Solid dispersion is molecular dispersion of drug in a polymer matrix which leads to improved solubility and hence better bioavailability. Solvent evaporation technique was employed to prepare films of different combinations of polymers, plasticizer, and a modal drug sulindac to narrow down on a few polymer-plasticizer-sulindac combinations. The sulindac-polymer-plasticizer combination that was stable with good film forming properties was processed by hot melt mixing, a technique close to hot melt extrusion, to predict its behavior in a hot melt extrusion process. Hot melt mixing is not a substitute to hot melt extrusion but is an aid in predicting the formation of molecularly dispersed form of a given set of drug-polymer-plasticizer combination in a hot melt extrusion process. The formulations were characterized by advanced techniques like optical microscopy, differential scanning calorimetry, hot stage microscopy, dynamic vapor sorption, and X-ray diffraction. Subsequently, the best drug-polymer-plasticizer combination obtained by hot melt mixing was subjected to hot melt extrusion process to validate the usefulness of hot melt mixing as a predictive tool in hot melt extrusion process. 1. Introduction Amorphization of drug increases the solubility of drug because of increased surface area and better ability of the solvent to wet the drug. Such a process can improve the bioavailability of drugs that are poorly soluble, namely, BCS class II and BCS class IV drugs [1–3]. For dissolution rate limited drug absorption, molecularly dispersed drug can improve dissolution and thus its absorption [4, 5]. Hot melt extrusion is a solvent free process that utilizes heat and pressure to disperse the drug molecularly in a given polymer-plasticizer combination [6–14]. The technique is similar to preparation of solid dispersion by melting method. Formulating a molecularly dispersed form of drug in a carrier matrix requires the optimum amount of drug along with polymer and plasticizer. In some instances a drug (Ibuprofen) itself acts as a plasticizer thus limiting the amount of plasticizer that can be added [8, 15]. Film casting method can be used as preliminary screening technique to determine the right amount of drug-polymer-plasticizer combination that can yield molecularly dispersed drug [16, 17]. The polymer and plasticizer are solubilized in a solvent and applied on a glass plate using a casting device. The film upon drying is visually and microscopically observed to determine any drug precipitation. DSC and X-ray diffraction are other advanced analytical
References
[1]
D. H？rter and J. B. Dressman, “Influence of physicochemical properties on dissolution of drugs in the gastrointestinal tract,” Advanced Drug Delivery Reviews, vol. 46, no. 1–3, pp. 75–87, 2001.
[2]
Y. Kawabata, K. Wada, M. Nakatani, S. Yamada, and S. Onoue, “Formulation design for poorly water-soluble drugs based on biopharmaceutics classification system: basic approaches and practical applications,” International Journal of Pharmaceutics, vol. 420, no. 1, pp. 1–10, 2011.
[3]
P. S. Yadav, V. Kumar, U. P. Singh, H. R. Bhat, and B. Mazumder, “Physicochemical characterization and in vitro dissolution studies of solid dispersions of ketoprofen with PVP K30 and d-mannitol,” Saudi Pharmaceutical Journal, vol. 21, no. 1, pp. 77–84, 2013.
[4]
P. Lepek, W. Sawicki, K. Wlodarski, Z. Wojnarowska, M. Paluch, and L. Guzik, “Effect of amorphization method on telmisartan solubility and the tableting process,” European Journal of Pharmaceutics and Biopharmaceutics, vol. 83, no. 1, pp. 114–121, 2013.
[5]
R. T. Y. Lim, W. K. Ng, and R. B. H. Tan, “Dissolution enhancement of indomethacin via amorphization using co-milling and supercritical co-precipitation processing,” Powder Technology, vol. 240, pp. 79–87, 2013.
[6]
T. Masuda, Y. Yoshihashi, E. Yonemochi, K. Fujii, H. Uekusa, and K. Terada, “Cocrystallization and amorphization induced by drug-excipient interaction improves the physical properties of acyclovir,” International Journal of Pharmaceutics, vol. 422, no. 1-2, pp. 160–169, 2012.
[7]
G. Loreti, A. Maroni, M. D. D. Curto, A. Melocchi, A. Gazzaniga, and L. Zema, “Evaluation of hot-melt extrusion technique in the preparation of HPC matrices for prolonged release,” European Journal of Pharmaceutical Sciences, vol. 52, pp. 77–85, 2014.
[8]
I. ？zgüney, D. Shuwisitkul, and R. Bodmeier, “Development and characterization of extended release Kollidon？ SR mini-matrices prepared by hot-melt extrusion,” European Journal of Pharmaceutics and Biopharmaceutics, vol. 73, no. 1, pp. 140–145, 2009.
