Investigating the crystallisation behaviour of pharmaceutical compounds confined within mesoporous materials

The research illustrated in this doctoral thesis aims to probe the crystallisation behaviour of pharmaceutical compounds confined in porous materials, when loaded at both ambient and high pressure. Review of the literature shows how the confinement of molecular compounds in porous material can influence their solid-state i.e., the polymorph of the crystalline state or the amorphous form. Prior to confinement, understanding the crystallisation behaviour of the pharmaceutical compound is imperative, in particular investigating their response to pressure and the influence of the solvent on the compound’s crystallisation. For this reason, the thesis is split into three sections as briefly detailed below. Isonicotinamide has been well characterised in literature, with six known polymorphs reported in the Cambridge Structural Database and common reference as a “model compound”. Nonetheless, its response to pressure is unknown until now with Chapter 3 investigating the compression of the thermodynamically stable polymorph – Form I isonicotinamide. Super-elastic behaviour is exhibited beyond 4.33 GPa, where a single crystal to single-crystal phase transition to new polymorph Form I’. Chapter 4 continues the investigation into the compression of isonicotinamide. This chapter looks to address the significance of hydrogen bonding pattern on the structure as hydrostatic pressure is applied to metastable polymorphs Form II, Form III and Form IV. These polymorphs are structurally similar, with layered structures and head-to-tail hydrogen bonding, differing to the dimeric structure of Form I isonicotinamide. Form II and Form IV exhibit a phase transition beyond 1.49 and 2.01 GPa respectively. Whilst the structure of Form III remains consistent up till the deterioration of the crystal beyond 4.27 GPa, suspected to be due to the additional hydrogen bond. Chapter 5 looks at the influence of solvent on the structure of pharmaceutical compound nifedipine. With the polymorphism of the compound known to be closely related by temperature, solvents were used in this study to further investigate the polymorph landscape. Two known and seven new solvates were crystallised during the investigation and characterised using low-temperature single-crystal XRD. The solvates were then subjected to variable-temperature XRD to capture the desolvation event, examining if this route could lead to additional polymorphs. The final experimental chapter utilises both high pressure and the use of solvents when loading isonicotinamide into porous silica, splitting the study into two sections: synthesis of mesoporous silica and loading isonicotinamide into porous silica. Mesoporous silica with pores ranging in diameter and volume are selected with characterisation by nitrogen sorption. Ethanol and chloroform are used as loading solvents due to the difference in binging energy with isonicotinamide, thus the affinity of isonicotinamide to move from the solvent and into the pores. This chapter also highlights difficulties faced when trying to reproduce literature methods.The research illustrated in this doctoral thesis aims to probe the crystallisation behaviour of pharmaceutical compounds confined in porous materials, when loaded at both ambient and high pressure. Review of the literature shows how the confinement of molecular compounds in porous material can influence their solid-state i.e., the polymorph of the crystalline state or the amorphous form. Prior to confinement, understanding the crystallisation behaviour of the pharmaceutical compound is imperative, in particular investigating their response to pressure and the influence of the solvent on the compound’s crystallisation. For this reason, the thesis is split into three sections as briefly detailed below. Isonicotinamide has been well characterised in literature, with six known polymorphs reported in the Cambridge Structural Database and common reference as a “model compound”. Nonetheless, its response to pressure is unknown until now with Chapter 3 investigating the compression of the thermodynamically stable polymorph – Form I isonicotinamide. Super-elastic behaviour is exhibited beyond 4.33 GPa, where a single crystal to single-crystal phase transition to new polymorph Form I’. Chapter 4 continues the investigation into the compression of isonicotinamide. This chapter looks to address the significance of hydrogen bonding pattern on the structure as hydrostatic pressure is applied to metastable polymorphs Form II, Form III and Form IV. These polymorphs are structurally similar, with layered structures and head-to-tail hydrogen bonding, differing to the dimeric structure of Form I isonicotinamide. Form II and Form IV exhibit a phase transition beyond 1.49 and 2.01 GPa respectively. Whilst the structure of Form III remains consistent up till the deterioration of the crystal beyond 4.27 GPa, suspected to be due to the additional hydrogen bond. Chapter 5 looks at the influence of solvent on the structure of pharmaceutical compound nifedipine. With the polymorphism of the compound known to be closely related by temperature, solvents were used in this study to further investigate the polymorph landscape. Two known and seven new solvates were crystallised during the investigation and characterised using low-temperature single-crystal XRD. The solvates were then subjected to variable-temperature XRD to capture the desolvation event, examining if this route could lead to additional polymorphs. The final experimental chapter utilises both high pressure and the use of solvents when loading isonicotinamide into porous silica, splitting the study into two sections: synthesis of mesoporous silica and loading isonicotinamide into porous silica. Mesoporous silica with pores ranging in diameter and volume are selected with characterisation by nitrogen sorption. Ethanol and chloroform are used as loading solvents due to the difference in binging energy with isonicotinamide, thus the affinity of isonicotinamide to move from the solvent and into the pores. This chapter also highlights difficulties faced when trying to reproduce literature methods