Fluid-bed coater modifications and study of their influence on the coating process of pellets

Objective: In this study, different modifications of bottom spray fluid-bed coater with draft tube inserted were characterized and evaluated. Materials and methods: After coating the neutral pellets with polymeric solution comprising coloring agent pellet batches were characterized for coating variation, yield and degree of agglomeration. Results: Funnel-shaped distribution plate was found to improve process yield and decrease the degree of agglomeration at selected values of process parameters, whereas coating uniformity was worse in all cases when compared to conventional Wurster chamber. Results of the coating chamber with the swirl airflow generator indicate more uniform deposition of the coating material and in some cases an improved process yield and decreased formation of agglomerates when compared to conventional Wurster chamber. In series of experiments using Wurster chamber, having tangentially oriented air intake slots, which enabled introduction of air above the distribution plate, coating layer was more uniformly deposited on the pellet cores and formation of agglomerates was lower compared to the results obtained in a conventional Wurster coating chamber. Conclusion: Modifications of Wurster coating process by introducing swirling air motion within the draft tube or by introduction of air above the distribution plate have at selected values of process parameters resulted in reduced per-particle coating variation, degree of agglomeration and improved process yield.     

Development of a Tamsulosin Hydrochloride Controlled-Release Capsule Consisting of Two Different Coated Pellets

Tamsulosin hydrochloride (TSH) controlled-release capsule (pellets) was successfully prepared using a novel, simple, and flexible multiunit drug delivery system, which consisted of two different coated pellets. The TSH-loaded core pellets consisting of microcrystalline cellulose (MCC), lactose, Carbopol^® 974P, and the active agent, were prepared by extrusion/spheronization method. Eudragit^® NE30D and Eudragit^® L30D-55 were used as the coating materials to prepare sustained-release (SR) pellets and enteric-release (ER) pellets. The coated pellets were prepared using two different equipments: centrifugal coater and fluidized-bed coater. By adjusting the ratio of SR and ER pellets, more than one blend ratios, which meet the in vitro release criterion were obtained. A similarity factor (f₂) was employed to choose the optimum proportion compared with the commercial product (Harnal^® capsule). The morphology of the pellet surfaces was examined by scanning electron microscopy (SEM) before and after dissolution. The release profiles were significantly affected by changing the proportions of SR and ER. The optimum ratio is SR:ER?=?2:1 using a centrifugal coater (f₂?=?61.93) and SR:ER?=?3:1 using a fluidized coater (f₂?=?66.42). This result suggests that blending these two-part pellets (SR and ER) can provide an alternative to preparing a controlled-release dosage form, instead of blending of the coating polymer.     

HWCVD of polymers: Commercialization and scale-up

GVD Corporation specializes in process development and equipment design for the production of ultra-thin polymer coatings using hot wire chemical vapor deposition (HWCVD, also known as initiated chemical vapor deposition, iCVD). HWCVD allows many coating compositions to be produced, including fluorocarbon and silicone polymers, copolymers, and vinyl hydrocarbon polymers. It is especially valuable for creating ultra-thin layers of insoluble, infusible polymers which are hard to process by conventional means, such as polytetrafluoroethylene (PTFE, Teflon^®). HWCVD PTFE coatings are chemically robust, comprised of essentially 100% CF₂, resistant to solvents, conformal to complex surface geometry, and have excellent adhesion to a wide range of substrates. Since the part to be coated remains at room temperature, fragile materials like plastics and fabrics can be coated with ease. GVD has focused on scale-up of the process equipment and has developed several standard coating systems, which will be discussed in this paper. These include laboratory-scale batch coating systems, a medium sized production batch coating system, a large scale custom batch coater, and a pilot scale roll-to-roll web coater. All of GVD's systems are complete with fully automated, computer based control systems and include options for effluent monitors and an exhaust scrubber.     

