Pharmaceutical and Formulation Considerations PDF

PHARM 130 Lec: Pharmaceutics 1 PHARMACEUTICAL AND FORMULATION CONSIDERATIONS Professor Ethel Andrea C. Ladignon Week 2 (February 2 & 6, 2024) OUTLINE Reasons Why We Make Dosage Forms Pharmaceutical and Formulation Considerations Preformulation Studies Development of Drugs and Vaccines Drug Discovery...

PHARM 130 Lec: Pharmaceutics 1 PHARMACEUTICAL AND FORMULATION CONSIDERATIONS Professor Ethel Andrea C. Ladignon Week 2 (February 2 & 6, 2024) OUTLINE Reasons Why We Make Dosage Forms Pharmaceutical and Formulation Considerations Preformulation Studies Development of Drugs and Vaccines Drug Discovery Drug Development Preformulation Studies Solubility Partition Coefficient Partitioning Crystal Form Solid State Drug and Drug Product Stability 5 Concerns of Stability Determining Stability Rate Reactions Drug and Drug Product Stability Stability Conditions/Stress Conditions Testing Other Properties Excipients Excipient Properties Dissolution Dissolution and Absorption of API Provide safe and convenient delivery of accurate dosage for the drug Protect the drug from degradation (humidity, oxygen) Those that are prone to experience degradation of their API due to humidity and oxidation can be avoided and eliminated sometimes when formulated as a dosage form. Protect the drug from degradation after oral administration Sometimes it is not enough for the drug to be formulated as a tablet, it needs an 🔊 🔊 ADALLA, DENOSTA, GEROLAGA, MAGALUED, MORATA 🔊 🔊 🔊 PHARMACEUTICAL AND FORMULATION CONSIDERATIONS REASONS WHY WE MAKE DOSAGE FORMS additional layer–render it as enteric-coated so that it is protected from enzymatic juices and so that it can be disintegrated on its desired target site. Conceal unpleasant taste of drugs You will never taste the bitter-tasting drug if you formulate it as a dosage form because suitable flavorants and sweeteners will mask certain drugs. Syrups are formulated for pediatric patients because it is a sweetener itself. Provide optimal drug action Some drugs require modified release, if not rendered as modified release, it can cause undesired side effects to the patient. Sustained release helps alleviate side effects but doesn't compromise therapeutic effect. Advantage is less frequency in drug intake. Provide rate-controlled drug action Rate-controlled drug action cannot be ensured by considering API alone, excipients are also needed to render the drug controlled in terms of release. 🔊 Preformulation studies Know first the physical and chemical attributes of API before mixing with excipient. Once mixing of API and excipients are observed, it’s called formulation studies. Needed for formulation of newly discovered synthetic compounds, and vaccines and other biological products. Drug stability Check stability as API alone, as well as until it’s mixed with excipients and formulated as dosage form and at the same time in the packaging material. Pharmaceutical Ingredients and Excipients Formulation Factors Affecting the Dissolution and Absorption of API Biopharmaceutics come into play because you need to know the fate of dissolution and 🔊 🔊 1 absorption of a drug because that is the determining factor in deciding the optimum dosage form design for a certain API. PREFORMULATION STUDIES Laboratory studies to determine the characteristics of active substance and excipients that may influence formulation and process design and performance. The idea must always be that the drug formulated will be beneficial to all when produced in a larger scale. 🔊 DEVELOPMENT OF DRUGS AND VACCINES 🔊 In 🔊 🔊 🔊 Phase I, we determine the safety and dosage. About 70.0% will move to the next phase. In phase II, we assess if the drug is effective and safe (short-term side effects) on human subjects. About 33.0% will move to the next phase. In phase III, safety and efficacy to patients (monitoring of adverse reactions). About 25% to 30% will move to the next phase. If adverse drug reactions arise, this will be reported under pharmacovigilance. 