PCEU 509 Exam #2 (Review)

introduction to the epithelium

• All internal and external body surfaces are lined with epithelium

• To be absorbed, drugs must penetrate that epithelium to reach systemic circulation

  • Injections (IM, SC) are an exception because they can bypass the skin

• After the epithelium, there is also fat, vasculature, etc. that needs to be passed to get to blood

For drug absorption in non-injection administration, what is the rate-limiting barrier?

epithelium

• It can define whether a drug is or doesn’t get absorbed

• This makes injection dosage forms the most effective way to administer the drug, but it’s not favored by many patients

types of epithelium

• Simple squamous

• Simple columnar/cuboidal

• Stratified squamous

• Pseudostratified columnar

• Transitional

simple squamous epithelium

a single layer of thin flattened cells

• Allows for good drug absorption

• Found in: Lung’s alveoli and kidney’s filtration tubule

• Endothelium (inner surface of blood vessels) is also similarly structured, which is what makes injections effective

simple columnar/cuboidal epithelium

a single layer of column/cube-shaped cells; ciliated or nonciliated

• Thicker than simple squamous, which makes it less good for drug absorption, but absorption still occurs since it’s not that much thicker

• Found in: Lung’s bronchioles, kidney’s distal tubule and collecting duct, stomach, and small and large intestines

stratified squamous epithelium

multi-layers of flattened cells, with outer cells keratinized or non-keratinized

• Much thicker than simple squamous and simple columnar/cuboidal

• Found in: Oropharynx cavity, esophagus, rectum, vagina, cornea, and skin (keratinized)

pseudostratified columnar epithelium

a single layer of columnar cells, each touching the basal lamina directly; their nucleus location gives a stratified look

• Thickness is similar to simple columnar

• Found in: Nose, larynx, trachea, and urethra

transitional epithelium

multilayers of differently shaped cells that allow stretching

• Found in: Urothelium of the bladder and ureter

Rank the permeability of the different types of epithelium from most permeable to least.

Simple squamous > Simple columnar/cuboidal and Pseudostratified columnar > Transitional epithelium > Stratified squamous

components of epithelium that influence their permeability

• Epithelial types vary across different body surfaces → Influence the kinetics of drug transport at each site

• Cell thickness:

  • Simple < Stratified

  •  Squamous < Columnar/cuboidal

• Tightness between cell junctions

  • When cells are super squished together, that makes it harder to permeate

• Functionality of specialized transport

cell membrane

• Made up of two layers of phospholipids

• A phospholipid itself has a hydrophilic head that faces toward extracellular and intracellular aqueous situations while the lipophilic tails face toward each other

• Lipophilic molecules get taken in, while hydrophilic molecules are repelled

diffusive sorting by the cell membrane

• We want drugs to be more lipophilic because they can get through the phospholipid bilayer without help

• Despite water being hydrophilic, it’s just so small and also not charged, allowing it to still can get in

• Ions are charged, hydrophilic molecules that can’t get through the phospholipid bilayer, so it needs a transporter/channel if it wants to get into the cell

What is diffusion generally driven by?

a concentration gradient, going from high to low concentration (in order to spread out)

Fick’s diffusion equation

describes drug transport across a membrane → predicts drug absorption rate

• Diffusion is faster when…

  • Diffusion coefficient (D) is larger (e.g., smaller MW drugs)

  • Surface area (A) is larger (e.g., intestine compared to skin)

  • (C1 - C2) is larger (e.g., higher concentration or dose)

  • Thickness of barrier (h) is smaller (e.g., intestine compared to skin)

What is Fick’s diffusion equation missing?

the cell membrane’s preference for lipophilic molecules

What is diffusion truly driven by?

membrane partitioning

• Creates a true concentration gradient for diffusion

• Partition coefficient (K_D) consists of a lipophilic numerator and hydrophilic denominator

modified Fick’s equation to take into account membrane partitioning and lipophilicity

• D is larger (e.g., small MW drugs > large MW drugs)

• Kd is larger (e.g., lipophilic drugs > hydrophilic drugs)

• A is larger

• (C1 - C2) is larger

• h is smaller

Ultimately, what sort of properties of a drug make it have the fastest diffuson and absorption?

