514 Compounding

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Hydrogenated Vegetable Oil Base

Oil Soluble - Fatty Base - used in Lab (more of a first line) - Similar to cocoa butter, less drawbacks --> a little more stable than cocoa butter - Melting point of 35˚ to 37˚C --> can be dispensed without melting and then melt for administration - Longer fatty chains, longer to liquify

Ointments, creams, gels, lotions, paste are ___? (Romero)

Semi-solid dosage forms intended for topical application - Skin, eye, nasally, vaginally, rectally - Non-medicated for Physical Effects: protectant, hydration, emollient, or lubricant - Medicated

Topical vs. Transdermal (Romero)

A Topical dermatological product is designed to deliver drugs onto the skin in treating dermal disorders. - Target site is the skin A Transdermal Drug Delivery System is designed to deliver drugs through the skin (percutaneous absorption) to the general circulation for systemic effects -Target site: Other than the Skin *Must penetrate stratum corneum (10-15 microns thick) to deliver drug to capillary beds between epidermis (50-150 microns) and dermis

Topical Therapeutic Agents (Romero)

Examples - Corticosteroids - Antiacne - Antibacterials / Antifungals - Antipruritics

Topicals- definition

"a route of administration characterized by application to the outer surface of the body" The USP <1151> Glossary definition - Includes *Ointments, Creams, and Gels* may all be used to deliver an API to the skin, as the target organ - *target is local*

Describe the 4 Ointment Bases and be able to list their properties and determine which base is the most appropriate base to use for a dermatologic applications - Know how occlusive (how it covers the skin) and their water content relative to one another (Romero)

(1) Hydrocarbon or Oleaginous bases - Wax & Petrolatum - no water - like Vaseline (2) Absorption bases a. Anhydrous - Hydrophilic petrolatum, lanolin, Aquaphor, can form W/O emulsion - *no water added but can add water* b. Emulsion W/O - Eucerin, hydrous, lanolin, already emulsion - *water present already* (3) Water-removable (washable) bases - Emulsion O/W - cream-like (4) Water-Soluble bases - greaseless, no oleaginous material - lots of water - feel nice

Compounding Terminology (Romero)

(1) Incorporation: mix together - mortar & pestle, spatula & slab - "levigating" or mixing the powder - The purpose of the levigating agent is to "wet" the active ingredient enough to incorporate into the base - *forms a paste of drug* with small amounts of liquid (water, propylene glycol, glycerin mineral oil; depends on drug powder properties) (2) Fusion: all or some components of an ointment melted together and cooled with constant stirring until congealed - add non-melting substances as the ointment is being cooled and stirred. - In porcelain dish or beaker, industry: steel-jacked kettles

Major Standards Organizations include:

*not enforced if required by a state* - United States Pharmacopeia (USP) - Pharmacy Compounding Accreditation Board (PCAB) --> voluntary (higher standard than bare minimum) - Accreditation Commission for Health Care (ACHC) --> same as PCAB

Beyond Use Dating

- " shall not exceed *180 days* from preparation or the shortest expiration date of any component in the compounded drug product..." - "Shorter dating than set forth may be used if it is deemed appropriate in the professional judgement of the responsible pharmacist." - 180 for non-aqueous, so this includes non-sterile compounding - CA law does not specify these USP <797> standards, but the pharmacist may use these as a conservative guideline in the absence of stability studies or other information - Risk Level: 1. Low (sterile to sterile; *no more than two punctures*): BUD for controlled room 48hrs, for cold storage 14 days, and for frozen storage 45 days 2. Medium (sterile to sterile; more than two punctures because multiple vials): BUD 30 hrs, 9 days, 45 days 3. High (non-sterile to sterile); BUD 24 hrs, 3 days, 45 days - non-sterile: liquid in a bottle, powder - sterile: vial, sterile water - freezing maintains sterility

How to achieve maximum release of API

- *Water soluble APIs should be placed in oil-soluble bases* - *Oil-soluble drugs may be placed in water-soluble bases* - Note: PEG bases must dissolve in mucosal fluids which can take longer than the melting process of oil-soluble bases --> PEG absorbs water and requires water to dissolve, so it could prolong the time to dissolve - because of the target environment will determine what kind of base we want: --> API and base won't interact with each other so drug will melt and go right into the appropriate environment --> if you wanted to prolong release, maybe you'd make the base have better interactions with API

Standards for Sterile Compounding - State Law

- 2 categories: sterile to sterile; non-sterile to sterile - CA Business & Professions Code (CA B&P) - CA Health and Safety Code (CA HS) - California Code of Regulations (CCR) *Pertains to all pharmacies licensed by the CA Board of Pharmacy* --> All pharmacies within CA and all pharmacies shipping medication to patients living in CA

Pharmacokinetic Considerations

- Absorption site physiology; pH; pKa - Solubility of the drug in the base - Vehicle or delivery system properties

Sterile Compounding

- Any medication compounded for use for injection, IV, inhalation, intrathecal (into spinal fluid), or ophthalmic --> based on CA law - Regularly performed in large hospitals and medical centers "IV compounding" --> a lot of pharmacies opt to out-source - Also done at the community pharmacy level --> same requirements apply to all

Patient consultation for topical

- Apply only to affected area - Use measuring spoon to estimate dose --> pumps can dispense a certain amount --> most distal part of digit is about 1 g - Wash hands after rubbing in until dissolves - May absorb into the skin over 3-4 hours --> depends on skin type - Do not apply with any other medications or after a long, hot shower or vigorous exercise --> don't change environment of skin; could open pores and get too much, or get really sweaty and wash it out --> other medications may interfere with the delivery of one --> Different hydration levels will affect drug delivery so need to *wait 2hrs* to apply after hot shower --> apply less occlusive topical first then wait before applying ointment --> can't just decrease dose because we don't know by how much delivery is affected - Report any sensitivity reactions to your prescribing doctor or pharmacist --> redness, burning

Capsule anatomy

- Body and Cap - Cap: rounded, hemispherical ends are mechanically stronger and more resistant to deformation - just pour powder or oil into the body then cap it

Quality Control- Powder Capsules

- Calculations to determine appropriate range in weight +/- 10% - In progesterone example each capsule's theoretical weight is 320mg. - Therefore: 288mg > x < 352mg - Alternate method is to take average weight of 10 capsules and apply same rule: - So, 2.88g > x < 3.52g - Can calculate CV or Coefficient of Variation: Standard Deviation / Mean weight

