PHARM 130 First Exam PDF

PHARM 130 Lec: Pharmaceutics 1 INTRODUCTION TO PHARMACEUTICS Professor Ethel Andrea C. Ladignon Week # 1 (January 30, 2024) OUTLINE 🔊 Aside from ensuring effective and safe...

PHARM 130 Lec: Pharmaceutics 1 INTRODUCTION TO PHARMACEUTICS Professor Ethel Andrea C. Ladignon Week # 1 (January 30, 2024) OUTLINE 🔊 Aside from ensuring effective and safe delivery through compounding, APIs should also be rendered stable. Pharmaceutics Pharmaceutics is the discipline of pharmacy Areas of Pharmaceutics that deals with the science of dosage form Biopharm vs Physical Pharm design and embraces all facets of the process Good Compounding Practices of turning a new chemical entity (NCE) into a [USP-NF] Compounding medication that can be safely and effectively Why do we perform compounding? used by patients in the community. [University Pharmaceutical Compounding - Nonsterile of Mississippi, Department of Pharmaceutics 🔊 Preparations and Drug Delivery] [USP Chapter 795] For as long as you have a drug and you Categories of Compounding make it into a drug delivery system, the safety and efficacy of a drug are more Compounder ensured. Compounding Facilities ○ Ex. Paracetamol powders alone will not Compounding Equipment ensure you the delivery of accurate dosing. Component (Ingredients) It will be delivered more accurately if it is Stability Criteria and Beyond - Use Dating (BUD) properly compounded into a dosage form. General Guidelines For Assigning Bud Pharmaceutics is a multidisciplinary science Packaging And Drug Preparation Containers that examines the development, production and Quality Control characterization of dosage forms, as well as the disposition and action of drugs in the body. 🔊 [University of Iowa, College of Pharmacy] PHARMACEUTICS It is a multidisciplinary science because it is Pharmaceutics refers to the wide range of not just one topic, it’s not only about the subject areas that are all associated with the preparation of drug delivery systems, steps to which a drug is subjected towards the instead, we also look into the formulation end of its development. [Aulton's design and the pharmacokinetic design Pharmaceutics] (what the body does to the drug). You also have to study the stability of a certain API when it is formulated into a drug delivery 🔊 system. 🔊 APIs may be made up of powders or oils, The 500 mg does not entirely go to the site of action (or target site) as parts are sometimes it's very hard for us to deliver also consumed in different areas of the the powder itself. If powder is ingested, it’s 🔊 body depending on the API. not pleasing and will lead to a gritty feeling There is a certain plasma concentration to the mouth of the patient. Moreover, the required to elicit the pharmacologic activity assurance of delivery of accurate dose is 🔊 of the drug. uncertain. This is why drugs are formulated Pharmacokinetic design is important to step by step to a drug delivery system to be determine the frequency of drug intake effectively and safely taken by the patient. because it relies on the established results of the drug’s pharmacokinetic design. ADALLA, DENOSTA, GEROLAGA, MAGALUED, MORATA 1  🔊 Absorption, Distribution, Metabolism, Physical Pharmacy Excretion (ADME) ○ Area of pharmacy that deals with the quantitative and theoretical principles of physicochemical science as they are applied to the practice of pharmacy AREAS OF PHARMACEUTICS ○ Basic physical chemistry necessary for the 🔊 effective design of dosage forms It is about how you relate the physicochemical properties in the application or preparation of the dosage 🔊 form. It is beneficial to know the physical and Dosage Form Design chemical attributes or properties of APIs ○ Design and formulation of medicines so that it is easier to formulate or Compounding 🔊 compound stable dosage forms. 🔊 ○ Preparation of medicines on a small scale Chemical Kinetics can be used to It is wrong if the statement is “We will establish the shelf life of a certain compound 100 kilos of paracetamol product leading to establishing the tablets”. expiration date of the product. Pharmaceutical Manufacturing ○ production of medicines on a large scale Biopharmaceutics (commercial use) ○ Examines the interrelationship of the Product Performance Testing physical/chemical properties of the drug, ○ Evaluation of medicines based on its design the dosage form in which the drug is given, 🔊 specifications and intended use and the route of administration on the rate Also known as Quality Control Testing. 🔊 and extent of systemic drug absorption. You look into the appearance of the Basis to decide what type of dosage product, taste, feel, odor, and other form shall be formulated for a certain physical characteristics by testing purity, 🔊 API density, and thickness (suspension or It simply talks about the liberation solution). You have to evaluate its process and absorption. 🔊 microbial limits. ○ Liberation process refers to the Ex. You are taking a solution that is release of the drug into the body supposed to be green and you happen from the formulation it is delivered to take it red, this means there’s a 🔊 in. problem in the preparation, thus, it has Study that determines the confirmatory to be prepared again to pass the design test and decision factor to be able to 🔊 specifications. find out the suitable dosage form for a Your aim when you compound or certain drug/API. formulate dosage forms is to eliminate 🔊 microorganisms in medicines. BIOPHARM VS PHYSICAL PHARM There are some formulations/dosage forms that require preservatives. PHYSICAL Usually if there’s a presence of a liquid BIOPHARMACEUTICS PHARMACY component or ingredient, it is required to have a preservative because liquids - Occurs in the body - looking into the are prone to microbial attack and this is and involves the physical and where microorganisms thrive in the body’s activity to chemical preparation that might disrupt the the drug. properties of API stability of the product. - Considers the fate and dosage form Pharmaceutical Microbiology of the drug once it is itself ○ Prevention and elimination of administered in the microorganisms in medicines ADALLA, DENOSTA, GEROLAGA, MAGALUED, MORATA 2  body BUT up until [USP-NF] COMPOUNDING ABSORPTION. [USP NF] Compounding includes the following: Preparation of drug dosage forms for both 🔊 human and animal patients. Patient-specific medications can also be prepared for animals/veterinary patients ○ Ex. Tablets for pets are best administered GOOD COMPOUNDING PRACTICES on the skin (given that the pet has skin [RA 10918] infection). Medicine was prepared as a ○ Compounding refers to the sum of paper tab to limit the amount applied on the processes performed by a pharmacist in skin as required by the veterinarian. drug preparation including the calculations, Preparation of drugs or devices in anticipation mixing, assembling, packaging, or labeling of prescription drug orders based on routine, of a drug: regularly observed prescribing patterns. (i) As the result of a prescription or drug Reconstitution or manipulation of commercial ordered by a physician, dentist or products that may require the addition of one or veterinarian. 