Dissolution testing explained

In the pharmaceutical industry, drug dissolution testing is routinely used to provide critical in vitro drug release information for both quality control purposes, i.e., to assess batch-to-batch consistency of solid oral dosage forms such as tablets, and drug development, i.e., to predict in vivo drug release profiles.[1] There are three typical situations where dissolution testing plays a vital role: (i) formulation and optimization decisions: during product development, for products where dissolution performance is a critical quality attribute, both the product formulation and the manufacturing process are optimized based on achieving specific dissolution targets. (ii) Equivalence decisions: during generic product development, and also when implementing post-approval process or formulation changes, similarity of in vitro dissolution profiles between the reference product and its generic or modified version are one of the key requirements for regulatory approval decisions. (iii) Product compliance and release decisions: during routine manufacturing, dissolution outcomes are very often one of the criteria used to make product release decisions.[2] [3] [4]

The main objective of developing and evaluating an IVIVC is to establish the dissolution test as a surrogate for human studies, as stated by the Food and Drug Administration (FDA).[5] Analytical data from drug dissolution testing are sufficient in many cases to establish safety and efficacy of a drug product without in vivo tests, following minor formulation and manufacturing changes (Qureshi and Shabnam, 2001). Thus, the dissolution testing which is conducted in dissolution apparatus must be able to provide accurate and reproducible results.

Equipment

Several dissolution apparatuses exist. In United States Pharmacopeia (USP) General Chapter <711> Dissolution, there are four dissolution apparatuses standardized and specified.[6] They are:

General Method

The vessels of the dissolution method are usually either partially immersed in a water bath solution or heated by a jacket. An apparatus is used on solution within the vessels for a predetermined amount of time which depends on the method for the particular drug. The dissolution medium within the vessels are heated to 37 °C with an acceptable difference of ± 0.5 °C [7]

The performances of dissolution apparatuses are highly dependent on hydrodynamics due to the nature of dissolution testing. The designs of the dissolution apparatuses and the ways of operating dissolution apparatuses have huge impacts on the hydrodynamics, thus the performances. Hydrodynamic studies in dissolution apparatuses were carried out by researchers over the past few years with both experimental methods and numerical modeling such as Computational Fluid Dynamics (CFD). The main target was USP Dissolution Apparatus 2.[8] [9] [10] [11] [12] [13] [14] The reason is that many researchers suspect that USP Dissolution Apparatus 2 provides inconsistent and sometimes faulty data.[15] [16] [17] [18] [19] [20] [21] The hydrodynamic studies of USP Dissolution Apparatus 2 mentioned above clearly showed that it does have intrinsic hydrodynamic issues which could result in problems. In 2005, Professor Piero Armenante from New Jersey Institute of Technology (NJIT) and Professor Fernando Muzzio from Rutgers University submitted a technical report to the FDA.[22] In this technical report, the intrinsic hydrodynamic issues with USP Dissolution Apparatus 2 based on the research findings of Armenante's group and Muzzio's group were discussed.

More recently, hydrodynamic studies were conducted in USP Dissolution Apparatus 4.[23] [24] [25]

Operation

The general procedure for a dissolution involves a liquid known as Dissolution Medium which is placed in the vessels of a dissolution unit. The medium can range from degassed or sonicated deionized water to pH adjusted chemically-prepared solutions and mediums that are prepared with surfactants.[26] Degassing the dissolution medium through sonication or other means is important since the presence of dissolved gases may affect results. The drug is placed within the medium in the vessels after it has reached sufficient temperature and then the dissolution apparatus is operated. Sample solutions collected from dissolution testing are commonly analyzed by HPLC or Ultraviolet–visible spectroscopy.[27] There are criteria known as 'release specifications' that samples tested must meet statistically, both as individual values and as average of the whole.[28] [29] One such criteria is the parameter "Q", which is a percentage value denoting the quantity of dissolved active ingredient within the monograph of a sample solution. If the initial sample analysis, known as S1 or stage 1 testing fails to meet the acceptable value for Q, then additional testing known as stage 2 and 3 testing is required. S3 testing is performed only if S2 testing still fails the Q parameter. If there is a deviation from the acceptable Q values at S3, then an OOS (Out of Specification) investigation is generally initiated.

