A new simple and informative excel sheet is provided for calculating F1/F2 with all the FDA features. Detailed regulatory requirements from different agencies for dissolution comparison is discussed.

1. Dissolution comparison, new calculation sheet, regulatory
requirements
Written by: Dr. Satish Puttachari
Email id: satishputtachari@gmail.com

2. Contents
 What is dissolution, its importance
 Different types of dissolution medium
 Comparison of dissolution profile.
 New excel sheet for comparison of dissolution profile
 New Excel sheet for comparison of dissolution profiles

3. What is dissolution
The dissolution study is one of the critical quality attributes of the oral pharmaceutical dosage forms. It is used for monitoring
the release of drug substance.
Its uses in different stages of product life cycle is as follows.
 During early drug development – To compare the release of drug from different formulation, helpful in checking the effect of
changes in formulation and asses the bio availability
 Generic drug development – To check how the prepared formulation matches with the reference listed drug. The data is
useful for assessing the bio equivalence leading to development of robust formulation.
 Commercial manufacturing – To check Batch to batch consistency and batch release.
 Post approval changes – The dissolution comparison used as per SUPAC guidelines to prove that there is no marked
change in the dissolution on making changes in Formulation, mfg site, changes in equipment, process, materials etc.
The use of suitable dissolution method is useful in predicting the In vivo release of drug, the effective use of the dissolution and
comparison method useful in avoiding the failure of the BE studies for the Generic products.

4. Different types of dissolution mediums
Different types of dissolution: Following are the different types of dissolution are being used based on their usages,
1. Discriminative dissolution method: The dissolution method is capable of detecting any changes in the mfg. process, critical
process parameters, product composition, change in the specification etc by marked by showing the changes in the %
dissolution/dissolution profile.
During the early product development many trials were taken to develop this method.
2. Bio relevant dissolution medium: The bio relavant medium provides result which closely indicate the In vivo performance of the
drug products.
They contain fluids as same found inside the body like Bile salts, Phospholipids and salts which replicate the condition found in the
gastrointestinal tract such as solubilizing properties, pH and osmolality.
3. QC dissolution medium: This media used for routine release of batches, some of the methods are mentioned in the USP and other
pharmacopieas. This method shall be capable of indicating major change in the formulation, mfg process and storage of a product.
In this Q is used for measuring the % dissolution against the standard time points.
4. Multimedia dissolution: The multimedia dissolution media consist of different types of buffers maintained at different pH. These are
used for knowing the % dissolution at different region of the GI tract. The media’s are as follows.
 0.1 N/0.01N HCl/Simulated gastric fluid
 Acetate buffer of pH 4.5
 Phosphate buffer of pH 6.8/Simulated intestinal fluid.
The medium is selected based drug’s Pka, , solubility, stability and other factors like area of absorption, pharmakinetic parameters like
tmax etc.

5. Comparision of dissolution profiles
The reasons for comparision of dissolution
1. Early development: During Clinical phase 1, 2, 3 stages many changes are made in drug product formulation in terms
of type of dosage form, mfg. process, equipment used and specification to get the desired safety and efficacy of the
drug product. The dissolution comparision is userful in knowing impact of the change on the dissolution by comparing
the dissolution of the pre and post changes.
2. Generic drug development: For comparing the dissolution at various stages and comparing with the Innovator
products.
3. Post commercialization: After the drug product is approved, many pharmaceutical companies make minor to moderate
changes in the formulation, changes in mfg process, raw materials specification or changes in source to reduce the cost of
the product or improve the quality of the product.
As per the SUPAC guidelines for moderate (level 2) changes, we need to compare the dissolution of pre and post change
and meet the requirement to implement the changes.
Following are the different methods recommended for comparing the dissolution profile as per FDA guidelines on
dissolution of IR dosage forms.
1. Model independent approach – Using similarity factor.
This method uses the difference factor (F1) and difference factor (F2) for comparing the dissolution profile of test and
reference product.

6. New Excel sheet for comparision of dissolution profiles
Ready made Excel is sheet is generally used for calculating the F1/F2 values. But most of these sheet just calculates these
values but set of conditions as per FDA guidelines are not built in the system, there is lot of possibility that the calculated
values not the actual values.
Hence author has developed new validated excel sheet which is built as per the FDA guidelines.
Salient features of the excel sheet.
 Selection of the method: It calculates % CV of dissolution at different time points and give message that the whether
model independent method or model dependent method to be used.
 Requirements of F1/F2: It check whether 85% drug is released within 15 minutes or not and gives message that the F2
calculation is required or not.
 How many time points to be taken for calculation purposes.
 Whether batches are passing the dissolution comparison or not.
Overall by using this Excel calculation sheet, the chances of error will be reduced significantly.
F1-F2 calculation
sheet

7. New Excel sheet for comparision of dissolution profiles
The screen shot of Excel sheet: Its easy, simple to use and informative

8. Requirements for the % dissolution comparison
The dissolution comparison F2 is accepted by most of regulatory agencies but they are few differences in the requirements
to be fulfilled. In this section we are discussing about the requirements from the different agencies.
1. Requirement of co efficient of validation (% CV).
a. As per the FDA guidelines recommends the % CV shall be less than 20% at initial time points and later on NMT 10%
for next time points.

9. Requirements for the % dissolution comparison
Dissolution comparison exemption: FDA recommends waive off dissolution comparison for the highly soluble products
across the physiological pH ranges and dosage form shall exhibits rapid dissolution.

10. Requirements for the % dissolution comparison
How many time points to be considered for dissolution comparision.