Pharmaceutics Exam 1 PDF

Dosage Forms: Necessity, Advantages, Disadvantages, and Composition Need for Dosage Forms Dosage forms play a vital role in ensuring the safe and convenient delivery of accurate drug doses. They provide alternative routes of administration, enable the control of physicochemical and biochemical proc...

Dosage Forms: Necessity, Advantages, Disadvantages, and Composition Need for Dosage Forms Dosage forms play a vital role in ensuring the safe and convenient delivery of accurate drug doses. They provide alternative routes of administration, enable the control of physicochemical and biochemical processes to influence drug response, and improve patient acceptability. Additionally, they enhance the drug's physicochemical stability, optimize absorption and bioavailability, and allow for controlled release for sustained action. Meeting population-specific needs is another crucial aspect of dosage form design. Advantages of Tablets Tablets, a common dosage form, offer several advantages, including: Accurate dosing with minimal variability. The absence of organic solvents or alcohols. The possibility of dosage adjustment through concentration variability. Elegant and compact design, leading to patient acceptance and convenience. Tamper-resistant features. From a manufacturing perspective, tablets: Offer cost-effectiveness in production, packaging, and shipping. Simplify production identification. Enable special release profiles. Suit large-scale production. Possess the best overall properties among all oral dosage forms. Disadvantages of Tablets Despite their advantages, tablets present some disadvantages, such as: Difficulties in swallowing for some patients. Challenges in extemporaneous preparation. Resistance to compression by certain drugs. Issues with poorly wetting drugs, slow-dissolving drugs, and intermediate to large dosages. Potential for bitter taste or bad odor (although this can be addressed). Susceptibility of oxygen/moisture-sensitive drugs, requiring coating. Composition of Dosage Forms Drug delivery systems typically comprise: The active drug or its chemical derivative (e.g., a salt). Excipients - substances other than the active drug, evaluated for safety and included in the system. Excipients aid in manufacturing, protect and enhance stability and bioavailability, improve patient acceptability, assist in product identification, and contribute to overall safety and effectiveness. Drug Stability: Half-life, Q10 Methods, and Approaches to Improving Stability Shelf Life Shelf-life refers to the duration a drug preparation remains suitable for use before its strength deteriorates due to chemical decomposition or physical changes. A drug product is deemed fit for use if its concentration or dose deviates from the nominal value by no more than ±10%, provided the decomposition products are not more toxic than the original substance. Chemical Kinetics and Stability Pharmaceutical kinetics focuses on understanding drug degradation over several half-lives in pure systems, aiming to elucidate reaction mechanisms. In contrast, stability studies investigate the dosage form as a whole, examining degradation down to about 90% of the remaining drug, with the goal of establishing a shelf life or expiration date. Shelf Life Estimation Using the Q10 Method The Q10 method estimates a drug product's shelf life under non-optimal storage conditions. It relies on the activation energy (Ea), which is independent of reaction order. Q10 represents the ratio of reaction rate constants (K2/K1) when the temperature difference is 10°K. Typical Ea values range from 12 to 24 kcal/mole at 25°C. Knowing Ea allows for Q10 calculation; otherwise, Q10 can be estimated using typical Ea values, with a commonly used Q value of 3. Shelf Life Calculation The following equation can be used for shelf life estimation: t90(T2) = t90(T1) / Q^(ΔT/10) where:  t90(T2): Estimated shelf life at temperature T2. t90(T1): Shelf life at a given temperature T1. ΔT: Difference between temperatures T1 and T2. An inverse relationship exists between ΔT and shelf life. Example of Shelf Life Calculation An antibiotic with a 48-hour shelf life at 5°C is predicted to have a shelf life of 5.33 hours at room temperature (25°C) using a Q value of 3. Enhancing Drug Product Stability Various approaches can enhance drug product stability, including: Adding excipients for protection: ○ Antioxidants (e.g., ascorbic acid) ○ Preservatives to prevent microbial growth ○ Chelating agents to inhibit metal-mediated oxidation ○ Buffering agents/pH adjustment to prevent hydrolysis and precipitation Using light-resistant containers for light-sensitive compounds: ○ Examples: phenothiazines, hydrocortisone, vitamin B12 Drug Absorption: Principles and Factors Affecting Absorption Definition of Absorption Absorption is the process of drug movement from