🔊 more ingredients. (ii) for the purpose of, in relation to, Some medications may require addition research, teaching, or chemical of flavoring or sweetener to counter the analysis. 🔊 unpleasant taste of the drug. [USP - NF] By simply adding a vehicle (water) to a ○ Compounding is the preparation, mixing, powder suspension, that is already assembling, altering, packaging, and considered as compounding. labeling of a drug, drug-delivery device, or Preparation of drugs or devices for the device in accordance with a licensed purposes of, or as an incident to, research practitioner’s prescription, medication order, (clinical or academic), teaching or chemical or initiative based on the practitioner/ analysis. patient/pharmacist/compounder relationship Preparation of drugs and devices for in the course of professional practice. prescriber’s office use where permitted by ○ Patient-specific medications (vs federal and state law. 🔊 manufacturing). Patient-specific medications refer to WHY DO WE PERFORM COMPOUNDING? medications found in the prescription or Drug dose and dosage forms are not physician’s order. commercially available. ○ Ex. Called for paper tabs of Sildenafil citrate Patients are allergic to excipients in which is a hypertensive agent– medicine is 🔊 commercially available products. for a pediatric patient that can not consume Ingredients are explicitly stated in high doses of sildenafil citrate, which is why packaging to inform consumers of paper tabs are necessary to adjust the potential triggers for allergic reactions. dose. Children’s medications must be prepared as ○ Patient-specific medications are for a liquids, flavored to enhance compliance, and particular patient only. prepared in alternative dosage forms such as ○ Patient-specific medications are small-scale lollipops, jellies, etc. only; also known as extemporaneous Some medications are not very stable and compounding wherein medications are require preparation and dispensing every few 🔊 freshly prepared by order. days. Manufacturing pertains to medicines Many drugs are reported in the literature but packaged in boxes, bottles, blister are not manufactured yet, so pharmacists can packs etc. that have undergone compound them for their physicians’ and production. patient’s use. ADALLA, DENOSTA, GEROLAGA, MAGALUED, MORATA 3  Many physicians desire to deliver products in Requires special calculations or procedures innovative ways and pharmacists can work with to determine the quantities of components them to solve medication problems. per preparation or per individualized dosage 🔊 Most products not available for veterinary units 🔊 patients must be compounded. Ex: Paper tablets They need adjustments in their dose 🔊 PHARMACEUTICAL COMPOUNDING - (lower via diluent) NONSTERILE PREPARATIONS Anything that has something to do with [USP CHAPTER 795] adjustment of dose and calculations. Categories of Compounding Stability data are not available, we do not Responsibilities of the Compounder need them. Compounding Process Complex Compounding Compounding Facilities Requires special training and environment Compounding Equipment facilities, equipment, and procedures to 🔊 Component Selection, Handling, and Storage ensure appropriate therapeutic outcomes. Ex: Sterile preparations such as Total 🔊 Stability Criteria and Beyond-Use Dating (BUD) Knowing about BUD allows us to know what Parenteral Nutrition (TPN). TPN is given our product should look like by the time we to patients who can not take food orally, do something. its content such as food, nutrients, etc. is administered intravenously (IV) and is 🔊 Packaging and Drug Preparation Containers 🔊 Suitable preparation containers since we directed to the digestive tract. would want to maintain the stability of a Sterile preparations can’t be prepared if 🔊 reagent over a long period of time. you are not trained properly. Ex: Radiopharmaceuticals as having 🔊 Compounding Documentation Documentation allows us to know at which lack of facilities, PPE, training, could point we stopped while doing a process, harm the compounders and even the what to do next, future plans. surrounding environment. 🔊 Quality Control Each dosage form renders differently from COMPOUNDER each other; hence their difference in quality Compound preparations of acceptable strength, control tests. quality, and purity and in accordance with the 🔊 🔊 Patient Counseling prescription or medication Knowing the science behind the preparation They cover prescription orders the of each dosage form is essential for patient most. counseling Adhere to the General Principles of Training Compounding Compounding for Animal Patients Dispense the preparation Must be proficient in compounding (training). CATEGORIES OF COMPOUNDING Must continually expand compounding Simple Compounding knowledge by participating in seminars or USP compounding monograph or studying appropriate literature. peer-reviewed journal with all specifications Maintain good hand hygiene and wear clean (ingredient, equipment, BUD) clothing appropriate to the type of compounding Reconstitution or manipulation of performed (proper lab attire). commercial product is directed by the COMPOUNDING FACILITIES 🔊 manufacturer Ex: Addition of water or shaking of a Adequate Space specifically designed for 🔊 🔊 bottle containing powder compounding of prescriptions Whatever is written in the prescription is To ensure that you prevent to be followed without any adjustments contamination, and having not enough in terms of volume, concentration space makes it not that conducive for Moderate Compounding compounder ADALLA, DENOSTA, GEROLAGA, MAGALUED, MORATA 4  🔊 Orderly placement of equipment and materials it cannot be ensured that the delivered It is sequenced step by step to prevent dose is complete because the potency 🔊 🔊 contamination would be low If not orderly mannered, unwanted Indications that it is not safe: molds, components may spill to the product changes in physical characteristics (e.g. 