Comparative Dissolution Profile

• Solid oral dosage tablets and capsules are the most effective and efficient means of treatment available in the pharmaceutical industry. These drugs, taken orally, dissolve in the gastrointestinal fluids and become bioavailable as it is absorbed into the systemic circulation. Routine in vivo measurement of the active pharmaceutical ingredient (API) in blood and urine is not possible in practice. Measurement methods are inherently error-prone due to matrix complications. Therefore, in vitro methods to measure the dissolution rate of the API from the solid oral form are officially recognized by regulatory agencies as an important consideration when formulating solid oral dosage forms.
• Dissolution tests are established valuable quality control tools to monitor batch-to-batch consistency. They are also useful in providing pharmaceutical product quality information following post-approval changes to the product such as changes in formulation, changes to the manufacturing process or the site of manufacture, and in-process scale-up. 
• In addition, dissolution data can be used in support of a biowaiver for lower strengths of such dosage forms where solid oral dosage forms have been proportionally formulated in different strengths. As long as an acceptable bioequivalence study has been carried out on one of the strengths, usually, the highest strength and the API release rate is linearly proportional to the concentration, a bio waiver is preferable.
• Dissolution and solubility of the API under physiological conditions, and its permeability through the membranes of the gastrointestinal tract, are important physicochemical factors. Due to the critical nature of these factors, the dissolution of a pharmaceutical product in vitro is relevant, in certain instances, in anticipating the in vivo characteristics or results. During the development of a pharmaceutical product, dissolution testing is used as a tool to identify formulation factors that influence and may have a significant effect on the bioavailability of the API. 

Biopharmaceutical Classification System and Special Cases:

The biopharmaceutical classification system (BCS) is an important classification used for the waiver of in vivo bioavailability and bioequivalence decisions by regulatory agencies. This classification system is based on the aqueous solubility and intestinal permeability of the API.

The system classifies API into four classes:

1. Class 1: High Solubility – High Permeability
2. Class 2: Low Solubility – High Permeability
3. Class 3: High Solubility – Low Permeability
4. Class 4: Low Solubility – Low Permeability

This system takes into account the dissolution of the drug product, its solubility, and API permeability. A BCS-based biowaiver can be requested for rapidly dissolving immediate release (IR) tablets containing class 1 API with a few additional considerations, such as dissolution profile and original dosage form.

If an active substance is considered highly soluble and if the dosage form rapidly dissolves at physiological pH, it is reasonable to expect that it will not cause any bioavailability problems. In those situations, a bioequivalence study may be waived based on the case history and similarity of dissolution profiles. It is essential to evaluate country-specific regulatory guidelines for the proposal of a biowaiver program.

If an active substance is considered to have low solubility and high permeability, the rate-limiting step for absorption may be dosage form dissolution. This is also the case when one or more of the excipients are controlling the release and subsequent dissolution step of the active substance. In those cases, a variety of test conditions is recommended, and adequate sampling should be performed to characterize the dissolution profile completely (e.g., at 10, 15, 20, 30, 45, and 60-minute time interval analysis).

For poorly water-soluble drug products, dissolution testing at more than the one-time point, preferably a dissolution profile, is recommended for quality control purposes. Alternatively, the use of the United States Pharmacopeia (USP) apparatus 4 (Flow-Through Method) should be considered for the development of dissolution specifications for such products.

If a monograph for a fixed-dose combination is not included in the USP or British Pharmacopoeia (BP), the monographs for the individual components should be used to set the dissolution requirements for each or an alternate dissolution method should be developed.

How many types of dissolution media are there?

• The selection of an appropriate dissolution medium is a fundamental stage of the dissolution test. It is more important that the test closely simulate the environment in the GI tract than necessarily produce sink conditions.
• The dissolution characteristics of oral formulations should be evaluated over the physiologic pH range of 1.2 -6.8.

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Data Analysis:

• Two scenarios for comparing the profiles obtained from multipoint dissolution are operative: 
• If both the test and reference product show more than 85% dissolution within 15 minutes, the profiles are considered similar (no calculations required). If not, see the next point. 
• Calculate the f2 value. If f2 ≥ 50, the profiles are normally regarded as similar such that further in vivo studies are not necessary. Note that only one measurement should be considered after 85 % dissolution of both products has occurred and excluding point zero. 
• The difference factor (ƒ1) calculates the percent (%) difference between the two curves at each time point & is a measurement of the relative error between the two curves: 

• The similarity factor (f2) is a logarithmic reciprocal square root transformation of the sum of squared errors and is a measurement of the similarity in the percentage (%) dissolution between the two curves. 

Where, 

     n = The number of time points 

     Rt = The dissolution value of the reference batch at time t 

     Tt = The dissolution value of the test batch at time t. 

• A specific procedure to determine difference and similarity factors is as follows: 
• Determine the dissolution profile of two products, i.e. of the test and reference products (using 12 units each). 
• For f2 calculations a minimum of three time points (excluding point zero) must be used, and only one measurement included after 85 % dissolution of both products has occurred. 
• For curves to be considered similar, f2 values should be close to 100. Generally, f2 values greater than 50 (50 to 100) ensure sameness or equivalence of the two curves and, thus, of the performance of the test and reference products. 
• This model-independent method is most suitable for dissolution profile comparisons when three to four or more dissolution time points are available. The following recommendations should also be considered:

• The dissolution measurements of the test and reference batches should be made under exactly the same conditions. The dissolution time points for both profiles should be the same (e.g. 10, 15, 20, 30, 45, 60 minutes, etc.). For rapidly dissolving products (profiles reaching 85 % at 30 minutes) the minimum time points are 10, 15, 20, and 30 minutes. 
• Only one measurement should be considered after 85 % dissolution of both products has occurred. 
• To allow the use of mean data, the percent coefficient of variation (CV) at the earlier time points (e.g. 15 minutes) should not be more than 20 %, and at other time points should not be more than 10 %.

Comparison of Dissolution Profile - Requirements

• Dissolution of test and reference products should be performed in USP Apparatus I at 100 rpm or Apparatus II at 50 rpm using 900 ml of the following dissolution media:
• Acidic media such as 0.1 N HCl or simulated Gastric Fluid USP without enzymes
• pH 4.5 Acetate Buffer
• pH 6.8 Phosphate Buffer or simulated Intestinal Fluid USP without enzyme
• Two scenarios for comparing the profiles obtained from multipoint dissolution are operative:
• If both the test and reference product show more than 85% dissolution within 15 minutes, the profiles are considered similar (no calculations required). If not,
• Calculate the f2 value. If f2 ≥ 50, the profiles are regarded as similar, and no further in vivo studies are necessary. Note that only one measurement should be considered after 85% dissolution of both products has occurred and excluding point zero. A minimum of 12 dosage units of the drug product should be evaluated.

Reporting of Comparative Dissolution Profile Study

Documentation of a comparative dissolution profile shall be prepared as per the attachment.

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