Investigation on influence of Wurster coating process parameters for the development of delayed release minitablets of Naproxen

The present work aims at studying process parameters affecting coating of minitablets (3?mm in diameter) through Wurster coating process. Minitablets of Naproxen with high drug loading were manufactured using 3?mm multi-tip punches. The release profile of core pellets (published) and minitablets was compared with that of marketed formulation. The core formulation of minitablets was found to show similarity in dissolution profile with marketed formulation and hence was further carried forward for functional coating over it. Wurster processing was implemented to pursue functional coating over core formulation. Different process parameters were screened and control strategy was applied for factors significantly affecting the process. Modified Plackett Burman Design was applied for studying important factors. Based on the significant factors and minimum level of coating required for functionalization, optimized process was executed. Final coated batch was evaluated for coating thickness, surface morphology, and drug release study.     

Enteric coating process of diclofenac sodium pellets in a fluid bed coater with a wurster insert: Influence of process variables on coating performance and release profile

The objective of this work was to study the coating process of diclofenac sodium pellets, with the commercial aqueous coating suspension for enteric release – Acryl-Eze® MP, in a fluid bed coater with a Wurster insert. Coating experiments were performed following a 2² factorial design to determine the influence of process variables on coating performance, measured by the two response variables: efficiency (η_%) and agglomeration index (m_agg%). Both response variables were found to be affected by inlet temperature and suspension flow rate with a 95% confidence level. This work also studied the release of diclofenac sodium coated and uncoated pellets in HCl 0.1 N and pH 6.8 phosphate buffer media. Results showed that the release of diclofenac sodium during the buffer stage was affected by the prior exposure to the HCl 0.1 N medium and a polymer weight gain above 9.7% (2.7 mg/cm²), was needed to modify the release in such a way that it remained below 10% for the first 120 min in HCl 0.1 N and above 75% in pH 6.8 for the next 45 min. Neither the drug content nor the release profiles were significantly affected by storage at 40 °C and 75% relative humidity.     

Project,Design, and Use of a Pilot Plant for Nanocapsule Production

The aim of this study was to find the scale-up parameters necessary for the preparation of nanocapsules (NCs) for pharmaceutical purposes. Starting from the laboratory scale (0.06 L), we designed and assembled a pilot plant (2 L) to produce NCs with the so-called emulsification-diffusion technique. We wanted to check if classical tools adequate for the pharmaceutical industry and for industrial scale-up purposes according to well-known chemical engineering technique could be used to perform the NC preparation. Experiments were carried out by varying some operative parameters, such as the impeller speed, the agitation duration for the emulsion preparation, and the reagent concentrations. As expected, good accordance between the NC produced at the laboratory scale and at the pilot plant scale was obtained. We conclude that the pilot plant can be used to perform a scale-up study of the industrial production of NC.     

Project, Design, and Use of a Pilot Plant for Nanocapsule Production

The aim of this study was to find the scale-up parameters necessary for the preparation of nanocapsules (NCs) for pharmaceutical purposes. Starting from the laboratory scale (0.06 L), we designed and assembled a pilot plant (2 L) to produce NCs with the so-called emulsification-diffusion technique. We wanted to check if classical tools adequate for the pharmaceutical industry and for industrial scale-up purposes according to well-known chemical engineering technique could be used to perform the NC preparation. Experiments were carried out by varying some operative parameters, such as the impeller speed, the agitation duration for the emulsion preparation, and the reagent concentrations. As expected, good accordance between the NC produced at the laboratory scale and at the pilot plant scale was obtained. We conclude that the pilot plant can be used to perform a scale-up study of the industrial production of NC.     

An optimized commercially feasible milling technique for molecular encapsulation of meloxicam in β-cyclodextrin

Background: The practical applicability of solid dispersions (SD) for improvement of oral bioavailability of poorly water-soluble drugs has still remained limited because of lack of feasibility for scale-up of manufacturing processes. The present research work deals with the preparation of SDs of meloxicam (MLX) with β-cyclodextrin (β-CD) by the ball-milling technique to overcome the scale-up issues.

Methods: Phase-solubility studies were conducted to analyze the influence of β-CD on solubility of MLX. In vitro dissolution studies on various complexes as well as tablets prepared on pilot scale in an industrial set up were performed and compared with the marketed products. Physicochemical characterization of optimized complexes was done using various methods to study drug-β-CD interaction.