• Small MW

• High lipophilicity (K_D)

However, as lipophilicity (K_D) increases, the rate of diffusion and absorption increases AS LONG AS…?

the drug is fully dissolved

• If not, you can’t define a meaningful concentration (C) of the drug and for the gradient

• When drugs are too lipophilic, they won’t get dissolved in water… so that is a big issue when designing for chemists is that you need enough lipophilicity to get past the cell membrane but not too much that it won’t get dissolved

diffusion

mass transfer of a dissolved substance from a region of high concentration to a region of low concentration in a single-phase system or across a permeable membrane

Stokes-Einstein equation

defines the diffusion coeffcient (D) in Fick’s diffusion equation and relates it to its attributes

• D is defined by the solute size, the medium’s viscosity, and the medium’s temperature

  • Smaller size → Larger D → Greater diffusion and absorption

  • Lower viscosity → Larger D → Greater diffusion and absorption

  • Higher temperature → Larger D → Greater diffusion and absorption

pH-partition hypothesis

• Only unionized, lipophilic (small MW) drugs can penetrate the cell membrane using trans(intra)-cellular diffusion, while ionized species are repelled

• The fraction of unionized drugs at the absorption site determines their diffusive permeation across cell membranes

• The Henderson-Hasselbalch’s principle allows estimation of a drug’s ionization/unionization state from its pKa

ionization effect on absorption

Bottom line: More % unionized = Higher diffusion rate and % absorption

What is a way hydrophilic, ionized (small MW) drugs can be absorbed then?

para(inter)-cellular diffusion (minor contribution)

• Occurs mainly in the small intestine

• Tight junctions filled with extracellular fluid within cellular membranes provide a diffusion pathway for hydrophilic and/or ionized drugs

• However, the tight junction needs to be wide enough for large molecules. Otherwise, we have steric hindrance, resulting in either absorption getting hindered or not possible

types of para(inter)-cellular diffusion

• Restricted diffusion (problem with the pore)

• Size exclusion (problem with the molecule size)

restricted diffusion

decrease in a particle's movement due to limited space or confined geometry, slowing down diffusion without changing the particle's size

size exclusion

• What is the size cutoff?

separation principle where larger molecules are completely excluded from porous media (= ZERO absorption)

• Size cutoff: 600 Da

rule of thumb for questions asking which type of diffusion (transcellular or paracellular) a drug will use

• For acids:

  • If put into a more acidic environment → Unionized

  • If put into a more basic environment → Ionized

• For bases:

  • If put in a more acidic environment → Ionized

  • If put in a more basic environment → Unionized

• Cutoff for paracellular diffusion: 600 Da (i.e., poor/insignificant absorption)

With lipid membranes, cells are naturally capable of taking in lipophilic molecules and repelling hydrophilic molecules. However, what mechanism is available then if we need to take in essential hydrophilic molecules and ALSO remove lipophilic ones?

Transporters!

diffusion versus transporters

• Most drug absorption occurs via diffusion

• Transporter-mediated absorption, which is occurring in parallel with diffusion, is critical for certain orally administered drugs

specialized transport mechanisms

• Uptake transporters

• Efflux transporters

• Cytosis

SLC uptake transporters

• Types?

SoLute Carrier (SLC) protein-mediated uptake transport of substrate molecules upon binding, increasing absorption

• Three different types:

  • Uniport: only one molecule needs to bind

  • Symport (cotransport system): two molecules need to bind on the same side and move in the same direction at the same time

  • Antiport: two molecules need to bind on opposite sides and move in different directions at the same time

uniport SLC uptake transporter

• Active or passive?

• Is cell energy required?

• Transport rate

• Does structure matter?

• Substrates (like vitamins and glucose) are passively transported into the cells via uniport proteins, following the concentration gradient

• Cell energy is not required

• The transport rate is…

  • Significantly greater than that predicted by diffusion (diffusion’s is arguably near 0 because it can’t take on hydrophilic molecules)

  • Nonlinear (unlike diffusion)

  • Not proportional to the concentration (dose) at all levels; it saturates at higher concentrations (doses)

• Structure-selective and inhibited by chemically similar molecules

symport/antiport SLC uptake transporter

• Active or passive?

• Is cell energy required?

• Transport rate

• Does structure matter?

