T. De Beer

Near infrared and Raman spectroscopy for the in-process monitoring of pharmaceutical production processes.

Within the Process Analytical Technology (PAT) framework, it is of utmost importance to obtain critical process and formulation information during pharmaceutical processing. Process analyzers are the essential PAT tools for real-time process monitoring and control as they supply the data from which relevant process and product information and conclusions are to be extracted. Since the last decade, near infrared (NIR) and Raman spectroscopy have been increasingly used for real-time measurements of critical process and product attributes, as these techniques allow rapid and nondestructive measurements without sample preparations. Furthermore, both techniques provide chemical and physical information leading to increased process understanding. Probes coupled to the spectrometers by fiber optic cables can be implemented directly into the process streams allowing continuous in-process measurements. This paper aims at reviewing the use of Raman and NIR spectroscopy in the PAT setting, i.e., during processing, with special emphasis in pharmaceutics and dosage forms.

In-Line and Real-Time Process Monitoring of a Freeze Drying Process Using Raman and NIR Spectroscopy as Complementary Process Analytical Technology (PAT) Tools

The aim of the present study was to examine the complementary properties of Raman and near infrared (NIR) spectroscopy as PAT tools for the fast, noninvasive, nondestructive and in-line process monitoring of a freeze drying process. Therefore, Raman and NIR probes were built in the freeze dryer chamber, allowing simultaneous process monitoring. A 5% (w/v) mannitol solution was used as model for freeze drying. Raman and NIR spectra were continuously collected during freeze drying (one Raman and NIR spectrum/min) and the spectra were analyzed using principal component analysis (PCA) and multivariate curve resolution (MCR). Raman spectroscopy was able to supply information about (i) the mannitol solid state throughout the entire process, (ii) the endpoint of freezing (endpoint of mannitol crystallization), and (iii) several physical and chemical phenomena occurring during the process (onset of ice nucleation, onset of mannitol crystallization). NIR spectroscopy proved to be a more sensitive tool to monitor the critical aspects during drying: (i) endpoint of ice sublimation and (ii) monitoring the release of hydrate water during storage. Furthermore, via NIR spectroscopy some Raman observations were confirmed: start of ice nucleation, end of mannitol crystallization and solid state characteristics of the end product. When Raman and NIR monitoring were performed on the same vial, the Raman signal was saturated during the freezing step caused by reflected NIR light reaching the Raman detector. Therefore, NIR and Raman measurements were done on a different vial. Also the importance of the position of the probes (Raman probe above the vial and NIR probe at the bottom of the sidewall of the vial) in order to obtain all required critical information is outlined. Combining Raman and NIR spectroscopy for the simultaneous monitoring of freeze drying allows monitoring almost all critical freeze drying process aspects. Both techniques do not only complement each other, they also provided mutual confirmation of specific conclusions.

Raman spectroscopy for the in-line polymer-drug quantification and solid state characterization during a pharmaceutical hot-melt extrusion process

The aim of this study was to evaluate the suitability of Raman spectroscopy as a Process Analytical Technology (PAT) tool for the in-line determination of the active pharmaceutical ingredient (API) concentration and the polymer-drug solid state during a pharmaceutical hot-melt extrusion process. For in-line API quantification, different metoprolol tartrate (MPT)--Eudragit® RL PO mixtures, containing 10%, 20%, 30% and 40% MPT, respectively, were extruded and monitored in-line in the die using Raman spectroscopy. A PLS model, regressing the MPT concentrations versus the in-line collected Raman spectra, was developed and validated, allowing real-time API concentration determination. The correlation between the predicted and real MPT concentrations of the validation samples is acceptable (R(2)=0.997). The predictive performance of the calibration model is rated by the root mean square error of prediction (RMSEP), which is 0.59%. Two different polymer-drug mixtures were prepared to evaluate the suitability of Raman spectroscopy for in-line polymer-drug solid state characterization. Mixture 1 contained 90% Eudragit® RS PO and 10% MPT and was extruded at 140°C, hence producing a solid solution. Mixture 2 contained 60% Eudragit® RS PO and 40% MPT and was extruded at 105°C, producing a solid dispersion. The Raman spectra collected during these extrusion processes provided two main observations. First, the MPT Raman peaks in the solid solution broadened compared to the corresponding solid dispersion peaks, indicating the presence of amorphous MPT. Second, peak shifts appeared in the spectra of the solid dispersion and solid solution compared to the physical mixtures, suggesting interactions between Eudragit® RS PO and MPT, most likely hydrogen bonds. These shifts were larger in the spectra of the solid solution. DSC analysis confirmed these Raman solid state observations and the interactions seen in the spectra. Raman spectroscopy is a potential PAT-tool for in-line determination of the API concentration and the polymer-drug solid state during pharmaceutical hot-melt extrusion.

