Wurster Technology-Assisted Step-by-Step Engineering of Multi-layered Pellets (Sprinkles): Microscopy, Micro-CT, and e-Tongue-Based Analysis.

The advancement in the formulation and characterization techniques have paved the path for development of new as well as modification of existing dosage forms. The present work explores the role of micro-computed tomography (micro-CT) as advanced characterization technique for multi-layered-coated pellets to ascertain the quality of coated pellets. The work further explored in-house e-tongue technique for understanding palatability of formulation in early stages of development thus by reducing clinical taste evaluation time. The developed multi-layered-coated pellets were characterized using microscopy (optical and electron microscopy). The obtained results demonstrated formation of spherical-shaped pellets with uniform coating. The uniform coating was further confirmed by results obtained from scanning electron microscopy (SEM) and cross-sectional SEM analysis, which showed visible difference in pellet surface before and after multi-layered coating. The micro-CT results confirmed the visible demarcation of layers (drug and polymer, i.e., hydroxypropyl methylcellulose (HPMC) and eudragit (EPO)) along with uniform thickness of various layering. The dissolution study of developed pellets suggested the role of layering EPO on drug release from pellets. The e-tongue analysis proved to be an excellent tool for early prediction of taste masking of drug via multi-layered pellets and can serve as potential platform for taste masking with high specificity. The overall results suggest the suitability of developed multi-layered platform as efficient dosage form (sprinkle) in pediatric/geriatric product development.

Integrated Purification and Formulation of an Active Pharmaceutical Ingredient via Agitated Bed Crystallization and Fluidized Bed Processing.

Integrated API and drug product processing enable molecules with high clinical efficacy but poor physicochemical characteristics to be commercialized by direct co-processing with excipients to produce advanced multicomponent intermediates. Furthermore, developing isolation-free frameworks would enable end-to-end continuous processing of drugs. The aim of this work was to purify a model API (sodium ibuprofen) and impurity (ibuprofen ethyl ester) system and then directly process it into a solid-state formulation without isolating a solid API phase. Confined agitated bed crystallization is proposed to purify a liquid stream of impure API from 4% to 0.2% w/w impurity content through periodic or parallelized operations. This stream is combined with a polymer solution in an intermediary tank, enabling the API to be spray coated directly onto microcrystalline cellulose beads. The spray coating process was developed using a Design of Experiments approach, allowing control over the drug loading efficiency and the crystallinity of the API on the beads by altering the process parameters. The DoE study indicated that the solvent volume was the dominant factor controlling the drug loading efficiency, while a combination of factors influenced the crystallinity. The products from the fluidized bed are ideal for processing into final drug products and can subsequently be coated to control drug release.

Production and Characterization of Controlled Release Urea Using Biopolymer and Geopolymer as Coating Materials.

Synthetic polymers-based controlled release urea (CRU) leaves non-biodegradable coating shells when applied in soil. Several alternative green materials are used to produce CRU, but most of these studies have issues pertaining to nitrogen release longevity, process viability, and the ease of application of the finished product. In this study, we utilized tapioca starch, modified by polyvinyl alcohol and citric acid, as coating material to produce controlled release coated urea granules in a rotary fluidized bed equipment. Response surface methodology is employed for studying the interactive effect of process parameters on urea release characteristics. Statistical analysis indicates that the fluidizing air temperature and spray rate are the most influential among all five process parameters studied. The optimum values of fluidizing air temperature (80 °C), spray rate (0.13 mL/s), atomizing pressure (3.98 bar), process time (110 min), and spray temperature (70 °C) were evaluated by multi-objective optimization while using genetic algorithms in MATLAB®. Urea coated by modified-starch was double coated by a geopolymer to enhance the controlled release characteristics that produced promising results with respect to the longevity of nitrogen release from the final product. This study provides leads for the design of a fluidized bed for the scaled-up production of CRU.

Application of Failure Mode Effect Analysis in Wurster-Based Pelletization Technology: a Technical Note.

