Introduction to Compounding

1. Introduction to Compounding • Compounding in Pharmacy refers to the special preparation of drug products that are uniquely tailored to a patient’s needs medically and otherwise. • Extemporaneous is often an adjective that describes this unique characteristic of compounding. • What is compounding?, what is Manufacturing? • According to the FDA, compounding is • Made to dispense a product on the basis of a Rx for a specific patient’s needs • Pharmacist can not compound a copy of a commercial available product • Pharmacist can not sell his/her product without an Rx • Can’t advertise the product (i.e. they can advertise their compounding service but not the product itself)

2. Extemperaneous Compounding • Pharmacy makes a unique product dose form for a specific patient, i.e acetaminophen 2% cream • USP 795 says that expiration dating for these products should not exceed 25% of the time remaining among the manufacturer drug product or six months into the future which ever is earliest • Any product where water is add to a solid dosage form is given 14 days under refrigeration unless published data state otherwise

3. Compounded items can be: creams, ointment, solutions, suspensions, intravenous solutions, capsules, suppository, etc. • Solutions are homogenized mixtures of drug in aqueous medium. • Suspensions are heterogeneous mixtures of a drug in aqueous medium. These mixtures often require the shaking of the drug before the suspension can be given. • Intravenous solutions are aqueous drug mediums that are free of particles; they are sterile and pyrogen free • Capsules are oral dosage forms that are enclosed in a gelatin casing that dissolves in the stomach and small intestine • Gelatin capsules come in sizes from 000 to 13. • 00o is the largest size • 13 is the smallest size • Suppositories are dosage forms that are applied rectally. They are usually made of material like glycerin which melts at slightly below body temperature. Used for patients that can’t swallow due to neurological disorders (dysphagia)

4. Special Compounded Dosage Forms • Emulsions are mixture of two non mixable liquids in a stabilized medium. Normally, oil in water do not mix; however, a compound can be made (an emulsion) where the two liquids can be “mixed” with each other. • Examples in pharmacy are creams and lotions. • Examples in food are mayonnaise and milk (fat mixed in water) • Two types of emulsion are oil in water (o/w) or (w/o)

5. References for Compounding • Remington’s Pharmaceutical Sciences • Trissel’s Stability of Compounded Formulations • Drug Facts and Comparisons • United States Pharmacopeia • The International Journal of Compounding Pharmacists

6. Compounding Equipment • A more complete list is mention in the text • The more important ones are following • Balance, class A, required in every pharmacy by the state board • Beakers • Filter papers • Graduated cylinders • Hotplates • Molds • Mortar and pestle • Ointment slab • Spatulas • Weighing paper

7. Mortar and Pestle • Very important in compounding • represents a symbol of the pharmacy profession. Shown as • Used to comminutate or triturate a substance to smaller particle sizes. Smaller particle sizes are a key to make certain compounds more appealing to the touch and taste. • Glass mortar is used to mix liquids with powder and porcelain is used for granular powders

8. Solutions • Aqueous or Hydroalcoholic mixtures that are solvents for homogenized solute/solvent system • Solute : drug that is mixed into the system • Solvent: the vehicle or medium used to carry the solute • Solvents include: • Purified water USP: contains no more than 10 ppm solids • Sterile water for injection USP: same as purified water except for sterility and pyrogen free state: used to mix IV drugs • Sterile water for Irrigation USP: used to make oral solutions

9. Types of solutions • Simple Syrup USP: 85% w/v sucrose in water. • Excellent vehicle for a sweeten drug dosage form for children • Self Preserving: no antibacterials • Elixirs • Water and alcohol cosolvent systems • Typically as some sugar also • Usually about 10%w/v to 40% w/v alcohol • Aromatic Waters • Mixture of water, alcohol, and a volatile oil • Jasmine water is water, alcohol and jasmine oil • Spirits or Essence • Mixture of water, alcohol and volatile oil where alcohol content is 50% to 90% • Tinctures • Hydroalcoholic mixtures where concentration of drug is 10% • 10% is the concentration of the whole plant source; 1% is the active drug • Ie. Opium Tincture is 10% in opium and 1% or morphine

