its tendency to form sedimentation. For this reason, during the film coating operation, the dispersion must be always kept under constant and proper agitation, however, the danger of blocking the piping and the spraying system of the equipment employed cannot be completely avoided.

On the bases of these observations, the aim of this research work is to evaluate the possibility of substituting talc with colloidal silica as separating agent in aqueous dispersion of film acrylic resins, normally used in the preparation of prolonged release systems.

Results concerning fluid bed coating processes of pellets prepared by extrusion-spheronization technique have been reported, with particular attention to usable concentration of colloidal silica and to possible influence of these on the drug release characteristics of the systems obtained.     

Acrylic Latices from Redispersable Powders for Peroral and Transdermal Drug Formulations

Aqueous dispersions of acrylic resins may be converted to pow ders by spray or freeze drying. Such solids contain loose ag glomerates of discrete latex particles, that disintegrate easily into the original latex particles of less than 2 µ;m in diameter. No film formation occurs, provided that the minimum film forming temperature of the latex is not exceeded during drying.

Such powders can be redispersed in water in the presence of 3-6 mol% of alkali or organic bases to obtain a stable latex system. This can be used for enteric film coating in the same way as the original latex dispersions.

Redispersed methacrylic acid copolymers can be mixed with neu tral, permeable emulsion polymers to adapt the release profile of drugs more specifically to match their pharmacokinetic prop erties. In this way the pH-dependent solubility of methacryic acid copolymers, which controls the release in the gut by dissolution or increasing permeability can be combined with the pH-independent permeability of neutral acrylic ester polymers, to give time controlled retardation. Similar formulations of acrylic resins can also be used to solve several problems of transdermal delivery systems.

The described redispersable polymer powders are stable under normal storage conditions, so their handling and use as redispersed aqueous coating formulations is much more easier and will open an extended field of application.     

The Design and Performance of an Instrumentation System for Aqueous Film Coating in an Industrial Tablet Coating Machine

In recent years tablet coating has undergone several fundamental changes. The original sugar coating technique has been largely replaced by film coating processes using organic solvents. The organic solvents are now being replaced by water because of the development of suitable polymers, improvements in the coating process, and impending government legislation regulating the discharge of pollutants into the environment.

This change has resulted in increased interest in equipment designed for film coating based on cylindrical shaped side vented pans which allow the drying air to be drawn through the tablet bed. However, the process is complex and requires careful monitoring and control to ensure satisfactory results. The empirically derived conditions are not fundamentally understood and there are important differences in the operation     

Research Papers: Preparation of Indobufen Pellets by Using Centrifugal Rotary Fluidized Bed Equipment Without Starting Seeds

ABSTRACT

Pellets containing Indobufen as model drug were prepared by using the centrifugal-rotary fluidized bed equipment without employing non-pareil seeds.

The influence of different amounts of spheronization enhancer (microcrystalline cellulose) and of different fillers (lactose, mannitol, calcium carbonate) on both processing and physical properties of the pellets were evaluated.

The preparation reproducibility was also investigated. The use of 30% w/w of microcrystalline cellulose was essential to produce a good quality pellets; the incorporation of filler decreased the qualitative characteristics of the pellets.

The water feeding rate proved to be an important parameter for the pellet growth.

Therefore, the results showed that this technology based on the rotary fluidized bed is a promising and alternative method in producing pellets.     

Eudragit RL and RS Pseudolatices: Properties and Performance in Pharmaceutical Coating as a Controlled Release Membrane for Theophylline Pellets

Theophylline Active pellets were coated with Eudragit RL and RS pseudolatices in a fluidized bed. The effects of polymer ratio, additional oven drying, addition of dispersed solids, and addition of water miscible organic solvents on sustained drug release through the lates film were determined by using a modified U.S.P. Paddle dissolution method.

The release rate of theophylline can be varied by changing the polymer ratio. permeability to the drug increases with an increase in the content of Eudragit RL. Additional oven drying at 60°C for 10 hours caused no significant change in the dissolution profiles. The addition of dispersed solids such as talcum and silica resulted in an increase in drug release rate. There is no significant change in dissolution profiles when 50% methanol or acetone was added to the Eudragit RS pseudolatex.     

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.     

