We will begin with the USP definition of suspensions, which are liquid preparations that consist of solid particles, dispersed throughout a liquid

Transcription

1 We will begin with the USP definition of suspensions, which are liquid preparations that consist of solid particles, dispersed throughout a liquid phase in which the particles are not soluble. Suspensions are typically compounded for two purposes, either to be used orally so the drug can be ingested, or to be used topically on the skin. Suspensions for oral use are by far the most common reason for a pharmacist to compound a suspension. This is because there is often a need to administer drugs that are only available in solid form, to patients who, because of age or medical condition, cannot swallow tablets or capsules. So this could obviously include children too young to know how to swallow a pill, but also include less obvious but not uncommon situations in adults such as those who have an N G tube placed for some medical purpose, and therefore can only be given liquids. Additionally, there are also geriatric patients who no longer have the ability to swallow pills, and thus need a pharmacist to create a liquid form of a drug otherwise only available as a solid tablet or capsule. This last point is important, a manufactured liquid product should always be used if it is available, because the manufacturer has conducted stability and bioavailability testing on the product. However, although pharmaceutical companies make a large number of oral liquid products, many therapeutic agents are still not available in a liquid dosage form. Moreover, in recent years there have been problems with product shortages, especially of the liquid products. When a manufactured liquid product is unavailable, pharmacists should be able to fill the gap by extemporaneously compounding suspensions for their patients who rely on oral liquid dosage forms. Therefore, in pharmacy skills lab we will primarily focus on compounding oral suspensions from commercially available tablets or capsules, for products that are not otherwise available in liquid form. However, I would be remiss not to remind you that suspensions can also be used topically. Compounding a topical suspension is usually required when a dermatologist finds it best to create a unique formula, customized for a specific patient with a particular skin condition. Nevertheless, we will be focusing the rest of this lecture on the preparation of oral suspensions. 1

2 I first want to clarify a term that I will be using throughout this lecture. When I speak of adding water, or using water within an oral suspension, understand that I am referring to using purified water. USP chapter 795 states that purified water must be used when compounding non-sterile drug preparations, whenever the formulations indicate the inclusion of water. So, whenever I talk about adding or using water, I always mean the use of purified water, as the USP defines it. Purified Water must meet requirements for ionic and organic chemical purity, and must be protected from microbial contamination. Purified water is produced by starting with the minimal quality of the source feed-water being drinking water. So, starting with drinking water, manufacturers further purify it by means of either distillation, ion exchange treatment, or reverse osmosis. Any of those sorts of purification methods can be used to take drinking water and create purified water. So remember, whenever I say water, in the context of compounding suspensions, I am actually referring to the use of purified water. 2

3 When creating a suspension, our compounding goal is to disperse or suspend the active drug, which is usually in an insoluble powdered form, throughout a liquid vehicle such that there is an even distribution, and thus uniform concentration of the drug throughout the entire liquid. Moreover, the distribution of particles must remain evenly suspended long enough to prepare and administer a dose. After shaking the bottle, typically 5 minutes might be required for the drug to remain suspended, so that the patient can then measure out and administer a dose. Suspensions do not have to remain suspended for hours or days. To achieve this compounding goal, our suspension must have 4 desirable properties. The first property is to have a fine, uniform particle size of the solid insoluble ingredient. The second property is to have a uniform dispersion of solids throughout the liquid vehicle. Third, the suspension should exhibit a slow sedimentation rate of the solids. And lastly, solids that have settled over time should be easily re-dispersed when shaken. We will discuss how to obtain each of these 4 desired properties in more detail on the following slides. 3

4 The first desired property to discuss is that suspensions should contain an insoluble solid, which has a very fine and uniform particle size. This property is desirable for both topical and oral suspensions. Uniform, finely divided particles give optimal dissolution and absorption of the drug, and is therefore particularly important for suspensions where the drug is intended for systemic use. Additionally, a fine particle size helps the suspension have a smooth, non-gritty feel in the mouth, or on the skin, which is important for patient acceptance. The rate at which the solid settles in the liquid can also be reduced. For all of these reasons, we want a suspension with a fine, uniform particle size. There are two main ways to help obtain this. The first is to choose the most appropriate form of the drug to begin with. If the drug or chemical is available in more than one form, and the prescription does not indicate a specific form to use, then choose the form that has the finest particle size. For example, crystals have a larger particle size then the same drug in powdered form. Even when starting with a powder, consider using, a sieve to obtain a uniform particle size. The second way is to use various compounding techniques to help further reduce the particle size of the powder. The main technique used is trituration. Place the powder into a mortar and use a pestle to grind it. It takes firm downward pressure, and several minutes of continual grinding to fully reduce the particle size. This reduction in particle size must be done prior to the addition of a liquid. Thus, the trituration of solids always occurs early in the compounding procedure, before any liquid is introduced into the formulation. 4

