Olivier Lecoq

Development of a Process Analytical Technology (PAT) for in-line monitoring of film thickness and mass of coating materials during a pan coating operation

The aim of this study was to perform in-line Near Infrared (NIR) measurements inside a pan coater to monitor a coating operation in real-time, by predicting the increases in mass of coating materials and coating thickness. A polymer combination of ethylcellulose/poly(vinyl-alcohol)-poly(ethylene-glycol) graft copolymer was used as functional aqueous coating. Coated tablets were sampled at regular intervals during the coating operation, then subjected to either simple and fast weighing (n=50) or accurate and non-destructive Terahertz Pulsed Imaging (TPI) measurements (n=3). Off-line NIR spectra analysis revealed that the coating operation could efficiently be controlled by focusing on two distinct NIR regions, related to absorption bands of ethylcellulose. Principal component analysis of in-line NIR spectra gave a clear classification of the collected coated tablets. Real-time quantitative monitoring of the coating operation was successfully performed from partial least square calibration models built using either TPI or weighing as reference method. Coating thicknesses as well as mass of coating materials used as primary values provided accurate NIR predictions. A comparison study demonstrated that both reference methods led to reliable and accurate real-time monitoring of the coating operation. This work demonstrated that in-line NIR measurements associated with multivariate analyses can be implemented to monitor in real-time a pan coating operation in order to fulfil the expectations of ICH Q8 guideline on pharmaceutical development, especially in terms of PAT control strategy and reduced end-product testing.

A grindability test to study the influence of material processing on impact behaviour

Abstract The behaviour of a powder impacted on a target depends on its size, its particle size distribution (PSD), the material mechanical properties and the industrial rig. A methodology for the study of impact in an air jet mill allows one to evaluate the relation between the impact energy and the grindability of the impacted solids. Moreover, the behaviour of an impacted powder is determined by its process conditions. An example is given with the study of different hydrargillites and aluminas produced in different ways and having different morphologies. The impact test allows one to classify these solids with grindability and attrition criteria. Morphological analysis relates them to external structural descriptors.

Fragmentation by high velocity impact on a target: a material grindability test

Abstract An experimental test rig for the study of impact in an air-jet mill (up to 500 m s −1 ) allows the evaluation of the relationship between the impact energy and the fineness of the impacted solids. In single impact tests, so far, three types of behaviour are found: brittle (for glass, sand, polyamide and NaCl), “complex” (for Al(OH) 3 ) and ductile (for PMMA). A classification is obtained from the definition of grindability parameters. A multi-impact study reveals the non-equivalence between multiple impact and single impact: a solid is not broken similarly if a given total energy is provided in one or several impacts.

Comprehensive study of dynamic curing effect on tablet coating structure.

The dissolution method is still widely used to determine curing end-points to ensure long-term stability of film coatings. Nevertheless, the process of curing has not yet been fully investigated. For the first time, joint techniques were used to elucidate the mechanisms of dynamic curing over time from ethylcellulose (Aquacoat)-based coated tablets. X-ray micro-computed tomography (XμCT), Near Infrared (NIR), and Raman spectroscopies as well as X-ray microdiffraction were employed as non-destructive techniques to perform direct measurements on tablets. All techniques indicated that after a dynamic curing period of 4h, reproducible drug release can be achieved and no changes in the microstructure of the coating were any longer detected. XμCT analysis highlighted the reduced internal porosity, while both NIR and Raman measurements showed that spectral information remained unaltered after further curing. X-ray microdiffraction revealed densification of the coating layer with a decrease in the overall coating thickness of about 10 μm as a result of curing. In addition, coating heterogeneity attributed to cetyl alcohol was observed from microscopic images and Raman analysis. This observation was confirmed by X-ray microdiffraction that showed that crystalline cetyl alcohol melted and spread over the coating surface with curing. Prior to curing, X-ray microdiffraction also revealed the existence of two coating zones differing in crystalline cetyl alcohol and sodium lauryl sulfate concentrations which could be explained by migration of these constituents within the coating layer. Therefore, the use of non-destructive techniques allowed new insights into tablet coating structures and provided precise determination of the curing end-point compared to traditional dissolution testing. This thorough study may open up new possibilities for process and formulation control.