• Substrates are actively transported into the cells via membrane proteins against a concentration gradient

• Cellular ATP hydrolysis energy is used indirectly

• The transport rate is nonlinear (unlike diffusion) and saturable

  • Transport rate is not proportional to the concentration (dose) at all levels

  • It saturates at higher concentrations (doses)

• Structure-selective and inhibited by chemically similar molecules

examples of uptake transporters

• PEPT1 (symporter that uses active transport)

• OATP (uses active transport)

ABC efflux transporters

• Active or passive?

• Is cell energy required?

• Transport rate

• Does structure matter?

ATP-Binding Cassette (ABC) protein-mediated efflux transport of substrate molecules upon binding

• Substrates are actively removed out of the cells against the concentration gradient, reducing intracellular concentration

• Cellular ATP hydrolysis energy is used directly

• The transport rate is nonlinear and saturable

• Structure-selective and inhibited by chemically similar molecules

example of ABC efflux transporter

P-glycoprotein (PgP): Multi-Drug Resistance (MDR) efflux protein expressed in the intestinal epithelium, hepatocytes, renal proximal tubular cells, and brain capillary endothelium

• Many tumor cells express this protein in order to protect themselves

How does PgP affect gastrointestinal absorption?

1. Substrate drugs readily enter the cells due to their lipophilic nature

2. PgP pumps drug out of the cell back into the intestinal lumen

3. Net absorption is reduced, resulting in reduced blood levels

“selectivity” of PgP

• PgP has many recognition sites, allowing for many molecules to be recognized. Chemically diverse drugs from different classes can act as substrates, including:

  • HIV protease inhibitors (e.g., rifampin)

  • Quinidine (antiarrhythmic)

• Besides certain drugs—excipients, diets, and supplements can act as PgP inducers or inhibitors

  • Inducing PgP (e.g., rifampin) → Decreased levels of drug in blood

  • Inhibiting PgP (e.g., quinidine, grapefruit juice) → Increased levels of drug in blood

endocytosis/transcytosis

• Cellular transport via phagocytosis and pinocytosis for certain macromolecules (e.g., insulin), fluids, and particulates

• Mechanisms are similar to those for symport/antiport. However, membrane proteins are internalized

• Example: Absorption of oral vaccine and transport of antibodies

• Note: Small drugs are not absorbed by this mechanism

The fraction of drug that gets absorbed is described as…?

bioavailability

Dosage forms have been defined by what regulatory agency(ies)?

USP and FDA

Additives and excipients have been defined and approved by what regulatory agency(ies)?

FDA

What are the various oral dosage forms?

• Liquid: Solution, syrup, elixir, tincture, suspension, and emulsion

  • The FDA discourages high-alcohol content in new, non-prescription oral products, which can affect the formulation of your traditional elixirs and tinctures

• Solid: Powder, granule, capsule, tablet, effervescent tablet (EVT), orally-disintegrating tablet (ODT), enteric-coated (EC) and extended-release (ER) dosage form

• Liquid in solid: Soft capsule, liquid gel

• (Buccal/sublingual: Tablet, spray, lozenge, and gum)

mouth and esophagus

• Type of epithelium?

• Transit time? What does it depend on?

• Luminal fluid pH?

• Does drug dissolution and absorption occur?

• Stratified squamous epithelium

• Transit time: 10-14 seconds

  • Dosage form size- and shape-independent

  • Posture-dependent (slower in a supine position than in an upright position)

• Luminal fluid has a pH of 5-7 (small buffer capacity)

• Drug dissolution and absorption are insignificant because of…

  • The type of epithelium

  • The muscle they’re covered in

  • The quick transit time

What is a complication that can occur in the esophagus with drugs?

• Can reach up to 20% when tablets and capsules are taken with little or no water

• Higher in elderly populations

• Adhesion and/or slower transit can cause:

  • Delayed drug appearance in the stomach and intestine, which can delay and/or reduce absorption (i.e., increased T_max, decreased C_max, and decreased AUC for acidic drugs)

  • Local esophageal damage (e.g., with NSAIDs)

• The FDA recommends taking a full glass (> 250 mL) of water to not only help with dissolving of the drug, but also prevent adhesion of dosage forms

stomach

• Type of epithelium?

• Size of pyloric sphincter and what it entails?

• Luminal fluid pH?

• Does drug dissolution and absorption occur?

• What does GI absorption depend on?