Results: Solubility of pure MLX in water at 25°C was found to be only 9.4 µg/mL. The AL type of phase-solubility profile of MLX with β-CD [stability constant (K_1:1)?=?22.056?M^?1 and Gibbs free energy (ΔF^o)?=?–7.665 KJ/mole] confirmed the solubility enhancement capability of β-CD. Milling time of 6?h was considered to be optimum and showed maximum enhancement of drug dissolution. The amorphous nature of the milled complex and mode of interaction of MLX with β-CD was confirmed by differential scanning calorimetry (DSC), x-ray diffractometry (XRD), Fourier transform infrared spectroscopy (FTIR) and proton nuclear magnetic resonance spectrophotometry (¹HNMR). Tablets containing MLX-β-CD (1:1.5?M) milled complexes showed the best release (T_90%?=?10.94?min) compared to the marketed products (T_90% ≥ 450?min). Stability studies performed confirmed the integrity of the amorphous complex.

Conclusion: Stable inclusion complexes of MLX-β-CD with enhanced aqueous solubility and dissolution rate were prepared by a highly efficient and controlled large-scale milling technique.     

Formation of metal agglomerates during carbonisation of chromated copper arsenate (CCA) treated wood waste: Comparison between a lab scale and an industrial plant

This paper compares the results obtained by scanning electron microscopy coupled to X-ray analysis (SEM-EDXA) of the solid product after carbonisation of treated wood waste in a lab scale and in an industrial installation. These setups (lab scale and industrial) are characterized by different operating conditions of the carbonisation process. Moreover, the wood waste input to the processes differs significantly. From this study, it is clear that some similarities but also some differences exist between the lab scale study and the study with the industrial Chartherm plant. In both reactors, a metal (and mineral) agglomeration process takes place, even in the case of untreated wood. The agglomerates initially present in the wood input may serve as a seed for the metal agglomeration process during "chartherisation". The industrial setup leads to a broader range of agglomerates' size (0.1-50 microm) and composition (all possible combinations of Cu, Cr, As and wood minerals). Some agglomerates contain the three metals but the major part is a combination of wood minerals and one or two of the three preservative metals, while all agglomerates analysed in the lab scale product contain the three metals. The separate influence of wood input characteristics and process conditions cannot be derived from these experiments, but the observations suggest that the higher the CCA retention in the wood input is, the easier is the metal agglomeration process during chartherisation of CCA treated wood waste. From the analyses performed in this study it seems that copper behaves differently in the sense that it agglomerates easily, but the resulting particles are small (<1 microm).     

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

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 %.     

Novel method to construct large-scale design space in lubrication process utilizing Bayesian estimation based on a small-scale design-of-experiment and small sets of large-scale manufacturing data

A large-scale design space was constructed using a Bayesian estimation method with a small-scale design of experiments (DoE) and small sets of large-scale manufacturing data without enforcing a large-scale DoE. The small-scale DoE was conducted using various Froude numbers (X₁) and blending times (X₂) in the lubricant blending process for theophylline tablets. The response surfaces, design space, and their reliability of the compression rate of the powder mixture (Y₁), tablet hardness (Y₂), and dissolution rate (Y₃) on a small scale were calculated using multivariate spline interpolation, a bootstrap resampling technique, and self-organizing map clustering. The constant Froude number was applied as a scale-up rule. Three experiments under an optimal condition and two experiments under other conditions were performed on a large scale. The response surfaces on the small scale were corrected to those on a large scale by Bayesian estimation using the large-scale results. Large-scale experiments under three additional sets of conditions showed that the corrected design space was more reliable than that on the small scale, even if there was some discrepancy in the pharmaceutical quality between the manufacturing scales. This approach is useful for setting up a design space in pharmaceutical development when a DoE cannot be performed at a commercial large manufacturing scale.     

