The Influence of Equipment Design and Process Parameters on Granule Breakage in a Semi-Continuous Fluid Bed Dryer after Continuous Twin-Screw Wet Granulation.

The drying unit of a continuous from-powder-to-tablet manufacturing line based on twin-screw granulation (TSG) is a crucial intermediate process step to achieve the desired tablet quality. Understanding the size reduction of pharmaceutical granules before, during, and after the fluid bed drying process is, however, still lacking. A first major goal was to investigate the breakage and attrition phenomena during transport of wet and dry granules, the filling phase, and drying phase on a ConsiGma-25 system (C25). Pneumatic transport of the wet granules after TSG towards the dryer induced extensive breakage, whereas the turbulent filling and drying phase of the drying cells caused rather moderate breakage and attrition. Subsequently, the dry transfer line was responsible for additional extensive breakage and attrition. The second major goal was to compare the influence of drying air temperature and drying time on granule size and moisture content for granules processed with a commercial-scale ConsiGma-25 system and with the R&D-scale ConsiGma-1 (C1) system. Generally, the granule quality obtained after drying with C1 was not predictive for the C25, making it challenging during process development with the C1 to obtain representative granules for the C25.

In-line temperature measurement to improve the understanding of the wetting phase in twin-screw wet granulation and its use in process development.

Wetting is the initial stage of wet granulation processes during which the first contact between the powder and the liquid occurs. Wetting is a critical step to allow granule growth and consolidation, but also to ensure uniform active pharmaceutical ingredient (API) distribution over all granule size fractions. A physical understanding of the wetting stage is therefore crucial to design a robust granulation process. In twin-screw granulation, wetting is physically separated from granule consolidation, growth, breakage and attrition. The present study used this particularity to investigate the wetting step in such a way that the fundamental mechanisms governing the wetting can be linked and understood. A modified granulator barrel was used allowing the collection of granules immediately after the wetting. A low drug-loaded pharmaceutical formulation containing a poorly soluble and poorly wettable API was used for this investigation. Granules obtained after the wetting zone were analysed for granule size distribution, API distribution over the different size fractions and granule temperature. It was found that "wetting efficiency" (i.e., fraction of powder being nucleated during the wetting stage) could be predicted using an energy balance based on in-line measurement of the granule temperature. Wetting efficiency could moreover be linked to final granule quality attributes (i.e., granule size distribution) at the outlet of the granulator. It was further demonstrated that granule growth and consolidation could only be achieved when complete wetting was achieved in the wetting zone of the granulator. This study suggested a methodology based on in-line temperature measurements to quickly determine wetting efficiency. The described methodology could therefore be used as a tool to gain more fundamental understanding of the wetting stage during twin-screw granulation as well as to define suitable formulation and process ranges for further granulation process development.

Heat Transfer Evaluation During Twin-Screw Wet Granulation in View of Detailed Process Understanding.

During the last decade, the pharmaceutical industry has shown a growing interest in continuous twin-screw granulation (TSG). Despite flourishing literature on TSG, limited studies focused on fundamental process understanding on its mechanisms. In current study, granule quality attributes along the length of the TSG barrel were evaluated together with heat transfer in order to achieve a more fundamental understanding of the granulation process. An experimental setup was developed allowing the collection of granules at the different TSG compartments. In addition to the determination of typical granule attributes, mechanical energy, barrel and granule temperature (measured using an in-line implemented infra-red camera) were measured to evaluate heat transfer occurring at the different compartments and to relate them to granulation mechanisms. Collected data identified wetting enthalpy and friction forces as the main sources of heat along the granulator length. Wetting occurred in the wetting zone and generated temperature increase depending on liquid-to-solid ratio and powder wettability. In the kneading zones, granule temperature increase was proportional to mechanical energy. While it is usually admitted that granule consolidation and reshaping are the consequence of the high shear experienced by the granules, it was highlighted that most of the mechanical energy is converted into thermal energy with no correlation between mechanical energy and granule size distribution. Combined mass and energy balance of the granulation process are therefore necessary to capture the interaction between granule properties and physico-chemical and mechanical phenomena occurring in each compartment.

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.

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.

Optimization of the inter-tablet coating uniformity for an active coating process at lab and pilot scale.