5 The second desired property was that suspensions should exhibit a uniform dispersion. Since the solid does not dissolve, it therefore needs to be evenly dispersed throughout the liquid vehicle to give a uniform concentration, which in turn ensures a correct dose for the patient. The first step to ensure a uniform dispersion of drug is to have the solid in as fine a particle size as possible. Next, we must displace the air on the surface of the drug molecules with liquid. In other words, we need to get the liquid to interact directly with the drug molecule, and to do that we must replace the air that is on its surface. To accomplish this we use the technique called wetting a powder. To explain the technique, we must first define some terms. The first term to define is surfactant. Surfactants are ions or molecules that are adsorbed at interfaces. Their molecular structures contain both hydrophilic and hydrophobic portions. The second term is a wetting agent. Wetting agents are surfactants that are dissolved in water, and lower the contact angle between the surface of the solid, and the aqueous liquid and thereby aids in displacing the air phase at the surface, and replacing it with the aqueous liquid phase. Therefore, we use a wetting agent, which is a surfactant, to accomplish wetting of a powder. Wetting occurs when a liquid displaces air at the surface of a solid, and the liquid spontaneously spreads over the surface of the solid. Now the question is, what do we used to accomplish wetting, what sort of liquid do we need to use? In rare cases, for hydrophilic powders, wetting can be accomplished by just using water, or commercial flavoring vehicles. However, most often powders are hydrophobic, and do not wet well using just water. Thus, wetting is usually accomplished using a high surface tension, or surfactant-containing vehicle. These types of liquids are commonly referred to as suspending agents. Most compounding procedures have the powder, once triturated, being slowly and carefully wetted, using a surfactantcontaining suspending vehicle that has a high surface tension. The suspending agent displaces the air from the solid and facilitates its dispersion throughout the liquid phase. Simply using a waterbased flavoring vehicle is inadequate for wetting powders because they do not contain surfactants, and have too low a surface tension for most powders. Failing to adequately wet powders, results in suspensions with clumps and causes non-uniform drug concentration and dosing. 5

6 The next two desired properties of suspensions will be discussed together because they are inter related. By that I mean, suspensions need to have a slow sedimentation rate, and yet at the same time be easily re-dispersed. Sedimentation of the solid particles begins as soon as we stop shaking the bottle. Gravity will begin to pull the particles down, through the liquid to the bottom of the bottle. While we can not prevent sedimentation from occurring, our suspension should be formulated to retard or slow this process. Sedimentation can be slowed by having a small particle size because these particles will settle more slowly. Secondly, sedimentation can be slowed by increasing the viscosity of the liquid vehicle. Most suspending agents not only have surfactants that increase surface tension, but also increase viscosity. The combination of small particle size solids, in a viscous liquid, both combine to slow sedimentation long enough to allow a dose to be measured and administered. However, caution must be taken to avoid creating a suspension which is too viscous. Suspensions should be sufficiently fluid, so that re-dispersion of settled particles is easily accomplished with normal shaking. The liquid should also pour freely from the container when a dose is to be administered or applied. Thus, careful use of viscosity-increasing agents is warranted. Besides being too viscous, another problem which can prevent a suspension from being easily redispersed is caking. Solids in a suspension can, over time, form a hard cake on the bottom of the bottle, when the preparation is allowed to stand. This can occur because very fine particles have a tendency to aggregate, and eventually fuse together into a non-dispersible cake. Because caking requires time to develop, a conservative beyond-use date should be assigned to the product. One way of minimizing caking is to use a commercially prepared suspending agent which is flocculated. Flocculation is a technique often used in the pharmaceutical industry, because it produces a controlled lacework like structure of particles, held together by weak bonds. These weak bonds hold the particles in the structure when the suspension is at rest, but break apart easily when the suspension is shaken. Thus, while shaking the bottle, the bonds are broken and the solids are free to re-disperse throughout the liquid. However, when shaking is stopped, the bonds reform and help keep the solids suspended, and work to slow the eventual sedimentation. 6

7 We have finished our discussion on the desired properties of suspensions, and will now talk about the three actual components used to formulate a suspension. The first is the active drug itself, usually in a powdered or solid form. The second is a suspending agent, used to wet the powder and increase the viscosity of the liquid, in order to maintain the drug dispersion. The third component is a liquid vehicle or diluent that is added to the suspending agent, so that the suspension has the correct final volume and concentration. However, note that the diluting vehicle is often under appreciated. The vehicle confers important properties to the suspension. The vehicle provides a certain degree of sweetness, as well as flavor, and color, all of which are for palatability and patient acceptance. This is particularly important as many compounded suspensions are formulated for children. Beyond flavoring, the vehicle must also provide a preservative for the prevention of microbial contamination. We will now discuss in more detail, how to prepare a suspending agent, and how to formulate an appropriate flavoring vehicle. 7

