Characterization of Controlled Release Drug Formulations

Characterization means the determination of the controlled release claim, which usually involve the determination of the following parameters.

• Effect of physiologic variables on drug release
• Effect of process variables on drug release
• Relation with currently marketed products
• Batch to batch uniformity

Characterization can either be done by in-vitro or in-vivo methods.

In-Vitro methods:

Testing requirements: An in-vitro testing instrument for the controlled release behavior must have the following requirements.

• As automated as possible
• Periodic change in simulated media
• Controllable fluid flow rate
• Calibrated parameters

The following instruments are usually employed for the in-vitro dissolution testing of the controlled release formulations.

Basket Apparatus:

The assembly consists of the following: a vessel, which may be covered, made of glass or other inert, transparentmaterial; a motor; a metallic drive shaft; and a cylindrical basket. The vessel is or heated by a suitable devicesuch as a heating jacket. The water bath or heating devicepermits holding the temperature inside the vessel at 37 ± 0.5°C during the test and keeping the bath fluid in constant, smooth motion. The vessel is cylindrical, with a hemispherical bottom, which contain the dissolution medium. The shaft is connected to a speed regulating device that control its rotating speed. A dosage unit is placed inside the dry basket at the beginning of the test. The distancebetween the inside bottomof the vessel and the bottom of the basket is maintained at25 ± 2 mm during the test.

Paddle Apparatus:

This apparatus has everything in common with the Basket Apparatus except the Cylindrical Basket, which is replaced with a Paddle. The dosage unit is dropped inside the vessel, directly into the dissolution medium.

Reciprocating Cylinders:

The assembly consists of a set of cylindrical, flat-bottomedglass vessels; a set of glass reciprocating cylinders; inert fittings and screens that are made of suitable nonsorbing and nonreactive material and that are designed to fit the tops and bottoms of the reciprocating cylinders; and a motor and drive assembly to reciprocate the cylinders vertically inside the vessels. The vessels arepartially immersed in a suitable water bath of any convenient size that permits holding the temperature at 37 ± 0.5°C during the test.  A device is used that allows the reciprocation rate to be selected and maintained at the specified dip rate within ±5%.

Flow through cell:

The assembly consists of a reservoir and a pump for the Dissolution Medium; a flow-through cell; and a water bath that maintains the Dissolution Medium at 37 ± 0.5°. The pump forces the Dissolution Medium upwards through the flow-through cell. The pump has a delivery range between 240 and 960 mL per hour, with standard flow rates.

 USP Acceptance criteria for Extended Release

Unless otherwise specified in the individual monograph,the requirements are met if the quantities of active ingredient dissolved from the dosage units tested conform to the table given below. Continue testing through the three levelsunless the results conform at either L1 or L2. Limits on theamounts of active ingredient dissolved are expressed interms of the percentage of labeled content. Where more than one range is specified in the individual monograph, the acceptancecriteria apply individually to each range.

 USP Acceptance Criteria for Delayed Release

Acid Stage:

Buffer Stage:

Disintegration test for Enteric Coated:

The test is conducted by using the Basket rack assembly in the Gastric Simulated Fluid and Intestinal Simulated Fluid, separately, that is maintained at 37±2°C. All the tablets should remain intact in the Gastric simulated fluid for 1 hour, while the Intestinal simulated fluid must allow them to disintegrate. If 1 or 2 tablets fail to pass the test (out of 6 tablets), repeat the test on 12 additional tablets. At least 16 out of 18 tablets should pass the test.  

In-Vivo evaluation

The controlled release claim can also be verified by in-vivo methods. The in-vivo drug behavior is usually determined by the following parameters.

• Drug blood levels
• Drug urinary excretion
• Serial Radiographs
• Pharmacologic activity

Subjects for in-vivo testing:

In-vivo testing can be either be done in animals, e.g. mice, rabbit, dog, monkey etc. or in the Human subjects. Lab animals are normally utilized at the formulation development stage where the tuning of the required controlled release parameters is required. However, the human testing of the drug is done for the Bioequivalence and Bioavailability studies. 

Pre-formulation studies:

Some physiochemical properties of the raw materials that are utilized in the development of the controlled release formulation must also be tested in order to develop a quality product. Some of such parameters and their testing techniques are briefly discussed below.

• Particle size analysis can be done by the following methods,

o   Microscope analysis

o   Sieving

o   Electrical sensing

o   Light scattering

• Partition coefficient is the ratio of the drug in two immiscible liquids. This parameter help to evaluate the permeability of the drug. Octanol-1 is mostly used for the determination of the partition coefficient along with water. The test is performed just like the solvent extraction in the separating funnel. After shaking the drug with the mixture of immiscible liquids, each layer of the solvents is separated and the concentration of the drug in each phase is determined. 

• Hygroscopicity is the measure of the ability of the material to absorb moisture. For this purpose, the water content measuring techniques like "Karl Fischer Titration" can be utilized.

• Flowability of the powdered or granulated material is tested by various methods. One of them is by Compressibility index.This method require the determination of the bulk and tapped volume of the powder or the grains. By substituting these values in the following equation gives the compressibility index.

Where,

V_o= Bulk volume

V_f = Tapped volume

References:

Applied Biopharmaceutics & Pharmacokinetics by Leon Shargel, Susanna Wu-Pong, Andrew B.C. Yu (Chapter 17 – Modified release drug products)

Industrial Pharmacy by Leon Lachman and Harbert A. Liberman

(Chapter 14 – Sustained release dosage forms, Chapter 8 – Preformulation)

2011 United State Pharmacopoeia (711 – Dissolution)

2008 United State Pharmacopoeia (701 – Disintegration)