RX 421: Principles of drug delivery of oral solid dosage forms and approaches to improving oral drug bioavailability

Physical Characterization of Powder Blend

- Particle Size
- Wetting & Dispersal
- Bulk-Tapped Density
- Hygroscopicity
- Flow
- Compressibility
- Crystal shape
- Homogeneity

Physical Characterization of Drug Substance

- Solubility
- Permeability
- Melting point
- Crystallinity
- Crystal form and shape (polymorphs)
- Particle Size
- True Density

Dry Excipients Classes

- Binders
- Colorants
- Diluents
- Disintegrants
- Film Coatings
- Flavoring agents
- Glidants
- Lubricants
- Opacifying agents
- Polymers
- Surfactants

Tablet Types

- Immediate release
- Delayed release
- Controlled release
- Dispersible
- Oral disintegration
- Chewable Effervescent
- Sublingual

Liquid Excipients Classes

- Solubilization agents
- Surfactants
- Solvents and Co-solvents
- Permeation Enhancers
- Preservatives
- Anti-oxidants

Direct Compression

powders compressed into tablets

Encapsulation

Powder blend filled into Hard Capsules

Chemical Stability of Drug Substance to...

- Acid
- Base
- Light
- Heat
- Moisture
- Oxidation

Reasons for Granulation

- Control drug segregation
- Improve content uniformity
- Improve flaw
- Increase bulk density
- Improve compression
- Improve wetting/dissolution
- Reduces dust production

Two Piece Hard Shell (Gelatin and HPMCI)

- Powder filled
- Granule Filled
- Drug only filled
- Semisolids

Single Piece Soft Shell

- Gelatin
- Emulsions
- Solutions
- Suspensions

Drug Property Influences on Manufacturing Platform Selection

- Drug Load and Estimated Dose Range
- Physical properties of mix (flmv, density, compressibility)
- Physical/chemical stability traits (thermal, water, sotvent stability)

Types of oral solid dosage forms

- Conventional compressed tablets
- Multiple compressed tablets
--- (e.g. polypill for secondary cardiovascular prevention)
- Buccal and sublingual tablets
--- (bypass first pass metabolism and rapid onset of action)
--- (eg. testosterone buccal tablets to overcome poor oral bioavailability)
- Chewable tablets
--- (eg.antacids, pediatric medicines)
- Orally disintegrating tablets (ODTs)
--- (eg.levetiracetam for epilepsy)
- Dispersible / soluble tablets
--- (eg.aspirin)
- Effervescent tablets
--- (eg.vitamin C)
- Modified release tablets
--- DR
--- SR
- Film coated tabs
- Capsules
--- Hard
--- Soft

Delayed release

drug release starts in small intestine or colon

Sustained release tablets

drug release sustained over 12 or 24 hrs

Film coated tablets

water soluble polymer coating does not delay or sustain drug release however may protect drug from light/moisture, improve tablet swallowability or enhance tablet appearance

Hard (two piece)

filled with powders/granules/pellets

Soft (one piece)

filled with liquids. Drug dissolved/dispersed in a liquid may improve drug bioavailability

"Patient centricity"

The specific needs of an individual patient or patient populations as the focal point in pharmaceutical drug product design

So what are tablets made from?

1. Drug + excipients
2. Blended to form homogenous powder mix
3. Powder compressed into tablets OR Granulated
4. Granules compressed into tablets

What are powders?

describes a formulation in which a drug powder has been mixed with another pharmaceutical producer to produce the final product.

Powders and dosage forms

Powders are themselves dosage forms or can be used as intermediate products in the manufacture of other dosage forms.

Main dosage forms powders are processed into

tablets and capsules

What do we need to know about our powder blends?

1. Particle size
2. Long range order of molecules (crystalline or amorphous)
3. Hygroscopicity
4. Density
5. Flow
6. Homogeneity of the powder blend

Particle (granule) size of the mix needs to be ___ for the production of formulated medicines.

homogenous

Particle size determines ___ as shown by the Noyes-Whitney equation.

rate of dissolution

Effect of particle size on oral drug bioavailability

smaller the particle size, the increase in bioavailability

2. Long range order of molecules

Polymorphism

Polymorphism

Drug molecules can exist in more than one crystal form with different packing arrangements in the crystal lattice.