• Simple columnar epithelium

  • Thinner (more permeable) than the membrane of the esophagus

  • Thicker (less permeable) than that of the small intestine

• Pyloric sphincter is only 7-10 mm in diameter, so drugs need to be small enough or dissolved enough in order to pass through

• 1.0-1.5 L/day of acid secretion

• Luminal fluid has a pH of 1.5-2.5 (almost no buffer capacity)

  • Food raises a pH to ~4.5, which can cause a change in the ionization state of the molecule and thus its absorption properties

  • Elderly populations often have an elevated pH

• Here, unionized, small MW drugs are absorbed. Drugs that are not absorbed include:

  • Hydrophilic or ionized drugs

  • Large MW (> 600 Da) drugs

  • Peptide, protein, polysaccharide, and antibody drugs (must be administered via injection)

• GI absorption depends on fat, calories, mass/volume, and temperature

How long does gastric emptying take? What does it depend on?

Gastric emptying is highly variable (1 to 7 hours), depending on dosage form, size, and food intake

Why do liquids leave the stomach faster than solids?

Liquids don’t require grinding/breakdown → faster gastric emptying → steeper disappearance slope and earlier peak concentration

How does dosage form affect time to peak concentration?

• Liquids → faster peak (earlier T_max)

• Solids → slower peak (delayed T_max)

How does fasting affect gastric transit time?

How do meals affect gastric transit time?

• Fasted state → rapid transit (~1 hour) for both large and small pellets

• Food increases transit time

  • Light meal → moderate delay

  • Heavy meal → significant delay

  • After meals, larger pellets empty slower than smaller pellets

What is the overall effect of food on drug absorption?

• Delays gastric emptying, subsequently delaying transit to the small intestine, which delays T_max

• May or may not improve or have an impact on absorption (AUC) by allowing more time for drug breakdown/dissolution but also leaving the drug prone to secretions and gastric fluids that cause the concentration of the drug to decrease

  • The latter is especially a problem for acid-labile drugs

How does taking certain medications affect gastric emptying?

• Some promote gastric emptying, which decreases T_max

• Others delay gastric emptying, which increases T_max

summary on physiological gastric emptying

• Highly variable (1 to 7 hours)

• Liquid (fast) > Small solid > Large solid (slow)

• Fasted (fast) > Fed (slow), which is fat- and mass-related

• Other factors that promote gastric emptying: Anxiety, body position (lying on the right side), liquid intake, antiemetic drugs, and NaHCO3

• Other factors that delay gastric emptying: Mental depression, body position (lying on the left side), ulcers, pyloric stenosis, and anticholinergics

gastric hydrolysis

• How can we protect drugs from degradation?

Acid-labile drugs are quickly dissolved and degraded in the stomach

• We can protect drugs using:

  • Enteric coating

  • Low-solubility salt (stearate)

  • Prodrug (ester)

  • Reducing particle size

small intestine

• Type of epithelium?

  • What makes it unique?

• Does drug dissolution and absorption occur here?

~6 m in length and arbitrarily divided into 3 segments (duodenum, jejunum, and ileum)

• Simple columnar epithelium

  • A total surface area of 200 m² due to epithelial folding, villi, and microvilli (so the surface area is not flat)

• A majority of drugs are absorbed here via diffusion and transporters

How long is small intestine transit? What does it depend on?

• Takes about 3 to 4 hours, irrespective of liquids or solids; large or small solids; or fed or fasted

  • A relatively short time window to complete absorption, but here is where most enzymatic degradation of drugs can occur (stomach only has pepsin)

  • Quite different from gastric emptying, which heavily depends on the presence of food

large intestine

• Type of epithelium? Is it unique?

• Luminal fluid pH?

• Transit time? What does it depend on?

• Does drug dissolution and absorption occur?

• Simple columnar epithelium, but has no folds and villi, surface area is 3 m²

• Luminal fluid pH = 5.5-7.8

• Transit time: 15 hours (fasted) to 48 hours (fed)

  • i.e., depends on food intake

• Drug absorption is limited in part by viscous and semisolid luminal contents; however, some drugs (e.g., theophylline and metoprolol) are well absorbed here in the large intestine. Furthermore, here lies the greatest water absorption and bacterial activity

What can a patient take to help improve dissolution and absorption of low-solubility or lipophilic drugs?

water

• Enhances dissolution and absorption, but the extent is unpredictable

BCS guidance by the FDA

BCS = Biopharmaceutics Classification System

• Framework for classifying drug substances based on aqueous solubility and intestinal permeability

process by which drugs undergo in the body, according to the BCS

• When is a drug considered to have high solubility?