Major Regulating Bodies include:

- California Board of Pharmacy - CA --> most important when practicing here - Food and Drug Administration (FDA) --> Outsourcing Facilities --> second entity you want to follow - California Department of Public Health - Other state boards of pharmacy --> like if shipping into another state --> usually CA law is sufficient since it's pretty strict - these entities can take your license and close your pharmacy down

Water-Removable (Washable) base Emulsion O/W - (Hydrophilic Ointment) (Romero)

- Can be washed from skin, clothing; cream like; can be diluted Contains: •White petrolatum 25% - oleaginous phase •Sodium lauryl sulfate 1% - emulsifying agent - can be irritating to certain people •Stearyl alcohol 25% •propylene glycol 12% - aqueous phase - can be irritating to certain people •*Water 37%* •Methyl (.025%) and propyl (.015%) • parabens are used to preserve the ointment against microbial growth (anti microbial preservative) - Example: *Versabase:Pre-made O/W; No Petro, No parabens; No propylene glycol*

Absorption base (Emulsion W/O) (Romero)

- Cold Cream USP, Eucerin, Hydrous Lanolin - They are *already W/O emulsions* and permit the *incorporation of small, additional quantities of aqueous solutions* --> like anhydrous but with more water - Glycerin, propylene glycol, mineral oil •Wax or Petrolatum 12% •Mineral Oil 55% •Stearyl alcohol 12.5%, - antibacterial •Sodium Borate 0.5% - *~20% water* - Example: Cold cream is white wax, mineral oil, sodium borate, purified water and soap (*fatty acid sodium salt*) to emulsify

Compounding Pharmacy

- Compounding is making a medication based on a doctor's order specific to a patient --> able to fine-tune strengths - Sterile vs Non-Sterile - Sterile compounding is for compounds delivered directly into person's circulation like blood or intramuscular

Water-Soluble bases (Romero)

- Contain *only water soluble components* - water-washable, "*greaseless*" - they do not contain oleaginous components - Soften greatly with the addition of water - PEG-Repeating unit of poylmer is H(OCH2CH3 )nOH - Poly(ethylene glycol)/PEG ointment: 60/40 (w/w) PEG400/PEG3350-typical ratio may contain 6-25 % water 5% stearyl alcohol

Compound Record (not necessary)

- Contains: • Date of compounding • ID of pharmacy personnel whom compounded • ID of RPh performing final review of preparation • Quantity of each ingredient • Equipment used to compound • Manufacturer and lot number of each ingredient (unless emergency in-patient compounded) • Pharmacy lot number • Total quantity of drug compounded - Generated from Master Formula Record - Documented by compounder (e.g. technician) - Maintained for all preparations compounded by pharmacy

Master Formula Record (not necessary)

- Contains: •Active ingredients in the preparation •All inactive ingredients •The entire compounding process •Quality checks at each step during compounding •The post-compounding procedures •Beyond use date requirements (See USP <795>) - Usually maintained electronically - Does not change

Environmental Sampling

- Currently *not required* by California law; required by USP <797> - way to check physical environment (like air quality, etc); helpful if you need to know where contamination is coming from - Sampling Plans test different areas/equipment *in each ISO classified area* (door handle, work bench, equipment, or somewhere at least 6 in inside hood) - USP allows recommended threshold for how much contamination you can have

Choosing between topical and transdermal

- Determine the target

Other Semisolid Products: Gels and Jellies (Romero)

- Gels are semisolid systems - more sparkly - has a net-like matrix that absorbs water and expands - Liquid phase - Polymeric matrix (Gelling agent) - In general, non-pourable

Liquefaction time

- Hydrogenated or cocoa butter: 3-7 min - Glycerinated Gelatin: 30-40 min - PEG: 30-50 min --> bigger molecular weight will take longer

Absorption base (Anhydrous) (Romero)

- Hydrophilic Petrolatum, lanolin, Aquaphor, Aquabase - Those that *permit the incorporation of small amounts of aqueous solutions* resulting in the formation of water-in-oil emulsions, *W/O* - Glycerin, propylene glycol, anhydrous lanolin •White petrolatum 86% •White wax 8% •Cholesterol 3% •Stearyl alcohol 3%, - Example: Aquaphor is not an emulsion but refined hydrophilic petrolatum that can absorb up to 3x its weight - can incorporate water

Glycerinated gelatin - disadvantages (Okamoto)

- Hygroscopic, so they should be packaged in tight containers - Physiological effect: osmosis occurs during dissolving in the mucous secretions of the rectum, producing a laxative or irritating effect --> may be moistened with water prior to insertion to reduce the initial tendency of the base to draw water from the mucous membranes and irritate the tissues - Unpredictable solution time - Microbial contamination likely - Long preparation time - Lubrication of the mold is essential --> put thin coat of mineral oil on mold surface; don't use something that is irritating

Standards for Sterile Compounding - United States Pharmacopeia

- Independent quasi-governmental organization - Has numerous boards of health care providers including pharmacists to create standards for compounding --> Compounding Expert Committee - Publishes standards that may be used for enforcement by any health care agency - *Chapters > 1000 are informational* - *Chapters < 1000 are enforceable* --> standards that are enacted upon if not followed - Some major chapters for sterile compounding • <797> Sterile Preparation • <71> Sterility Tests • <85> Bacterial Endotoxin Test • <800> Hazardous Drugs (in full effect Dec 2019)

Coloring/Dye

- Inert ingredient - "powdered food coloring" - Used to differentiate a drug or strength - Must be used with a clear capsule (clear gelatin or veggie) - Sometimes preferred to be omitted --> if just using to differentiate you don't have to use coloring because you could just choose a colored capsule instead --> some people prefer not to have colorings - Could be used to tell if we've made a homogenous powder (food coloring is an indicator of quality)

Characteristics and Examples for Water-in-Oil Emulsion base?

- Insoluble in water --> Not water washable - Will absorb water --> Contains water - Emollient, Occlusive, Greasy (mostly oily) - Examples: Lanolin, hydrous, Hydrocream, Eucerin, Nivea --> lotions

Characteristics and Examples for Oleaginous base?