🔊 Well lighted, properly ventilated color) To increase productivity and aids in Components with no expiration dates 🔊 airflow in the facility ○ Assign a date of receipt Humidity may affect products that are ○ Assign a conservative expiration date 🔊 sensitive with moisture based on the nature of the component (max There are products that are 3 years) light-sensitive so know how to protect STABILITY CRITERIA AND BEYOND - USE them DATING (BUD) Potable water supply (hand and equipment Beyond-Use Date (BUD) - date after which a washing) compounded preparation SHALL NOT BE Purified water supply (formulation, rinsing, of USED and is determined from the date when equipment and utensil) 🔊 the preparation is compounded. Shelf life of compounded materials are COMPOUNDING EQUIPMENT 🔊 short Appropriate design and capacity When we do compounding, it is for Surfaces that contact the product components specific patients are neither reactive, additive, nor sorptive. Routinely inspected and calibrated Considerations in assigning BUD: Must be appropriately cleaned after use ○ Nature of the drug and its degradation 🔊 Dedicated equipment for preparations that mechanism require special precautions (or use disposable Ex. Aspirin: moisture sensitive, 🔊 ones to reduce contamination bio-burden) hydrolyzed into salicylic acid and acetic Plastic components in the equipment acid, “nangangasim”, it contacts present must be cleaned regularly, especially if moisture in the air, thus, it should not be it is contacted with liquid or semi solids, compounded with material that is prone even if rinsed with water, if not wiped off to absorption of moisture or dried properly, it will leave a foul ○ Dosage form and its components smell and biofilm (brown deposits) ○ Potential for microbial proliferation ○ Container in which it is packaged COMPONENT (INGREDIENTS) USP, NF, or FCC (Finished Compounded Some containers are incompatible with 🔊 Components) materials for compounding preparations Must have present expiration date both for API and excipients Basic solutions should not be stored Components with expiration date in the in glass containers as it can leech and container NOTE cap can lock in, use polyethylene ○ Can be used provided it is in the original bottles container, minimal exposure occurs every Organic solvents should not be time a material is withdrawn, and stored in polyethylene bottles as it may withdrawals are done by authorized, dissolve the bottle, use glass trained, personnel. containers ○ If transferred, it must be assessed to contain the component in the same or 🔊 ○ Expected storage conditions 🔊 better integrity. Reconstituted suspensions become Yes, it is safe to take a drug that is less stable so it should be refrigerated beyond the expiration date, HOWEVER, to maintain stability. ADALLA, DENOSTA, GEROLAGA, MAGALUED, MORATA 5  🔊 ○ Intended duration of therapy Should not compound too much or too little, it has to be well calculated so that we will only get the amount needed for a certain period of time for a particular patient. GENERAL GUIDELINES FOR ASSIGNING BUD In the absence of stability information to drug or preparation BUD by type of formulation ○ Non-aqueous formulations Not less than (NLT) the expiration of any API or 6 months, whichever is lower. ○ Water-containing oral formulations NLT 14 days when stored at controlled room temperature. ○ Water-containing topical/dermal and mucosal liquid and semisolid formulations NLT 30 days. PACKAGING AND DRUG PREPARATION CONTAINERS Appropriate container and container closures must be used. Container should not alter the quality, strength, or purity of the compounded preparation (no container-drug interaction) QUALITY CONTROL Compounding controls ○ Documentation ○ Verification of critical step ○ Guidelines for checking tests of product characteristics (e.g. weight) ADALLA, DENOSTA, GEROLAGA, MAGALUED, MORATA 6 PHARM 130 Lec: Pharmaceutics 1 PHARMACEUTICAL AND FORMULATION CONSIDERATIONS Professor Ethel Andrea C. Ladignon February 2, 6, 13, 2024 Protect the drug from degradation after oral OUTLINE 🔊 administration Sometimes it is not enough for the drug to Reasons Why We Make Dosage Forms be formulated as a tablet, it needs an Pharmaceutical and Formulation Considerations additional layer–render it as enteric-coated Preformulation Studies so that it is protected from enzymatic juices Development of Drugs and Vaccines and so that it can be disintegrated on its Drug Discovery desired target site. 🔊 Drug Development Conceal unpleasant taste of drugs Preformulation Studies You will never taste the bitter-tasting drug if you formulate it as a dosage form because Solubility suitable flavorants and sweeteners will Partition Coefficient mask certain drugs. Syrups are formulated Partitioning for pediatric patients because it is a Crystal Form sweetener itself. Solid State 🔊 Provide optimal drug action Drug and Drug Product Stability Some drugs require modified release, if not 5 Concerns of Stability rendered as modified release, it can cause Determining Stability undesired side effects to the patient. Rate Reactions Sustained release helps alleviate side Drug and Drug Product Stability effects but doesn't compromise therapeutic Stability Conditions/Stress Conditions effect. Advantage is less frequency in drug Testing intake. 🔊 Other Properties Provide rate-controlled drug action Excipients Rate-controlled drug action cannot be Excipient Properties ensured by considering API alone, Dissolution excipients are also needed to render the drug controlled in terms of release. Dissolution and Absorption of API Factors that Affect Dissolution Rate in the Body PHARMACEUTICAL AND FORMULATION CONSIDERATIONS API Properties Influence on Dissolution 🔊 Preformulation studies Know first the physical and chemical REASONS WHY WE MAKE DOSAGE attributes of API before mixing with FORMS excipient. Once mixing of API and Provide safe and convenient delivery of excipients are observed, it’s called accurate dosage for the drug formulation studies. Needed for formulation Protect the drug from degradation of newly discovered synthetic compounds, and vaccines and other biological products. 