The objective of this study was to enhance the inter-tablet coating uniformity in an active coating process at lab and pilot scale by statistical design of experiments. The API candesartan cilexetil was applied onto gastrointestinal therapeutic systems containing the API nifedipine to obtain fixed dose combinations of these two drugs with different release profiles. At lab scale, the parameters pan load, pan speed, spray rate and number of spray nozzles were examined. At pilot scale, the parameters pan load, pan speed, spray rate, spray time, and spray pressure were investigated. A low spray rate and a high pan speed improved the coating uniformity at both scales. The number of spray nozzles was identified as the most influential variable at lab scale. With four spray nozzles, the highest CV value was equal to 6.4%, compared to 13.4% obtained with two spray nozzles. The lowest CV of 4.5% obtained with two spray nozzles was further reduced to 2.3% when using four spray nozzles. At pilot scale, CV values between 2.7% and 11.1% were achieved. Since the test of uniformity of dosage units accepts CV values of up to 6.25%, this active coating process is well suited to comply with the pharmacopoeial requirements.

Evaluation of critical process parameters for intra-tablet coating uniformity using terahertz pulsed imaging.

The purpose of this study was to evaluate the intra-tablet coating uniformity and the identification of critical process parameters in an active pan coating process using terahertz pulsed imaging (TPI). A design of experiments (DoE) was performed with drum load, drum speed, spray rate, run duration and spray pressure as factors. Different measures of intra-tablet uniformity were investigated: the average thickness on the individual tablet faces, spatial variation in layer thickness over the tablet surface, and the coefficient of variation (CV(intra)). Data analysis revealed that the process parameters in the investigated parameter space had hardly any influence on the difference in layer thickness of the tablet faces and centre band. No increase or decrease in layer thickness--as described in the literature--was found towards the edges of the tablet face. In overwetted process conditions a higher layer thickness at the centre band edges could be observed. Still, the highest variability in coating thickness was found along the circumference of the centre band rather than the height. In general, higher CV(intra) of layer thickness were found on the centre bands in comparison with the tablet faces. The analysis of the DoE model revealed that the run duration had the highest influence on the CV(intra) on the tablet faces. TPI showed high potential in the assessment of intra-tablet uniformity and layer thickness distributions over the whole tablet surface. It was successfully used to identify critical process parameters regarding intra-tablet coating uniformity.

Critical factors in the measurement of tablet film coatings using terahertz pulsed imaging.

The present work gives an insight into some key measurement and signal processing considerations in terahertz pulsed imaging (TPI). TPI is increasingly used for the measurement of the spatial variation of coating thickness on coated solid dosage forms. The potential of TPI for the assessment of coating thickness distributions and the use in process development is described in recent literature. However, some critical factors need to be taken into account when working with this technique. These are (1) the signal processing of the raw data, (2) the influence of the composition of the sample matrix on the TPI signals and subsequent coating analysis, (3) signal distortions that can occur at tablet edges or areas with defects, and (4) the refractive index as a key parameter in the quantification of layer thickness. In this paper, we will highlight to what extent these factors impact on the qualitative and quantitative analysis of TPI data and how artifacts and misinterpretation of data can be avoided to ensure fully quantitative and robust measurements.

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.

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.

Novel poloxamer-based nanoemulsions to enhance the intestinal absorption of active compounds.

On the basis of Pluronic P104 as primary emulsifier and Lauroglycol 90 as amphiphilic oil phase, two nanoemulsion systems were developed with Pluronic((R)) L62 or L81 as secondary emulsifiers. The possible nanoemulsion region of combinations of these excipients was described in ternary phase diagrams. Three formulations were selected from the nanoemulsion region and their potential impact on oral absorption was examined in the Caco-2 monolayer model of the small intestine. The apparent permeability of the BCS class III compound Atenolol was enhanced 2.5-fold, of BCS class II compound Danazol 3.2-fold and of BCS class I compound Metoprolol 1.4-fold. The three formulations were very well tolerated by the Caco-2 cells, which was confirmed by TEER measurements, a MTT test and a LDH release test.

Comparison of permeation enhancing strategies for an oral factor Xa inhibitor using the Caco-2 cell monolayer model.

FXai, a direct inhibitor of the clotting factor Xa, provides high water solubility but poor membrane permeability due to multiple sites of ionization and a molecular weight exceeding 500 Da, making it a Class III drug according to the Biopharmaceutics Classification System. To overcome the ionization problem and increase the transcellular permeability, various ester and hydroxyamidine prodrugs exhibiting a reduced number of ionization sites were studied in the Caco-2 monolayer model for intestinal permeation. Alternatively, the potential transcellular permeation enhancement of Imwitor 742 and the potential paracellular enhancement of three chitosan formulations were investigated in the same model. FXai has an apparent permeability (P(app)) of about 1 nm/s, which is generally regarded as very low. The butylester-hydroxyamidine double-prodrug was found to provide a markedly increased permeability (40.4 nm/s) as did the co-application of chitosan (43.3 nm/s). Other prodrugs slightly increased permeability (1.3-9.2 nm/s) but were inferior to the previous attempts to enhance permeability while the Imwitor admixture showed no effect (1.1 nm/s). Moreover, a bioactivating metabolism towards the hydroxyamidine mono-prodrug was detected in the Caco-2 cell permeation model. Although esterases were overexpressed and mainly located apically, an acceptable permeation was reached. In addition, the prodrugs triggered an efflux system that is not inhibited by verapamil but by quinidine, suggesting the involvement of an organic cation transporter.