the administration site to the site of measurement. For drugs administered extravascularly (e.g., oral, sublingual, intramuscular, topical, patches, inhalation), absorption is essential for systemic pharmacological effects. Principles of Drug Absorption The primary mechanisms of drug absorption include: Passive Diffusion: This involves the passage of drug molecules through a membrane without active participation from the membrane itself. The absorption process is driven by the concentration gradient of the drug across the membrane. Specialized Transport Mechanisms:  ○ Active transport: Utilizes a "carrier" to move the drug against a concentration gradient (from low to high concentration). ○ Facilitated diffusion: Employs a "carrier" but doesn't move the drug against a concentration gradient. This process can become saturated. Factors Affecting Oral Drug Absorption Various factors influence oral drug absorption, categorized as: 1. Physiological Factors: ○Membrane physiology: The cell membrane, primarily composed of a phospholipid bilayer with embedded proteins, acts as a barrier between the cell's interior and exterior. The lipid nature of the membrane, interspersed with small aqueous channels or pores, influences drug passage. ○ Passage of drugs across membranes: This depends on factors such as molecular size, shape, degree of ionization, and lipid solubility. ○ Gastrointestinal (GI) physiology: The GI tract significantly impacts oral absorption. Factors like blood flow, gastric emptying time and motility, and the presence of food can affect drug absorption. Blood Flow: High blood flow can enhance drug absorption if the membrane offers little resistance. However, if the membrane presents high resistance, changes in blood flow have minimal impact. Gastric Emptying Time and Motility: The time a drug spends in different regions of the GI tract with varying pH levels can affect its absorption. Effect of Food on Drug Absorption: Food can influence drug absorption through various mechanisms, including complexation, pH changes, altered blood flow, and the introduction of bulk into the stomach. 2. Physicochemical Factors: ○ pH-partition theory: The degree of ionization of a drug, influenced by its pKa and the surrounding pH, dictates its ability to cross membranes. Unionized drugs generally exhibit better membrane permeability. ○ Lipid solubility: Highly lipid-soluble drugs tend to be absorbed more readily due to their compatibility with the lipid-rich cell membrane. ○ Dissolution and pH: Dissolution, the process of a drug dissolving in a solvent, plays a crucial role in absorption. The pH of the environment can significantly affect the dissolution rate, particularly for weak acids and bases. ○ Drug stability and hydrolysis in the GI tract: The stability of a drug in the GI environment is essential for absorption. Some drugs may undergo hydrolysis or degradation, hindering their absorption. ○ Complexation: Drug complexation with other substances can either enhance or hinder absorption.  ○Adsorption: Adsorption of the drug onto insoluble substances (e.g., charcoal, kaolin, talc) can reduce its absorption. 3. Formulation Factors: ○ Dissolution and Solubility: Dissolution: The Noyes-Whitney equation describes the rate of dissolution, highlighting the influence of surface area, solubility, and the concentration gradient between the dissolving particle and the bulk fluid. Solubility: A drug's solubility in a given solvent (typically determined in 250mL buffer with a pH range of 1.0-8.0) is crucial for pharmaceutical development. Rate-limiting steps: Dissolution often limits the absorption of poorly water-soluble drugs, while permeability tends to be the limiting factor for highly water-soluble drugs. ○ Permeability: Permeability, an indirect measure of absorption, reflects the rate of drug mass transfer across the human intestinal membrane. In vitro tests using human and non-human systems can assess permeability. In certain cases, permeability testing can even waive in vivo bioavailability studies for bioequivalence assessments. ○ Surface Area: Decreased particle size increases the surface area available for dissolution, potentially enhancing the dissolution rate. However, factors like adsorption and wetting can influence the effective surface area. ○ Crystal or Amorphous Drug Form: Crystalline: Represents the lowest energy state with an ordered structure. Amorphous: A metastable state that gradually reverts to the crystalline form over time. Amorphous drugs typically dissolve faster than their crystalline counterparts. ○ Salt Forms: Salts generally exhibit higher solubility and faster dissolution rates compared to the free acid or base form of the drug. ○ Other Factors: State of hydration: Anhydrous forms of drugs tend to dissolve faster and may be absorbed to a greater extent than their hydrated counterparts. Complex