🔊 History of Lagundi and Sambong Figure 1. Development of Drugs and Vaccines 🔊 Before 🔊 🔊 🔊 🔊 🔊 🔊 the discovery stage, there’s a pre-discovery stage where you make literature searches and you understand the disease itself. In pre-clinical research, you do laboratory testing. In-vitro screening by using cell lines enzymes, and chemical tests to prove the chemical activity of your drug In-vivo screening may use animal testing to substantiate the result of the in-vitro testing In this stage, effectivity is being tested and can set the effective dose for your drug of choice or preliminary result for its safety. Before proceeding to clinical trial, pre-clinical test results must be submitted first to the INDA or Investigational New Drug Application Formulation must be optimized at the end pre-clinical trial. ADALLA, DENOSTA, GEROLAGA, MAGALUED, MORATA After formulating the Lagundi and Sambong, they were scaling up to a manufacturing scale. At that time, not a lot of local pharmaceutical companies manufactured herbal medicines. There used to be a pilot plan (8304) from the DOST project where they manufacture for clinical trials. The project that was conducted in the University of the Philippines - College of Pharmacy was given the code 7901. The clinical trials of Lagundi and Sambong took place until the 1990s until such time that all trials passed, and they submitted the necessary documents to turn it into a product. They applied for a utility model, and a company pitched to them to work on the Lagundi syrup as well as Sambong. 2 🔊 The diagram above shows how the stages of preformulation and formulation studies come into play in terms of drug discovery and drug development 🔊 In lead optimization, you choose the compound from a formulation or manufacturing perspective. In drug development, this is where you determine with the help of the result of in vivo (animal studies) screening in terms of determination of effective dose, as well as the lethal dose. 🔊 There are researches that provide reference on how to provide an estimated dose for humans based on the one given to animals during in vivo studies. This depends on the type of animal involved in the study. DRUG DEVELOPMENT Figure 2. The new drug development process of a new chemical entity from discovery through preclinical and clinical studies, FDA review of the NDA, and postmarketing activities 🔊 Before proceeding to clinical studies, all of the 🔊 🔊 🔊 tests must be submitted to the Investigational New Drug Application (INDA) and will be then further reviewed by the FDA. After correlating the pre-clinical trials to the clinical trials, it can now be submitted for application to the New Drug Application (NDA). There are a lot of reviews to be conducted, which is why developing a new product may take years. After passing the NDA, it can now be marketed provided that continuous monitoring is conducted. DRUG DISCOVERY Figure 4. Preformulation studies at various stages of development. 🔊 In Preclinical studies, while the clinical trial is going on, there are developments that occur in the formulation. 🔊 Volunteer Studies is the stage wherein we look for human subjects to determine the best formulation (for volunteer study). You base on the characteristics of your subjects to find what will best fit for the drug to be formulated. 🔊 In Phase II, findings from Phase I will be considered to have an idea whether the dosage must be adjusted or not. 🔊 Based on the results of Phases I and II, the focus will now be on the aspect of adjusting the Figure 3. Early stage preformulation studies. ADALLA, DENOSTA, GEROLAGA, MAGALUED, MORATA 3 formulation to its best form in order to launch for scale up. 🔊 🔊 Preformulation and formulation studies are parallel in the drug development process. While you are performing tests, you are also developing the dosage forms. 🔊 🔊 PREFORMULATION STUDIES Solubility Solubility profile of the API so that we can create the dosage form that is easiest to formulate There are a lot of considerations in deciding the appropriate dosage form. Ex.: if the API is stable in all conditions, has little to no taste, you might consider formulating it into a solution. For the drug to elicit therapeutic activities inside the body, the drug must be rendered in solution for it to be absorbed in the systemic circulation. Dissolution If the solubility is the problem, you need to consider where else it could be dissolved (dissolution) What enzymatic juices will interact with the fdrug that can aid or inhibit the drug to dissolve further? You should not include ingredients that will precipitate inside the body Partition Coefficient In dissolution, another problem occurs where in the medications might be distributed to different parts of the body Partition of the drug may occur Crystal Form Amorphous vs