- Insoluble in water (oily) --> Not water washable - Emollient, Occlusive (offers protection), Greasy - Examples: White petrolatum and White ointment --> Vaseline

Ointments

- Largely hydrophilic bases - Semisolid in nature (in-between liquid and solid) - Intended for external use --> including vaginal ointments - Also for mucous membranes (like on a canker sore) - May melt at body temperature --> depends on the formulation - Spreads easily, so less messy - Don't really need penetration enhancers

Personnel Training

- Legal Requirements (CA): have to have a training program a. Sterile to Sterile: Less strict - sterile bag to sterile IV bag has very small risk b. Non-Sterile to Sterile: sterilization process is very important and has strict requirements - guaranteed to have microbes because starting from non-sterile product like powder so there has to be sterility tests - need to be trained in: • *Media Fill*: Process reflecting most complex manipulations; end product is medium for microbial contamination • Aseptic Technique • Pharmaceutical calculations and terminology - how to calculate doses and withdrawing the right amount • Documentation - that you were clean and did the dose correctly • Quality Assurance procedures • Proper gowning and gloving technique - usually have to redo training and redocument every 6 months • General conduct in the controlled area • Cleaning sanitizing and maintaining equipment - disinfecting things before it goes into the buffer room • Sterilization techniques - glove fingertip test (need to have 3 negative readings in order to compound sterilely in CA)

Cleaning capsules

- Limit residual excess powder from capsule machine - Necessary for clean appearance and avoidance of unwanted foul taste / odor - Can be done manually by sliding around in a paper towel or cloth - Oil caps should be laid out to dry overnight and blotted with paper towels the next day then immediately refrigerated - Have patients put them in refrigerator so that the oil doesn't leak

Urethral Suppositories (Okamoto)

- Males: weigh 4 g each - Females: weigh 2 g each - thinner and tapered - unusual dosage form - local action - example: MUSE is a prostaglandin insert for erectile dysfunction

Creams

- Most common - Opaque, soft solids or thick liquids - Intended for external use - Medication suspended within cream - Two groups: 1. water-in-oil 2. oil-in-water emulsion - Made to vanish or disappear - Can contain *penetration enhancers* (sinks into the skin better) --> most common in creams - generally compatible with most APIs

Gels

- Most versatile in terms of delivery - Contains *different PEGs* - Clear or opaque, gelatinous - Semisolid in nature - Very *versatile* delivery system (most versatile) - Can contain penetration enhancers --> second most common - Inorganic or organic gel types - Broadly compatible with APIs - Needs to be easily spread

Advantages and Disadvantages of Dermatological Preparations (Romero)

- Non-invasive - Avoids First Pass Metabolism (directly absorbed in systemic circulation) and GI disturbances - Provides for multi-day therapy --> sustained/extended release - Capacity to terminate quickly --> Just pull off patch - Local or Systemic Delivery - Potent drugs needed --> can't cover the entire body so the drug needs to be potent - Skin irritation can develop --> usually can avoid by rotating which area is used, but allergic reactions may develop

Dispensing & Consultation

- Packaging: Vial or Light-protected vial ; glass may also be used - Storage: Room temperature, away from humidity - Cellulose can absorb moisture, as may excipient - Do not open capsules, especially controlled release E4M caps Swallowing large capsules may be difficult (only open in certain cases for specific formulations) - Oil caps may leak; KEEP REFRIGERATED --> if they leak, we don't know how much of the dose leaked out (might not be safe), so don't let pt keep taking it - Contact pharmacy if accidentally left out, causing a major leakage

Packaging and Storage of Suppositories (Okamoto)

- Partitioned boxes - Screw-capped glass containers - Individually wrapped

Beyond Use Date - capsules

- Powder and Oil caps (non-aqueous, non-topical) - Per USP <795> can have *6 months (180 days) but not beyond the earliest expiration date of any ingredient* - Divided into non-aqueous (like powder and oil), oral, or topical - Oral (aqueous): *14 days* under refrigeration - Topical (aqueous): *30 days*

Dermatologic Topical Preparations (Romero)

- Primarily localized to the site of application --> protect, heal, moisturize, rash, sunburn, etc. - Underlying layers of skin for local drug penetration - doesn't go into systemic circulation - Medication is usually sub-therapeutic --> small quantities are absorbed --> care should be taken if pregnant or nursing

Topical Delivery-Active agent into S.C. or Epidermis Transdermal or Percutaneous Absorption-Systemic (Romero)

- Prominent mech: transcellular or in between cells (intracellular) - Also: Penetrate pores (through follicle or sebaceous glands) --> but not really a good place for drug absorption because they make up so little

pH and lack of buffering capacity of rectal fluids (Okamoto)

- Rectal fluids (1-3 mL) are essentially neutral and have no effective buffer action - *Incorporation of a buffer* into suppository can effectively buffer the pH of rectal fluids --> optimizes stability

Three main routes of suppositories

- Rectal: most common - Vaginal - Urethral

Major Components of Cleanroom Facilities

- Required by law to compound sterile preparations -Walls, ceilings, floors constructed of easily cleanable material --> Easy cleanable, nonporous, no seams, and can't degrade after cleaned --> like stainless steel or epoxy - HEPA-filtered air --> can be made to different specifications - Ante-Room: ISO *Class 8 air* for garbing and washing --> for preparation; kept separate because you might generate a lot of particles from washing hands, etc --> could have a little more particles in the air here - Buffer Room: ISO *Class 7* air where LAFW is located - Hood has to be ISO *Class 5* (with PEC or primary engineering control) --> Within hood is the Direct Compounding Area (DCA) --> clean air provided by primary engineering control (PEC)

Anorectal Anatomy (Okamoto)

- Rich in blood vessels, which is good for drug absorption - Whatever doesn't get into vasculature will get into the lymphatic system (also avoids first-pass effect) - Want to place suppository so that it is *in contact with lower vessels* (rectal/hemorrhoidal veins) --> farther up will be circulated to the liver --> avoid first pass effect by being careful with placement and retention --> don't want suppository moving around, as it could affect systemic bioavailability

Filling Oil Caps

- Similar calculation - Still have to find the right proportions of excipient and API - Use of different equipment - *Harder to prevent loss* - Tedious manual process - if you don't lock one capsule, oil will leak out and be very messy - usually put in refrigerator so less likely to leak

Patient Counseling for Suppositories

- Storage: *refrigerated*, remove when ready. *Do not freeze.* - Proper insertion: • lubricate the suppository - might not have to because should start to melt a little after putting in hand • lie on side with upper leg flexed - tuck leg up to gut • gently insert a finger's depth and angled toward umbilicus - angle it inward • after removing finger, hold buttocks together until the urge to expel has passed - gently use muscles to hold in place while it melts - relax after urge to expel has passed • no need to lie down for long, carefully stand then go business as usual - there is a possibility of oily spotting but it's rare (suppositories could leak out)

Common Active Ingredients

- Thyroid Hormones-T3,T4 combinations - Progesterone and Estradiol - B-Vitamin Complex - Dehydroepiandrosterone (DHEA) --> hormonal support chemical

BUD of suppositories?

