SEMMELWEIS UNIVERSITY SCHOOL OF DOCTORAL STUDIES Doctoral (Ph.D.) thesis Application of microwave and near infrared electromagnetic radiation in recent pharmaceutical technological procedures and investigations ÁDÁM ZOLTÁN DÁVID Director of studies: Dr. István Antal Ph.D. Consultant: Dr. Imre Klebovich D.Sc. Semmelweis University Department of Pharmaceutics Budapest, 2006 12 1
Introduction and objectives Application of electromagnetic radiation, especially microwave radiation has become part of our everyday life for the 21 st century. The advantages that the technique enclose are used in many industries. These applications can be divided into two main parts: high energy-, from 100 Watt to many kilo Watt, and low energy uptaking, using only milli Watt, instruments. Near infrared (NIR) radiation belongs to another part of the electromagnetic spectrum. Spectroscopic methods relying on the NIR wavelength range can be applied in many analytical investigations connected to pharmaceutical technology. With this non-destructive technique the qualitative and quantitative investigation of solid materials can be performed without prior sample preparation. My objectives are: studying the scale-up in a microwave vacuum granulator with special concern about relationship between the radiation dose and its effect. The powder rheologic investigation of prepared granules using a new granulometric investigation method relying on nonlinear physics. application of low energy uptaking moisture determination equipment in combination with NIR spectroscopy to investigate the changes during moistening in case of model active ingredient. examination of microwave drying kinetics of pharmaceutical excipients. qualitative and quantitative investigation of powder and tablet dosage forms with NIR spectroscopy directly and after OPLC separation. Introduction of a newly developed off-line coupled technique (OPLC-NIR) for pharmaceutical analytical applications compared to the routine UV-densitometric method. Dávid Á., Ács Z., Greskovits D., Dávid Á.Z.: Időszerű gyógyszertechnológiai kutatási témák. Gyógyszerkémiai és Gyógyszertechnológiai Szimpóziuma, Visegrád, 2002. szeptember 30-október 1. 11. előadás. Benkóczy Z.; Dávid Á.Z.; Őszi Zs.; Gál L.; Gyulai G.: Porinhaláló antidotum kapszula gyógyszerforma vizsgálata. Gyógyszerkémiai és Gyógyszertechnológiai Szimpóziuma, Visegrád, 2002. szeptember 30-október 1. 13. előadás Benkóczy Z.; Dávid Á.Z.; Őszi Zs.; Gál L.; Gyulai G.: Porinhaláló gyógyszerkészítmények fejlesztése, a készítmény vizsgáló módszerének elővalidálása. XIV. Országos Gyógyszertechnológiai Konferencia, Hévíz, 2002. november 8-10. P04. poszter Dávid Á.Z.; Gyulai G.; Gacsályi A.; Fűrész J.: Inhalált radioizotópok dekorporálásának lehetőségei. XXVIII. Sugárvédelmi Továbbképző Tanfolyam, Mátrafüred, 2003. május 6-8. Abstr. p. 32. Őszi Zs., Gál L., Dávid Á.Z., Dávid Á.: Karbamid-peroxid tabletta (HYPEROL) bomlási folyamatainak vizsgálata. Gyógyszerkémiai és Gyógyszertechnológiai Szimpózium, Eger, 2003. szeptember 22-23. poszter-a, Dredán J., Dávid Á.Z., Dinya M., Zelkó R., László K., Antal I.: Surface characterisation of multicomponent pharmaceutical systems using physicochemical methods. International Meeting on Pharm., BioPharm. and Pharmaceutical Technology, Nuremberg, 2004. március 15-18. Abstr. p. 169-170. Antal I., Dredán J., Dávid Á.Z., Lengyel M., Zsigmond Zs., Fekete P., Dévay A.: Concanetations of dissolution profile comparison performed by calculating similarity factor and parameters of the Weibull distribution simultaneously. International Meeting on Pharm., BioPharm. and Pharmaceutical Technology, Nuremberg, 2004. március 15-18. Abstr. p. 199-200. 2 11
