Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320
* Corresponding author: Analytical R&D, Amgen Inc., One Amgen Center Dr., Mailstop 8-1-C, Thousand Oaks, CA 91320-1799. E-mail: [email protected]. Phone: (805) 313-6514. Fax: (805) 376-8505.
†Current address: School of Pharmacy, University of Connecticut, 69 North Eagleville Road, Unit 3092, Storrs, CT 06269-3092. E-mail: [email protected]
‡Current address: Department of Chemistry, Rm 419 Latimer Hall, University of California, Berkeley, CA 94720-1460. E-mail: [email protected]
§Current address: US FDA; White Oak CDER Office Building 21, 10903 New Hampshire Avenue, Silver Spring, MD 20993. E-mail: [email protected]
∥Current address: Kythera Biopharmaceuticals Inc., 27200 Agoura Road, Agoura Hills, CA 91301.
Abstract
Dissolution testing is frequently used to determine the rate and extent at which a drug is released from a dosage form, and it plays many important roles throughout drug product development. However, the traditional dissolution approach often emphasizes its application in quality control testing and usually strives to obtain 100% drug release. As a result, dissolution methods are not necessarily biorelevant and meaningful application of traditional dissolution methods in the early phases of drug product development can be very limited. This article will describe the development of a biorelevant in vitro dissolution method using USP apparatus 4, biorelevant media, and real-time online UV analysis. Several case studies in the areas of formulation selection, lot-to-lot variability, and food effect will be presented to demonstrate the application of this method in early phase formulation development. This biorelevant dissolution method using USP apparatus 4 provides a valuable tool to predict certain aspects of the in vivo drug release. It can be used to facilitate the formulation development/selection for pharmacokinetic (PK) and clinical studies. It may also potentially be used to minimize the number of PK studies, and to aid in the design of more efficient PK and clinical studies.
KEYWORDS:
This article is cited by 6 publications.
- Nadia Bou-Chacra, Katherine Jasmine Curo Melo, Ivan Andrés Cordova Morales, Erika S. Stippler, Filippos Kesisoglou, Mehran Yazdanian, Raimar Löbenberg. Evolution of Choice of Solubility and Dissolution Media After Two Decades of Biopharmaceutical Classification System. The AAPS Journal2017,19 (4) , 989-1001. DOI: 10.1208/s12248-017-0085-5.
- Tomokazu Tajiri, Shigeaki Morita, Ryosaku Sakamoto, Hisahi Mimura, Yukihiro Ozaki, Christos Reppas, Satoshi Kitamura. Developing dissolution testing methodologies for extended-release oral dosage forms with supersaturating properties. Case example: Solid dispersion matrix of indomethacin. International Journal of Pharmaceutics2015,490, 368-374. DOI: 10.1016/j.ijpharm.2015.05.054.
- May Almukainzi, Nádia Araci Bou-Chacra, Roderick B. Walker, Raimar Löbenberg. Biorelevant Dissolution Testing. 2014,, 335-365. DOI: 10.1002/9781118903681.ch12.
- Edmund S. Kostewicz, Bertil Abrahamsson, Marcus Brewster, Joachim Brouwers, James Butler, Sara Carlert, Paul A. Dickinson, Jennifer Dressman, René Holm, Sandra Klein, James Mann, Mark McAllister, Mans Minekus, Uwe Muenster, Anette Müllertz, Miriam Verwei, Maria Vertzoni, Werner Weitschies, Patrick Augustijns. In vitro models for the prediction of in vivo performance of oral dosage forms. European Journal of Pharmaceutical Sciences2014,57, 342-366. DOI: 10.1016/j.ejps.2013.08.024.
- Keiichi Otsuka, Yasushi Shono, Jennifer Dressman. Coupling biorelevant dissolution methods with physiologically based pharmacokinetic modelling to forecast in-vivo performance of solid oral dosage forms. Journal of Pharmacy and Pharmacology2013,65 (10.1111/jphp.2013.65.issue-7) , 937-952. DOI: 10.1111/jphp.12059.
- Deirdre M. D’Arcy, Bo Liu, Owen I. Corrigan. Investigating the effect of solubility and density gradients on local hydrodynamics and drug dissolution in the USP 4 dissolution apparatus. International Journal of Pharmaceutics2011,419, 175-185. DOI: 10.1016/j.ijpharm.2011.07.048.
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.
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- 1Equipment
Usp 4 Dissolution Technology 2017
Equipment[edit]
Different types of Dissolution Units: A Water-bath unit equipped with USP Dissolution Apparatus 2 - Paddle (Top-left), A amber vessel water bath unit that has been equipped with USP Dissolution Apparatus 1 without baskets being placed on yet (Top-right), and a dissolution unit that uses a heating jacket (bottom)
Several dissolution apparatuses exist. In United States Pharmacopeia (USP) General Chapter <711> Dissolution, there are four dissolution apparatuses standardized and specified.[6] They are:
- USP Dissolution Apparatus 1 – Basket (37 °C)
- USP Dissolution Apparatus 2 – Paddle (37°C)
- USP Dissolution Apparatus 3 – Reciprocating Cylinder (37 °C)
- USP Dissolution Apparatus 4 – Flow-Through Cell (37 °C)
General Method[edit]
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.[1][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.
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More recently, hydrodynamic studies were conducted in USP Dissolution Apparatus 4.[23][24][25]
Operation[edit]
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. Zombie mode wiki. 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.
References[edit]
- ^ abBai, 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
- ^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. doi:10.3109/03639045.2015.1078349. ISSN0363-9045. PMID26294289.
- ^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. 13 (3): 328. doi:10.1208/s12248-011-9272-y. ISSN1550-7416.
- ^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: 492–495. doi:10.1002/[email protected]/(ISSN)2163-8306.IMMUNOLOGYINFLAMMATION. ISSN2163-8306.
- ^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. 18 (6): 1379–1390. doi:10.1208/s12248-016-9966-2. ISSN1550-7416.
- ^United States Pharmacopeia 34/National Formulary 29, 2011.
- ^USP 29 General Chapter <711> 2011 The United States Pharmacopeial Convention
- ^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
- ^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
- ^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.
- ^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.
- ^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.
- ^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
- ^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.
- ^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.
- ^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.
- ^Moore TW., Hamilton JF., Kerner CM., 1995. Dissolution testing: Limitation of USP prednisone and salicylic acid calibrator tablets. Pharmacopeial Forum 21 (5), 1387–1396.
- ^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.
- ^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
- ^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.
- ^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.
- ^[1]
- ^Kakhi, M.,'Mathematical modeling of the fluid dynamics in the flow-through cell',International Journal of Pharmaceutics, 376 (1-2), pp. 22-40, 2009
- ^Kakhi, M.,'Classification of the flow regimes in the flow-through cell', European Journal of Pharmaceutical Sciences, 37 (5), pp. 531-544, 2009
- ^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
- ^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.
- ^ “UV Spectroscopy Gains Use in Dissolution Testing,' Pharmaceutical Technology Partnerships in Outsourcing Supplement 40 (13) 2016.
- ^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.
- ^http://www.uspnf.com/?_ga=2.222865939.900266506.1519146191-1602732763.1519146191
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