Continuous twin screw granulation: Influence of process variables on granule and tablet quality

The aim of the current study was to screen theophylline (125 mg) tablets manufactured via twin screw granulation in order to improve process understanding and knowledge of process variables that determine granule and tablet quality. A premix of theophylline anhydrate, α-lactose monohydrate and PVP (ratio: 30/67.5/2.5,w/w) was granulated with demineralized water. Experiments were done using the high-shear wet granulation module (based on twin screw granulation) of the ConsiGma™-25 unit (a continuous tablet manufacturing system) for particle size enlargement. After drying, granules were compressed using a MODUL™ P tablet press (compression force: 10 kN, tablet diameter: 12 mm). Using a D-optimal experimental design, the effect of several process variables (throughput (10-25 kg/h), screw speed (600-950 rpm), screw configuration (number (2, 4, 6 and 12) and angle (30°, 60° and 90°) of kneading elements), barrel temperature (25-40°C) and method of binder addition (dry versus wet)) on the granulation process (torque and temperature increase in barrel wall), granule (particle size distribution, friability and flowability) and tablet (tensile strength, porosity, friability, disintegration time and dissolution) quality was evaluated. The results showed that the quality of granules and tablets can be optimized by adjusting specific process variables (number of kneading elements, barrel temperature and binder addition method) during a granulation process using a continuous twin screw granulator.

Raman spectroscopy as a process analytical technology (PAT) tool for the in-line monitoring and understanding of a powder blending process

The aim of this study is to propose a strategy to implement a PAT system in the blending step of pharmaceutical production processes. It was examined whether Raman spectroscopy can be used as PAT tool for the in-line and real-time endpoint monitoring and understanding of a powder blending process. A screening design was used to identify and understand the significant effects of two process variables (blending speed and loading of the blender) and of a formulation variable (concentration of active pharmaceutical ingredient (API): diltiazem hydrochloride) upon the required blending time (response variable). Interactions between the variables were investigated as well. A Soft Independent Modelling of Class Analogy (SIMCA) model was developed to determine the homogeneity of the blends in-line and real-time using Raman spectroscopy in combination with a fiber optical immersion probe. One blending experiment was monitored using Raman and NIR spectroscopy simultaneously. This was done to verify whether two independent monitoring tools can confirm each others endpoint conclusions. The analysis of the experimental design results showed that the measured endpoints were excessively rounded due to the large measurement intervals relative to the first blending times. This resulted in effects and critical effects which cannot be interpreted properly. To be able to study the effects properly, the ratio between the blending times and the measurement intervals should be sufficiently high. In this study, it anyway was demonstrated that Raman spectroscopy is a suitable PAT tool for the endpoint control of a powder blending process. Raman spectroscopy not only allowed in-line and real-time monitoring of the blend homogeneity, but also helped to understand the process better in combination with experimental design. Furthermore, the correctness of the Raman endpoint conclusions was demonstrated for one process by using a second independent endpoint monitoring tool (NIR spectroscopy). Hence, the use of two independent techniques for the control of one response variable not only means a mutual confirmation of both methods, but also provides a higher certainty in the determined endpoint.

Ethylene vinyl acetate as matrix for oral sustained release dosage forms produced via hot-melt extrusion.

Different ethylene vinyl acetate grades (EVA9, EVA15, EVA28 and EVA40 having a VA content of 9%, 15%, 28% and 40%, respectively) were characterized via differential scanning calorimetry. Glass transition temperature (T(g)), polymer crystallinity, melting point and polymer flexibility were positively influenced by the vinyl acetate content. The processability of EVA-based formulations produced by means of hot-melt extrusion (2mm die) was evaluated in function of VA content, extrusion temperature (60-140°C) and metoprolol tartrate (MPT, used as model drug) concentration (10-60%). Matrices containing 50% MPT resulted in smooth-surfaced extrudates, whereas at 60% drug content severe surface defects (shark skinning) were observed. Drug release from EVA/MPT matrices (50/50, w/w) was affected by the EVA grades: 90% after 24h for EVA15 and 28, while EVA9 and EVA40 formulations released 80% and 60%, respectively. Drug release also depended on drug loading and extrusion temperature. For all systems, the total matrix porosity (measured by X-ray tomography) was decreased after dissolution due to elastic rearrangement of the polymer. However, the largest porosity reduction was observed for EVA40 matrices as partial melting of the structure (melt onset temperature: 34.7°C) also contributed (thereby reducing the drug release pathway and yielding the lowest release rate from EVA40 formulations). The Simulator of the Human Intestinal Microbial Ecosystem (SHIME) used to evaluate the stability of EVA during gastrointestinal transit showed that EVA was not modified during GI transit, nor did it affect the GI ecosystem following oral administration.