Á.Z. Dávid, M. Lengyel, J. Dredán, I. Antal, I. Klebovich: Determination of Theophylline in semi-solid dosage forms - comparison of methods. 1st BBBB Conference on Pharmaceutical Sciences, Siófok, 2005. szeptember 26-28. P08. poszter Antal, J. Dredán, M. Lengyel, Á.Z. Dávid, P. Szilárd, I. Klebovich, A. Dévay: Prediction of dissolution profile stability based on diffuse reflectance spectra and solvent adsorption kinetics of coated pellets. 5th World Meeting on Pharmaceutics Biopharmaceutics and Pharmaceutical Technology, Genf, 2006. március 27-30. 34. előadás, Progr. p. 16. Á.Z. Dávid, G. Rajkai, K. Ludányi, M. Lengyel, I. Antal, I. Klebovich: Evaluation of microwave-assisted extraction for the preparation of medical teas. 5th World Meeting on Pharmaceutics Biopharmaceutics and Pharmaceutical Technology, Genf, 2006. március 27-30. 87. poszter, Progr. p. 64. Other publications Dávid Á.Z.: Dr. Dávid Ágoston bibliográfiája. Acta Pharm. Hung., 74, 68-78, 2004. Lengyel M., Dávid Á.Z., Dredán J., Klebovich I., Antal I.: Dissolution profile and solvent-uptake stability of theophylline containing pellets coated by methacrylate copolymers. Eur. J. Pharm. Sci. 25S1, S150 S151, 2005. Bárdos A., Dávid Á.Z., Benkóczy Z., Őszi Zs., Gyulai G.: Új hatástani kategória: radioaktív izotópmérgezés ellenes gyógyszerkészítmények. Gyógyszer az Ezredfordulón IV. Konferencia, Sopron, 2001. október 24-27. 17. előadás Dávid Á., Ács Z., Dávid Á.Z., Gál L., Greskovits D.: Adatok a tabletta gyógyszerformuláció bioekvivalenciát befolyásoló tényezőihez. 30 éves Jubileumi Farmakokinetika és Gyógyszermetabolizmus Szimpózium, Mátraháza, 2002. április 4-6. P15. plenáris előadás Methods For preparation of granules a Mi-Mi-Pro (Pro-C-epT, Zelzate, Belgium) laboratory microwave vacuum granulator has been applied. Mixing, wetting, molding, granulation, drying and regranulation of the powders were performed in a one-pot way. Flowability of granules was investigated with granule massflow densitometry. Wetting for the investigation of moisture uptake of model active ingredient has been performed manually in a mortar. Moisture content was determined with heated analytical balances, with a MOM Q1500D derivatograph, Hitachi U-3501 UV/VIS/NIR diffuse reflectance spectrophotometer (Hitachi Co., Tokyo), and an MW2300 microwave moisture measuring device (Tews-Elektronik Co., Hamburg). For drying kinetic investigation of excipients, wetting has been carried out manually in a mortar. The materials were closed in air tight containers for 24 hours, then dried with a Goldstar ER65 I 3D type microwave instrument using 650 Watt. Loss on drying was followed with weight measurements. Preparation of tablets, following dry mixing of components was performed with Dühring (Dühring-Maschinen-Ges., Berlin) eccentric press. Control qualitative and quantitative chromatographic investigation of both actives and excipient was performed with a Shimadzu CR4AX Chromatopac HPLC system (Shimadzu Co., Kyoto). A Personal OPLC 50 System and special OPLC layers have been used for OPLC chromatographic separations (OPLC-NIT Ltd., Budapest). The separated materials were investigated directly on the layer with a Desaga Densitometer CD 60 (Desaga, Heidelberg), and a Nicolet Antaris Near-IR Analyzer equipped with SabIR Fiber Optic system and InGaAs 2.6 µm detector (Thermo Electron Co., Waltham, USA). 10 3
Summary of results Aim of my studies was to broaden the applicability of both microwave and NIR techniques in the field of pharmaceutical technology. I have investigated the common applicability of these two techniques with scaleup studies in a microwave vacuum granulator, with the examination of molecular changes during moistening of model active ingredient, and furthermore with the investigation of multicomponent drug combinations by determining the constituents in powder and tablet dosage forms directly, and with the newly developed coupling of a fast, effective OPLC chromatographic separation combined with NIR spectroscopy, without any sample preparation, directly on the chromatographic layer. New scientific results: 1. The process of scale-up in a microwave vacuum granulator has been investigated with special regards to radiation dose effect through the preparation nof placebo and model granules: as a result the microwave dose absorbed by the granules have been determined. With this data the two most important parameter of scale-up, the operation time and required radiation dose could be calculated and optimized. the drying kinetic of the multicomponent system has been characterized, and the rate of moisture loss in a given t time could be determined. Rate constants for different microwave powers have been calculated for which the Arrhenius relationship could be applied. By using the Clausius-Clapeyron relationship special energy values were determined from the results, which were then used for the determination of remaining water in the sample during drying thus automation and optimization became possible. 