Development of Suitable Plant-Scale Drying Conditions That Prevent

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Development of suitable plant-scale drying conditions that prevent API agglomeration and dehydration Julie Adamson, Neil Faiber, Alex Gottlieb, Lexi Hamsmith, Frederick Hicks, Christopher Mitchell, Bhavi Mittal, Kouji Mukai, and Charles Dimitrios Papageorgiou Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.5b00327 • Publication Date (Web): 30 Nov 2015 Downloaded from http://pubs.acs.org on December 1, 2015

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Organic Process Research & Development

Development of suitable plant-scale drying conditions that prevent API agglomeration and dehydration Julie Adamson1, Neil Faiber2, Alex Gottlieb2, Lexi Hamsmith2, Frederick Hicks2, Christopher Mitchell2, Bhavi Mittal3, Kouji Mukai4 and Charles D. Papageorgiou2* 1

Takeda Pharmaceuticals International Co., Analytical Development Laboratories-Boston, 40

Landsdowne St, Cambridge, MA, 02139, United States 2

Takeda Pharmaceuticals International Co., Chemical Development Laboratories-Boston, 40

Landsdowne St, Cambridge, MA, 02139, United States 3

Takeda Pharmaceuticals International Co., Pharmaceutical Technology R&D Laboratories-

Boston, 40 Landsdowne St, Cambridge, MA, 02139, United States 4

Takeda Pharmaceutical Company Limited, Chemical Development Laboratories-Osaka, 17-85,

Jusohonmachi 2-chome Yodogawa-ku, Osaka 532-8686, Japan

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ACS Paragon Plus Environment


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Table of Contents Graphic

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Abstract

Alisertib sodium, an investigational oral oncology drug posed some challenges towards developing a robust and scalable drying process employing an agitated filter dryer that manifested themselves during the technical transfer to a new manufacturing site. The API studied was a monohydrate that was found to readily dehydrate and agglomerate, impacting both drug product (DP) manufacture and in vitro dissolution. A scale down agitated filter dryer was designed that was used to study the drying unit operation and identify key process parameters. Through a combination of lab- and pilot plant-scale experiments, suitable drying conditions were developed that minimized agglomeration, eliminated dehydration, and produced API that behaved acceptably in downstream DP manufacture.

KEYWORDS: Alisertib sodium, agitated filter dryer, agglomeration, scale-down model, dehydration, monohydrate

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INTRODUCTION

Immediately preceded by crystallization and filtration, drying is typically the final stage in the production of active pharmaceutical ingredients (APIs). Yet, despite its ubiquity, it is a unit operation that is poorly understood for a number of reasons. The concepts of heat and mass transfer in the solid phase are less familiar within the pharmaceutical industry as compared to the food and fine chemical industries, and there has historically been a lack of methodology and analytical techniques to examine drying processes in detail. In addition, the representative scaledown of the drying unit operation into the laboratory, where it can be readily studied with lower material requirements, has only recently emerged in the literature.1-3 There are a number of undesirable outcomes that can be encountered as a result of a poorly understood and controlled drying operation, such as agglomeration, attrition and chemical and physical instability including polymorphism, loss of crystallinity, as well as dehydration or desolvation.4-7 Recently much focus has been devoted to the concept of particle engineering in an attempt to deliver APIs with desirable bulk powder and physical properties that can be incorporated into the DP, increasing the burden on the drying unit operation.8, 9 These properties in many instances cannot easily be achieved or controlled through milling or other dry processing steps.10 Alisertib sodium, a selective Aurora A inhibitor currently in multiple clinical trials in hematological malignancies and solid tumors (herein referred to as “API”), has posed many challenges towards developing a robust and scalable drying process.11, 12 The issues observed during various stages of development included agglomeration, attrition and the loss of crystalbound water from the API, which is isolated as a monohydrate. As is common within the 4


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pharmaceutical industry and especially when handling highly potent compounds such as this API, the final filtration and drying operations were performed using an agitated filter dryer (AFD). These filter dryers tend to have more limited heat- and mass-transfer as compared to other dryers used within the chemical industry (such as cone and fluidized bed dryers) but are preferred when high containment is a necessity due to the potent nature of the compound being isolated.13 The investigational API in question was filtered post-crystallization before being subjected to an agitated slurry wash regime. This was followed by extensive deliquoring under vacuum until the wet cake ceased to drip. The wet cake was then agitated under vacuum (typically

Development of Suitable Plant-Scale Drying Conditions That Prevent

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