Preparation of a controlled release drug delivery system of indomethacin: Effect of process equipment,particle size of indomethacin,and size of the nonpareil seeds

Abstract

Indomethacin pellets (IS) were prepared by spraying a slurry of indomethacin, Eudragit® S-100, dibuty1 sebacate and alcohol onto an appropriate mesh fraction of nonpareil seeds using appropriate processing equipment. Factors affecting this layering process were studied and identified. The average particle diameter and the overall particle size distribution of the indomethacin powder were found to be critical factors influencing the physical properties of the IS pellets. Micronized indomethacin powder, having an average particle diameter of four microns and a particle size distribution ranging from one to thirteen microns, was found to be the optimum for this layering process. Altering the mesh fraction of the starting nonpareil seeds for the layering process was found to greatly affect the release characteristics of the drug from the beadlets. The Wurster column process was found to be better than a fluid-bed granulator process for the manufacture of IS beadlets.     

In-line particle sizing for real-time process control by fibre-optical spatial filtering technique (SFT)

Sizing of particles in industrial processes is of great technical interest and therefore different physical-based techniques have been developed. The objective of this study was to review the characteristics of modern sizing instruments based on a modified fibre-optical spatial filtering technique (SFT). Fibre-optical spatial filtering velocimetry was modified by fibre-optical spot scanning in order to determine simultaneously the size and the velocity of particles. Sizing in-line instruments of Parsum GmbH use these measuring principles and may be adapted to different process conditions. Particles with sizes of 50–6000 μm and velocities up to 50 m/s may be measured by the probe system IPP 70. An overview is given to real-time sizing of particles in different technical applications: fluid-bed granulation, high shear wet granulation, Wurster coating, mixing, spray drying, crystallization and milling.     

Development of a new esomeprazole delayed release gastro-resistant pellet formulation with improved storage stability

This study describes the development of a new esomeprazole (ESO) delayed release gastro-resistant formulation with improved storage stability. A three-step (drug-, sub(seal)- and enteric-) coating process was employed with the aid of a fluid bed coater. Several formulation factors (namely, size and quantity of starting non-pareil sugar spheres, binder quantity during drug-layering, sub(seal)-coating polymer type, and quantity and enteric coating quantity) were evaluated and the whole process was modeled with the aid of feed-forward back-propagation artificial neural networks (ANNs). Results showed that the selection of small-sized starting spheres (45/60 mesh size) leads to pellet agglomeration, while as sub(seal)-coating weight gain increases a reduction in ESO dissolution rate is observed. The enteric-coating applied (Eudragit L30D-55) showed good gastro-resistant performance in both 0.1 N HCl and pH 4.5 media, while immediate release profiles with more than 85% of ESO being released in less than 30?min were obtained. The effect of cellulose-based sub(seal)-coating polymers, (namely, hydroxypropyl cellulose and hydroxypropylmethyl cellulose) on formulation’s storage stability at 40?±?2?°C/75?±?5%RH indicated that only hydroxypropylmethyl cellulose was able to stabilize ESO delayed-release formulations in terms of assay, dissolution, impurities, and gastro-resistance performance. Finally, scanning electron microscopy (SEM) analysis revealed smooth and homogeneous external surface/coating layers in all three levels (drug-, sub(seal)-, and enteric- coating), while x-ray diffraction showed no polymorphic transformations.     

Pellet Starters in Layering Technique Using Concentrated Drug Solution

Characteristics of inert starters in drug solution layering are important for successful active pellet formation. Four types of starters composed of sucrose or microcrystalline cellulose (MCC) or lactose and MCC were compared in our study. The active pellets were prepared using Wurster type apparatus. Yield and pellet quality parameters were determined. The highest yield (85.66–89.41%) was obtained for cores composed of MCC due to their insolubility in water (the drug solvent) and good mechanical properties. On the contrary, soluble and brittle sucrose cores dissolved partially during the process forming undesirable agglomerates and giving lower yield (76.2%). All pellet samples showed good flow properties and drug content from 82.4 to 94.5% of the theoretical drug amount.     

Pellet starters in layering technique using concentrated drug solution

Characteristics of inert starters in drug solution layering are important for successful active pellet formation. Four types of starters composed of sucrose or microcrystalline cellulose (MCC) or lactose and MCC were compared in our study. The active pellets were prepared using Wurster type apparatus. Yield and pellet quality parameters were determined. The highest yield (85.66-89.41%) was obtained for cores composed of MCC due to their insolubility in water (the drug solvent) and good mechanical properties. On the contrary, soluble and brittle sucrose cores dissolved partially during the process forming undesirable agglomerates and giving lower yield (76.2%). All pellet samples showed good flow properties and drug content from 82.4 to 94.5% of the theoretical drug amount.     

