Dissolution. Lynda Paleshnuik. Training workshop: Training workshop on regulatory requirements for registration of Artemisinin based combined medicines and assessment of data submitted to regulatory authorities, February 23-27, 2009, Kampala, Uganda. Overview.
Training workshop: Training workshop on regulatory requirements for registration of Artemisinin based combined medicines and assessment of data submitted to regulatory authorities, February 23-27, 2009, Kampala, Uganda.
The pharmaceutical scientist would like to find a relationship between an in vitro characteristic of a dosage form, and its in vivo performance.
Disintegration was originally thought to be this characteristic. The USP introduced its disintegration test in 1950.
With advances in methodology, the disintegration test was found to be too insensitive, and dissolution test methods were introduced in the USP in 1968.
Dissolution is principally useful as a QC test. It can be predictive of in vivo behaviour, but this must be demonstrated by an in-vivo in-vitro correlation study (IVIVC).
“No product, including suspensions and chewable tablets, should be developed without dissolution or drug release characterization where a solid phase exists.”
“Dissolution testing is required for all solid oral Pharmacopeial dosage forms in which absorption of the drug is necessary for the product to exert the desired therapeutic effect. Exceptions are for tablets meeting a requirement for completeness of solution or for rapid (10 to 15 minutes) disintegration for soluble or radiolabeled drugs.”
The International Pharmacopeia Supplement 1 to the 4th Edition (2008) is available at:
For the latest monographs, including a list of those under development:
ACT’s include 7 API’s present in 4 possible combinations.
ACT’s (multiple API FPPs):
Artemether/lumefantrine tablets (new)
Artemether/lumefantrine oral suspension (new)
Note that the above are available under monograph development (second link on previous slide), not in the online PhInt (first link on previous slide).
Monographs under development and future monographs:
Monographs in progress:
Proposed for work:
Artemether capsules - Dissolution. Carry out the test as described under 5.5 Dissolution test for solid oral dosage forms.
Artemether tablets – as above
Artesunate tablets – as above
Artemether/lumefantrine tablets – no reference to dissolution
Artemether/lumefantrine oral suspension – no reference to dissolution, including in the referenced general monograph:
“Liquid preparations for oral use” under the section, “Powders for oral solutions/suspensions/drops”
API’s: amodiaquine, amodiaquine HCl, mefloquine
For both of the above, dissolution limits are included.
Amodiaquine HCl Tablets
(The above are in USP 2009 and USP 2009 S1)
For highly soluble API’s, the rate is largely determined by the disintegration of the dosage form.
ICH Q6: Disintegration may be substituted for dissolution when:
-rapidly dissolving FPP’s (dissolution >80% in 15 minutes at pH 1.2, 4.0 and 6.8) and FPP’s containing API’s which are highly soluble throughout the physiological range (dose/solubility volume < 250 mL from pH 1.2 to 6.8)
Most appropriate when:
- relationship between DT and dissolution is established, or
- DT shown to be more discriminating than dissolution.
In these cases development information should be provided to support the robustness of the formulation and manufacturing process with respect to the selection of dissolution vs. disintegration testing (see Decision Tree #7(1)).
Suggested media for comparative dissolution studies:
Water may be used as an additional medium, especially when the API is unstable in buffered media to the extent that data is unusable.
Calculation of similarity:
f2 is the similarity factor, n is the number of time points, R(t) is the mean %drug dissolved (reference product), and T(t) is the mean %drug dissolved (test product).
The evaluation of similarity is based on the conditions of:
1) Purpose of study
2) Products / batches information
Note that the batches tested must be the batches of test and comparator product used in the BE study.
3) Full dissolution conditions and method, as well as the number of units (tablets, capsules, etc) per study. It should be indicated how and when the samples were filtered. Any problems with pH related stability of samples should be indicated and discussed in terms of preventative handling measures, analysis and interpretation of data.
4) Analytical method (validated) or reference to part of dossier
5) Results (% API dissolved)
a) discriminating, and
b) rugged and reproducible enough for day-to-day operation, and capable of transfer between labs.
The acceptance criteria should be representative of multiple batches with the same formulation/manufacturing process, including key batches (eg BE).
The method should be discriminating enough:
The procedure should be capable of distinguishing significant changes in composition or manufacturing process that might be expected to affect in vivo performance.
The method should not be overly sensitive:
Assessing the results from multiple batches that represent typical variability in composition and manufacturing parameters may assist this evaluation.