formation: Drug complexation can either enhance or hinder absorption depending on the complexing agent. Adsorption: Adsorption of the drug onto insoluble excipients can reduce its absorption. Effect of Formulation on Absorption The formulation of a drug product significantly impacts its delivery to the site of action and subsequent absorption. In general, the bioavailability of a drug is expected to decrease in the following order: solution > suspension > capsule > tablet > coated tablet. Bioavailability and Bioequivalence Bioavailability Bioavailability describes the rate and extent to which an active drug ingredient or therapeutic moiety is absorbed from a drug product and reaches its site of action. Absolute Bioavailability: Compares the systemic circulation bioavailability (estimated as area under the curve or AUC) of a drug following non-intravenous administration (e.g., oral, rectal, transdermal, subcutaneous) with its bioavailability after intravenous administration. Relative Bioavailability: Measures the bioavailability of a drug in one formulation compared to another formulation of the same drug, usually an established standard or administration via a different route. First-pass Metabolism First-pass metabolism refers to the drug metabolism that occurs in the liver (and sometimes the gut wall) before it reaches systemic circulation. This can significantly reduce the amount of drug available for pharmacological effect. Factors Affecting Bioavailability Factors influencing drug bioavailability include: Release and Dissolution: The rate and extent of drug release from the dosage form and its subsequent dissolution in bodily fluids. Absorption: The process of drug movement from the site of administration into the bloodstream. Permeation: The ability of the drug to cross biological membranes. Elimination: The processes by which the body removes the drug from circulation. Metabolism: The chemical modification of the drug by enzymes, primarily in the liver. Bioequivalence Bioequivalence compares the bioavailability of a drug in two different formulations. It's crucial for assessing the comparability of generic products with brand-name counterparts. Bioequivalence testing often involves human pharmacokinetic studies to evaluate the rate and extent of absorption. FDA Orange Book The FDA Orange Book provides information on approved drug products with therapeutic equivalence evaluations, including bioequivalence data. It aids healthcare professionals in making informed decisions about generic drug substitution. Drug Release from Tablets, Capsules, and Powders Tablets Types of Tablets Tablets come in various forms, each designed for specific purposes: Compressed tablets: Prepared by a single compression cycle, containing active ingredients and excipients. Examples include aspirin, Tylenol®, and Valium®. Multiple compressed tablets: Undergo multiple compression cycles to create layered tablets, tablets within tablets, or compression-coated tablets. This allows for the separation of incompatible ingredients, staged drug release, and enhanced appearance. Sugar-coated tablets: Coated with sugar layers for protection, taste masking, and improved appearance. Film-coated tablets: Coated with a thin polymer film for durability, taste masking, and modified drug release. Gelatin-coated tablets: Coated with gelatin for ease of swallowing. Enteric-coated tablets: Designed to bypass the stomach and release the drug in the intestine, protecting the drug from acidic degradation and the stomach from irritation. Buccal and sublingual tablets: Dissolve in the buccal pouch or under the tongue for rapid absorption and avoidance of first-pass metabolism. Chewable tablets: Formulated for easy chewing, often flavored to improve palatability. Effervescent tablets: Contain effervescent salts that release carbonation when dissolved in water, enhancing dissolution and masking taste. Molded tablets/triturates: Prepared by molding rather than compression, designed for rapid and complete dissolution in water. Hypodermic tablets: Historically used by physicians to prepare injections, now obsolete. Lozenges and dental cones: Dissolve slowly in the mouth for local drug delivery to the oral mucosa. Instantly disintegrating or dissolving tablets: Dissolve rapidly in the mouth for ease of administration. Implants: Small, sterile tablets implanted surgically for prolonged drug release. Vaginal tablets: Inserted vaginally for local treatment. Excipients in Tablets Excipients are essential components of tablet formulations:  Diluents: Provide bulk and improve tablet properties such as cohesion and flow. Examples include lactose, starch, microcrystalline cellulose, dibasic calcium phosphate, and mannitol. Binders: Hold the powder together to form granules or cohesive compacts. Examples include acacia, tragacanth, cellulose