PHAR 423 Exam 2

What are the dosage form components?

• API

• Excipients

• Packaging

• Administration Devices

• Package insert

Why do we use solid dosage forms?

• Easy to deal with

• Easy to handle

• Ease of administration

• Preference of patients

• But hard for incapacitated patients

What are the components of preformulation?

• Chemical stability

• Physical form - taking solubility, dissolution rate into account

  • you cannot change solubility… you can change the molecule and you can change the solvent

• Transition to solution - disintegration and dissolution

Are excipients inert?

No! —> in compounding you need to make sure the excipients don’t cause issues

How do you create a solid dosage form?

• API + excipient, when blended, make a powder blend

• You can potentially bind these into granules

• Then you compress into the solid dosage form

How does an API become active in a human?

• Disintegration —> breaking apart dosage form into smaller particles

• Dissolution —> molecules transitioning from dosage form into the solution phase

• The dissolved molecules will permeate!

Are all APIs compressible?

• No - e.g. fluffy API

• If not, add excipients

Can you predict which form of API will dissolve the best or make the best crystals?

NO

Can you predict which form of API is absorbed the best?

YES → unionized

Is diamond the crystal or amorphous form? Is graphite the crystal or amorphous form?

Diamond - crystal (we have polymorphs, i.e. different arrangements)

Graphite - amorphous (random positioning of the molecules)

There’s also lots of forms in between!

Explain the interconversion of crystals.

• The crystal might exist as needles, prisms, and plates

• But upon dissolution, the shapes might shift towards prisms and plates (but note that the same amount of total crystal is there!)

Explain how crystals dissolve.

Different faces of crystals dissolve differently.

How do you determine intrinsic solubility rate?

• API compact is placed in fluid

• The surface area is known

• Then you can determine the solubility rate

What is the moral of Dr. G’s PBS buffer story?

• ___hydrate forms of crystals dissolve differently!

• Sodium Phosphate Monobasic (Monohydrate) - this is called a solvate (crystal + solvent)

What is in a standard solid dosage form?

• API

• Diluent/ Filler - makes the system compressible

• Glidant - improve flow characteristics

• Lubricant - make sure the powder doesn’t stick

• Super Disintegrant - make the powder separate into smaller particles

• Binder - hold things together

• Coating agents

How does reyataz utilize inactive ingredients?

• Reyataz is an oral powder.

• It has very little API, while the rest of the formulation includes aspartame, sucrose, and orange-vanilla flavor

• Aspartame = sweetening agents

• Sucrose = diluent (can’t use aspartame as filler because it’s way too sweet)

Why is particle size important?

• Smaller particles dissolve faster

How do you make industrial scale powders? How can we overcome some of these challenges?

• Use a V-blender

• You add ingredients and add for __ turns

• You can overmix or undermix

• If the particles are different sizes, you will get DEmixing

• To overcome this, you can do wet granulation (you add solids + liquids + binders —> you get pea sized pieces —> food processor type beat)

How are granules formed?

• Granules are formed by bridging particles

• Spraying = adding water

• Wetting = water bridges

• Solidifying = solid bridges in which the particles clump together

• The final granule = raspberry type beat

How do you turn wet granules into dry granules?

• Wet granules are added to the chamber along with warm, dry air

• This can be done static in an oven

• Dry granules are then recovered

• This is lowkey like making granola

What is the process of dry granulation?

• Small particles are mixed under pressure

• Binder (no liquid) holds together the particles

• You can make compacts, briquettes, and granulating —> based on the pressure you apply!

How do we properly size these dried particles for mixing?

• Sieve type beat?

• If too big, you can mill the particles

• if too small, just reprocess

What kind of dosage form is the Jadenu sprinkle?

• Sprinkle = granule

• Tablets and granules have the same ingredients

• you can get up to the granules and decide from there… will we be compressing tablets or will we be filling packets today?

What is the function of microcrystalline cellulose?

• This is one of the most widely used diluents in pharmaceutical science

What is the function of Povidone?

• Binder!

What is the function of Crospovidone?

• Disintegrant (same structure as Povidone —> just has crosslinks —> it pulls in water and blows things up)

• A disintegrant like crospovidone is added to pharmaceutical tablets and capsules to help them break apart (disintegrate) quickly after they are swallowed.

• Crospovidone works mainly by absorbing water and swelling, creating pressure within the tablet that causes it to burst apart.

How can we overcome an insoluble API?