The deployment of oral multi-unit pellet formulation has gained significant attention in recent years conferring to numerous applications, especially in achieving modified release and acid resistance property. The fluidized bed coating, specifically Wurster technique is commercially utilized for pellet manufacturing, which is a complex process involving too many variables. Risk assessment tools can be employed to determine the critical variables affecting the pre-defined quality profile and screen out important parameters out of literally hundreds of variables to develop a robust product. The present review aims to describe possibly all the variables involved in Wurster coating process and application of FMEA in pellet manufacturing. A brief case study regarding applicability of FMEA to study the effects of critical factors is outlined. Risk assessment tools assist to reduce number of trials to manageable levels with aid of prior art, literature, and preliminary trials to develop an optimized product.

Fundamental evaluation and optimization of porous spherical silica for developing functional fine particles via fluidized bed coating.

Particle coating, a taste-masking technique for drugs, is limited by its long manufacturing time, which is caused by the decrease in the spray rate required to prevent particle agglomeration. Mesoporous silica particles, which have a high surface area and pore sizes in the range of 2-50 nm, possess high surface free energy; they have attracted significant interest for numerous applications in adsorption, separation, and catalysis and drug delivery. A form of mesoporous silica, microbead silicate, can prevent particle aggregation because of its good water absorbency and drying properties. Hence, it has been suggested to be applicable for particle coating. This study evaluated the physical properties and drug release capability of microbead silicate with different pore sizes. Although microbead silicate with small pores displayed a rapid drug release profile, drug release was incomplete. Contrastingly, microbead silicate with large pores achieved complete drug release even with high drug loading. Furthermore, in the case of 100% layering, the porosity of microbead silicate was maintained, thus sufficiently preventing aggregation due to the prevention of formation of liquid bridging of the coating solution. These results suggest that using microbead silicate with large pores for particle coating enables complete drug release while improving manufacturability.

Evaluation of the suitability of a fluidized bed process for the coating of drug-eluting stents.

Drug-eluting stents are often coated using single-stent coating techniques. In pharmaceutical industry, single-tablet coating is unthinkable. Instead large batches of tablets are coated in fluidized bed apparatuses or pan coaters. Therefore, it was the aim of this work to evaluate whether stents can be coated using a fluidized bed process. For this purpose stents were coated with the model fluorescent drug triamterene embedded in ammonium methacrylate copolymer. Different stent lengths as well as different coating yields were assessed and also a drug-free topcoat was evaluated. The coated stents were analysed regarded coating layer mass, drug content, surface structure, coating thickness and drug release. Furthermore, coating yield and stent defect rate were examined. Except for one stent configuration good results were obtained without optimization of process parameters which indicates the suitability of the method to coat large amounts of stents simultaneously in principle. Drug release was tuneable over a wide range of time spans and a wide range of drug loadings was produced. Further work will be necessary to transform the results of this study from a model stent to a clinically relevant product.

An application of deep learning to detect process upset during pharmaceutical manufacturing using passive acoustic emissions.

The multivariate nature of a fluidized bed system creates process complexity that increases the risk of production upset. This research explores the use of passive acoustic emissions monitoring paired with an artificial neural network to detect fluidized bed distributor plate blockage. In many cases, early process failure detection can allow for immediate intervention, thus lowering operation costs. Blockages were simulated by actively covering portions of a top-spray fluidized bed distributor plate. Piezoelectric microphones were placed within the fluidized bed exhaust and attached externally to the vessel wall. Several time and frequency domain feature vectors were extracted from the monitoring data using the open source pyAudioAnalysis library in Python. Through deep learning, the artificial neural network used these feature vectors to train against each distributor plate blockage condition. The deep learning model was then evaluated using k-fold cross validation. The findings were very positive and successfully demonstrated an application of deep learning to detect process upset.

Inline acoustic monitoring to determine fluidized bed performance during pharmaceutical coating.