• When is a drug considered to have high permeability?

1. Disintegration (tablet breaking down into smaller particles in the stomach)

2. Dissolution (smaller particles are dissolved into solubilized drug) 

• High solubility: when the highest dose strength is soluble in 250 mL or less of aqueous media at pH = 1-7.5

3. Permeability (drug was able to be absorbed)

• High permeability: when the extent of absorption in humans is determined to be 90% or more of the administered dose

Rank dosage forms from fastest to slowest complete dissolution and gastric emptying.

• Solution, syrup, elixir

• Powder, granule, EVT, ODT

• Suspension, emulsion

• Capsule

• Tablet

• Coated tablet

• Enteric-coated (EC), extended-release (ER)

What can happen to a drug after GI absorption before reaching systemic circulation?

“competing losses” or “post-absorption events”

• Drug can enters the portal vein → goes to liver → may be metabolized (loss) before reaching plasma

• Metal complexation forms insoluble complexes that decrease absorption (e.g., antacids with Mg(OH)₂ or Al(OH)₃ decrease Cmax and AUC by ~90%)

What determines how much drug reaches systemic circulation?

Amount absorbed - amount metabolized (especially in liver)

• First-pass metabolism is hepatic metabolism of a drug after GI absorption but before reaching systemic circulation. Thus, this decreases bioavailability; however, it does not affect T_max

• High bioavailability is determined by all three of these factors: low first-pass metabolism + high GI absorption + minimal post-absorption events

  • This means that high GI absorption does not necessarily equate to high bioavailability, because there are other factors at play

What causes double-peak plasma concentration profiles?

• Food after dosing

• Enterohepatic recycling

  • Drug is excreted in bile → reabsorbed in intestine by bacterial enzymes → causes secondary peak

summary on how food affects drug absorption

• Delays gastric emptying

• Alters GI pH

• Changes solubility

• Causes drug-food interactions

• Affects transporters

• ↑ viscosity, bile flow, blood flow

The effects, if any, are greatest when drugs are taken shortly after food intake

summary on factors affecting GI absorption

• Physiologic factors

  • Membrane physiology

  • GI tract physiology

• Physicochemical factors

  • pKa

  • Lipophilicity

  • MW

  • Dissolution (formulation factor as well)

advantages of oral solution

• Disintegration, deaggregation, and dissolution are not required for absorption

• Gastric emptying is faster than for solid dosage forms, and food intake causes only a small delay

→ Fastest absorption among oral dosage forms

• Homogeneity in solution allows drug doses to be measured and administered by volume

→ Dose strength is expressed as concentration

PK of an acidic drug (solution versus solid)

Solutions enable faster and greater/equal absorption than solids

PK of a basic drug (solution versus solid)

• Absorption only begins when reaching the small intestine, not in the stomach

• Solutions enable slightly faster and equivalent absorption relative to solids

disadvantages of oral solution

• Maintaining chemical and physical stability is more challenging than for solids; the shelf-life is shorter

• Drug solubility can be a challenge in formulations with doses of 5 mL (1 teaspoonful) to 15 mL (1 tablespoonful)

• Dose measurements by patients and caregivers can be inaccurate and variable

• Bulkier and less portable than solids

• Drugs may precipitate in the GI tract as water intake is not instructed, which affects C_max but does not affect T_max

types of oral solution

• Ready-to-use oral solution

• Dry powder mixtures/granules for oral solution

  • Reconstitution by pharmacists (product shelf-life is shorter after reconstitution)

  • Less popular than suspension

• Syrup, elixir, and tincture

ready-to-use oral solution

• Stable in solution with R.T. storage

• Preservatives and sweetening agents are added

  • Some sweetening agents, like glycerin, can also help improve solubility

syrup

• Medicated?

• Sucrose?

• Ingredients?

