Pharmaceutics III Lecture 1 - University of Sadat City PDF

Pharmaceutics III – PPH (305) &Pharmaceutical dosage forms III – PPH (506 c) Faculty of Pharmacy, University of Sadat city Third year students (2024-2025) Course coordinator: Dr- Shaymaa Khater Lecture 1  Pharmaceutics III Dr Moham...

Pharmaceutics III – PPH (305) &Pharmaceutical dosage forms III – PPH (506 c) Faculty of Pharmacy, University of Sadat city Third year students (2024-2025) Course coordinator: Dr- Shaymaa Khater Lecture 1  Pharmaceutics III Dr Mohamed Dr Shymaa 1 Preformulation 4 Tablets 2 Powders 5 Capsules 3 Granules 6 Aerosols  Marks Midterm Practical Oral Final Total 15 25 10 50 100  Preformulation Objectives What is the meaning of preformulation? Before manufacture Goals and importance:where I want to go? Studies included in preformulation :different types  Preformulation Pharmaceutical manufacturing Definition of preformulation Preformulation Dosage form Quality Physicochemical investigation development control of a drug substance - alone and/or when combined with excipients Fundamental determination of physical and chemical properties of the drug molecule and excipients  Preformulation Goals to establish (know) necessary physicochemical parameters of a new drug substance to help in dosage form design appropriately(selection of dosage form) (safe, stable and effective) to study physical and chemical drug-excipients compatability Preformulation Drugs Most widely used Physical properties Chemical properties Biological properties Solid Amorphous less organised or crystalline more organized Description Structure ability to get Particle size Form to a site of Used in less extent Crystalline structure Melting point Reactivity action and elicit a biologic Liquid (ethers used as anaethetic) response Solubility (insulin can not be taken orally) Gas Rare e.g O2 and N2  Preformulation Limitation of liquid drugs 2-cannot generally be formulated 3-Mixing the drug with a 1-Volatile liquids into tablet form, the most popular form of solid or melted semisolid material (carrier) oral medication, without chemical modification must be physically sealed from A-soft gelatin capsule. Vitamins A, D, Example a high molecular the atmosphere to prevent and weight polyethylene glycol. evaporation loss. The melted mixture is E are liquids commercially poured into hard gelatin available in capsule form capsules to harden, and the Amyl nitrite (vasodilator) and capsules are sealed. Propylhexedrine B-Develop solid ester or salt form that (vasoconstrictor) will be suitable for tablets or drug capsules. Ex scopolamine hydrobromide is a solid salt of the liquid drug scopolamine and is easily pressed into tablets.  Preformulation Organoleptic (what is required to be known? ) properties I. Physical Description Color (red-orange) Odor ( apple orange lemon) Taste (bitter-sweety) Color is a function of a drug’s The substance may exhibit an If taste is considered as inherent chemical structure inherent odor characteristic of unpalatable, consideration is to relating to a certain level of major functional groups be given to the use of a less unsaturation. present. soluble chemical form of the Color intensity relates to the Odor greatly affects the flavor drug.(more solubility more extent of conjugated of a preparation or food stuff. appearance of bad taste) unsaturation as well as the The odor and taste may be presence of chromophores. suppressed by using appropriate Some compound may appear to flavors and excipients or by have color although structurally coating the final product. saturated.  Preformulation 2-Purity(analysis) Purity is designed to estimate the levels of all Study performed in an impurity can affect known & significant analytical research & stability, & appearance. impurities in the drug development group. e.g. Metal contamination substance under evaluation. Thin layer High performance liquid gas chromatography chromatography “TLC” chromatography “HPLC” differential scanning colorimetry “DSC  Preformulation 3-Microscopic Examination Photomicrographs of the initial and It gives an indication of subsequent batch lots of the drug particle size and size range substance can provide important information in case of problems in of the raw material along formulation processing attributable