Notes and References

  1. Bai, G., Wang, Y., Armenante, P. M., "Velocity profiles and shear strain rate variability in the USP Dissolution Testing Apparatus 2 at Different Impeller Agitation Speeds, " International Journal of Pharmaceutics, 403 (1-2), Pages 1–14, 2011
  2. Wang. Yifan. Snee. Ronald D.. Keyvan. Golshid. Muzzio. Fernando J.. 2016-05-03. Statistical comparison of dissolution profiles. Drug Development and Industrial Pharmacy. 42. 5. 796–807. 10.3109/03639045.2015.1078349. 0363-9045. 26294289. 34517111.
  3. Anand. Om. Yu. Lawrence X.. Conner. Dale P.. Davit. Barbara M.. 2011-04-09. Dissolution Testing for Generic Drugs: An FDA Perspective. The AAPS Journal. en. 13. 3. 328–335. 10.1208/s12248-011-9272-y. 21479700. 1550-7416. 3160163.
  4. Zhang. X.. Duan. J.. Kesisoglou. F.. Novakovic. J.. Amidon. G. L.. Jamei. M.. Lukacova. V.. Eissing. T.. Tsakalozou. E.. 2018. Mechanistic Oral Absorption Modeling and Simulation for Formulation Development and Bioequivalence Evaluation: Report of an FDA Public Workshop. CPT: Pharmacometrics & Systems Pharmacology. 6. 8. en. 492–495. 10.1002/psp4.12204. 28571121. 5572334. 2163-8306.
  5. Suarez-Sharp. Sandra. Li. Min. Duan. John. Shah. Heta. Seo. Paul. 2016-11-01. Regulatory Experience with In Vivo In Vitro Correlations (IVIVC) in New Drug Applications. The AAPS Journal. en. 18. 6. 1379–1390. 10.1208/s12248-016-9966-2. 27480319. 2560096. 1550-7416.
  6. United States Pharmacopeia 34/National Formulary 29, 2011.
  7. http://www.usp.org/sites/default/files/usp_pdf/EN/USPNF/2011-02-25711DISSOLUTION.pdf USP 29 General Chapter <711>
  8. Bai, G., Armenante, P. M., "Hydrodynamics, Mass transfer and Dissolution Effects Induced by Tablet Location during Dissolution Testing," Journal of Pharmaceutical Sciences, Volume 98, Issue 4, Pages 1511-1531, 2009
  9. Bai, G., Armenante, P. M., " Velocity Distribution and Shear Rate Variability Resulting from Changes in the Impeller Location in the USP Dissolution Testing Apparatus II, " Pharmaceutical Research, Volume 25, Issue 2, Pages 320-336, 2008
  10. Bai, G., Armenante, P. M., Plank, R. V., "Experimental and Computational Determination of Blend Time in USP Dissolution Testing Apparatus II," Journal of Pharmaceutical Sciences, Volume 96, Issue 11, Pages 3072-3086, 2007.
  11. Bai, G., Armenante, P. M., Plank, R. V., Gentzler, M., Ford, K. and Harmon P., "Hydrodynamic Investigation of USP Dissolution Test Apparatus II," Journal of Pharmaceutical Sciences, Volume 96, Issue 9, Pages 2327-2349, 2007.
  12. Kukura J., Baxter JL., Muzzio FJ., "Shear distribution and variability in the USP Apparatus 2 under turbulent conditions". Int J Pharm. 279 (1-2), Pages 9–17, 2004.
  13. Baxter JL, Kukura J, Muzzio FJ. "Hydrodynamics-induced variability in the USP Apparatus II Dissolution Test". Int J Pharmaceutics 292 (1-2), Pages 17–28, 2005
  14. McCarthy L., Bradley G., Sexton J., Corrigan O., Healy AM., "Computational fluid dynamics modeling of the paddle dissolution apparatus: Agitation rate mixing patterns and fluid velocities". AAPS Pharm Sci Tech 5 (2), 2004.
  15. Cox DC., Furman WB., Thornton LK., 1983. Systematic error associated with Apparatus 2 of the USP Dissolution Test III: Limitation of Calibrators and the USP Suitability Test. J Pharm Sci. 72 (8), 910– 913.
  16. Cox DC., Furman WB., 1982. Systematic error associated with Apparatus 2 of the USP dissolution test I: Effects of physical alignment of the dissolution apparatus. J Pharm Sci 71 (4), 451–452.
  17. Moore TW., Hamilton JF., Kerner CM., 1995. Dissolution testing: Limitation of USP prednisone and salicylic acid calibrator tablets. Pharmacopeial Forum 21 (5), 1387–1396.
  18. Costa P, Lobo JMS . 2001 . Influence of dissolution medium agitation on release profiles of sustained release tablets. Drug Devel Ind Pharm 27 (8), 811–817.
  19. Qureshi SA., McGilveray IJ., 1999. Typical variability in drug dissolution testing: study with USP and FDA calibrator tablets and a marketed drug (glibenclamide) product. Eur J Pharm Sci. 7 (3), 249-258
  20. Qureshi SA., Shabnam J., 2001. Cause of high variability in drug dissolution testing and its impact on setting tolerances. Euro J Pharm Sci. 12 (3),271–276.
  21. Mauger J., Ballard J., Brockson R., De S., Gray V., Robinson D., 2003. Intrinsic dissolution performance of the USP dissolution apparatus 2 (rotating paddle) using modified salicylic acid calibration tablets: Proof of principle. Dissol Technol 10(3), 6–15.
  22. Web site: Archived copy . . 2019-12-16 . 2017-05-24 . https://web.archive.org/web/20170524224222/https://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4187B1_01_04-Effect-Hydrodynamics.pdf . dead .
  23. Kakhi, M.,"Mathematical modeling of the fluid dynamics in the flow-through cell",International Journal of Pharmaceutics, 376 (1-2), pp. 22-40, 2009
  24. Kakhi, M.,"Classification of the flow regimes in the flow-through cell", European Journal of Pharmaceutical Sciences, 37 (5), pp. 531-544, 2009
  25. D'Arcy, D.M., Liu, B., Bradley, G., Healy, A.M., Corrigan, O.I.,"Hydrodynamic and species transfer simulations in the USP 4 dissolution apparatus: Considerations for dissolution in a low velocity pulsing flow", Pharmaceutical Research 27 (2), pp. 246-258, 2010
  26. Gregory P. Martin And Vivian A. Gray. "Selection of Dissolution Medium for QC Testing of Drug Products." Journal of Validation Technology (n.d.)(2011): 7-11.
  27. “UV Spectroscopy Gains Use in Dissolution Testing," Pharmaceutical Technology Partnerships in Outsourcing Supplement 40 (13) 2016.
  28. http://www.dissolutiontech.com/DTresour/200508Articles/DT200508_A04.pdf Meneces, Nora S., Carlos D. Saccone, and Julio Tessore. "USP Dissolution Test with Pooled Samples Statistical Analysis of the Third Stage." Dissolution Technologies 12.3 (2005): 18-21. Web.
  29. Web site: Usp–Nf | Usp-Nf.

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