Pharmaceutics III – PPH Lecture 2 PDF

Pharmaceutics III – PPH (305) &Pharmaceutical dosage forms III – PPH (506 c) Faculty of Pharmacy, University of Sadat city Third year students (2024-2025) Dr Mohamed Hamdy Course coordinator: Dr- Shaymaa Khater Lecture 2 ...

Pharmaceutics III – PPH (305) &Pharmaceutical dosage forms III – PPH (506 c) Faculty of Pharmacy, University of Sadat city Third year students (2024-2025) Dr Mohamed Hamdy Course coordinator: Dr- Shaymaa Khater Lecture 2  Preformulation Objectives Preformulation testing (continue) 2  7-Membrane Permeability Preformulation studies on membrane permeability involve understanding how a drug compound passes through biological membranes, which is crucial for predicting its absorption, distribution, and bioavailability. Membrane permeability is a key factor in the development of effective oral, transdermal, and other dosage forms, as it helps determine the compound's potential for crossing cellular barriers and reaching its site of action. 3  7-Membrane Permeability To produce a biologic response, the drug molecule must first cross a biologic membrane. The biologic membrane acts as a lipid barrier to most drugs and permits the absorption of lipid soluble substances by passive diffusion, while lipid-insoluble substances can diffuse across the barrier with considerable difficultly. 4  Main aspects considered during preformulation for membrane permeability 1. Lipophilicity and Solubility Lipophilicity: This is measured by the partition coefficient (log P) and influences how well a compound can cross lipid membranes. A balance between lipophilicity and hydrophilicity is necessary for optimal permeability. Example: Propranolol is a drug with moderate lipophilicity (log P around 3), allowing for good membrane permeability and absorption through the gastrointestinal tract. In contrast, mannitol is hydrophilic and has low permeability across lipid membranes, leading to poor absorption when administered orally. Solubility: High solubility is required for adequate drug absorption, as the compound needs to be in a dissolved state to pass through biological membranes. 5 Main aspects considered during preformulation for membrane permeability 2-Molecular Size and Shape Smaller molecules generally have higher permeability. Molecular shape also plays a role in how easily a compound can cross a membrane, with more compact molecules tending to permeate more effectively. Example: Aspirin (molecular weight ~180 Da) has high membrane permeability due to its small size. On the other hand, insulin (a peptide drug with a large molecular weight of ~5800 Da) has poor permeability and cannot cross the intestinal membrane effectively, necessitating parenteral (injection) administration. 6  Main aspects considered during preformulation for membrane permeability 3. pH and Ionization pKa and Ionization State: The pH of the environment and the drug’s pKa determine its ionization state. Non-ionized forms of drugs are more lipophilic and typically exhibit higher membrane permeability compared to their ionized counterparts. Example: Ibuprofen has a pKa of around 4.9. In the stomach (pH ~1-2), it exists mostly in a non-ionized, lipophilic form, enhancing membrane permeability. However, in the intestines (pH ~6-7), a greater fraction is ionized, reducing permeability. Formulations are sometimes designed to improve absorption in specific pH environments. 7 Main aspects considered during preformulation for membrane permeability 4. Transport Mechanisms Passive Diffusion: The primary mechanism for most drugs, relying on concentration gradients. Example: Diazepam is a highly lipophilic drug that crosses cell membranes by passive diffusion, making it quickly absorbed after oral administration. Active Transport and Efflux: Some compounds are actively transported across membranes via transport proteins, or are effluxed out by proteins like P-glycoprotein, which can influence bioavailability. Example of Active Transport: Levodopa is actively transported across the blood-brain barrier, allowing it to reach its target in the brain, making it an effective treatment for Parkinson's disease. 8 Main aspects considered during preformulation for membrane permeability 5. Physiological Factors GI Tract Conditions: Factors like gastric pH, enzyme activity, and intestinal motility affect permeability. Membrane Composition: Different biological membranes (e.g., intestinal, blood-brain barrier) have varying lipid and protein compositions, influencing permeability. Permeability and Drug Absorption A balance between permeability and solubility (Biopharmaceutics Classification System - BCS) helps classify drugs into categories to predict oral absorption. 