Development of a Raman method to follow the evolution of coating thickness of pellets.

CONTEXT: Although several methods have been investigated to measure the film thickness of tablets and its correlation with the dissolution behavior, much fewer such investigations exist for pharmaceutical pellets. OBJECTIVE: To study the possibility of measuring the film thickness and predicting the dissolution behavior of pellets produced in different fluid bed equipments with Raman spectroscopy. MATERIALS AND METHODS: Pyridoxine hydrochloride-layered pellets were produced and coated in two different Strea-1 equipments. Raman spectra were collected and analysed to set up a calibration model based on the film thickness data calculated from Camsizer analysis results. Dissolution tests were done according to Ph. Eur. standards. RESULTS: Raman spectroscopy proved to be a good tool in the measurement of film thickness. Polymer weight gain showed a linear correlation with film thickness but was a poor predictor of dissolution results below a threshold value. CONCLUSION: The Raman spectroscopic measurement of a small sample can provide accurate data of the film thickness. The investigation suggests that a threshold value might exist for the film thickness above which it can be used to judge future dissolution results.

Preparing of pellets by extrusion/spheronization using different types of equipment and process conditions.

INTRODUCTION: The focus of this work was to produce matrix pellets made by extrusion/ spheronization using two types of equipment. The aim was to accomplish the laboratory-scale I process that has been already optimized and accepted with another type of equipment (laboratory-scale II). METHODS: A matrix pellet formulation consisting of MCC, Eudragit NE 30D and diclofenac sodium was used in the two types of equipment. Physico-chemical parameters and the dissolution profiles of the pellets in phosphate buffer pH 6.8 were compared. RESULTS: Pellets from both processes were similar in shape and tensile strength. They differed in particle size and dissolution profile. This may be contributed to different spheronization conditions.

When Polymorphism in Metal-Organic Frameworks Enables Water Sorption Profile Tunability for Enhancing Heat Allocation and Water Harvesting Performance.

The development of thermally driven water-sorption-based technologies relies on high-performing water vapor adsorbents. Here, polymorphism in Al-metal-organic frameworks is disclosed as a new strategy to tune the hydrophilicity of MOFs. This involves the formation of MOFs built from chains of either trans- or cis- µ-OH-connected corner-sharing AlO4(OH)2 octahedra. Specifically, [Al(OH)(muc)] or MIP-211, is made of trans, trans-muconate linkers, and cis-µ-OH-connected corner-sharing AlO4(OH)2 octahedra giving a 3D network with sinusoidal channels. The polymorph MIL-53-muc has a tiny change in the chain structure that results in a shift of the step position of the water isotherm from P/P0 ≈ 0.5 in MIL-53-muc, to P/P0 ≈ 0.3 in MIP-211. Solid-state NMR and Grand Canonical Monte Carlo reveal that the adsorption occurs initially between two hydroxyl groups of the chains, favored by the cis-positioning in MIP-211, resulting in a more hydrophilic behavior. Finally, theoretical evaluations show that MIP-211 would allow achieving a coefficient of performance for cooling (COPc) of 0.63 with an ultralow driving temperature of 60 °C, outperforming benchmark sorbents for small temperature lifts. Combined with its high stability, easy regeneration, huge water uptake capacity, green synthesis, MIP-211 is among the best adsorbents for adsorption-driven air conditioning and water harvesting from the air.

Experimental analysis of tablet properties for discrete element modeling of an active coating process.

