Compounding II: Equipment, Stability & Excipients PDF

COMPOUNDING & HAZARDOUS DRUGS • CHAPT ER 16 COMPOUNDING II: EQUIPMENT, STABILITY & EXCIPIENTS EQUIPMENT The first section of this chapter covers equipment used for compounding. Most equipment is used for non-sterile compounding (e.g., ointment mills and tablet molds), some is used for both nonste...

COMPOUNDING & HAZARDOUS DRUGS • CHAPT ER 16 COMPOUNDING II: EQUIPMENT, STABILITY & EXCIPIENTS EQUIPMENT The first section of this chapter covers equipment used for compounding. Most equipment is used for non-sterile compounding (e.g., ointment mills and tablet molds), some is used for both nonsterile and sterile compounding (e.g., syringes) and a small number is used for sterile compounding only (e.g., the automated compounding equipment used to prepare parenteral nutrition). Equipment should be kept clean, in proper working order and free from contamination. DEDICATED EQUIPMENT FOR HAZARDOUS DRUGS The Compounding I chapter describes the space (and equipment) requirements for hazardous drug (HD) preparation and how nonhazardous drugs should be prepared in separate spaces with separate equipment. HDs cause contamination. Equipment used for HDs, including routine equipment such as counting trays and spatulas, should be dedicated for HD preparation and sanitized after use. CAUTIONARY NOTE ON CALIBRATION AND MATERIALS Equipment must be calibrated regularly to confirm accuracy. For some types of equipment, the calibration can be frequent (e.g., electronic balances are calibrated routinely before use). Complex equipment can require calibration by an outside expert. Equipment should be made of material that does not react with the compounding ingredients (e.g., metal spatulas should not be used with compounds containing metal ions). 254 RxPREP 2022 COURSE BOOK Pharmacists use various equipment to measure the volume of ingredients, and nurses and patients use some of the same equipment (such as oral syringes and pipettes} to administer medication. When measuring, select a device that has a measuring capacity equal to or slightly larger than the amount being measured to get the most accurate measurement (e.g., if an R mL dose is needed, and the syringe sizes available are 1 mL, 3 mL, 5 mL, 7.5 mL and 10 mL, the 10 mL syringe should be used} . Measurements should be made in the metric system. Cylindrical and Conical Graduates E 8 '-' 2 j'j ::., ..c: l'.'.! .Se 8 0 6 " 0 C. "" 6i § _______, ~ - - - - - ~ Graduated cylinder Conical graduate ©2021, ©2022 Syringes MEASURING VOLUME -0< I RxPREP Graduates are measuring equipment with lines on the glass that are used to measure the volume, and include graduated cylinders (left image}, conical (coneshaped) graduates (right image}, graduated beakers and graduated medication containers. A graduated cyHn de.t· has the same diameter from the !Q)?_ to the bottom of the container and provides more accurate measurements than conical graduates, which have a wide mouth (makes it easier to stir mixtures with a glass stirring rod}. The wider the mouth, the lower the accuracy. Some important points about measuring volume using graduates include: Syringes used for Non-Sterile Compounding Oral syringes and hypodermic (injection) syringes (also called parenteral syringes) can be used for measuring volume. See images on the next page. Syringes are most accurate for measuring small volumes. They are especially useful for measuring viscous (thick) liquids, such as glycerin and mineral oil. Patients receiving a liquid who require a very accurate dose should use an oral syringe for measurement rather than a small dosing cup, which has lower accuracy. Oral syringes are useful for squirting the medication into the side of the mouth (as are small pipettes or droppers), which can be useful for children and animals. Oral syringes can be used to deliver small amounts of topical preparations. Caution with Oral Syringes in an Acute Care Setting There have been multiple deaths due to patients receiving oral medications as an injection. Safety measures must be in place to prevent oral medications from being given by the wrong route (see next page). Syringes used for Sterile Compounding Hypodermic (parenteral) syringes are commonly used for sterile compounding to transfer drugs and additives into IV bags. All syringe packages should be wiped off with isopropyl alcohol (IPA) 70% to remove contaminants and dust, prior to being brought into the secondary engineering control (SEC) or into the primary engineering control (PEC) if working in a segregated compounding area. A graduate should not be used to measure volumes less than 20% of the graduate's capacity. • Sterile