Comparative Dissolution, General Overview
[][]Comparative Dissolution, Oral dosage form like Table & Capsule are more popular than IV/IM(Intravenous/Intramuscular) Injection formulation. From the very beginning, people are most familiar with oral solid dosage form (Tablet, Capsule, Powder etc.) and becoming more popular till today as no special technique or device is not require to administer these products and associated pain is not involved here.
[][]In the period of time its are considered as the most effective and efficient method to treat the patient. This orally taken drugs are dissolved in GI (Gastro Intestinal) fluid and then bioavailable at the systemic circulation as it absorbed here. To measure the bioavailability of a certain drugs (in vivo Analysis, vivo is Latin for “within the living, test perform in living organism) is not accurately possible due to its complex nature.
[][]For this reason, in vitro (vitro is Latin for “within the glass, test perform outside the living organism) methods are followed to measure the dissolution rate of a certain drugs. This method is officially recognized by certain regulatory authority and it(in vitro study) considered most convenient way to develop new formulation of oral solid dosage form.
Comparative Dissolution Consideration
[][]Dissolution method is the best option for the lower strength drug where different strength is proportionally formulated to acquire the biowaiver of certain formulated drug. For a certain product which higher strength bioequivalence study has been carried out and found proportional to the concentration then biowaiver is conceivable to the lower strength.
Dissolution test are considering the most quality control tool for the commercial batch to batch product to monitor its consistency over a certain period of time. It also provides significant information during post approval changes of the certain product as changes made in formulation, manufacturing process and different scale up procedure.
[][]The most physiological factor is considered as the dissolution and solubility of the API and its permeability through the membrane of the GI[Gastro Intestinal] tract. As this measurement is so prone to error due to its complex nature then in vitro study consider the most convenient and reliable procedure to achieve the required target. During development of a certain solid dosage form, dissolution is considered as the best option to determine its quality parameter which have the great impact on the bioavailability of the formulated product.
Comparative Dissolution, Waiver of in vivo bioavailability
[][]BCS system applied in this case so that waiver for in vivo analysis can be assured. BCS [Biopharmaceutical Classification System] is a system which measure the permeability and solubility of drugs in a certain prescribed condition.
[][]The actual aim of BCS is to aid the post approval changes and arranging approval activities based on in vitro data studies.
This system has been optimized based on the oral solid dosage unit as most of the market products are available at oral dosage form [More than 50% total market share, US$23.4 Bn in 2021, US$24.7 Bn in 2022 as estimated, growth rate 5.9%).
[][]Waivers[ means giving permission to skip in vivo bioequivalence study] is actually reserved for those products that meet the specific requirements of solubility & permeability & most of the cases rapid dissolve in body fluid.
[][]Using the BCS, appropriate formulation study shall be developed such as Type II drugs designed as Permeable but insoluble, this class is not the actual right candidate for development of a new moiety.
[][]So, solubility shall be developed to acquire the right dissolution profile. Based on the solubility and permeability BCS has classified the four categories of the product as depicted below
Dosage form challenge
[][]Comparison has been drawn from old drug to new drug formulation, where older drugs compare to the current products are more prone to solubilities. Class II compound has been remarkably increased as 30% to 60% where class I compound has down to 40% to 20% where low solubility has the main cause to encounter the issue.
A oral solid dosage form is the preferred option but all time this can’t possible the suspension or solution is continued to prove its existence
[][]Generally a highly soluble active substance and rapidly dissolve dosage form provide better bioavailability and in this case biowaiver can be waived for bioequivalence studies base on its dissolution profile.
[][]If a active substance found low solubility but high permeability then the rate limiting steps of absorption may be consider as dissolution. Most of the cases dissolution profile control the more than one of excipients or special design matrix compounds. So Test condition may be consider as various time frame (10, 15, 20,30, 45 & 6 minutes).
[][]Drugs that are poor soluble in water then various time frame are considered and accepted timeframe is set for dissolution profile. Here USP Type 4 apparatus to be used to develop such type dissolution profile. Most of the time, monograph for combination product is not available at BP or USP the individual monograph shall be used to set the dissolution profile.
Selection of Dissolution Media
Selection of the dissolution media is the vital point to achieve the goal. pH of the media as the key role as all of the dosage form goes to GI[Gastro Intestinal] tract so pH shall be simulate with the GI Tract environment. pH shall be 1.2 to 6.8 which is the physiologic pH range of the body.
| Zone | pH |
|---|---|
| [A]Pre-prandial Stomach | 1.8(1~3) |
| Duodenum | 6.0(4~7) |
| Upper Jejunum | 6.5(5.5~7) |
| Lower Jejunum | 6.8(6~7.2) |
| Upper Ileum | 7.2(6.5~7.5) |
| Lower Ileum | 7.5(7~8) |
| Proximal Colon | (5.5 ~6.5) |
| [B]Post-prandial Stomach | 4.0(3~6) |
| Duodenum | 5.0(4~7) |
| Upper Jejunum | 5.5(5.5~7) |
| Lower Jejunum | 6.5(6~7.2) |
| Upper Ileum | 7.2(6.5~7.5) |
| Lower Ileum | 7.5(7~8) |
| Proximal Colon | (5.5 ~6.5) |
Dissolution Statistics
Different cases obtaining after multipoint dissolution which is calculative as follows:
[][]If Test Product and Reference Product both shows dissolution rate more than 85% within first 15 minutes then no calculation is required, they are considered as similar. If it didn’t achieved then seek for next step.
[][]Seek for f2 value[ f2, similarity factor] if f2>50% then it consider similar then in vivo study is not required.
[][]Difference Factor [f1] is the percentage (%) difference between the two curve at the each time period and also measure the relative error between two curve.
How it works
To determine the difference and similarity factor(f2) following pont shall be noted:
[][]Use the Two different products for study, from each product collect 12 unit [12 unit from Test Product & 12 Unit from Reference Product].
[][]Three time point shall be considered[Exclude Point Zero], only one measurement after 85% shall be measured.
[][]Produced curve shall be similar, f2 values shall be close to 100. Most of the time f2 value more than 50 denote similarity of the two curves as well as equivalence of the two products.
If Three/Four Time points come to the test then following points shall be considered.
[][]The measurement for the Test Product and the Reference product shall be same. Dissolution Time point shall be same for the both product (10,15,20,30,45,60 minutes etc.). Products which tend to faster dissolution (85% dissolve within 30 minutes) then time frame shall be consider as 10, 15, 20, 30 minutes.
[][]Only One measurement shall be consider after completion of 85% dissolution of both sample and reference products.
System Requirements to Perform Comparative Dissolution
Dissolution Activities shall be continued on USP Type I Dissolution apparatus at 100 RPM or USP Type II Apparatus at 50 RPM using 900 ml of different dissolution media mentioned below.
[][]Media Use in Comparative Dissolution
[][]Acid Media: 0.1N HCL or Simulated Gastric Fluid USP without Enzyme
[][]Acetate Buffer pH 4.5
[][]Phosphate Buffer pH 6.8 or Simulated Intestinal Fluid without Enzyme
[][]If both the Test Product and Reference product shows more than 85% dissolution within first 15 minutes then no calculation required. If not meets the above requirements then calculate f2 Value.
[][]If found f2>50, then the profile considered as similar and in vivo study is not required. Minimum 12 unit of each shall be consider for comparative dissolution.