Coating of solid dosage forms is an important unit operation in the pharmaceutical industry. In recent years, numerical simulations of drug manufacturing processes have been gaining interest as process analytical technology tools. The discrete element method (DEM) in particular is suitable to model tablet-coating processes. For the development of accurate simulations, information on the material properties of the tablets is required. In this study, the mechanical parameters Young's modulus, coefficient of restitution (CoR), and coefficients of friction (CoF) of gastrointestinal therapeutic systems (GITS) and of active-coated GITS were measured experimentally. The dynamic angle of repose of these tablets in a drum coater was investigated to revise the CoF. The resulting values were used as input data in DEM simulations to compare simulation and experiment. A mean value of Young's modulus of 31.9 MPa was determined by the uniaxial compression test. The CoR was found to be 0.78. For both tablet-steel and tablet-tablet friction, active-coated GITS showed a higher CoF compared with GITS. According to the values of the dynamic angle of repose, the CoF was adjusted to obtain consistent tablet motion in the simulation and in the experiment. On the basis of this experimental characterization, mechanical parameters are integrated into DEM simulation programs to perform numerical analysis of coating processes.

Validation of Terahertz coating thickness measurements using X-ray microtomography.

Terahertz pulsed imaging (TPI) is a recently developed nondestructive and noncontact method to measure the coating thickness of coated pharmaceutical tablets. The method requires no calibration in order to resolve the coating structure of tablets. The relative coating thickness over a tablet surface or between different tablets of the same batch can be determined with high precision. However, in order to determine the absolute coating thickness accurately the refractive index, n, of the coating layer needs to be known. For all published studies to date the value of n was based on estimates or bulk measurements, which were based on the assumption that n is constant for a given coating formulation. We have developed a measurement technique using X-ray microtomography to independently quantify the coating thickness. These data were then used to validate the terahertz imaging results, and we found that the intertablet variation of n for coating layers of 25-270 µm thickness is less than 4% and that there is less than 3% intratablet variation in n. Based on our results we estimate that, depending on the pigment content, the absolute value of n in a typical pharmaceutical coating formulation will be in the range of 1.45 < n < 2.01. We conclude that TPI is a robust technique and that, due to its very simple measurement principle, it is an ideal measurement technique to quantify the coating thickness in process control and quality monitoring applications.

Pellet layering: scale-up considerations using different kinds of processing equipment.

OBJECTIVE: In this study an aqueous suspension of poorly water-soluble HCT (hydrochlorothiazide) was layered on small spherical starter cores with a drug content in the final pellets of 30%. The aim was to compare different kinds of processing equipment (Wurster fluid-bed, CPS rotor fluid-bed and drum coater) in view of process efficiency, process duration and feasibility to scale-up. RESULTS: In a pilot scale drum coater, it was possible to achieve the desired LE (layering efficiency) and yield specifications (both >95%), but the process duration was at least 202 min. In the small scale Wurster fluid-bed machine, it was possible to reduce the process time for an optimized process from 67 min to 41 min. However, the acceleration of the process led to an increase of agglomerates and the same process took at least 114 min in the scale-up experiments. A small scale CPS rotor processor with a cone-shaped disc was superior to the conventional planar rotor disc design, regarding yield and agglomerates. This rotor process was both, fast and highly efficient (yield: 98.4%; LE: 99.3%). The high quality of the process was also observed for the pilot scale batches, in which neither considerable losses of drug (LE ≥ 98.6%) nor formation of agglomerates occurred. The absolute spray rate in this pilot scale process was 85 kg/h. CONCLUSION: Best results were achieved with the CPS rotor technology. With a duration of 29 min (small scale) and 44 min (pilot scale) it was the fastest option to produce layered pellets.

Feasibility of Raman spectroscopy as PAT tool in active coating.

BACKGROUND: Active coating is a specific application of film coating where the active ingredient is comprised in the coating layer. This implementation is a challenging operation regarding the achievement of desired amount of coating and coating uniformity. To guarantee the quality of such dosage forms it is desirable to develop a tool that is able to monitor the coating operation and detect the end of the process. METHOD: Coating experiments were performed at which the model drug diprophylline is coated in a pan coater on placebo tablets and tablets containing the active ingredient itself. During the active coating Raman spectra were recorded in-line. The spectral measurements were correlated with the average weight gain and the amount of coated active ingredient at each time point. The developed chemometric model was tested by monitoring further coated batches. Furthermore, the effects of pan rotation speed and working distance on the acquired Raman signal and, hence, resulting effect of the chemometric model were examined. RESULTS: Besides coating on placebo cores it was possible to determine the amount of active ingredient in the film when coated onto cores containing the same active ingredient. In addition, the method is even applicable when varying the process parameters and measurement conditions within a restricted range. CONCLUSION: Raman spectroscopy is an appropriate process analytical technology too.

