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Polymorph Selection with Morphology Control Using Solvents and Additives

Parmar, MM (2016) Polymorph Selection with Morphology Control Using Solvents and Additives. Doctoral thesis, Liverpool John Moores University.

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Sulphathiazole is a highly polymorphic model system exhibiting at least five polymorphic forms: I, II, III, IV, and V. Polymorph stability is known to be susceptible to solvent environment, and it is established that 1-propanol stabilizes the most metastable form I. This study examines the effect of a range of alcohols on polymorph selection and attempts to elucidate the mechanism. The role of the alcohol functional group in the polymorph selection process is thus investigated and evaluated. Crystals were characterized using optical microscopy, SEM, PXRD, DSC, IR, and single-crystal X-ray diffraction for their polymorphic identity. The role of solvent in the stabilization of polymorphs was investigated by visualizing and calculating energy requirements for the interaction of each solvent molecule with α- and β-dimers of sulphathiazole, using Cerius2 modeling software and GRID based systematic search simulation. These studies showed that solvent had a significant impact on polymorph selection. In common with 1-propanol, 1-butanol was found to stabilize form I by inhibiting the formation of the β-dimer, which is necessary for nucleation of and transformation to forms II-IV. Shorter chain alcohols and branched chain alcohols such as methanol, 2-propanol, and ethanol did not stabilize form I but stabilized forms II, III, and IV, respectively, showing that it is not only the alcohol functionality but also the steric effects of the alkyl chain that contributed to the effect. Sulphathiazole form I normally has a needlelike morphology. Form I with a modified rodlike morphology was produced by crystallization from 1-propanol with the addition of methanol in low concentration, showing that it is possible to control the morphology and selectively isolate polymorphs.

Indomethacin is known to exhibit at least five polymorphs but only the stable γ Form and metastable α Form are reported to be reliably produced by standard methods. The metastable α Form has an undesirable fibrous needle-like morphology. The current study focused on producing crystals of α Indomethacin with a well-defined morphology using additives. Adipic acid, myristic acid, oleic acid and structurally related 3-indoleacetic acid were selected as additives and their impact on the morphology and polymorphism of indomethacin were investigated in this study. Additives did not change the needle-like morphology of α-indomethacin but less fibrous and less aggregated well defined needles were observed in presence of adipic acid, oleic acid and 3-indole-3-acetic acid.

Item Type: Thesis (Doctoral)
Uncontrolled Keywords: Sulphathiazole, Indomethacin, polymorphs, crystallization, Morphology Control, Additive, polymorph selection using solvents, Cerius2, molecular modeling, GRID based systematic search
Subjects: R Medicine > RM Therapeutics. Pharmacology
R Medicine > RS Pharmacy and materia medica
Divisions: Pharmacy & Biomolecular Sciences
Date Deposited: 17 Oct 2016 11:23
Last Modified: 03 Sep 2021 23:26
DOI or ID number: 10.24377/LJMU.t.00004399
Supervisors: Seton, Linda and Roberts, Matthew
URI: https://researchonline.ljmu.ac.uk/id/eprint/4399
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