crystalline; the disorderly manner (amorphous) and the lattice formation (crystalline) has something to do with the drug release of a certain drug. Drug and Drug Product Stability Other properties (e.g. moisture uptake) 🔊 🔊 Precipitates will show in our solution and we don’t want that. Some solutions are very dependent on temperature in a way that their solubility increases with temperature. Ex. Some preservatives such as Methylparaben and Propylparaben do not dissolve in room temperature, and will only dissolve in heated or warm environments. Calcium compounds have an inverse relationship between solubility and temperature, it becomes less soluble in warmer temperatures, and more soluble in lower temperatures.. We have to take note of these concepts as we would want to retain the solubility of a solution. 🔊 NOTE 🔊 🔊 🔊 🔊 🔊 🔊 The solubility of an API is dependent on the quantity of the API added and the temperature when the API was added. We always have to render those in solutions; otherwise, when we change the temperature and concentration, the solubility of the API may be affected. 🔊 Water-soluble and Oil-soluble ingredients These will determine how we will formulate our dosage forms. We combine oil-soluble ingredients with oil and water-soluble ingredients with water. These are the case when preparing emulsions as we do not combine ingredients that are not miscible with each other, we need to combine ingredients with the same polarity first. Intermolecular Forces of Attraction (IMFAs) also has an application when formulating dosage forms, but will be more focused when solid dosage forms are to be discussed. SOLUBILITY The concentration of solute in a saturated solution at a certain temperature We are dealing with how saturated is the content of a particular API within the solvent we are using. Once it exceeds the saturation point, the solution precipitates out, supersaturation. 🔊 🔊 ADALLA, DENOSTA, GEROLAGA, MAGALUED, MORATA 4 🔊 🔊 Figure 5. Solubility Descriptive Terms (USP) Solubility decreases when the denominator increases, the substance then becomes more insoluble. Absolute (Intrinsic) Solubility ○ Saturation point of an API that when exceeded, the API starts to precipitate. ○ Very pH-dependent Solubility of the uncharged drug molecule (unionized) of the drug compound. ○ Includes salicylic acid because it is unionized; but does NOT include sodium salicylate because it is ionized. Provide insight into the state of the drug substance as it is subjected to a variety of different pH environments. For weak acids, when we make the pH of the medium lower (acidic) and place the weak acid drug, the drug will precipitate out in acidic medium. If pH is less than pKa, the weak acid would precipitate. NOTE For weak bases, when we make the pH of the medium higher (basic) and place the weak basic drug, the drug will precipitate out in basic medium. If pH is greater than pKa, the weak base would precipitate. drugs must be in basic medium to be rendered in a solution. Molecular dissociation, pKa ○ Degree of ionization ○ Henderson-Hasselbalch Equation: pKa = pH + log[HA] / [A-] Solubility in other solvents ○ Useful for choice of excipients and the dosage form ○ Though water is the most commonly used solvent, there are still other options that can be used; however, we must still observe and follow the “Generally Recognized As Safe” (GRASS) Water & Ethanol (at a certain level): GRASS level 1 Ethyl Acetate, Methanol: GRASS level 3. PARTITION COEFFICIENT A measure of the unionized drug distribution between an aqueous and an organic phase at equilibrium. Analogy: When facebook was launched, people signed up for it and when twitter came, some people moved to twitter and this created a dispersion. Body fats absorb other APIs and help alleviate the side effects of other drugs. Sometimes fats are essential in enhancing the activity of a certain drug (e.g. Griseofulvin: antifungal agent) Based on the Nernst Distribution Law. [solute] oil phase / [solute] aq phase = K When the value of K is around 2, it is more soluble in oil When the value of K is around 0.2, it is more soluble in water Use of n-octanol (simulated lipid) 🔊 🔊 🔊 🔊 The pH should be equal to the pKa to prevent the drug from precipitating out. 🔊 Basic drugs must be in acidic medium to be rendered in a solution, then Acidic ADALLA, DENOSTA, GEROLAGA, MAGALUED, MORATA 5 🔊 Emulsion - milky in appearance, water and oil do not mix but we know that it is stable because it is being stabilized by an emulsifying agent. 