Combination of a rotating tube sample divider and dynamic image analysis for continuous on-line determination of granule size distribution.

The granule size distribution is a critical quality attribute of granules. It has a great impact on further packaging or processing. Due to increasing interest in continuous manufacturing techniques, it is of high interest to develop an in-line or on-line tool to monitor the granule size distribution. However, development of an in-line measurement tool for granule size distribution was challenging since large throughput and inhomogeneous product stream are limiting factors for current particle size analyzers. In this study, continuous sampling was tested in conjunction to a continuous on-line method of size determination using dynamic image analysis. A rotating tube sample divider was used to split previously compacted material in representative samples at different ratios and the sample was directly conveyed to the particle size analyzer where the granule size distribution was determined. The method was tested for different granule sizes to determine limits of detection and its ability to detect these changes immediately, as this enables real-time monitoring of the process. This research is the base for development of control tools concerning the granule size distributions for continuous granulation processes.

Evaluation of the composition of the binder bridges in matrix granules prepared with a small-scale high-shear granulator.

The aim of this work was to evaluate the binder bridges which can form in hydrophilic matrix granules prepared with a small-scale high-shear granulator. Matrices contained hydroxypropyl methylcellulose (HPMC) as a matrix-forming agent, together with lactose monohydrate and microcrystalline cellulose as filler. Water was used as granulating liquid. A 2(4) full factorial design was used to evaluate the effects of the operational parameters (impeller speed, chopper speed, dosing speed and wet massing time) on the granulation process. The temperature of the sample increased relevantly during the preparation in the small-scale apparatus. The same setup induced different temperature increases for different amounts of powder. This alteration enhances the solubility of lactose and decreases that of HPMC, and thus the quantities of the dissolved components can vary. Accordingly, changes in composition of the binder bridge can occur. Since exact determination of the dissolution of these materials during granulation is difficult, the consequences of the changes in solubility were examined. Differential scanning calorimetry (DSC), thermomechanical analysis (TMA) and X-ray diffraction (XRD) measurements were made to evaluate the films prepared from liquids with different ratios of soluble materials. The DSC and XRD measurements confirmed that the lactose lost its crystalline state in the film. The TMA tests revealed that increase of the quantity of lactose in the film decreased the glass transition temperature of the film; this may be attributed to the interaction of the additives. At a lactose content of 37.5%, a second glass transition appeared. This phenomenon may be indicative of a separate amorphous lactose phase.

Xanthan gum as a rate-controlling polymer for the development of alcohol resistant matrix tablets and mini-tablets.

The vulnerability of controlled release formulations when co-ingested with alcohol represents a current major concern of regulatory agencies. Dose dumping might occur when drugs and/or excipients exhibit higher solubility in ethanolic solutions compared to water. In this study, xanthan gum was chosen as rate-controlling polymer for the development of alcohol resistant matrix formulations and theophylline as model drug. Two polymer particle sizes (75 and 180µm) and concentrations (30 and 60% w/w) were used to assess their influence on the in-vitro drug release from directly compressed tablets and mini-tablets, in 0% and 40% ethanol for 2h (pH 1.2). For both, tablets and mini-tablets, by using 60% xanthan gum similar dissolution profiles in hydrous and hydroalcoholic media were obtained, independently of the polymer particle size. By decreasing the polymer concentration a risk of alcohol-induced dose dumping was recognised, however only when larger polymer particles were used. In particular, mini-tablets underwent disintegration and released the entire dose within 5min in alcohol. Nevertheless, finer polymer particles used at lower concentration led to the formation of a more coherent and less porous gel layer and alcohol resistance could be tailored in regard to both matrix tablets and mini-tablets.

