Solid dispersion systems represent an attractive formulation route to achieve fast release of the active compound. Despite its promising potentials, recrystallization tendency of the amorphous dispersed drug is an issue of concern. This necessitates formulation and stability investigations with different polymers and drug polymer ratios. In early stability trials, preparation of thin solid dispersion films and investigation of these under polarized light microscopy for birefringence have shown to be fast and nondestructive way in screening formulation quality and stability of these systems [1]. Despite its usefulness, a quantitative method for measuring the degree of birefringence is lacking, limiting the full potential of polarized light microscopy for solid dispersion characterization. In the current study, we have developed a semi-automatic and user-friendly method for the estimation of number of birefringence spots and their relative coverage area on the image obtained from polarized light microscopy. The method comprises binarisation, morphological structuring, labeling connected component, area estimation of binary pixels and counting. Because air bubbles left on samples due to fast evaporation during film formation also gave raise to birefringence, a method is proposed to semi-automatically removing these bubble-related artifacts from images prior to estimation of birefringence from the crystallized drug. Image parameters estimated are subsequently used as responses in an experimental design and further used to investigate the importance of evaporation temperature, drug polymer ratio and polymer grades on solid dispersion stability. The suggested method provides insight and understanding of so far unanticipated role of evaporation rateon the stabilization of solid dispersion systems. Reference: [1] Eerdenbrugh B.v., Taylor L.S.; Small Scale Screening To Determine the Ability of Different Polymers To Inhibit Drug Crystallization upon Rapid Solvent Evaporation; Molecular Pharmaceutics 2010, 7(4): 1328-1337.
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Herman Offerhaus
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Martin Jurna
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A few years ago Solid Crystal Suspensions (SCS), made via hot-melt-extrusion, were proposed as sufficient technique to increase the bioavailability of poorly soluble drugs of BCS Class II. The drug particle size and the dispersity of these systems are crucial properties because they determine the drug release. The nonlinear imaging techniques, Coherent Anti Stokes Raman Scattering (CARS) and Second Harmonic generation (SHG) microscopy, were used to characterize SCS in order to understand the dissolution behaviour of different formulations. CARS microscopy is based on the detection of molecular vibrations similar to Raman spectroscopy. The advantage in comparison to conventional Raman spectroscopy is the detection of a single vibrational resonance allowing for much faster imaging with CARS. The setup consists of a laser and an optical parametric oscillator. The beams were scanned over the sample by galvano-mirrors and focused by an objective lens into the sample. The generated CARS signal is shifted to a higher frequency in comparison to the incident beam. The SHG signal is created when the sample contains non-centrosymmetric structures. The generated signal is created simultaneous with the CARS signal in the sample and detected on a different detector. The SCS consisted of drug (Griseofulvin) and matrix (Mannitol). The matrix is detected with CARS microscopy and the drug with SHG microscopy offering high contrast between the compounds. The nonlinear microscopy images of the SCS showed a homogeneous distribution of the drug particles. There were no agglomerates and the drug distribution in the centre was almost the same as at the surface of the objects. The drug particle size was also investigated and similar results like in laser diffraction were found. The combination of the two nonlinear microscopy techniques, CARS and SHG where identified as promising tools to characterize drug distribution and drug particle size in this Solid Crystal Suspension.
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Maria Støier Fullerton
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Signe Hougaard Nielsen
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Purpose To compare the formation of the adsorbed lysozyme layer at the oil-water interface with two different methods and to scrutinize the possibilities of avoiding film-formation by addition of model surfactants. Methods Surface tension measurements were carried out using pendant drop (KRÜSS, Germany). An aqueous droplet of 70 mL was formed with a needle (diameter 1.83 mm) in a glass cuvette containing the oil-phase. Film formation was evaluated by withdrawal of the aqueous phase after 10 minutes emersion in the oil phase. Rheological properties were measured by use of a TA AR-G2 rheometer equipped with a double wall ring (DWR) geometry. The system consists of a ring and a Delrin® trough with a circular channel (interfacial areal=1882.6 mm2). Oscillatory shear measurements were conducted at constant frequency of 0.1 Hz, temperature of 25°C and the strain was set to 1%. Results The adsorption of lysozyme to the oil-water interface results in the formation of a flexible protein film. This formation can be prevented by addition of surfactants, in a manner that is dependent on the concentration and the type of surfactant. According to the rheological method the more hydrophilic surfactants are more effective in hindering lysozyme adsorption to oil-water interfaces whereas the hydrophobic surfactants seem to be more effective according to the surface tension measurements. According to the rheological method the larger surfactants are more persistent in preventing film formation whereas the smaller eventually give place for the lysozyme on the interface. Conclusion The two methods can be used to detect the interfacial adsorption of lysozyme and can be used to evaluate the performance of model surfactants in hindering film formation. This will aid in processing of any delivery systems for proteins where the protein will be introduced to oil-water interfaces that could affect the stability of the protein.
