PR5304 NOTES for CA TEST 1 PDF

Introduction to Semi-Solid Dosage Form 1. Liquid system a. What is it? i. Made up of water, organic solvent or both in varying weight or volume ratio b. What is inside? ii. Solute (drug and excipients) dissolved in liquid system/phase (molecul...

Introduction to Semi-Solid Dosage Form 1. Liquid system a. What is it? i. Made up of water, organic solvent or both in varying weight or volume ratio b. What is inside? ii. Solute (drug and excipients) dissolved in liquid system/phase (molecularly distributed) c. How does it look like? iii. Its either solid in liquid or immiscible liquid in liquid 1. The liquid solvent is continuous or bulk phase 2. The solid or immiscible liquid is the dispersed phase 2. Sequence d. Atom e. Molecule f. Crystal: assembly of molecules g. Particle: aggregation of particles 3. Stokes Law h. What is it? iv. The rate of particle settling i. Formula? j. States? v. Imagine you're dropping a small ball into a thick liquid like honey. Hen you drop it, the ball doesn't just fall as fast as it would through the air. It slows down because the honey pushes against it. Stokes law helps to explain how fast the ball falls into the thick liquid. Factors that affects speed include: 3. Size of the ball/ Particle diameter a. Small particle = slower sedimentation rate i. Small particle wont settle due to Brownian movement b. Bigger particle = faster sedimentation rate c. Note: change in temperature affects velocity of sedimentation of small particles 4. How thick the liquid is/ Viscosity d. Suspension viscosity is affected by viscosity of solvent or dispersion medium and volume fraction of solute ii. High conc of solute in excess of 20% will hinder settling rate 5. How sticky or resistant the liquid 6. Density difference e. Determines the location of sedimentation (top/bottom) vi. Stokes law tells us how liquid resists things that are trying to move through them vii. Application 7. Sedimentation profile of concentrated suspension 4. Flocculated and Deflocculated Suspensions k. What is it? viii. Process where colloids (suspended particles that are too light and small to settle and causes turbidity) aggregate to form larger particles called flocs by addition of chemical called flocculants l. How does it work? m. Why does it happen? ix. Due to thermodynamic instability x. Aggregation profile dependent on the net interaction of attractive and repulsive forces n. Graph 5. Sedimentation Parameter o. What is it? xi. Ratio of the volume of sediment to the original volume of suspension before settling occurred p. Formula? q. Range? Fundamental Topics in Pharmaceutical Science 1. Solutions a. Examples of solutions b. Solubility i. Factors: 1. Temperature: change in free energy (delta G) a. +: endothermic b. --: exothermic c. Imagine dissolving sugar in cold vs. hot water. In cold water, it takes a longer time because water is moving slower than when its hot. The sugar molecules are not bumping to each other as much and the water molecule doesn't have energy to help the sugar molecules break down. In hot water, water molecules have more energy so it bumps to sugar molecule and breaking it apart faster. The heat gives water molecules more energy to help the solute break apart. 2. Molecular structure of solute: d. Weak acid/base or strong acid/base i. Not related to crystalline structure of the molecule ii. Weak acid or bases tend to have stronger intermolecular bonds than strong acid or bases. Strong a/b dissociates in water fast while weak a/b doesn't, which makes them "weak". They tend to have less driving force to donate/accept protons which is how acid and base typically react. Weak a/b holds their protons more tightly so they prefer to stay as a whole unit than break apart. e. We can increase solubility and modify chemical structure by: iii. Introducing polar/hydrophobic substituent iv. Salt formation 3. Crystal characteristics f. Polymorphs with varying solubility values v. Polymorphs: solid crystalline phase of a given compound resulting from the possibilities of at least two different arrangements of the molecules of that compound in the solid state (carbon and diamond) g. Metastable polymorphs have higher solubility value than the stable one vi. Metastable polymorph is like a messy blocks that's loosely arranged so it is not tightly packed or sturdy. Water molecules can bump into it and start breaking pieces off. That's why it dissolves faster and more easily. Compared to stable polymorphs, its tightly packed stack and its hard to break apart, which is why its more difficult to dissolve in water. 