Hot Melt Extrusion and Spray Drying of Co-amorphous Indomethacin-Arginine With Polymers.

Co-amorphous drug-amino acid systems have gained growing interest as an alternative to common amorphous formulations which contain polymers as stabilizers. Several preparation methods have recently been investigated, including vibrational ball milling on a laboratory scale or spray drying in a larger scale. In this study, the feasibility of hot melt extrusion for continuous manufacturing of co-amorphous drug-amino acid formulations was examined, challenging the fact that amino acids melt with degradation at high temperatures. Furthermore, the need for an addition of a polymer in this process was evaluated. After a polymer screening via the solvent evaporation method, co-amorphous indomethacin-arginine was prepared by a melting-solvent extrusion process without and with copovidone. The obtained products were characterized with respect to their solid-state properties, non-sink dissolution behavior, and stability. Results were compared to those of spray-dried formulations with the same compositions and to spray-dried indomethacin-copovidone. Overall, stable co-amorphous systems could be prepared by extrusion without or with copovidone, which exhibited comparable molecular interaction properties to the respective spray-dried products, while phase separation was detected by differential scanning calorimetry in several cases. The formulations containing indomethacin in combination with arginine and copovidone showed enhanced dissolution behavior over the formulations with only copovidone or arginine.

Micropellet-loaded rods with dose-independent sustained release properties for individual dosing via the Solid Dosage Pen.

Individual dosing of medicines is relevant for paediatrics, geriatrics and personalised medicine. The Solid Dosage Pen (SDP) allows for individual dosing by cutting monolithic, tablet-like drug carriers of pre-defined heights. The aim of the present study was to develop micropellet-loaded rods (MPLRs) with dose-independent sustained release properties for individual dosing via the Solid Dosage Pen. Therefore, micropellets were successfully layered with carbamazepine and coated with polyvinyl acetate (PVAc) and PVAc/polyvinyl alcohol-polyethylene glycol (PVA-PEG). The tensile strength of the sustained release micropellets (300-450 µm) was more than two times higher (12.6-17.1 MPa) than pressures occurring during ram-extrusion of the MPLRs (below 5.8 MPa). Due to relative crystallinities above 93% for PVAc and PVA-PEG a low solubility of the coating films within the PEG-matrix was observed. The sustained release micropellets were successfully incorporated into MPLRs. Drug release properties of the pellets maintained after embedding into the matrix. Hence, the MPLRs provided dose-independent prolonged drug liberation which was not achieved for drug-loaded rods before. The MPLRs permitted the application of the SDP with a precise drug delivery from individually cut single doses. Storage stability was proven for MPLRs containing PVAc/PVA-PEG coated pellets. In conclusion, the MPLRs combined the advantages of multiparticulate dosage forms with the SDP as a device for individual dosing.

Evaluation of the tablets' surface flow velocities in pan coaters.

The tablet pan coating process involves various types of transverse tablet bed motions, ranging from rolling to cascading. To preserve satisfactory results in terms of coating quality after scale-up, understanding the dynamics of pan coating process should be achieved. The aim of this study was to establish a methodology of estimating translational surface velocities of the tablets in a pan coater and to assess their dependence on the drum's filling degree, the pan speed, the presence of baffles and the selected tablet properties in a dry bed system and during coating while varying the drum's filling degree and the pan speed. Experiments were conducted on the laboratory scale and on the pilot scale in side-vented pan coaters. Surface movement of biconvex two-layer tablets was assessed before, during and after the process of active coating. In order to determine the tablets' surface flow velocities, a high-speed video of the tablet surface flow was recorded via a borescope inserted into the coating drum and analysed via a cross-correlation algorithm. The obtained tablet velocity data were arranged in a linear fashion as a function of the coating drum's radius and frequency. Velocity data obtained during coating were close to those of dry tablets after coating. The filling degree had little influence on the tablet velocity profile in a coating drum with baffles but clearly affected it in a coating drum without baffles. In most but not all cases, tablets with a lower static angle of repose had tablet velocity profiles with lower slopes than tablets with higher inter-tablet friction. This particular tablet velocity response can be explained by case specific values of tablet bed's dynamic angle of repose.

