PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of aapspharmspringer.comThis journalToc AlertsSubmit OnlineOpen Choice
 
AAPS PharmSciTech. 2000 June; 1(2): 63–71.
Published online 2015 February 19. doi:  10.1208/pt010214
PMCID: PMC2784825

Scale-up effects on dissolution and bioavailability of propranolol hydrochloride and metoprolol tartrate tablet formulations

1bstract

This study evaluated the effects of batch size on the in vitro dissolution and the in vivo bioavailability of immediate release formulations of propranolol hydrochloride and metoprolol tartrate. The formulations were manufactured as small and large batches (6 kg and 60 kg for propranolol; 14 kg and 66 kg for metoprolol), and dissolution was performed using USP Apparatus I at 100 rpm and pH 1.2. Two panels of 14 subjects each were randomly assigned to receive the small and large batches of either propranolol or metoprolol in an open randomized single-dose study. Blood samples were collected over a 24-hour (propranolol) or 18-hour (metoprolol) period and analyzed by validated methods. As determined by thef2 metric (similarity factor), the dissolution of the small and large batches of propranolol and metoprolol was similar. The mean Cmax and AUCinf for the small batch of propranolol were 79.0 μ g/L and 536 μ g/L/hr and for the large batch they were 83.5 μ g/L and 575 μ g/L/hr. Cmax and AUCinf for the small batch of metoprolol were found to be 95.5 μ g/L and 507 μ g/L/hr and for the large batch, 95.1 μ g/L and 495 μ g/L/hr. The 90% confidence intervals for the small and large batches were within the 80% to 120% range for InCmax, and InAUCinf for both the propranolol and metoprolol formulations. These results suggest that the scale-up process does not significantly affect the bioavailability of highly soluble, highly permeable drugs and in vitro dissolution tests may be useful in predicting in vivo behavior.

Keywords: Metoprolol, Propranolol, Scale-up, 2ioavailability, 4issolution

Full Text

The Full Text of this article is available as a PDF (458K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
1. Skelly JP, Van Burskirk GA, Savello DR, et al. Workshop report, scale-up of immediate release oral solid dosage forms. Pharm Res. 1993;10:313–316. doi: 10.1023/A:1018915700942. [PubMed] [Cross Ref]
2. Immediate Release Solid Oral Dosage Forms; Scale-Up and Postapproval Changes: Chemistry, Manufacturing and Controls:In Vitro Dissolution Testing:In Vivo Bioequivalence Documentation Guidance. Fed. Reg. 60, 61638-61643, November 30, 1995.
3. Amidon GJ, Lennernas H, Shah VP, Crimson IR. A theoretical basis for a biopharmaceutical drug classification: The correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm Res. 1995;12:413–420. doi: 10.1023/A:1016212804288. [PubMed] [Cross Ref]
4. Augsburger LL, Shangraw R, Lesko LJ, Williams R. An approach toward establishing a scientific foundation for interpreting regulations and workshop reports on scale-up and post approval changes. Pharm Res. 1994;11:143–143.
5. Eddington ND, Ashraf M, Augsburger LL, et al. Identification of formulation and manufacturing variables that influence in vitro dissolution and in vivo bioavailability of propranolol hydrochloride tablets. Pharm Dev Tech. 1998;3:535–547. doi: 10.3109/10837459809028636. [PubMed] [Cross Ref]
6. Rekhi GS, Eddington ND, Fossler MJ, Schwartz P, Lesko LJ, Augsburger LL. Evaluation ofin vitro release rate andin vivo absorption characteristics of four metoprolol tartrate immediate release tablet formulations. Pharm Dev Tech. 1997;29:11–24. doi: 10.3109/10837459709022605. [PubMed] [Cross Ref]
7. USP XXIII chapter 1088, United States Pharmacopeial Convention. Inc.: Rockville, Maryland, pp 1927–1929.
8. Moore JW, Elanner HH. Mathematical comparison of curves with an emphasis on dissolution profiles. Pharm Tech. 1996;6:64–74.

Articles from AAPS PharmSciTech are provided here courtesy of American Association of Pharmaceutical Scientists