Crystal shape influences what?

particle 'feel' and powder packing and flow

What can lead to polymorphic changes as well as alteration in particle shape?

Particle size reduction

Is the powder crystalline or amorphous?

Amorphous materials: Materials are in the solid state however the molecules are not packed in a repeating long-range ordered fashion.

Amorphous powders have higher solubility but lower stability compared to what?

their crystalline counterparts.

3. Hygroscopicity

- Amorphous form of the drug has higher solubility and faster dissolution rate
- Amorphous form is thermodynamically unstable.
- Amorphous form is hygroscopic
- Absorbed water reduces powder flow, and may impact physical and chemical stability

The volume occupied by a powder in a container depends on what?

particle size, shape, and surface properties

Bulk density =

Bulk density = Mass of Powder/Volume occupied by powder

Minimum bulk density = ?

poured powder

Maximum bulk density = ?

tapped powder

How do these differ in the volume occupied by the powder?

- Poured powder occupying a high volume
- Tapped powder occupying a low volume

Powder density: why is it important in production of tablets?

Powder density determines tablet size. Volume occupied by powder in tablet die is dependent on powder density which in turn is dependent on particle size, shape and surface properties.

Tapped bulk density

in theory maximum bulk density.

Hausner's ratio =

Hausner's ratio = Tapped bulk density/Poured bulk density

Hausner'sratio < 1.25

indicative of good powder flow

Hausner'sratio > 1.25

indicative of poor powder flow

Why are we interested in powder flow?

- Good powder flow is a prerequisite for successfully manufacturing both tablets and capsules.
- Good powder flow is essential for achieving uniform tablet weight.

It's a property of all powders to resist differential movement between particles when subjected to stress. The resistance arises due to what?

interparticulate cohesive forces which may include:
- van der Waals forces
- Electrostatic forces
- Forces due to moisture

What is important to ensure drug content uniformity?

Homogeneity of drug and excipients

Powder Mixing

Some powder segregation (separation between the different mixture components) will occur. It is only possible to achieve a maximum degree of randomness

How do we determine the state of a powder mix?

by taking samples from different regions of the mixture and at different times

Mixing Equipment

- Tumbler mixers
--- Rotating vessel
--- For free-flowing powders and granules
- Convective mixers
--- Vessel is fixed in position, moving/rotating impellers
--- For cohesive powders and wet mixing

Powder segregation

separation between the different mixture components.

Factors promoting particle segregation

1. Differences in particle density
--- Heavier particles move to the bottom of the powder bed.
2. Differences in particle size
--- In a static powder bed, large particles rise to the top, fine particles move to the bottom of the container.
3. Differences in crystal shape
--- Spherical Vs needle Vs angular Vs irregular

Several medicines use what technology to achieve higher bioavailability and reduce food effect on bioavailability?

nanosizing

Nanosizing drug Particle size

100 -200 nm

Rapamune®, immunosuppressant sirolimus and Nanosizing

Improved bioavailability and reduction in variability due to food effect are achieved through faster dissolutiondue to an increase in surface area of drug particles.

Bioavailability of posaconazole suspension vs nanosuspension

reduced the gap between fed and fasted state

How should Noxafil® oral suspension be administered?

Shake Noxafiloral suspension well before use. Administer with measured dosing spoon provided.

Lofibra and Nanosizing

Fenofibrate as an adjunctive therapy to diet to reduce LDL, total cholesterol and triglycerides

Emend and Nanosizing

Aprepitant for chemotherapy induced nausea and vomiting

ASDs

Amorphous Solid Dispersions

Amorphous Solid Dispersions

The drug is dispersed in its amorphous form in an inert carrier (polymer / surfactant and polymer). 'Solid solution' is formed.

ASDs have improved apparent dissolution rates and solubility, however...

they are inherently unstable.

The polymeric carrier in Amorphous Solid Dispersions improves what?

dissolution of the drug as well as its solid-state physical stability.

What % of oncology drugs have poor solubility?