🔊 (humidity, oxygen) 🔊 Those that are prone to experience Drug stability degradation of their API due to humidity and Check stability as API alone, as well as until oxidation can be avoided and eliminated it’s mixed with excipients and formulated as sometimes when formulated as a dosage dosage form and at the same time in the form. packaging material. Pharmaceutical Ingredients and Excipients ADALLA, DENOSTA, GEROLAGA, MAGALUED, MORATA 7  Formulation Factors Affecting the 🔊 Formulation must be optimized at the end 🔊 🔊 In Phase I, we determine the safety and Dissolution and Absorption of API pre-clinical trial. Biopharmaceutics come into play because you need to know the fate of dissolution and dosage. About 70.0% will move to the next 🔊 absorption of a drug because that is the phase. determining factor in deciding the optimum In phase II, we assess if the drug is effective dosage form design for a certain API. and safe (short-term side effects) on human subjects. About 33.0% will move to the next 🔊 PREFORMULATION STUDIES phase. Laboratory studies to determine the In phase III, safety and efficacy to patients characteristics of active substance and (monitoring of adverse reactions). About 25% 🔊 excipients that may influence formulation and to 30% will move to the next phase. If adverse drug reactions arise, this will be 🔊 process design and performance. The idea must always be that the drug reported under pharmacovigilance. formulated will be beneficial to all when produced in a larger scale. DEVELOPMENT OF DRUGS AND 🔊 History of Lagundi and Sambong VACCINES 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 Figure 1. Development of Drugs and Vaccines necessary documents to turn it into a product. 🔊 Before the discovery stage, there’s a They applied for a utility model, and a company pitched to them to work on the pre-discovery stage where you make literature searches and you understand the Lagundi syrup as well as Sambong. 🔊 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 ADALLA, DENOSTA, GEROLAGA, MAGALUED, MORATA 8  🔊 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, Figure 4. Preformulation studies at various stages which is why developing a new product may of development. 🔊 take years. After passing the NDA, it can now be marketed 🔊 In Preclinical studies, while the clinical trial is provided that continuous monitoring is going on, there are developments that occur in conducted. the formulation. DRUG DISCOVERY 🔊 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 9  formulation to its best form in order to launch Precipitates will show in our solution and we 🔊 for scale up. don’t want that. 🔊 Preformulation and formulation studies are Some solutions are very dependent on temperature in a way that their solubility parallel in the drug development process. While 🔊 increases with temperature. you are performing tests, you are also Ex. Some preservatives such as developing the dosage forms. Methylparaben and Propylparaben do not dissolve in room temperature, and will only PREFORMULATION STUDIES 🔊 dissolve in heated or warm environments. 🔊 Solubility Calcium compounds have an inverse Solubility profile of the API so that we can relationship between solubility and create the dosage form that is easiest to temperature, it becomes less soluble in 🔊 formulate warmer temperatures, and more soluble in There are a lot of considerations in deciding lower temperatures.. the appropriate dosage form. Ex.: if the API is stable in all conditions, has little to no We have to take note of these taste, you might consider formulating it into concepts as we would want to retain 🔊 a solution. the solubility of a solution. For the drug to elicit therapeutic activities inside the body, the drug must be rendered The solubility of an API is dependent in solution for it to be absorbed in the on the quantity of the API added and systemic circulation. NOTE the temperature when the API was 🔊 Dissolution added. We always have to render If the solubility is the problem, you need to those in solutions; otherwise, when we consider where else it could be dissolved change the temperature and 🔊 (dissolution) concentration, the solubility of the API What enzymatic juices will interact with the may be affected. fdrug that can aid or inhibit the drug to 🔊 dissolve further? 🔊 Water-soluble and Oil-soluble ingredients You should not include ingredients that will These will determine how we will formulate precipitate inside the body our dosage forms. 🔊 Partition Coefficient We combine oil-soluble ingredients with oil and In dissolution, another problem occurs water-soluble ingredients with water. These are where in the medications might be the case when preparing emulsions as we do 🔊 distributed to different parts of the body not combine ingredients that are not miscible Partition of the drug may occur with each other, we need to combine 🔊 Crystal Form ingredients with the same polarity first. Amorphous vs crystalline; the disorderly Intermolecular Forces of Attraction (IMFAs) manner (amorphous) and the lattice also has an application when formulating formation (crystalline) has something to do dosage forms, but will be more focused when with the drug release of a certain drug. solid dosage forms are to be discussed. Drug and Drug Product Stability Other properties (e.g. moisture uptake) 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 10  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) Figure 5. Solubility Descriptive Terms (USP) Water & Ethanol (at a certain level): 🔊 GRASS level 1 Solubility decreases when the denominator Ethyl Acetate, Methanol: GRASS level increases, the substance then becomes more 3. insoluble. Absolute (Intrinsic) Solubility PARTITION COEFFICIENT ○ Saturation point of an API that when exceeded, the API starts to precipitate. A measure of the unionized drug distribution ○ Very pH-dependent between an aqueous and an organic phase at 🔊 Solubility of the uncharged drug molecule equilibrium. (unionized) of the drug compound. Analogy: When facebook was launched, ○ Includes salicylic acid because it is people signed up for it and when twitter unionized; but does NOT include sodium came, some people moved to twitter 🔊 salicylate because it is ionized. and this created a dispersion. Provide insight into the state of the drug Body fats absorb other APIs and help substance as it is subjected to a variety of alleviate the side effects of other drugs. different pH environments. Sometimes fats are essential in enhancing the activity of a certain drug For weak acids, when we make the (e.g. Griseofulvin: antifungal agent) pH of the medium lower (acidic) and Based on the Nernst Distribution Law. 