Failure Mode and Effects Analysis (FMEA) is a procedure which is performed after a failure mode effects analysis to classify each potential failure effect according to its severity and probability of occurrence. FMEA is a systematic proactive method for evaluating a process to identify where and how it might fail and to assess the relative impact of different failures, in order to identify the part of the process that are most in need of change. Subjected a controlled release tablet formulation to a Failure Mode and Effects Analysis, including technical risks as well as risks related to human failure which broke down the formulation into the process steps and identified possible failure modes for each step. Each failure mode was ranked on estimated frequency of occurrence (0), probability that the failure would remain undetected later in the process (D) and severity (S). Human errors turned out to be the most common cause of failure modes. Failure risks were calculated by Risk Priority Number (RPNs) O*D*S. Failure modes with the highest RPN scores were subjected to corrective action and FMEA was repeated. FMEA is particularly useful in evaluating a new process prior to implementation and in assessing the impact of a proposed change to an existing process which depends on product and process understanding. FMEA is most effective when it occurs before a design is released rather than "after the fact". The aim of this paper is to demonstrate an application of process failure mode and effect analysis (process FMEA) as a performance improvement tool, based on a case analysis of process improvement conducted in an early drug discovery project.
Thomas De Beer
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Jean Paul Remon
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Chris Vervaet
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The objective of this study is to evaluate Raman spectroscopy as a PAT tool for the in-line determination of the 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® RLPO mixtures, containing 10, 20, 30, and 40% MPT respectively, were extruded and monitored in-line in the die using Raman spectroscopy. Two different polymer-drug mixtures were prepared to evaluate Raman spectroscopy for in-line polymer-drug solid state characterization. Mixture 1 contained 90% Eudragit® RSPO and 10% MPT, and was extruded at 140°C, hence producing a solid solution. Mixture 2 contained 60% Eudragit® RSPO and 40% MPT, and was extruded at 105°C, producing a solid dispersion. DSC analysis and ATR FT-IR were used to confirm the observations. 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 (R²=0.997). The predictive performance of the calibration model is rated by the root mean square error of prediction, which is 0.59%. The Raman spectra collected during extrusion of mixtures 1 and 2 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 MPT in the amorphous state. Secondly, 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 and ATR FT-IR confirmed these observations. Raman spectroscopy is a potential PAT-tool for in-line determination of API-concentration and polymer-drug solid state during pharmaceutical hot-melt extrusion processes.
Thomas De Beer
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Chris Vervaet
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Jean Paul Remon
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Mario Hellings
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Tom Van Den Kerkhof
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Anneleen Burggraeve
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De Beer, T.; Vervaet, C.; Remon, J.; Hellings, M.; Van Den Kerkhof, T.; Burggraeve, A. Real-Time Particle Size Distribution Evaluation during Fluid Bed Granulation, in Proceedings of the 1st Electronic Conference on Pharmaceutical Sciences, 1–31 March 2011, MDPI: Basel, Switzerland, doi:10.3390/ecps2011-00511
Fluid bed granulation has extensively been used for several decades within the pharmaceutical industry to improve powder properties (i.e., flowability, compressibility, etc.) for downstream processes. During this 2-phased process (spraying and drying period), primary particles aggregate due to the addition of a binder liquid which results into the formation of granules. The granule size distribution (GSD) is of major importance to the final quality of the granulated product as an inappropriate GSD influences the density, flowability and dustiness of the end product. In this study, a particle size analyser (Parsum IPP 70; Gesellschaft für Partikel-, Strömungs- und Umweltmesstechnik, Chemnitz, Germany) was mounted into a laboratory scale top-spray fluid bed granulator. A design of experiments (DoE) was performed to study the influence of several process (inlet air temperature during spraying and drying) and formulation variables (HPMC and Tween 20 concentration) upon the GSD, continuously in-line measured and compared to off-line laser diffraction data. Next, the in-line collected granule size data were related to off-line-determined end granule properties (tapped density and Hausner ratio) using univariate, multivariate and multiway models. The in-line particle size analyser provided every 10 s information about the granulation process, which allowed a clarification and better understanding of the (in)significance of the studied DoE variables upon granulation. In addition, we were able to predict end granule properties based on in-line GSD data, which can be valuable during development and routine production. The results of this study demonstrate the beneficial use of a particle size analyser during granulation. The tool was sensitive to any particle size changes during granulation and aids to increase granulation process understanding. Due to the continuous and rapid GSD measurements, granulation efficiency and control might be improved.
Purpose: To prepare solid lipid nanoparticles (SLN) of curcumin (CRM) by microemulsion method and assessing its effect on oral bioavailability in Sprague-Dawley rats. Methods: CRM SLN composed of Gelucire 50/13 were prepared by microemulsion method followed by freeze drying and characterized for mean particle size by Photon Correlation spectroscopy. The SLN were administered (p.o., 100 mg/kg) to male Sprague-Dawley rats (225-275g) and plasma samples were analyzed using a validated HPLC-UV/VIS method. An aqueous suspension of CRM was used as the reference (administered p.o. 250 mg/kg). The pharmacokinetic parameters AUC(0-5h), Cmax and Tmax were calculated using non compartmental modeling. Results: The mean particle size of the SLN was found to be 375 nm. The results for AUC(0-5h), Cmax and Tmax were found to be 28.0 ng.h/mL, 28.9 ng/mL and 0.5 h, respectively for reference; and 75.5 ng.h/mL, 31.3 ng/mL and 1.0 h, respectively for SLN. A statistically significant increase (P= 0.035, 2 sample unpaired t-test) of 647% was observed after dose normalization in the oral bioavailability of CRM (in terms of AUC (0-5h)). Conclusion: The oral bioavailability of CRM can be significantly improved by developing SLN of CRM.