9  How to assess Membrane permeability ? Everted intestinal sac 10 How to assess Membrane permeability ? Preparation of Intestinal Segment: A segment of the small intestine is excised, cleaned, and carefully everted. Mounting the Sac: One end of the everted segment is tied to form a closed sac, and the sac is filled with a physiological buffer. Incubation in Test Solution: The sac is submerged in a drug- containing solution (mucosal side) and incubated at 37°C with oxygenation and gentle agitation. Sampling and Analysis: Samples are taken from both the mucosal and serosal sides over time to measure drug transport across the intestinal wall. 11  Solubility: Defined as "high" when the maximum dose is soluble in 250 mL or less of aqueous media. Permeability: Considered "high" if the extent of absorption in humans is 85% or more of the administered dose. Biopharmaceutical classification system "BCS" Solubility Permeability 12 Class I: High Solubility, High Permeability Characteristics: Drugs that dissolve rapidly and are well absorbed in the gastrointestinal (GI) tract. Absorption: Immediate and complete, often independent of formulation. Example: Metoprolol, propranolol. Regulation Impact: Usually no need for extensive in vivo bioavailability studies if the drug dissolves quickly. Class II: Low Solubility, High Permeability Characteristics: Drugs that are well absorbed but have low solubility, making dissolution the rate- limiting step in absorption. Absorption: Limited by how quickly the drug dissolves in the GI fluids. Example: ketoconazole. Formulation Strategies: Techniques to enhance solubility, such as particle size reduction or use of solubilizers, are often needed. 13 Class III: High Solubility, Low Permeability Characteristics: Drugs that dissolve easily but are poorly absorbed due to limited permeability across the intestinal membrane. Absorption: Limited by the permeability of the drug across the intestinal wall. Example: Cimetidine, ranitidine. Formulation Strategies: Enhancing permeability through the use of absorption enhancers or modifying the drug molecule can be considered. Class IV: Low Solubility, Low Permeability Characteristics: Drugs with poor solubility and permeability, resulting in limited absorption and bioavailability. Absorption: Limited by both dissolution and permeability factors. Example: Chlorothiazide, amphotericin B. Challenges: These drugs often require advanced formulation techniques, like nanoparticles or prodrug approaches, to improve bioavailability. 14  8-Partition Coefficient The partition coefficient (log P) is a measure of a drug’s distribution between a hydrophobic (octanol) where and a hydrophilic (water) phase, indicating its lipophilicity and K is the distribution constant or ability to cross biological partition constant membranes. It provides insights CU is the concentration of the into a drug’s solubility, drug in the upper phase permeability, absorption, and distribution, (organic=octanol) CL is the concentration of the drug in the lower phase K=[Corganic]/ (aqueous). [Caqueous] 15  Partition coefficient importance 1.Solubility and Permeability: Log P indicates a drug's balance between lipophilicity and hydrophilicity. Optimal log P (1-3) suggests good membrane permeability and solubility. 2.Distribution and Pharmacokinetics: Influences drug distribution in the body, tissue uptake, and half-life. 1. Example: Amiodarone has a high log P (around 7), making it highly lipophilic. As a result, it distributes extensively into tissues and has a long half-life, contributing to its sustained action. 3.Formulation Design: Guides formulation strategies, e.g., solubilization methods for highly lipophilic drugs or permeability enhancers for hydrophilic ones. 1. Example: Highly lipophilic drugs like cyclosporine (log P > 3) require lipid-based formulations to enhance their solubility and absorption. In contrast, hydrophilic drugs like metformin (log P < 0) may benefit from permeation enhancers 4.Protein Binding: Higher log P often leads to higher plasma protein binding, affecting drug activity. 1. Example: Warfarin has a log P of about 2.7 and is highly bound to plasma proteins (about 99%), which affects its free concentration and pharmacological effect. 