Optimization and validation of a micellar electrokinetic chromatographic method for the analysis of several angiotensin-II-receptor antagonists

We have optimized a micellar electrokinetic capillary chromatographic method for the separation of six angiotensin-II-receptor antagonists (ARA-IIs): candesartan, eprosartan mesylate, irbesartan, losartan potassium, telmisartan, and valsartan. A face-centred central composite design was applied to study the effect of the pH, the molarity of the running buffer, and the concentration of the micelle-forming agent on the separation properties. A combination of the studied parameters permitted the separation of the six ARA-IIs, which was best carried out using a 55-mM sodium phosphate buffer solution (pH 6.5) containing 15 mM of sodium dodecyl sulfate. The same system can also be applied for the quantitative determination of these compounds, but only for the more stable ARA-IIs (candesartan, eprosartan mesylate, losartan potassium, and valsartan). Some system parameters (linearity, precision, and accuracy) were validated.

Co-extrusion as manufacturing technique for fixed-dose combination mini-matrices

The aim of this study was to develop a multilayer (core/coat) dosage form via co-extrusion, the core providing sustained drug release and the coat immediate drug release. In this study polymers were selected which can be combined in a co-extruded dosage form. Several thermoplastic polymers were hot-melt extruded and evaluated for processability and macroscopic properties (surface smoothness, die swell). Metoprolol tartrate (MPT) and hydrochlorothiazide (HCT) were incorporated as sustained and immediate release model drugs, respectively. Based on the polymer screening experiments a combination of polycaprolactone (core) and polyethylene oxide (coat) was selected for co-extrusion trials, taking into account their drug release profiles and extrusion temperature (70 °C). This combination (containing 10% HCT in the coat and 45% MPT in the core) was successfully co-extruded (diameter core: 3 mm/thickness coat: 0.5 mm). Adhesion between the two polymer layers was good. HCT release from the coat was complete within 30 min, while MPT release was sustained over 24 h (55%, 70%, 85% and 100% after 4, 8, 12 and 2 4h, respectively). DSC, XRD and Raman spectroscopy revealed that MPT remained crystalline during extrusion, whereas HCT was dissolved in the polyethylene oxide matrix. The in vivo study revealed no significant differences between the experimental formulation and the reference formulation (Zok-Zid tablet). Fixed-dose combination mini-tablets with good in vitro and in vivo performance were successfully developed by means of co-extrusion, using a combination of polycaprolactone and polyethylene oxide.

Impact of screw configuration on the particle size distribution of granules produced by twin screw granulation.

Twin screw granulation (TSG) has been reported by different research groups as an attractive technology for continuous wet granulation. However, in contrast to fluidized bed granulation, granules produced via this technique typically have a wide and multimodal particle size distribution (PSD), resulting in suboptimal flow properties. The aim of the current study was to evaluate the impact of granulator screw configuration on the PSD of granules produced by TSG. Experiments were performed using a 25 mm co-rotating twin screw granulator, being part of the ConsiGma™-25 system (a fully continuous from-powder-to-tablet manufacturing line from GEA Pharma Systems). Besides the screw elements conventionally used for TSG (conveying and kneading elements), alternative designs of screw elements (tooth-mixing-elements (TME), screw mixing elements (SME) and cutters) were investigated using an α-lactose monohydrate formulation granulated with distilled water. Granulation with only conveying elements resulted in wide and multimodal PSD. Using kneading elements, the width of the PSD could be partially narrowed and the liquid distribution was more homogeneous. However, still a significant fraction of oversized agglomerates was obtained. Implementing additional kneading elements or cutters in the final section of the screw configuration was not beneficial. Furthermore, granulation with only TME or SME had limited impact on the width of the PSD. Promising results were obtained by combining kneading elements with SME, as for these configurations the PSD was narrower and shifted to the size fractions suitable for tableting.

Evaluation of in-line spatial filter velocimetry as PAT monitoring tool for particle growth during fluid bed granulation

In this study, the feasibility of spatial filter velocimetry (SFV) as process analytical technology tool for the in-line monitoring of the particle size distribution during top spray fluidized bed granulation was examined. The influence of several process (inlet air temperature during spraying and drying) and formulation variables (HPMC and Tween 20 concentration) upon the particle size distribution during processing, and the end product particle size distribution, tapped density and Hausner ratio was examined using a design of experiments (DOE) (2-level full factorial design, 19 experiments). The trend in end granule particle size distributions of all DOE batches measured with in-line SFV was similar to the off-line laser diffraction (LD) data. Analysis of the DOE results showed that mainly the HPMC concentration and slightly the inlet air temperature during drying had a positive effect on the average end granule size. The in-line SFV particle size data, obtained every 10s during processing, further allowed to explain and better understand the (in)significance of the studied DOE variables, which was not possible based on the LD data as this technique only supplied end granule size information. The variation in tapped density and Hausner ratio among the end granules of the different DOE batches could be explained by their difference in average end granule size. Univariate, multivariate PLS and multiway N-PLS models were built to relate these end granule properties to the in-line-measured particle size distribution. The multivariate PLS tapped density model and the multiway N-PLS Hausner ratio model showed the highest R(2) values in combination with the lowest RMSEE values (R(2) of 82% with an RMSEE of 0.0279 for tapped density and an R(2) of 52% with an RMSEE of 0.0268 for Hausner ratio, respectively).