10. Characteristics of Solutions • Benefits • Provides an easy way to measure doses for small patients and babies • Provides a way to increase bioavailability of the drug • Drugs can be sweeten and flavored to mask bad taste • Disadvantages • Bulky dosage form • Susceptible to hydrolysis with water

11. Suspensions • Heterogeneous mixture of drug into a medium that normally it does not dissolve in. • System consists of water, drug powder, sweetener, flavorants, colorants and an agent called an surfactant which “thickens” the medium to allow particles of drug to remain “suspended” • In systems with no surfactant the drug particles quickly settle to the bottom and aggregate. • Surfactants allow the system to be uniform long enough to measure a dose • “Shake before using” is normally require as an auxiliary label

12. Surfactants • Acacia • Methylcellulose • Carboxymethylcellulose • Xanthan gum • Carrageenan • Amylopectin • Bentonite magma 5% (exhibit thixotropy: gels on standing and liquefies on shaking) • Other name for surfactants are Suspending agents • A Common commercially available suspending agent is OraPlus ®

13. Emulsion • A pharmaceutical system where two immiscible liquids are mixed together to form a stable system • Normally two immiscible liquids like water and canola oil don’t mix and the less dense oil beads to the top • Purpose of Emulsion • Increased drug stability (drug that under hydrolysis in water may be more stable in emulsion) • Better applicability in topical administration • Two phase of the emulsion • Internal phase- the dispersed liquid • External phase-the dispersion medium liquid • If water is the dispersed liquid you have a w/o emulsion • If oil is the dispersed liquid you have a 0/w emulsion • The type of emulsion formed depends on the phase volumes and the type of surfactant or emulsifier used to stabilize this system

14. Emulsion Types • A classic o/w emulsion is vanishing cream • A classic w/0 emulsion is a lotion

15. Emulsifying Agents • Emulsifier or surfactants are agents that stabilize an emulsion. • As emulsions age, they destabilize and separate in two phase (i.e. milk that is old separates). This is called cracking and means the emulsion is destabilized • Emulsifiers can be natural or synthetic • HLB (hydrophilic Lipophilic Balance) Scale is measure of what type of an emulsion is created when used a given emulsifier • HLB<9 tend to form w/o • HLB>9 tend to form 0/w

16. Emulsifier • Natural • Acacia • Tragacanth • Agar • Methylcellulose • Carboxylmethylcellulose • Synthethic • Sodium Lauryl Sulfate medium HLB • Sorbitan esters (Spans) low HLB • Polysorbates (Tweens) high HLB’s (o/w)

17. Popular non medicated Emulsion bases • Alamay Base • 0/w • Vanishing cream (moisturizer) • Cetaphil • 0/w • Non soap cleaner • Eucerin • w/0 • Moisturizing cream • Keri Lotion • 0/w • Moisturizing cream

18. Ointment Bases • Ointment are semisolid mixture of a drug (in liquid) incorporated into a oily stiffen base. • Oleaginous base • Petrolatum is a high hydrocarbon mixture base used to carry water insoluble drug into the skin • Petrolatum is not washable and can’t absorb any water • Forms occlusive layer and used as an emollient • For example : Vaselin ® • Absorption base • Can absorb water • Hydrophilic Petrolatum (Aquaphor ®) • Water soluble base • Can absorb water • Can wash easily with soap and water • Consists of PEG 3350 and PEG 400, which are water soluble bases

19. Propylene glycol-ethanol systems when mixed with 2% hydroxypropyl cellulose forms a clear gel • A gel is emulsion system where a solid is the dispersed phase and water is dispersion medium • Exhibit thixotrophy: shaking and agitation causes the honey like substance to flow more easily (like water) • Absorbs considerable water into the gel “sponge effect” • Used in wound care to sieve pus