syringes are individually wrapped, and must be opened along the seal (not torn open) to avoid shedding (i.e., release of particles into the sterile space) . o The smaller the percentage of the graduate's measuring capacity that is used, the higher the measuring error (e.g., measuring 5 mL in a 100 mL graduate will have a higher measuring error than measuring 87 mL in a 100 mL graduate. A 5 mL measurement needs a smaller graduate.) Caution with Hypodermic Syringe Needle-Sticks Recapping needles leads to needle-stick injuries. In sterile compounding, a needle-stick can injure the staff and cause contamination to the compounded sterile products (CSPs). In patient care settings, needle-stick injuries carry infection risk. To read the volume in a graduate, place it on a flat surface and view the height of the liquid in the cylinder at eye level. The liquid can curve downward from both sides, especially with viscous liquids. This curve is called the meniscus. The bottom of the meniscus, at the center is where the measurement is read (see image} . - - 21 In general, do not recap syringes. It is preferable to use syringes with safety features, such as safety shields that cover the needle immediately after use. =1 Measure the level at the bottom of the meniscus (i.e., the curve), at eye level. This graduated cylinder contains 20 mL. • If the needle must be recapped, it is safer to place the cap on the work surface (rather than holding it) and slip the tip of the needle into the cap, without letting the needle tip touch the work surface. Luer Locks Improve Patient Safety Luer locks make secure, Leak-free connections between syringes, catheters and IV lines. They have male and female ends that screw together, forming a tight seal (see image). 255 16 I COMPOUNDING II: EQUIPMENT, STABILITY & EXCIPIENTS Using a Syringe Plunger: do not touch; causes contamination Syringes can be used to inject into the IV bag (as shown) or can be used to inject directly into a vein or into a catheter if the patient has IV access [i.e., a port (vein entry) placed under the skin, with IV tubing extended out for the entry of injections or infusions]. Providing a quick bolus dose into a vein (directly) or into a vein through a catheter is called an IV push. r ~-~]Luer Lock Tip ( ... ', ,,,,-, Luer Lock Connector Luer locks The syringe has a luer lock tip that is designed to screw into the luer lock connector on the patient's IV access catheter (as shown in the image) or onto a needle. tfi.1 @RxPrep Syringe Types Hypodermic (Injection) Syringes These come with cannulas (needles) attached, or the cannula is separate and can be screwed onto the tip of the syringe. Hypodermic (or parenteral injection) syringes are available in many sizes, (e.g., 1 ml, 3 ml, 5 ml, 10 ml and others). Choose the Correct Size Syringe For drawing up medication, do not use the exact size syringe needed because the plunger can easily become dislodged. Select the closest syringe size above the size needed. Do not add two different syringe sizes for a dose. r Oral Syringes These are used to administer drugs orally or through a feeding tube [e.g., nasograstric (NG)]. To avoid fatal medication errors, safety measures include: • Placing a "For Oral Use Only" sticker over the syringe cap Using a syringe design that prevents connection to an IV port Using oral syringes with brightly colored plungers/caps that differentiate them from IV syringes Clearly communicating the correct route of administration to the nurse Fdi @RxPrep 256 RxPREP 2022 COUR SE BOOK Pipettes and Droppers Pipettes Pipettes are thin plastic or glass tubes used to measure small volumes. Pipettes can be used by patients to take medication because they are easy to draw up a dose (insert tip into liquid medication, squeeze and release the bulb, remove). If the pipette is being inserted into an opening such as a mouth or nose, it is important to keep the bulb squeezed after the dose is delivered and when withdrawing it, to avoid contaminating the inside of the pipette. RxPREP ©2021, © 202 2 YE OLD TORSION BALANCE I Class 111 (Class A) torsion balances have internal weights, which are used to weigh quantities s 1 gram. When weighing> 1 gram, external weights (see picture) are placed on one pan and the substance to be weighed is placed on the other. The external weights must be handled with a forceps (pincers) to avoid getting oil from the skin on the weights. ' Mohr pipette (graduated) 1 Torsion balances have a sensitivity requirement (SR) that is most often 6 mg, meaning 6 mg can be added or removed before the dial moves 1 division. Torsion balance Disposable pipette Pipettes can be referred to as droppers, because they release