16  9-Hydrates and Solvates In summary, hygroscopic Powder powders absorb and retain moisture, deliquescent powders absorb moisture Hydrate/ to the point of dissolving, Solvate and efflorescent powders release moisture when exposed to drier Hygroscopic Deliquesce Efflorescent conditions. These powders nt powder powders properties have implications for the handling, storage, and tend to absorb give up their water of formulation of moisture from the absorb moisture crystallization and may pharmaceutical air(Ammonium from the air and even become damp and substances, and it is bromide, even pasty Atropine sulfate, sodium carbonate and important to consider these liquefy(calcium Ammonium characteristics when Ammonium chloride chloride and magnesium sulfate chloride) working with powders in Ammonium chloride potassium hydroxide) the pharmaceutical industry 17  Hydrates and Solvates Solvates and hydrates must be When working with these packaged in “tight” containers to powders, extra care must be prevent the loss or gain of moisture taken. Storage at the indicated If a hygroscopic or deliquescent powder temperatures is also important and is being weighed on a balance, the powder may absorb moisture from the air and to minimize any exposure to very weigh heavier than it should. high humidity levels Correction of solvate/hydrate required Therefore, weighing should be made 𝑀𝑜𝑙𝑒𝑐𝑢𝑙𝑎𝑟 𝑤𝑒𝑖𝑔ℎ𝑡 𝑜𝑓 ℎ𝑦𝑑𝑟𝑎𝑡𝑒 quickly after opening the bulk weight = 𝑀𝑜𝑙𝑒𝑐𝑢𝑙𝑎𝑟 𝑤𝑒𝑖𝑔ℎ𝑡 𝑜𝑓 𝑎𝑛ℎ𝑦𝑑𝑟𝑜𝑢𝑠 chemical containers and then 𝑊𝑒𝑖𝑔ℎ𝑡 𝑜𝑓 ℎ𝑦𝑑𝑟𝑎𝑡𝑒 resealing them. 𝑊𝑒𝑖𝑔ℎ𝑡 𝑜𝑓 𝑎𝑛ℎ𝑦𝑑𝑟𝑜𝑢𝑠  Hydrates and Solvates Correction of solvate/hydrate required weight Example: 𝑀𝑜𝑙𝑒𝑐𝑢𝑙𝑎𝑟 𝑤𝑒𝑖𝑔ℎ𝑡 𝑜𝑓 ℎ𝑦𝑑𝑟𝑎𝑡𝑒 = 𝑊𝑒𝑖𝑔ℎ𝑡 𝑜𝑓 ℎ𝑦𝑑𝑟𝑎𝑡𝑒 𝑀𝑜𝑙𝑒𝑐𝑢𝑙𝑎𝑟 𝑤𝑒𝑖𝑔ℎ𝑡 𝑜𝑓 𝑎𝑛ℎ𝑦𝑑𝑟𝑜𝑢𝑠 𝑊𝑒𝑖𝑔ℎ𝑡 𝑜𝑓 𝑎𝑛ℎ𝑦𝑑𝑟𝑜𝑢𝑠 If a prescription for lidocaine 288.81 𝑋 = hydrochloride 2% gel (100 g) is 270.8 2 to be made, what is the required X= 2.133 g weight of lidocaine hydrochloride monohydrate if Mol wt of anhydrous lidocaine hydrochloride is 270.80 g/mole and of lidocaine hydrochloride monohydrate is 288.81 g/mole 19  10-Organic Salt Considerations sodium salts are often made many drugs are either they are often used as from weak acids (Na salicylate weak acids or weak their “salts” to is the salt of the weak acid, bases and have limited increase their aqueous salicylic acid and a strong water solubility solubility base, NaoH combination of a weak base, ephedrine hydrochloride can be codeine, and a weak acid, prepared between a weak base, phosphoric acid, can be used, ephedrine, and a strong acid, HCL. as in codeine phosphate 20  10-Organic Salt Considerations Organic Salt Considerations When salts are placed in an aqueous environment, they will dissolve to some extent, based upon their solubility in the aqueous media and the pH of the media. Some are dissolved (ionized) and some are undissolved (unionized) Generally, it is the “unionized” portion of the drug in solution that will be absorbed for systemic effect. This is described by the “dissociation constant” or “pKa” of the drug. 𝑀𝑜𝑙𝑒𝑐𝑢𝑙𝑎𝑟 𝑤𝑒𝑖𝑔ℎ𝑡 𝑜𝑓 𝑠𝑎𝑙𝑡 𝑊𝑒𝑖𝑔ℎ𝑡 𝑜𝑓 𝑠𝑎𝑙𝑡 Correction of salt required weight = 𝑀𝑜𝑙𝑒𝑐𝑢𝑙𝑎𝑟 𝑤𝑒𝑖𝑔ℎ𝑡 𝑜𝑓 𝑝𝑎𝑟𝑒𝑛𝑡 𝑚𝑜𝑙𝑒𝑐𝑢𝑙𝑒 𝑊𝑒𝑖𝑔ℎ𝑡 𝑜𝑓 𝑝𝑎𝑟𝑒𝑛𝑡 𝑚𝑜𝑙𝑒𝑐𝑢𝑙𝑒 21  Organic Salt Considerations Example Fentanyl weight= A prescription calls for 10 mL of fentanyl 50 μg/0.1 mL 50 µg in 0.1 mL topical gel. How much fentanyl X in 10 mL= 5000µg = 5 mg citrate will be required? If 𝑀𝑜𝑙𝑒𝑐𝑢𝑙𝑎𝑟 𝑤𝑒𝑖𝑔ℎ𝑡 𝑜𝑓 𝑠𝑎𝑙𝑡 Fentanyl MW = 336.47 = 𝑀𝑜𝑙𝑒𝑐𝑢𝑙𝑎𝑟 𝑤𝑒𝑖𝑔ℎ𝑡 𝑜𝑓 𝑏𝑎𝑠𝑒 𝑊𝑒𝑖𝑔ℎ𝑡 𝑜𝑓 𝑠𝑎𝑙𝑡 Fentanyl citrate MW = 528.59 𝑊𝑒𝑖𝑔ℎ𝑡 𝑜𝑓 𝑏𝑎𝑠𝑒 528.59 𝑊𝑒𝑖𝑔ℎ𝑡 𝑜𝑓 𝑠𝑎𝑙𝑡 = 336.47 5 So wt of salt= 7.85 mg 22  12-Drug and Drug Product Stability knowledge of the drug’s chemical structure is essential solid-state stability of the drug alone to anticipate the possible degradation reactions. Stability in solution-phase preformulation stability It is essential that these initial studies be conducted using stability in the drug samples of known purity. presence of The presence of impurities can expected excipients lead to erroneous conclusions in such evaluations. 23  Stability types Chemical Physical Microbiological Therapeutic Toxicological The original Sterility or Each active physical resistance to The therapeutic No significant ingredient properties, effect remains increase in retains its microbial including unchanged. toxicity occurs. chemical growth is appearance, retained integrity and palatability, labelled according to uniformity, the specified potency dissolution, within the requirements. and Antimicrobial specified suspendabilit limits agents retain y, are effectiveness retained. within specified limits. 