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Dissolution (Modified Release) — USP <711>

Multi-time-point dissolution profiles for extended, delayed, or pulsatile release products. Independent evaluation at each time point.

USP <711> Extended Release Multi-Point
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Industry Use

Modified Release Product Testing

Modified release (MR) dissolution testing verifies that extended release (ER), sustained release (SR), delayed release (DR), and pulsatile release products deliver API according to their specified pharmacokinetic profile across multiple time points. Modified release dissolution is more complex than immediate release testing because the product must be evaluated at multiple time intervals to confirm the release mechanism is functioning correctly.

Applications for Modified Release Dissolution:

Each time point in an MR profile has its own Q specification and is evaluated independently using the same S1/S2/S3 acceptance criteria as immediate release.

USP <711> FDA ER Guidance ICH M9
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Calculation Explanation

Multi-Time-Point Stage Evaluation

Modified release dissolution evaluates each time point independently against its own Q specification. Each time point is assessed using the same S1/S2/S3 sampling plan and acceptance logic as immediate release dissolution.

General Process:

Multi-Time-Point Evaluation
• Define Q for each time point
• At each time point, evaluate Stage 1 (n=6)
• If all units ≥ Q+5%, pass that time point
• If any unit < Q+5%, advance to Stage 2 (n=12)
• Continue to Stage 3 if needed (n=24)
• Batch passes only if all time points pass

Typical Extended Release Profile Example:

Time Point Q Specification Purpose Acceptance Criterion (S1)
1 hour 15% Initial release verification Each unit ≥ 20%
4 hours 45% Mid-profile check Each unit ≥ 50%
8 hours 75% Primary evaluation point Each unit ≥ 80%
12 hours 85% Extended release endpoint Each unit ≥ 90%

Key Point: ALL time points must pass their respective acceptance criteria for the batch to be acceptable. Failure at any single time point causes batch rejection and requires investigation.

USP <711> Time-Point Q Values S1/S2/S3 Per Point
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Variable Definitions

Modified Release Dissolution Parameters

Symbol Parameter Name Units Description
Time Point Sampling Time hours (h) Time at which dissolution is measured. MR products have multiple time points (e.g., 1h, 4h, 8h, 12h).
Q(t) Time-Point Q Specification % Released Target dissolution percentage at a specific time point. Each time point has its own Q value per monograph.
n Number of Vessels vessels Stage 1: n=6; Stage 2: n=12; Stage 3: n=24. Applied per time point.
Individual Dissolution(t) Result per Vessel at Time t % Released Dissolution value for each vessel at the specific time point.
Average Dissolution(t) Mean at Time t % Released Arithmetic mean of all n results at that time point.
Stage Testing Phase per Time Point S1/S2/S3 Each time point has its own stage progression. All time points must pass to approve batch.
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Step-by-Step Tutorial

Worked Example with Extended Release Tablet

Scenario: A pharmaceutical company manufactures an extended release tablet containing 500 mg metformin. The product is designed for once-daily dosing over 12 hours. Dissolution is tested using USP Apparatus II (paddle) in water pH 6.8 at 37°C. The specification requires evaluation at four time points.

Stage 1 Dissolution Results at All Four Time Points (n=6 vessels)
Time Point 1 (1 hour, Q=15%): 18%, 22%, 20%, 19%, 21%, 23%
Time Point 2 (4 hours, Q=45%): 52%, 48%, 50%, 51%, 49%, 47%
Time Point 3 (8 hours, Q=75%): 82%, 80%, 78%, 84%, 79%, 83%
Time Point 4 (12 hours, Q=85%): 94%, 92%, 96%, 93%, 91%, 95%
  1. Evaluate Time Point 1 (1 hour):
    Q + 5% = 15% + 5% = 20%
    Acceptance: Each unit ≥ 20%
    Results: 18% (FAILS), 22% ✓, 20% ✓, 19% (FAILS), 21% ✓, 23% ✓
    Result: Two units fall below 20%. Stage 1 FAILS; proceed to Stage 2 for this time point.
  2. Stage 2 Analysis for Time Point 1:
    Test 6 additional units (n=12 cumulative).
    Assume additional results: 21%, 20%, 22%, 19%, 23%, 20%
    Combined 12 results: 18, 22, 20, 19, 21, 23, 21, 20, 22, 19, 23, 20
    Average = (18+22+20+19+21+23+21+20+22+19+23+20) / 12 = 248 / 12 = 20.67%
    Stage 2 Acceptance: Average ≥ 15% ✓ and no unit < 0% (Q−15%) ✓
    Result: Time Point 1 PASSES Stage 2.
  3. Evaluate Time Point 2 (4 hours):
    Q + 5% = 45% + 5% = 50%
    Results: 52%, 48%, 50%, 51%, 49%, 47%
    Acceptance: Each unit ≥ 50%
    One unit at 47% fails. Proceed to Stage 2.
    (Assume Stage 2 average ≥ 45% and no unit < 30%)
    Result: Time Point 2 PASSES Stage 2.
  4. Evaluate Time Point 3 (8 hours):
    Q + 5% = 75% + 5% = 80%
    Results: 82%, 80%, 78%, 84%, 79%, 83%
    One unit at 78% fails. Proceed to Stage 2.
    (Assume Stage 2 average ≥ 75% and no unit < 60%)
    Result: Time Point 3 PASSES Stage 2.
  5. Evaluate Time Point 4 (12 hours):
    Q + 5% = 85% + 5% = 90%
    Results: 94%, 92%, 96%, 93%, 91%, 95%
    All results ≥ 90%.
    Result: Time Point 4 PASSES Stage 1.
  6. Final Batch Decision:
    All four time points pass their respective acceptance criteria.
    Batch is RELEASED.
✓ BATCH PASSES ALL TIME POINTS
Profile is consistent with ER specification.
Ready for batch release and distribution.

Interpretation: The extended release profile demonstrates appropriate release kinetics across the 12-hour period. While some earlier time points required Stage 2 evaluation, all averaged results and individual limits were met, confirming consistent manufacturing and reliable extended release performance.

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