• Poloxamer - solubilize other molecules

• Micelle forming - hydrophobic piece in the middle

What is the function of colloidal silicon dioxide?

• Glidant —> usually somewhere between 0.1-1% of your tablet is glidant (kinda similar in structure to glass)

How does a glidant work?

• Let’s take colloidal silicon dioxide for example

• This will break apart and surround microcrystalline cellulose for example (this is a really popular pharmaceutical diluent)

• You mix —> coating

• Then, they act as wheels between the different diluent particles

What is the function of magnesium stearate?

• Lubricant

How does a lubricant work?

• Powder enters a tablet press

• You don’t want anything to stick to the metal

• You want things to come out of the press really nicely

• So you use a lubricant

What is the most popular nongelatin capsule?

HPMC

How do we secure capsules?

• Band secures the powder or liquid in the capsule

• Band can demonstrate whether or not there has been tampering

What is the function of lactose?

• Diluent/ filler

What is the function of sodium lauryl sulfate?

• Surfactant

• Wetting agent

What is the function of sodium stearyl fumarate?

• Lubricant

What is disintegration apparatus?

• You put 6 different tablets in

• You go up and down until the tablets disintegrate

• WHY: Do you go from being a full tablet to little pieces quickly?

What is a dissolution apparatus?

• You put tablet in water + agitation

• How much dissolves into the fluid?

• Measuring single molecules in the fluid

What is the dissolution curve?

• The amount of product in solution is measured at each time in a specified media

  IR dosage forms usually only last 1-2hours

What is the difference between disintegration and dissolution?

• Disintegration: How quickly is it going into particle form

• Dissolution: How quickly is it going into solution

How can we promote the solubilization of isotretinoin?

• They are hard capsules filled with paste

• Isotretinoin (the API) is insoluble

• All of the excipients are oils and fats

• Your digestive system will break everything into globules to be solubilized

What do we test in pharmaceutical testing?

Drug + packaging (bottle material, size of opening, thickness)

What are the different times we can product test?

• Real time: during manufacturing process (e.g. testing for powder moisture)

• Final: Stability, potency, uniformity

What are some common pharmaceutcial tests?

• Dissolution rate - how quickly does the drug dissolve?

  • Every dosage form has standard dissolution properties (e.g. IR has Q of 80% at 30 minutes)

• Potency test - how much drug is in multiple units (what is the average per unit); must be within 90-110% (e.g. statins —> over time the levels will even out and everything will be ok)

• Content uniformity test - potency in one unit (e.g. birth control —> you could get pregnant if each birth control pill doesn’t have the same amount of API as others)

What is the international council on harmonization? (ICH)

• Establish a single set of global specifications for all drug products

• Considered a guidance by the FDA (not a regulation)

What is QbD?

• This is the quality by design protocol

• This is a roadmap for the development of a product

• E.g. you need certain moisture content —> how are we going to make sure you are hitting this requirement?

• E.g. If a powder has high moisture content, might add pre-set extra drying time in the protocol

  • This would be an example of risk determination (determine what step has more risk and put more effort into that stop)

  • Another example of this is adding extra mixing time for high potency tablets

• We are building in quality control during the manufacturing process, not just all at the end!

What is PAT?

• Process Analytical Technology

• Mechanism to design, analyze, and control pharmaceutical manufacturing process in real time

• Examples: Drying parameters (might need to increase temperature or air velocity), granulating (you might want to adjust massing time), compressing (you can adjust compression force if tablets are not hard enough), coating (adjust amount needed to make sure the product is sufficiently coated)

What are the long-term goals of PAT?

• Reduce product cycling time —> “very important”

  • how long it takes to go from start to finish for a drug

  • We want to get things through the pipeline as quickly as possible without waste

• Prevent rejection of batches

• Enable real time release

• Increase automation and control

• Improve energy and material use- minimize waste

• Facilitate continuous processing

What is GMP?

• Good Manufacturing Practices

• Rule book for manufacturing

• Tells you what to do, not how to do it (just end goals!)

What is validation?

• The collection and evaluation of data that proves that everything is working as it should

• Everything needs to validated that was involved in your process! (even the cleaning products and the air vents in the building)

What are the 3 stages of validation?

Stage 1: Process design. —> before (design manufacturing processes)

Stage 2: Process qualification —> during (validation/qualification —> prove it works as intended)

Stage 3: Continued process verification —> after (review to confirm good performance)

Why does Bartel’s lecture matter?

