Physical Pharmacy I PDF

Physical pharmacy I Lec.3 Dr. Hayder Kadhim Drais SOLIDS AND THE CRYSTALLINE STATE Crystalline Solids The structural units of crystalline solids, such as ice, sodium chloride, and men...

Physical pharmacy I Lec.3 Dr. Hayder Kadhim Drais SOLIDS AND THE CRYSTALLINE STATE Crystalline Solids The structural units of crystalline solids, such as ice, sodium chloride, and menthol, are arranged in fixed geometric patterns or lattices. Crystalline solids, unlike liquids and gases, have definite shapes and an orderly arrangement of units. Gases are easily compressed, whereas solids, like liquids, are practically incompressible. Crystalline solids show definite melting points, passing rather sharply from the solid to the liquid state. Crystallization occurs by precipitation of the compound out of solution and into an ordered array. Note that there are several important variables here, including the solvent(s) used, the temperature, the pressure, the crystalline array pattern, salts (if crystallization is occurring through the formation of insoluble salt complexes that precipitate), and so on, that influence the rate and stability of the crystal. The various crystal forms are divided into six distinct crystal systems based on symmetry. They are, together with examples of each, cubic (sodium chloride), tetragonal (urea), hexagonal (iodoform), rhombic (iodine), monoclinic (sucrose), and triclinic (boric acid). The morphology of a crystalline form is often referred to as its habit, where the crystal habit is defined as having the same structure but different outward appearance The units that constitute the crystal structure can be atoms, molecules, or ions. 1 The sodium chloride crystal, shown in Figure 2–6, consists of a cubic lattice of sodium ions interpenetrated by a lattice of chloride ions, the binding force of the crystal being the electrostatic attraction of the oppositely charged ions. In diamond and graphite, the lattice units consist of atoms held together by covalent bonds. Solid carbon dioxide, hydrogen chloride, and naphthalene form crystals composed of molecules as the building units. In organic compounds, the molecules are held together by van der Waals forces, Coulombic forces, and hydrogen bonding, which account for the weak binding and for the low melting points of these crystals. Polymorphism and Amorphism Depending upon the internal structure, a solid can exist either in a crystalline or amorphous form. When a substance exists in more than one crystalline form, the different forms are designated as polymorphs and the phenomenon as polymorphism. Polymorphs are of two types: 1. Enantiotropic polymorph is the one which can be reversibly changed into another form by altering the temperature or pressure e.g. sulphur, and 2. Monotropic polymorph is the one which is unstable at all temperatures and pressures e.g. glyceryl stearates. The formation of polymorphs of a compound may depend upon several variables pertaining to the crystallization process, including: 1. Solvent differences (the packing of a crystal might be different from a polar versus a nonpolar solvent); 2. Impurities that may favor a metastable polymorph because of specific inhibition of growth patterns; 3. The level of supersaturation from which the material is crystallized (generally the higher the concentration above the solubility, the more chance a metastable form is seen); 4. The temperature at which the crystallization is carried out; 2 5. Geometry of the covalent bonds (are the molecules rigid and planar); 6. Attraction and repulsion of cations and anions; 7. Fit of cations into coordinates that are energetically favorable in the crystal lattice; 8. Temperature; 9. Pressure. The polymorphs differ from each other with respect to their physical properties such as solubility, melting point, density, hardness and compression characteristics. They can be prepared by crystallizing the drug from different solvents under diverse conditions. The existence of the polymorphs can be determined by using techniques such as optical crystallography, X-ray diffraction, differential scanning calorimetry (DSC), etc. Crystalline form of solid Amorphous form of solid Solvate / Hydrates of solid Depending on their relative stability, one of the several polymorphic forms will be physically more stable than the others. Such a stable polymorph represents the lowest energy state, has highest melting point and least aqueous solubility. The remaining polymorphs are called as metastable forms which represent the higher energy state, have lower melting points and 3 higher aqueous solubilities. Because of their higher energy state, the metastable forms have a thermodynamic tendency to convert to the stable form. A metastable form cannot be called unstable because if it is kept dry, it will remain stable for years. Since the metastable forms have greater aqueous solubility, they show better bioavailability and are therefore preferred in formulations—for example, of the three polymorphic forms of chloramphenicol palmitate -A, B and C, the B form shows best availability and the A form is virtually inactive biologically. However, because of their poor thermodynamic stability, aging of dosage forms containing such metastable forms usually result in formation of less soluble, stable polymorph—for example, the more soluble crystalline form II of cortisone acetate converts to the less soluble form V in an aqueous suspension resulting in caking of solid. Such a transformation of metastable to stable form can be inhibited by dehydrating the molecule environment or by adding viscosity building macromolecules such as PVP, CMC, pectin or gelatin that prevent such a conversion by adsorbing onto the surface of the crystals. Some drugs can exist in amorphous form (i.e. having no internal crystal structure). Such drugs represent the highest energy state and can be considered as supercooled liquids. They have greater aqueous solubility than the crystalline forms because the energy required to transfer a molecule from crystal lattice is greater than that required for non-crystalline (amorphous) solid—for example, the amorphous form of novobiocin is 10 times more soluble than the crystalline form. Chloramphenicol palmitate, cortisone acetate and phenobarbital are other examples where the amorphous forms exhibit higher water solubility. Thus, the order for dissolution of different solid forms of drugs is: Amorphous > Metastable > Stable. Hydrates/Solvates (Pseudopolymorphism) The crystalline form of a drug can either be a polymorph or a molecular adduct or both. The stoichiometric type of adducts where the solvent molecules are incorporated in the crystal lattice of the solid are