24  Drug and Drug Product Stability Drug Stability: Mechanisms of Degradation (chemical degradation in details) Chemically, drug each with reactive The main two substances are chemical groups degradation alcohols, phenols, having different pathways are aldehydes, susceptibilities to hydrolysis and ketones, esters, chemical oxidation ethers, acids, instability salts, alkaloids, glycosides, and others 25  Drug and Drug Product Stability 1-Hydrolysis solvolysis process in which (drug) molecules interact with water molecules to yield breakdown products. the most important single cause of drug decomposition, mainly because a great number of medicinal agents are esters, substituted amides, lactones, and lactams, which are susceptible to the hydrolytic process. Eg: aspirin, (acetylsalicylic acid), combines with a water molecule and hydrolysis into one molecule of salicylic acid and one molecule of acetic acid. 26  Drug and Drug Product Stability 2-Oxidation Oxidation destroys many drug types, including aldehydes, alcohols, phenols, sugars, alkaloids, and unsaturated fats and oils Inorganic Organic chemistry chemistry oxidation is loss of electrons from an atom or a molecule. Each electron lost is Oxidation is accompanied accepted by other atom or molecule, by an increase in the oxidation is the reducing the recipient. positive valence of an loss of element, for example, hydrogen ferrous (+ 2) oxidizing to (dehydrogenati ferric (+ 3). on) from a molecule. 27  Drug and Drug Product Stability Oxidation Free radicals are molecules Oxidation frequently or atoms containing one or These radicals tend to take more unpaired electrons, electrons from other involves free chemical such as molecular chemicals, thereby oxidizing radicals (atmospheric) oxygen ( O— the donor. O ) and free hydroxyl ( OH). 28  Drug and Drug Product Stability Oxidation chain reaction commencing with the Autoxidations occur union of oxygen with the spontaneously under drug molecule and the initial influence of continuing with a free atmospheric oxygen radical of this oxidized and proceed slowly at molecule participating in first and then more the destruction of other rapidly. drug molecules and so forth. 29 Examples of stability problems and suggested solutions 30 1. Physical Stability Polymorphic Forms: For instance, the drug Carbamazepine exhibits multiple polymorphic forms, where Form III is the most stable. However, during processing or storage, a transformation from Form III to a less stable Form II might occur, which can affect the drug's solubility and bioavailability. 31 2. Chemical Stability Hydrolysis: Penicillin is prone to hydrolysis, especially in acidic or alkaline environments. Preformulation stability studies help identify the need for buffering agents or protective coatings to minimize hydrolysis and maintain efficacy. Oxidation: The drug Vitamin C (Ascorbic Acid) is sensitive to oxidation, which can lead to degradation and loss of potency. In stability studies, antioxidants like sodium metabisulfite might be added to stabilize the formulation against oxidation. Photostability: Some drugs, like Nifedipine, are photosensitive and degrade upon exposure to light. Preformulation studies can identify this instability, leading to the use of light-resistant packaging to prevent degradation. 32 3. Microbial Stability A product containing natural plant extracts, such as those in herbal supplements, can be prone to microbial contamination if not adequately preserved. Stability studies may involve testing the effectiveness of preservatives like parabens to ensure the product remains free of microbial growth throughout its shelf life. 33 4-Thermal Stability Some drugs, like Amoxicillin, degrade at higher temperatures. Thermal stability studies help determine appropriate storage conditions, such as refrigeration, to prolong the shelf life and maintain drug efficacy. 34 5-pH Stability Erythromycin, an antibiotic, is unstable in acidic pH but more stable in neutral or slightly alkaline pH. Stability studies can help determine the optimal pH range for formulation and guide the selection of buffering agents to stabilize the drug in its intended dosage form. 35  13-Storage and shelf life Stability is the extent to which a product retains within specified limits and throughout its period of storage and use (i.e., its shelf life) the same properties and characteristics that it possessed at the time of its manufacture 36