🔊 The problem here is that preservatives are both soluble in water and oil. What happens is that when you mix preservative with oil and water it tends to distribute to the oil phase and aqueous phase of the emulsion 🔊 What happens to the preservation action: the oil phase won’t be prone to microbial attacks but the aqueous phase would be susceptible to it. The preservation of water is lower compared to other solvents. Figure 6: Use of n-octanol (simulated liquid) to check for partition coefficient 🔊 Best example of experiment to check for the partition coefficient of a certain weak electrolyte or weakly basic or weakly acidic drug Because the weak electrolyte is now distributed in n-octanol, the result will show that the content of weak electrolyte in water is low. The ability of the drug to transfer across membranes can be highly dependent on its capacity to partition into and cross lipophilic substrates, e.g. components of cell walls. 🔊 PARTITIONING Partitioning is the movement of molecules from one phase to another. Two immiscible liquids: oil and water Weak electrolytes are both soluble in oil and in water. When mixed in water, and shaken with oil, there are contents of weak electrolytes in the oil phase and contents in the aqueous phase will be reduced, that is partition coefficient. Useful when preparing for emulsions, especially when you place preservatives in an emulsion. Liquid dosage forms need preservatives as they are prone to microbial attack so they are needed to be preserved. 🔊 🔊 🔊 CRYSTAL FORM Chemical compounds can exist in different forms depending on their chemical composition and method of isolation or crystallization → exhibit polymorphism. 🔊 If you have a different lattice arrangement of the same active pharmaceutical ingredient, it does not have the same fate or absorption because crystalline solid melts longer than amorphous solid. Polymorphism are chemical entities, including pharmaceutical agents, that may exist in more than one crystalline structure. ○ Chloramphenicol has a lot of polymorphs. And there’s only one polymorph of Chloramphenicol that is pharmacologically active. Usually, the beta polymorph of Chloramphenicol is used. 🔊 You may have one compound but it consists of different polymorphs. They have different melting points and this is essential in determining which of the polymorphs are suitable to use as formulation for dosage forms. 🔊 You’ll now be able to ensure that we get 100% reservation for solutions because you still meet the required amount of preservation action of your preservative, that will be a problem when you formulate it into an emulsion ADALLA, DENOSTA, GEROLAGA, MAGALUED, MORATA Figure 7. Melting Point Ranges of the different polymorphs of cocoa butter 6 Cocoa Butter - suppository base - contains around more than five (5) polymorphs and exhibits varying melting points. It has to melt at room temperature and normal body temperature. B1 is best suitable because it is the closest to a human's normal body temperature. 🔊 Cocoa butter is extracted from the seed of Theobroma cacao, the ingredient used to make chocolate is the same component used to make a suppository base. Different polymorphic forms may possess very different physicochemical characteristics, such as solubility, melting point, optical properties, etc., which can significantly affect the drug bioavailability and stability 🔊 Bioavailability: Measures the rate and extent of absorption. One example of stability is the selection of B1 polymorph of cocoa butter because it is the best suppository base and it will prevent you from handling suppositories that will melt in your hands, instead it should melt in its appropriate route of administration. Figure 8. Types of Crystals ○ 🔊 Not all polymorphs are pharmacologically active. Excipients are pharmacologically inactive and inert with API and other ingredients in the formulation of a certain dosage form. Desired polymorph: sufficiently stable at room temperature and to define the temperature conditions under which polymorphic change occurs (during manufacture and storage). 🔊 SOLID STATE Crystal Solids ○ The molecules or atoms are arranged in repetitious three-dimensional lattice units infinitely throughout the crystal. ○ There are seven (7) crystal systems. They are defined by the length (a,b,c) and angles (α, β, γ) of the lattice. 