8 There are three main types or categories of suspending agents, that are used to increase the viscosity of extemporaneously compounded suspensions. The first category includes the semi synthetic cellulose derivatives. Examples are all closely related compounds, and include methylcellulose, and sodium carboxy methylcellulose. When not using a commercially prepared product, semi synthetic cellulose derivatives are the most commonly used agents for formulating oral suspensions. Nevertheless, they are not the only category of viscosity inducing agents that can be used. The second category are natural polymers, which are naturally occurring gums. Examples include tragacanth, xanthan gum, but the most commonly used natural gum is acacia. Acacia is also known as Gum Arabic, and is harvested from the stems and branches of various species of the Acacia tree. Acacia has been used for many years and is most frequently used in the preparation of emulsions. Thus, we will not further discuss the use of acacia or natural gums for compounding suspensions, but rather discuss their use in more detail during the lecture on emulsions. The third category of suspending agents are synthetic polymers, including the carbomers and poloxamers. Carbomer is a high molecular weight copolymer of acrylic acid, whereas poloxamer is a copolymer of ethylene oxide and propylene oxide. Interestingly, poloxamer has a unique property that allows it to create thermo reversible gels at concentrations above 20%. Because of their unique gelling properties, both carbomer and poloxamer are commonly used for compounding topical gels. As such, we will not discuss them further for oral suspensions, but cover both of them in more detail during the lecture on gels. In summary, of the three categories of suspending agents, semi synthetic cellulose derivatives are the most commonly used agents for increasing the viscosity of oral suspensions. 8

9 The prototype semi synthetic cellulose derivative used in the formulation of oral suspensions is methylcellulose. However, while methylcellulose is the most commonly used form, there are other derivatives such as sodium carboxy methylcellulose, and hydro propyl cellulose. Nevertheless, methylcellulose is most often used because it has several advantages. It produces a gel-like matrix which is clear, colorless, and odorless. Methylcellulose has a neutral ph, and is stable over a wide ph range, going as low as 3 and as high as 12, making it compatible with many drugs. Its compatibility is also increased because it is not an electrolyte, and thus non-ionic. Different concentrations of methylcellulose can be used depending on the desired viscosity of the final product. For oral suspensions, methylcellulose within a range of 1 to 2% is typically used. Using methylcellulose does have some disadvantages. For example, methylcellulose solutions and gels are susceptible to bacterial and mold growth, and therefore require the use of preservatives like benzalkonium chloride to prevent spoilage. Secondly, flavoring and sweetening are required to improve the palatability of methylcellulose suspensions, meaning they taste bad by themselves. Lastly, and most importantly, and is why we do not have students prepare methylcellulose suspensions in lab anymore, is that they are difficult, and time consuming to prepare. However, it is precisely because we do not have you practice preparing one in lab, that I want to be sure and cover the step-by-step procedure in this lecture. The procedure for creating a methylcellulose suspension is given on the next slide. 9

10 To make a 1% methylcellulose suspension, begin by weighing the required amount of methylcellulose powder. Next, in a glass beaker measure out a volume of water that is onethird of the total volume to prepare, place this beaker on a hot plate, and heat the water to near boiling. Add a stir bar and get the hot water stirring very quickly. Next, slowly sift in the methylcellulose powder into the very quickly stirring hot water. All of this technique is needed to prevent the methylcellulose powder from clumping together. So, sift in a little powder, let it disperse, sift in a little more, let it disperse, and continue this routine until all of the methylcellulose has been added to the hot water. As soon as it has all been added, take the beaker off the hot plate, and continue stirring while adding ice chips to cool down the solution as quickly as possible. Continue to add ice chips, which will quickly melt, until you have added another one-third of the total volume. As it cools, the solution will start to become much more viscous. Lastly, add enough room temperature water to get the correct, final volume. The final solution will be clear, colorless, odorless, and viscous enough to make a proper oral suspension. In summary, methylcellulose is a very effective suspending agent, but unfortunately requires a lot of time and patience to prepare. 10

11 We have finished reviewing how methylcellulose can be used to create a viscous, gel-like fluid for formulating suspensions. The main disadvantage to using methylcellulose is its time-consuming preparation. Fortunately, pharmacists are not limited to having to prepare their own suspending agents. There are commercially prepared suspending agents, which possess many of the desired properties we have discussed. These products provide increased viscosity, and are highly flocculated systems that prevent caking and facilitate redispersion. Commercially prepared suspending agents are preserved and buffered to accommodate a range of ph. Most commercial suspending agents are available as unflavored and unsweetened, basically being a bland tasting, cloudy white appearing liquid, that allows the pharmacist to flavor and color the final product as desired. Newer products even combine, or pre-blend suspending and flavoring vehicles into one product for even quicker compounding. The take home message is, having a suspending agent premade in a bottle saves the compounding pharmacist a lot of time and effort. Because these products work well, and are easily obtainable through common pharmaceutical vendors, their use is standard practice for compounding suspensions. Therefore, we no longer have students prepare methylcellulose suspensions. Rather you will learn and practice how to use the commercial products correctly. Please understand, while suspending agents are available commercially, and no longer have to be prepared, they still have to be used correctly, meaning the correct type of product must be used in the correct volume and mixed in an appropriate ratio with other vehicles. Moreover, having many different commercial products means the pharmacist must know the brand names of the products, and whether they are suspending agents, or flavoring agents, or a pre-blended combination of both. 11