- USP <795> - Generally considered non-aqueous - If stored protected from heat moisture, *180 days* - Major storage limitation is excessive softening --> If it gets too soft, you don't want people inserting that --> usually a problem with cocoa butter since it has a quicker liquefaction time - Monitor for oil stains on packaging --> can be used to tell if suppository has an oil leak

Quality Control of suppositories

- Uniformity in weight - Uniformity in texture and appearance --> make sure no chunks --> evenly pour it into the suppository mold - Evenly poured into suppository mold - May cut a cross-section to verify attributes - Comes from properly dissolving and mixing

Some Transdermal Products Method of Deliver and Indications (Romero)

- Usually patches - Topical emulsions - Iontophoresis: patch with electrical current to help with delivery - Ultrasound: disturb stratum corneum makes it easier to penetrate skin Examples: - Dramamine for motion sickness; put behind ear - Nitroglycerin patches for vasodilation - Catapres for HTN - Fentanyl for pain - Oxytrol for overactive bladder

Sterile Compounding process

- Very tedious, calculated process --> garbing --> wash up to elbows with a certain soap --> can't talk too much - Must follow established laws and regulations - Must take place in carefully constructed facilities - Utilizes specialized, calibrated equipment

Hydrocarbon or Oleaginous bases (Romero)

- Water insoluble; Vaseline - Not water washable, hydrophobic, occlusive, difficult to incorporate aqueous solutions, protects skin (emollient) - Yellow or White petrolatum (ointment) and wax (stiffening) --> 95 % petrolatum + 5 % purified wax - Petrolatum: semisolid hydrocarbon, melting point 38-68˚C - Mineral oil: liquid hydrocarbon from petrolatum)

Characteristics and Examples for Water Soluble base?

- Water soluble --> water washable - Will absorb water - Anhydrous or hydrous - Nonocclusive, nongreasy - Example: Polyethylene glycol ointment (*PEG gel*) --> water-based gel like an alcohol gel

Glycerinated gelatin (Okamoto)

- Water-soluble and water-miscible - glycerin often used as a laxative - glycerin from animal sources - most frequently used in preparation of vaginal suppositories b/c of prolonged local action - two types with different ranges of molecules depending on how you prepare it (choose based on which is compatible to drug): 1. Pharmagel A - creates acidic environment (4.8-5.2) 2. Pharmagel B - creates basic environment (6.5-9.2)

Pharmacist Considerations for suppository base

- What effect is needed? Will it require local or systemic use? - What is the route of administration? Is it a rapid release? or slow and prolonged release of med? - What are the chemical features of the active ingredient(s)? - Which type of base will give the desired effect? (solubility) --> don't want something to slowly melt if we want fast-acting systemic release --> have to make sure there isn't stability issues prior to drug being delivered (don't want compatibility issues)

Vaginal suppositories (Okamoto)

- called pessaries - usually globular (ball), oviform, or cone-shaped and weigh about 5 grams - Composition: PEG base, surfactants, preservatives (parabens), and buffer to pH 4.5 --> acidity discourages pathogenic organisms and provides a favorable environment for eventual recolonization by the acid-producing bacilli normally found in the vagina - Local action: yeast and bacterial infection (antimycotics and antibiotics), return tissues to normal state (estrogens and progesterone), and spermicides

Overview on Capsules

- capsules typically used in oral dosage form - Used for more than a century - Relatively simple to make - Can vary the bioavailability and rate of release (liquid absorbs faster than powder) - Various sizes, shapes, colors, and ROA - Capsules could be used to adjust delivery rate

Release of propranolol hydrochloride (PHC) From a Gel or Cream (Romero)

- does not permeate well in a gel --> propanolol has a high affinity for the gel - better permeation in a cream --> base pushes the propanolol away so that it releases

Effect of suppository base on absorption (Okamoto)

- influences the release of drug - cocoa butter, an oily suppository base, melts rapidly at body temperature and will release fat-soluble drugs slowly - polyethylene glycol, a water-soluble suppository base, dissolves readily in rectal fluids - rate of drug released from a suppository and absorbed by the rectal mucous membrane is directly related to its solubility in the vehicle, or the partition coefficient of the drug between the vehicle and the rectal fluids --> more compatible the drug is with the base, the more likely it will be retained

4.5% hydrophilic matrix

- intermediate release - matrix is somewhat strong

Clindamycin 100mg vaginal suppository - L or S?

- local (most likely)

Nifedipine, Lidocaine, Nitroglycerine Suppository - L or S?

- local for hemorrhoids and anal fissures - Nifedipine: Ca++-channel blocker

Factors that help with drug absorption from suppositories (Okamoto)

- melting point of base - liquefaction time - spreading capacity: greater the spreading, the better the absorption (determined by viscosity) - viscosity of base - smaller the particles, the better dissolution and absorption - if drug dissolves away from suppository base, the drug can partition more quickly (so don't want base and drug to have favorable interactions) - pKa of drug - pH of rectal fluids - presence of buffers - partition coefficient of drug

Suppository base - ideal characteristics? (Okamoto)

- melts at body temp or dissolves in bodily fluids - non-toxic/non-irritant - compatible with any drug (chemical compatibility) - releases any drug as base melts/dissolves (physical and chemical interaction) - easily moulded and removed from mold - stable to heating above the melting point --> don't want to melt it and then the base degrades/changes chemical characteristics - easy to handle --> can be easily dispensed - stable on storage Types: 1. fatty or oleaginous 2. water-soluble and water-miscible 3. misc. bases-combination of lipophilic and hydrophilic

oil soluble drug; water miscible base

- moderate release

water-miscible and water-miscible base (Okamoto)

- moderate release - based on diffusion - all water soluble

Characteristics and Examples for Oil-in-Water Emulsion base?

