Pharmaceutical Formulations and Drug Delivery

What are the filling characteristics of hard-shell gelatin capsules?

Primarily filled with solids; can be semisolid or liquid.

What is the water content of hard-shell gelatin capsule shells?

13-16% water for plasticizer.

What is the shell permeability of hard-shell gelatin capsules?

Low permeability of shell.

What is the filling process for hard-shell gelatin capsules?

Two-step filling process (shell formed then fill).

What are the filling characteristics of soft-shell gelatin capsules?

Primarily filled with liquid; can be semisolid or solid.

What is the water and plasticizer content of soft-shell gelatin shells?

5-8% water and 30-40% glycerin for plasticizer.

What are the shell and process characteristics of soft-shell capsules?

Thick shells, high permeability, and a one-step fill process.

Why is free water avoided in capsule filling formulations?

Free water will soften the capsule shell.

Why are hygroscopic ingredients avoided in capsule fillings?

They will dry out the shell and make it brittle.

Why are aldehydes avoided in capsule formulations?

They will crosslink gelatin to form insoluble shells.

What are the general formulation requirements for capsule fillings?

No free water, no hygroscopic ingredients, no aldehydes, good flowability, and added glidants and lubricants.

What are the storage condition requirements for capsules and why?

Dry, cool conditions, because water or heat could cause shells to rupture or soften.

What is the rationale for using soft-gel capsules?

Better patient acceptance, easier to make, increased absorption and bioavailability, avoids airborne powder safety issues, and allows solid oral dosage for oils/low melting point drugs.

What is required of capsule shells for content release after oral administration?

The capsule shells have to disintegrate after oral administration.

What could cause a capsule shell to fail to disintegrate?

Crosslinking or improper formulation.

What are the mechanisms for aerosol deposition in the lung?

The API is within a continuous gas phase, and the dispersed phase can be solid or liquid administered through pulmonary inhalation.

What parameter determines aerosol deposition in the lung?

Particle size influences deposition and where particles go in the respiratory tract.

Where do small aerosol particles (1 to 5 um) go in the respiratory tract?

Lower airways like the deep lung.

Where do larger aerosol particles (larger than 5 um) go in the respiratory tract?

Upper airways like the throat, resulting in product loss.

How does a spacer assist with aerosol inhalers?

It breaks up particles to reduce airflow volatility, making them small and slow for longer action.

How does respiratory flow rate affect aerosol deposition?

Increasing respiratory flow rate enhances deposition in larger airways.

How does inhaled volume affect aerosol deposition?

Larger inhaled volume results in better distribution.

How does breath-holding affect aerosol deposition?

Breath holding after inhalation increases deposition of particles.

What is the optimal aerosol deposition method for pMDI?

Slow deep inhalation to total lung capacity, followed by breath-holding.

How does a pMDI device deliver aerosols?

Drug is suspended in liquid propellant; the patient shakes the container, inhales slowly, and holds their breath.

How does a DPI device deliver aerosols?

Micronized drug particles (1-5 um) are inhaled deeply and vigorously from a blister or capsule to create turbulent airflow.

How do nebulizers deliver aerosols?

Large drug volumes in a suspension are used for physically challenged patients who cannot coordinate other options.

What are the formulation considerations for pMDI devices?

Suspending agents, surfactants, and particle size of 2-5 um.

What are the formulation considerations for DPI devices?

Good flowability, uniformity, deaggregation, and carrier particles that are swallowed not inhaled.

What are the formulation considerations for nebulizers?

Aqueous solutions or suspensions, large doses, and no preservatives.

What is the preparation requirement for all aerosol devices?

Sterile preparation.

What are the sterility requirements for parenteral products?

Must be sterile during manufacturing, storage, and use.

What visual requirement applies to parenteral solutions?

Solutions have to be free from visible particulates.

What endotoxin and pyrogen requirements apply to parenterals?

Limited endotoxins under allowable EU limits, and no pyrogens (dry at 250°C to depyrogenate).

What types of containers are used for IV, SC, and IM injections?

Single or multiple-dose airtight containers like vials, bottles, bags, and prefilled syringes made of Type I borosilicate glass or DEHP-free plastic.

What excipients are used in parenteral products?

Preservatives, buffers, antioxidants, and chelating agents (no coloring agents).

How do parenteral excipient requirements compare to nonsterile products?

They do not have the same requirements; parenteral requirements are much more strict.

How does steam sterilization work and what are its limits?

Autoclaves use high-temperature steam and pressure; unsuitable for oleaginous preparations.

When is dry heat sterilization suitable?

High heat for a long time; only suitable for heat-stable APIs.

How are plastic bags sterilized?

Using ionizing radiation with gamma rays.

How are parenteral containers sterilized?

Gaseous sterilization using ethylene oxide.

How does membrane filtration sterilize solutions or gases?

Sterile-grade membranes nominally at 0.22 micrometers trap particulates.

What environment is required for aseptic techniques?

An ISO 5 environment using sterile cleaning throughout the procedure.

What is the mechanism and application of lyophilization?

Based on sublimation, freezing an aqueous solution, and reducing pressure below the triple point with heat to dry heat-sensitive APIs.

What are the general characteristics of pharmaceutical excipients?

Can have multiple functions, available in different grades, can be blends or active, can have adverse events, and are critical attributes for some dosage forms.

What is the difference between Mn and Mw for polymers?

Mn is average molecular weight based on the number of polymer chains (measured by colligative properties); Mw depends on molecular size (measured by light scattering).

What does polydispersity mean in polymers?

It describes the distribution of molecular weights in a polymer sample.

What is the role of a plasticizer?

Increases the mobility of polymer chains to reduce glass transition temperature, commonly used for film coating or patches.

How do polymers dissolve and how is this applied in gels?

They dissolve like water ('like dissolves like') and are used to increase the viscosity of gels (e.g., HPMC and carbomer).

Why is polymer grade important?

Different grades have varying properties such as particle size, density, and flow property (e.g., lactose).

What are the types of polymer incompatibilities?

Sensitivity to pH change, addition of electrolytes, cation-anion interactions creating polyelectrolyte complexes, and interpolymer complexation via hydrogen bonds.

What are the main biopharmaceutical considerations in formulations?

Drugs must be in suspension for absorption; primary absorption is via passive diffusion; transit time in the GI tract matters; first-pass effect occurs in the liver; solubility can change from food or pH; ADME.

What therapeutic considerations guide dosage form design?

Systemic or local therapy site of action, duration of action and release pattern, emergency use, and special populations.

How do polymorphism and amorphous forms affect drug factors?

Metastable and amorphous forms have higher solubility and dissolution rates than crystalline forms.

What must be addressed in oral formulations for BCS II drugs?

Chemical/physical form, particle size, and excipients to improve dissolution.

What processes must occur before oral drug absorption?

Disintegration, deaggregation, and dissolution.

What techniques improve dissolution and oral bioavailability?

Micronization, salt formation, surfactants, cyclodextrin complexation, and lipid-based formulations.

What are the characteristics of immediate-release products?

Quick therapeutic effect as soon as ingested or taken.

What are the characteristics of delayed-release products?

Designed to break down later in the GI tract; pH-resistant to pass through the stomach.

What are the characteristics of extended-release products?

Releases drug after the GI tract or over an extended duration.

What formulation strategies address BCS II drugs or first-pass effect?

Improve dissolution through micronization, salt formation, surfactants, wetting agents, and polymers, or use release methods that avoid the first-pass effect.