• A typical dose is how much?

concentrated aqueous solutions of sugar or sugar substitute with or without flavorant (usually viscous)

• Medicated or non-medicated

  • Non-medicated syrups (e.g., Syrup NF: 85% sucrose in purified water) are used to prepare medicated syrups

•  Sucrose- or non-sucrose-based

  • 60-80% sucrose for sweetness and viscosity

  • Artificial sugars (e.g., sorbitol, saccharin, aspartame, and maltitol) provide sweetness but lack viscosity. So, cellulose-based viscosity increasing agents (e.g., MC and HPMC) are also needed

• Syrup ingredients:

  • API

  • Purified water

  • Stabilizer

  • Sucrose or artificial sugar + viscosity increasing agent

  • Preservative

  • Flavorant and colorant

  • Note: By definition (but not the case in reality), nonaqueous solvents (e.g., alcohol) are not used, and the formulation is viscous (i.e., 100% aqueous, viscous, and sweet)

• A typical dose of volume is a tablespoonful

advantages of syrup dosage form

• Use and acceptance by patients (especially pediatric and elderly), but not biopharmaceutics (When talking about PK, syrup had an earlier T_max but a possibly smaller C_max than tablet)

• Does NOT need to be taken with water, as syrups are already aqueous, sweetened solutions meant to be taken as-is

elixir

• Medicated?

• Ingredients?

• Comparison to syrups and suspensions?

clear, sweetened hydroalcoholic solutions, generally with flavorants

• Medicated or non-medicated

• Alcohol can be ethanol and/or sugar alcohol (e.g., glycerol, propylene glycol, and sorbitol)

• Hydroalcohol dissolve both water- and alcohol-soluble ingredients (easier to prepare solutions than syrups)

• Less sweet and less viscous than syrup

• Less popular as suspensions gain popularity

non-medicated elixir

• For extemporaneous filling of a prescription…

  • As a pleasant-tasting solvent for powder drugs

  • For dilution of medicated elixirs

• Alcohol % can be low (8-10%), intermediate (25%), or high (75-78%)

• Sweetening agents and colorants are added

• Be aware of solubility and stability when mixing!

  • Alcohol concentration must be maintained

  • Chemical/physical compatibility must be ensured

  • Color and flavor must not have a conflict

medicated elixir

• Commercial products contain alcohol (ethanol) by 5-20%

• Those with ≥ 10% alcohol are self-preserving (i.e., no need to add preservatives)

• A typical dose of volume is a “teaspoonful” or 5 mL

• Generally not for children

tincture

alcoholic or hydroalcoholic extracts or solutions of substances (e.g., drugs)

• Alcohol % can be 25-80%; many commercial products contain 45% or more

  • Tight closure to prevent evaporation loss

  • Mixing requires caution because of the higher concentration of alcohol

  • Storage should avoid heat/high temperatures and ignition

• Very limited availability, but some USP products are popularly used (e.g., Paregoric USP, Opium USP)

suspension

• Should be 100% Purified Water, USP that gets used to reconstitute and suspend the drug

• Two types:

  • Ready-to-use oral suspension

  • Dry powder mixtures/granules for oral suspension

    • Reconstitution by pharmacists (product shelf-life is shorter after reconstitution)

• Used to be a compromise of solutions, but now has become a preferable option, even over solids

• Popular APIs: Antibiotics, antifungals, and antacids

pros of oral suspensions

• Dissolution can be faster than for solids

• Gastric emptying is faster than for solid dosage forms, and food intake causes only a small delay → Absorption and onset is faster or equivalent compared to solids

• Drugs can be chemically stable, with a longer shelf-life compared to solutions

cons of oral suspensions

• Formulation is challenging for water-soluble drugs (they often end up with a solution instead)

• Dose measurement and physical size present practical disadvantages, like solutions

  • If the liquid is relatively heavy and bulky, that creates higher transportation costs

When comparing the PK of different dosage forms, what should you take note of?

• T_max is directly comparable

• C_max requires the dose to be equivalent before comparisons can be made

emulsion

oil-in-water (o/w) disperse systems with emulsifying agents

• As of today, we do not have any emulsion dosage forms that contain the APIs you typically think of. Pharmacological agents are not formulated; the oil itself is the active ingredient!

• Currently used only for local GI effects, not for systemic absorption or action

advantages of oral solid dosage forms

• Natural and pain-free

• Simple, small, and convenient

• Accurate dose (i.e., essentially already measured for the patient when it’s a tablet)

  • Exception: Some laxative products requires the patient to scoop out the current amount of powder

• Increased stability and longer shelf-life

• Relatively inexpensive

disadvantages of oral solid dosage forms (compared to liquid)

• Absorption and onset of action are slower because it takes a while to disintegrate and dissolve

• Absorption is more influenced by food intake

types of oral solid dosage forms

• What do all solid dosage forms require?

