Important Note
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When dissolution conditions are modified, (such as a change in the spindle speed or a change in temperature or volume of dissolution media) it will invariably result in a change in the valume of the dissolution rate constant

Evolution of Dissolution Testing

Timeline

The above timeline shows the period from 1850 to present day. Each of the three 50 year time periods and the time period 2000 onwards can be selected with your cursor to view more information about that particular era of dissolution history. Significant years are indicated with blue flags. Click on the flags to view more information.

1900
1897
1904
1930
1931
1932
1934
1950
1955
1958
1960
1960s
1962
1967
1969
1970
1970s
1975
1977
1978
1984
1990
1995
1996
1997
2000
2003
2006
2007
2009
2010
2011
Click on any of the historical event flags to display the information for that year.

1900 Brunner and Tolloczko

Brunner and Tolloczko prove the dissolution rate depends on the chemical and physical structures of the solid, the surface area exposed to the medium, agitation speed, medium temperature and the overall design of the dissolution apparatus.

1897 Noyes and Whitney

Noyes and Whitney publish a paper of 'The Rate of Solution of Solid Substances in Their Own Solution' suggesting dissolution rate is controlled by a layer of saturated solution that forms instantly around a solid particle.

1904 Nernst and Brunner

Nernst and Brunner use laws of diffusion to introduce a new relationship between the dissolution rate constant and the diffusion coefficient of the solute.

1930 Experiments

Experiments begin with in vitro/in vivo correlation and bioavailability.

1931 Hixson and Crowell

Hixson and Crowell develop a mathematical model describing the dissolution process.

1932 Solvometer

The Solvometer is introduced. Chemical substances were compressed into a tablet of uniform surface area to study surface rate dissolution … the forerunner of modern intrinsic studies.

1934 Disintegration Test

Pharmacopoeia Helvetica in Bern, Switzerland is the first regulatory body to incorporate a disintegration test for tablets.

1950 Official Approval of Disintegration Test

The disintegration test becomes an official USP method. (USP XIV).

1955 Solid Dosage Form Test

USP XV requires the disintegration test for most solid dosage forms.

1958 Rotating Bottle Method

The rotating bottle method is developed to study timed-release formulations.

1960 Levy and Hayes

Levy and Hayes, utilizing a beaker and three-blade stirrer at 30-60 RPM, find significant differences in the in vitro dissolution rate of different brands of aspirin tablets and link them to the incidence of gastrointestinal irritation caused by various brands of aspirin tablets due to their slow dissolution rates.

1960 and Later

  • It becomes apparent that disintegration has little to do with biological activity. Disintegration was important, but deaggregation was essential for bioavailability.
  • USP-NF Joint Panel recognizes a need for a dissolution test.
  • William Mader and Dr. Lee T. Gradey with the Drug Standards Laboratory, experiment with a variety of basket and stirring devices.
  • USP-NF Joint Panels adopt the rotating basket apparatus to test individual dosage units.


1962 Amendments Passed

Kefauver-Harris Drug Effectiveness and Safety Amendments are passed.

1967 Regulations

USP-NF Panel on Physiological Availability establish regulations to assure drug effectiveness.

1969 Flow Through Cell

The circulating Flow Through Cell is developed.

1970 Rotating Basket

  • USP XVII incorporates the first official dissolution test for solid dosage forms
  • Twelve monographs are published in USP-NF with the official dissolution test - rotating basket

Early 1970s

  • Scientists evaluate variability seen in dissolution results from one apparatus to another.
  • NCDA (FDA) finds variability between apparatus-to-apparatus and lab-to-lab.
  • FDA and USP push for standardization of dissolution testing.

1975 Calibrators

  • The USP Revision Subcommittee on General Chapters begins development of calibrators for dissolution testing.
  • The USP Subcommittee recommends two apparatus - the Rotating Paddle and Rotating Basket.

1977 Bioequivalence Testing

FDA publishes the need for bioequivalence testing.

1978 Further Study

  • FDA publishes Guidelines for Dissolution Testing.
  • USP publishes Pharmaceutical Manufactures Association (PMA) Collaborative Study result for three colibrators - Prednisone, Salicylic Acid and Nitrofuration.
  • USP proposes conditions 50, 100, and 150 RPM for baskets; 50 and 100 RPM for paddles; time points: 15, 30, 45, and 60 minutes (40 tests).
  • PMA suggests averaging and standard deviation as acceptance criteria.
  • FDA - USP finds individual tablet criteria unacceptable. Averages are too wide.
  • USP issues first official refrence standard calibrator tablets.
  • All dissolution equipment used for compendial dissolution testing must meet USP calibrator acceptance criteria.


1984

FDA/DPA publishes the 'Guidelines for Dissolution Testing Addendum'.

1990 Transdermal Dissolution

Transdermal dissolution methods incorporated into USP XXII.