🔊 place the weak acid drug, the drug will [solute] oil phase / [solute] aq phase = K precipitate out in acidic medium. When the value of K is around 2, it is 🔊 If pH is less than pKa, the weak acid more soluble in oil would precipitate. When the value of K is around 0.2, it is more soluble in water For weak bases, when we make the Use of n-octanol (simulated lipid) NOTE 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. 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 11  🔊 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 Figure 6: Use of n-octanol (simulated liquid) to susceptible to it. The preservation of water check for partition coefficient 🔊 Best example of experiment to check for the is lower compared to other solvents. CRYSTAL FORM partition coefficient of a certain weak electrolyte or weakly basic or weakly acidic Chemical compounds can exist in different 🔊 drug forms depending on their chemical composition Because the weak electrolyte is now and method of isolation or crystallization → distributed in n-octanol, the result will show exhibit polymorphism. that the content of weak electrolyte in water is low. 🔊 If you have a different lattice arrangement of The ability of the drug to transfer across the same active pharmaceutical ingredient, it membranes can be highly dependent on its does not have the same fate or absorption capacity to partition into and cross lipophilic because crystalline solid melts longer than substrates, e.g. components of cell walls. amorphous solid. Polymorphism are chemical entities, including PARTITIONING pharmaceutical agents, that may exist in more Partitioning is the movement of molecules from than one crystalline structure. one phase to another. ○ Chloramphenicol has a lot of polymorphs. 🔊 Two immiscible liquids: oil and water Weak electrolytes are both soluble in oil And there’s only one polymorph of and in water. When mixed in water, and Chloramphenicol that is pharmacologically shaken with oil, there are contents of weak active. Usually, the beta polymorph of electrolytes in the oil phase and contents in Chloramphenicol is used. the aqueous phase will be reduced, that is 🔊 You may have one compound but it consists of 🔊 partition coefficient. different polymorphs. They have different Useful when preparing for emulsions, melting points and this is essential in especially when you place preservatives in determining which of the polymorphs are 🔊 an emulsion. suitable to use as formulation for dosage forms. Liquid dosage forms need preservatives as they are prone to microbial attack so they are needed to be preserved. 🔊 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 Figure 7. Melting Point Ranges of the different into an emulsion polymorphs of cocoa butter ADALLA, DENOSTA, GEROLAGA, MAGALUED, MORATA 12  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 Figure 8. Types of Crystals that will melt in your hands, instead it should ○ Types of Crystals: melt in its appropriate route of administration. 1. Cubic (exhibited by sodium chloride) 🔊 Not all polymorphs are pharmacologically 2. Rhombohedral (exhibited by iodine) 3. Orthorhombic (exhibited by Ritonavir active. Excipients are pharmacologically form 2) inactive and inert with API and other 4. Tetragonal (exhibited by urea) ingredients in the formulation of a certain 5. Hexagonal (exhibited by iodoform) dosage form. 6. Triclinic (exhibited by Boric acid) 7. Monoclinic (exhibited by sucrose, Desired polymorph: sufficiently stable at room 🔊 Ritonavir form 1) temperature and to define the temperature They are being classified based on their conditions under which polymorphic change nature as crystalline solid. When dissolved occurs (during manufacture and storage). in water, it also affects the solubility of a SOLID STATE certain crystalline solid because lattice arrangement should be broken down first Crystal Solids before they get dissolved in an appropriate ○ The molecules or atoms are arranged in solvent. repetitious three-dimensional lattice units Amorphous Solids infinitely throughout the crystal. ○ Solid material is referred to as amorphous ○ There are seven (7) crystal systems. They when there is no long-range order over are defined by the length (a,b,c) and angles many molecular units to produce a lattice (α, β, γ) of the 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: ADALLA, DENOSTA, GEROLAGA, MAGALUED, MORATA 13  ○ Ex. Insulin can be either crystalline or ○ To determine the shelf life of the product amorphous. This will determine the and to ensure the patient’s health and 🔊 administration of either a long-acting safety (correct dose, no toxic substance) effect/slow onset vs short-acting effect/rapid Best explanation as to why we should ensure onset. Because amorphous insulin has a the stability of a drug or drug product is due to disorderly manner, it's usually used for rapid the care for the patient’s health and safety. We onset. On the other hand, crystalline insulin ensure that over a given period of time, we still is used for longer duration of action. have the correct dose and there is no significant production of toxic substances. There is NO such thing as “Bad Quality.” Quality indicates a positive word NOTE where a drug or product meets Figure 9. Molecular Properties of Crystalline and standards according to what is being Glass (Amorphous) Solids set in the indicated specifications for that certain product. ○ Insulin - can be crystalline or amorphous depending on the effect you want (rapid onset (amorphous) or short onset 5 CONCERNS OF STABILITY (crystalline)) Chemical: Each active ingredient retains its Polymers (can act as pharmaceutical chemical integrity and labeled potency within 🔊 excipients to render stability of API) the specified limits. ○ Large molecules formed by the covalent Ex: The solutions being titrated must always assembly of smaller molecules (monomers) be within the range of the official 🔊 into a chain or network of repeating requirement given. structural units. Presence of degradation product ○ The number of repeating units in the We need to