Fabrication of Graded, Spray, and Fused Coatings and Their High Temperature Erosion Performance

Thermally sprayed coatings are often used industrially to protect bulk metal structural and heat exchange surfaces against wear and corrosion at high temperature. Spray and fused coatings of Ni-based alloys are dense, with metallurgical coating adhesion and have provided excellent industrial corrosion resistance. This process allows the addition of hard particles to improve coating wear resistance in a functionally graded manner, and the first such coating is developed. There has been few wear studies of such functionally graded materials (FGMS), particularly as coatings. Because such materials provide a gradation in properties such as hardness and thermal expansion coefficient between the coating and the substrate, it is thought that they may have potential in aggressive environments such as high temperature energy conversion processes (resisting spallation and erosion).

In a low velocity fluidized bed erosion environment the effects of erodent particle size and bed temperature on the erosion rate through the section of a functionally graded spray and fused coating was studied. The coating consisted of a varying fraction of WC particles (0-42 vol.%) in a Ni-Cr-based, self-fluxing matrix. The erodent particle size varied from 200 to 600 μm, testing was between 25 and 600°C, with impact angles of 30° and 90°.     

Eudragit NE40–Drug Mixed Coating System for Controlling Drug Release of Core Pellets

This study was aimed at developing a controlled-release coating system around core pellets with aqueous dispersion, along with some water channeling agents. Core pellets of diltiazem were prepared using the extrusion-spheronization technique and subsequently coated with aqueous dispersion of Eudragit NE40 alone, or drug–polymer mixtures using bottom-spray fluidized bed coater. The lag time in drug release profiles increased as the coating levels of Eudragit NE40 were increased, whereas no lag time was observed in core pellets coated with drug–polymer mixtures. Mixed coating at the 7% level exhibited comparatively better release profiles and provided desirable release rates during the 12-hour testing interval. Diltiazem HCl release from mixed coating was fairly independent of pH and drug loading. Curing of coated pellets was found to be an essential step for stable drug release profiles. The selection of core size range had remarkable effect on drug release rate and was considerably reduced by using greater core size.     

Eudragit NE40-Drug Mixed Coating System for Controlling Drug Release of Core Pellets

This study was aimed at developing a controlled-release coating system around core pellets with aqueous dispersion, along with some water channeling agents. Core pellets of diltiazem were prepared using the extrusion-spheronization technique and subsequently coated with aqueous dispersion of Eudragit NE40 alone, or drug-polymer mixtures using bottom-spray fluidized bed coater. The lag time in drug release profiles increased as the coating levels of Eudragit NE40 were increased, whereas no lag time was observed in core pellets coated with drug-polymer mixtures. Mixed coating at the 7% level exhibited comparatively better release profiles and provided desirable release rates during the 12-hour testing interval. Diltiazem HCl release from mixed coating was fairly independent of pH and drug loading. Curing of coated pellets was found to be an essential step for stable drug release profiles. The selection of core size range had remarkable effect on drug release rate and was considerably reduced by using greater core size.     

Eudragit NE40-drug mixed coating system for controlling drug release of core pellets

This study was aimed at developing a controlled-release coating system around core pellets with aqueous dispersion, along with some water channeling agents. Core pellets of diltiazem were prepared using the extrusion-spheronization technique and subsequently coated with aqueous dispersion of Eudragit NE40 alone, or drug-polymer mixtures using bottom-spray fluidized bed coater. The lag time in drug release profiles increased as the coating levels of Eudragit NE40 were increased, whereas no lag time was observed in core pellets coated with drug-polymer mixtures. Mixed coating at the 7% level exhibited comparatively better release profiles and provided desirable release rates during the 12-hour testing interval. Diltiazem HCl release from mixed coating was fairly independent of pH and drug loading. Curing of coated pellets was found to be an essential step for stable drug release profiles. The selection of core size range had remarkable effect on drug release rate and was considerably reduced by using greater core size.     

Correlating bilayer tablet delamination tendencies to micro-environmental thermodynamic conditions during pan coating

Objective: The objective of this study was to determine the impact that the micro-environment, as measured by PyroButton data loggers, experienced by tablets during the pan coating unit operation had on the layer adhesion of bilayer tablets in open storage conditions.

Materials and methods: A full factorial design of experiments (DOE) with three center points was conducted to study the impact of final tablet hardness, film coating spray rate and film coating exhaust temperature on the delamination tendencies of bilayer tablets. PyroButton data loggers were placed (fixed) at various locations in a pan coater and were also allowed to freely move with the tablet bed to measure the micro-environmental temperature and humidity conditions of the tablet bed.