[9]
J. Djuris, I. Nikolakakis, S. Ibric, Z. Djuric, and K. Kachrimanis, “Preparation of carbamazepine-Soluplus solid dispersions by hot-melt extrusion, and prediction of drug-polymer miscibility by thermodynamic model fitting,” European Journal of Pharmaceutics and Biopharmaceutics, vol. 84, no. 1, pp. 228–237, 2013.
[10]
Z. Dong, A. Chatterji, H. Sandhu, D. S. Choi, H. Chokshi, and N. Shah, “Evaluation of solid state properties of solid dispersions prepared by hot-melt extrusion and solvent co-precipitation,” International Journal of Pharmaceutics, vol. 355, no. 1-2, pp. 141–149, 2008.
[11]
A. Kalivoda, M. Fischbach, and P. Kleinebudde, “Application of mixtures of polymeric carriers for dissolution enhancement of fenofibrate using hot-melt extrusion,” International Journal of Pharmaceutics, vol. 429, no. 1-2, pp. 58–68, 2012.
[12]
J. E. Patterson, M. B. James, A. H. Forster, R. W. Lancaster, J. M. Butler, and T. Rades, “Preparation of glass solutions of three poorly water soluble drugs by spray drying, melt extrusion and ball milling,” International Journal of Pharmaceutics, vol. 336, no. 1, pp. 22–34, 2007.
[13]
K. Six, C. Leuner, J. Dressman et al., “Thermal properties of hot-stage extrudates of itraconazole and eudragit E100. Phase separation and polymorphism,” Journal of Thermal Analysis and Calorimetry, vol. 68, no. 2, pp. 591–601, 2002.
[14]
J. Liu, F. Cao, C. Zhang, and Q. Ping, “Use of polymer combinations in the preparation of solid dispersions of a thermally unstable drug by hot-melt extrusion,” Acta Pharmaceutica Sinica B, vol. 3, no. 4, pp. 263–272, 2013.
[15]
C. Wu and J. W. McGinity, “Influence of ibuprofen as a solid-state plasticizer in Eudragit RS 30？D on the physicochemical properties of coated beads,” AAPS PharmSciTech, vol. 2, no. 4, p. 24, 2001.
[16]
A. Shanbhag, S. Rabel, E. Nauka et al., “Method for screening of solid dispersion formulations of low-solubility compounds-Miniaturization and automation of solvent casting and dissolution testing,” International Journal of Pharmaceutics, vol. 351, no. 1-2, pp. 209–218, 2008.
[17]
N. Wyttenbach, C. Janas, M. Siam, et al., “Miniaturized screening of polymers for amorphous drug stabilization (SPADS): rapid assessment of solid dispersion systems,” European Journal of Pharmaceutics and Biopharmaceutics, vol. 84, no. 3, pp. 583–598, 2013.
[18]
A. Forster, J. Hempenstall, I. Tucker, and T. Rades, “Selection of excipients for melt extrusion with two poorly water-soluble drugs by solubility parameter calculation and thermal analysis,” International Journal of Pharmaceutics, vol. 226, no. 1-2, pp. 147–161, 2001.
[19]
A. Paudel, Z. A. Worku, J. Meeus, S. Guns, and G. Van den Mooter, “Manufacturing of solid dispersions of poorly water soluble drugs by spray drying: formulation and process considerations,” International Journal of Pharmaceutics, vol. 453, no. 1, pp. 253–284, 2013.
[20]
K. Six, J. Murphy, I. Weuts et al., “Identification of phase separation in solid dispersions of itraconazole and eudragit？ E100 using microthermal analysis,” Pharmaceutical Research, vol. 20, no. 1, pp. 135–138, 2003.
[21]
S. R. Vippagunta, K. A. Maul, S. Tallavajhala, and D. J. W. Grant, “Solid-state characterization of nifedipine solid dispersions,” International Journal of Pharmaceutics, vol. 236, no. 1-2, pp. 111–123, 2002.
[22]
K. Adibkia, M. Barzegar-Jalali, H. Maheri-Esfanjani, et al., “Physicochemical characterization of naproxen solid dispersions prepared via spray drying technology,” Powder Technology, vol. 246, pp. 448–455, 2013.
[23]
Y. Guo, E. Shalaev, and S. Smith, “Physical stability of pharmaceutical formulations: solid-state characterization of amorphous dispersions,” TrAC Trends in Analytical Chemistry, vol. 49, pp. 137–144, 2013.
[24]
C. R. Clark, C. L. McMillian, J. F. Hoke, K. D. Campagna, and W. R. Ravis, “Liquid chromatographic determination of sulindac and metabolites in serum,” Journal of Chromatographic Science, vol. 25, no. 6, pp. 247–251, 1987.