Fluidized beds are used by pharmaceutical manufacturers for multi-particulate drug coating. They provide effective mass and heat transfer; however, unit optimization can be difficult due to the multivariate nature of a fluidized bed system. This research explores the use of passive acoustic emissions monitoring as a method to improve temperature management during pellet coating. A piezoelectric microphone was placed inside the exhaust of a conical top spray fluidized bed. Spherical 1000 µm pellets were coated while recording acoustic emissions. Fluidization air temperature was adjusted between trials as a controlled variable to determine if pellet drying rate could be extracted from the data. During each trial, pellets became damp as the coating solution was applied. Drying stages were used to remove moisture whereby pellet fluidization continued without spraying. The moving standard deviation of the acoustic emissions increased by approximately 40 mV during each 2-min coating stage. The emissions then decreased during drying. This decrease was at a rate proportional to pellet drying independently measured at each controlled temperature. The overall coating-drying emissions profile was similar for trials using either sugar or Acryl-EZE® coating solutions. Passive acoustic emissions monitoring is non-invasive and provides reliable coating and drying information during fluidized bed operation.

In-line agglomeration degree estimation in fluidized bed pellet coating processes using visual imaging.

Agglomeration of pellets in fluidized bed coating processes is an undesirable phenomenon that affects the yield and quality of the product. In scope of PAT guidance, we present a system that utilizes visual imaging for in-line monitoring of the agglomeration degree. Seven pilot-scale Wurster coating processes were executed under various process conditions, providing a wide spectrum of process outcomes. Images of pellets were acquired during the coating processes in a contactless manner through an observation window of the coating apparatus. Efficient image analysis methods were developed for automatic recognition of discrete pellets and agglomerates in the acquired images. In-line obtained agglomeration degree trends revealed the agglomeration dynamics in distinct phases of the coating processes. We compared the in-line estimated agglomeration degree in the end point of each process to the results obtained by the off-line sieve analysis reference method. A strong positive correlation was obtained (coefficient of determination R2=0.99), confirming the feasibility of the approach. The in-line estimated agglomeration degree enables early detection of agglomeration and provides means for timely interventions to retain it in an acceptable range.

Near-infrared spectroscopy monitoring and control of the fluidized bed granulation and coating processes-A review.

The fluidized bed granulation and pellets coating technologies are widely used in pharmaceutical industry, because the particles made in a fluidized bed have good flowability, compressibility, and the coating thickness of pellets are homogeneous. With the popularization of process analytical technology (PAT), real-time analysis for critical quality attributes (CQA) was getting more attention. Near-infrared (NIR) spectroscopy, as a PAT tool, could realize the real-time monitoring and control during the granulating and coating processes, which could optimize the manufacturing processes. This article reviewed the application of NIR spectroscopy in CQA (moisture content, particle size and tablet/pellet thickness) monitoring during fluidized bed granulation and coating processes. Through this review, we would like to provide references for realizing automated control and intelligent production in fluidized bed granulation and pellets coating of pharmaceutical industry.

Preparation of colon-targeted pellets of Prunellae Spica effective components and the in vitro drug-release behaviors / 中成药

AIM To prepare colon-targeted pellets of Prunellae Spica effective components and to evaluate the in vitro drug-release behaviors.METHODS Fluidized bed coating method was adopted in the preparation of pellets.With in vitro accumulative release rate as an evaluation index,hydroxypropyl methyl cellulose (HMPC),polyacrylic resin (Eudragit S100) and triethyl citrate (TEC) amounts as influencing factors,orthogonal test was applied to optimizing the formulation.The in vitro drug-release behaviors were evaluated with rosmarinic acid content as an index.RESULTS The optimal formulation was determined to be 5％ for HPMC amount,70％ for Eudragit S100 amount,and 20％ for TEC amount.The obtained pellets attained an accumulative release rate of more than 90％ in pH 7.6 PBS (transportation for 2 h),while no drug dissolution was found in pH 1.0 HCl (transportation for 2 h) or pH 6.8 PBS (transportation for 3 h).CONCLUSION Colon-targeted pellets of Prunellae Spica effective components can achieve in vitro colon-targeted effect.