Development of matrix patches for transdermal delivery of a highly lipophilic antiestrogen.

The aim of this study was to develop matrix-type transdermal systems (TDSs) containing the highly lipophilic (log P = 5.82) antiestrogen (AE) and the permeation enhancers propylene glycol and lauric acid. For that purpose, permeation of AE from various adhesive matrices through excised skin of hairless mice was evaluated. It was found that pretreatment of the skin with permeation enhancers raised the transdermal flux of subsequently applied antiestrogen. Highest steady-state transdermal fluxes (1.1 microg cm(-2) h(-1)) were obtained from Gelva, polyacrylate adhesive, followed by 0.55 microg cm(-2) h(-1) from Oppanol polyisobutylene, 0.31 microg cm(-2) h(-1) from BIO-PSA silicone, and 0.12 microg cm(-2) h(-1) from Sekisui polyacrylate matrices. In order to develop TDS with high content of fluid permeation enhancer propylene glycol, two different strategies were investigated. One strategy was the addition of hydroxypropyl cellulose (HPC) as thickening agent to Gelva matrices. This allowed for propylene glycol loading levels of up to 30%, resulting in transdermal AE fluxes of 0.09 microg cm(-2) h(-1). On the other hand, a fleece-laminated backing foil was loaded with the described permeation enhancer formulation and laminated with polyacrylate adhesive layer, resulting in transdermal AE fluxes of 0.06 microg cm(-2) h(-1). However, application of these TDSs on skin pretreated with permeation enhancers raised the fluxes to 2.6 microg cm(-2) h(-1) from Gelva/HPC and 0.46 microg cm(-2) h(-1) from fleece/Sekisui.

In-vitro release and transdermal fluxes of a highly lipophilic drug and of enhancers from matrix TDS.

Transdermal systems (TDS) are a well-known application form for small, moderately lipophilic molecules. The aim of this study was to investigate the possibility of applying a highly lipophilic drug, the antiestrogen AE (log P=5.82) transdermally by polyacrylate-based matrix TDS. For this purpose, two effects of both drug and enhancer concentration in TDS were investigated: in-vitro release and transdermal permeation of drug and enhancers. In the TDS investigated, in-vitro release as well as in-vitro permeation of AE through excised skin of hairless mice was found to be independent of concentrations of both drug and enhancers. The steady-state fluxes observed were low (about 50-100 ng cm(-2) h(-1)). But skin pretreatment with permeation enhancers resulted in a markedly enhanced permeability (1400 ng cm(-2) h(-1)). Therefore, the permeation of this highly lipophilic drug seems to be limited by the stratum corneum barrier function. In contrast, the transdermal permeation of the enhancers was dependent on the TDS composition. Increase in enhancer content resulted in a higher permeation of enhancers, whereas skin pretreatment did not. In conclusion, it was shown that the highly lipophilic antiestrogen can be administered transdermally by pretreating the skin with the fluid permeation enhancer combination propylene glycol-lauric acid (9+1) and then applying a matrix TDS.

Transdermal delivery of highly lipophilic drugs: in vitro fluxes of antiestrogens, permeation enhancers, and solvents from liquid formulations.

PURPOSE: Highly lipophilic basic drugs, the antiestrogens AE 1 (log P = 5.82) and AE 2 (log P = 7.8) shall be delivered transdermally. METHODS: Transdermal permeation of drugs, enhancers, and solvents from various fluid formulations were characterized by in-vitro permeation studies through excised skin of hairless mice. Furthermore, differential scanning calorimetry (DSC) measurements of skin lipid phase transition temperatures were conducted. RESULTS: Transdermal flux of highly lipophilic drugs was extraordinarily enhanced by the unique permeation enhancer combination propylene glycol-lauric acid (9 + 1): steady-state fluxes of AE 1 and AE 2 were as high as 5.8 microg x cm(-2) x h(-1) and 3.2 microg x cm(-2) x h(-1), respectively. This dual enhancer formulation also resulted in a marked increase in the transdermal fluxes of the enhancers. Furthermore, skin lipid phase transition temperatures were significantly reduced by treatment with this formulation. CONCLUSION: Transdermal delivery of highly lipophilic drugs can be realized by using the permeation enhancer combination propylene glycol-lauric acid. The extraordinary permeation enhancement for highly lipophilic drugs by this formulation is due to mutual permeation enhancement of these two enhancers and their synergistic lipid-fluidising activity in the stratum corneum.