4. Solvate/Hydrate h. Solvate: compound in which solvent molecules are physically or chemically integrated into the structure of solid material. It is a crystal or solid that has trapped some of the liquid/solvent it was dissolved in when it formed. i. Hydrate: substance that contains water and its constituent elements j. Hydrated crystals is less soluble in water than anhydrous counterparts because it has stronger intermolecular bonding and reduced energy liberation. vii. Think of water as extra support beams holding the crystal together. These water molecules strengthen the bonds between atoms in the solid, making the structure more resistant to breaking down when its placed in water or other solvent. Anhydrous compound doesn't have that extra support beams so its less tightly held together so when exposed to water, it can break apart easily and dissolve faster 5. Amorphous structure k. Amorphous: any non-crystalline solid that doesn't organize the atoms and molecules in a definite lattice form viii. Higher solubility due to reduced lattice energy 6. Particle size of a solid l. Solubility rate increases = particle size decreases ix. Imagine a large sugar cube vs. same amount of sugar broken into tiny grains. Sugar cube has smaller surface area exposed to water so it takes longer for water molecules to interact with sugar and dissolve it. m. Note: rate or speed of drug solubilizing is different 7. Nature of solvent n. Like dissolves like 8. pH o. formation of ionized species and more soluble salt as a result of acid/base reaction p. solubility decreases = pH increases q. at low pH, protonation of anion (conjugate base of weak acid) increases solubility of salt r. nature of solute can increase or decrease solubility depending on the pH. If you have weak acid and you increases pH, then acid will lose protons, making them a charged ion and will be soluble in water. If pH is lowered, weak acid will be neutral, making it insoluble. x. Ionized or charged forms are more soluble xi. Non-ionized are less soluble ii. What agents can help with solubility? 9. Additives s. Other substances incorporated into solvent in which the solute dissolves xii. Common ion effect: reduces solubility of ionizable drug 1. If you have a salt (ionizable drug) dissolving in water, breaking into +/- ions. If you add more of one of the ions, the solution will have too much of that ion, creating imbalance, so the solution cant dissolve more of the drug because its "crowded" with the same ions. The excess of one type of ion in the solution will slow down the dissolving process, which decreases the overall solubility of the ionizable drug. xiii. Indifferent electrolyte: promote solubility of ionizable drug 2. The electrolyte can shield the drug ions away from one another which reduces the electrostatic interactions between the drug ions. They can break apart and stay in the solution more effectively. This increase the overall ionic strength can stabilize the dissolved ions, increasing solubility of the ionizable drug. xiv. Non-electrolyte 10. Surfactant t. Chemical agent that cause decrease in the solvent's surface tension u. Works by shielding the drug molecules from interacting with each other and eventually aggregating. Surfactant can also work by shielding the containers the drug is in to reduce the chances of drug molecules adsorbing to the surface of the container. c. Case Study for Esomeprazole for injection (lyophilized esomeprazole via Qbd) iii. Components: 11. Esomeprazole sodium v. Drug in salt form has higher solubility 12. Disodium edetate w. Complexing agent: chemicals that are able to form complexes with one of the ions involved in precipitation x. Part of indifferent electrolyte additives y. Reduced the activity of ion and increases stability 13. Sodium hydroxide z. pH adjuster xv. pH of injectables has to be the same as blood (7.5-8.2/8.3) 14. Water a. Solvent for injection xvi. Why not saline? 3. We use water because salt can affect solubility via the common ion effect. Saline and other salts can lead to a too high osmolarity d. Template iv. Determine the characteristic of the drug v. Which solvent is used vi. What is the pH of solution vii. Which complexing agent should be used? viii. Which additives should be used? e. Isotonicity: when concentration of solute in a cell and in the environment of cell is the same, so no net movement of water and permeable solutes f. Buffer: mixtures of a weak acid and its salt (conjugate base) or weak base and its salt (conjugate acid) ix. Can resist small pH changes which can affect solubility 2. Suspensions g. What is it? x. Dispersion of finely divided solid particles in a liquid medium h. What are the types? xi. Colloidal suspension -- small particles xii. Coarse suspension -- big particles i. What is the limit of individual suspended solid particle size? xiii. 50-75 um j. Uses: xiv. Oral xv. Skin/mucous membrane xvi. Injection k. When to choose suspension over solution? xvii. When the solubility of drug is not good l. Particle separation xviii. What is primary and secondary minimum energy? 15. Primary: deflocculation 16. Secondary: flocculation xix. What is stability of particle in solution dependent on? 17. Its total potential energy xx. What separates particles? 18. Repulsive force xxi. What can make particles attracted to one another? 