The dissolution procedure requires an apparatus, a dissolution medium, and test conditions that together provide a method that is sensitive to changes in critical quality attributes of a drug product, yet it is sufficiently rugged and reproducible for day-to-day operation. The method should be transferrable between laboratories.
2 main criteria for choosing Dissolution media of a drug substance:
- Solubility &
- Stability in that media
Stability
- stability investigation of a drug substance in various media is done.
- duration of stability is selected based on the time required to complete entire dissolution procedure.
- acceptance criteria: 98% - 102%
Typical media of choice & volume
- diluted HCl
- buffers (phosphate / acetate) in pH range 1.2~7.2.
- simulated gastric/intestinal fluid (with/without enzymes)
- water
- sometimes surfactant is used to provide sink condition.
- volume can range 500 ml - 1000 ml
- rare case volume 2L - 4L / 100 ml - 200 ml
Apparatus
- Apparatus 1 (Basket): most frequently used in OSD with 50 rpm - 100 rpm (typical)
- Apparatus 2 (Paddle): most frequently used in OSD with 50rpm (typical) - 75rpm (if coning occurs).
- Apparatus 3 (reciprocating cylinder): useful for chewable tablets, soft gelatin capsules, DR dosage forms, coated beads with dipping rate 5 - 30 dips/min.
- Apparatus 4 (flow through cell): for MR products & IR products with limited solubility, soft gelatin capsules, beaded products, suppository, depot dosage forms, suspension type ER products with flow rate 4,8& 16 ml/min.
- Apparatus 5 (Paddle over disk): Transdermal products
- Apparatus 6 (Rotating cylinder): Transdermal products
- Apparatus 7 (Reciprocating holder): non- disintegrating oral MR products, stents, implants, trans dermal products.
Acceptance criteria for IR products
During development profile is recommended with f2 comparison:
- 10, 15, 20, 30, 40, 50 min / 15, 20, 30, 45, 60 min
- profiling not required if 85% /+ release occur in 15 minutes.
- after development specification set with single time points.
3 stages (S1, S2, S3) of acceptance criteria for IR products:
Example: For a drug containing 200 mg active, dissolution spec is NLT 80% (Q) of the labelled amount of drug substance is dissolved in 30 min.
S1: for 6 tablets.
NLT 85% label claim (LC) (170mg) must be dissolved in 30 minutes.
S2: if S1 not achieved, additional 6 tablets dissolution to be done.
For 12 tablets
- avg. must be =\>80% LC (160mg) &
- no tablets less than Q-15% (65% LC; 130mg)
S3: if S2 not achieved, additional 12 tablets dissolution to be done.
For 24 tablets
- avg. must be =\>80% LC (160mg)
- NMT 2 tab. less than Q-15% (65% LC; 130 mg)
- No tablets less than Q-25% (55% LC; 110 mg)
· For delayed release dosage form:
- For the acid stage, the acceptance criteria have 3 levels. Level 1 (A) testing is passed if no individual value exceeds 10% dissolved.
- If the A criteria are not met, then the dissolution test is performed on 6 additional units for level 2 (A) testing. Level A criteria are passed if the average of all 12 units in the acid stage is NMT 10% dissolved and if no individual units more than 25% dissolved.
- Level 3 testing is performed if the A criteria are not met. The A criteria are passed if the average of all 24 units in the acid stage is NMT 10% dissolved and if no individual unit is more than 25% dissolved.
- If the dosage form is designed for immediate release of the drug in the intestinal tract, these calculated values are then compared to staged acceptance criteria that are based on a Q value as like immediate release criteria.
· For extended release dosage form:
- If the dosage form is designed for extended release of the drug in the intestinal tract, the sum of the measured amounts in the acid and buffer stages for each individual unit are then compared to criteria of extended release.
- Six units are analyzed at level 1 (L1); acceptance criteria are met if no individual value lies outside each of the stated ranges, and no individual value is less than the percentage specified for the final time point. If the L1criteria are not met, then 6 additional units are analyzed at level 2 (L2). The L2 criteria are met if these 3 conditions are met:
(1) The average value of the 12 units lies within each of the stated ranges and is NLT the stated range of the final time point.
(2) None of the 12 units is >10% of the labeled content outside each of the stated ranges.
(3) None of the 12 units is >10% of the labeled content below the stated amount at the final test time.
- If the L2 criteria are not met, then 12 additional units are tested at level 3 (L3). The L3 criteria are met if these 5 conditions are met:
(1) The average value of the 24 units lies within each of the stated ranges and is NLT the stated range of the final time point.
(2) NMT 2 of the 24 units are >10% of labeled content outside each of the stated ranges.
(3) NMT 2 of the 24 units are >10% of the labeled content below the stated amount at the final test time.
(4) None of the 24 units is >20% of the labeled content outside each of the stated ranges.
(5) None of the 24 units is >20% of the labeled content below the stated amount at the final test time.
References:
- USP-NF 〈711〉
- USP-NF 〈1092〉