2002. november 8-10. E33. előadás Ács P.; Bárdos A.; Dávid Á.Z.: Mérőeszközök a gyógyszergyártásban, a tömegáramsűrűség mérőrendszer (GMD). XIV. Országos Gyógyszertechnológiai Konferencia, Hévíz, 2002. november 8-10. P2. poszter Dávid Á.Z.: Application of microwave measurements and near infrared spectroscopy in formulation studies. Pharmacia Leonardo Award Symposium, Nerviano, Olaszország, 2002. április 5-6. 4. előadás Á.Z. Dávid, I. Antal, S. Marton: The evaluation of diffuse near infrared reflectance spectra a new approach. Congressus Pharmaceuticus Hungaricus XII. Budapest, Gyógyszerészet Különszám 47, 61-62, 2003. Á.Z. Dávid; I. Antal: Dose-effect relationship during microwave drying of solid systems with different dielectric properties. 4th International Conference of PhD Studies, Miskolc, 2003. augusztus 11-17. Abstr. p. 69. Dávid Á.Z., Lengyel M., Dredán J., Greskovits Á., Bárdos A., Ács P., Greskovits D., Antal I.: Granulometriai mérőmódszerek és rendszerek összehasonlítása. IX. Szemcseméret-analitikai, Környezetvédelmi és Portechnológiai Szimpózium, Balatonfüred, 2004. szeptember 5-7. P05. poszter Dávid Á.Z., Lengyel M., Marton S., Klebovich I., Antal I: Tabletták hatóanyagainak és segédanyagainak egymás melletti meghatározása HPLC módszerrel és alternatív NIR spektroszkópiás vizsgálatokkal. Elválasztástudományi Vándorgyűlés, Hévíz, 2004. szeptember 22-24. P07. poszter D ávid Á.Z., Lengyel M., Antal I.: Microwave drying of solid systems with different dielectric properties a kinetic study. International Meeting on Pharm., BioPharm. and Pharmaceutical Technology, Nuremberg, 2004. március 15-18. Abstr. p. 297-298. 4 9
Á. Kelen, E. Pallai-Varsányi, Á.Z. Dávid, Á. Hegedűs, K. Pintye-Hódi: Select the most suitable diluent to formulate a heat sensitive active in case of microwave vacuum drying. Eur. J. Pharm. Sci. 25S1, S25-S27, 2005. M. Hajdú, G. Lekszikov, I. Antal, Á.Z. Dávid, I. Klebovich: Modification of dissolution parameters by different technological procedures. Eur. J. Pharm. Sci. 25S1, S108 S110, 2005. J. Dredán, R. Zelkó, Á.Z. Dávid, I. Antal: Quantitative estimation of film forming polymer-plasticizer interactions by the Lorentz-Lorenz Law. Int. J. Pharm., 310, 25-30, 2006. Dávid Á.Z., Mincsovics E., Antal I., Furdyga É., Zsigmond Zs., Klebovich I.: OPLC Combined with NIR Spectroscopy: a Novel Application for Pharmaceutical Analysis JPC. J. Planar Chromatogr., in press, 2006. Presentations in connection with the thesis Dávid Á.Z.: Beszámoló a granulátum tömegáram sűrűség mérővel szerzett új mérési tapasztalatokról. 5. Clauder Ottó Emlékverseny, Budapest, 2000. szeptember 21-23. 13. előadás Dávid Á.Z., Bárdos A., Antal I.: Többkomponensű formulációk NIR spektrumainak újabb értékelési lehetősége. Gyógyszerkémiai és Gyógyszertechnológiai Szimpózium, Visegrád, 2001. október 13-15. 17. előadás Dávid Á.Z.; Greskovits Á.: Mikrohullámú dielektrometriás méréstechnika alkalmazása gyógyszer-anyagok, a Hyperol tabletta nedvességtartalmának meghatározására. 6. Clauder Ottó Emlékverseny, Budapest, 2002. szeptember 28-28. 1. előadás Dávid Á.Z., Lengyel M., Antal I., Marton S.: Többkomponensű rendszerek vizsgálata közeli infravörös reflektancia spektroszkópiával (NIR), preformulációs vizsgálatok során. XIV. Országos Gyógyszertechnológiai Konferencia, Hévíz, Change in heat has been investigated as well by using research data and the endothermic evaporation energy values determined by the Clausius-Clapeyron relationship. Characterization of the nonadditive permittivity of multicomponent systems became possible with the application of the findings. 