19. Its forced with sufficient energy (ex: increase temp) so they can adhere strongly and irreversibly together xxii. What if particles have high repulsion? 20. The dispersion will resist flocculation and colloidal system will be stable xxiii. A close-up of a piece of paper Description automatically generated xxiv. Controlled flocculation: flocculated agents can be added to solutes ad solvents in order to increase stability 21. Common flocculating agent b. Electrolyte xvii. By adding electrolytes, it introduces ions that will neutralize the charges on the surface of the particle, which will reduce the electric potential between particles. This reduces the repulsive force and particles can come together and form flocs. 4. Flocs can easily be redispersed with gentle shaking, enhancing stability and uniformity of suspension c. Surface active agent xviii. The surfactant will adsorb to the surface of the dispersed particles and it will neutralize the electrostatic repulsion between similarly charged particles Surfactants reduce surface tension between particles and reduces repulsive forces, allowing them to form flocs. d. Polymer xix. Same concept as surfactant where it will adsorb to the particle's surface through multiple points of attachment and create steric barrier that prevents the particle from coming too close and aggregating irreversibly e. Immiscible liquid xx. Same concept as polymer 3. Gel m. Characteristics: xxv. Semi-solid xxvi. Liquid constrained in 3 dimensional matrix xxvii. High degree of cross-linking (physical/chemical) xxviii. Greater aqueous fraction than creams/lotions (higher content of fatty acids) which allow higher drug release n. Types: xxix. Organogel: composed of liquid organic phase (organic solvent, oil) xxx. Hydrogel: water swollen polymer matrix that has tendency to absorb water 22. More suitable for administration than organogel o. How to manufacture a gel? xxxi. Solubilization of lecithin (lipid) in organic media (non-polar) xxxii. Addition of polar additive xxxiii. Spontaneous formation of organogel p. Hydrogel examples: xxxiv. Natural polymer: 23. Protein: collagen, gelatin 24. Polysaccharide: agar, alginic acid, sodium/potassium carrageenan, tragacanth xxxv. Semisynthetic polymer 25. Cellulose derivatives f. Carboxymethylcellulose g. Methylcellulose h. Hydroxypropylcellulose xxxvi. Synthetic polymer 26. Carbomer: Carbopol series 27. Poloxamer 28. Polyacrylamide 29. Polyvinyl alcohol xxxvii. Inorganic substances 30. Aluminium hydroxide 31. Bentonite xxxviii. Surfactant 32. Cetostearyl alcohol 33. Brij-96 4. Emulsion q. Characteristics: xxxix. 2 liquid that is not miscible (o/w or w/o) r. 2 types: xl. Emulsion xli. Nano-emulsion: dispersed phase \20% water, volatile, and \ xxi. Aseptic processing 9. Removal or separation of microorganisms 10. Higher risk of contamination 11. More variables and harder to control 12. Fewer issues with materials 13. Ex: aseptic filtration and lyophilization  j. Sterilization methods xxii. Moist/dry heat sterilization 14. Expose item to required temperature and pressure for specific amount of time h. Heat destroys microorganisms by irreversible coagulation and denaturation of enzyme and structural proteins xxiii. Aseptic filtration 15. Performed using 0.22um 16. Applied to thermosensitive objects and can be used to remove pyrogens 17. Container needs to be sterile 18. Note: for suspension, it has to be nano sized or else the particles can be removed by filtration xxiv. Gamma radiation 19. By ionizing radiation, no high temperature 20. Ex: cobalt 60, cesium 137, electron accelerators 21. Mostly for medical products and packaging materials 22. Disadvantage: i. Induced oxidation in polyethylene j. Cracking in polyethylene knee bearings xxv. Chemical sterilization 23. Using liquid sterilants in cold systems using: k. Ethylene oxide: alkylating agent l. Peracetic acid: highly biocidal oxidizer vi. Usually for endoscopic tubes m. Gas plasmas (hydrogen peroxide): reactive oxygen will inactivate organic materials xxvi. Lyophilization 24. What is it? n. Freeze-drying process which water is removed from a product after it is frozen and placed under a vacuum o. Process: vii. Freezing viii. Primary drying (sublimation) 1. Drying under vacuum 2. All energy transferred to water from solid to gas ix. Secondary drying (desorption) 3. For water that is strongly attached to product 4. Humidity in air can resolubilized the product p. Main critical point: x. Water content: to know if product is successfully lyophilized xi. Cold: crystal can change property xii. Heat: monitor to know if sublimation is done xiii. Gas content: not an issue xiv. Vacuum: stronger vacuum = less time 2. Sterile products k. Sterile powder xxvii. Necessary when drug is not stable in liquid form xxviii. Have to be reconstituted with a sterile diluent before administration l. Multi-dose vials (MDVS) xxix. Used multiple times for multiple doses xxx. Using preservatives to retain sterility after needle puncture xxxi. Remainder of vial have to be stored properly