Crystal Engineering of Active Pharmaceutical Ingredients with Low Aqueous Solubility and Bioavailability

Approximately 75% of new molecular entities approved by the Food and Drug Administration (FDA) for use in the pharmaceutical industry are found to have poor aqueous solubility. This undesirable attribute leads to consequences such as higher doses required to reach therapeutic levels, greater vulnerability to food effects, lesser fraction absorbed in the small intestine and damage to the environment due to increased quantity of excretion. The addition of an excipient (i.e. a FDA approved inactive ingredient) to the molecular structure of an active pharmaceutical ingredient (API) through intermolecular bonding is of growing interest because the properties of the API can be tuned without further clinical testing. Crystal engineering utilizes the knowledge of intermolecular interactions to design new solids with improved properties (e.g. solubility, stability, bioavailability, dissolution rates). In this thesis, these techniques are applied to increase the solubility of three APIs with low solubility: esomeprazole magnesium, curcumin and rufinamide. Through an intense screening process, novel solid states were discovered including a water/butanol solvate of esomeprazole magnesium and a co-amorphous mixture comprised of curcumin and folic acid dihydrate. The co-amorphous mixture was found to have increased dissolution rate compared to curcumin and can be repositioned as a prenatal drug. Characterization of these products include powder and single crystal X-ray diffraction, differential scanning calorimetry, thermogravimetric analysis, Fourier Transform infrared spectroscopy, solution nuclear magnetic resonance spectroscopy and dynamic vapour sorption. Screening of rufinamide did not lead to the discovery of any new forms, but the refined molecular structure of the metastable form is reported

The crystal structure, morphology and mechanical properties of diaquabis(omeprazolate)magnesium dihydrate

The crystal structure of diaqua¬bis(omeprazolate)magnesium dihydrate (DABOMD) in the solid state has been determined using single-crystal X-ray diffraction. Single crystals of DABOMD were obtained by slow crystallization in ethanol with water used as an antisolvent. The crystal structure shows a dihydrated salt comprising a magnesium cation coordinating two omeprazolate anions and two water molecules (W1) that are strongly bound to magnesium. In addition, two further water molecules (W2) are more weakly hydrogen-bonded to the pyridine nitro¬gen atom of each omeprazolate anion. The crystal structure was utilized to estimate key material properties for DABOMD, including crystal habit and mechanical properties, which are required for improved understanding and prediction of the behaviour of particles during pharmaceutical processing such as milling. The results from the material properties calculations indicate that DABOMD exhibits a hexagonal morphology and consists of a flat slip plane through the (100) face. It can be classed as a soft material based on elastic constant calculation and exhibits a two-dimensional hydrogen-bonding framework. Based on the crystal structure, habit and mechanical properties, it is anticipated that DABOMD will experience large disorder accompanied by plastic deformation during milling

Crystallization of Esomeprazole Magnesium Water/Butanol Solvate

The molecular structure of esomeprazole magnesium derivative in the solid-state is reported for the first time, along with a simplified crystallization pathway. The structure was determined using the single crystal X-ray diffraction technique to reveal the bonding relationships between esomeprazole heteroatoms and magnesium. The esomeprazole crystallization process was carried out in 1-butanol and water was utilized as anti-solvent. The product proved to be esomeprazole magnesium tetrahydrate with two 1-butanol molecules that crystallized in P63 space group, in a hexagonal unit cell. Complete characterization of a sample after drying was conducted by the use of powder X-ray diffraction (PXRD), 1H-nuclear magnetic resonance (NMR), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), infrared spectroscopy (IR), and dynamic vapor sorption (DVS). Investigation by 1H-NMR and TGA has shown that the solvent content in the dried sample consists of two water molecules and 0.3 butanol molecules per esomeprazole magnesium molecule. This is different from the single crystal X-ray diffraction results and can be attributed to the loss of some water and 1-butanol molecules stabilized by intermolecular interactions. The title compound, after drying, is a true solvate in terms of water; conversely, 1-butanol fills the voids of the crystal lattice in non-stoichiometric amounts

Curcumin eutectics with enhanced dissolution rates: binary phase diagrams, characterization, and dissolution studies

Curcumin is a potentially viable pharmaceutical ingredient obtained from the rhizome of a turmeric plant, Curcuma longa. It is a polyphenolic compound which is known to possess antibacterial, anti-inflammatory, antitumor, and anticancer properties. Its use in pharmaceutical applications has been limited because of its poor aqueous solubility and hence poor bioavailability. In this work, attempts were made to formulate new solid forms of Curcumin with several coformers, mainly to enhance the dissolution rate of curcumin in aqueous medium. Ibuprofen, succinic acid, paracetamol, carbamazepine, ethyl paraben, glycine, tyrosine, N-acetyl d,l-tryptophan and biotin are the coformers investigated in this study. Binary phase diagrams were constructed for each binary system which helped in identifying the nature and the composition of the solid phase. All binary systems except curcumin–ibuprofen exhibited eutectic formation. The curcumin–ibuprofen system resulted in a physical mixture. These solid phases were further characterized through powder X-ray diffraction, differential scanning calorimetry, Fourier transform infrared spectroscopy and Raman spectroscopy. Dissolution studies conducted for eutectics showed enhanced dissolution rates as compared to raw curcumin. The results obtained were compared with the literature reports to present a consolidated account of research being conducted to enhance aqueous solubility of curcumin by developing new solid forms of curcumin such as eutectics, coamorphous solids, and cocrystals. Further, attempts have been made to understand how molecular geometry and intermolecular interactions influence the formation of a specific solid form.by Indumathi Sathisaran, Jenna Marie Skieneh,Sohrab Rohani and Sameer Vishvanath Dalv

Exploring co-crystallization of curcumin

Curcumin is an active pharmaceutical ingredient (API) present in the Indian spice turmeric, Curcuma longa. Among theseveral solid-state properties of an API, dissolution has an immediate effect on its bioavailability. Inspite of its medicinalproperties, curcumin has very low aqueous solubility. Efforts have been already made for increasing solubility andbioavailability of curcumin by preparing various solid forms. In this work attempts have been made to investigatecocrystallization of curcumin with various coformers. The work focused on understanding curcumin cocrystallization withcoformers namely N-acetyl D, L-Tryptophan, tyrosine, glycine, biotin, paracetamol, carbamazepine, ibuprofen, folic acid,suberic acid, succinic acid, ethyl paraben and dextrose. The coformers chosen belong to different categories like amino acids,API, acids and sugars. Binary Phase diagrams were constructed for the investigated systems. The relationship betweenmelting point and dissolution properties has been analyzed in detail. With the obtained phase diagrams, attempts have beenmade to correlate the dissolution properties of each system with curcumin. Cocrystallization of curcumin with ethyl paraben(Eutectic melting temperature: 110.3 °C) and succinic acid (Eutectic melting temperature: 154.2°C) resulted in formation ofeutectic mixtures whereas with ibuprofen and dextrose, curcumin resulted in a physical mixture. In depth understanding ofthe explored systems are being developed by characterizing the physical mixtures, eutectic mixtures or cocrystals by FTIRanalysis, solid-state NMR and single crystal X-RD analysis. This will be followed by investigating the extent of dissolutionachieved by the solid forms. This kind of thorough investigation will enable us to fine-tune the solubility of curcumin bychoosing structurally-related coformers that can potentially enhance solubility of curcumin.by Indumathi Sathisaran, Jenna Marie Skieneh, Sameer V Dalvi and Sohrab Rohan