ensure that over a given polymer (n subscript on the repeat unit) period of time, it still meets the limit or 🔊 determines its size and molecular weight minimum value of a certain presence of Those polymeric chains are used in order to a degradation product. If it exceeds, ensure the stability of API by the time it is then it indicates a failure in terms of its 🔊 being formulated as dosage forms. stability. A chain or network of repeating structural Physical: The original physical properties, units, which is also why their chemical including appearance, palatability, uniformity, 🔊 composition is “n = #” dissolution, and suspendability are retained. It is dependent on number, size, and ○ Change in physical characteristics is also a 🔊 🔊 molecular weight. change in chemical change involved Polymers are able to function as a binder This signifies that adjustments have taken due to their capability to glue the place; change of color may mean a failure ingredients together. If a polymer acts as a in assay or exceeded value of degradation. suspending agent, it coats the active ○ Palatability includes the taste feel of the ingredient so that it doesn’t go down to the drug (ex.: is it still pleasing to the mouthfeel bottom of the container immediately. or is it gritty), changes may indicate changes in the product (one indication that DRUG AND DRUG PRODUCT STABILITY it is unstable). Stability is the extent to which a product retains Microbiologic: Sterility or resistance to within specified limits and throughout its period microbial growth is retained according to the of storage and use (i.e, its shelf life) the same specified requirements specified limits. properties and characteristics that it possessed ○ Sterility is the absence of viable at the time of its manufacture. microorganisms ADALLA, DENOSTA, GEROLAGA, MAGALUED, MORATA 14  Therapeutic: The therapeutic effect remains 🔊 The only zero-order type of reaction for unchanged. degradation are products that are formulated as ○ Ex. a large molecule antibiotic on top of the suspensions. assay is supported with antimicrobial assay. (ex.: Streptomycin, categorized as one the DRUG AND DRUG PRODUCT STABILITY macrolides, requires an additional Degradation mechanism (chemical, antimicrobial susceptibility test since it is a physicochemical, biological) large molecule). ○ Hydrolysis ○ Antimicrobial susceptibility test - if the ○ Isomerization Minimum Inhibitory Concentration (MIC) ○ Oxidation does not have the same desired value ○ Polymerization (meaning the antibacterial activity has ○ Solid-state phase transformation lessened), it fails the therapeutic aspect. ○ Dehydration or desolvation Toxicologic: No significant increase in toxicity. ○ Cyclization ○ Photolytic degradation DETERMINING STABILITY ○ Microbial attack Determine the conditions under which the drug or product undergoes degradation. STABILITY CONDITIONS/STRESS ○ Prevent degradation and provide methods CONDITIONS TESTING to stabilize the product (changing Stability Conditions / Stress Conditions Testing formulations when necessary) ○ Based from: ○ Determine limitations in shelf life (expiry 1. ASEAN Guideline on Stability Study of and stability) Drug Product When the drug is exposed to stressed 2. International Conference on conditions, determined shelf life may Harmonization of Regulatory still change. Requirements (ICH) Drug stability test Ex.: Drug labels that indicate ‘must not 🔊 guideline Q1A (R2) be stored in temperature exceeding In some cases, the following tests are 30°C is under the context that during preliminary tests wherein the product is not yet the drug stability testing, when in its final form: subjected to stressed conditions, ○ Chemical degradation significant changes have taken place. ○ pH-dependent stability ○ Determine storage conditions (exposure to ○ Photostability 🔊 air or light and use of appropriate container) Subject it to light; simply expose it to the Based on ASEAN Guidelines, what you want to sun/artificial light/dark region achieve during stability testing is to determine ○ Oxidative stability the conditions under which the drug or product ○ Stability-Compatibility studies goes under degradation. This is where ○ pH-different buffers chemical kinetics come into play; chemical Exposure to atmospheric oxygen kinetics is used to determine degradation in Temperature conditions: 40m 60, 80 terms of degradation of the product outside the Humidity conditions body, as well as degradation once administered 25℃, 85% RH 🔊 inside the body. 40℃, RH Drug stability is learned to ensure that 🔊 *Stability/oven chamber degradation is being prevented by providing These are done before mixing with other methods to stabilize the product. ingredients and are commonly done to natural products such as plants. Phytochemical RATE REACTIONS screening is performed. Because it would help Drug concentration over time determine what are the present constituents in Zero-order, first-order reactions (common) the plant. Literature search should be done ○ Order of reaction for most drug substances next. ADALLA, DENOSTA, GEROLAGA, MAGALUED, MORATA 15. [Updated from 02/13/24 meeting] OTHER PROPERTIES Hygroscopicity EXCIPIENTS ○ Capability to absorb and desorb water Excipients depending on their chemical and physical ○ Inactive ingredients, at all times state ○ Comprise of all ingredients except the 🔊 ○ Hygroscopic, Deliquescent, Efflorescent active pharmaceutical ingredients (API) Hygroscopic substances such as Excipients vary based on the different types of NaOH absorb moisture but DO NOT dosage forms. 🔊 dissolve. Excipients are a major component of almost all Deliquescent substances such as drugs, as well as foods, cosmetics, and dietary Ca(OH)2 absorb moisture AND get supplements (90%) 🔊 dissolved. Disintegrants → excipients that facilitate Efflorescent substances are related to breakdown of the tablet. the water of hydration. ○ From the tablet, it will be converted into Powder properties granules, and then further broken down into ○ Flowability → the ability of powdered powder. material to flow. ○ Powder will be solubilized in the body in ○ Compressibility → the ability of a solution. 