All of this (meaning quality/ testing/ validation parameters) must be approved by the FDA —> this is included with the NDA!

What is lyophilization?

• Freeze drying under a vacuum to remove solvent and residual moisture to form dry powder

• Product can be very hygroscopic

• Mostly used for unstable drugs

Why do we lyophilize?

• Extend the shelf life of products

  • Parenteral products —> powders are more stable than liquid

  • Oral —> ODT

• Allows for easy storage and shipping

• Crystalline —> amorphous form (why is this important?)

  • Advantage: more soluble!

  • Disadvantage: less stable! —> storage is really important here

What are the advantages of lyophilization?

• Improved stability

• Enhanced shelf-life

• No need of high heat for drying

• Easy storage and transport

• Rapid reconstitution (because these materials are porous!)

• Can protect oxygen sensitive products (there is a vacuum!)

What are the disadvantages of lyophilization?

• Very expensive process

• Loss of volatile components

• Specialized equipment needed

• Lengthy process

What is the principle of lyophilization?

• Sublimation = going from solid to gas form

• Sublimation is an interplay between temperature and pressure!

• No high heat is required

• Ideal for heat sensitive products like biologics, injectable drugs, and antibiotics

What are the 3 steps of lyophilization?

• Freezing

• Drying (sublimation)

• Secondary drying (desorption)

  • removing residual bound water

  • enhances stability

  • Heat can be applied (but we don’t extend beyond 30-40°C)

What is the ideal solids content?

• 5-30%

• You add in bulking agents like mannitol, cryoprotectants such as sucrose (minimizes shock of freezing), and buffering agents

Do you think lyophilization can create a sterile product without extra steps?

No! You still need to follow sterilization steps. Everything must be sterilized before, liquids sterilized by filtration, and aseptic processing.

What is the significance of a DPI?

• This is a device used to administer an inhalation powder in a finely divided state suitable for oral inhalation by the patient

• Delivers micronized particles of medication in measured quantities

• They are non-pressurized and breath activated

• Can be unit or multi-dose

  • Capsule or blister pack

• Rely on the patient’s inspiratory flow to deliver the medication

What is unique about the lungs in terms of drug distribution?

• Lungs have a high surface area and a rich blood supply

• Favor rapid drug distribution

• drugs administered here - affect pulmonary function and treat allergic symptoms

What are some formulation considerations for DPIs?

• API + excipients

  • Particle size (bioavailability)

  • Prevent moisture (excipient + packaging)

  • Powder flow (excipient)

  • Filler (excipient)

Explain how a patient will use a commercially available DPI.

• Must pierce the blister pack or the capsule

• Pt may need to manually put the drug into the inhalation device

• Some kind of mechanical motion will pierce the blister pack or capsule

• When the patient inhales, powder becomes dislodged and is brought into the pulmonary tract

What are the advantages of a DPI?

• Propellant free deign

• rapid drug onset - small particles, no liberation

• High drug dose capacity - bypass first pass metabolism

• Provides local action within the respiratory tract

• Portability

What are disadvantages of DPIs?

• Dependent on patient inspiratory flow (problem with dose uniformity here)

• Less protection from environment

• Cost - more expensive than MDI

How do you counsel a patient on DPIs?

• hold the device sideways like a sandwich

• Make sure you breathe in hard (no propellant like your traditional MDI)

• Advair - roll of blister packs already loaded, just pull the lever

• Spiriva - must load the capsule every time, counsel them not to swallow the capsule

What are inhalation solutions?

• Prepared under sterile conditions

• Administered via nebulizer

• Great for kids or for people who have trouble coordinating their breathing (just breathe normally for this type of treatment)

• takes longer… 5-10 minutes

• Allows administration of larger doses of medications

  • Albuterol inhaler - 90 mcg/ actuation

  • 2.5 mg per dose in a nebulizer (can get a lot more drug into these patients)

What is a nebulizer? What are the 3 types of nebulizers?

• Nebulizer

  • Atomizing unit in a chamber

  • Produces smaller droplets than an MDI

  • Nebulizer changes the solution into fine mist

  • Small portable or large tabletop

  • Types: Jet (compressed gas to make aerosol), ultrasonic (aerosol thru high frequency vibrations), mesh (liquid passes thru very fine mesh to form the aerosol)

What are inhalants?

• High vapor pressure

• Nasal passage

• Cylindrical rolls of fibrous material + drug infused

• Aromatic substance in addition to API

• Cap to prevent drug loss

How would you counsel a patient to use inhalants?