Fast dissolution of poorly water soluble drugs from fluidized bed coated nanocomposites: Impact of carrier size.

Formation of core-shell nanocomposites of Fenofibrate and Itraconazole, model poorly water soluble drugs, via fluidized bed (FB) coating of their well-stabilized high drug loaded nanosuspensions is investigated. Specifically, the extent of dissolution enhancement, when fine carrier particles (sub-50µm) as opposed to the traditional large carrier particles (>300µm) are used, is examined. This allows testing the hypothesis that greatly increased carrier surface area and more importantly, thinner shell for finer carriers at the same drug loading can significantly increase the dissolution rate when spray-coated nanosuspensions are well-stabilized. Fine sub-50µm lactose (GranuLac® 200) carrier particles were made fluidizable via dry coating with nano-silica, enabling decreased cohesion, fluidization and subsequent nanosuspension coating. For both drugs, 30% drug loaded suspensions were prepared via wet-stirred media milling using hydroxypropyl methyl cellulose and sodium dodecyl sulfate as stabilizers. The stabilizer concentrations were varied to affect the milled particle size and prepare a stable nanosuspension. The suspensions were FB coated onto hydrophilic nano-silica (M-5P) dry coated sub-50µm lactose (GranuLac® 200) carrier particles or larger carrier particles of median size >300µm (PrismaLac®40). The resulting finer composite powders (sub-100µm) based on GranuLac® 200 were freely flowing, had high bulk density, and had much faster, immediate dissolution of the poorly water-soluble drugs, in particular for Itraconazole. This is attributed to a much higher specific surface area of the carrier and corresponding thinner coating layer for fine carriers as opposed to those for large carrier particles.

Comparison of film-coated retarded release pellets manufactured by layering technique or by bed rotor pelletization.

In order to investigate the influence of coatings for controlled active pharmaceutical ingredient (API) release, two types of pellets were used. Microcrystalline pellets were coated with a model API using the Wurster fluidized bed technique in laboratory scale (layered Cellets). Another type of pellets consisting of microcrystalline cellulose and model API was manufactured by fluidized bed rotor pelletization (matrix pellets (MP)). Both kinds of pellets were coated in a Wurster fluidized bed process with a polymer mixture of ethylcellulose to achieve retarded API release. With layered Cellets and an increased thickness of the ethylcellulose layer, the lag-time was increased and the release rate was decreased. In the case of MP, retardation was less pronounced probable due to inhomogeneous polymer film formation as a result of the porous particle surface. To reduce the surface roughness, the MP were coated with polyvinylpyrrolidone (PVP) as an intermediate smoothing layer, in a first trial step by step. In a second trial, pelletization and the coating steps were performed in an uninterrupted process. Intermediate PVP coating improved the ethylcellulose film formation and led to a more pronounced retardation of API release. The uninterrupted process of matrix pellet manufacturing and coating results in a product with only low retarded release.

Organic-aqueous crossover coating process for the desmopressin orally disintegrating microparticles.

The purpose of the present study was to prepare desmopressin orally disintegrating microparticles (ODMs) using organic-aqueous crossover coating process which featured an organic sub-coating followed by an aqueous active coating. Sucrose beads and hydroxypropyl cellulose (HPC) were used as inert cores and a coating material, respectively. Characterizations including size distribution analysis, in-vitro release studies and in-vitro disintegration studies were performed. A pharmacokinetic study of the ODMs was also conducted in eight beagle dogs. It was found that sucrose beads should be coated using organic solvents to preserve their original morphology. For the active coating, the aqueous coating solution should be used for drug stability. When sucrose beads were coated using organic-aqueous crossover coating process, double-layer ODMs with round shapes were produced with detectable impurities below limit of US Pharmacopeia. The median size of ODMs was 195.6 µm, which was considered small enough for a good mouthfeel. The ODMs dissolved in artificial saliva within 15 s because of hydrophilic materials including sucrose and HPC in the ODMs. Because of its fast-dissolving properties, 100% release of the drug was reached within 5 min. Pharmacokinetic parameters including Cmax and AUC24 indicated bioequivalence of the ODMs and the conventional immediate release tablets. Therefore, by using the organic-aqueous crossover coating process, double-layer ODMs were successively prepared with small size, round shapes and good drug stability.

