Mechanical and Some other Physico-Chemical Properties of Pharmaceutical Co-Crystals: A Crystal Engineering Approach

Ghosh, Soumyajit (2013) Mechanical and Some other Physico-Chemical Properties of Pharmaceutical Co-Crystals: A Crystal Engineering Approach. PhD thesis, Indian Institute of Science Education and Research Kolkata.

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It is well-known that fundamental physical properties of crystalline materials stem from the molecular arrangement within the solid, and altering the interactions between the molecules has a direct impact on the properties of solids. Currently, solid state chemists alter the physical and chemical properties of Active Pharmaceutical Ingredients (APIs) by employing different strategies and end up with the formation of salts, polymorphs, hydrates, solvates, and co-crystals. The work presented in this thesis is an attempt to design a series of pharmaceutical co-crystals by crystal engineering approach and establish structure-property correlation in these series of crystals. Chapter 1 gives an overview of current trends in crystal engineering. It discusses about several pharmaceutical solid forms that can be designed by crystal engineering approach. Mechanical and other physico-chemical properties can be fine tuned by making co-crystals, salts and hydrates. Mechanical properties of crystals are related with underlying crystal packing. Chapter 2 deals with structure-property correlation in a series of caffeine and theophylline based co-crystals. Nine new co-crystals of caffeine (CAF) and six new theophylline (THP) co-crystals were synthesized by slow evaporation crystallization method. The series of crystals allowed to establish a structure-mechanical property relationship by using a simple mechanical deformation (qualitative) method. Layered crystals with strong intralayer interactions and weak and nonspecific interlayer interactions undergo shearing upon application of shear stress while 3D interlocked structures are brittle in nature. Chapter 3 demonstrates that two structurally similar polymorphs of a 1:1 co-crystal of caffeine and 4-chloro-3-nitrobenzoic acid show distinctly different mechanical stabilities and hardness. Form I is harder but unstable while the Form II is softer and stable. Structural analysis, nanoindentation and theoretical studies reveal that the small differences in the weak (sp3 or sp2) C–H···O and -stacking interactions (uneven and smooth potential energy surfaces) in Forms I and II respectively account for the observed differences. It remains a challenge to simultaneously achieve both flexibility and crystallinity in organic materials because crystallinity positively correlates with brittleness. For example, compared to the highly ordered molecular crystals, liquid crystals show a higher flexibility, but are less crystalline. Chapter 4 deals with a remarkably flexible, elastically bendable co-crystal solvate, 1, formed from caffeine (CAF), 4-chloro-3-nitrobenzoic acid (CNB) and methanol in 1:1:<1 ratio, which retains a high internal order by an efficient stress dissipation mechanism, hence is important in the context of crystal engineering and for the design of flexible organic materials. Chapter 5 deals with combined micro Raman and HRTEM to probe deformation in bending molecular crystals. In Raman spectra for bent crystals there is no change in wavenumber shift but there is a relative intensity change which may be correlated with population of molecules in particular modes. In bent region few modes become more intense while intensity of others lowered significantly. Defects in bent region result in less population in particular modes. The loss in orderness is associated with defects in bent region. This change is manifested by significant change in Raman spectra. Ten new co-crystals of sulfamethazine, SFZ, with various carboxylic acid and amide coformers were described in Chapter 6. These co-crystals also gave a chance to study the hydrogen bonding preferences of the acceptor and donor groups present on both SFZ and the co-formers. This series was extended to include carboxylic amides to study hydrogen bond preferences in SFZ co-crystals. Co-crystals of sulfamethazine in this study served as a useful model system, readily lending themselves to an exploration of a number of intriguing facets of solid-state cocrystallization. Chapter 7 deals with twelve co-crystals/salts of fenamic acids (flufenamic acid, niflumic acid, mefenamic acid and tolfenamic acid). Out of them six are drug-drug co-crystal/salts. Combination drugs have the potential for development of medication compliance in patient’s long term drug therapy. In this case sulfamethazine (SFZ) and trimethoprim (TMP) were used as drug co-formers. Fenamic acids form co-crystal/salts with trimethoprim as can be understood from ΔpKa rule. The present series of co-crystals also gave a chance to study the hydrogen bond preferences of the acceptor and donor groups in both fenamic acids and co-formers.

Item Type: Thesis (PhD)
Additional Information: Supervisor: Dr. C. Malla Reddy
Uncontrolled Keywords: Bent Crystals; Caffeine Co-crystals; Crystal Engineering; Crystal Plasticity; Crystal Structure; Mechanical Properties; Pharmaceutical Co-Crystals; Physico-Chemical Properties; Polymorphs; Raman Spectroscopy; Theophylline Co-crystals
Subjects: Q Science > QD Chemistry
Divisions: Faculty of Engineering, Science and Mathematics > School of Chemistry
Depositing User: IISER Kolkata Librarian
Date Deposited: 21 Nov 2014 06:39
Last Modified: 21 Nov 2014 06:53

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