• Powders and granules

• Capsules

  • Hard and soft

• Tablets

  • Uncoated and coated

  • Orally-disintegrating tablets (ODTs)

  • Effervescent tablets (EVTs) (not directly placed into the mouth; must be placed in a glass of water or tea and drunk all together, which makes the body process this in a similar way to a suspension)

  • Enteric-coated (EC) tablets

  • Extended-release (ER) tablets

(All solid dosage forms require nice powder formulations and to also be taken with water except for some ODTs!)

diluent

an essential excipient to increase bulk, compressibility, and homogeneity so that patients have something already accurately measured and can be physically handled

• Enables accurate handling and administration of drugs in a small quantity

• Other names: Filler, bulking agent

powders

finely divided drug particles

• Fast dissolution → Fast absorption

• Flexible dosing (can adjust amount easily)

  • Maximum tablet mass: ~2 g (otherwise, the patient can’t swallow it)

• Drug stability in solution does not need to be ensured (since the patient is reconstituting it)

• However, there are often issues with flow, making it hard to handle/manufacture

Content uniformity must be ensured (i.e., no matter where the powder is scooped, you will have the same amount of drug in it proportionally), but powders often segregate due to differences in particle size, shape, and density. What is a possible solution?

turning the drug particles into granules

granules

2-5 mm irregular agglomerates of small particles, prepared by wet or dry methods

• Unlike/relative to powders:

  • Each agglomerate contains all the ingredients

  • Better content uniformity

  • Larger in size, enabling better flow properties in manufacturing, but requires an extra processing step

  • Higher in density, which allows smaller dosage forms and reduced storage space

  • Slightly slower dissolution

types of powders and granules

• Bulk powders

• Single dose-unit powders

How should oral powders and granules be administered?

must be added to water first and then drunk, not just taking the powder directly into the mouth

• Behaves like a suspension in our system

• Don’t need to worry about ensuring the stability because the patient “reconstituted” it themselves and took it immediately after; however, there is a concern of inaccurate measuring of doses

advantages of powders and granules

• Easier in swallowing with water intake

• High drug doses can be formulated (e.g., > 2 g)

  • It is really difficult to fill 2 g of a drug into a capsule or compress into a tablet because it’s just too large

• Quick dispersion and dissolution → Fast absorption

• Faster gastric emptying (less influenced by food intake) than capsules/tablets

disadvantages of powders and granules

• Bulk powders are less convenient for carrying/storage

• Acid-labile or hygroscopic drugs are unsuitable for this dosage form

  • Acid-labile drugs dissolve and degrade quickly at the stomach’s pH, which can reduce their effectiveness significantly

  • Hygroscopic drugs absorb water from their environment, leading to poor flowability, caking, instability, and degradation. They become moist clumps that makes them sticky, causing processing issues and inconsistent, inaccurate dosing

two types of capsules

• Powders/granules in a hard shell

• Liquid in a soft gelatin shell (→ has a layer of protection, but possible barrier for dissolution)

gelatin capsule ingredients

• Gelatin: main ingredient; animal-derived; soluble at 37 °C in 10-60 min (i.e., not instantaneous, delaying onset of action)

• Water: to provide flexibility and maintain 13-16% moisture

• Preservative (e.g., parabens)

• Plasticizer: used only in soft capsules for sealing (e.g., glycerin, sorbitol)

preservative

prevent microbial growth that could result from using water as an ingredient for either the powder or the coating (if applicable)

innovation in capsules

• Hydroxylpropyl methylcellulose (HPMC) capsule

• Pullulan capsule

hydroxylpropyl methylcellulose (HPMC) capsule

• Made up of?

• Compared to gelatin capsules…

• Tidbit

• Plant-derived, suitable for vegetarians/vegans

• Compared to gelatin capsules…

  • More stable, and less sensitive to temperature or humidity

  • Lower in water content (4-6%), often allowing no use of preservatives

  • More resistant to moisture sorption

  • Slower in disintegration

  • More expensive

• Tidbit: Used in approved oral products (e.g., Talzenna)