Modeling of an Active Tablet Coating Process.

Tablet coating is a common unit operation in the pharmaceutical industry, during which a coating layer is applied to tablet cores. The coating uniformity of tablets in a batch is especially critical for active coating, that is, coating that contains an active pharmaceutical ingredient. In recent years, discrete element method (DEM) simulations became increasingly common for investigating tablet coating. In this work, DEM was applied to model an active coating process as closely as possible, using measured model parameters and non-spherical particles. We studied how operational conditions (rotation speed, fill level, number of nozzles, and spray rate) influence the coating uniformity. To this end, simulation runs were planned and interpreted according to a statistical design of (simulation) experiments. Our general goal was to achieve a deeper understanding of the process in terms of residence times and dimensionless scaling laws. With that regard, the results were interpreted in light of analytical models. The results were presented at various detail levels, ranging from an overview of all variations to in-depth considerations. It was determined that the biggest uniformity improvement in a realistic setting was achieved by increasing the number of spray nozzles, followed by increasing the rotation speed and decreasing the fill level.

Solid-state properties and dissolution behaviour of tablets containing co-amorphous indomethacin-arginine.

Co-amorphous drug formulations provide the possibility to stabilize a drug in its amorphous form by interactions with low molecular weight compounds, e.g. amino acids. Recent studies have shown the feasibility of spray drying as a technique to manufacture co-amorphous indomethacin-arginine in a larger production scale. In this work, a tablet formulation was developed for a co-amorphous salt, namely spray dried indomethacin-arginine (SD IND-ARG). The effects of compaction pressure on tablet properties, physical stability and dissolution profiles under non-sink conditions were examined. Dissolution profiles of tablets with SD IND-ARG (TAB SD IND-ARG) were compared to those of tablets containing a physical mixture of crystalline IND and ARG (TAB PM IND-ARG) and to the dissolution of pure spray dried powder. Concerning tableting, the developed formulation allowed for the preparation of tablets with a broad range of compaction pressures resulting in different porosities and tensile strengths. XRPD results showed that, overall, no crystallization occurred neither during tableting nor during long-term storage. Dissolution profiles of TAB SD IND-ARG showed an immediate release of IND by erosion. The solubility of crystalline IND was exceeded by a factor of about 4, which was accompanied by a slow crystallization. For TAB PM IND-ARG, an in situ amorphization of IND in the presence of ARG was observed. As a result, a supersaturation was obtained, too, followed by a faster crystallization compared to TAB SD IND-ARG. In conclusion, the AUC24h of TAB SD IND-ARG was twofold higher than the AUC24h of TAB PM IND-ARG. Interestingly, different plateaus were obtained for TAB SD IND-ARG, TAB PM IND-ARG and pure SD IND-ARG after 24h dissolution, which could be explained by the formation of different polymorphic forms of indomethacin.

Mechanical strength test for orodispersible and buccal films.

There are no test procedures, definitions and specifications available how to determine mechanical strength of orodispersible or buccal films. Aim of the study was to develop an appropriate and discriminating method to feature the evaluation of marketed and newly developed film products covering well-known and new approaches. The limits for mechanical strength were set starting from a puncture strength of 0.06 N/mm(2) according to the obtained results from marketed products. Furthermore, elongation to break of the marketed films (1.03-6.54%) and prepared film samples (4.51-33.17%) offered information on the film properties. The developed mechanical strength test method was suitable for all film types without the need of a pre-defined specimen. A mechanical strength threshold could be specified for future orodispersible film development.