Development of controlled release dosages forms requires thorough understanding of the formulation and process parameters as well as robust process control solutions. In this study the effect of four selected process parameters; coating amount, concentration of the polymer in coating solution, spray rate of the coating solution and fluidising air flow rate on the surface roughness of the film coated extrudates has been evaluated. The film coating was performed in a typical lab system coater equipped with a Wurster insert by using a mixed full factorial design resulting in 16 batches. The surface roughness was measured with Flashsizer 3D which applies a photometric imaging technique [1]. This technique uses two white light sources that allow the reconstruction of a 3D image of the extrudates surface. The light source has been placed 180°C from each other in a horizontal plane. The extrudates batches were presented to the instrument in a continuous feed and were imaged through a glass window. Approximately 270 extrudates were measured per one feeding-cycle and each batch was measured on average 15 times resulting in measurement of roughly 4000 extrudates per batch. Different surface roughness values were calculated from the digital image information and are based on change in grey scale values in the surface images. An increased coating amount decreased the surface roughness described by Ra which is the arithmetic average of the roughness profile. The same effect was observed by increasing the spray rate of coating solution whereas an increased fluidising air flow rate increased the Ra surface roughness. No effect of Ra surface roughness was observed by increasing the ethyl cellulose concentration in the coating solution. The suggested approach is a promising tool for evaluating surface roughness of film coated extrudates in a continuous manner. References: 1. Sandler, N., Photometric imaging in particle size measurement and surface visualization. Int. J. Pharm. (2010)
Nanocrystalline solid dispersions (NCSDs) of Indomethacin were prepared by antisolvent precipitation followed by spray drying, using hydrophilic polymers like polyvinyl pyrrolidine (PVP K30), hydroxyl propyl methyl cellulose (HPMC E15) and polyvinyl alocohol (PVA) in the ratio of 90:10 w/w. Methonolic solution of Indomethacin was added to aqueous polymeric solution to obtain nano-crystals of Indomethacin, and was spray dried to obtain NCSDs. Crystallite size of Indomethacin in dispersion was measured using by Scherrer equation, which uses powder X-ray diffraction peak broadening of nano-crystallites over micro-crystallites. The average crystallite size of Indomethacin in dispersions was lowest in PVA dispersion followed by HPMC E15 and PVP K30. NCSDs showed considerably higher dissolution rate over crystalline solid dispersions and "as received" Indomethacin in water. NCSDs released 80 - 90% of Indomethacin within 10 min in comparison to 25-50% in case of crystalline solid dispersion and < 5% incase of "as received" Indomethacin. Higher dissolution efficiency of nanocrystalline solid dispersions could be attributed to the nano-size of Indomethacin crystallites, and crystal growth inhibition role of polymers. Influence of viscosity and drug-excipient miscibility (solubility parameter), of polymers used in the present study, on the crystallite size is discussed.
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Rantanen, J.; Rades, T.; Pajander, J.; Berg, F.v.; Yang, M.; Wu, J.X. The Influence of Solvent Evaporation Rate on Solid Dispersion Initial Quality and Stability: A Fast Screening Approach, in Proceedings of the 1st Electronic Conference on Pharmaceutical Sciences, 1–31 March 2011, MDPI: Basel, Switzerland, doi:10.3390/ecps2011-00516
The potential of increased drug release and thus increasing bioavailability of poorly water soluble drugs formulated as solid dispersion is well recognized. When preparing solid dispersions, an important aim is to disperse the drug compound in amorphous form within the polymer, and thus exploit the increased solubility of the amorphous drug. Due to the increased free energy of the amorphous drug, recrystallization during solid dispersion preparation and storage are issues of concern. Up to date, one of the preferred approaches in preparing solid dispersions is the solvent evaporation based methods due to its convenience and possibility for larger scale manufacturing. The methods include rotation evaporation, evaporation using a stream of nitrogen, spin coating and spray drying. However, the evaporation rateis often uncontrolled and in many cases even unknown. In the present study, the effect of evaporation rate on the initial solid state of the solid dispersion was investigated using piroxicam as a low solubility model drug and polyvinylpyrrolidone (PVP) as a model polymer. In addition, the stability of these preparations was examined upon storage up to one month. Using experimental design, the evaporation rate was compared against drug:polymer ratio and polymer molecular weight. The results show that the so far unanticipated effect of evaporation rate accounts for the largest effect followed by drug:polymer ratio on both the initial quality of solid dispersion and the physical stability of the amorphous drug upon storage. This study demonstrated the importance of careful evaluation of the evaporation rate profile when comparing solid dispersion systems prepared by different solvent evaporation methods.