Preformulation Studies PDF

Preformulation Studies Dr. Rania Ghanem  Preformulation Preformulation: is branch of Pharmaceutical science that utilizes biopharmaceutical principles in the determination of physicochemical properties of the drug substance. Prior to the development of any dosage form...

Preformulation Studies Dr. Rania Ghanem  Preformulation Preformulation: is branch of Pharmaceutical science that utilizes biopharmaceutical principles in the determination of physicochemical properties of the drug substance. Prior to the development of any dosage form of a new drug, it is essential that certain fundamental physical & chemical properties of drug powder are determined. This information may dictate many of subsequent event & approaches in formulation development.  Preformulation Investigation of physico-chemical properties of the new drug compound that could affect drug performance and development of an effective dosage form. Preformulation starts when a newly synthesized drug shows a sufficient pharmacologic promise in animal model to warrant evaluation in man.  Preformulation The preformulation is the first step in the rational development of a dosage form of a drug substance alone and when combined with excipients. Objective of the preformulation: - To generate useful information to the formulator to design an optimum drug delivery system.  Preformulation It is defined as the phase of research and development in which preformulation studies characterize physical and chemical properties of a drug molecule in order to develop safe, effective and stable dosage form.  GOALS OF PREFORMULATION To establish the necessary physicochemical parameters of new drug substances. To determine kinetic rate profile. To establish physical characteristics. To establish compatibility with common excipients. To choose the correct form of the drug substance. It provides insights into how drug products should be processed and stored to ensure their quality.  Pharmaceutical excipients Pharmaceutical excipients are formulation additives that aid in: - Solubilization - Suspending agents - Thickening - Preservation - Emulsification - Modification of dissolution - Improve compressibility - Flavouring - Sweetening  Physical Description It is important to understand the physical description of a drug substance (whether it is solid, semisolid or liquid) prior to dosage form development. Most drugs in use today are solid materials and less number are liquid in nature.  Physical Description Liquid drugs have two problems in the design of a dosage form which are: 1. The volatility: they must be physically sealed from the atmosphere to prevent evaporation. 2. They cannot generally be formulated into tablet (the most popular form of oral medication).  Physical Description To solve these problems, two easy methods are used to formulate liquid drugs into solid dosage forms. First, by soft gelatin capsule, e.g.,vitamin-A. The second method involves the conversion of the liquid drug into solid derivatives such as salt or ester. For instance, scopolamine is liquid but its hydrobromide salt is solid.  Melting Point Each a pure substance has a definite melting point. If not pure, the substance will exhibit a change in melting point. The pure substances have always higher melting points than their impure mixtures. This phenomenon is called melting point depression and commonly used to determine the purity of a drug substance.  Organoleptic properties Unfortunately, many drug substances in use today are unpalatable and dosage forms containing such drugs (oral preparations may require the addition of flavors and/or colors).  Organoleptic properties 1- COLOR: Color is generally a function of a drug’s inherent chemical structure relating to a certain level of unsaturation. Color intensity relates to the extent of conjugated unsaturation as well as the presence of chromophores. Some compound may appear to have color although structurally saturated. A chromophore is the part of a molecule that gives it its color. Within a specific visible light wavelength spectrum, the color we experience is the color that is not absorbed by the reflecting item.  Organoleptic properties 2- ODOR: The substance may exhibit an inherent odor characteristic of major functional groups present. Odor greatly affects the flavor of a preparation or food stuff.  Organoleptic properties 3- TASTE: If taste is considered as unpalatable, consideration is to be given to the use of a less soluble chemical form of the drug. The odor and taste may be suppressed by using appropriate flavors and excipients or by coating the final product Organoleptic properties Principal areas of Preformulation  Bulk Characterization Crystal properties: polymorphism All drugs are handled in powder form at some stage during their manufacture. Drugs can be: - Amorphous: without regular molecular lattice arrangement. - Crystalline. - Solvate forms (crystal with entrapped solvent).  