Research paper Influence of hydroxypropyl methylcellulose polymer on in vitro and in vivo performance of controlled release tablets containing alprazolam Vorapann Mahaguna a,1 , Robert L. Talbert a,b , Jay I. Peters b , Sandra Adams b , Thomas D. Reynolds c,2 , Francis Y.W. Lam b , Robert O. Williams III a, * a College of Pharmacy, Austin, TX, USA b Department of Pharmacology, The University of Texas-Health Science Center at San Antonio, San Antonio, TX, USA c Larkin Laboratory, The Dow Chemical Company, Midland, MI, USA Received 28 February 2003; accepted in revised form 30 June 2003 Abstract The purpose of this study was to investigate the influence of hydroxypropyl methylcellulose (HPMC) molecular weight on pharmacokinetic and pharmacodynamic parameters of controlled release formulations containing alprazolam. Tablet formulations contained alprazolam, excipients, and either HPMC K4MP or HPMC K100LVP. A ten patient in vivo clinical trial using a randomized, open-label, four-way crossover design was conducted in the fed and fasted states. Plasma alprazolam concentrations were determined for 72 h. The pharmacodynamic effects of alprazolam were monitored using subject rated sedation on visual analogue scale for wakefulness, observer rated sedation, and symbol digit modalities test (SDMT). Results indicated that the tablet formulations containing either HPMC K4MP or HPMC K100LVP had similar dissolution profiles, and the dissolution profiles did not change through 6 months at 408C/75% RH or 12 months at 258C/65% Relative Humidity (RH). The area under the plasma concentration-time curve, time to peak concentration, and peak plasma concentration were not significantly different between the two tablet formulations investigated in either the fed or fasted states. Pharmacodynamically, no significant differences in SDMT scores between the two formulations were found. In vitro dissolution results predicted in vivo pharmacokinetic and pharmacodynamic results irrespective of formulation or diet used in the controlled release tablet. The controlled release tablets were bioequivalent and pharmacodynamically equivalent irrespective of the tablet formulation. q 2003 Elsevier B.V. All rights reserved. Keywords: Hydroxypropyl methylcellulose; Alprazolam; Pharmacokinetics; Pharmacodynamics; Bioequivalence; Molecular weight 1. Introduction Controlled release tablets may contain hydrophilic polymer, drug, and other excipients. Controlled release of drug from the matrix is dependent on polymer wetting, polymer hydration, and polymer dissolution. Hydroxypro- pyl methylcellulose (HPMC), a non-ionic cellulose ether polymer, is widely used in controlled released matrix tablets. The hydration rate of HPMC depends on the nature of the constituents, such as the molecular structure and the degree of substitution. Specifically, the hydration rate of HPMC increases with an increase in the hydroxypropoxyl content. The viscosity of the aqueous solution can be increased by increasing the average molecular weight (MW) of the polymer, the concentration of the polymer or decreasing the temperature of the solution. HPMC polymers are non-toxic, have the capacity to accommodate high levels of drug loading, and are not pH dependent [1,2]. The release of drug from controlled release tablets is influenced by factors relating to the physicochemical properties of the drug substance and to the dosage form. Factors associated with polymers, such as MW type (nominal viscosity) [3–6], concentration [2–4,7–9], degree of substitution [1,10], and particle size [1,9], have been 0939-6411/$ - see front matter q 2003 Elsevier B.V. All rights reserved. doi:10.1016/S0939-6411(03)00116-4 European Journal of Pharmaceutics and Biopharmaceutics 56 (2003) 461–468 www.elsevier.com/locate/ejpb 1 Present address: PharmaForm, L.L.C., 1006 East Yager Lane, Building D Suite 101, Austin, TX 78753, USA. 2 Present address: Pfizer, Ann Arbor Laboratories, 2800 Plymouth Road, Ann Arbor, MI 48105, USA. * Corresponding author. College of Pharmacy, Mail code: A1920, The University of Texas at Austin, 2409 West University Avenue, Austin, TX 78712-1074, USA. Tel.: þ1-512-471-4681; fax: þ 1-512-471-7474. E-mail address: williro@mail.utexas.edu (R.O. Williams III).