12 2 We will start by comparing and contrasting two commonly used commercially available suspending agents. A very commonly used suspending agent in retail practice is Ora-Plus. Ora-Plus is an oral suspending vehicle, formulated from a combination of both sodium carboxy methylcellulose and xanthan gum, and is buffered and preserved. Ora-Plus does not contain any flavor or sweetening in it, and therefore tastes very bland. Another commonly used suspending agent is Suspendol-S. Suspendol-S is formulated differently, using a combination of carbomer and polysorbate 80, but is likewise a solution that comes already buffered and preserved, but not flavored or sweetened. This product was first marketed primarily for use compounding different types of external suspensions including vaginal and rectal use suspensions. However, it can just as well be used in the preparation of an oral suspension. It is worth remembering that while either product can be used for oral suspensions, Suspendol-S would be the more appropriate choice if compounding a suspension for external use. Now, regardless of which of these two products you intend to use, they are typically used by mixing them in a 1 to 1 ratio with a flavoring vehicle. So, choose an appropriate suspending agent and use one-half the total volume to compound as suspending agent, and the other one-half of the volume as flavoring vehicle. For example, if compounding a suspension with a final volume of 100 ml, you would use 50 ml of suspending agent, and 50 ml of flavored vehicle. How, and the order in which these products are combined is very important, but we will discuss the actual compounding procedure in much more detail later. For now, it suffices that you understand commercial suspending agents are generally used in a 1 to 1 combination by volume with a flavoring vehicle. 12

13 Note that we have now discussed two out of the three components of a suspension, namely the active drug or solid powder being one component, and the second being the suspending agent. The third and only remaining component of a suspension to discuss is the vehicle or diluent to use. A too simplistic understanding of the vehicle is that it is only used to complete and give us the final correct volume, and thus correct drug concentration. If that were its only purpose, then we could simply use water. While water might work to give us the correct final volume, the final product would simply taste and look bad. Water by itself does not confer properties to our suspension that are absolutely required. Vehicles that flavor, sweeten, and color, are added to oral suspensions to improve patient acceptance of the preparation. Selecting a desirable flavor is especially important, because patient adherence to a medication may depend on the flavor, especially for children. So, the vehicle is really our unsung hero, it not only provides for the correct final volume, but also helps create a suspension that is acceptable to our patient. 13

14 So, if we were to make our own vehicle or diluent for a suspension, we would start with water. Next, we would have to sweeten it, using a natural sweetener like sucrose, or an artificial sweetener like sorbital, or saccharin. Next, we would have to flavor it, to mask the bitter taste of most drugs, by adding oils or alcoholic concentrates of various flavors such as cherry, grape, or orange. However, the choice of flavor to use often differs by the age of the patient. For example, children tend to prefer sweet, fruity and bubblegum flavors, whereas adults often prefer flavors like chocolate, coffee, licorice or butterscotch. Flavoring is so important there are actually commercial flavoring systems like Flavor R x, and PCCA flavors, that come with all of the flavoring solutions, as well as recipes for masking specific drug tastes. Next, the vehicle would need to be colored, often in a way to psychologically match the flavor, meaning a cherry-flavored product should be red, while a grape-flavored product should be purple. In either case, the colors should be light, nobody wants to consume a blood red, or dark purple almost black medicine. On the other hand, there are some patients who would prefer to have a dye free product, or may have had a reaction to a commonly used food dye. Coloring is certainly optional. Finally, our vehicle would need to be free from microbial growth, through the addition of a preservative such as sodium benzoate, potassium sorbate, or methylparaben. All of these properties, namely sweetness, flavor, color and preservatives are necessary in our vehicle. Wow, that would be a lot of work to make one our self. Thankfully, we can save a lot of time and effort using a commercially-prepared flavoring vehicle. These vehicles are available from a variety of manufacturers and in many different combinations. By combinations I mean, a sweetened product can be either flavored or unflavored, colored, or not colored, sweetened naturally by sucrose, or artificially to be a sugar-free product. Thus, while using a commerciallyprepared vehicle is simple, choosing the correct product requires the pharmacist to know what brand name products are available, and when to choose which product. 14