drops. Medicine droppers are also called droppers. A volumetric pipette draws up a set volume only, which is the volume the pipette can hold. A Mohr pipette is graduated and is used to measure different volumes. Mohr pipettes are commonly used in compounding. Medicine Droppers Medicine droppers come in graduated and non-graduated versions. Graduated droppers that meet USP criteria (such as the dropper in the image) release drops of water that weigh 45 - 55 mg, when held vertically. I Graduated dropper The weight is given for water drops; other compounds will have different weights for the same size drops, depending on the liquid's specific gravity. • Non-graduated medicine droppers that meet the USP criteria release a similarly-sized drop. The minimum weighable quantity (the minimum amount that can be weighed) is calculated based on the SR and acceptable error rate (typically 0.05 or 5%): • I - - - -- MWQ "' -----::-::-7 SR / acceptable error rate (0.05 or 5%) MWQ = 6 mg / 0.05 = 120 mg The top-loading electronic balance (called an analytical balance or a scale) is used most commonly. This type of balance is simple to use and has higher sensitivity (i.e., can weigh with more precision, including very small amounts). It is not necessary to calculate the MWQ with a modern electronic balance. When using an electronic balance, the compounder must "tare" or "zero out" the balance after placing the weigh boat or glassine paper on the scale. This ensures that only the ingredients are weighed and the container or paper used to hold the ingredients are not included in the weight. With either balance, never place material to be weighed (e.g., powder) directly on the balance. The material will be placed on a weigh boat (a shallow dish) or on glassine weighing ~ , which is coated to reduce moisture penetration. The weigh boats are made of plastic or other material. WEIGHING EQUIPMENT Balances There are two types of balances used to weigh ingredients. The older balance is the Class III torsion balance (sometimes called a Class A balance). This type of balance is still used, though less commonly than the electronic balance [see "Ye Old Torsion Balance" for a description and the calculation for the minimum weighable quantity (MWQ)]. Fagron© Electronic balance Weigh boats 257 16 I COM PO U N DIN G II : EQU I PMENT, STAB I LIT Y & EXC I PIENTS GRINDING, MIXING AND TRANSFERRING EQUIPMENT Mortars and Pestles Mortars and pestles are used to grind substances into a finer consistency, and can be used to stir and mix small amounts of ingredients. The mortar is the bowl, and the pestle is the blunt, heavy stick. A compounding pharmacy needs at least one glass and one Wedgwood or porcelain mortar and pestle. Glass mortars are used for liquids, such as suspensions and solutions, and for mixing compounds that are oily or can stain. Wedgwood m ortars have a rough surface, and are preferred for grinding dry crystals and hard powders. Porcelain mortars have a smooth surface, and are preferred for blending powders and pulverizing gummy consistencies. • Mixtures that have a higher water content than an ointment, such as a cream, can he mixed on an ointment slab if the mixture will hold its shape (and not flow off the slab). Otherwise, different equipment can be used to hold the preparation, such as a mortar bowl or a beaker. Powder Sieves Sieves are sifters similar to those used in baking. • After a powder has been ground fine, it is sifted in order to ensure a uniform particle size. Sieve ELECTRIC MIXING EQUIPMENT Mixing can be performed manually or with electric mixing equipment. Electric mixing speeds up the process. • Ointment milJs, homogen izers and grinders are used to mix ingredients. • Ointment mills and grinders reduce the particle size, which increases the surface area and the rate of drug absorption. Glass mortar & pestle Wedgwood mortar & pestle Porcelain mortar &pestle Spatulas Spatulas are used to mix and transfer (move) ingredients from one place (such as an ointment slab) to another place (such as a container). The flat part of the blade can be used to flatten and grind down ingredients, and to pack preparations such as ointments into containers. Spatulas are made of stainless steel, plastic or hard rubber. Stainless steel and disposable plastic spatulas are used commonly. The type of spatula used depends on what ingredients are being transferred or mixed. A steel (metal) spatula would not be used if making a mixture that contains metallic ions. • A rubber spatula is used to handle corrosive material. Ointment Slabs Ingredients are mixed into ointments on a compounding (or ointment) slab, which is a flat board made of porcelain or