Synthesis of New Solid Forms of Bumetanide and their Characterization


Bumetanide (BUM) is a loop diuretic of the sulfamyl category, (3-(butylamino)-4-phenoxy-5-sulfamoylbenzoic acid) most often used to treat heart failure. Most often used in the people whom high dose of furosemide or other diuretics are ineffective.

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The main differences between bumetanide and furosemide are the bioavailability and potency. Mostly 60 percent of furosemide is absorbed in the intestine, and these are substantial inter and intra-individual differences in the bioavailability (range 10-90%). About 80 percent of bumetanide is absorbed, and these absorption does not change when it is taken with food. It is said to be a more diuretics, meaning that the predictable absorption is reflected in a more predictable effect. Bumetanide drug are 40 times more potent than furosemide for patients with normal renal function. It is sometimes used for weight loss because, use as a diuretic, and removes water from body. The study of solid state chemistry of pharmaceutical solid focuses on all disciplines right from drug discovery to successful marketing. A clear understanding of the molecular structure can lead to a better design and control of the drug performance. Moreover, interest in the subject of pharmaceutical solids stems in the part from FDA’s substance guideline that states appropriate analytical procedures to be used to detect polymorphic, cocrystals, hydrated or amorphous forms of the drug substance. Solid forms are usually more stable than liquid counterpart. The main factors which affect the oral route absorption are aqueous solubility, physical/chemical stability, and permeability. The fundamental parameters, i.e. aqueous solubility and gastrointestinal permeability which define oral drug absorption are used as the basis for the BCS classification scheme. These biopharmaceutical classes are defined as below figure.-01 Solubility and permeability parameters defined by FDA and according to it, ‘A drug substance is considered highly soluble when the highest strength is soluble in 250 mL or less of aqueous media within the pH range of 1- 6.8 at 37 ?± 1?°C’ and ‘A drug substance is considered to be highly permeable when the systemic Bioavailability or the extent of absorption in the humans is determined to be 85 percent or more in to the administered dose based on a mass balance determination (along with evidence showing stability of the drug in the GI tract ) or in comparison to an intravenous reference dose’.

1 Bumetanide is the diuretics agent, belongs to BCS class II. A survey by Lin et al.3 revealed that almost 40% of marketed medicines and 90% of emerging new chemical entities suffer from poor solubility which allows them to be eliminated from the gastrointestinal tract before they get completely dissolved and absorbed into the blood circulation, thus results in low bioavailability, less potency, and higher dose strength. For these classes of drugs, higher dose strength would be required to ensure therapeutic concentration in blood but it may lead to adverse or toxic effects on the recipient’s body. Thus, new solid forms of the API, which may overcome these problems without affecting the chemical nature of it, greatly reduces the risk, time and cost in development.

1.1. Types of solids forms: Longer range order shorter range order Crystalline Amorphous Liquid crystalline Single component multiple component Ionic non-ionic Polymorphs Salt Molecular adduct Solvates/Hydrates Cocrystal Solid is one of the four fundamental states of matter (the others are liquid, gas, and plasma). Solids molecules are closely packed. These are characterized by structural rigidity and resistance to changes in the shape or volume. Unlike a liquid, or a solid object does not flow to take on the shape of its container, nor does it expand to fill the entire volume available to it like a gas does. All atoms in a solid are tightly bound to each other, either in a regular geometric lattice (crystalline solids, which include metals and ordinary ice) or irregularly (an amorphous solid such as common window glass). Solids cannot be compressed within the little pressure whereas gases can be compressed within little pressure because in gases molecules are loosely packed. In materials science, polymorphism is the ability in a solid material to exist in more than one form or crystal structure. Polymorphism can potentially be found in the any crystalline material including polymers, minerals, and metals, and is compare to allotropy, which refers to chemical elements. Most pharmaceutical molecules are polymorphic. Polymorphism is an ability of a chemical compound to crystallize depending on the crystallization conditions in different crystal structures alias polymorphs. Molecules in the crystal structure of a Polymorphs are bonded by weak interactions (H-bridges, Van-der Waals forces, ??- ?? interactions). Amorphous materials have an internal structure made up of inter-connected structural blocks. This blocks can be similar to the basic structural units found in the corresponding crystalline phase of the same compound. Whether a material is liquid or solid depends upon the primarily connectivity between its elementary building blocks so that solids are characterized by a high degree of connectivity whereas structural blocks in fluids have lower connectivity. In pharma industry, the amorphous drugs are shown to have higher bioavailability than their crystalline counter parts due to the high solubility of amorphous phase. Moreover, certain compounds can undergoes precipitation in their amorphous form in vivo, and they can decrease each other’s bioavailability if administered together.

1.2. Crystal Engineering: Crystal engineering developed over the past 65 years as a natural outcome of the interplay between crystallography and chemistry. Chemistry deals with the molecules while crystallography deals with regularly arranged molecules. The term ‘Crystal engineering’ was coined by pepinsky in the year 1955. According to pepinsky, crystallization of organic ions with a metal-containing complex ion of suitable sizes, charges and solubility’s result in structures with cells and symmetries determined chiefly by packing of complex ions. These cells and symmetries are to be good extent controllable; hence crystals with advantageous properties can be engineered.” Crystal engineering is an interdisciplinary area in chemistry, which bridges, chemistry and crystallography. In the present decade, research is mainly focused on controlling the directionality and strength of intermolecular interaction in the design of molecular crystals. A. I. Kitagorodskii gave the definition of the molecular crystal which state that, within a molecular crystal, it is possible to identify groups of atoms such that for every atom of a group, at least one inter atomic distance within this group is significantly shorter than the smallest inter atomic distance to an atom in another group.