15 We will divide our discussion of commercially-prepared vehicles into those that are sweetened naturally using sucrose, which are discussed here, and those that are artificially sweetened and are thus sugar free, and will be discussed on the next slide. So here, all of these products are commonly used, sugar or sucrose sweetened vehicles. In my opinion, they are also the best tasting, since they are much sweeter than their sugar-free versions. The first example given is Ora-Sweet, which is a very sweet product but only mildly flavored with what is described as citrus berry. The flavor is pleasant, but mild, and as such works better for adults in general, as well as for drugs that do not have a strong or bitter taste that needs to be masked. In contrast, Syr Palta, which is another commonly used vehicle, while also sweet, also gives a strong, robust grape flavor. The stronger flavor would be preferred by children in general, and could help mask a mildly bitter drug. Syr Palta is also an example of a vehicle which is available either colored to match its grape flavor, or without added color. Probably the oldest example of commercially produced vehicles are called simple syrups. Simple syrup is just that, meaning it is very sweet but with no discernable flavor. Other versions of simple syrup are made by adding very distinct flavors, such as orange syrup, or my personal favorite, cherry syrup. These fruit flavors work well for children, and myself, but there are also flavors more directed towards adults such as chocolate or cola. In summary, sugar or sucrose based vehicles may have different flavors, but all are very sweet, more so than the sugar-free versions discussed next. Examples to remember are Ora- Sweet, Syr Palta, and Cherry Syrup. 15

16 More recently, manufacturers now prepare flavored vehicles which are artificially sweetened. These products are targeted for use in patients who need to avoid, or limit their sugar intake, such as patients with diabetes. The first example is Ora-Sweet SF, which is formulated with the same mild citrus berry taste as the regular Ora-Sweet, but is sweetened here using a combination of sorbitol and saccharin. Another sugar-free alternative that provides a stronger, more child friendly cherry taste, is the product Oral Syrup SF, made by Medisca. Alternatively, sorbitol solution USP is a 70% weight per weight solution of sorbitol, which is like simple syrup in that it is sweet, but with no flavor. This product could then be flavored as desired. The take home point is that there is a sugar-free way to meet whatever flavoring requirement you have, when compounding a suspension for a patient needing to avoid sugar. 16

17 At this point I want to summarize the commercial products we have discussed. I have described both commercially-prepared suspending agents, such as Ora-Plus, as well as flavoring vehicles, such as Ora-Sweet. Remember, I said that these pure suspending agents are to be used in a 1 to 1 ratio with a flavoring vehicle. What could be simpler? Well, what if there was a commercially-prepared product that was actually a preblended mixture of suspending agent and flavoring vehicle. This slide gives various examples of just such products. But before describing specific examples, I want to emphasize that all of these products contain both a suspending agent, and as such have an increased viscosity, as well as already being sweetened, flavored, and possibly colored. They are also all buffered and preserved. The first specific example is Ora-Blend, which is a pre-blended, 1 to 1 mixture, of Ora-Plus and Ora-Sweet. The combination product Ora-Blend is available in both regular and sugar-free formulations. Alternatively, the company that makes the flavoring vehicle SyrPalta, has combined it with a suspending agent and calls it SyrSpend. It is actually available in multiple flavors, and in sugar-free formulations. One interesting variation is SyrSpend SF Alka, which is a formulation designed for use with drugs that are stable at a higher ph, like omeprazole. At this point I want to stop and point out something very important. All of these commercially-prepared products are easy to use, but students often have problems remembering what specific products do, by their brand name. For example, the use of the word Ora in the name, helps create brand loyalty, but also can cause confusion and potentially misuse. In pharmacy skills lab, we will only accept a formulation made using Ora-Plus in a 1 to 1 combination with Ora-Sweet, or the single use of Ora-Blend. It would be considered inappropriate to use Ora-Plus in combination with Ora-Blend, since that combination exceeds the required amount of suspending agent needed, would not taste as well due to having less flavoring vehicle, and is simply not the way the products were intended to be used. Moreover, we have had students in lab use only Ora-Sweet, thinking it was the pre-blend combination product Ora-Blend. A take-home point is this, while pharmacists no longer have to make their own suspending and flavoring products, they must use the commercially-prepared products correctly. Using commercially-prepared products, in a way they were not intended to be used, is considered a compounding error. On exams, we often set out all types of bottles, and expect that a pharmacy student should be able to examine a bottle, know what the product is, and know how or if, the product should be used in their formulation. 17

18 We will now begin our discussion of the actual compounding procedures to follow, when compounding a suspension using commercially-prepared suspending agents and flavoring vehicles. From the beginning, it is crucial to understand that there are actually two distinctly different methods that can be employed to prepare a suspension. I attempt to help you distinguish between the two methods by calling the first, the exact method, and the second, the excess method. Each method has its own advantages and disadvantages, and students must understand both how, and when to prepare a suspension using each method. So, beginning with the exact method, as the name implies, we will base our calculations and procedures on the preparation of the exact quantity prescribed. This methods greatest advantage is that its calculations and procedures are straightforward. You calculate and prepare exactly what was prescribed. From a practical standpoint, we can prepare a suspension using the exact amount to dispense because by using commercially-prepared suspending and flavoring vehicles, as well as employing careful and conscientious compounding techniques, there is very little if any loss of product during the compounding procedure. Now, I said the exact method was the most straightforward, I did not say it was the quickest. The title of quickest way to compound a suspension goes to the excess method. Many pharmacists are busy, and would prefer slightly more complicated calculations, if in the end it saves them preparation time. The excess method accomplishes this by having the pharmacist determine a volume, greater than that prescribed, but that allows the suspension to be compounded using an even number of tablets or capsules. This reduces the amount of weighing and other procedural steps, which we will discuss later, all of which results in less time needed to compound the suspension. It is also important to understand that while we compound excess volume using this method, only the prescribed volume would be dispensed to the patient, the remainder would be discarded. Thus, one clear disadvantage to the excess method, besides the more complicated calculations, are the extra costs associated with discarded drug, and the fact that it should not be used for controlled substances, which can not be freely discarded. The next couple of slides will cover the calculations and procedures for both the exact, and excess methods. However, I want to first reemphasize that the two methods differ in both calculations and procedures. For example, pharmacy students often make mistakes by calculating drug amounts using the excess method, but then actually compound the suspension using the exact method procedure. This results in a serious compounding error, and a suspension with an incorrect concentration that could potentially lead to an overdose. It is crucial to associate together both the methods calculations as well as its procedure. 18