glass. Ointment slabs are used as a work surface for other purposes besides making ointments since the material is hard and non-reactive. For example, an ointment slab can be used to form pills (in which case it can be referred to as a pill tile) and for rolling out suppositories. • Disposable parchment ointment pads can be used as a work surface if the water content of the mixture will not cause the paper to tear. 258 Ointment Mills An ointment mill draws the ointment (or another semi-solid preparation) between rollers that grind and homogenize (i.e., make non-gritty, smooth and uniform) the ingredients in the preparation (see image) . FosrortC> Ointment mill Homogenizers A homogenizer (also called an electric mortar and pestle) can be used to mix ointments, creams or other semi-solid preparations. The homogenizer is similar to a smoothie blender, although with more power, and at a higher cost (see image) . Homogenizers can be small and handheld. • GAKO® Homogenizer (also called an electric mortar & pestle) A popular brand of homogenizer is called the Unguator. • There are other homogenizer manufacturers that make various models (e.g., PharmaRAM or Mazerustar Mixer) . Grinders Electric grinders are similar to coffee bean grinders. In fact, coffee bean grinders are used in some pharmacies. When used for compounding, they must be dedicated for compounding use only (i.e., not for coffee bean grinding) . A grinder is useful for grinding hard tablets down. The powder will need further preparation to produce a fine powder. RxPREP 2022 COUR SE BOOK Hot Plate with Magnetic Stirrer A hot plate (see next section) with a magnetic stirrer can save time by continuously stirring the mixture to dissolve and mix the ingredients. The stirrer has a rotating magnet under the ceramic plate, which causes the stir bar (placed inside the glass) to spin and stir the components (see image). Hot plate with a stir bar in the glass. A magnet inside the hot plate moves the stir bar. Hot plates are used without the stir bar to heat only (a glass stirring rod can be used to mix contents manually). HEATING DEVICES Heating with Hot Plates Hot plates provide direct heat to soften and melt ingredients, and to hasten chemical reactions. Heat must be carefully controlled to avoid burning. A water bath is helpful when the temperature needs to be carefully controlled. The water bath protects the ingredients from overheating and burning. I Rx PREP ©2021. © 2022 Capsules Capsules can be soft gels or hard shells, which are more commonly used for compounding. The shells are made of gelatin, which is pork-derived and will not be suitable for some patients, or from hypromellose or a similar plantderived product. Hypromellose is a cellulose product, as the name implies. Capsule sizes for human use range from 000 (the largest size) to§_ (the smallest size). Veterinary pharmacists can order larger capsule sizes for use in large animals. Capsule bodies are filled with the drugs and excipients, and the capsule caps are placed over the bodies by hand or with a capsule machine. Tube Sealers Tube-sealers heat and squeeze the ends of tubes shut; the end will look similar to the crimped end of a toothpaste tube. Fogron© Suppository mold Lozenge mold The ingredients to be melted will be in a container (e.g., a beaker) that is placed into a larger container filled with water. The water in the outer container separates the inner container from the direct heat source, to prevent burning. Heating with Microwave Ovens Microwave ovens heat quickly; be careful that the heat is applied uniformly as some microwaves provide uneven heat. MOLDS, TABLET PRESSES AND CAPSULE MACHINES Reusable or disposable molds are used to prepare tablets, lozenges/troches (orally-dissolving tablets) and suppositories. With soft delivery vehicles, such as suppositories and lozenges, the medication is often dispensed in a disposable plastic mold. This helps keep the product in the correct shape. Refrigeration helps soft products retain shape. Tablets A tablet press (or tablet mold) is two plastic or metal plates used to compress damp powder into tablets. • Similar to forcing Play-Doh into a mold to form a shape, the compounder takes the pasty mass and uses the tablet press to form tablet shapes. • After the mold shapes the tablets, the tablets are removed, and given time to dry. Tablet press Tube sealer (sealed at bottom) COMPOUNDING INGREDIENTS All medications, whether compounded or not, include the drug/s (called the active pharmaceutical ingredients, or APis) and the excipients. Excipients do not produce therapeutic effect, but are needed to make the dosage form stable, functional and, with some oral dosage