COMPENDIAL METHODS OF

DISSOLUTION
AND BIOPHARMACEUTIC
CONSIDERATIONS IN DRUG
PRODUCT DESIGN

ALELI C. BAES, RPh, MS Pharm.

Learning Objectives :
At the end of the session, the students should be able to :

1. Define Dissolution and Dissolution testing.

2. Describe the 7 types of Compendial Dissolution Apparatus.
3. Discuss the Dissolution Acceptance Criteria.
4. Enumerate the Alternative Methods of Dissolution Testing.
5. Discuss the Biopharmaceutic Considerations in Drug
Product Design.
 Dissolution and Dissolution Testing
DISSOLUTION - Is the process by which a solid drug substance
becomes dissolved in a solvent.
In the pharmaceutical industry, it may be defined as “the
amount of drug substance that goes into solution per unit time
under standardized conditions of liquid/solid interface,
temperature and solvent composition”.

Dissolution is considered one of the most important quality

control tests performed on pharmaceutical dosage forms.
Dissolution is one of the three primary tests used to release a finished
drug product:

1. Assay – determines the overall potency of the batch and ensures

the
accuracy of the finished drug product.
2. Dose Uniformity – determines the consistency among the
individual
dosage units and ensures the precision of the manufacturing process.
3. Dissolution - ensures that the performance of the finished drug
product is consistent with the release rates of the API (Active
Pharmaceutical Ingredient) as determined in bioavailability studies
during the clinical trials.
Dissolution assesses the performance of drug products.

To be effective, the test should be:

• Predictive
• Comparative
• Discriminatory
• Reproducible (testable, consistent, standardized)

A drug can only go into the market if only it passes a

dissolution test and is approved.
DISSOLUTION TESTING - measures the extent and rate of
solution formation from a dosage form, such as tablet, capsule,
ointment, etc.

The dissolution of a drug is important for its bioavailability and

therapeutic effectiveness.

A dissolution test uses an apparatus with specific test

conditions in combination with acceptance criteria to evaluate
the performance of the product.
Compendial Dissolution Medium

1. Water
2. Simulated Gastric Fluid TS
3. Simulated Intestinal Fluid TS
Simulated Gastric Fluid TS
- This medium contains hydrochloric acid and sodium
chloride, as well as pepsin and water, and has a pH of 1.2.

Simulated Intestinal Fluid TS

- This medium contains Potassium phosphate monobasic
(KH2PO4), sodium hydroxide (NaOH) and Deionized water,
and has a pH of 6.8.
USP-NF Dissolution Apparatus
1. Apparatus 1 (Rotating Basket Method)
2. Apparatus 2 (Paddle Method)
3. Apparatus 3 (Reciprocating Cylinder Method)
4. Apparatus 4 (Flow-through-Cell Method)
5. Apparatus 5 (Paddle-over-Disk Method)
6. Apparatus 6 (Cylinder/Rotating Cylinder
Method)
7. Apparatus 7 (Reciprocating Disk Method)
 APPARATUS 1 (Rotating Basket
Method)

- It comprises borosilicate glass and holds a capacity

of up to 1,000 ml
- Consists of Cylindrical basket held by a motor shaft.
- The basket holds the sample and rotates in a round
flask containing the dissolution medium.
- The entire flask is immersed in a constant-
temperature bath set at 37’C.
- Rotating speed : 100 rpm
- It is used for capsules or tablets, suppositories,
floating dosage forms and a delayed release.
APPARATUS 2 (Paddle Method)

- The paddle apparatus consists of a special,

coated paddle that minimizes turbulence due
to stirring
- The paddle is attached vertically to a variable-
speed motor that rotates at a controlled speed.
- The apparatus is housed in a constant-
temperature water bath maintained at 37’C
- Rotating speed : 50 rpm (solid dosage forms);
25 rpm (suspensions)
- There is a sinker (platinum wire) used to
prevent a capsule or tablet from floating
- Generally preferred for tablets.
APPARATUS 3 (Reciprocating Cylinder
Method)

- Consists of a cylindrical, flat-bottomed glass

vessels equipped with reciprocating cylinders for
dissolution testing of extended-release products,
particularly bead-type modified-release dosage
forms and chewable tablets
- 6 units are tested, and the dissolution medium is
maintained at 37’C.
- Rotation speed : 635 dpm (dips per min)
APPARATUS 4 (Flow-through-Cell
Method)

- Consists of a reservoir for the dissolution

medium and a pump that forces dissolution
medium through the cell holding the test
sample
- Flow rate ranges from 4 to 16 ml/min.
- 6 samples are tested during the dissolution
testing
- Medium is maintained at 37’C
- May be used for modified-release dosage
forms that contain active ingredients having
very limited solubility and implants
 APPARATUS 5 (Paddle-over-
Disk Method)
- Consists of a sample holder or disk assembly
that holds the product
- The entire preparation is placed in a
dissolution flask filled with specified medium
maintained at 32’C.
- The paddle is placed directly over the disk
assembly
- Rotation speed : 25-50 rpm
- Samples are drawn midway between the
surface of the dissolution medium and the
top of the paddle blade at specified times
- Similar to dissolution testing with capsules
and tablets, 6 units are tested during each
run.
- It is used for transdermal preparations
APPARATUS 6 (Cylinder/Rotating Cylinder
Method)