19 9 I will start by reviewing the calculations required for compounding a suspension using the exact method. An important concept to begin with is the source of active ingredient. One possibility is that the source of active ingredient is from bulk powder. That is the simplest situation, because bulk powder is 100% active ingredient, so the amount you need, is the amount you weigh. However, this is not often the case when extemporaneously compounding suspensions. What is more likely, is that the source of your active ingredient will be powder obtained from a commercially-prepared tablet or capsule. Unlike a bulk powder, drug powder from tablets and capsules is not 100% active ingredient. Most of the time there are other ingredients such as binders, or fillers, or other excipients. For example, you might have counted and dispensed 100 microgram tablets of the commonly used drug levothyroxine, or Synthroid. Clearly, there has to be excipients in these tablets because 100 microgram, which is one-tenth of a milligram, is so very little, you could not hold or probably even see that small of an amount. Regardless of what is actually in the powder, all excipients have weight, and that weight must be accounted for when calculating how much powder is needed to provide the correct amount of the active ingredient. Another point to make is that when compounding suspensions, we can only use a drug source that is in powdered form. Therefore, tablets containing our drug, need to be crushed into a fine powder using trituration and a mortar and pestle. Capsules can likewise be used for providing drug powder, by separating the two parts of the capsule shell and carefully squeezing out the powder and discarding the shell. Remember, when obtaining drug from a capsule, only weigh the powder, or contents of the capsule, do not include the capsule shell. So, whether from a crushed tablet, or the contents of a capsule, the powder has both active drug and excipient. We will refer to powder that has both active drug and excipient as crushed tablet powder, abbreviated CTP. Please note that the term CTP also applies to powder obtain from inside a capsule. I could not think of an abbreviation that encompassed both situations so I just went with CTP to include both tablets and capsules. Next, you must know how to determine how much CTP powder is needed to provide a specific amount of active ingredient, abbreviated A I, in these calculations. Remember, because of the presence of excipients, CTP will always weigh more than A I. 19

20 The calculations when using the exact method start by determining the total weight of active ingredient, or A I, needed for the suspension. The total weight of A I required, can be calculated by taking the desired concentration, and multiplying it by the exact volume to prepare. Next, using a digital balance, determine the weight of 2 tablets, or the contents of 2 capsules. The reason for weighing 2 of them is to reduce the amount of error introduced by variations in tablet or capsule weight. Note, at this point tablets should not be crushed, 2 intact tablets weigh the same as 2 that have been crushed, so do not crush them yet. Also, I can not emphasize enough that when using capsules, obtain the weight of the powder contents within 2 capsules, without the shells. I have often seen in lab, a student place two intact capsules on the scale to obtain the weight. This is wrong, open the capsules and only weigh the powder contained in the two capsules. Now, at this point we have all the information needed. Next, set up a ratio as shown on this slide. Begin by specifying the amount of A I in the two tablets or capsules. This comes from the product labeling. For example, if using 100 microgram levothyroxine tablets, then 2 of those tablets contain a total of 200 micrograms. Below the amount of A I in 2 tablets or capsules, place the actual weight of the 2 tablets or capsules. This amount comes from your weighing. Set this ratio equal to, the total weight of A I required, over x. Solving for x, equals, the weight of crushed tablet powder, or CTP needed to provide the required amount of A I. The next slide will work through these calculations using a specific example. 20

21 To illustrate these calculations, we will use an example. We need to compound 30 ml of a suspension of drug Z, with a concentration of 19 mg/ml. Begin by calculating the total weight of A I needed. Take the exact volume to prepare, which is 30 ml, and multiply by the concentration, which is 19 mg/ml, which equals 570 mg of drug Z needed. Next, identify our source of drug Z, which turns out to be available only as 100 milligram tablets. Next, determine the weight of 2 of these 100 milligram, drug Z tablets. Using a digital balance, we determine that 2 tablets weigh 320 mg. Next, set up the proportion of the amount of A I in two tablets, which was 200 mg, over, the weight of these 2 tablets, which was 320 mg. Set that proportion equal to, the total amount of drug Z needed, which was 570 mg, over, x. Solving for x, we determine that 912 mg of crushed tablet powder or CTP, will provide exactly 570 mg of drug Z. 21

