Subject(s)
Biomedical Research/legislation & jurisprudence , Biotechnology/legislation & jurisprudence , Drug Industry/legislation & jurisprudence , Patents as Topic/legislation & jurisprudence , Technology, Pharmaceutical/legislation & jurisprudence , Diffusion of Innovation , Drug Design , Humans , Intellectual Property , Legislation, Drug , Pharmaceutical Preparations/standards , Research Design , Technology, Pharmaceutical/methods , Technology, Pharmaceutical/standards , United StatesABSTRACT
This review article focuses on the interaction among certain scientific, legal, and regulatory aspects of pharmaceutical crystal forms. The article offers an analysis of pharmaceutical cocrystals as patentable inventions by drawing upon recent scientific developments in the field. Several potential commercial advantages of pharmaceutical cocrystals are highlighted, and a number of recent court decisions involving salient issues are summarized. The article provides an outlook on how the developing field of cocrystallization may impact the pharmaceutical intellectual property landscape.
Subject(s)
Pharmaceutical Preparations/chemistry , Crystallization , Drug Industry/legislation & jurisprudence , Intellectual Property , Investigational New Drug Application/legislation & jurisprudence , Patents as Topic , United StatesABSTRACT
A cancer candidate, compound 1, is a weak base with two heterocyclic basic nitrogens and five hydrogen-bonding functional groups, and is sparingly soluble in water rendering it unsuitable for pharmaceutical development. The crystalline acid-base pairs of 1, collectively termed solid acid-base complexes, provide significant increases in the solubility and bioavailability compared to the free base, 1. Three dicarboxylic acid-base complexes, sesquisuccinate 2, dimalonate 3, and dimaleate 4, show the most favorable physicochemical profiles and are studied in greater detail. The structural analyses of the three complexes using crystal structure and solid-state NMR reveal that the proton-transfer behavior in these organic acid-base complexes vary successively correlating with Delta pKa. As a result, 2 is a neutral complex, 3 is a mixed ionic and zwitterionic complex and 4 is an ionic salt. The addition of the acidic components leads to maximized hydrogen bond interactions forming extended three-dimensional networks. Although structurally similar, the packing arrangements of the three complexes are considerably different due to the presence of multiple functional groups and the flexible backbone of 1. The findings in this study provide insight into the structural characteristics of complexes involving heterocyclic bases and carboxylic acids, and demonstrate that X-ray crystallography and 15N solid-state NMR are truly complementary in elucidating hydrogen bonding interactions and the degree of proton transfer of these complexes.
Subject(s)
Amines/chemistry , Dicarboxylic Acids/chemistry , Heterocyclic Compounds/chemistry , Crystallography, X-Ray , Drug Design , Hydrogen Bonding , Hydrogen-Ion Concentration , Macromolecular Substances/chemistry , Magnetic Resonance Spectroscopy , Molecular Structure , Nitrogen Isotopes , Receptor, ErbB-2/antagonists & inhibitors , SolubilityABSTRACT
The crystal form adopted by the respiratory drug theophylline was modified using a crystal engineering strategy in order to search for a solid material with improved physical stability. Cocrystals, also referred to as crystalline molecular complexes, were prepared with theophylline and one of several dicarboxylic acids. Four cocrystals of theophylline are reported, one each with oxalic, malonic, maleic and glutaric acids. Crystal structures were obtained for each cocrystal material, allowing an examination of the hydrogen bonding and crystal packing features. The cocrystal design scheme was partly based upon a series of recently reported cocrystals of the molecular analogue, caffeine, and comparisons in packing features are drawn between the two cocrystal series. The theophylline cocrystals were subjected to relative humidity challenges in order to assess their stability in relation to crystalline theophylline anhydrate and the equivalent caffeine cocrystals. None of the cocrystals in this study converted into a hydrated cocrystal upon storage at high relative humidity. Furthermore, the theophylline:oxalic acid cocrystal demonstrated superior humidity stability to theophylline anhydrate under the conditions examined, while the other cocrystals appeared to offer comparable stability to that of theophylline anhydrate. The results demonstrate the feasibility of pharmaceutical cocrystal design based upon the crystallization preferences of a molecular analogue, and furthermore show that avoidance of hydrate formation and improvement in physical stability is possible via pharmaceutical cocrystallization.
Subject(s)
Dicarboxylic Acids/chemistry , Theophylline/chemistry , Bronchodilator Agents/chemistry , Chemistry, Pharmaceutical , Crystallization , Drug Stability , Feasibility Studies , Glutarates/chemistry , Hydrogen Bonding , Maleates/chemistry , Malonates/chemistry , Molecular Structure , Oxalic Acid/chemistry , Water/chemistryABSTRACT
Neat grinding and solvent-drop grinding methods are found to be effective screening tools for indicating the potential for crystalline salt formation involving a given acid-base pair, as demonstrated with two model pharmaceuticals.
ABSTRACT
The unexpected appearance of a new polymorph of maleic acid is reported and a computational study addresses the predictability of this new polymorph and future potential polymorphism.
ABSTRACT
A method of inducing specific polymorph transformations is exemplified with two single-component systems, whereby a given crystal form undergoes conversion when subjected to solid state grinding in the presence of a minor quantity of a certain solvent.
Subject(s)
ortho-Aminobenzoates/chemistry , Combinatorial Chemistry Techniques/methods , Crystallization , Molecular Structure , Powder Diffraction , Solvents/chemistryABSTRACT
By grinding with a minimal addition of a solvent of appropriate polarity, control over the polymorphic outcome of a novel cocrystallisation involving the model pharmaceutical compound caffeine may be achieved.