20. Incorporation of drug into ointments or emulsions involves the following: • Comminution • Break down and crushing solid particles into smaller particle sizes to increase its surface area • Trituration is comminution by frictional shear force (rubbing) • In practice comminution is done in a porcelain wedgewood mortar and pestle • Levigation is the process of increasing particle size by an a small amount of mineral oil to the reduced drug powder. This act “wets” the powder • The drug/levigating oil mix is then incorporated into the base when heated to near molten state (Fusion method) • Alternatively the drug/oil mix is incorporated little by little into the base via geometric dilution on an ointment slab • Geometric dilution

21. PLO Organogel System • PLO Organogel Systems are o/w type emulsion system • Has excellent skin penetration ability • Drugs can be incorporated into the organic phase or the aqueous phase • The organic phase is a lecithin emulsifier • The aqueous phase contains a poloxamer polymer in water • PLO stands for Pluronic Lecithin Organogel. Pluronic is the trade name for poloxamer(s) compounds which were synthesize for the first time in the 1970’s

22. Prepacking and Unit dose systems • Helps in inventory management in hospitals • Prepacked and unit dose blister cards by law are permitted to be return to inventory upon return • Expiration dating are one of two systems • 50% of the expiration date on the manufacturer drug or 1 year whichever is sooner (my hospital uses this) • 25% or six months whichever is sooner

23. Medications that should not be prepacked (unit dose) • The standard unit dose prepackage machine as a mechanical dial that rotates between metal plates that are heated to high temperatures. Oral dose forms are placed on the dial and the metal plates seal the blister pack material around the medication with heat • Some medications should not be prepacked with a standard machine because the machine will become contaminated with dust particles from these drugs • At times a dedicated machine can be used for some of these drugs • Common highly allergic potential drugs include: • Penicillins, Cephalosporins, sulfa drugs • Moisture Sensitive medications • HIV medications • Praxada ® • Pyridostigmine (Mestinon) • Prasugrel (Effluent) • Emtriva • Most orally melting tablets : Risperdal M

24. Capsules • Most gelatin capsules will melt when exposed to heat • Ritonovir • Omega 3 Fatty Acids capsules • Chemotherapy drugs and Teratogenic drugs • Chlorambucil (Leukeran) • Cyclophosphamide (Cytotaxan) • Cyclosporin (Gengraf) • Bosentan (Tracleer): Pregnancy category X • In general, always inquire about the pregnancy rating and the cytotoxic potential of drugs before you are asked to prepack anything. (especially if you are a woman of childbearing potential) • For a more complete listing visit: • http://www.ashp.org/s_ashp/docs/files/MedNO_unit-dosedpackage.pdf

25. Introduction to Sterile Products • A sterile product is a product that is free of contamination, microorganism free, and pyrogen free • Examples of sterile products are intravenous products (IV), ophthalmic products (for the eye), and nasal products (for the nose), Intramuscular (into the muscle) and subcutaneous (under the skin) • Aseptic technique refers to the procedure of properly performing the preparation of sterile products. • Includes the environment, equipment, and personnel garb • Provides guidelines for the procedure

26. Normally any agent that bypasses the skin or the gastrointestinal tract must be both sterile and pyrogen free. This is because the skin and the GI tract have a protective role in filtering out damaging foreign substances or microorganisms. • The blood is a sterile body fluid that requires sterile drug products. Blood is filtered by the spleen and then by the lymph nodes as its becomes lymph; however, when a drug is introduced directly into the blood it must be sterile. • Consequences of contaminated IV products can be serious

27. Most IV drug products are contaminated by touch contamination. • Bacteria, fungus, and other microorganism colonize the skin • Common skin microorganisms are: Candida, Dermatophytes, and Staphylococcus bacteria. Others are common as well. • Contaminated products can “colonize” the blood and produce bacteremia and fungemia. Infections can evolve into septic shock and death. • Watch : http://www.youtube.com/watch?v=KC8qgxNB2FA