🔊 powdered material to be compressed. Excipients functions These properties are essential to be ○ Stability and bioavailability of the API 🔊 checked for the formulation of tablets and ○ Drug product’s manufacturability capsules as we will be able to determine It is easier to develop a dosage form how much anti-frictional agents must be rather than maintaining your 🔊 🔊 added to aid in the flowability of the sample. API/powder alone as a product. It also allows us to know if we should do In order for the manufacturability of a granulation methods to improve the product to increase, there must be the flowability and compressibility of the presence of excipients. 🔊 material. When we convert powders to ○ Appearance, texture and taste granules, we improve compressibility and We can not be able to swallow powder 🔊 flowability. alone. As syrups and suspensions, we need Powders stick on the inner walls of flavorants and sweeteners to mask the equipment, they are difficult to initial bitter taste of powders. moisturize due to their small particle Manufacturing process: size, and poor compressibility and ○ Tablet compression flowability. ○ Manufacturing process has an effect on the NOTE process of drug release (sufficient amount Powder alone will not be able to be of binder in the formation of granules) and compressed into a tablet because its drug stability. flowability will clog the tableting Transdermal preparations (via skin) machine. ○ Vehicle (penetrate the skin) Emulsions 🔊 Melting ○ Choice of oil Dosage forms that are meant to be melted (e.g. suppositories, sublingual tablets, oral EXCIPIENT PROPERTIES dispersible tablets) all have certain melting Physiologically inert ranges that should be observed to ensure Physically and chemically stable that the drug gets released from the dosage Free of any bacteria or other microorganisms forms. considered to be pathogenic or otherwise objectionable. ADALLA, DENOSTA, GEROLAGA, MAGALUED, MORATA 16  🔊 There are normal microbiota which are 🔊 In Pharm 130 Lab, when we say dissolution, we 🔊 There are microorganisms that good bacteria that aid in digestion. are not talking about the dissolution of all are components of the dosage form, it is the 🔊 pathogenic which are not desired in our dissolution of API within the dosage form. formulation. Dissolution Testing - QC test for dissolution of 🔊 Must be compatible with the API. the API Must not interfere with the bioavailability of the It is beneficial to look at the dissolution of drug. the API because it is our assurance that Must be commercially available in form and when the drug is dissolved, this is most purity commensurate to pharmaceutical likely what will be absorbed in the systemic 🔊 standards. circulation going to the target site of action. 🔊 If an API is of pharmaceutical grade, we Drug particles → solution must match the grade of the excipients as Will interact with the biological fluids to form 🔊 well to ensure the safe quality. a solution. When we formulate suspensions, there are Dissolution model (in vitro dissolution) 🔊 many ingredients to consider in liquid USP Dissolution Apparatus II (Paddle) dosage forms such as preservatives, Simulates what happens inside the body. suspending agents, viscosity agents, The temperature control is 37±0.5 °C to 🔊 sweeteners, flavorants, buffering agents. give allowance in the variation in In making formulations, we consider adding temperature changes. less ingredients as possible, because when we add more ingredients, the risk of DISSOLUTION AND ABSORPTION OF API incompatibility increases which increases Dissolution → process of solution formation the risk of the drug not eliciting its full 🔊 ○ Drug particles → solution therapeutic activity. Will interact with the biological fluids to 🔊 Must be relatively inexpensive. form a solution. When we choose suitable excipients for a ○ Prerequisite for absorption for certain certain API, we have to consider its 🔊 dosage forms. cost-effectiveness. Particularly immediate release (IR) An excipient that is expensive but dosage forms 🔊 multifunctional could be an example of it Sometimes, when formulating tablets, we A drug will NOT be absorbed and will have to consider cheaper options such as never reach its target site if it is NOT lactose and starch, which are common in solution. excipients that are being used for one of the tablet components for compression of Its rate and extent of absorption will tablets. be reduced if it is not completely NOTE rendered as a solution. DISSOLUTION Dissolution is the process in which a substance Dissolution is the rate-limiting step of forms a solution [USP, NF] absorption. If the dissolution of a drug Dissolution testing measures the extent and is slow, then the absorption will be rate of solution formulation from a dosage form, slow as well. such as tablet, capsule, ointment, etc. Rate at which a drug or excipient dissolves in FACTORS THAT AFFECT DISSOLUTION 🔊 any particular medium. Given an appropriate solvent, buffer, or RATE IN THE BODY 🔊 media, we can ensure that an API will be Biological fluid system 🔊 dissolved, while the remaining undissolved pH-dependent substances are the other excipients that In the GI tract, there is peristalsis which can not be dissolved in the solvent. aids dissolution through agitation. Some In ADALLA, DENOSTA, GEROLAGA, MAGALUED, MORATA 17  vitro tests simulate what happens in the ○ When it's less than 2.98, it's in its unionized body. form but it's not present in the solution. It 🔊 Agitation precipitates because it's subject to acidic When the agitation rate increases, the conditions. dissolution rate also increases. ○ The ionized form cannot be absorbed 🔊 Particle size because it requires a carrier to transport The smaller the particle size, the bigger or from one region to another. greater the surface area, the faster the ○ Candidacy for Absorbance: 🔊 dissolution rate. (1) unionized form, and (2) lipophilic. 🔊 Particle size reduction aids in dissolution. ○ If unionized form, solubility is less than the Coarse vs Fine - which can be more ionized form dissolved, the smaller or bigger particle ○ The essence of this is Handerson size? - Smaller Hasselbach, where you need an equal 🔊 Wettability amount of ionized and unionized form to Wetting agents are placed in suspensions achieve a pH = pKa. At this point, you have to aid in dissolution of the API inside the the assurance that it is in the saturation 🔊 body. phase. Although it's 50-50%, at least you If the wetting agent contact angle have somehow retained its saturation point. decreases, water or detergent is spread, It will dissolve as the unionized form and which indicates good wettability. If you have will be absorbed into the systemic good wettability, in terms of detergency, it is circulation. 