In-line spatial filtering velocimetry for particle size and film thickness determination in fluidized-bed pellet coating processes.

A spatial filtering velocimetry (SFV) probe was applied to monitor the increase in particle size during pellet Wurster coating processes in-line. Accuracy of the in-line obtained pellet sizes was proven by at-line performed digital image analysis (DIA). Regarding particle growth, high conformity between both analytical methods (SFV/DIA) was examined for different coating processes. The influence of ring buffer size and the process of filling the buffer were investigated. With buffer sizes of 30,000-50,000 particles best results were obtained in this study. Investigated process parameters, such as inlet air volume and spray rate, had different effects on the impact of the SFV probe. While the particle rate (the number of particles detected by the SVF probe per second) was highly dependent on the inlet air volume, different spray rates of up to ・}1 g/min did not affect the detected particle growth. Artefacts and delays in SFV particle sizing appeared especially at the beginning of the coating processes. The slope of the particle growth during the final spraying period was therefore used to determine coating thickness.

Evaluation of critical process parameters for inter-tablet coating uniformity of active-coated GITS using Terahertz Pulsed Imaging.

The aim of this study was the evaluation of critical process parameters (CPP) for inter-tablet coating uniformity in an active pan coating process using nondestructive Terahertz Pulsed Imaging (TPI). Coating uniformity was assessed by calculating the coefficient of variation (CV) of coating thickness measured by TPI, and the CV of API content measured by high performance liquid chromatography (HPLC). A design of experiments (DoE) was performed at pilot scale with drum load, drum speed, spray rate, run duration and spray pressure as factors. Good agreement in the CV of both analytical techniques was shown. The DoE models both revealed the same CPP: a low drum load, high drum speed, low spray rate and high run duration were beneficial for coating uniformity. The spray pressure was only significant in one of the DoE models. It was further shown that the negative impact of a high drum load on the CV cannot only be compensated by high drum speed, but also be compensated by a low spray rate and long run duration. It was demonstrated that TPI is a feasible tool for the measurement of inter-tablet coating uniformity and for the evaluation of CPP in an active pan coating process.

PAT-tools for process control in pharmaceutical film coating applications.

Recent development of analytical techniques to monitor the coating process of pharmaceutical solid dosage forms such as pellets and tablets are described. The progress from off- or at-line measurements to on- or in-line applications is shown for the spectroscopic methods near infrared (NIR) and Raman spectroscopy as well as for terahertz pulsed imaging (TPI) and image analysis. The common goal of all these methods is to control or at least to monitor the coating process and/or to estimate the coating end point through timely measurements.

Monitoring of an active coating process for two-layer tablets-model development strategies.

Incorporation of an active pharmaceutical ingredient (API) into the coating layer of film-coated tablets is a method mainly used to formulate combination tablets. Uniform and precise spray coating of an API represents, however, a substantial challenge that could be overcome by applying Raman spectroscopy as process analytical tool. In the present work, active-coating experiments for osmotic-controlled-release oral delivery system (OROS) tablets were performed in a side-vented lab-scale pan coater. During the process, Raman spectra were recorded in-line and off-line after sampling. Quantitative multivariate calibration models were built up by correlating these spectra with the coated API amount at each sampling point. Three different modeling approaches were tested on a second batch with regard to their predictive ability and robustness. By applying the in-line model development approach on OROS tablets, it was possible to overcome the difficulties of this dosage form with each layer contributing differently to the resulting spectroscopic signal and to determine accurately the applied API amount on two-layer tablets. Thereby, the present study demonstrated that Raman spectroscopy can be successfully implemented as a process analytical technology tool to control and monitor an active-coating process of OROS tablets.