forms, palatable. HIGH QUALITY INGREDIENTS REQUIRED High-quality ingredients ensure the purity and safety of the formulation. Ingredients that are recommended for use will be listed in either: The USP National Formulary (USP-NF) The Food Chemicals Codex (FCC) substances list Preferably, ingredients should be manufactu red at an FDAregistered facility. If any substance comes from a non-FDA registered facility, a Certificate of Analysis (CoA) should be obtained that confirms the specifications and quality. If any component is moved to a different container, the new container should be labeled with the component name, original supplier, lot or control number, transfer date and expiration date. 259 16 I COMPOUND I NG II: EQU IPMENT, STABILITY & EXCIPIEN TS MISSING EXPIRATION DATE This has two immiscible liquids. Ingredients degrade, and expiration dates are important to ensure that the product retains potency and is non-toxic. If there is an ingredient without an expiration date, the pharmacist will assign a conservative (cautious) date that is no more than 3 years from the date of receipt (the day the pharmacy received the item). The label on the container should include: H,O - loving end Oil (lipid) - loving end t We will use a surfactant that has a H1 0 ·loving end and a lipid-loving end. Here is an enlargement. The date of receipt The assigned expiration date SURFACTANTS • ••• • SALAD DRESSING CHEMISTRY Preparations can have multiple phases, similar to an oil and vinegar salad dressing, which has an oil phase that will become dispersed in the watery phase (the vinegar) when shaken. The dressing will quickly settle back into the two distinct phases because the "tension" between the two surfaces is high; the oil and water will repel each other. A surfactant added to the salad dressing will lower the tension between the two surfaces, and keep the phases from quickly sepal.'ating. This is an o/w emulsion, with the oil dispersed in the water, - - .. --- - --= - Lowering the Surface Tension Surfactant is a contraction of the words surface active agent. Surfactants lower the surface tension (i.e., the interfacial tension) between two ingredients (01· phases) in a preparation to make them more miscible (i.e., easier to mix together). The side of the phase that is close to the other phase is the "face" of the phase, and the interfacial tension is the tension at the interface. The surfactant lowers the interfacial tension, to help the phases move closer together. The emulsion is unstable and separates. SURFACTANT MECHANISM OF ACTION The common mechanism of action of a surfactant involves forming a micelle structure (see micelle figure, in first box to the right), which can reverse (turn inside-out). If oil and water are mixed, the oil will interact with the lipophilic (lipidloving) end of the surfactant, and the water will interact with the hydrophilic (water-loving) end of the surfactant. Surfactants are amphiphilic; they are both hydrophilic (on one side) and hydrophobic (on the other side). 260 The surfactant is added, and forms around the oil droplets. The surfactant stabilizes the emulsion, and the oil droplets stay dispersed longer. RxPREP 2022 COUR SE BOOK I RxPREP ©2021, ©2022 Non-Micelle Mechanisms Surfactants do not always form micelles; some form a film between the surfaces, or form an electrically-charged layer to keep the phases separate. With all mechanisms, the surface tension is lowered, which helps with drug preparation and stabilization. SURFACTANTS HAVE MANY USES Surfactants have practical uses in addition to aiding in the formation of homogenous preparations. By keeping the drug dispersed, a consistent dose is delivered. In manufacturing, the micelles formed by surfactants are used to facilitate gut absorption of lipophilic drugs, similar to the way bile acids facilitate absorption of cholesterol, and are used to control the rate of drug release. When the surface tension is lowered, it is easier to grind particles down, and to mix ingredients. Surfactants are called by a variety of names, depending on the use or the type of preparation, as described below. TYPES OF SURFACTANTS Wetting Agents Wetting agents are substances that reduce the surface tension between a liquid and a solid to permit the substance to more easily spread. A fine powder that will be incorporated into a suspension is wetted with a wetting agent and stirred into a thick paste prior to being put into the delivery vehicle. Levigating agents (see next column) can be referred to as wetting agents. Emulsifiers An emulsion is two or more liquids which are not able to be blended together (immiscible), such as water droplets dispersed in oil, or oil