- most common - Soluble in water --> Water washable - Will absorb water --> Contains water - Nonocclusive, nongreasy --> doesn't offer as much hydration - will vanish easily - Examples: Hydrophilic ointment, Dermabase, Velvachol, Unibase --> face moisturizer

components of skin (Romero)

- most common protein is keratin (40%) --> 10-25 layers of keratinized cells - ceramide and cholesterol are the most common lipids present (40%) - in between protein and lipid, there is some water (20%) --> depends on age, environment

anatomy of skin (Romero)

- most important layer of the skin that controls absorption is the *stratum corneum*, the uppermost layer of skin - the dead layer - protective --> most difficult to penetrate this layer - filled with layered dead cells with protein and lipid - "brick": mortar is lipid layer and bricks are the cells filled with keratin - epidermis, the dermis, and the subcutaneous or the hypodermis (where fat cells are) --> below that is muscle --> arteries and veins go up to dermis

vaginal suppositories

- progesterone to prevent pre-term birth --> systemic - locally to treat vaginal atrophy --> estriol for menopause - w/abx locally to treat infections - w/ muscle relaxant to treat local spasms/pain

Typical functions of suppository dosage forms (Okamoto)

- promote defecation - introduce drugs into the body - treat anorectal diseases

1% hydrophilic matrix

- quick rate of release - weaker matrix

Water-soluble and oily base

- rapid release

Oil-soluble drug and oily base?

- slow release and poor escaping tendency

pH-rate profile of fluocinolone acetonide in aqueous and Cream Vehicles (Romero)

- stability in water matters - want a low log(kobs) because it means there is slow rate of reaction - cream allows drug to last longer (lower on graph, slower the rate of reaction) --> doesn't show how well it permeates - aqueous solution like a spray is worse

Oxycodone 20mg suppository - L or S?

- systemic

20% hydrophilic matrix

- very slow release - strong matrix - patient can take medication less frequently

Calculations

- you're allowed +/- 10% of medication dispensed vs intended dose - Packing study: mostly for punch method - Study done by packing capsules with excipient and API and taking an average weight - Then do calculations to determine formulation - i.e. Size 0 capsule holds 322mg of Avicel powder - Prescription for 65mg Progesterone in Avicel #100 Step 1. Calculate total amount of API 65mg x 100 capsules = 6.5g Step 2. Calculate total amount of drug + diluent 0.320g x 100 capsules = 32g Step 3. Subtract API from Total to get diluent weight 32g - 6.5g = 25.5g of Avicel powder NOTE: Most pharmacists calculate for 10% overage to prevent loss Calculations for individual capsules: 32g total / 100 capsules = 320mg per capsule 25.5g Avicel / 100 = 255mg Avicel and 65mg Progesterone per capsule

Capsule sizes

000 (largest) - 00 - 0 - 1 - 2 - 3 - 4 - 5 (smallest) Various sizes allow pharmacist to formulate capsule with correct amount of excipient

Factors Affecting Absorption (Romero)

1. *Drug* - Drug concentration --> higher concentration has more flux - Physiochemical Properties of Drug: a. MW < 500 (small) b. *solubility in the vehicle* (the cream, lotion, or ointment, patch carrying the drug) *and the skin* - needs to dissolve so that it can penetrate skin and dissolve in skin c. partitioning coefficient (Log P ~1-3) - can't be too hydrophobic or hydrophilic d. H-bonding e. pKa - can't be too highly ionized or won't diffuse through stratum corneum 2. *Vehicle* - Surface Area: more SA, more absorption - Time: longer time, more absorption - Absorption Enhancer: chemical like urea (breaks up skin and helps hydrate) or water so that drug is absorbed easier through skin --> also alcohol (strips skin), tape (strips skin), heat (exercise alters absorption rate) - Drug Affinity --> have to consider when you change the base --> different vehicles have different hydrophobicities (if API and base too favorable/alike, API might not leave the base) 3. *Skin* - Hydration: need hydrated skin to up absorption, making more pathways for the drug to penetrate - Skin Thickness --> larger layer of stratum corneum at hands and foot - Health --> presence of lesions, etc

Water-soluble and water-miscible: what can you add to help with formulation? (Okamoto)

1. *surfactants* can enhance dissolution - polyoxyethylene sorbitan fatty acids esters (e.g. stearate) - gelatin: Pharmagel A creates an acidic environment, and Pharmagel B creates a basic environment --> comes from animal sources 2. sometimes you incorporate molecules like aerosil (*suspending agent*) to help with evenly distributing drug particles throughout the base by enhancing viscosity, which prevents sedimentation of drug as base hardens

Drug release and absorption from suppositories (Okamoto)

1. Fusion and dissolution - drug particles get dispersed throughout the solid base - base either melts or dissolves in the rectal fluids, depending on the composition of the base - Factors: melting pt of base, liquefaction time 2. Diffusion - once particles are liberated and in the rectal area, we get drug dissolution and drug spreads out - free drug particles sediment down through base and become closer in contact with tissue - Factors: spreading capacity, viscosity of base at rectal T, particle size of drug, and solubility of drug in vehicle/retention of drug in vehicle 3. Absorption - wetting causes drug to dissolve - dissolved drug goes through rectal tissue - no transporters here to help with absorption - so best absorbed drugs have high hydrophobicity - Factors: pKa of drug, pH of rectal fluids, presence of buffers, partition coefficient of drug

Other considerations for suppository compounding

1. Presence of water could affect oxidation of fat, degradation 2. Hygroscopicity: PEGs are hygroscopic; higher molecular weight - higher molecular weight, the longer it'll take to melt and the more water that it will absorb from the environment - humid environments will make this suppository more slimy 3. Viscosity- too viscous or not viscous enough - usually don't have to worry about this, but if you're co-administering a drug or environment is being altered then you have to consider this 4. Bioequivalence: e.g. prevent degradation of prodrugs - don't want degradation of prodrug because want drug to absorbed in its prodrug form - if drug is getting degraded faster than it is released, whatever is absorbed is even less - so you may want a faster release and absorption of prodrug

Required for compounding *non-sterile to sterile*

1. Sterility Test - sample of end product combined with growth medium to detect microbial contamination - Sample collected and incubated in medium *for 14 days* - Product is quarantined until results indicate product is clean 2. Endotoxin Test - sample of end product combined with special medium (Gel Clot Limit Test) used to detect endotoxins (microbial byproduct that indicate microbes are around) within sample - Usually done at same time as sterility test, results available before 14 days, but must wait until sterility test is completed Can do these simultaneously, but have to ensure you wait the proper time *All results must be documented and archived as part of the QA requirements*