🔊 🔊 ADALLA, DENOSTA, GEROLAGA, MAGALUED, MORATA Types of Crystals: 1. Cubic (exhibited by sodium chloride) 2. Rhombohedral (exhibited by iodine) 3. Orthorhombic (exhibited by Ritonavir form 2) 4. Tetragonal (exhibited by urea) 5. Hexagonal (exhibited by iodoform) 6. Triclinic (exhibited by Boric acid) 7. Monoclinic (exhibited by sucrose, Ritonavir form 1) They are being classified based on their nature as crystalline solid. When dissolved in water, it also affects the solubility of a certain crystalline solid because lattice arrangement should be broken down first before they get dissolved in an appropriate solvent. Amorphous Solids ○ Solid material is referred to as amorphous when there is no long-range order over many molecular units to produce a lattice or crystalline structure. Disorderly manner, no lattice arrangement. Powders are classified as amorphous solids, no defined lattice arrangement, thus they are easily dissolved in water. Importance of differentiation between crystalline solid and amorphous solid: 7 ○ Ex. Insulin can be either crystalline or amorphous. This will determine the administration of either a long-acting effect/slow onset vs short-acting effect/rapid onset. Because amorphous insulin has a disorderly manner, it's usually used for rapid onset. On the other hand, crystalline insulin is used for longer duration of action. ○ 🔊 To determine the shelf life of the product and to ensure the patient’s health and safety (correct dose, no toxic substance) Best explanation as to why we should ensure the stability of a drug or drug product is due to the care for the patient’s health and safety. We ensure that over a given period of time, we still have the correct dose and there is no significant production of toxic substances. There is NO such thing as “Bad Quality.” NOTE Figure 9. Molecular Properties of Crystalline and Glass (Amorphous) Solids ○ Insulin - can be crystalline or amorphous depending on the effect you want (rapid onset (amorphous) or short onset (crystalline)) Polymers (can act as pharmaceutical excipients to render stability of API) ○ Large molecules formed by the covalent assembly of smaller molecules (monomers) into a chain or network of repeating structural units. ○ The number of repeating units in the polymer (n subscript on the repeat unit) determines its size and molecular weight Those polymeric chains are used in order to ensure the stability of API by the time it is being formulated as dosage forms. A chain or network of repeating structural units, which is also why their chemical composition is “n = #” It is dependent on number, size, and molecular weight. Polymers are able to function as a binder due to their capability to glue the ingredients together. If a polymer acts as a suspending agent, it coats the active ingredient so that it doesn’t go down to the bottom of the container immediately. Quality indicates a positive word where a drug or product meets standards according to what is being set in the indicated specifications for that certain product. 5 CONCERNS OF STABILITY 🔊 🔊 🔊 🔊 🔊 🔊 DRUG AND DRUG PRODUCT STABILITY 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. ADALLA, DENOSTA, GEROLAGA, MAGALUED, MORATA Chemical: Each active ingredient retains its chemical integrity and labeled potency within the specified limits. Ex: The solutions being titrated must always be within the range of the official requirement given. Presence of degradation product We need to ensure that over a given period of time, it still meets the limit or minimum value of a certain presence of a degradation product. If it exceeds, then it indicates a failure in terms of its stability. Physical: The original physical properties, including appearance, palatability, uniformity, dissolution, and suspendability are retained. ○ Change in physical characteristics is also a change in chemical change involved This signifies that adjustments have taken place; change of color may mean a failure in assay or exceeded value of degradation. ○ Palatability includes the taste feel of the drug (ex.: is it still pleasing to the mouthfeel or is it gritty), changes may indicate changes in the product (one indication that it is unstable). Microbiologic: Sterility or resistance to microbial growth is retained according to the specified requirements specified limits. ○ Sterility is the absence of viable microorganisms 🔊 8 Therapeutic: The therapeutic effect remains unchanged. ○ Ex. a large molecule antibiotic on top of the assay is supported with antimicrobial assay. (ex.: Streptomycin, categorized as one the macrolides, requires an additional antimicrobial susceptibility test since it is a large molecule). ○ Antimicrobial susceptibility test - if the Minimum Inhibitory Concentration (MIC) does not have the same desired value (meaning the antibacterial activity has lessened), it fails the therapeutic aspect. Toxicologic: No significant increase in toxicity. 