Results: The variance in the measured micro-environment via PyroButton data loggers accounted for 75% of the variance in the delamination tendencies of bilayer tablets on storage (R^2?=?0.75). A survival analysis suggested that tablet hardness and coating spray rate significantly impacted the delamination tendencies of the bilayer tablets under open storage conditions. The coating exhaust temperature did not show good correlation with the tablets’ propensity to crack indicating that it was not representative of the coating micro-environment. Models created using data obtained from the PyroButton data loggers outperformed models created using primary DOE factors in the prediction of bilayer tablet strength, especially upon equipment or scale transfers.

Conclusion: The coating micro-environment experienced by tablets during the pan coating unit operation significantly impacts the strength of the bilayer interface of tablets on storage.     

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.     

Phenylpropanolamine HCl Microcapsules: Preparation and release studies

Microcapsules of phenylpropanolamine HCL were prepared by three techniques, viz. coacervation-phase separation, air suspension, and pan coating, using different polymers and/or waxes as wall-forming materials.

Formulations showed reasonable dissolution behaviour, viz. microcapsules prepared by air suspension with polymer level of 20% polyvinyl acetate copolymer (PVAC) associated with 40% carnauba wax (II) and microcapsules prepared by pan coating with polymer level of 25% Rodopace^R (III), were evaluated for their absorption rates by demonstrating their toxicities compared to pure grug (I) by the LD₅₀ method. Toxicity assessment showed close agreement between the increase in lethal dose and the decrease in dissolution rate and revealed that Formula III has more prolonged action than Formulae II and I.     

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.     

A New Linear Model for Stability Prediction

Based upon Okusa's observation (Chem. Pharm. Bull. 1975) that the slopes of a linear plot of logo log fraction of active substance degraded vs log time for first order decay kinetics and a linear plot of log of drug remaining vs log time for a zero order decay kinetics are both unity, an algorithm has been developed to resolve both the energy of activation (E) and the rate constant (K_o or L_o) at the desired shelf-life temperature (T_o) by analysis of the y-intercepts of parallel slopes at more than one elevated temperature (T).

Preliminary estimates of both E and either K_o or L_o are then substituted into a series of mathematical expressions based upon well known Arrhenius relationship:

k = A ·exp -E/1.987) (1/T-l/T_o) where A = K_o or L_o

Using converging and interative techniques to treat elevated temperature data, the resulting mean loss rate (eithri K_o or L_o at the designated shelf-life temperature plus a residual error term thus obtained, is used to distinguish statistically between zero and first order treatments. A program called POTENCYLOSS, based upon the algorithm, has been written in business BASIC language for use with an IBM-PC micro-computer.

The program is ideally suited for use in preformulation studies or in assigning provisional expiration dating and overage requirements during the early stages of formulation development when there is limited potency stability test data available at accelerated, elevated temperature storage conditions.     

The Strength and Compaction of Millispheres: The design of a controlled-release drug delivery system for ibuprofen in the form of a tablet comprising compacted polymer-coated millispheres

This paper reviews a case study of the design of a controlled-release drug delivery system for ibuprofen in the form of a tablet comprising compacted polymer-coated millispheres (multiparticulate pellets). The particular challenge was to prepare coated millispheres of ibuprofen (a high-dose drug) with the addition of minimal excipients so that the drug-release retarding polymeric membrane surrounding the millispheres remains intact during and after tablet compression, disintegration and release of the millispheres. The study included (a) the design of the uncoated core and its manufacture by wet massing, extrusion, spheronization and drying; (b) the coating of these millispheres with a range of possibly suitable polymers; (c) an assessment of the drug release profiles from these pellets; (d) the quantification by indentation rheology of the mechanical properties of the polymer films used to coat the spheres; (e) the measurement of the mechanical properties of individual uncoated and coated millispheres and f. the design, manufacture and evaluation of compressed tablets containing coated millispheres

The matching of millisphere and polymer mechanical properties was found to be essential in order to ensure minimal damage to the millispheres and the release of virtually intact coated spheres without destruction of their retarded drug-release characteristics. Aqueous polymeric dispersions which formed a film with similar elastic and tensile properties to the uncoated millisphere formulation resulted in the most satisfactory film coating for application to spherical particles which must withstand compaction. Those polymeric films exhibiting significantly greater resilience than the uncoated cores were inappropriate for the film coating of millispheres for compaction into tablets