Polymorphic Transformation of Indomethacin during Hot Melt Extrusion Granulation: Process and Dissolution Control
Tóm tắt
To study and elucidate the effect of the intensity and duration of processing stresses on the possible solid-state changes during a hot melt extrusion granulation process. Blends of α-indomethacin and PEG 3350 (w/w 4:1) were granulated using various screw sizes/designs on the melt extruder under different temperature regimes. Differential Scanning Calorimetry and X-ray Powder Diffraction were employed for characterization. The dissolution behavior of the pure polymorphs and the resulting granules was determined using in-situ fiber optic UV testing system. An XRPD quantitation method using Excel full pattern fitting was developed to determine the concentration of each constituent (amorphous, α and γ indomethacin and PEG) in samples collected from each functioning zone and in granules. Analysis of in-process samples and granules revealed that higher temperature (≥130°C) and shear stress accelerated the process induced phase transitions from amorphous and/or the α form to γ indomethacin during heating stage. However, rapid cooling resulted in an increased percentage of the α form allowing isolation of the meta-stable form. By determining the conditions that either prevent or facilitate process induced transformations of IMC polymorphs during melt granulation, a design space was developed to control the polymorph present in the resulting granules. This represents the conditions necessary to balance the thermodynamic relationships between the polymorphs of the IMC system and the kinetics of the possible transformations as a function of the processing stresses.
Tài liệu tham khảo
Singhal D, Curatolo W. Drug polymorphism and dosage form design: a practical perspective. Adv Drug Deliv Rev. 2004;56(3):335–47.
Kaneniwa N, Otsuka M, Hayashi T. Physicochemical characterization of indomethacin polymorphs and the transformation kinetics in ethanol. Chem Pharm Bull. 1985;33(8):3447–55.
Aguiar AJ, Krc J, Kinkel AW, Samyn JC. Effect of polymorphism on the absorption of chloramphenicol from chloramphenicol palmitate. J Pharm Sci. 1967;56(7):847–53.
Byrn SR, Pfeiffer RR, Stowell JG. Solid-State Chemistry of Drugs. 2nd ed. West Lafayette: SSCI., Inc.; 1999.
Chen X, Morris KR, Griesser UJ, Byrn SR, Stowell JG. Reactivity differences of indomethacin solid forms with ammonia gas. J Am Chem Soc. 2002;124(50):15012–9.
Di Martino P, Guyot-Hermann A, Conflant P, Drache M, Guyot J. A new pure paracetamol for direct compression: the orthorhombic form. Int J Pharm. 1996;128(1-2):1–8.
Beyer T, Day GM, Price SL. The prediction, morphology, and mechanical properties of the polymorphs of paracetamol. J Am Chem Soc. 2001;123(21):5086–94.
Aguiar AJ, Zelmer JE. Dissolution behavior of polymorphs of chloramphenicol palmitate and mefenamic acid. J Pharm Sci. 1969;58(8):983–7.
Censi R, Di Martino P. Polymorph impact on the bioavailability and stability of poorly soluble drugs. Molecules. 2015;20(10):18759–76.
Morris KR, Griesser UJ, Eckhardt CJ, Stowell JG. Theoretical approaches to physical transformations of active pharmaceutical ingredients during manufacturing processes. Adv Drug Deliv Rev. 2001;48(1):91–114.
Shanmugam S. Granulation techniques and technologies: recent progresses. BioImpacts: BI. 2015;5(1):55.
Yang D, Kulkarni R, Behme RJ, Kotiyan PN. Effect of the melt granulation technique on the dissolution characteristics of griseofulvin. Int J Pharm. 2007;329(1):72–80.
Van Melkebeke B, Vermeulen B, Vervaet C, Remon JP. Melt granulation using a twin-screw extruder: a case study. Int J Pharm. 2006;326(1):89–93.
Martin C. Twin screw extrusion for pharmaceutical processes. Melt Extrusion: Springer; 2013. p. 47–79.
Yamamoto H. 1-Acyl-indoles. II. A New Syntheses of 1-(p-chlorobenzoyl)-5-methoxy-3-indolylacetic Acid and Its Polymorphism. Chem Pharm Bull. 1968;16(1):17–9.
Borka L. The polymorphism of indomethacine. New modifications, their melting behavior and solubility. Acta Pharmaceutica Suecica. 1974;11(3):295–303.
Surwase SA, Boetker JP, Saville D, Boyd BJ, Gordon KC, Peltonen L, et al. Indomethacin: new polymorphs of an old drug. Mol Pharm. 2013;10(12):4472–80.
Yoshioka M, Hancock BC, Zografi G. Crystallization of indomethacin from the amorphous state below and above its glass transition temperature. J Pharm Sci. 1994;83(12):1700–5.
Fukuoka E, Makita M, Yamamura S. Some physicochemical properties of glassy indomethacin. Chem Pharm Bull. 1986;34(10):4314–21.
Hancock BC, Shamblin SL, Zografi G. Molecular Mobility of Amorphous Pharmaceutical Solids Below Their Glass Transition Temperatures. Pharm Res. 1995;12(6):799–806.
Groom CR, Bruno IJ, Lightfoot MP, Ward SC. The Cambridge Structural Database. Acta Crystallogr Sect B: Struct Sci Cryst Eng Mater. 2016;72(2):171–9.
Pakula R, Pichnej L, Spychala S, Butkiewicz K. Polymorphism of indomethacin. Part I. Preparation of polymorphic forms of indomethacin. Pol J Pharmacol Pharm. 1976;29(2):151–6.
Burger A, Ramberger R. On the polymorphism of pharmaceuticals and other molecular crystals. I. Microchim Acta. 1979;72(3-4):259–71.
Chen X, Bates S, Morris KR. Quantifying amorphous content of lactose using parallel beam X-ray powder diffraction and whole pattern fitting. J Pharm Biomed Anal. 2001;26(1):63–72.
Otsuka M, Otsuka K, Kaneniwa N. Relation Between Polymorphic Transformation Pathway During Grinding and the Physicochemical Properties of Bulk Powders for Pharmaceutical Preparations. Drug Dev Ind Pharm. 1994;20(9):1649–60.
Wildfong PL, Hancock BC, Moore MD, Morris KR. Towards an understanding of the structurally based potential for mechanically activated disordering of small molecule organic crystals. J Pharm Sci. 2006;95(12):2645–56.