Pharmaceutical Technology I Lec. 1 Dispersed Systems PDF

2024-09-22 PHARMACEUTICAL TECHNOLOGY I Lec. 1 DISPERSED SYSTEMS Definition Classification Comparisons between different systems Shape of colloidal particles Dispersed systems o They are consisting of particulate matter, known as t...

2024-09-22 PHARMACEUTICAL TECHNOLOGY I Lec. 1 DISPERSED SYSTEMS Definition Classification Comparisons between different systems Shape of colloidal particles Dispersed systems o They are consisting of particulate matter, known as the dispersed (internal) phase, distributed throughout a continuous or dispersion medium. o The particles of the dispersed phase could be solid, liquid, or gas. o Also, they vary widely in size. 1  2024-09-22 Classification of Dispersed System 1. According to particle size: - Molecular dispersion (True solution). - Colloidal dispersion. - Coarse dispersion. 2. According to the interaction between two phases: - Lyophilic dispersion (solvent loving) such as Alcohol & Water. - Lyophobic dispersion (solvent hating) such as oil & water. - Association colloids (surfactant) such as micelle in water. 3. According to the physical state of their components: - Liquid in liquid (emulsion). - Solid in liquid (suspension, solution). - Gas in liquid (Foam). - Liquid in gas (Liquid aerosol). - Solid in gas (Solid aerosol). - Liquid in solid (Gel). - Solid in solid (Solid solution). - Gas in solid (Solid foam). 2 2024-09-22 3  2024-09-22 Shape of colloidal particles: The shape adopted by colloidal particles in dispersion is important because the more extended t the greater its specific surface and the greater the opportunity for attractive forces to develop between the particles of the dispersed phase and the dispersion medium. The following properties are affected by changes in the shape of colloidal particles: a) Flowability b) Sedimentation c) Osmotic pressure d) Pharmacological action 4  2024-09-22 PHARMACEUTICAL TECHNOLOGY I Lec. 2 liquid dosage forms: Solutions Definition Classification Excipients for liquid pharmaceutical preparations Aqueous Solutions liquid dosage forms: solutions Solutions are traditionally one of the oldest dosage forms used in treating patients and afford rapid and high absorption of soluble medicinal products. Pharmaceutical solutions are liquid preparations containing one or more chemical substances dissolved in a suitable solvent or mixture of miscible solvents. It is a one-phase system of two or more substances that are homogeneously mixed. 1  2024-09-22 1. Drug available immediately for absorption. Advantages of 2. Flexible dosing. solutions as dosage 3. May be designed for any route of administration. forms: 4. No need to shake the container. 5. Facilitates swallowing in difficult cases. 1. Drug stability is often reduced in solution. 2. Difficult to mask unpleasant tastes. Disadvantages 3. Bulky, difficult to transport, and prone to container breakages. of solutions as 4. Technical accuracy is needed to measure dose on dosage forms: administration. 5. Some drugs are poorly soluble. 6. Measuring device needed for administration. Pharmaceutical solutions According to pharmaceutical use Classification According to their composition According to the solvent used According to pharmaceutical use, 1- Oral 2- Otic 3- Ophthalmic 4- Topical 2  2024-09-22 According to their composition, Syrups: aqueous solutions containing a sugar of 60% to 85% with or without flavoring agents and medicinal substances. Elixirs: sweetened hydroalcoholic solutions. Spirits: hydroalcoholic solutions of aromatic or volatile substances. Aromatic waters: aqueous solutions of aromatic or volatile substances. Tinctures or fluid extracts. solutions of chemical substances dissolved in alcohol or a hydroalcoholic solvent. Injections: sterile and pyrogen-free solutions that are intended for parenteral administration are expected to occur more rapidly than from suspension or solid dosage forms of the same medicinal agent. According to the solvent used, whether the solvent is water or not solutions may be classified as: Aqueous solution – When a solute is dissolved in water. E.g., salt in water, sugar in water, and copper sulfate in water. Non-aqueous solution – When a solute is dissolved in a solvent other than water. E.g., iodine in carbon tetrachloride, sulphur in carbon disulfide, and phosphorus in ethyl alcohol. 3  2024-09-22 Pharmaceutical Solutions Aqueous Sweet &/or Viscid Non-aqueous 1. Douches 1. Syrups 1. Elixirs 2. Enemas 2. Honeys 2. Spirits 3. Gargles 3. Mucilages 3. Collodions 4. Mouthwashes 4. Jellies 4. Glycerins 5. Nasal washes 5. Liniments 6. Juices 6. Oleo Vitamin 7. Sprays 8. Otic solutions 9. Inhalations Excipients for liquid pharmaceutical preparations In addition to solubility, solvent selection is based on clarity, toxicity, viscosity, compatibility with excipients, chemical inertness, palatability, odor, color, and economy. In most cases, especially solutions for oral, ophthalmic, or parenteral administration, water is the preferred solvent, because it meets the majority of the above criteria better than other available solvents. 