Bulk Characterization Crystallinity: Crystal habit & internal structure of drug can affect bulk and physicochemical property of molecule. Crystal habit is description of outer appearance of crystal. Internal structure is molecular arrangement within the solid. Change with internal structure usually alters crystal habit. Eg. Conversion of sodium salt to its free acid form produce both change in internal structure & crystal habit. (eg; Sodium acetate and acetic acid).  Bulk Characterization Crystals have definite shapes, melting points, solubility. NaCl Crystals. Different Shapes of Crystals Different Shapes of Crystals  Polymorphism Poly – more than one + Morph – shape. Reasons for polymorphism: 1- Solvent differences. 2- Impurities (inhibits growth pattern). 3- Level of supersaturation. 4- Temperature. 5- Pressure. Polymorphism Polymorphism  Polymorphism- effect on pharmaceutical formulations Theobroma oil (cacao butter) is used in making suppositories. It has 4 polymorphs: Melting point  18 ° C The stable β form is used in  22 ° C suppositories. It melts, casted, ° 28 ° C then cooled. But if it is  34.5 ° C overheated, it may form other polymorphs upon cooling (the nuclei dissolves with heat).  Drug case- Insulin Differing activity can be obtained by changing the crystalline form. In the presence of acetate buffer, zinc combines with insulin to form a complex. The complex can be crystalline or amorphous depending on pH. Amorphous Crystalline < 2 m 10-40 m Rapidly absorbed, short half Slowly absorbed life Long duration of action  Pseudopolymorphs - Solvates They are co-crystals of a certain material with trapped solvent. Occur when the material is crystallized from organic solvents. Can change with time to “unsolvated” forms. Crystalline Vs. Amorphous form ANALYTICAL METHODS FOR THE CHARACTERIZATION OF SOLID FORMS Microscopy Hot Stage Microscopy Thermal Analysis Thermal Analysis 4 Thermal Analysis Thermal Analysis Thermal Analysis  Thermal Analysis Application of TGA in preformulation study: - Desolvation and decomposition processes are monitored. - Comparing TGA and DSC data recorded under identical conditions can greatly help in the explanation of the thermal process. X-Ray Diffraction X-Ray Diffraction Hygroscopicity Testing of Hygroscopicity  Karl Fischer Titration The elementary reaction responsible for water quantification in the Karl Fischer titration is oxidation of sulfur dioxide with iodine: 2 H2O + SO2 + I2 → H2SO4 + 2 HI  Gas chromatography (GC) Gas chromatography (GC) is a common type of chromatography used in analytical chemistry for separating and analyzing compounds that can be vaporized without decomposition. Typical uses of GC include testing the purity of a particular substance, or separating the different components of a mixture.  Significance of Hygroscopicity Test 1- To decide special handling procedure (with respect to time). 2- Equilibrium moisture content to decide: (i) the storage condition i.e. at low humidity environment. (ii) special packaging – e.g. with desiccant. 3- Moisture level in a powder sample may affect the flowability and compactibility which, are important factors during tableting and capsule filling.  Significance of Hygroscopicity Test 4- After adsorption of moisture, if hydrates are formed then solubility of that powder may change affecting the dissolution characteristics of the material. 5- Moisture may degrade some materials. So humidity of a material must be controlled.  Particle Chatacterization Particle characterization is determined by: 1- Particle size. 2- Powder Flow. 3- Particle shape. 4- Surface area. 5- Surface Morphology. (1) Particle Size Methods of determination of Particle size Sieving. Microscopy. Sedimentation rate method. Light energy diffraction. Laser holography. Cascade impaction Methods of determination of Particle size 1- Sieving method: Range : 50 – 150 µm Simple. Inexpensive. If powder is not dry, the apertures get clogged. 2- Microscopy Method: Range : 0.2 – 100 µm. Particle size can be determined by the use of calibrated grid background. Most direct method. Slow & tedious method. Methods of determination of Particle size 3- Sedimentation method: Range : µm Andreasen pipette is used. 4- Cascade impaction: The principle that a particle driven by an airstream will hit a surface in its path, provide that its inertia is sufficient to overcome the drug force that tends to keep it in airstream. Methods of determination of Particle size 5- Light energy diffraction: Range: 0.5 – 500 µm. Particle size is determined by the reduction in light reaching the sensor as the particle, dispersed in a liquid or gas, passes through the sensing zone. Quick & fast. Methods of determination of Particle size 6- Laser holography: Range: 1.4 – 100 µm. A pulsed laser is fired through an aerosolized particle spray & photographed in three dimensional with holographic camera, allowing the particles to be individually imaged & sized. (2) Powder Flow Properties Determination of Powder Flow Properties Determination of Powder Flow Properties Determination of Powder Flow Properties Determination of Powder Flow Properties Determination of Powder Flow Properties  (3) Particle shape Particle shape will influence the surface area, flow of particles, packing & compaction properties of the particles. A sphere has minimum surface area per unit volume. Therefore, these properties can be compared for spheres & asymmetric particles, in order to decide the shape.  (4) Surface Area Particle size & surface area are inversely related to each other. Smaller the drug particle, greater the surface area.  Solubility Studies Dissolution: is the transfer of molecules or ions from a solid state into solution. Solubility The amount of a substance that passes into solution when equilibrium is established between the solution and excess (undissolved substance). How do you measure solubility! The solution that is obtained under these conditions is said to be saturated. Solubility Studies Solubility Studies Solubility Studies Solubility Studies  Intrinsic solubility Co The solubility value obtained in acid for a weak acid or in base for a weak base, ie. the fundamental solubility when completely unionized. Should be measured at two temperatures: - 4 C to ensure physical and chemical stability - 37 C to support biopharmaceutical evaluation.  Decide which is correct! The intrinsic solubility of amphetamine is measured at pH 8 The intrinsic solubility of Ascorbic acid is measured at pH 8  Drug salts A solubility of less than 1 mg/ml indicates the need for a salt, particularly if the drug will be formulated as a tablet or capsule. If the approach is not adequate, the drug is filled as a liquid in hard or soft gelatin capsules. Acceptable pharmaceutical salt counter-ions are: - For basic drugs: hydrochloride, sulphate, maleate, phosphate, salicylate, lactate, citrate, tartarate, acetate - For acidic drugs: Sodium, potassium, lithium, calcium, magnesium, zinc, etc  Salt formation Salt formation is essentially a three component system involving an acid (A), a base (B) and one or more solvents. A salt is formed by the transfer of a proton (H+) from an acid (A) to a base (B): A-H + B → (A-)(B+-H) The majority of drugs are basic (B) and therefore a large proportion of the work involves selecting a suitable acid former. Typically, the first step in a salt selection procedure is the formation of a wide variety of salts, followed by the selection of the most crystalline salt form produced. Insoluble acid soluble acid salt Furosemoide salt  Metformin salt Metformin :Water Solubility, 1.38 mg/mL Metf HCL solubility = 1000 mg /ml Enhancement of solubility of chlordiazepoxide (are all salts equal?) Salt solubility (mg/ml) Base 2 HCl 165 Maleate 57.1 Tartarate 17.9 Benzoate 6  Salt formation- considerations Salts prepared from strong acids or bases are generally highly soluble, but very hygroscopic. Injections should ideally lie in the pH range 3-9 to prevent vessel damage and pain at the injection site. Oral syrups should not be too acidic, to enhance palatability. In packaging, alkalinity may attack glass. Hydrochloric salts should not be used in aerosol cans.  Salt formation- considerations Different salts of a drug rarely change pharmacology, but only physical properties. The regulatory authorities treat each salt as a different chemical entity, particularly in the context of toxicity testing. pKa Determination Drug Factors In dosage form design Partition coefficient and pKa The majority of drugs are weak acids or bases. Depending on pH they exist in an ionized or un- ionized form. Membranes are more permeable to un-ionized form: - Greater lipid solubility on un-ionized form. - Highly charged nature of the membrane.  pKa The proportion of the un-ionized form present (and thus the drug’s ability to cross a membrane) is determined by the environmental pH and the drug’s pKa (acid dissociation constant). The pKa is the pH at which concentrations of ionized and un- ionized forms are equal. When the pH is lower than the pKa, the un-ionized form of a weak acid predominates, but the ionized form of a weak base predominates. the gastric mucosa. For a weak base with a pKa of 4.4, the outcome is reversed; most of the drug in the stomach is ionized.  pKa Thus, in plasma (pH 7.4), the ratio of un-ionized to ionized forms for a weak acid (eg, with a pKa of 4.4) is 1:1000; in gastric fluid (pH 1.4), the ratio is reversed (1000:1). Therefore, when a weak acid is given orally, most of the drug in the stomach is un-ionized, favoring diffusion through the gastric mucosa. For a weak base with a pKa of 4.4, the outcome is reversed; most of the drug in the stomach is ionized pKa  pKa Two drugs, one having pka of 2 and one having pka of 6. Decide where can these two drugs be absorbed better, in the stomach or intestine? (pH stomach = 2, pH intestine = 7). pH= pka+log salt/acid  Pka = 6 In the intestine 7=6+log (S/A) Log S/A= 1, S/A= 10 So salt to acid = 10:1 ------ poor absorption %? In the stomach 2=6+log (S/A) pKa Solubilization Solubilization Methods for Increasing Solubility  Partition Coefficient It is the ratio of unionized drug distributed between organic and aqueous phase at equilibrium. P o/w = ( C oil / C water ) equilibrium. Stability Analysis Stability Analysis Stability Analysis Drug excipient compatibility