2. Flowability of prepared granules have been investigated with massflow density measurements, using an apparatus relying on nonlinear physics. I have proved with measurements that the method is capable of simulating the filling process of tabletting, capsule filling and other equipments working in the transport of powder materials. Furthermore the mathematical description of the flow characteristic of granules became possible. By comparing the results to angle of repose measurements it can be concluded that massflow density measurements give more complex, thus better usable information concerning the flowability of solids than the methods described in pharmacopoeias. 3. I have investigated the moistening of piracetam with low energy uptaking microwave moisture determinations in combination with NIR and IR spectroscopic techniques. Investigating the phenomena in different temperatures different kinetics could be observed. Relying on the findings it can be concluded that during moistening chemical reactions take place as well due to secondary chemical bonds. 4. Behavior of pharmaceutical excipients can be explained by the applied mathematical transformations during the investigation of kinetic phenomena in microwave drying. 5. I have determined paracetamol, caffeine model substances in powder and tablet forms with nondestructive NIR spectroscopy quantitatively in the present of excipient, which method can prove to be an alternative determinatnio beside liquid chromatography. 8 5
6. A method has been developed for the fast OPLC chromatographic separation of powder mixtures and commercially available tablet samples containing caffeine, paracetamol and acetylsalicylic acid followed by direct off-line NIR spectroscopy. With the application of this newly developed coupled technique near infrared spectral data can be collected from directly the OPLC layer. Practical aspects of the results: Experiences gained so far in the Semmelweis University Department of Pharmaceutics show that the non-additive permittivity characteristics of multicomponent systems can be described by research data, which can also be used for the optimization of scale-up process parameters during microwave vacuum granulation. These parameters can be used for automation and optimization of the process. Characterization and material properties of pharmaceutical excipients can be performed by microwave drying kinetic investigations. With the new OPLC-NIR coupled technique spectral information can be gathered for qualitative and quantitative pharmaceutical analytical investigations following fast separation of compounds. List of own publications Publications in connection with the work Á.Z. Dávid, I. Antal, Z. Ács, L. Gál, D. Greskovits: Investigation of water diffusion in piracetam by microwave moisture measurement and near-infrared spectroscopy. Hung. J. Ind. Chem., 28, 267-270, 2000. Á. Dávid, Z. Benkóczy, Z. Ács, D. Greskovits, Á.Z. Dávid: The theoretical basis for scaling-up by the use of the method of microwave granulation. Drug Dev. Ind. Pharm., 26, 943-951, 2000. R. Zelkó, I. Antal, J. Dredán, Á.Z. Dávid, I. Rácz: Study of drug distribution in tray-dried granules with diffuse reflectance spectroscopy. STP Pharma Sci., 10, 210-212, 2000. Antal I., David A.Z., Dredán J., Zsigmond Zs., Hódi K., Révész P., Erős I.: Characterization of solid dosage forms by diffuse reflectance spectroscopy. Pharmaceut. J. Slov., 54S, 371-372, 2003. Dávid Á.Z.: Granulátumok gördülékenységének vizsgálata nemlineáris fizika elvén alapuló új mérési eljárással. Acta Pharm. Hung., 74, 123-127, 2004. Dávid Á.Z., Lengyel M., Marton S., Klebovich I., Antal I.:Példa a NIR spektroszkópia alternatív alkalmazhatóságára: porkeverékek és tabletták komponenseinek egyidejű meghatározása. Acta Pharm. Hung., 75, 141-145, 2005. Á.Z. Dávid, Á. Kelen, M. Lengyel, I. Antal, I. Klebovich: Microwave drying and drying-kinetic study of solid pharmaceutical compounds. Eur. J. Pharm. Sci., 25S1, S77 S79, 2005. Dávid Á.Z., Lengyel M., Marton S., Klebovich I., Antal I.: The quantitative determination of active ingredients and an excipient in powders and tablets with a new alternative NIR spectroscopic application. Eur. J. Pharm. Sci., 25S1, S79 S81, 2005. 6 7