with the crystal structure. to changes in particle or crystal characteristics of the drug. Generally : Spherical and oval During some processing procedures, powders flow more easily than the solid drug powders must flow needle- shaped powders and make processing easier. freely and not become entangled. (Methamphetamine) 3-Melting Point Depression Preformulation Pure defined melting point or melting range substance Change in melting point Impurities Compatibility Melting point could be used as indicator for compatibility (incompatability change mp) Drugs with a low may soften during a processing step in which heat is generated, such as particle size reduction, compression, melting point sintering, and so on.  Preformulation Phase rule  Preformulation Phase rule Completely Two-component miscible in the mixture molten state There is a point on this phase diagram at which a minimum melting point occurs (i.e., the eutectic point).  Preformulation Phase diagram I II Solid Solid A+ A+ Solid B melt Liquid Solid melt B+ melt IV III  Preformulation 4-Particle size (can affect) Drugs affected by particle size reduction solubility griseofulvin, Bioavailability Stability Particle nitrofurantoin size Spironolactone Flow and procaine penicillin Dissolution sedimentation(large rate and small particles) Griseofulvin is commercially available for oral administration as griseofulvin microsize (4 μm Preformulation particle size) and griseofulvin ultramicrosize (1 μm particle size). The oral availability of the micronized formulation is variable, 25–70%; ultramicronized griseofulvin, in contrast, is almost completely absorbed.  Preformulation Particle size Various chemical and physical properties of drug substances are affected by their poorly soluble drugs showing a dissolution particle size distribution and shapes. rate limiting step in the absorption process will be more bioavailable when administered in a finely subdivided state rather than as a coarse material. Affect the biopharmaceutical behavior. fine materials are relatively more open to attack from atmospheric oxygen, humidity In case of tablets, size and shape influence and interacting excipient than are coarse the flow and the mixing efficiency of materials.(limitations of low particle size) powders and granules.  polymorphism, is the condition in which a solid chemical compound Preformulation exists in more than one crystalline form; the forms differ somewhat in physical and, sometimes, chemical 5-Polymorphism properties Amorphous More soluble Solid More stable Polymorph with different characters as flow, Crystalline compaction and melting point Cocoa butter has polymorphic Detected by DSC, hot stage microscope, x-ray forms: γ, α, β′, and β. Melting ranges diffraction and infrared spectroscopy were were −5–5°C for the γ form, 17– 22°C for the α form, 20–27°C for the β′ form, and 29–34°C for the β form.  Preformulation 6-Solubility A drug must possess some aqueous solubility for therapeutic efficacy. For a drug to enter the systemic circulation and exert a therapeutic effect, it must first be in solution. Relatively insoluble compounds often exhibit incomplete or erratic absorption. If the solubility of the drug substance is less than desirable→ consideration must be given to improve its solubility. The methods to accomplish this depend on the chemical nature of the drug and the type of drug product under consideration. Chemical modification of the drug into salt or ester forms is frequently used to increase solubility. A drug’s solubility is usually determined by the equilibrium solubility method, by which an excess of the drug is placed in a solvent and shaken at a constant temperature over a long period until equilibrium is obtained. Chemical analysis of the drug content in solution is performed to determine degree of solubility.  Solubility equilibrium is the equilibrium associated with dissolving solids in water to form aqueous solutions. At the point where no more solid can dissolve, the solution is saturated. The solubility product constant is an equilibrium constant used in solubility equilibrium. Solubility and Particle Size (what is the relation)? 