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    Understanding Transformations of Trehalose in the Solid State

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    Pyszczynski_ku_0099D_12809_DATA_1.pdf (43.14Mb)
    Issue Date
    2013-05-31
    Author
    Pyszczynski, Sarah Jane
    Publisher
    University of Kansas
    Format
    295 pages
    Type
    Dissertation
    Degree Level
    Ph.D.
    Discipline
    Pharmaceutical Chemistry
    Rights
    This item is protected by copyright and unless otherwise specified the copyright of this thesis/dissertation is held by the author.
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    Abstract
    Trehalose has many applications as an excipient in pharmaceutical formulations; however, its use is limited in part because the transformations among the solid forms of trehalose are not yet understood. Form changes that occur during manufacturing or storage of a pharmaceutical formulation can be detrimental to the stability of a drug product, and therefore, understanding the solid-state transformations of trehalose is critical to its increased use in the pharmaceutical industry. In this dissertation, the solid forms of trehalose and the transformations among them are investigated using a variety of techniques, most importantly, differential scanning calorimetry (DSC) and 13C solid-state NMR spectroscopy (SSNMR). Currently, trehalose is thought to exist in four solid forms: a crystalline dihydrate (Th), the β-anhydrate (Tβ), the α-anhydrate (Tα), and the amorphous form (Tam). Using SSNMR, we showed that there is a fifth solid form (Tδ) that is formed when Th is dehydrated at or below 100 ºC. This form is metastable, and like Tα, it rapidly reverts to Th upon exposure to ambient conditions. Tδ was not detected using powder X-ray diffraction (PXRD), often considered the "gold standard" for polymorph identification, demonstrating the utility of SSNMR in analyzing pharmaceutically relevant systems. There is significant confusion in the literature regarding which anhydrous forms of trehalose are generated when Th is dehydrated, and we have demonstrated that source variability and lot-to-lot variability of Th is a likely source of this confusion. Using DSC, we showed that when sieved Th is heated at 10 ºC/minute, three distinct behaviors are observed: 1) the sample will dehydrate to form Tβ directly, 2) the sample will dehydrate to form Tam which crystallizes to Tβ upon further heating, or 3) the sample will dehydrate to form Tam that remains amorphous. The DSC results were used to develop a classification system that can be used to predict the products of dehydration of Th under various conditions. SSNMR was also used to analyze Tam prepared via lyophilization and dehydration of Th, and the results indicate that the subtle structural differences between the samples are not consistent with polyamorphism. However, lyophilized Tam appears to be more homogeneous and at a higher energy state than dehydrated Tam. A SSNMR subtraction method was developed in order to determine if low levels of Tβ or Tβ nuclei are present in Tam samples, and for several samples with higher tendencies to crystallize to Tβ, peaks corresponding to Tβ were detected. The greater understanding of the solid forms of trehalose that was achieved during the experiments described in this dissertation will: 1. Allow materials scientist to explicitly define the relationships among the solid forms of trehalose. 2. Assist pharmaceutical scientists in the development of more stable formulations that contain trehalose. 3. Aid biologists in determining the mechanism by which trehalose stabilizes biomolecules.
    URI
    http://hdl.handle.net/1808/11469
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    • Dissertations [4475]
    • Pharmaceutical Chemistry Dissertations and Theses [141]

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    785-864-8983

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    Lawrence, KS 66045
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    Contact KU ScholarWorks
    785-864-8983
    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    Image Credits
     

     

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