Characterization of Mixing in a Stirred Tank by Planar Laser Induced Fluorescence (P.L.I.F.)

The mixing of two water feedstreams is investigated in a 0.02 m 3 continuous stirred tank, from concentration measurements. These measurements are carried out with a laser sheet in a very thin vertical plane through the vessel tangent to the impeller. The proportionality between the grey level obtained by planar laser induced fluorescence and the local concentration has been previously determined. The fields of instantaneous concentration, temporal variance and mixing index are processed from the grey level images.

Effect of roll-compaction and milling conditions on granules and tablet properties

Dry granulation is an agglomeration process used to produce size-enlarged particles (granules), improving the handling properties of powders such as flowability. In this process, powders are compacted using a roll press to produce ribbons, which are milled in granules used further in the tableting process. The granule and tablet properties are influenced by the existence of different designs of the roll compactors, milling systems and the interaction between process parameters and raw material properties. The main objective of this work was to investigate how different roll-compaction conditions and milling process parameters impact on ribbons, granules and tablet properties, highlighting the role of the sealing system (cheek plates and rimmed roll). In this context, two common excipients differing in their mechanical behaviour (MCC and mannitol) are used. The study is based on the analysis of granule size distribution together with the characterization of loss of compactability during die compaction. Results show that the tensile strength of tablets is lower when using granules than when the raw materials are compressed. Moreover, the plastic material (MCC) is more sensitive than the brittle one (mannitol). Regarding the roll-force, it is observed that the higher the roll force, the lower the tensile strength of tablets from granulated material is. These findings are in agreement with the literature. The comparison of sealing systems shows that the rimmed-roll system leads to slightly stronger tablets than the use of cheek plates. In addition, the use of the rimmed-roll system reduces the amount of fines, in particular when high roll force is applied. Overall, it can be concluded that roll-compaction effect is predominant over the milling effect on the production of fines but less significant on the tablet properties. This study points out that the balance between a good flowability by reducing the amount of fines and appropriate tablet strength is achieved with rimmed-roll and the highest roll-force used.

Comparative static curing versus dynamic curing on tablet coating structures

Curing is generally required to stabilize film coating from aqueous polymer dispersion. This post-coating drying step is traditionally carried out in static conditions, requiring the transfer of solid dosage forms to an oven. But, curing operation performed directly inside the coating equipment stands for an attractive industrial application. Recently, the use of various advanced physico-chemical characterization techniques i.e., X-ray micro-computed tomography, vibrational spectroscopies (near infrared and Raman) and X-ray microdiffraction, allowed new insights into the film-coating structures of dynamically cured tablets. Dynamic curing end-point was efficiently determined after 4h. The aim of the present work was to elucidate the influence of curing conditions on film-coating structures. Results demonstrated that 24h of static curing and 4h of dynamic curing, both performed at 60°C and ambient relative humidity, led to similar coating layers in terms of drug release properties, porosity, water content, structural rearrangement of polymer chains and crystalline distribution. Furthermore, X-ray microdiffraction measurements pointed out different crystalline coating compositions depending on sample storage time. An aging mechanism might have occur during storage, resulting in the crystallization and the upward migration of cetyl alcohol, coupled to the downward migration of crystalline sodium lauryl sulfate within the coating layer. Interestingly, this new study clearly provided further knowledge into film-coating structures after a curing step and confirmed that curing operation could be performed in dynamic conditions.

Dry Particle High-Impact Coating of Biopowders: Coating Strength

The aim of this study is to develop a fundamental knowledge on dry coating, to understand the coating strength of different bio-couples with a theoretical and experimental approach and how the dry coating is affected by the size of host particle and choice of dry particle coating equipment. For this purpose, we examine the feasibility of dry coating of two different particle size distributions of Cellets particles with talc using a Nara Hybridizer NHS-0, a 1 L Cyclomix, and a Turbula blender. Special care is required to choose suitable operating conditions in order to achieve surface modification without breakage phenomena. An experimental methodology based on a commercial granulometer is used to study the coating strength of the composites and allows us to study the influence of particle size. The conclusion is that the smaller the guest-to-host size ratio, the stronger the coating. This result is in agreement with the estimation of particle adhesion with the help of a van der Waals approach. The influence of the coating equipment is also studied. The Hybridizer leads with the chosen operating conditions to the stronger coating.