22 We are now ready to discuss the procedures for compounding a suspension using the exact method. The first step would be to perform the calculations just described to determine how much crushed tablet powder to use. Next, we would crush and grind tablets to a fine powder using a mortar and pestle, and then weigh the required amount of crushed tablet powder. Place all of that powder into the bottom of a clean dry mortar. The next step is to wet the powder using the suspending agent. This is a very important step. To successfully wet the powder you must use a suspending agent, because of its higher viscosity, and you absolutely must begin by adding very small amounts. Remember, wetting is the process of displacing air from the surface of the powder, and replacing it with liquid. It requires a viscous liquid, and energy in the form of trituration in order to accomplish wetting. If too much liquid is added at first, clumps of powder will begin to float in the liquid, and the energy required to force air off that powder can not be applied, because the powder clumps simply float away from the pestle when you try to grind or break them up. If too much liquid has been added too quickly, there is nothing that can be done besides starting over again. To avoid this problem, use the correct technique from the start, which is, depending upon how much powder you have, add no more than 2 to 5 ml of suspending agent. Then, use the pestle to actively force the liquid into the powder. Clumps will form, but all of the liquid, because of its relatively smaller volume, should be absorbed. Thus, you can still actively triturate and grind the liquid into the powder, which is the process of wetting. Once the initial amount of liquid has been completely absorbed, add another addition of 2 to 5 ml, and continue the process. As enough liquid is added, in small portions, the powder slowly transforms into a paste, and then further into a slurry. Once the powder has become a thick, but liquid slurry, then you can increase the volume of suspending agent added, always thoroughly mixing between additions, until all of the suspending agent has been added. By the end of the wetting process, all of the suspending agent should have been added to the mortar, and a uniform mixture obtained. I will emphasize again, the key to creating a good suspension is completely wetting the powder. This process can not be done too slowly, but it can be done too quickly, causing the compounder to have to start all over again. The video on the next slide illustrates the wetting procedure. 22

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24 Once the powder is completely wetted, and all of the suspending agent has been added, the next step is to pour this primary suspension into a calibrated prescription bottle. Ensure the bottle has markings to indicate the final volume to prepare, as well as being oversized enough to allow room at the top for shaking the product prior to use. Once all of the primary suspension has been added to the bottle, begin the process of rinsing the mortar and pestle using small increments, about 5 to 10 ml of the flavoring vehicle. This is also an important step for the exact method. This method assumes that all of the drug will be transferred into the final bottle. Thus, care must be taken to ensure drug is not lost or left on the sides of the mortar, or attached to the pestle, or a spatula. Use flavored vehicle rinsings to recapture all the drug by rubbing it along the sides of the mortar, and on top of the pestle. Always pour the rinsing into the dispensing bottle before rinsing again. Continue the process of rinsing, cleaning and pouring into the final bottle over and over again, until all of the drug has been retrieved. From our experience in lab, it takes most students from 3 to 5 rinsings to thoroughly clean and retrieve all of the drug into their dispensing bottle. The last step, is add enough flavoring vehicle to the dispensing bottle to ensure the correct final volume. The exact volume to add at this step is unknown, as some amount of flavoring vehicle will have already been added during the rinsing steps. What is important, is that enough flavoring vehicle is added to get the correct final volume of suspension. An important quality assurance step for suspensions, is that it has the correct final volume. Once enough flavoring vehicle has been added, cap the bottle tightly and shake vigorously to create the final suspension. That completes the procedure for using the exact method to create a suspension. Before proceeding, the video on the next slide illustrates the very important rinsing process required when using the exact method. 24

