Controlled release and QC

What is a controlled release dosage form?

Release a drug in a regulated manner, typically slowing down the release rate. Responsive to physiological conditions, steady constant release

What is biphasic release?

Release a portion of the drug quickly, followed by a slower release

What is the pH of the stomach during fasting and fed state?

Fast→ 1.4-2.1, Fed→ 3-7

What is the pH of the Jejunum during fasting and fed state?

fast→ 4.4-6.6, fed→ 5.2-6.2

What is the pH of the Ileum during fasting and fed state?

fast→6.8-8.6, fed→ 6.8-8.0

What is the pH of the Colon during fasting and fed state?

fast and fed→ 5-8

What are enteric coated dosage forms?

Resist dissolution in the gastric fluid. Used for substanes that are inactivated in the stomach (erthromycin, enzymes, biascodyl) or substances that irritate the gastric mucosa (ASA, steroids, iron), and fish oil supps

How do enteric polymer coatings work?

The intestinal pH causes the polymer to become negatively charged and more water-soluble

Stomach: low pH, molecule is more hydrophobic and less soluble because of fully protonated carboxylic acids

Intestine: higher pH, molecule is now hydrophilic and more soluble because charged carboxylic acids

Common types of enteric polymer coatings?

esters of cellulose and phthalic acid, copolymer of methacrylic acid and ethyl methacrylate

What is extended release?

Achieve more favorable pharmacokinetic profile (decrease variations in the blood levels), improves patient compliance by decreasing number of doses

What are characteristics of first order release?

Fraction of drug released per unit time is constant. ex: 10% of initial amount in the 1st min, then 10% of that remaining amount in the 2nd min. Exponential equation

What are characteristics of zero-order release?

the amount of drug released per unit time is constant. ex: 1mg in 1st min, 1mg in 2nd min, linear rate equation

What is a multistage release system?

Surface-layer immediate release, core is slow-release. Used when both rapid and prolonged onset are needed

What is the absorption window?

Mouth to ileocaecal junction: 3-7h, to colon-rectum: 20h, most drugs are absorbed in the duodenum-small intestine

What is diffusion (coating)-controlled release?

polymer coating solubility, thickness, porosity, etc. Hypromellose. Low water solubility, low permeability, pH independent swelling

What is erosion (matrix)-controlled release?

Prevents rapid release via a) binding the drug b) slowing down water penetration (xanthan gum, hypromellose), or c) slow degradation by hydrolysis (poly-lactic acid)

What is OROS?

Osmotic [controlled] release oral [delivery] system; osmotically active compartment→ inorganic salts, controlled release through polymer coating

Newer strategies to control retention of a dosage form in the narrow absorption window?

Bioadhesive (mucoadhesive) coatings that stick to the upper intestinal mucosa. Mech: entanglement of polymer chains within the mucin chains, charge (positively charged polymers interact with negatively charged mucin) and GRRDS

How does GRDDS work?

Gastro retentive drug delivery system; swelling dosage forms or floating delivery systems to increase retention in the stomach

What is dose dumping?

Unintended, rapid drug release in a short period of time of the drug contained in a modified release dosage form due to compromise of the release-rate-controlling mechanism, ex: breaking the tab or consuming alcohol

What is QC checking?

General appearance, thickness, hardness and friability, chemical uniformity, and release of the drug (dissolution test)

How do you fix a lamination/capping issue?

Change moisture/binder/lubricant/pressure/check wear of punches

How do you fix mottling?

residual moisture causes drug migration/color migration

How do you fix film peeling?

Not enough plasticizer, polymer overdried

How do you fix changes in thickness?

Change in granulation process, speed and force of compression

How do you fix changes in hardness/friability?

Change in granulation process/humidity. Change in binds/other excipients. Change in compression force

What is a dissolution test?

lab test to measure how fast an API is released from a tab/cap. Dissolution rate and drug absorption are usually the rate limiting steps

What is USP Apparatus-1 Basket?

Dosage form contained within basket, dissolution should occur within basket, useful for tab, caps, beads, floaters, pH change by media exchange

What is USP apparatus-2 Paddle?

Dosage form should remain at the bottom center of the vessel, if disintegration occurs— dissolution should proceed throughout the medium. Useful for tabs, caps, suspensions