Suppository Base Requirements

1. delivery 2. solubility of API 3. stability of API - Water-Soluble, e.g. PEGs - Oil-Soluble, e.g. Cocoa butter - Hydrogenated Vegetable oil, fatty-acid

Ointments (Romero)

Are semisolid preparations intended for external application to the skin or mucous membranes. Ointments can be: • Medicated • Non-medicated (ointment bases) -emollient or lubricant -vehicle for the preparation of medicated ointments - ointments trap water and don't contain water Example: Vaseline

Dosage Formulation

Components Include: a. *Active Ingredient* (or active pharmaceutical ingredient or API) b. *Filler / Excipient* - choosing the right excipient will help with mixing process and dissolution in the gut after swallowed - helps disperse powder once it's absorbed c. *Coloring* - optional - ensures you're making a homogenous mixture (indicator for quality) - helps with differentiation too

The Cleanroom

Controlled environment with HEPA (or other filter) filtered air provided to an enclosed environment --> filters out particles that could cause sterility issues

Preparation when skin type is: Dry

Creams, Ointments - ointments helps to hydrate skin

Preparation for Intertriginous areas

Creams, lotions - somewhere where the skin meets like armpit or thighs

Preparation for Wet, vesicular, weeping lesions

Creams, lotions, gels - like cirrhosis

T/F: The absorption pathway of a drug is the same through intact and diseased skin (Romero)

False - affects how quickly drug penetrates the skin

CA sterility Important Requirements:

For both sterile to sterile and non-sterile to sterile: - Training and competency evaluations - Refrigerator and freezer temperatures --> monitor to show that you're controlling microbial growth - Certification of sterile compounding environment - Other facility quality control logs (e.g. cleaning logs) --> have company take air samples --> document everything - Inspection for expired or recalled products or bulk ingredients - Preparation records including master formula record, results of end product testing

Aseptic Technique

How you keep the DCA clean - Set of actions and procedures needed to limit the risk of microbial contamination throughout the compounding procedure - Personnel Garbing Procedure - Hand Hygiene - Critical site manipulations --> Examples: needle, the barrel the needle is housed - Disinfecting and cleaning of components, ingredients, workstation - *read assessment sheet*

Put the bases in order of occlusiveness and emolliency (Romero)

Hydrocarbon: High Water-removable O/W: Low Water soluble bases: Low Absorption a & b W/O: high to Med - anhydrous is high - med with water

Put the bases in order of washability (Romero)

Hydrocarbon: Poor Water-removable O/W: High - can thin out to form a lotion Water soluble bases: High - can thin out to form a lotion Absorption a & b W/O: Poor to Med - Poor with anhydrous (can incorporate small amounts of water) - Med with W/O emulsion (depends on amount of water in base)

Release of drugs of varying solubility from suppositories base? (Okamoto)

If suppository is fat-based, hydrophilic drug would escape more readily and hydrophobic drug would be trapped

Lotions (Romero)

Liquid preparations containing finely powdered substances that are insoluble in the dispersion medium *and are suspended* through the use of suspending agent, or have as the dispersed phase liquid substances that are immiscible with the vehicle and are usually dispersed by means of emulsifying agents - Most commonly, the vehicles of lotions are aqueous and should be shaken - lotions are liquid-like and pourable (most water content)

Preparation when skin type is: Normal to dry

Lotions

Preparation when skin type is: Hairy

Lotions, gels (also sprays)

Capsule Administration

METHOCARBAMOL - Route: oral - Use: Eliminate unpleasant odor or taste BORIC ACID - Route: vaginal - Use: Direct delivery of active ingredient to target area for tx of infection APAP (acetaminophen) - Route: rectal - Use: Modified release of active ingredient for quicker antipyretic action, and could be smaller so you don't have to hold in place like a suppository --> suppositories melt at different temperatures so have to wait for it to melt

Who takes suppositories?

Mainly people who don't have good ability to swallow or keep it down - infants or small children - For severely debilitated patients - oral route of administration unavailable - Parenteral route of administration may be unsuitable (if pt has bleeding disorder so no needle sticks) --> can still have systemic absorption

Compounding Process

Master Formula Record! - the unchangeable template from which you compound - states how to compound - Legal requirement; specific items have to be present (BUD, etc) a. Calculations - Packing study with excipients b. Geometric dilution of API with excipients - when have to triturating and mixing (using a mortar and pestle) so that it's evenly distributed in separate dilutions - adding in how much is in the mortar (1:1) c. Encapsulation - by hand or with capsule machine - 'punch' method (manual filling) d. Cleaning caps - manual or automated process to remove excess residual powder e. Good idea to use in a powder hood (plastic enclosure with inward airflow), especially hormones and dangerous drugs!

Controlled Release

Methocel E4M - Contains Hydroxypropyl methylcellulose - Various lengths determine properties - "Non-ionic, *water soluble* cellulose ether consisting of different hydroxy propyl and methoxyl substitutions" - Hydrophilic matrix allows some active ingredients to dissolve and diffuse out, while *less soluble APIs remain held* until the surrounding gel complex erodes --> can fine-tune how many repeating units there are and the side chain --> acetaminophen will be trapped because it is hydrophilic, so it takes longer to get delivered - Goal is to *mimic slow-release of manufactured SR drugs* - Commonly used for drugs with short half-life that require frequent dosing - how hydrophilic the matrix is will determine how strong the gel formed when in aqueous solution will be (*more hydrophilic means more strong gel which means slower release*) - the drug in the gel can slowly release over time - In order to be absorbed for use, the drug must diffuse through the gel-matrix, or must erode - The mechanism by which drug release is controlled in this type of matrix depends on many variables including: a. *Choice of API* b. *Number of APIs* c. *Particle size of API* - bigger will have harder time getting through gel d. *Presence of other excipients* - Patient's individual transit time in the gut effects drug delivery as well (like if they have Crohn's disease or something)

Cocoa Butter or Theobroma Oil

Oil Soluble - Great choice for suppository base - Softens at 30˚C and melts at 34˚C --> can be dispensed without melting and then melt for administration - Mixture of liquid triglycerides entrapped in network of crystalline, solid triglycerides - Immiscible with body fluids, so risk of leaking

