Professional Documents
Culture Documents
Lynda Paleshnuik
Overview
Starting Point: Establishing Dissolution Criteria
Monograph Availability in the International Pharmacopeia Other Pharmacopeia and Sources
Disintegration vs Dissolution
Prequalification Requirements - Comparative Dissolution
2|
Dissolution - Introduction
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 can be predictive of in vivo behaviour, but this must be demonstrated for a given method applied to a given product.
3|
Dissolution - Introduction
USP <1088>: No product, including suspensions and chewable tablets, should be developed without dissolution or drug release characterization where a solid phase exists.
and
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.
4|
5|
For the latest monographs, including a list of those under development: https://www.who.int/medicines/publications/pharmacopoei a/mono_dev/en/index.html
6|
7|
8|
9|
10 |
11 |
12 |
For highly soluble APIs, the rate is largely determined by the disintegration of the dosage form.
13 |
14 |
Disintegration vs Dissolution
ICH Q6: Disintegration may be substituted for dissolution when: -rapidly dissolving FPPs (dissolution >80% in 15 minutes at pH 1.2, 4.0 and 6.8) and FPPs containing APIs 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)).
15 |
16 |
Disintegration vs Dissolution
In the preface to the current PhInt, it states that dissolution testing has been added to monographs for tablets and capsules containing highly soluble APIs, for example chloroquine sulfate tablets and isoniazid tablets, as an alternative to disintegration.
the disintegration test is considered to be generally satisfactory for such products.
17 |
Prequalification Requirements
A discriminating dissolution method should be developed for the final composition of the FPP, when applicable. This is a general requirement for solid orals.
Limits should be set for each API in fixed-dose FPPs. The dissolution method should be incorporated into the stability and quality control programs (release and shelflife specifications). Release limits = Shelf-life limits. Multipoint dissolution profiles of both the test and the reference FPPs should be compared.
18 |
19 |
Water may be used as an additional medium, especially when the API is unstable in buffered media to the extent that data is unusable.
20 |
21 |
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: A minimum of three time points (zero excluded); time points for comparator and test products should be the same. 12 dosage units of each formulation;
22 |
Assessment of Interchangeable Multisource Medicines, Kenya, August 2009
23 |
24 |
25 |
6) Conclusion/recommendation
26 |
27 |
Assessing the results from multiple batches that represent typical variability in composition and manufacturing parameters may assist this evaluation.
28 |
29 |
30 |
Development Strategy
Documented dissolution study focuses on three factors:
1: -the physicochemical characteristics of the product (solubility, pH and quantitation of API released)
31 |
Physicochemical characteristics
Solubility
pH API quantitation
32 |
Physicochemical characteristics
pH: water may be used as medium, however the effect of the formulation on the pH of water must be investigated and if it changes, the use of buffers or HCl should be considered.
pH should have in-vivo relevance if possible; Stability and solubility of API should be considered, for example some ACTs are unstable in acidic medium
34 |
Physicochemical characteristics
API quantitation: UV is often used; for UV the applicant should have demonstrated: a) non-interference with formulation components (spectra of API in the formula and in standard solutions should be identical in shape/magnitude); b) linearity (absorbance vs concentration) up to the highest expected concentration.
Performance Checks
Performance checks include calibration of the system with suitable calibrators (PhInt). The USP calibrator tablets are considered acceptable for dissolution method calibration. System suitability testing (SST) is required to be included in methodology. For a dissolution method, limits should be established for: - Precision ( 2%) plus (for HPLC) either:
Development Strategy
Establish dissolution profiles in at least two media within the physiological pH range. One should be a compendial medium, if a monograph exists.
Investigation of more than one medium, or a single buffer with different pH values or ionic strength, can aid in determining the optimum medium for use in quality control (eg to evaluate lot-to-lot changes).
37 |
Development Strategy
If no compendial monograph exists, a suitable procedure should be developed based on the physicochemical properties of both the API and the FPP.
Choosing a medium in which dissolution is relatively slower, for eg pH close to the pKa value of the drug, may be advantageous as it may be more discriminating. Once a satisfactory system is achieved, the factors in its development should be summarized so the assessor can follow the evolution and determine whether the system is appropriate.
38 |
Method Description
The written procedure should include: Apparatus Standard and sample preparation Method of analysis (eg UV, HPLC) Sampling procedure (intervals, filtration*, handling of samples, dilutions) Calculations Acceptance Criteria
39 |
Assessment of Interchangeable Multisource Medicines, Kenya, August 2009
Method Description
Filtration:
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.
40 |
Sample Stability
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.
41 |
Appropriateness of Method
Check:
1) Whether BCS Class 1 or 3 2) Results (BE batch characteristics, COAs, stability data) 3) Has data been provided to demonstrate the method is discriminatory? 4) Published methods
42 |
BCS Classification
PhInt monographs for class 1 or 3 APIs have (or will have) a standard dissolution method:
Paddle, 75 rpm
44 |
Published Methods
Compendial general chapters
- PhInt: Methods of Analysis: 5.5 Dissolution test for solid oral dosage forms.
Published Methods
2) FDA dissolution site
http://www.accessdata.fda.gov/scripts/cder/dissolution/
- Gives reference to USP monograph if one exists - Gives approved method parameters where no monograph exists.
46 |
Published Methods
Example for tenofovir (no compendial monograph):
2FDC, 3FDC and monotherapy tablets. Monotherapy tablets: Apparatus: Speed: Medium: Sampling:
47 |
48 |
Validation
Validation:
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.
49 |
Validation
Compendial dissolution methods should be revalidated (verified) for: Specificity Accuracy Precision (repeatability).
50 |
Validation
House dissolution methods (HPLC, UV) should be fully validated: Specificity Linearity Accuracy Repeatability
Intermediate precision
Robustness (performed but not provided)
51 |
Validation
Specificity: Chromatograms: sample containing placebo excipients vs sample without these components.
Linearity: range to be validated: 20% of limits; eg if limits cover from 20% to 90% l.c. (controlled release), linearity should cover 0-110% of l.c. Coefficient of Determination (r2) 0.997 Accuracy: assay samples/placeboes spiked with API; analysis in triplicate. A bias of 2% or less is acceptable.
52 |
Validation
Precision:
System precision Repeatability (method precision) Intermediate precision (precision with variations, eg days, analysts, equipment) Reproducibility (inter-laboratory trial)
53 |
Validation
Repeatability determination:
9 determinations covering the range, eg 3 concentrations in triplicate (n=3)
OR
2 or 3 determinations on each of 3 days OR 6 determinations at 100% of the concentration
54 |
Assessment of Interchangeable Multisource Medicines, Kenya, August 2009
Validation
Intermediate Precision:
Variations: days, analysts, equipment (matrixing allowed) Precision Results: RSD 2.5%
55 |
Example Issues
Example 1:
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.)
56 |
Example Issues
Example 2
For some FDCs, 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.
57 |
Questions?
58 |