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Title: Polymorphic Crystallization Process Development
Keywords: tolbutamide,crystallization,polymorphism,process analytical technology,quality by design,design space
Issue Date: 20-Jan-2011
Citation: SATYANARAYANA THIRUNAHARI (2011-01-20). Polymorphic Crystallization Process Development. ScholarBank@NUS Repository.
Abstract: This study aims at developing a robust crystallization process for the isolation of desired polymorph of an antidiabetic drug, Tolbutamide (TB). To this aim, first, the structural and stability features of various polymorphs of this drug were characterized using different analytical techniques. It has been found that the conformational flexibility of the TB molecule and strong hydrogen bonding ability of secondary amide via carbonyl and sulfonyl groups facilitate TB to crystallize into different polymorphic forms (Forms (IL, IH), II?IV). The relative thermodynamic relationships of TB polymorphic pairs were evaluated and the stability domains were elucidated in the form of a schematic energy-temperature diagram. Form II is found to be the thermodynamically stable polymorph from absolute zero to ~353 K and beyond which Form IH is the stable polymorph. Based on this information, Form (IL, IH) has been chosen as the desired form for this drug. Using QbD (Quality by Design) based strategy, a robust cooling crystallization process was developed to achieve the desired form. In applying QbD, crystallization characterization studies were carried out using process analytical technology (PAT). Solvent mediated polymorphic transformation (SMPT) study of TB polymorphs Form IL? Form II suggests that the primary nucleation of the stable Form II is the controlling step for the transformation. Metastable zone width (MZW) measurements indicate that the cooling rate has a strong influence on the nucleation energy barrier of TB polymorphs. Finally, using this information, a crystallization design space was derived and a crystallization batch process was successfully operated within the design space to achieve the desired form. This work also demonstrates the application of two PATs, ATR-FTIR combined with orthogonal partial least squares-principal component analysis (OPLS-PCA), a robust chemometric method, and Raman combined with a dynamic PCA based multivariate statistical process monitoring (MSPM) in crystallization process characterization and monitoring.
Appears in Collections:Ph.D Theses (Open)

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