- Apparatus 3 (Paddle over disk)

- Apparatus 4 (Cylinder)

- Apparatus 5 (Reciprocating disk)

1995 Extended Release Methods

USP XXIII adds two extended release methods and renumbers all apparatus:

1 - basket

2 - paddle

3 - reciprocating cylinder

4 - flow through cell

5 - paddle over disk

6 - cylinder

7 - reciprocating disk

1996 An Alternative Approach to PVT

  • A Subcommitte on dissolution Calibration is formed within the dissolution Subcommitte of the Pharmaceutical Research and Manufacturers (PhRMA) in 1996.
  • A collaborative on pertubation is performed by twelve PhRMA laboratories; the goals are to:

    - Evaluate alternative dissolution apparatus suitablity test requirements


    - Identify which aspects of colibration add value to the evalution of bath   performance


    - Evaluate non-value added activities performed during dissolution calibration,
      including the potential elimination of calibrator tablets




1997 Pooled Sampling, USP Calibration Requirements, FDA Guidance

Pooled Sampling

  • Pooled sampling is added to USP XXIII seventh Suplement. It is later removed.
  • Food And Drug Administration Modernization Act reauthorizes Prescription Drug User Free Act of 1992 and mandates the most wide-ranging reforms in agency practices since 1938. Provisions include measures to accelerate review of devices, regulate advertising of unapproved uses of approved drugs and devices, and regulate health claims for foods.

USP Calibration Requirements

  • USP Calibration requirements are reduced to 4 tests total:

    - Disintegrating and non-disintegrating tablets

    - 50 and 100 RPM - one speed each apparatus

    - Each test had individual acceptance ranges (4 total)

    - Apparatus dedicated for paddle for basket require only two tests

FDA Guidance for industry Documents Introduced

  • 'Dissolution Testing of Immediate Release Solid Oral Dosage Forms' (August)
  • 'Extended Release Oral Dosage Forms: Development, Evaluation, and Application of In Vitro/In Vivo Correlations' (September)
  • 'Scale-Up and Postapproval Changes for Modified Release Solid Oral Dosage Forms "SUPAC-MR" ' (September)




2000 Guidance for Industry, An Alternative Approach to PVT

Guidance for Industry
FDA Guidance for Industry 'Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System (BCS)'.

An Alternative Approach to PVT
The results of the perturbation study are published in a US Pharmacopeial Forum Stimuli article 'Dissolution Calibration: Recommendations for Reduced Chemical Testing and Enhanced Mechanical Calibration'; Vol. 26, No. 4, 2000. The results are as follows:
- Perform enhanced mechanical calibration every three months
- The use of a calibrator should be maintained until enhanced mechanical calibration   is further defined including establishment of a definitive vibration technique
- Eliminate Salicyclic Acid Calibrator Tablet




2003 FIP/AAPS Guidelines - Novel/Special Dosage Forms

FIP/AAPS Guidelines to Dissolution In Vitro Release Testing of Novel/Special Dosage Forms.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2750303/pdf/12249_2008_Article_
41043.pdf

2006 ICH and Drug Release, Mechanical Qualification

ICH and Drug Release

  • As part of the International Conference on Harmonization (ICH) effort USP 29 incorporates two of the following drug release tests into the <711> Dissolution chapter from the <724> Drug Release chapter:

    - Apparatus 3 - Reciprocating Cylinder

    - Apparatus 4 - Flow-Through Cell

  • <724> Drug Release chapter now contains:

    - Apparatus 5 - Paddle over Disk

    - Apparatus 6 - Rotating Cylinder

    - Apparatus 7 - Reciprocating Holder

Mechanical Qualification of Dissolution Apparatus 1 and 2

  • US Food and Drug Administration (FDA), DPA-LOP.002, Version 2.0 Effective Date: 2 June 2006

    - First official Mechanical Qualification procedure




2007 Qualification of Apparatus, Toolkit Dissolution Procedure, Chapter <1092>

Qualification of Basket and Paddle Dissolution Apparatus

  • Standard Practice for Qualification of Basket and Paddle Dissolution Apparatus American Society for Testing and Materials, International (ASTM), Designation E 2503-07, Effective Date: 15 March 2007.

    http://www.astm.org/Standards/E2503.htm

    - Cost: $32.00 USD

    - E2503 is under the jurisdiction of ASTM Committee E55 on Manufacture of   Pharmaceutical Products and is the direct responsibility of Technical   Subcommittee E55.03 on General Pharmaceutical Standards

Toolkit Dissolution Procedure

USP Added General Chapter <1092>

  • USP added General Chapter <1092> The Dissolution Procedure: Development and Validation.




2009 FIP Position Paper on Qualification

FIP Position Paper on Qualification of Paddle and Basket Dissolution Apparatus:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2802143/

2010 Use of Mechanical Calibration, USP PVT, Toolkit Dissolution Procedure V2

The Use of Mechanical Calibration of Dissolution Apparatus 1 and 2

USP Performance Verification Test (PVT)

  • As of March 1 2010, Lot P1I300 becomes the official USP prednisone calibrator tablet. With the new lot, a new set of acceptance criteria based on both geometric mean and %CV is adopted.
  • In addition to the changes in acceptance criteria, some minor changes to the dissolution test recommendations occur.

Toolkit Dissolution Procedure Version 2.0




2011 FDA Guidance for Industry

FDA Guidance for Industry: Q4B Evaluation and Recommendation of Pharmaceutical Texts for Use in ICH Regions, Annex 7(R2) Dissolution Test General Chapter:

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatory
Information/Guidances/ucm085366.pdf

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