🔊 The only zero-order type of reaction for degradation are products that are formulated as suspensions. DRUG AND DRUG PRODUCT STABILITY DETERMINING STABILITY 🔊 🔊 Determine the conditions under which the drug or product undergoes degradation. ○ Prevent degradation and provide methods to stabilize the product (changing formulations when necessary) ○ Determine limitations in shelf life (expiry and stability) When the drug is exposed to stressed conditions, determined shelf life may still change. Ex.: Drug labels that indicate ‘must not be stored in temperature exceeding 30°C is under the context that during the drug stability testing, when subjected to stressed conditions, significant changes have taken place. ○ Determine storage conditions (exposure to air or light and use of appropriate container) Based on ASEAN Guidelines, what you want to achieve during stability testing is to determine the conditions under which the drug or product goes under degradation. This is where chemical kinetics come into play; chemical kinetics is used to determine degradation in terms of degradation of the product outside the body, as well as degradation once administered inside the body. Drug stability is learned to ensure that degradation is being prevented by providing methods to stabilize the product. RATE REACTIONS Drug concentration over time Zero-order, first-order reactions (common) ○ Order of reaction for most drug substances ADALLA, DENOSTA, GEROLAGA, MAGALUED, MORATA Degradation mechanism (chemical, physicochemical, biological) ○ Hydrolysis ○ Isomerization ○ Oxidation ○ Polymerization ○ Solid-state phase transformation ○ Dehydration or desolvation ○ Cyclization ○ Photolytic degradation ○ Microbial attack STABILITY CONDITIONS/STRESS CONDITIONS TESTING 🔊 🔊 Stability Conditions / Stress Conditions Testing ○ Based from: 1. ASEAN Guideline on Stability Study of Drug Product 2. International Conference on Harmonization of Regulatory Requirements (ICH) Drug stability test guideline Q1A (R2) In some cases, the following tests are preliminary tests wherein the product is not yet in its final form: ○ Chemical degradation ○ pH-dependent stability ○ Photostability Subject it to light; simply expose it to the sun/artificial light/dark region ○ Oxidative stability ○ Stability-Compatibility studies ○ pH-different buffers Exposure to atmospheric oxygen Temperature conditions: 40m 60, 80 Humidity conditions 25℃, 85% RH 40℃, RH *Stability/oven chamber These are done before mixing with other ingredients and are commonly done to natural products such as plants. Phytochemical screening is performed. Because it would help determine what are the present constituents in the plant. Literature search should be done next. 9. OTHER PROPERTIES Hygroscopicity ○ Capability to absorb and desorb water depending on their chemical and physical state ○ Hygroscopic, Deliquescent, Efflorescent Hygroscopic substances such as NaOH absorb moisture but DO NOT dissolve. Deliquescent substances such as Ca(OH)2 absorb moisture AND get dissolved. Efflorescent substances are related to the water of hydration. Powder properties ○ Flowability → the ability of powdered material to flow. ○ Compressibility → the ability of a powdered material to be compressed. These properties are essential to be checked for the formulation of tablets and capsules as we will be able to determine how much anti-frictional agents must be added to aid in the flowability of the sample. It also allows us to know if we should do granulation methods to improve the flowability and compressibility of the material. When we convert powders to granules, we improve compressibility and flowability. 🔊 🔊 🔊 🔊 🔊 🔊 🔊 🔊 🔊 NOTE Powders stick on the inner walls of equipment, they are difficult to moisturize due to their small particle size, and poor compressibility and flowability. Powder alone will not be able to be compressed into a tablet because its flowability will clog the tableting machine. 