derivatives, gelatin, glucose, polyvinylpyrrolidone (PVP), starch paste, and sodium alginate. Disintegrants: Facilitate tablet disintegration upon contact with water in the GI tract. Examples include starch, starch derivatives, clays, cellulose derivatives, alginate, and cross-linked PVP. Lubricants and Glidants: ○ Lubricants: Prevent adhesion of tablet materials to dies and punches, reduce interparticle friction, and improve flow. Examples include stearic acid, stearic acid salts, talc, polyethylene glycols (PEGs), and surfactants. ○ Glidants: Promote the flow of granules or powders by reducing interparticle friction. Examples include corn starch, talc, and silica derivatives. Other Excipients: ○ Coloring agents ○ Flavoring agents ○ Sweetening agents Tablet Manufacturing Several manufacturing methods exist for tablets, including wet granulation, dry granulation, and direct compression. Wet Granulation: Involves mixing the drug and excipients, adding a liquid binder to form granules, drying the granules, and compressing them into tablets. Dry Granulation: Used for moisture-sensitive drugs, this method involves blending the drug and excipients, compacting the mixture into slugs, breaking down the slugs into granules, and compressing them into tablets. Direct Compression: This method involves directly compressing a blend of drug and excipients without prior granulation, requiring excipients with good flowability and compressibility. Fluid Bed Granulation: A more efficient method that combines blending, granulation, and drying in a single piece of equipment. This is particularly beneficial for moisture- and heat-sensitive drugs. Processing Problems During tablet manufacturing, various processing problems can occur, including:  Capping: Separation of the top or bottom crown from the tablet body. Lamination: Separation of the tablet into distinct layers. Sticking: Adhesion of tablet material to the die wall. Picking: Removal of tablet surface material by a punch. Mottling: Uneven color distribution on the tablet surface. Double impression: Imprinting of the tablet with two impressions from the punch. Tablet Quality Control To ensure quality and efficacy, tablets undergo various tests: General Appearance: Evaluation of size, shape, markings, and organoleptic properties. Drug Content and Release: Official tests include weight variation, disintegration, dissolution, and drug stability. Non-official tests include tablet hardness and friability. ○ Weight Variation: Assessment of individual tablet weight uniformity against the average weight. ○ Content Uniformity: Assay of individual tablets to ensure consistent drug content. ○ Disintegration: Evaluation of the time required for a tablet to disintegrate in a specified medium. ○ Dissolution: Measurement of the rate and extent of drug release from a tablet in a specific medium. Capsules Definition and Types Capsules are solid dosage forms consisting of a drug enclosed in a hard or soft gelatin shell. Hard Gelatin Capsules: Composed of two pre-formed cylindrical sections, one fitting inside the other, filled with the drug formulation. Soft Gelatin Capsules: One-piece hermetically sealed capsules containing liquid or semi-solid drug formulations. Gelatin Gelatin, the primary component of capsule shells, is derived from animal collagen through irreversible hydrolytic extraction. Types of Gelatin: ○ Type A: Produced by acid hydrolysis, mainly from pork skin. ○ Type B: Produced by alkaline hydrolysis, mainly from animal bones. The two types differ in their isoelectric points, viscosity building properties, and film-forming characteristics. Capsule Sizes and Fill Weight Capsules are available in various sizes, ranging from 000 (largest) to 5 (smallest), to accommodate different drug dosages. The fill weight of a capsule depends on the drug's density and the capsule size. Excipients in Capsules Similar to tablets, capsules utilize excipients to improve their properties: Diluents or fillers: Provide bulk and cohesion. Examples include lactose, microcrystalline cellulose, and starch. Disintegrants and wetting agents: Facilitate capsule content breakup and distribution in the stomach. Examples include pregelatinized starch, sodium starch glycolate, and sodium lauryl sulfate. Lubricants or glidants: Enhance powder flow. Examples include silicon dioxide, magnesium stearate, calcium stearate, stearic acid, and talc. Advantages of Soft Gelatin Capsules Encapsulation of liquids: Allows for the delivery of liquid, suspension, or paste formulations. Rapid release of contents: The gelatin shell dissolves quickly, releasing the drug rapidly. Protection from oxidation: Provides a barrier against atmospheric oxygen. Reduced GI irritation: Suitable for drugs that may irritate the GI tract. Disadvantages of Soft Gelatin Capsules Adherence: Soft gelatin capsules may stick together, requiring special