called as the solvates, and the trapped solvent as solvent of crystallization. The solvates can exist in different crystalline forms called as pseudopolymorphs. This phenomenon 4 is called as pseudopolymorphism. When the solvent in association with the drug is water, the solvate is known as a hydrate. Hydrates are most common solvate forms of drugs. Generally, the anhydrous form of a drug has greater aqueous solubility than the hydrates. This is because the hydrates are already in interaction with water and therefore have less energy for crystal break-up in comparison to the anhydrates (thermodynamically higher energy state) for further interaction with water. The anhydrous form of theophylline and ampicillin have higher aqueous solubilities, dissolve at a faster rate and show better bioavailability in comparison to their monohydrate and trihydrate forms respectively. On the other hand, the organic (nonaqueous) solvates have greater aqueous solubility than the non-solvates—for example, the n-pentanol solvate of fludrocortisone and succinylsulphathiazole and the chloroform solvate of griseofulvin are more water-soluble than their non-solvated forms. Like polymorphs, the solvates too differ from each other in terms of their physical properties. In case of organic solvates, if the solvent is toxic, they are not of therapeutic use. X-Ray Diffraction X-rays are a form of electromagnetic radiation having a wavelength on the order of interatomic distances (about 1.54 °A for most laboratory instruments ). X-rays are diffracted by the electrons surrounding the individual atoms in the molecules of the crystals. Using computational methods, it is possible to determine the conformation of the molecules as well as their relationship to others in the structure. This results in a full description of the structure including the smallest building block, called the unit cell. 5 Melting Point and Heat of Fusion The temperature at which a liquid passes into the solid state is known as the freezing point. It is also the melting point of a pure crystalline compound. The freezing point or melting point of a pure crystalline solid is strictly defined as the temperature at which the pure liquid and solid exist in equilibrium. In practice, it is taken as the temperature of the equilibrium mixture at an external pressure of 1 atm; this is sometimes known as the normal freezing or melting point. The heat (energy) absorbed when 1 g of a solid melts or the heat liberated when it freezes is known as the latent heat of fusion, and for water at 0◦C it is about 80 cal/g (1436 cal/mole). 6 Changes of the freezing or melting point with pressure can be obtained by using a form of the Clapeyron equation, written as: Where: Vl and Vs are the molar volumes of the liquid and solid, respectively. Molar volume (volume in units of cm3/mole) ∆Hf is the molar heat of fusion, that is, the amount of heat absorbed when 1 mole of the solid changes into 1 mole of liquid, and ∆T is the change of melting point brought about by a pressure change of ∆P. Example: 7 THE SUPERCRITICAL FLUID STATE Supercritical fluids have properties that are intermediate between those of liquids and gases, having better ability to permeate solid substances (gaslike) and having high densities that can be regulated by pressure (liquidlike). THERMAL ANALYSIS A number of physical and chemical effects can be produced by temperature changes, and methods for characterizing these alterations upon heating or cooling a sample of the material are referred to as thermal analysis. The most common types of thermal analysis are: 1. Differential scanning calorimetry (DSC), 2. Differential thermal analysis (DTA) and 3. Thermomechanical analysis (TMA). These methods have proved to be valuable in pharmaceutical research and quality control for the characterization and identification of compounds, the determination of purity, polymorphism, and moisture content, amorphous content, stability, and compatibility with excipients. Generally, thermal methods involve heating a sample under controlled conditions and observing the physical and chemical changes that occur. These methods measure a number of different properties, such as melting point, heat capacity, heats of reaction, kinetics of decomposition, and changes in the flow(rheologic) properties of biochemical and pharmaceutical materials. DSC, and DTA in particular, in conjunction with infrared spectroscopy and x-ray diffraction. Using these techniques, they characterized various solid forms of drugs, such as sulfonamides, and correlated a number of physical properties of crystalline materials with interactions between solids, dissolution rates, and stabilities in the crystalline and amorphous states. Differential Scanning Calorimetry (DSC) In DSC, heat flows and temperatures are measured that relate to thermal transitions in materials. Typically, a sample and a reference material are placed in separate pans and the temperature of each pan is increased or decreased at a predetermined rate. When the sample, for 8 example, benzoic acid, reaches its melting point, in this case 122.4◦C, it remains at this temperature until all the material has passed into the liquid state because of the endothermic process of melting. A temperature difference therefore exists between benzoic acid and a reference, indium (melting point [mp] = 156.6◦C), as the temperature of the two materials is raised gradually through the range 122◦C to 123◦C. A second temperature circuit is used in DSC to provide a heat input to overcome this temperature difference. In this way the temperature of the sample, benzoic acid, is maintained at the same value as that of the reference, indium. The difference is heat input to the sample, and the reference per unit time is fed to a computer and plotted as dH/dt versus the average temperature to which the sample and reference are being raised. The data collected in a DSC run for a compound such as benzoic acid are shown in the thermogram in Figure 2–18. 9 Differential Thermal Analysis (DTA) In DTA, both the sample and the reference material are heated by a common heat source (Fig. 2–20) rather than the individual heaters used in DSC (Fig. 2–21). Thermocouples are placed in contact with the sample and the reference material in DTA to monitor the difference in temperature between the sample and the reference material as they are heated at a constant rate. The temperature difference between the sample and the reference material is plotted against time, and the endotherm as melting occurs (or exotherm as obtained during some decomposition reactions) is represented by a peak in the thermogram. The DSC, although more expensive, is needed for accurate and precise results. 10