🔊 easier to clean. Partition coefficient An increase in wettability means high Surface area 🔊 dissolution rates. Particle size In solvency or dissolution rate, when Salt formation contact angle gets smaller, the faster the dissolution rate Porosity Bigger pores mean that the liquid diffuses easier; therefore, it solubilizes easier. The higher the number of pores that penetrate interstitial spaces in water, the easier it is to be dissolved or wet. Porous material can be made wet easier in comparison to compact material. API PROPERTIES INFLUENCE ON DISSOLUTION Solubility ○ All water-soluble materials should be mixed or dissolved in water. ○ Watching the saturation points of each component to be dissolved in water pKa ○ Solubility depends on pH ○ Ex. 2.98 pKa of the drug and the pH is higher than 2.98. ○ Usually what happens is that according to the Henderson-Hasselbalch equation, there are more ionized forms compared to unionized ones, or either trace to none of the unionized forms. ADALLA, DENOSTA, GEROLAGA, MAGALUED, MORATA 18 Pharm 130 Lec: Pharmaceutics 1 PHARMACEUTICAL SOLUTIONS Professor Ethel Andrea C. Ladignon February 13-27, 2024 Partition Coefficient of Weak Acid OUTLINE Partition Coefficient of Weak Base Solute: Strong Electrolytes Pharmaceutical Solutions Applications Advantages of Solutions Phase Equilibria Disadvantages of Solutions Gibbs Phase Rule Solvent System One Component System Purified Water Phase Diagram of Water Classification of Solutions: Solvent System Used Two Component System Syrups Phase Diagram of Thymol - Salol Spirits Eutectic Mixture Tinctures Applications Aromatic Waters Tonicity Adjusting Agents Elixirs Sample Problem Classification of Solutions: Route of Administration General Formula: Oral Solutions Oral Solution General Formula: Oral Solutions Topical Solution Co-Solvents Otic Solution Viscosity Enhancers Nasal Solution Preservatives Inhalations Ph Adjusting Agents Ophthalmic Solutions Sweeteners Irrigating Solutions Flavorants Parenteral Solutions Colorants Other Solutions Other Excipients in Solutions Douches Solutions Formulation Consideration Enemas Solutions Methods of Preparing Solution Gargles Solution via Extraction Mouthwashes Maceration Non Aqueous Solutions Infusion Liniments Digestion Collodions Decoction Preparation and Evaluation of Products Continuous Extraction Solubility of Weak Acids/Bases in Water as Percolation Influenced by pH Evaluation Of Solutions (General Tests) Ionic Equilibria Specific Gravity Weak Acids Weak Bases PHARMACEUTICAL SOLUTIONS Sample Problem A solution is a homogeneous mixture that is Partition Coefficient of Different Solutes prepared by dissolving a solid, liquid, or gas in Electrolyte Vs Non-Electrolyte another liquid and represents a group of Solute: Strong Electrolytes preparations in which the molecules of the Solute: Strong Non-Electrolyte solute or dissolved substance are dispersed Weak Electrolyte among those of the solvents ADALLA, DENOSTA, GEROLAGA, MAGALUED, MORATA 19  ○ Aim is to avoid any foreign matter to be left ○ Alcohol 🔊 undissolved in the preparation Ethanol, glycols, glycerol Liquid preparations that contain one or more ○ Fixed vegetable oils chemical substances dissolved in a suitable Non-volatile oil from plants (cottonseed solvent or mixture of mutually miscible solvents oil, corn oil) ○ Esters ADVANTAGES OF SOLUTIONS Ethyl oleate 🔊 ○ Other co-solvents 🔊 Completely homogenous doses Immediate availability for absorption and The formation of a complex increases the solubility of the product. 🔊 distribution Medicine is already in solution so the rate and length of absorption is no longer a PURIFIED WATER problem [USP ] 🔊 Doses are easily adjusted Excipient in the production of non parenteral A specific amount of liquid can indicate the preparations and in other pharmaceutical 🔊 amount of medicine consumed. applications such as cleaning of certain Ex.: Label of a syrup claims that it has equipment and non parenteral product-contact 125mg/5mL – each 5mL of the formulation components 125mg of Paracetamol or other active Also to be used for all tests and assays for ingredient. which water is indicated Taken on administered by patient who have difficulty in swallowing CLASSIFICATION OF SOLUTIONS: Easy to manufacture SOLVENT SYSTEM USED Spirits DISADVANTAGES OF SOLUTIONS Tinctures Many drugs and chemicals are less stable in Aromatic Waters 🔊 solution than they are in dry form Elixirs 🔊 Not all drugs must be in solution Syrups Not ideal for drugs with unpleasant taste Some drugs are not soluble in solvents that are SYRUPS 🔊 acceptable for pharmaceutical use Oral solutions that contain a high concentration Ex.: Lipophilic Drug - soluble for ethyl of sucrose or other sugars (aqueous) acetate; ethyl acetate can not be used as a ○ Does not use any solvent other than water solvent for pharmaceutical preparations Concentrated, viscous, aqueous solutions of because it is not to be consumed. Ethyl sugar or a sugar substitute with or without acetate is not Generally Recognized As flavors and medical substances. Safe (GRASS). Simple Syrup, NF - 85% sucrose Bulky and heavy. ○ Can be medicated, or only used as 🔊 The usage of many different excipients. sweetener. The more you add excipients, the more risk ○ 85% - Percentage at which syrups are that a product may form incompatibilities self-preserved, meaning that a syrup with because of the different excipients present. that much concentration of sucrose is able to preserve the formulation itself without the SOLVENT SYSTEM need of adding preservatives. Aqueous solvent ○ If the syrup is medicated → adjust the ○ Purified water (Most common, for amount of sucrose due to capping non-sterile products) Capping → solid deposits, ○ Water for injection recrystallization due to high ○ Sterile water for injection concentration of sucrose. ○ Bacteriostatic Water for injection It is not being added as 85%, but is Non-aqueous solvents being added with the adjusted ADALLA, DENOSTA, GEROLAGA, MAGALUED, MORATA 20  concentration already in the formulation Contain vegetable material or chemical the more components get added. substances in alcoholic or hydroalcoholic It will not be 85% in the formulation solution because there are other components Made by direct dissolution or by extraction 🔊 included other than the