4 He invoked a question, molecule to crystal, he stated that packing of molecular solids was largely governed by considerations of size and shape, the so-called principle of packing. Today, X-ray crystallography is a matured science and has a far-reaching impact on material characterization. The structural insights obtained from crystal structure analysis led to unprecedented developments in electronic devices, mineralogy, geosciences, material science, and pharmaceuticals. Detailed knowledge of accurate structural information of active pharmaceutical ingredients (APIs) is a prerequisite for rational drug design and synthesis of new chemical entities for the development of new medicines. As research progressed with time, the focus shifted to multicomponent molecular crystals (cocrystals). The knowledge obtained from the analysis of the crystal structures is used in the selection of conformer for cocrystal design. A successful cocrystal synthesis requires the understanding of supramolecular synthons that occur most frequently between the functional groups of cocrystals components. Hence, the design of cocrystals for a given molecule starts with analyzing the functional groups available on that molecule and finding complementary functional groups which would likely form predictable supramolecular synthons. Thus, the conformer selection in a cocrystal design strategy reinforces a more significant role of the knowledge of intermolecular interactions which is often drawn from X-ray crystal structure analysis. In a crystal, molecules are associated with a specific pattern of non-covalent interactions such as hydrogen bonds, halogen bonds,5 and ??-stacking. Over the past century, single-crystal X-ray diffraction has proven to be an important tool for unambiguous determination of crystal structure, and thus, assisted in ground-breaking analysis of material properties. Concerning cocrystals, structural characterization (a) establishes the reliability of cocrystal design strategy, (b) reveals hydrogen bind preferences of the functional groups, and (c) provides insights into structure-property correlation. Crystal engineering is a concept of great application and scope. Presently, it focuses on more practical applications such as pharmaceutical cocrystals and high energy materials, etc. Fig.1. Crystal engineering involves modification Of the crystal packing of a solid material by changing the intermolecular interactions.6 1.3. Non-covalent Interactions: Non-covalent interactions are ubiquitous in chemistry and are the primary source of stability for many molecular complexes in biological, pharmacological. Chemical, physical, and material sciences, etc. while traditional chemistry focuses on the covalent bond, crystal engineering and supramolecular chemistry exploit the non-covalent interactions which hold molecules together in a crystal lattice. These forces include hydrogen bonding, metal coordination, hydrophobic forces, Van-der Waals forces, ??-?? interactions and electrostatic effect.

1.4. Hydrogen Bond (strong and weak): Hydrogen bonds are electrostatic and play an essential role in stabilizing the molecular aggregates. Nernst first introduced the phenomenon of hydrogen bong formation in 1891.7 Bernel and huggins proposed the term Hydrogen bond in the year of 1935-36.8 In the year of 1939, Linus pauling defined the hydrogen bond as under certain conditions, an atom of hydrogen is attracted by rather strong forces to two atom instead of only one, so that it may be considered to acting as a bond between them. The more elaborative and expanded definitions were given by many scientists as the increased interest of research in this field, which include Pimentel and McClellan (1960),9 IUPAC stated that the hydrogen bond (designated as D-H—A, where acceptor A and donor D are electronegative atoms) is an attractive interaction between a hydrogen atom from a fragment or molecule D-H in which D is more electronegative is that H, and an atom or a group of atoms A, in the same or different molecule where there is evidence of bond formation. Depending on the nature of the donor and acceptor atoms which constitute the bond, their geometry, and environment, the energy of a hydrogen bond can vary between 1 and 40 kcal/mol. The hydrogen bond is not a simple interaction but a complex conglomerate of at least four component interaction types: electrostatics (acid/base), polarization (hard/soft), van der Waals (dispersion/repulsion) and covalency (charge-transfer). It is neither a strong van der Waals interaction nor a weak covalent bond. It is not even a strong directional dipole-dipole interaction. For geometrical parameters of hydrogen bond see figure-2. This interaction characterized through X-ray diffraction, neutron diffraction, NMR, FT-IR and RAMAN spectroscopes. Three types of hydrogen bond exist very strong, strong and weak(table 1.1).

11 Because of this dual nature (very strong/weak), it attract many scientists all over the world. Hydrogen bonds are electrostatic interactions, but the proportions of electrostatic character can vary. A more expanded proposed definition of a hydrogen bond is as any interaction X-H—A with a shallower energy/distance dependence should be termed as a hydrogen bond. Table No.01: Classification of Jeffrey11 for strong, moderate, and weak hydrogen bonds (the numerical data are guiding values only) Strong Moderate Weak interaction type strongly covalent mostly electrostatic electrostatic/dispersive bond length [?…] H—A 1.2-1.5 1.5-2.2 >2.2 lengthening of X-H 0.08-0.25 0.02-0.08 130 >90 bond energy [kcal/mol] 15-40 4-15

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