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26 We will now start discussing an entirely different approach to formulating a suspension, namely the excess method. Recall, the advantage to using the excess method is that by spending a little more time on calculations, we can save a lot of time on the actual physical procedure. Specifically, the excess method avoids having to perform crushed tablet powder weighing and calculations, as well as the need for having to repeatedly rinse the mortar. This is accomplished because the excess method creates a volume of suspension that allows an even or whole number of tablets or capsules of active ingredient to be used. Moreover, the entire suspension is made in the mortar and then only the prescribed amount poured into the dispensing bottle, eliminating the need to rinse the mortar. The excess method is probably best described using an example. On this slide we will perform calculations for the excess method of preparation for 60 ml, of aceta zolamide 30 mg/ml oral suspension. The source of active ingredient is aceta zolamide 250 milligram tablets. Begin by calculating the total amount of active ingredient required, by multiplying the total volume of 60 ml by the concentration of 30 mg/ml, which equals 1800 mg. This step is the same as the exact method. However, with the excess method we stop and ask ourselves, how many tablets would that be? The answer is obtained by taking the required amount of active ingredient, 1800 mg, and dividing it by the amount of drug per tablet, which is 250 mg, which equals 7.2 tablets. A savvy pharmacist would say to themselves, that amount is inconvenient, it would be much easier if it were eight or more tablets exactly. So, the next step in the excess method is to determine how much excess suspension to compound, in order to make the required number of tablets convenient. This process takes some trial and error. Also, remember that regardless of how much excess we compound, the suspension must always have the prescribed concentration of 30 mg/ml. So, begin by asking what would happen if you chose to use 8 tablets. In that case, 8 tablets, times 250 mg, equals, 2000 mg of aceta zolamide. Next, take that amount, and divide it by the required concentration of 30 mg/ml, to discover that 8 tablets, or 2000 mg, would make a final volume of 66.7 ml, to have the correct concentration of 30 mg/ml. So, while the number of tablets is more convenient, the final volume is not. Scratch that idea, start again. We need the total amount of drug required to be evenly divisible by both the tablet strength, which is 250 mg, and also by the concentration of 30 mg/ml. Wait, so instead of 2000 mg, as was the case for 8 tablets, what about 3000 mg? That would be divisible by both 250 and 30, lets give it a try. Start by taking 3000 mg and dividing it by 250 mg of aceta zolamide per tablet, which equals exactly 12 tablets. So far so good. Next determine the volume of suspension to prepare by dividing the total amount of drug, which is 3000 mg, by the required concentration of 30 mg/ml, to find that using 12 tablets would make 100 ml of a suspension have a concentration of 30 mg/ml. Perfect! In summary, using the excess method, we have formulated a suspension that will use 12 tablets of aceta zolamide, and prepare a suspension with a total volume of 100 ml, but will only dispense 60 ml to the patient, with the remaining volume discarded. Many of you may be thinking that this is a lot more work than the exact method, and it is, in terms of the calculations. However, with practice it becomes easy to quickly work a couple of possibilities, until a convenient combination is found. The benefit to the excess method really becomes evident on the next slide where we describe the compounding procedure. 26

27 We will now describe the procedure for compounding a suspension using the excess method. Begin by performing all of the calculations just described. Once those calculations have been performed, begin by placing the required number of tablets in a mortar, which was 12 in our aceta zolamide example, and crush and grind the tablets into a fine powder using the pestle and trituration. Next, carefully wet the powder using a suspending agent. This step is exactly the same as I described for the exact method. It suffices for me to reiterate the need to go slowly, with small initial volumes of the suspending agent, and continue, until the powder is completely wetted, and all of the suspending agent has been added. Now, at this point comes a fundamental difference between the two methods. When performing the excess method, do not pour this primary suspension into the final dispensing bottle. Let me repeat myself. Do not pour the primary suspension into the bottle. Instead, begin adding the required amount of flavoring vehicle, in portions, into the mortar. Be sure and thoroughly mix between additions of the vehicle. Continue until the entire volume of flavoring vehicle has been added and mixed. At this point, the entire compounded suspension should be in the mortar. Using our aceta zolamide example, there would be all 100 ml of the suspension in the mortar, and because we had started with 3000 mg of drug, the suspension in the mortar would have a concentration of 30 mg/ml. This is what I mean by making the entire suspension in the mortar first when performing the excess method. The last step in the method is simply, but carefully, pour the prescribed amount of suspension into a graduated final dispensing bottle. Using the aceta zolamide example, we would pour exactly 60 ml of suspension into a graduated 3 or 4 ounce oversized bottle, to allow for shaking. Once the correct volume has been added, the bottle would be tightly capped. This method simplifies the compounding process by eliminating the need to perform CTP calculations and procedures as well as eliminating the time consuming need for rinsing the mortar. Nevertheless, remember that with the excess method there are additional costs, and controlled substances should not be used. 27

28 Next we will discuss preparation guidelines for compounding suspensions. The first guideline to discuss is quality assurance. To ensure the quality of the final product, the pharmacist should document in the compounding record, the final volume of suspension dispensed, the size of the dispensing bottle, color of the suspension and any odor, the extent of particulate settling, the ease of re-dispersibility, as well as pour ability. The pharmacist might consider measuring the extent of settling in a formulation when preparing a master formula, by allowing the product to sit for a day and then measuring the height of the settled particles. The second preparation guideline is beyond use dating. Always look for published stability data for any formulation. However, in the absence of stability information, use USP chapter 795 general recommendations for water-containing, oral formulations, which states that the beyond use date is not later than 14 days when stored at controlled cold temperatures. Cold temperatures, in this context, is generally accepted as between 2-8 C, or between F. This conservative, 14 day, beyond-use date is due to concern over drug stability, since drug powder, once liquefied, becomes physically unstable by nature. There is actually less concern about the potential for microbial contamination, since most suspensions use commercially-prepared suspending or flavoring vehicles which already contain preservatives. Nevertheless, refrigeration is required to help slow the growth of any potential contamination. 28