🔊 Melting Dosage forms that are meant to be melted (e.g. suppositories, sublingual tablets, oral dispersible tablets) all have certain melting ranges that should be observed to ensure that the drug gets released from the dosage forms. EXCIPIENTS ADALLA, DENOSTA, GEROLAGA, MAGALUED, MORATA Excipients ○ Inactive ingredients, at all times ○ Comprise of all ingredients except the active pharmaceutical ingredients (API) Excipients vary based on the different types of dosage forms. Excipient are a major component of almost all drugs, as well as foods, cosmetics, and dietary supplements (90%) Excipients functions ○ Stability and bioavailability of the API ○ Drug product’s manufacturability It is easier to develop a dosage form rather than maintaining your API/powder alone as a product. In order for the manufacturability of a product to increase, there must be the presence of excipients. ○ Appearance, texture and taste We can not be able to swallow powder alone. As syrups and suspensions, we need flavorants and sweeteners to mask the initial bitter taste of powders. EXCIPIENT PROPERTIES Physiologically inert Physically and chemically stable Free if any bacteria or other microorganisms considered to be pathogenic or otherwise objectionable. There are normal microbiota which are good bacteria that aid in digestion. There are microorganisms that are pathogenic which are not desired in our formulation. Must be compatible with the API. Must not interfere with the bioavailability of the drug. Must be commercially available in form and purity commensurate to pharmaceutical standards. If an API is of pharmaceutical grade, we must match the grade of the excipients as well to ensure the safe quality. When we formulate suspensions, there are many ingredients to consider in liquid dosage forms such as preservatives, suspending agents, viscosity agents, sweeteners, flavorants, buffering agents. In making formulations, we consider adding less ingredients as possible, because 🔊 🔊 🔊 🔊 🔊 10 when we add more ingredients, the risk of incompatibility increases which increases the risk of the drug not eliciting its full therapeutic activity. Must be relatively inexpensive. When we choose suitable excipients for a certain API, we have to consider its cost-effectiveness. An excipient that is expensive but multifunctional could be an example of it Sometimes, when formulating tablets, we have to consider cheaper options such as lactose and starch, which are common excipients that are being used for one of the tablet components for compression of tablets. 🔊 DISSOLUTION AND ABSORPTION OF API 🔊 Dissolution is the process in which a substance forms a solution [USP, NF] Dissolution testing measures the extent and rate of solution formulation from a dosage form, such as tablet, capsule, ointment, etc. Rate at which a drug or excipient dissolves in any particular medium. Given an appropriate solvent, buffer, or media, we can ensure that an API will be dissolved, while the remaining undissolved substances are the other excipients that can not be dissolved in the solvent. Several factors affect the dissolution rate in the body ○ Biological fluid system pH-dependent ○ Agitation When we increase the agitation rate, the dissolution rate will increase as well. ○ Particle size Smaller particle size increases the surface area, causing an increase in dissolution rate. Particle size reduction aids in dissolution. ○ Wettability Wetting agents are placed in suspensions to aid in dissolution of the API inside the body. An increase in wettability means high dissolution rates. ○ Porosity 🔊 Dissolution → process of solution formation ○ Drug particles → solution ○ Prerequisite for absorption for certain dosage forms. A drug will NOT be absorbed if it is NOT in solution. DISSOLUTION Bigger pores mean that the liquid diffuses easier; therefore, it solubilizes easier. Dissolution model (in vitro dissolution) ○ USP Dissolution Apparatus II (Paddle) NOTE Its rate and extent of absorption will be reduced if it is not completely rendered as a solution. Dissolution is the rate-limiting step of absorption. If the dissolution of a drug is slow, then the absorption will be slow as well. API Properties influence on dissolution ○ Solubility ○ pKa ○ Partition coefficient ○ Surface area ○ Particle size ○ Salt formation 🔊 🔊 🔊 🔊 🔊 🔊 ADALLA, DENOSTA, GEROLAGA, MAGALUED, MORATA 11