Redispersible fast dissolving nanocomposite microparticles of poorly water-soluble drugs.

Enhanced recovery/dissolution of two wet media-milled, poorly water-soluble drugs, Griseofulvin (GF) and Azodicarbonamide (AZD), incorporated into nanocomposite microparticles (NCMPs) via fluidized bed drying (FBD) and spray-drying (SD) was investigated. The effects of drying method, drug loading, drug aqueous solubility/wettability as well as synergistic stabilization of the milled suspensions on nanoparticle recovery/dissolution were examined. Drug nanoparticle recovery from FBD and SD produced NCMPs having high drug loadings was evaluated upon gentle redispersion via optical microscopy and laser diffraction. During wet-milling, hydroxypropyl cellulose (HPC) alone stabilized more wettable drug (AZD) nanoparticles with slight aggregation, but could not prevent aggregation of the GF nanoparticles. In contrast, well-dispersed, stable nanosuspensions of both drugs were produced when sodium dodecyl sulfate (SDS) and HPC were combined. The FBD and SD NCMPs without SDS exhibited incomplete nanoparticle recovery, causing slower dissolution for GF, but not for AZD, likely due to higher aqueous solubility/wettability of AZD. For high active loaded NCMPs (FBD ∼50 wt%, SD ∼80 wt%) of either drug, HPC-SDS together owing to their synergistic stabilization led to fast redispersibility/dissolution, corroborated via optical microscopy and particle sizing. These positive attributes can help development of smaller, high drug-loaded dosage forms having enhanced bioavailability and better patient compliance.

Enhanced recovery and dissolution of griseofulvin nanoparticles from surfactant-free nanocomposite microparticles incorporating wet-milled swellable dispersants.

Nanocomposite microparticles (NCMPs) incorporating drug nanoparticles and wet-milled swellable dispersant particles were investigated as a surfactant-free drug delivery vehicle with the goal of enhancing the nanoparticle recovery and dissolution rate of poorly water-soluble drugs. Superdisintegrants were used as inexpensive, model, swellable dispersant particles by incorporating them into NCMP structure with or without wet-stirred media milling along with the drug. Suspensions of griseofulvin (GF, model drug) along with various dispersants produced by wet-milling were coated onto Pharmatose® to prepare NCMPs in a fluidized bed process. Hydroxypropyl cellulose (HPC, polymer) alone and with sodium dodecyl sulfate (SDS, surfactant) was used as base-line stabilizer/dispersant during milling. Croscarmellose sodium (CCS, superdisintegrant) and Mannitol were used as additional dispersants to prepare surfactant-free NCMPs. Nanoparticle recovery during redispersion and dissolution of the various GF-laden NCMPs were examined. Suspensions prepared by co-milling GF/HPC/CCS or milling GF/HPC/SDS were stable after 30 h of storage. After drying, due to its extensive swelling capacity, incorporation of wet-milled CCS in the NCMPs caused effective breakage of the NCMP structure and bursting of nanoparticle clusters, ultimately leading to fast recovery of the GF nanoparticles. Optimized wet co-milling and incorporation of CCS in NCMP structure led to superior dispersant performance over incorporation of unmilled CCS or physically mixed unmilled CCS with NCMPs. The enhanced redispersion correlated well with the fast GF dissolution from the NCMPs containing either CCS particles or SDS. Overall, swellable dispersant (CCS) particles, preferably in multimodal size distribution, enable a surfactant-free formulation for fast recovery/dissolution of the GF nanoparticles.