and used before expiration date m. IV bags xxxii. Base solutions + medications xxxiii. Dilution before administration n. Patient-controlled analgesia xxxiv. Container of mixture of pain killers attached to chest/belly by a controlled device o. Epidurals xxxv. Inserted intrathecally for pain control in surgery or obstetrics xxxvi. Anesthetic alone or with narcotic xxxvii. Must be preservative free or else will result in paralysis p. Ophthalmic xxxviii. Prepared using aseptic filtration before packaged xxxix. Instilled onto external (topical), inside the eye (intraocular) or adjacent (periocular) 3. Example: nanosuspension for IV q. Omeprazole: proton pump inhibitor xl. Characteristics: 25. Lipophilic 26. Weak base with low water solubility 27. Sensitive to low pH and warm temperature xli. Problem: coated capsule/tablet 28. Pass through the stomach, released to the intestine, circulate in the blood stream and back to the stomach q. Time-consuming 29. Cannot be injected as an IV due to its instability and low solubility xlii. What is the issue with the substance in preparing an IV injection? 30. Solubility is an issue and can affect the amount of drug in the dosage form xliii. How to improve? 31. Increase in temperature: NO r. Consider manufacturing and storage, temp will go to RTP or even lower and you can't inject warm injectable into the patient 32. In-situ salification: YES s. In situ salification is a process where drug is converted into its salt form directly within the environment where it is intended to be used xv. The drug is mixed with a suitable counter-ion (strong base/acid) in the formulation xvi. Ionic drugs are more soluble in water 33. Dilution: NO t. Volume is an issue and not viable 34. Amorphous solid dispersion: YES u. To enhance the solubility of poorly water soluble drugs by transforming the drug into amorphous non-crystalline state and dispersed within polymer xvii. Increase SA xviii. Stabilization: polymer stabilizes drug preventing it from crystallizing xix. Improve wettability: easily penetrated by water so improve dissolution and absorption in GI tract 35. Use of organic solvent: YES v. Pay attention to which type and how much you can use xx. Ex: ethanol can be injected in small amount xliv. Administered as nanodispersion with sodium carbonate (buffering agent) and poloxamer (stabilizer) 36. Using sodium carbonate may induce common ion effect if the drug underwent in situ salification xlv. Best way to manufacture: lyophilization or aseptic filtration 4. Eye administration r. Structure of the eye divided into: xlvi. Anterior segment: cornea, iris, lens xlvii. Posterior segment: sclera, optic nerve s. Eye drops xlviii. Most ocular medications delivered topically to maximize anterior segment concentration and minimize systemic toxicity xlix. Passive absorption through drug gradient from tear reservoir to corneal and conjunctival epithelium l. Limitation: 37. Drug concentration: tonicity 38. Solubility: aqueous or suspension 39. Viscosity: increases residence time 40. Lipid solubility: to go through the membrane 41. pH and ionic charge: most eye drops are weak base and exist in both charged and uncharged form to enhance absorption li. most common issue: 42. reflex tearing: ocular irritation and secondary tearing will wash out the drug and reduce contact time with cornea w. happens when drug is not isotonic, have non-physiological pH and has irritants 43. tissue binding: proteins in tears and ocular surface can bind to the drug which makes the drug unavailable or create slow release x. affect peak effect and duration of action and delayed local toxicity t. eye ointments lii. characteristics: 44. mixture of petrolatum and mineral oil 45. water soluble drugs are not soluble in ointment and present as microcrystals y. surface microcrystals will be dissolved in tears whereas the ones in the ointment will wait to be dissolved until ointment melts away 46. increases contact time of drug to the ocular surface since its not easily washed away by tears 47. the drug has to have high lipophilicity and some water solubility in order to be able to penetrate to the posterior segment u. intraocular injections liii. characteristics: 48. allows instant drug delivery at therapeutic concentration to target site 49. intracameral: directly deliver the drug into the anterior chamber 50. intravitreal: shot of medicine near the retinal at the back of the eye liv. drugs with higher lipid solubility pass better through blood ocular barrier 51. passive drug permeation influenced by: z. lipophilicity a. molecular weight b. ionization v. example: dexamethasone eye drops lv. characteristics of dexamethasone: 52. steroid 53. soluble in organic solvent but not water lvi. how to improve and increase dexamethasone delivery? 