𝑆 2𝛾𝑉 Log = 𝑆0 2.303𝑅𝑇𝑟 where S is the solubility of the small particles, Particle S0 is the solubility of the large particles, size γ is the surface tension, V is the molar volume,(molar mass/molar density) R is the gas constant, T is the absolute temperature Increase r is the radius of the small particles. solubility  Preformulation Example What is the required particle size 𝑆 2𝛾𝑉 Log = if the desired increase in 𝑆0 2.303𝑅𝑇𝑟 solubility was 5%?. If a powder S0=100% has a surface tension of 125 S=100+5%= 105% dynes/cm, molar volume of 45 105 2∗125∗45 cm3, and temperature of 27°C Log = 100 2.303∗8.314∗107∗(27+273)∗𝑟 =9.2*10-6 cm= 9.2*10-5 mm= 0.092 µm  Preformulation Solubility and pH(what is the pH = pKₐ + log(salt/acid) relation?) Henderson–Hasselbalch equation 𝐾𝑎 ST=Sa[1+ ] ( 𝐻+ where ST is the saturation solubility of the salt form. Sa is the saturation solubility of the free acid and Ka is the acid dissociation constant H+ is the hydrogen ion concentration  𝑲𝒂 ST=Sa[1+ ] 𝑯+ Example Preformulation A pharmacist prepares a 3%(salt Molecular weight 285 (salt) 263 (free acid) form) solution of an antibiotic as Acid form solubility (Sa) 3.1 mg/mL an ophthalmic solution and dispenses it to a patient. A few Ka 5.86 * 10 –6 days later, the patient returns the Molecular weight of drug 285 3% means 3 g in 100 mL eye drops to the pharmacist (salt form) and concentration So 30 g in 1L because the product contains a is 3% 285 g in 1L=1M 30 g in 1L=0.105 M precipitate. The pharmacist, checking the pH of the solution Molecular weight of drug is 3.1 mg in 1mL 263 (free acid) and Acid form So 3.1 g in 1L and finding it to be 6, reasons solubility (Sa) 3.1 mg/mL 263g in 1L=1M that the problem may be pH 3.1 g in 1L= 0.0117 M related. The physicochemical Ka 5.86 * 10 –6 5.86 * 10 –6 information of interest on the antibiotic includes the following: pH =6 H+ = 1*10-6  Preformulation Data 𝐾𝑎 Molecular weight 285 (salt) and 3% means 3 g in 100 mL ST=Sa[1+ ] concentration is 3% So 30 g in 1L 𝐻+ 285 g in 1L=1M 5.86∗10 –6 ST=0.0117[1+ ] 30 g in 1L=0.105 M 1∗10 –6 Molecular weight 263 (free acid) and 3.1 mg in 1mL ST= 0.0808 M current Acid form solubility (Sa) 3.1 mg/mL So 3.1 g in 1L solubility at pH 6 263g in 1L=1M So this is a pH problem 3.1 g in 1L= 0.0117 M Ka 5.86 * 10 –6 5.86 * 10 –6 Salt solubility is 0.0808 ….how to modify p H to achieve 0.105 M pH =6 H+ = 1*10-6  𝑲𝒂 ST=Sa[1+ ] 𝑯+ Preformulation So Recalculate to determine pH 5.86∗10 –6 0.105=0.0117[1+ ] 𝐻+ 5.86∗10 –6 [1+ ]=0.105/0.0117= 8.9 𝐻+ 5.86∗10 –6 = 7.9 𝐻+ H+= 7.38*10-7 pH =-log H+ pH= 6.13 Adjust pH to above 6.13 (≈6.2)  Preformulation 6-Dissolution The dissolution rate of drugs may be increased by When the dissolution rate decreasing the drug’s Variations in the biologic activity of is the rate-limiting step, particle size. a drug substance may be brought anything that affects it will about the rate at which it becomes also affect absorption and It may also be increased available to the absorption. control the overall by(increasing bioavailability concentration) in the diffusion layer so dissolution rate, or the time it takes enhances its solubility for the drug to dissolve in the fluids at the absorption site, is the rate The most effective means of obtaining higher limiting step in absorption. dissolution rates is to use a highly water-soluble salt of the parent substance. This is true for drugs administered Although a soluble salt of a weak acid will orally in solid forms, such as tablets, precipitate as the free acid in the bulk phase of an capsules, or suspensions, and for acidic solution, such as gastric fluid, it will do so in those administered intramuscularly. the form of fine particles with a large surface area.(e.g sodium acetate)  Preformulation Dissolution mechanism The rate of dissolution will depend on the slowest step, migration through boundary layer, and explained by Diffusion layer model dC/dt = K ∆C Where K: the rate constant ∆C: the difference in concentration of solution at the solid surface (Cs) and the bulk solution (Cb).  The Noyes–Whitney equation describes the rate of drug dissolution from a Preformulation tablet Dissolution mechanism Noyes-Whitney equation dm/dt = DACs/ h Where dm/dt is the rate of dissolution Cs is the concentration of the solute at surface available D is the diffusion coefficient (m2/s) A is the area available for molecular migration h is the thickness of the boundary layer