Factors to consider:
Adopt the compendial method if one exists
- exception: unsuitable (example interference)
When no compendial method exists:
- develop a method using compendial methodology (general chapters) and a study of three factors.
Documented dissolution study focuses on three factors:
1: -the physicochemical characteristics of the product (solubility, pH and quantitation of API released)
2: -the extent and rate of release of API from the FPP
3: - QC of the system (performance checks)
Solubility of the API in 37◦C in water, other media (ie HCl) or buffers of different pH should meet “sink condition” (volume of medium at least three times that required in order to form a saturated solution of API).
In the absence of sink conditions, investigate methods to enhance solubility, eg use of a surfactant. If a surfactant is used, its concentration should be properly justified (e.g. typically <2% Sodium Lauryl Sulfate (SLS)).
UV is often used; for UV the applicant should have demonstrated:
Note that these will be determined as part of routine validation.
Chromatography is often necessary instead of UV when there is excipient interference, it is low dose or it is a FDC-FPP that requires more sensitivity and/or selectivity.
- Precision (≤ 2%) plus either:
- Peak asymmetry/tailing factor (preferable) (≤ 2) or
- Theoretical plates (≥ 2000) or
- Resolution (>2)
The written procedure should include:
Standard and sample preparation
Method of analysis (eg UV, HPLC)
Sampling procedure (intervals, filtration*, handling of samples, dilutions)
It should be indicated how and when samples are filtered. An inert filter is required with a suitable pore size. The intent is to avoid a) adsorption of active from solution or b) interference due to substances extractable by the dissolution medium.
Stability of samples:
Any problems with pH related stability of samples should be indicated and discussed in terms of preventative handling measures, analysis and interpretation of data.
Note that some of the ACT molecules are unstable in acidic medium.
Paddle, 75 rpm
500 mL pH 6.8 phosphate buffer
Criteria: NLT 80% l.c. in 30 minutes
DT NMT 10 min
Example 1: FDC product with fairly rapid release of both API’s;
> 80% dissolution is reached at 20 minutes (for both APIs in product)
The next time point can be chosen, ie NLT 80% in 30 minutes. This would be considered an acceptable limit.
Example 2: for slow dissolution of immediate release tablets, it is recommended that two points be used.
The following behaviour is observed for a product:
Time (min): 10 20 30 45 60 90 120
% released: 15 33 49 68 83 98 102
Applicant proposed: ≥ 75 % (Q) in 120 minutes
Limits requested: (1) Limit should be tightened to Q = 75% in 90 minutes. (2) A limit should also be established at 45 minutes and implemented immediately during stability studies.
Compendial general chapters
- PhInt: Methods of Analysis: 5.5 Dissolution test for solid oral dosage forms.
- USP <711> Dissolution and <724> Drug Release
- USP <1088> In-Vitro and In-Vivo Evaluation of Dosage Forms
- USP <1092> The Dissolution Procedure: Development and Evaluation
2) FDA dissolution site
- Gives reference to USP monograph if one exists
- Gives approved method parameters where no monograph exists.
Speed: 100 rpm
Medium: 900 mL SGF without enzyme
Sampling: 10, 20, 30, 45, and 60 minutes
Testing a method to demonstrate it is suitable for its intended purpose and the results obtained are meaningful.
Provides confidence that the method will perform properly under intended conditions.
Compendial dissolution methods should be revalidated (verified) for:
House dissolution methods (HPLC, UV) should be fully validated:
Robustness (performed but not provided)
Coefficient of Determination (r2) ≥ 0.997
9 determinations covering the range, eg 3 concentrations in triplicate (n=3)
2 or 3 determinations on each of 3 days
6 determinations at 100% of the concentration
Variations: days, analysts, equipment (matrixing allowed)
Precision Results: RSD ≤ 2.5%
Granules are formulated to be dispersed in water prior to administration. The API is very bitter and granules are coated to mask the taste.
The dissolution studies provided should include a demonstration that the coating serves its purpose, ie it can withstand the dispersion process. (Failure would result in a product which cannot be taken due to bitterness.)
For some FDC’s, the comparator is in the form of more than one tablet. When running comparative dissolution, only one tablet should be placed in any one vessel. Therefore the evaluation may have to be performed one API at a time.
If the study uses more than one tablet per vessel, solubility issues arise.