4  2024-09-22 - Often, an auxiliary solvent is also employed to augment the solvent action of water or to contribute to a product’s chemical or physical stability. Ex. Alcohol, glycerin, and propylene glycol. - Solvents, such as acetone and isopropyl alcohol, are too toxic for use in oral pharmaceutical preparations, but they are useful as solvents in organic chemistry and the preparatory stages of drug development. Also, pharmaceutical solutions contain a range of excipients, each with a defined pharmaceutical purpose. Examples include Vehicles, surface-active agents, Preservers, sweeteners, rheology (viscosity) modifiers, antioxidants, and buffers. Excipients for liquid pharmaceutical preparations  Dosage form (drug product) = API+ Excipients 1- The vehicle - Water:  Major ingredient in most of the dosage forms.  It is used both as a vehicle and as a solvent for the desired flavoring or medicinal ingredients.  Its tastelessness,  Freedom from irritating qualities.  Lack of pharmacological activity makes it ideal for such purposes. 5  2024-09-22 Types of Water Used Purified water is water obtained by a suitable process; distillation, deionization, reverse osmosis, and ion exchange. Sterile purified water is purified water that is sterilized and suitably packaged in suitable single-dose containers. It contains no antimicrobial agent. It is not to be used for preparations intended for parenteral administration. Water for injection is water purified by distillation or by reverse osmosis. It is intended for use in preparing parenteral solutions. Sterile water for injection is prepared from water for injection that is sterilized and suitably packaged. It contains no antimicrobial agent or other added substance. It is used as a parenteral product diluent and for prescription compounding. Bacteriostatic water for injection is prepared from water for injection that is sterilized and suitably packaged; it contains one or more suitable antimicrobial agents. 6  2024-09-22 Sterile water for irrigation is prepared from water for injection that is sterilized and suitably packaged. It contains no antimicrobial agent or other added substance. Sterile water for inhalation is prepared from water for injection that is sterilized and suitably packaged. It contains no antimicrobial agents, except when it is prepared for use in humidifiers or similar devices, and is liable to contamination over a period of time, and no other added substances. - Alcohols It is the most commonly used solvent in pharmacy for many organic compounds. When mixed with water, a hydroalcoholic mixture is formed capable of dissolving both alcohol-soluble and water-soluble substances. Alcohol USP Contains between 94.9 and 96.0 % v/v ethyl alcohol (ethanol). Commonly used as a co-solvent, both as a single and with other co- solvents, e.g., glycerol. 7  2024-09-22 2- Surface-active agents, specifically to enhance the solubility of the therapeutic agent in the vehicle. 3- Preservatives, e.g. parahydroxybenzoate esters, boric acid, and borate salts. 4- Sweeteners, e.g. glucose, saccharin, aspartame. 5- Rheology (viscosity) modifiers, e.g. hydrophilic polymers (cellulose derivatives, alginic acid, polyvinyl pyrrolidone) 6- Antioxidants, e.g. sodium formaldehyde sulphoxylate, butylated hydroxy anisole, butylated hydroxytoluene. 7- Buffers to regulate the pH of the formulation, e.g. citrate buffer. Aqueous Solutions: 1- Aromatic Waters: It is a clear, saturated aqueous solution of volatile oils or other aromatic or volatile substances. They are used, principally, as flavored or perfumed vehicles. Ex. peppermint Water USP. 2 - Gargles: are aqueous solutions frequently containing antiseptics, antibiotics, and/or anesthetics used for treating the pharynx (throat) and nasopharynx by forcing air from the lungs through the gargle, which is held in the throat; subsequently, the gargle is expectorated. 8  2024-09-22 3- Enemas: These preparations are rectal injections employed to evacuate the bowel. 4- Douches: An aqueous solution, which is directed against a part or into a cavity of the body. It functions as a cleansing or antiseptic agent. For example, eye douches are used to remove foreign particles, Pharyngeal douches, and nasal and vaginal douches. 5- Mouth washes: it can be used for therapeutic & cosmetic purposes. Therapeutically can be formulated to reduce plaque, gingivitis, dental caries, and stomatitis. 