droplets dispersed in water. Emulsifiers are added to an emulsion to help keep the liquid droplets dispersed throughout the liquid vehicle. This helps prevent the two liquids from separating into distinct (separate) phases. Emulsifiers can be called emulgents. Suspending Agents A suspension is a solid dispersed in a liquid (e.g., sulfamethoxazole powder does not dissolve in water, and is delivered as a suspension). Suspending agents are added to suspensions to help keep the solid particles from settling. Suspending agents do not keep suspensions separated for long, and suspensions must be shaken to redisperse the solid prior to use. Suspending agents can be called dispersants (or dispersing agents). A suspending agent can be a plasticizer, where plasticizer means that it will make the preparation easier to shape or mold. Sorbitol can be used as a plasticizer for gelatin capsules. Ora-Plus: Composed of a gel-hke structure that keeps drug particles suspended and prevents settling Slightly acidic to prevent drug degradation through oxidation Bland taste; must be combined with Ora-Sweet for flavor Ora-Sweet: I 1 I I - c::. I ---- Similar to simple syrup Provides flavor to Ora-Plus J Ora-Blend is a commercially available combination of Ora-Plus and Ora-Sweet Ora-Sweet and Ora-Blend are available in sugar-free formulations sweetened with saccharin (Ora-Sweet SF, Ora-Blend SF) Levigating Agents Levigation and trituration are both used to grind down particles (i.e., make particles smaller); the difference is that levigation uses a levigating agent (also called a levigant) such as glycerin or mineral oil to aid in the grinding. Trituration is the grinding of particles without the addition of a liquid (the powder stays dry). Mineral oil is a commonly used levigating agent for lipophilic (oil-soluble) compounds, and glycerin or propylene glycol are used for aqueous (water-soluble) compounds. Foaming Agent Foaming agents help foam to form (e.g., in soap) by lowering the surface tension of water. An enormous use of surfactants in manufacturing is in detergents, where they foam and remove dirt. In non-sterile compounding, anti-foaming agents are more commonly used (e.g., simethicone). Glycols & Gels are Used as Surfactants and Delivery Vehicles The commonly used products polyethylene glycol (PEG) and poloxamer, by itself or as the_!'. in _!'.LO gel (described later), are both delivery vehicles and surfactants. PEG and poloxamer have both hydrophilic and hydrophobic parts, which makes them useful for a variety of preparations. For example, poloxamer gel can be used to distribute ingredients in a preparation into the "like" phase [i.e., the hydrophobic compound distributes into the organic (lipophilic) phase, and the hydrophilic compound distributes into the water-based phase]. Poloxamer is useful for topical drug delivery. 261 16 I COM PO UNDIN G II : EQ UIP M ENT, STA B ILITY & EXC IPI ENT S THE HYDROPHILIC-LIPOPHILIC BALANCE When a pharmacist wishes to disperse a liquid into a liquid to form an emulsion, selecting the right surfactant is important to keep the liquid droplets adequately dispersed. A primary consideration in selecting the surfactant to use in an emulsion will be whether the emulsion is a water-in-oil (w/o) emulsion or an oil-in-water (o/w) emulsion. The taste of w/o formulations is not palatable; they are primarily used topically. . ..... I Surfactants with a low HLB number(< 10) are more lipid-soluble and are used for water-in-oil (w/o) emulsions. Surfactants with a high HLB number(> 10) are more -,4-,A water-soluble and are used for oil-in-water (o/w) emulsions. 10 Q I Lower HLB # More Lipid Soluble (w/ o) i Higher HLB # 20 More H 2 O Soluble (o/ wl Oral formulations are typically o/w formulations. The hydrophilic-lipophilic balance (HLB) number determines the type of surfactant required to make an emulsion (see Study Tip Gal to the right). We are Miscible. We mix well together. The following table has examples of surfactants and their HLB values. There are many available surfactants; these are just a handful. No, we are Immiscible. We do not mix well at all. In the table, PEG 400 and Tween 85 have HLB values greater than 10, and would be possible options for forming an o/w emulsion. The HLB values that are less than 10 (e.g., Span 65) would be possible options for forming a w/o emulsion. Examples of Surfactants and their HLB Values COMMERCIAL NAME Glyceryl monostearate PEG 400 monool-ea-te- - : :_ __ _ _-_ CHEMICAL NAME HLBVALUE TGlyceryl monostearate 3.8 l I Polyoxyethylene monoo leate 11.4 2.1 Span 65 Sorbitan tristearate Tween 81 Polyoxyethylene sorbitan monooleate Tween 85 Polyoxyethylene sorbitan trioleate _ ]_10 11 STABILITY AND DEGRADATION STABILITY OF COMPOUNDED PREPARATIONS USP defines stability as the extent to which a product retains, within specified limits, and throughout its period of storage and use (i.e., the shelf-life), the same properties and characteristics it possessed at the time it was made. The stability of compounded products can be easily compromised if they are not prepared or stored properly. This can be recognized by changes in texture, color, smell or development of precipitates. 