• To use, remove cap

• Put into nostril

• Inhale

• The drug vapor will be delivered

What are opthalmic preparations?

• Preparations applied to the eye to treat surface or intraocular conditions

• Common Opthalmic Medications

  • Anesthetics

  • Antibiotic

  • Anti-inflammatory

  • Glaucoma

  • Mydiatrics (dilate) and Cycloplegics

  • Protectants and artificial tears

  • Vasoconstrictors

• Can have systemic effect

  • Can be absorbed through the conjunctiva

What are the different types of ophthalmic preparations?

• Solutions: aqueous solution free of foreign particle

• Suspensions: liquid preparation containing solid particles dispersed in a vehicle

• Ointments and gels: semisolid preparation

• Inserts/strip: single use strip containing the drug

What are some important counseling points for ophthalmic preparations?

• How to properly instill eyedrops

  • 1 drop per administration (if you need to administer multiple drops, you should wait a few minutes between drops, if you don’t wait you might get spillage)

• Do not touch tip of the dropper! This can lead to contamination and infection

• Ointments: mix of mineral oil / white petrolatum/ melting point close to body temp —> can blur patient’s vision

• Pt should use ointment at night in combo with daytime eyedrops

• 3.5g ointment/ bottle w/ narrow gauge tips to create those ribbons!

• Strips: place in the eye for infusion of drug —> not compounded but manufactured

  • Disadvantage: they tend to float around the eye which is bothersome to vision

How do we create sterile ophthalmic preparations?

• Prepared under sterile conditions (Laminar Airflow Hood)

• Autoclave in their FINAL containers

• Microbial filter (0.22 micron)

• Multi-dose products contain preservatives to maintain sterility once the container has been opened!

  • Make sure the patient will not have an allergic reaction to the preservative!

What excipients can you find in an ophthalmic preparation?

• Preservative (multi-dose products)

• Buffering/ isotonicity agent

  • greater comfort to the eye

  • enhance stability

  • enhance solubility

  • enhance bioavailability

  • maximize preservative efficacy

• Viscosity/thickening agents

  • aid in maintaining the drug in contact with the tissues

What are 3 ways you can lose drug following ophthalmic administration?

• Immediate loss due to spillage

  • Emphasize one drop at a time!

  • You get loss anytime you administer an eye drop!

• Lacrimal drainage

  • Rapid washing and turnover = loss

• Drug absorption into the conjunctiva = loss d/t blood flow

What is most common form of otic preparation?

• Solutions are frequently used!

What are popular indications for otic preparations?

• Earwax removal

  • Carbamide peroxide - mechanical bubbling that softens and breaks up earwax, anti-infective

  • Glycerin - absorbs moisture, softens earwax

  • Hydrogen peroxide - mechanical bubbling that softens and breaks up earwax, anti-infective

  • Olive oil - softening agent, keeps formulation in ear longer

• Infections

  • Cipro

  • Neomycin

  • Polymyxin-B

  • Vehicles: glycerin, vegetable oil, Propylene Glycol, PEG, or mineral oil (adhere to canal wall better than H2O or EtOH)

• Inflammation

  • Otic gels and ointments for itching due to psoriasis —> petrolatum as the base —> directly applied to skin of the ear

• Pain

  • Pain d/t ear infection —> Benzocaine in PEG or Glycerin

What are important counseling points for otic preparations?

• Earwax: instill and then remove with syringe

• Infection, inflammation, pain: instill and leave in

• Tilt head

• Don’t instill these drops into your eyes!

What is the particle size necessary for drug delivery to the bottom of the pulmonary tree?

0.5 - 1.5 µm

What are the differences between the product concentrate as a solution, suspension, and emulsion?

• Solution aerosols: API is soluble in the propellant

• Suspension aerosols: API is insoluble in the propellant

  • The propellant rapidly vaporizes and leaves a dispersion of the API

• Emulsion aerosol: API + aqueous and/or nonaqueous vehicle + surfactant

  • Note that — in all examples — the propellant is O

  • Foam: API is dispersed through the propellant where the propellant is the internal phase (O/W emulsion)

  • Sprays or wet streams: Propellant is the external phase (W/O emulsion)

  • Patients will need to shake prior to use

What are the differences between propellants?