> 65%

Amorphous Solid Dispersions(ASDs)

"Spring and Parachute" model

- Drug 'springs' into a supersaturated state, i.e. exists at concentrations above its equilibrium solubility.
- Polymers allow the polymer to slowly precipitate or 'parachute' to its lower equilibrium solubility.
- Polymers act as precipitation inhibitors.

How are amorphous solid dispersions fabricated?

- Hot melt extrusion for fabrication of ASDs
- The molten liquid is passed towards the die where cooling and shaping of the extrudate into strands takes place
- On heating, the drug is molecularly dispersed in molten polymer

Examples of commercially available amorphous solid dispersion products

Vemurafenib (Zelboraf®, Roche)

Zelboraf is what?

an amorphous solid dispersion (ASD) of vemurafenib-hypromellose acetate succinate polymer (30:70, w/w)

Vemurafenib is indicated for what?

unresectable or metastatic melanoma.

Vemurafenib (RO5185426) ASD formulation results is how many times higher of vemurafenib concentrations compared to the crystalline formulation?

5 times

Two types of Capsules

Hard and Soft

Hard Capsules

two-piece composed of cap and body filled with powders/granules/pellets

Soft Capsules

one piece filled with liquids. Drug dissolved/dispersed in a liquid may improve drug bioavailability of hydrophobic drugs

Note about capsule size

capsule size is inversely proportional to capsule #

Soft gels consist of what?

a liquid or semi-solid matrix inside a one piece outer gelatin shell.

Why soft gels?

- Faster rate of drug absorption
- Improved extent of absorption
- Decreased plasma variability

Types of soft gel fill materials

- Water miscible liquids
- Lipophilic liquids/oils
- Self-emulsifying systems

Water miscible liquids fills

- Polar liquids with a sufficiently high molecular weight (polyethylene glycol (PEG) 400, 600)
- Low concentrations of ethanol and water may be tolerated
- Water alone is not used as a liquid fill!

Example of water-miscible liquids fill

Naproxen sodium

Lipophilic liquids fills

- Triglyceride oils (eg. soya bean oil, sesame oil) or fatty acids (oleic acid, palmitic acid) to solubilize poorly soluble, lipophilic drugs
- Co-solvents and/or surfactants may be included to solubilize a wider range of drugs

Example of lipophilic liquids fill

Drisdol (Vit D)

SEDDS

Self emulsifying drug delivery systems

Self emulsifying drug delivery systems (SEDDS)

- Pharmaceutical oil, non-ionic surfactant
- Pharmaceutical oil, polar liquid, surfactant
- Pharmaceutical oil (e.g. oleic acid, hydrolyzed corn oil), polar liquid (e.g. glycerol) and non-ionic surfactant (e.g. polysorbates)

Self-emulsifying drug delivery systems (SEDDS) uptake

- A micellar solubilization process occurs with SEDDS in the duodenum.
- Drug is entrapped into a colloidal micelle called a chylomicron which passes the enterocytes (by transcytosis and paracellular pathways).
- The chylomicron is too big to go through blood vessels and is absorbed into the lymphatic system (rate limiting step for drug absorption).

Sandimmune (cyclosporin) is what?

a BCS Class IV Immunosuppressant cyclic peptide.

Cyclosporine notes

- The first oral formulation, Sandimmune, is a mixture of maize oil and ethanol in which cyclosporin is dissolved (lipophilic liquid fill).
- An investigation in 18 heart transplant patients revealed low bioavailability and wider intra- and inter-subject variability of Sandimmune®.

Neoral® (cyclosporin) SEDDS

A lipid surfactant-polar liquid system composted of hydrolyzed corn oil (triglyceride oil), glycerol (polar liquid), and polyoxyethlyene-castor oil derivative (surfactant).

Summary of causes of poor oral drug bioavailability and mitigation approaches

- Low permeability
--- permeation enhancers
- slow dissolution
--- surfactant
--- particle size reduction
- crystallinity
--- solid dispersions
--- salts, ionization
- lipophilicity
--- micellar solubilization
--- complexation
--- cosolvents
--- self-emulsifying drug delivery systems
- salts/ionization