296 Introduction Poor bioavailability resulting from poor aqueous solubil- ity of the drug is of increasing concern as greater than 60% of new chemical entities (NCEs) coming from Discovery fall into that category. [1,2] ere are numerous approaches reported in literature to enhance drug solubility. [3–6] e approach chosen is based on the drug characteristics, and formulation and process considerations. It is well-established in literature that Vitamin E TPGS or TPGS (d-α tocopheryl polyethylene glycol 1000 succi- nate) can enhance the oral bioavailability of poorly water- soluble drugs, [7–10] and it does so by: a) stabilization of amorphous drug form, b) enhancing drug solubilization due to its surfactant properties, and c) enhancing drug permeability by P-glycoprotein efflux inhibition. TPGS also finds other uses in the pharmaceutical industry that include use as an emulsion vehicle in self-emulsifying formulations, and as a thermal binder in melt extrusion granulations. [11] Even though TPGS is widely used in the pharmaceutical industry for bioavailability enhance- ment, there is very limited published literature on its use in solid dosage forms such as tablets. A high concentra- tion of TPGS in the formulation would be desirable to enhance potentially the bioavailability of a poorly water- soluble drug. It has been reported that presence of low-melting excipients in a formulation can lead to tableting difficulties, such as sticking, picking, localized melting and tablet softening. [12] Given that TPGS is a waxy solid with a low-melting point (37°C), it presents the possibility of these tableting challenges especially when incorporated in the formulation at a high concentration. Other energy-intensive unit operations such as milling and fluid-bed drying can also pose a challenge for TPGS- containing formulations due to the potential for localized melting. Some studies have used successfully TPGS as a melt-binder during granulation at a concentration range of 2–10% w/w. [13–15] In a recent study by Jin and Tatavarti 2010, [13] the use of TPGS in a high-shear wet granulation RESEARCH ARTICLE Processing challenges with solid dosage formulations containing vitamin E TPGS Preetanshu Pandey, Patrick D. Sinko, Dilbir S. Bindra, Rhye Hamey, Shruti Gour, and Chandra Vema-Varapu Drug Product Science and Technology, Bristol-Myers Squibb, 1 Squibb Drive, New Brunswick, NJ 08901, USA Abstract The objective of this study is to investigate processing challenges associated with the incorporation of Vitamin E TPGS (d-α tocopheryl polyethylene glycol 1000 succinate) into solid pharmaceutical dosage forms. For this work, a wet granulation process (high-shear and fluid bed) was used and Vitamin E TPGS was added as part of the binder solution during granulation. It was shown that Vitamin E TPGS can be incorporated into a prototype formulation at 10% w/w concentration without any significant processing challenges. However, the resulting granulations could only be compressed successfully at low tablet press speeds (dwell time ~100 ms). When compressed at low dwell times (<20 ms) representative of commercial tablet manufacturing, a significant loss in compactability was observed. In addition, several other tablet defects were observed. It was shown that intragranular incorporation of Aeroperl® 300, a granulated form of colloidal silicon dioxide, was able to overcome these compaction problems. The formulation consisting of Aeroperl® 300 showed significantly lower granule particle size, higher granule porosity and higher compactability as compared to the formulation without Aeroperl® 300. Keywords: Wet granulation, vitamin E TPGS, compaction, dwell time, colloidal silicon dioxide, Aeroperl® 300 Address for Correspondence: Preetanshu Pandey, Drug Product Science and Technology, Bristol-Myers Squibb, 1 Squibb Drive, New Brunswick, NJ 08901, USA, preetanshu.pandey@bms.com (Received 05 June 2012; revised 25 September 2012; accepted 26 September 2012) Pharmaceutical Development and Technology, 2013; 18(1): 296–304 © 2013 Informa Healthcare USA, Inc. ISSN 1083-7450 print/ISSN 1097-9867 online DOI: 10.3109/10837450.2012.737807 Pharmaceutical Development and Technology Downloaded from informahealthcare.com by Takeda Pharmaceuticals North America Inc on 07/19/15 For personal use only.