Preparation for Dry, thickened, scaly lesions

Ointment, pastes - emollient effect helps keep water in the area

Transdermal

Ointments, Creams, and Gels may all be used to deliver an API into *circulation* as the target - *target is systemic circulation* - example: testosterone cream

Preparation when skin type is: Normal to oily

Ointments, pastes, gels

Drug Absorption across rectal tissue (Okamoto)

Physiologic factors • Anorectal-vasculature anatomy • pH and buffering capacity Physicochemical factors of the drug • Lipid-water solubility - affects balance between solubility and permeability • pKa (vs. pH), degree of ionization or polarity • Particle size - impacts rate of solubility and therefore the absorption of drug Physicochemical factors of the suppository base • Suppository vehicle • Nature of the base-drug interaction

Pharmaceutically elegant

Proper attention to quality, using proper principles - use just enough excipient for good distribution of powder to fill capsules with correct dose

Patient is a 40 YO M w/ PMH of GI ulcers. Current medications include misoprostol 100mcg PO qid. Pt presents to MD with complaints of knee pain after a weekend of vigorous exercise. Pt says he has been playing flag football for months and upon examination the MD prescribes RICE, also asks you for a recommendation on anti-inflammatory medication. Rx: Ketoprofen 20% c ream Apply 1g to affected area TID prn pain #90g Transdermal or Topical?

Transdermal - Want to treat knee pain so it's inflammation in the supporting areas - Topicals are limited to the superficial layers of the skin (warts, scars, keloids) - Most anti-inflammatory medications inhibit the inflammatory response

Excipients

Used for proper distribution of active ingredient and proper release of active ingredient upon mixing in gastric acids - help disperse powder once it's absorbed • Methylcellulose e.g. Methocel E4M (brand name) • Microcrystaline Cellulose (more granular and fine) e.g AVICEL • Silica Gel - used for suppositories - hurts lung tissue • Lactose (in salt form: lactose monohydrate)

PEG-Polyethylene Glycol

Water-soluble - Most popular choice for base - Dissolves and mixes with aqueous body fluids --> rectal cavity is aqueous so water-soluble base makes dissolution favorable - May cause some dehydration of rectal mucosa by taking up water to dissolve, possible irritation --> chains allow water to absorb (might be too hydroscopic) - Advantage: *Can be prepared to have specific melting point* --> chain links can be changed, allowing it to dissolve at different temperatures (get more clinical options) --> *longer the chain/heavier MW, higher the melting point* (more heat to melt a bigger PEG chain) --> avg. molecular weigh of 1000 would have a melting point ~37-40˚C

Rectal Suppositories (Okamoto)

Weigh 2g for adults, 1 g for children - tapered end goes in first a. Local action: relieve constipation, pain, irritation, itching, inflammation, infection - ex. hemorrhoids (vasoconstriction like phenylephrine), topical analgesics (cortisone), laxative (glycerin) b. Systemic action (circulate through the bloodstream) advantages over oral include: - avoids the needs to swallow pills (ASA, APAP, diclofenac, opiates) - effective for treatment in patients with vomiting episodes (antiemetics like ondansetron) - avoids the pH or enzymatic activity of the stomach or intestines - avoids irritation to the stomach - bypass the liver

(Okamoto) The disadvantages of suppositories and the reasons given for the infrequent use of suppositories include the following:

a. A perceived lack of flexibility regarding dosage of commercially available suppositories resulting in underuse and a lack of availability - some people don't know this is an option b. If suppositories are made on demand, they may be expensive c. Suppositories as a dosage form are safe, but they exhibit variable effectiveness, depending upon many factors, including the pathology of the anorectal lesions - some drugs are absorbed better orally than rectally d. Different formulations of a drug with a narrow therapeutic margin, such as aminophylline, cannot be interchanged without risk of toxicity - once we've introduced it, we can't modulate the the amount - whereas with an IV you can get control drug levels and be precise

Benefits of Transdermal Approach

a. Avoid oral route of administration - Less cause for worry about past hx of gastic ulcers - Gets medication into circulation without affecting the stomach - won't have that local effect of inhibiting the cyclooxygenase in the lining of the stomach b. Direct application - Avoid first pass metabolism (oral drugs can get broken down through this) c. Ability include other agents - e.g. lidocaine for further pain relief (lidocaine would be like a topical for local relief) --> use a low concentration of lidocaine --> but could also put local anesthetic and systemic anti-inflammatory in one cream - likely to be more adherent with less drugs d. Extended delivery time - Short-half life of drug overcome - Get longer exposure over a period of time (so can get a bigger dose and the skin will make it last longer)

(Okamoto) The advantages of rectal administration include the following:

a. First-pass effect: Avoiding, at least partially, the first-pass effect that may result in higher blood levels for those drugs subject to extensive first-pass metabolism upon oral administration. - rectal suppository will deliver higher concentration, which hopefully means a stronger therapeutic effect for the same dosage b. Drug stability: Avoiding the breakdown of certain drugs that are susceptible to gastric degradation - Some drugs are absorbed better rectally than orally c. Large dose drugs: Ability to administer somewhat larger doses of drugs than using oral administration d. Irritating drugs: Ability to administer drugs that may have an irritating effect on the oral or gastrointestinal mucosa when administered orally e. Unpleasant tasting or smelling drugs: Ability to administer unpleasant tasting or smelling drugs whose oral administration is limited f. In children, the rectal route is especially useful - An ill child may refuse oral medication and may fear injections g. In patients experiencing nausea and vomiting or when the patient is unconscious - The presence of disease of the upper gastrointestinal tract that may interfere with drug absorption i. Achievement of a rapid drug effect systemically - as an alternate to injection

Disadvantages of water-soluble and water-miscible (Okamoto)

a. PEG + glycerin are hygroscopic (pulls water from the surrounding environment), so they may cause irritation to the mucosa - can be overcome by instructing pt to dip in water before insertion - could also create a laxative-type effect b. good solvent properties may result in retention of the drug in the liquefied base with consequent reduction in therapeutic effect - so poor bioavailability of drug c. incompatibility with several drugs and packaging materials (e.g. benzocaine, penicillin, and plastic) d. brittleness: if cooled too quickly and in storage - physical stability might be an issue - less brittle products, which release the drug more readily, can be prepared by mixing high polymers with medium and low polymers e. Higher proportions of high molecular weight polymers produce preparations that release the drug slowly (b/c more viscous) and are also brittle - low MW PEG is a liquid at RT, and higher MW PEGs are solids at RT so sometimes you have to combine different types to get what you want in a suppository