packaging. Storage sensitivity: Susceptible to temperature and humidity changes. Drug-shell interactions: Potential for interactions between the drug and the gelatin shell. Capsule Quality Control Capsules undergo similar quality control tests to tablets, including: Content uniformity: Ensures consistent drug content among capsules. Weight variation: Assesses uniformity of capsule weight. Disintegration: Evaluates the time required for the capsule shell to disintegrate. Dissolution: Measures the rate and extent of drug release from the capsule. Visual Checks Visual inspection is crucial to ensure capsules are uniform in appearance and free from defects. Packaging and Storage Capsules are typically packaged in unit doses or strips for sanitation, identification, and safety. They should be stored in tightly capped, light-resistant containers in a cool, dry place. Moisture permeation testing is also conducted to evaluate container integrity. Powders Definition and Uses Pharmaceutical powders are mixtures of finely divided drugs or chemicals in dry form, used internally or externally. They can be administered directly or used as ingredients in various dosage forms. Advantages of Powders Formulation flexibility: Allow for the incorporation of multiple ingredients. Chemical stability: Offer good chemical stability in dry form. Rapid dispersion: The small particle size allows for quick dissolution and absorption. Disadvantages of Powders Time-consuming preparation: Powder formulations can be time-consuming to prepare. Dose inaccuracy: Measuring accurate doses can be challenging for patients. Unsuitability for certain drugs: Not suitable for hygroscopic, deliquescent, or unpleasant-tasting drugs. Comminution/Milling Comminution or milling is the process of reducing the particle size of a solid substance. This is often necessary before mixing with other ingredients, further processing, or incorporation into a final product. Advantages of Milling Increased surface area: Leads to faster dissolution rates and improved bioavailability. Enhanced extraction efficiency: Facilitates drug extraction from plant materials. Improved drying: Allows for efficient drying of wet masses. Better mixing and uniformity: Minimizes segregation and ensures even distribution of ingredients. Uniform color distribution: Ensures consistent color in artificially colored products. Improved texture and stability: Enhances the texture and physical stability of ointments, creams, and pastes. Manual Comminution Methods  Trituration: Grinding a substance into fine particles using a mortar and pestle or a pill tile and spatula. Levigation: Reducing particle size by triturating while moistened with a liquid in which the powder is insoluble. Pulverization by intervention: Utilizing a volatile solvent to dissolve the substance, followed by solvent evaporation to obtain a fine powder. Importance of Particle Size Particle size affects several crucial properties of powders: Dissolution: Uniform particle size aids in consistent dissolution and drug release. Suspendibility: Particle size influences the settling rate of particles in a suspension. Uniformity of mixtures: Ensures even distribution of drugs in liquid formulations. Penetrability: Important for powders intended for inhalation. Nongrittiness: Essential for topical formulations to avoid a gritty texture. Micrometrics Micrometrics is the study of the characteristics of solid particles. It includes parameters such as particle size, size distribution, shape, angle of repose, porosity, volume, and density, all of which affect powder properties and behavior. Blending/Mixing Blending or mixing involves randomizing dissimilar particles within a system to create a homogeneous mixture. Small-scale blending: Commonly used in compounding, employing techniques like spatulation, trituration, and sifting. Large-scale blending: Employed in manufacturing, utilizing equipment like v-blenders and ribbon blenders. Geometric dilution: A technique used in compounding to ensure the uniform distribution of potent drugs in a diluent. Powder Applications Powders find use in various applications, including: Dentifrices: Powders for cleaning teeth. Insufflations: Powders applied to body cavities. Powder aerosols: Dispersed powders for various uses, including antiperspirants, deodorants, and dry lubricants. Challenges with Powders  Dose accuracy: Accurate dose measurement can be challenging, especially with potent drugs. Incorporation of liquids: Incorporating liquids into powder formulations can be difficult. Volatility: Loss of volatile components can occur. Hygroscopicity and deliquescence: Absorption of moisture from the air can affect powder flow and stability. Efflorescence: Loss of water of crystallization can lead to powder liquefaction. Eutectic mixtures: Formation of low-melting-point mixtures can result in liquefaction.