Pellets for oral administration of low-molecular-weight heparin

Background: Oral absorption of low-molecular-weight heparin (LMWH) is limited by its molecular size and negative charge. It has been shown previously that orally administered polymeric nano- or microparticles containing encapsulated LMWH have led to gastrointestinal absorption of heparin in rabbits. Method: Based on these investigations, pellets containing two LMWHs, enoxaparin (MW 4500 Da) or bemiparin (MW 3600 Da), and Eudragit®RS30D (ERS), were prepared using extrusion/ spheronization technique. Uncoated or coated (ERS) pellets were evaluated in vitro and in vivo on rabbits. Results: Enoxaparin pellets showed fast in vitro release in phosphate buffer (pH 7.4) and prolonged in vivo drug absorption after a single oral dose of 600 anti-Xa IU/ kg of body weight, leading to relative bioavailabilities ranging from 9.7 ± 1.9% to 12.8 ± 2.7% and anti-Xa activity over the curative dose. Bemiparin included in matrix pellets of ERS and coated with ERS exhibited in vitro prolonged release up to 4 hours and in vivo anti-Xa activity below the therapeutic minimum value of 0.1 IU/mL. Conclusion: This study presents LMWH in a pellet dosage form, which compared to nano- or microparticles, may offer a more convenient and industrializable way of manufacture leading to an easier scale-up process.     

毒死蜱/脲醛树脂微胶囊的制备工艺优化及缓释动力学

随着人们健康与环保意识的不断加强,农药施用量大、效率低、高残留等问题日益受到人们的重视,对农药进行微胶囊化,有助于有效解决当前农药使用过程中所面临的问题。采用脲醛树脂作为壁材,以十二烷基硫酸钠为乳化剂,采用原位聚合法制备毒死蜱/脲醛树脂微胶囊。研究了乳化剂种类和用量、pH值、酸化时间对微胶囊粒径及其分布的影响,并进一步探讨微胶囊的载药量、包封率及释放动力学。结果表明,采用3%(质量分数)的十二烷基硫酸钠为乳化剂,在酸化时间为90min、酸化终点pH值为2.5、搅拌速度为1 200r/min、芯壁比为1∶3、固化温度为60℃时,所制备的毒死蜱/脲醛树脂微胶囊的粒径分布窄,平均粒径约为113μm,载药量达53%以上,包封率达62%以上。毒死蜱/脲醛树脂微胶囊的缓释性能及动力学研究结果显示,所制备的毒死蜱/脲醛树脂微胶囊的缓释效果明显,10天内能释放90%的药物,释放过程遵循Fick扩散机理。可见,制备的毒死蜱/脲醛树脂微胶囊具有较高的载药量、较好的包封率以及缓释性能,可进一步开发为新型的农药制剂,并为开发缓释农药新剂型提供理论支持与实践参考。     

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.     

A novel co-processing method to manufacture an API for extended release formulation via formation of agglomerates of active ingredient and hydroxypropyl methylcellulose during crystallization

A novel process for generating agglomerates of active pharmaceutical ingredient (API) and polymer by swelling the polymer in a water/organic mixture has been developed to address formulation issues resulting from a water sensitive, high drug load API with poor powder properties. Initially, the API is dissolved in water, following which hydroxypropyl methylcellulose (HPMC) is added, resulting in the imbibing of water, along with the dissolved API, into the HPMC matrix. The addition of acetone and isopropyl acetate (anti-solvents) then causes the API to crystallize inside and on the surface of HPMC agglomerates. The process was scaled up to 20?kg scale. The agglomerates of API and HPMC generated by this process are ～350?µm diameter, robust, and have significantly better flow than the API as measured by Erweka flow testing. These agglomerates exhibit improved bulk density, acceptable chemical stability, and high compressibility. The agglomerates process well through roller compaction and tableting, with no flow or sticking issues. This process is potentially adaptable to other APIs with similar attributes.