6- Nasal Solutions: They are usually aqueous solutions designed to be administered to the nasal passages in drops or sprays. A vehicle for a nasal solution should have a pH in the range of 5.5 to 7.5 and a mild buffer capacity. Ex. Xylometazoline Hydrochloride Nasal Drops. 7- Sprays: Sprays are solutions of drugs in aqueous vehicles and are applied to the mucous membrane of the nose and throat by means of an atomizer or nebulizer. 9  2024-09-22 8- Otic Solutions: The main classes of drugs used for topical administration to the ear include local anesthetics, e.g.: benzocaine; antibiotics These preparations include the main types of solvents used, namely glycerin or water. The viscous glycerin vehicle permits the drug to remain in the ear for a long time. Anhydrous glycerin, being hygroscopic, tends to remove moisture from surrounding tissues, thus reducing swelling. Viscous liquids like glycerin or propylene glycol either are used alone or in combination with a surfactant to aid in the removal of cerumen (ear wax). 10 PHARMACEUTICAL TECHNOLOGY I Lec. 3 solubility and dissolution o Solubility quantitative terms as the concentration of solute in a saturated solution at a certain temperature. o Solubilization of the API, that is, increasing the soluble concentration of the API in the vehicle, is frequently required to prepare aqueous solutions. o Drugs that are poorly soluble in water may be dissolved in a mixture of water and a water-miscible solvent such as alcohol, glycerol, polyethylene glycol, or propylene glycol. o The concept of solubility is very important because it governs the preparation of solutions as dosage forms and a drug must be in solution before it can be absorbed by the body or have any biological activity, o For example, the drug Taxol has low aqueous solubility and frequently presents problems in relation to its formulation and bioavailability. # If the aqueous solubility of the drug is high at the selected pH of the formulation, so therapeutic drug is readily incorporated into a vehicle and formulated as an oral solution. # If the aqueous solubility of the drug is moderate at the selected pH of the formulation, i.e. aqueous solubility is less than the requested concentration of the drug, the solubility of the drug in solution must be enhanced using co-solvents. # If the aqueous solubility of the drug is low at the selected pH of the formulation, the difference between the aqueous solubility of the drug and the required concentration is too great for the use of cosolvents or surfactants in the solubilized form & toxic when administered orally, therefore the drug is formulated as suspension. Solubility expression The solubility can be expressed by : Quantity per quantity; mg/mL, g/L , Percentage; % w/w, % w/v % v/v , Molarity; mol/L (of solution), Molality, mol/kg (of solvent), Mole fraction , normality……. Description form Parts of solvent required for one part of Example (Solubility definition) solute Very soluble (VS) 10000 Sulfadiazine  Factors Affecting Solubility 1- Physicochemical Properties of Therapeutic agent: Molecular weight, volume, density, and number of hydrogen bonds& particle size. As the melting point of the drug increased, the solubility decreased. The solubility of a drug is directly affected by the type of chemical substituent groups, those drugs containing hydrophilic groups (e.g. OH, COO, ammonium ion) will accordingly be greater than those containing lipophilic substituent groups. 2-Polarity: Polar compounds are more soluble in polar solvents such as water & ethanol. Nonpolar compounds are more soluble in non-polar solvents such as chloroform.  3- pH: The vast majority of drug substances are either weak acids or weak bases. The solubility of acids and bases increases as the degree of ionization increases and may be easily calculated using the following equations: For acidic drugs S: total solubility for both dissociated and undissociated forms For basic drugs Sᵒ: molar solubility of undissociated form The solubility of acidic compounds increases as the pH of the solution increases (pH> pKa). The solubility of basic compounds increases as the pH of the solution is lowered (pH< pKa).  4- Temperature: If a substance is to be dissolved, the intermolecular forces between the solute molecules must be overcome. The separation of solute molecules requires a certain amount of energy which can be provided in the form of heat when the temperature is raised. Thus, the solubility of a solid in a solution depends on the temperature of the solution. 5- Agitation: It increases the speed of the particles which leads to speeds up the dissolving process when dissolving solids into liquids but decreases the dissolving process in gases.  