• CFC: depletes the ozone layer

  • Gases at room temperature that can liquify

• HCFC or HFC: lower ozone depletion effect, greater miscibility with water (great solvents)

• Hydrocarbons: Used in topical aerosols (low toxicity, immiscible with water, flammable)

• Compressed gases: for products dispensed as foams or semisolids (used for food or hair products usually) —> propellant can be depleted (pressure diminishes as the product is used) —> different doses as the propellant is depleted

Compare and contrast continuous versus metered valve systems.

• Valves regulate the flow of the product concentrate from the container

  • Valves must be able to withstand pressure, be non-corrosive, easy to turn on and off, and emit the desired form of the product

• Continuous valve

  • Keeps emitting product as long as the actuator is being pressed

  • You can hold it down until the canister is empty

• Metered valve

  • For metered dose inhaler!

  • Accurately dose medication

  • UPRIGHT: solution aerosols, contain dip tube

  • INVERTED: suspension and dispersion aerosols, no dip tube

What are the components of two phase and three phase systems?

• Two Phase System: homogenous system

  • Product is dissolved or dispersed in liquified propellant and solvents

  • Propellant exists in both the liquid phase and vapor phase

• Three Phase System: heterogenous system

  • Consists of a layer of aqueous product concentrate, water immiscible liquid propellant, and vapor layer

  • Location of the dip tube is important!

    • CFC, HCFC, HFC - will reside on bottom of the container, so the dip tube needs to be in the middle of the container

    • Hydrocarbons - reside on the aqueous layer, dip tube should be at the bottom of the container

  • Ex: Foam Aerosols

What are the advantages and disadvantages of aerosols?

• ADVANTAGES

  • Drug is delivered to target organ

  • Less dose required, less systemic exposure, less toxicity

  • Aerosol doses are generally smaller than systemic doses

  • Systemic side effects are less frequent and severe vs parenteral delivery

  • Fast onset of action

  • Portion of the drug can be withdrawn without contaminating remaining product

  • Aerosol container protects active ingredient from degradation

  • The physical form and particle size of the emitted product can be controlled

  • Ease of application (topical formulations) —> avoids need for cleanup, rubbing

  • Avoids first pass effect

• DISADVANTAGES

  • Number and variability of devices can confuse patients

  • Difficult for patients to administer properly (have to coordinate breathing with actuation)

  • Infections (e.g. from steroids which compromise the immune system, can lead to oral thrush)

  • Cost

What are some counseling points for aerosols?

• MDI

  • Take a breath at the same time as you press on the canister

  • Check the # of doses you have remaining for MDI

  • You should instruct patient to rinse their mouth out after using a steroid-containing inhaler (to lessen risk of developing oral thrush)

  • Always counsel the patient which direction to hold their inhaler

• Lingual aerosols

  • Counsel patient whether they should spray onto or under the tongue

  • Remind them this is not for inhalation

  • Do not rinse mouth after spraying

What formulation is best for each container type?

• Glass: solution (like fluticasone nasal spray)

• Tin-plated: topical

• Aluminum: topical or MDI

• Stainless steel: high cost, but useful for concerns about packaging interacting with the product

• Plastic: not great because of permeability issues

What is the pressure fill process?

• More common that cold filling

• Done at room temp

• Product concentrate is placed in the container

• Valve assembly is inserted and crimped into place

• Then liquified gas, under pressure, is added through the valve

• The valve is then tested

What kind of medication is heparin?

High Alert Medication, this is not the same as a hazardous medication (does not need to follow USP 800)

Can you use preservatives for children and neonates?

No! Benzyl Alcohol should never be used for children due to the potential of gasping baby syndrome. This syndrome can cause CNS depression or CV collapse, which can be fatal.

What are some characteristics of vancomycin?

• This is an acidic drug, meaning it can cause issues when added to an alkaline compound (can cause precipitation)

How can we overcome precipitation issues with vancomycin?

• This is dependent on pH and [ ]

• You want to avoid mixing vancomycin > 5 mg/mL in presence of heparin to avoid precipitation

• You also will want to add vancomycin to the heparin solution (not the other way around)

What is the pH of the final ophthalmic solution?

7.7

What is the pH of natural tears?

7.4

What is the average osmotic pressure of an ophthalmic preparation?

310 mOsm/kg

What is the osmotic pressure of natural tears?

280 mOsm/kg

What kind of filter do you use?

0.22 uM

Why does epinephrine contain antioxidant in the formulation?

Epinephrine is prone to oxidative degradation resulting in reduced potency and yellow-brown discoloration

How do you calculate how much base you use when you are using the salt form?

g of pure substance / MW of pure substance = g of salt/ MW of salt