Types of capsules by ingredient

a. Powder capsules - e.g. liothyronine b. Oil capsule - e.g. progesterone in canola oil (T3) capsule --> for bio-identical hormone replacement treatment --> progesterone in oil will be easier dissolved

Preparation of Suppositories (Okamoto)

a. Rolled (hand-shaped) suppositories with cocoa butter base are rarely used b. *Fusion or melt molding* with water-soluble bases, cocoa butter - no pressure required c. *Compression-molded* (fused) suppositories - no heat, mold under pressure - suited for making suppositories that contain heat-labile medicinal substances or a great deal of substances that are insoluble in the base - example: glycerinated gelatin suppositories - disadvantages: special suppository machine is required and some limitation as to the shapes of suppositories that can be made

Fatty or oleaginous bases (Okamoto)

a. cocoa butter (theobroma oil) - naturally occuring solid triglyceride (40% unsaturated fatty acid component) - *polymorphic*: must be slowly and evenly melted, not to be heated above 40-50˚C to avoid change in crystal form and melting point, and it takes several days to revert to its more stable form - melts at 31-34˚ - squishy, so you can counteract it by adding waxes to increase hardness (some drugs or additives will decrease the melting point) --> acetyl esters wax or beeswax --> must not be too hard to interfere with drug chemically or physically b. fattibase c. wecobee bases --> other options are basically fats like cocoa butter

Types of capsules by composition

a. hard gelatin (most common) b. soft gelatin - don't typically compound with these - usually liquid-filled c. veggie capsule - comes from a vegetable source, usually transparent

Advantages of water-soluble and water-miscible (Okamoto)

a. no laxative effect b. less microbial contamination - oils are usually good for microbial growth, so better to avoid this c. the base contracts upon cooling and no lubricant is necessary - easy to remove from mold d. melting point is above body temperature - need them to dissolve in bodily fluids and not dissolve at room temperature - don't have to worry about physical instability e. cool storage is not so critical (compared to cocoa butter) - suitable for hot climates f. the base dissolves in the body and disperses the medications slowly, providing a sustained effect - in between very slow and very fast g. produces high-viscosity solutions, so leakage is less likely h. good (aqueous) solvent properties

Pastes (Romero)

are concentrates of absorptive powders dispersed - (usually) in petrolatum or hydrophilic petrolatum - some can absorb water depending on the powder you use - can be very stiff - Contain a larger percentage of solid material than ointments (thicker and stiffer) - Will not soften and flow after application

Creams (Romero)

are viscous liquids or semisolid emulsions of either the w/o or o/w -Examples: 1. w/o (cold creams, and emollient creams) 2. o/w (shaving creams, hand creams, foundation creams) - Easier to spread and easier to remove than ointments

Standards for Sterile Compounding - Federal Regulations

more like regulations to follow and can be enforced, but state law is more relevant - The Food Drug and Cosmetic Act of 1938 (FDCA) --> Specifies federal laws for pharmacy compounding - In 2013, the Drug Quality and Security Act (DQSA) modified the FDCA to create a new category termed *Outsourcing Facilities* --> creation of outsourcing facility (503B; larger scale) and traditional compounding pharmacy (in *503A*; on a per-patient basis) --> intent was to allow the FDA greater oversight of compounding pharmacies - Outsourcing Facilities are to be under the authority of the FDA - The purpose of the OF is to provide sterile medication to patients around the country without a patient-specific prescription --> work with large volumes like hospitals

Elements of the Quality Assurance Program

part of monitoring how someone does - Integrity, potency, quality, labeled strength (qualitative and quantitate examination) - Verification and monitoring of process e.g. End Product Testing (like growth medium testing) --> don't have to do end product testing if you are doing sterile-to-sterile on an as needed basis, but if you make like 10 IV bags you should do an end product test - Procedures for substandard preparations --> what happens when something goes wrong (example: recall, contact pts) - Policies and procedures for recall procedures --> if you used a product that you thought was sterile but company tells you that it actually isn't, what do you do

Suppositories

solid dosage forms of various weights and shapes usually medicated for insertion into the rectum, vagina, or the urethra - after insertion, suppositories soften, melt, or dissolve in the cavity of fluids, releasing incorporated drug for local or systemic activity - intended action: local (treating just the area it's delivered) and/or systemic target (if someone is vomiting or lost ability to swallow) --> hemorrhoids, itching, and infections would be local --> aninauseants, anti asthmatics, analgesics, and hormones would be systemic

Regulatory Overview for compounding (not necessary)

• Highly regulated practice in California • Board of pharmacy enforces all laws • PIC is responsible for all records • Strict policies and procedures are required • All staff must be trained to perform duties - Documentation: 1. Master Formula Record (MFR) 2. Compounding Record

Formulation considerations of Topicals and Transdermals

• How much skin penetration is needed? • Characteristics of the skin on desired location - thick, hairy, dry • Dose needed for condition being treated • Compatibility with active ingredient(s) to be used (several) - use ointment if API is susceptible to hydrolysis because it doesn't have much water • Option of utilizing penetration enhancers - usually if skin is really thick • Skin type of the individual - like sun-exposed, damaged

Resources for establishing a BUD:

• International Journal of Pharmaceutical Compounding • Trissel's Stability of Compounded Formulations • Reputable, peer-reviewed stability studies • Handbook of Injectable Drugs • Stability Indicating Methods (SIM) study by analytical laboratory

(Romero) Selection of the Appropriate Base is Based on:

•Desired Release Rate •Desirability of absorption •Chemical Stability of the Drug •Influence of drug on consistency or other features of the base which could affect physical stability •Advisability of occlusion •Patient factor-dry or weeping (oozing skin), washed off -occulsiveness would protect skin of baby if preventing diaper rash (but if you have diaper rash before, don't want an occlusive base)

Other Topical Preparations (Romero)

•Foams •Liniments •Plasters, tapes and gauzes •Topical aerosols, glycerogelatins

Preservatives/Antimicrobials (Romero)

•Microbial content (Pseudomonas aeruginosa, Staphylococcus aureas) determined and controlled •Sterile preparations (some) •Chemical antimicrobial preservatives: p-hydroxybenzoates, phenols, benzoic acid, sorbic acid, quaternary ammonium salts, mercury compounds, formaldehyde, sodium borate •Packaging - Storage-jars and tubes --> tube reduces contamination


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