Biopharmaceutics Classification System (BCS) Highly soluble: the highest clinical dose strength is soluble in 250 mL or less of aqueous media over a pH range of 1–7.5 at 37 °C. Highly permeable: the extent of the absorption (parent drug plus metabolites) in humans is determined to be ≥90% of an administered dose based on a mass balance determination or in comparison to an intravenous reference dose. BCS class Solubility Permeability Limiting step for drug absorption Example Class I High High Gastric emptying process Acetaminophen Class II Low High Dissolution rate Glibenclamide Class III High Low Permeability cimetidine Class IV Low Low Case by case Furosemide  Methods to enhance/optimize the solubility 1- Appropriate selection of drug salt In the pharmaceutical industry, the salt formation approach is commonly used for an ionizable drug to increase solubility and dissolution rate. For example, sodium and potassium forms of diclofenac have been approved as oral medications. 2- Use of co-solvents A cosolvent is a water-miscible organic solvent used to increase the solubility of a hydrophobic drug in water. The commonly employed co-solvents include glycerol, propylene glycol, ethanol, and polyethylene glycol. 3- Optimization of the pH of the formulation The solubility of ionized therapeutic agent is a function of both the pKa and the pH of the formulation. The acceptable pH range for oral solutions is large, ranging from 5 to 8 pH units. Control of the pH in the formulation is achieved using a buffer that does not adversely affect the solubility of the therapeutic agent.  Dissolution o For a drug to be absorbed, it must first be dissolved in the fluid at the absorption site. For instance, a drug administered orally in tablet or capsule form cannot be absorbed until the drug particles are dissolved by the fluids in the gastrointestinal tract. o When the solubility of a drug depends on either an acidic or basic medium, the drug dissolves in the stomach or intestines, respectively. o Dissolution is the process in which solid substances solubilize in a given solvent. o Dissolution rate is defined as the amount of solid substance that goes into solution per unit time. o Dissolution is the rate-determining step for hydrophobic, poorly aqueous soluble drugs such as Griseofulvin and spironolactone. o When the dissolution rate is the rate-limiting step, anything that affects it will also affect absorption. Consequently, the dissolution rate can affect the onset, intensity, and duration of response and control the overall bioavailability of the drug. Dissolution rate is a dynamic process and is expressed by ʺNoyes-Whitney Equationʺ: dc/ dt: rate of dissolution (concentration with respect to time); K: dissolution rate constant. S: surface area of the dissolving solid. Cs: concentration of the drug in the immediate proximity of the dissolving particle, that is, the solubility of the drug. Ct: concentration of the drug in the bulk fluid. The dissolution process involved several steps: 1. Initial mechanical lag. 2. Wetting of the dosage form. 3. Penetration of the dissolution medium into the dosage form. 4. Disintegration. 5. Deaggregation of the dosage form and dislodgement of the granules. 6. Dissolution and occlusion of some particles of the drug. Wetting is often the limiting factor in the dissolution process as it controls the liquid access to the solid surface.  The speed of wetting directly depends on: 1- The surface tension at the interface (interfacial tension). 2- The contact angle between the solid surface and the liquid. Generally, a contact angle of more than 90° indicates poor wettability. Incorporation of a surfactant, either in the formulation or in the dissolution medium, lowers the contact angle or enhances dissolution. Also, the presence of air in the dissolution medium causes the air bubbles to be entrapped in the tablet pores and act as a barrier at the interface. For capsules, the gelatin shell is extremely hydrophilic, and, therefore, no problems in wettability exist for the dosage itself, although it may exist for the powders inside. Factors affecting the dissolution rate 1- Surface area/particle size: The greater the surface area, the faster it dissolves. 2- Temperature: Most solids dissolve faster at higher temperatures. 3- Agitation: Stirring/shaking will speed up dissolution. 4- Saturation: Unsaturated solution: is able to dissolve more solute. Most pharmaceutical solutions… Saturated solution: has dissolved the maximum amount of solute. Supersaturated solution: has dissolved excess solute (at a higher temperature). Dissolution is a kinetic process quantified by the rate while Solubility is a dynamic equilibrium state achieved when the rate of dissolution equals the rate of precipitation.