262 to the compound's core structure and the bonds that hold the compound together. Reactions involving the functional groups are common causes of dr ug degc•adation and can make the drug ineffective, unpalatable and toxic. Reactions that Cause Drug Degradation USP emphasizes three types of chemical reactions that cause most drug products to become unstable and degrade: Oxidation-Reduction Functional Groups Are Susceptible to Degradation Hydrolysis The differences between drugs with similar chemical structures lies in the functional groups that are attached Photolysis Rx PREP 20 22 CO UR SE BOOK I Rx PREP ©202 1, © 2022 The following section describes each of these reactions and methods that reduce the likelihood of these reactions (e.g., light and moisture protection) to extend the stability of the preparation. Drug degradation in the body (i.e., metabolism) is reviewed in the Drug Interactions and Pharmacokinetics chapters. OXIDATION A compound is oxidized when it loses electrons and is reduced when it gains elech·ons. Oxidation and reduction reactions occur together; when one compound is oxidized, another must be reduced at the same time. This is called the re-dox reaction. With some drugs, oxidation is visible with a color change, such as epinephrine becoming amber-colored (yellow/orangish). Other compounds turn pink/reddish when oxidized. Which Compounds are Likely to Become Oxidized? The molecular structures most likely to oxidize are those with a hydroxyl (-OH) group directly bonded to an aromatic ring, such as catecholamines (e.g., epinephrine), phenolics (e.g., phenylephrine) and aldehydes (e.g., various structures used as flavorings). An example epinephrine oxidation is shown below. Another example of oxidation that can be seen (and enjoyed) is cooking onions to cause caramelization. The sugar is caramelized in a series of reactions, which begins when th~ alcohol func tional group in the sugar is oxidized. An alcohol is a hydroxyl functional group (-OH) bound to a carb2!!_. The water is removed when the steam evaporates. The end product has a visible color change and a change in taste (i.e., brown, caramel-flavored onions). Example: Oxidation of Epinephrine. The presence of the hydroxyl groups on the ring make oxidation more likely. OH OH H N...,. "CHI ·2e · 2 H' +1e,+2 H" HO 0 OH 0 Epinephrine How can Oxidation be Prevented? Oxidation is catalyzed by heat, light and metal ions. Changes in temperature and pH must be carefully controlled; either can exponentially increase oxidation (and will do the same for hydrolysis reactions, described next). Light protection I Adequate storage With amber glass, UV light-blocking containers (e.g., plastic) and light-protective sleeves (bags) for IV bags, IV lines and syringes. --- - Chelating agents --- Temperature control with refrigeration, control of room temperatures and (occasionally) freezer storage. - Use chelators to chelate metal ions that have an unshared electron in the outer shell. These are free radicals, which can catalyze o,cldation chain rea ctions. The chelating agent ties up the catalyst, preventi ng the reaction. Common chelators have the letters ED: EDetate disodium ( ~ ) . EDetate calcium disodium and EDetic Acid . - - - - - - - - t-- Antioxidants Also called: free radical scavengers Oxidation produces free radicals, which are highly reactive with other compounds, and cause a chain reaction that damages the compound (see chelating agents above). Autoxidation is when oxidation reactions occur routinely during preparation and storage. Antioxidants inhibit free radicals. Common antioxidants include ascorbic acid (vitamin C), t ocopherols (vi tamin E), ascorbyl palmitate, Na ascorbate, Na bisulfate, Na sulfoxylate and Na thiosulfate. Control pH Maintain pH with a buffer; see pH discussion that follows. HYDROLYSIS Hydrolysis occurs when water causes the cleavage of a bond in a molecule. Compounds likely to undergo hydrolysis should not be exposed to moisture. Counseling should include to avoid storing products susceptible to hydrolysis in the bathroom and to close containers tightly. Desiccants are sometimes used to soak up any moisture that enters the container. 263