- It uses a vessel instead of a basket cylinder and it

also has a cylinder made out of stainless steele
- The apparatus is placed on cuprophan (a brand of
cellulose fiber ) to follow the cylinder
- The dosage quantity is placed inside the cylinder
and it would be extracted from outside into the
water bath
- Samples are drawn midway between the surface
of the dissolution medium and the top of the
rotating cylinder for analysis
- It is used for transdermal preparations ex.
Transdermal patches
APPARATUS 7 (Reciprocating Disk
Method)

- This apparatus has a flat bottom cylinder shaped

vessel with a volume capacity of 50-200ml
- It is usually placed on a disk shape holder
- The test is carried out at 32’C, and reciprocating
frequency is about 30 rpm
- It is used for controlled release dosage forms
and only applies to small dosages
 Alternative Methods of Dissolution Testing

1. Rotating Bottle Method

- It was used mainly for controlled-release beads.
- consists of rotating rack that holds the sample drug
products in bottles.
- the bottles are capped tightly and rotated in a 37’C
temperature bath.
- at various times, the samples are removed from the
bottle, decanted through a 40-mesh screen, and the residues
are assayed.
2. Intrinsic Dissolution Method

Intrinsic Dissolution - the dissolution of a drug powder by

maintaining a constant surface area.
- is usually expressed as mg/cm2/min.

3. Peristalsis Method
- it simulate the hydrodynamic conditions of the GIT in an
in-vitro dissolution device.
- the apparatus consists of a rigid plastic cylindrical tubing
fitted with a septum and rubber stoppers at both ends.
- the dissolution medium is pumped with peristaltic action
through the dosage form.
4. Diffusion Cells
- Static and Flow-through diffusion cells are commercially
available to characterize in-vitro drug release and drug
permeation kinetics from a tropical drug product (e.g.
ointment, cream) or transdermal drug product.

- the Franz diffusion cell is a static diffusion system that is

used for characterizing drug permeation through a skin model.
It is useful for comparing in-vitro drug release profiles and skin
permeation characteristics to aid in selecting an appropriate
formulation that has optimum drug delivery.
 Biopharmaceutic Considerations in
Drug Product Design
 The prime considerations in the design of a drug product
are Safety and Efficacy.

1. Pharmacodynamic Considerations
Therapeutic considerations
- concerns the pharmacodynamic and pharmacologic
properties of the drug, including :
a. desired therapeutic response
b. type and frequency of toxic and/or adverse reactions of
the drug
2. Drug Considerations
- the physico-chemical properties of the drug are major
factors that are controlled or modified by the formulator.

a. Physical properties of the drug – such as dissolution,

particle size, and crystalline form – are influenced by
methods of processing and manufacturing.
b. Chemical instability or chemical interactions with certain
excipients will also affect the type of drug product and its
method of fabrication.
3. Drug Product Considerations

a. Pharmacokinetic of the Drug

- knowledge of the pharmacokinetic profile of the drug is
important to estimate the appropriate amount (dose) of the
drug product and a release rate that will maintain a desired
drug level in the body.
b. Bioavailability of the Drug

Bioavailability - is defined as the rate and extent to which the

active constituent or active moiety of a drug is absorbed from
a drug product and reaches the systemic circulation.

For a drug taken orally, the ‘first-pass effect’ of hepatic

metabolism reduces bioavailability.

Bioavailability is practically 100% following an intravenous

administration.
c. Dose considerations
1. Variation in the size of the dose – needed for different
patients (due to differences in the pharmacokinetic and
bioavailability of the drug)
Therefore, the drug product must be available in several
dose strengths to allow for individualized dosing.

2. The size and shape of a solid oral drug product – are

designed for easy swallowing.
- example : large tablets and capsules (difficult to swallow)
d. Dosing Frequency

Example : Drug with a short duration of action must be given

more frequently.

Extended-release drug product – improve patient compliance.

- contains 2 or more doses of the drug that are released
over a prolonged period
4. Patient Considerations
- Includes Compliance and Acceptability of drug product.

 The drug product must be acceptable to the patients.

 Poor patient compliance may result from poor product
attributes, such as difficulty in swallowing, disagreeable
odor, bitter medicine taste, or 2 frequent and/or unusual
dosage requirements.
 Innovation (creative packaging) improves patient
compliance.
 Pharmacodynamic factors such as side effects of the drug
or an allergic reaction, influence patient compliance.
5. Manufacturing Considerations

Includes :
a. Cost
b. Availability of raw materials
c. Stability of drug products
d. QC
e. Method of manufacturing
In the design of a drug dosage form, the pharmaceutical
manufacturer must consider the following :

a. Intended route of administration

b. The size of the dose
c. The anatomic and physiologic characteristics of the
administration site, such as membrane permeability and blood
flow.
d. The physicochemical properties of the site, such as pH,
osmotic pressure and presence of physiologic fluids.
e. The interaction of the drug and drug dosage form at the
administration site, including alteration of the administration
due to the drug and/or dosage form.
THANK YOU! 