28. Environment for Sterile Products Preparation • Class 100 environment is an environment that has air that contains no more than 100 particles (0.5 microns) or larger in one cubic foot of air. • Laminar flow hoods provide this environment. • Horizontal flow hoods filter air and pass it through a HEPA filter and outward out of the hood. • Vertical flow hoods blow filtered air down towards the surface of the hood. • Biological Safety Cabinets are vertical flow hoods that pulls air through vents in the front and back of the hood to prevent the preparer from receiving this air. It is used to make chemotherapy drugs.

29. USP 797 • Introduced in 2004 by the US Pharmacopeia. • Consists of standards for the environment to be considered in the preparation of sterile products • Endorsed by JCAHO and other regulatory agencies • Followed in most hospitals with others moving towards compliance. • Standards include wall/ceiling, wall/wall and wall/floor junction specifications, etc

30. In general, sterile products are prepared in laminar flow hoods in similarly compliance air quality rooms • Such rooms are called “clean rooms” • Usually have partitions that separate areas of the room for storage of IV products, gloves, and needle and syringes • Rooms are usually positively pressurized to “push” contaminates out and to keep other particles from being pulled in.

31. Other Sterile Product Equipment • Needle are sterile puncturing devices meant to access drug solutions in vials and to administer drugs to patients. • Normally are 3/8 of an inches to 3.5 inches in length • The diameter, or bore, of the needle is determined by its gauge. • The larger the gauge the smaller the bore of the needle • In general, 25 or 27 gauge needles are under for subcutaneous injections, 22 gauge for IM injections with 18 gauge and 16 gauge meant for pharmacy compounding of IV products. 13 gauge is typically the larger bore needle you will find.

32. Syringes are the containers that hold the drug solution after its been drawn from a vial. • Consists of a tube with graduations marks, a piston, a plunger with grip collar and at the other end a luer lok tip (most syringes). • This luer lok tip is designed to be a twist on to attached to a needle or to a injection port on a catheter to administer an injection Author: William Rafti of the William Rafti Institute from Wikipedia

33. Source: wikimedia commons page

34. Intravenous Solutions • Normal saline (0.9%) is one of the most common because its isotonic with plasma. Isotonic means equal to it in terms of “tonicity”. i.e. plasma has a tonicity valve of about 290 mOsm. Normal saline or NS is about 300 mOsm. • Tonicity of a solution determines if bodily fluid shifts will occur • Dextrose 5% in water (D5W) is the second most common type. Consists of glucose or dextrose in water to make it 285 mOsm (isotonic) • D5WNS is a combination of the two and is used when some calories in the form of glucose is needed. Hypertonic (580 mOsm about) but it is Ok to use. • 3 % Saline (NaCL) is only used to treat certain brain conditions. Very hypertonic and can cause death if used improperly • 23.4% saline (NaCL) used only in certain rare conditions and in small volumes. Will cause death if used improperly (remember Emily Jerry?)

35. Type of IV therapy • IV primary infusion consists of a drug that is given continuously through a large volume parenteral solution • IV Piggyback is a IV administration of a drug that is normally piggybacked to another primary IV via a Y site connection on the primary IV tubing. • IV Piggyback sets are designed to be small in volume usually 50 ml to 100 ml and are hung above the primary bag on the IV pole. (see next page) • Rate of infusion can be controlled by gravity and a roller clamps or by an electronic pump

36. Picture of IV Piggyback set up

37. A word about filters • At times a filter is needed to filter IV solutions • i.e. when breaking an ampule you need to use a filter needle to draw the solution to prevent glass particles from entering the IV. • A 0.22 micron filter is a special filter that is called a “sterilizing” filter that can sterilize a fluid as it is passed through the filter.