Screening of Pharmaceutical Solid Forms, Tabletability and Crystal Engineering

Bag, Partha Pratim (2013) Screening of Pharmaceutical Solid Forms, Tabletability and Crystal Engineering. PhD thesis, Indian Institute of Science Education and Research Kolkata.

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Abstract

Crystal engineering, the design of organic solids with specified structural designs and desired physical and chemical properties, continues to fascinate chemists. Supramolecular synthon is a spatial arrangement of intermolecular interactions, simplifies the retrosynthesis which is important in non-covalent synthesis of crystal structures just like organic retrosynthesis for the formation of covalent bonds. The work presented in this thesis is to (i) develop the efficient screening techniques for identifying new solid forms and scale up, (ii) establishing a reliable relationship among structuremechanical properties and tabletability of APIs and (iii) the synthesis of new multicomponent solid forms by employing the crystal engineering approach. Chapter 2 describes the efficiency and complementarities of the FE method to the existing techniques for selective preparation and scale up of API polymorphic forms and new cocrystals, including a previously unknown Form II of niflumic acid (NFA) with high purity. But the Form II of niflumic acid could not be detected either by slow evaporation or liquid assisted grinding. ASC is known to be unstable in solution, so difficult to obtain its co-crystals. But by this method ASC formed co-crystals with isonicotinic acid (INA), nicotinamide (NIM) and carbamazepine (CBZ). Previous studies have identified six forms of SST and characterization was done by IR and PXRD. Among them two were suggested to be unsolvated forms and other four solvated forms. In the due course, single crystal structures were reported for two solvates, (SST∙1-butanol and SST∙1,4-dioxane). In this study, the FE method is employed to obtain the previously identified monohydrate form, two polymorphs and two new solvates. The polymorphs or other solvates are not obtainable from liquid assisted grinding (LAG), except hydrated form which is also obtainable only by neat grinding (NG). The crystal structures of all these forms are determined. SST is known to form cement-like precipitates, and has difficult resuspendability. Systematic investigation on SST helped to demonstrate the utilities of the FE method for obtaining API solvates, which are described in Chapter 3. New co-crystal forms of isoniazid (INH) and their mechanical behaviour is described in Chapter 4. INH itself shows brittle nature. The mechanical behaviour of APIs is an important factor for the design of formulation method. If the mechanical behavour can be improved, it may provide solution for tablet formation. Isoniazid (INH) co-crystallizes with different aromatic carboxylic acids, phathalic acid (PA), isophathalic acid (IPA), pyridine-3,5-dicarboxilic acid (PyDCA), trimesicacid (TMA), salicylic acid (SA), 3-hydroxy-2-napthoic acid (3H2NA) and fumaric acid (FUM). Among seven co-crystals INH/PA and INH/PyDCA are of the shearing type, while the others, INH/IPA, INH/3H2NA, INH/SA, INH/TMA and INH/FUM in this series are brittle. So, the shearing type forms are expected to show the improved tabletability behavior. Chapter 5 deals with the quantitative experiments demonstrating the direct relationship between such qualitative mechanical behavior and powder tabletability of the three types of crystals. For this a trimorphic compound, 6-chloro-2,4-dinitroaniline (cda) was considered, as a model for APIs. Because, the polymorphism in cda has not only eliminated the complexity caused by different molecular structures, but also provided a classic case covering all three distinct types, shearing, bending, and brittle, of crystals. Pure powder forms were obtained for tabletability studies by fast evaporation (FE) technique. Flat faced round tablets (250 mg, 8 mm diameter) were prepared at pressures ranging from 10 to 300 MPa (n = 3 at each pressure). The compaction studies revealed that the tabletability order of Form II (bending) > Form I (shearing) > Form III (brittle). This is correlate to the macroscopic mechanical properties and crystal structure of the three froms.

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