54. Using cyclodextrin to increase solubility as it forms complexes with dexamethasone c. Can also be used as permeation enhancer 55. Using suspension since it increases contact time to the cornea 56. Use preservatives and salts w. Example: vitrasert intraocular device lvii. Controlled release via polymer 57. Soluble drugs go through the gelled polymer 58. Insoluble drugs are released when the polymer erode enough to physically release particles of the drug trapped in the polymeric matrix x. Microneedles lviii. Designed to penetrate only hundreds of microns into the sclera so damage to deeper ocular tissue can be avoided 59. Mainly for delivery to posterior segment of eye lix. Needles help deposit drug/carrier system into sclera or suprachoroidal space lx. Puncturing sclera and depositing drug solution can facilitate diffusion of drug to deeper ocular tissues y. Example: progesterone insert/drop lxi. Characteristics: 60. For treatment of retinite pigmentosa 61. Has low solubility in water and PBS d. Doesn't allow delivery of proper dose lxii. Solution: using methyl beta cyclodextrin as complexing agent to increase solubility Tablets and Capsules 1. Tablets a. What is it? i. Solid dosage form preparations containing one or more active ingredients b. Advantages: ii. Stable iii. Easy to use and convenient iv. Reliable manufacturing c. Disadvantage: v. Mainly for poorly soluble or hygroscopic drugs vi. Coating or encapsulation may be necessary vii. Not suitable for liquid viii. Young and elderly patient compliance d. Classified by: ix. Composition: 1. Compressed 2. Multilayered 3. Triturates x. Release: 4. Immediate 5. Rapid disintegration 6. Extended release 7. Combined release xi. Consistency 8. Chewable 9. Effervescent 10. Site of application a. Buccal/sublingual tablets b. Vaginal c. Depot -- hybrid of device and tablet to ensure controlled release e. Major excipients: xii. Diluents/fillers 11. To increase volume of powder if the drug is too small in amount 12. Able to improve compression 13. Examples: d. CaHPO4 e. Kaolin f. Lactose g. Mannitol h. Carbonate i. Sorbitol j. Starch xiii. Polymers 14. Used for controlled release 15. Used for solid or liquid coating 16. It can be natural/synthetic and soluble or insoluble 17. How do polymer release drug? k. Gel matrix i. Polymer + water form a gel that slow down the drug particle movement l. Biodegradable ii. Degradable particles break down over time to release drug particle m. Coated system iii. Caused delayed release iv. Drug molecule has immediate release when coating dissolution happens n. Encapsulated system v. Caused delayed release vi. Coating wont disintegrate like the coated system but water can come in to the system and drug can be dissolved and permeated through the capsule xiv. Disintegrants 18. Helps to break down tablet and modify drug release o. Catch water and swell to physically break down the tablet 19. Mechanisms: swelling, wicking, bubbling, hydrogen bonding 20. Examples: p. Starch q. Microcrystalline cellulose r. Sodium starch glycolate s. Cross linked polyvinylpyrrolidone xv. Super disintegrants 21. Swell 5x the volume 22. Examples: t. Cross linked PVP u. Cross linked CMC xvi. Binder 23. Used for powder adhesion especially in tablet granulation 24. Examples: v. Synthetic polymers (PVO, PEG, Gelatin) w. Sugars (lactose/sorbitol/starch) xvii. Glidant/lubricants 25. Glidant x. Reduce friction between particles y. Used during mixing or granulation z. Example: vii. Magnesium stearate viii. Colloidal silica ix. Talc x. starch 26. Lubricants/antiadherents a. Used to reduce friction during tablet compression and ejection b. Example: xi. Magnesium stearate xii. Mineral oil xiii. Stearic oil xiv. Talc f. Minor excipients: xviii. Colourants 27. Mask color of drugs xix. Absorbents 28. Give the product a dry appearance 29. Take up some water from wet granulation process 30. Example: c. Kaolin d. Magnesium carbonate e. Colloidal silica xx. Wetting agents 31. Help tablet disintegration by increasing wettability and water uptake 32. Example: Polysorbate 80 xxi. Stabilizers 33. Improve stability of drug f. Example: g. Ascorbic acid h. Alpha tocopherol  2. Tablet Manufacturing g. Granules: agglomerates of small particles of powder (\~220-4000um) xxii. Have better flowability and compaction than fine powder h. Wet granulation xxiii. Process: 34. Drug is mixed with filler and disintegrants 35. Binder is added to help with adhesion (dry or wet) 36. Screening into pellets: wet mass pressed through screen/sieve 37. Drying 38. Sizing the granules: granules passed through smaller sieve 39. Blending with disintegrants and lubricants xxiv. Fluid bed: all in one step 40. Aeration xxv. Spray dryer 41. Liquid droplets sprayed into a steam of hot air so that each droplet dries to an individual solid particle i. Dry granulation xxvi. Roller compaction 42. Powder squeezed into brittle sheets that are milled to granules xxvii. Slugging 43. Powder compressed to large tablets then milled to granules j. Direct compression xxviii. Powder compressed in the center of the die by two hardened steel punches that fit top and bottom of the die 3. Quality control of tablets k. Dimension xxix. Tablet thickness: \