Modulation of microenvironmental pH and crystallinity of ionizable telmisartan using alkalizers in solid dispersions for controlled release Phuong Ha Lien Tran, Huyen Thi Thanh Tran, Beom-Jin Lee ⁎ National Research Lab. for Bioavailability Control, College of Pharmacy, Kangwon National University, Chuncheon, Republic of Korea ABSTRACT ARTICLE INFO Article history: Received 28 January 2008 Accepted 7 April 2008 Available online 13 April 2008 Keywords: Telmisartan Solid dispersion Alkalizers Dissolution rate Structural behavior pH modulation The present work is an original evaluation of the microenvironmental pH (pH M ) and crystallinity of an ionizable drug in order to enhance its dissolution using alkalizers in polyethylene glycol 6000 (PEG 6000) based solid dispersions (SDs). Telmisartan (TEL) was chosen as a model drug due to its poor and pH- dependent water solubility. The nine alkalizers used to modify the pH of TEL were MgO, NaOH, KOH, Na 2 CO 3 , NaHCO 3 , bentonite, Na 2 HPO 4 ,K 2 HPO 4 and arginine. MgO, NaOH, KOH and Na 2 CO 3 in the SD system significantly increased the drug dissolution rate in intestinal fluid (pH 6.8) and water. Modulation of pH M was clearly observed as a function of time at different fractional dimensions of tablet. Structural change in drug crystallinity to an amorphous form was also a contributing factor based on differential scanning calorimetry (DSC) thermograms and powder X-ray diffraction (PXRD) patterns. The drug frequency of the CfO band decreased and the O–H broad band in the Fourier transform infrared (FTIR) spectra disappeared when these alkalizers were added. It was evident that the alkalizers in PEG 6000 based SDs synergistically enhanced dissolution of TEL not only by modulating pH M but also by changing drug crystallinity to an amorphous form via molecular interactions. © 2008 Elsevier B.V. All rights reserved. 1. Introduction Numerous studies have been carried out in order to modify the dissolution kinetics of poorly soluble drugs to improve their bioavailability. A common method used to improve the dissolution rate of a poorly water- soluble drug is by formation of a solid dispersion (SD) with hydrophilic polymers such as polyethylene glycol, hydroxypropylcellulose, polyvinyl- pyrrolidone, and other diverse carriers [1–3]. Briefly, an SD is defined as a molecular mixture of drug in carriers. The changes of drug crystallinity to an amorphous form and the reduced particle size for better wettability are the main mechanisms whereby SD enhances drug dissolution. Alternatively, it has also been reported that the modulation of pH in dosage forms is a promising way to modify the release rate of several pH-dependent and ionizable drugs [4–6]. For example, the addition of water soluble or insoluble pH modifying agents to mini tablets was found to maintain high pH values within the tablets, thus resulting in improved release of 8-prenylnaringenin, a weakly acidic drug with an extremely poor solubility [6]. Incorporation of weak acids as pH modifiers in hydrophilic matrix tablet also enhances release rate of weakly basic drugs by reducing the microenviron- mental pH (pH M ) [5]. The pH M can be defined as the pH of the saturated solution in the immediate vicinity of the drug particles and has been used to modify the dissolution of ionizable drugs from pharmaceutical formulations in a predictable manner. The importance of pH M control on the dissolution behaviors of water-insoluble drugs in SD systems became apparent a decade ago [7,8]. For example, an internal buffer system comprised of disodium hydrogen orthophosphate and citric acid incorporated into frusemide- polyvinylpyrrolidone SD was used to control the pH M and conse- quently increased the dissolution rate of weakly acidic frusemide in acidic media and retarded the rate in alkaline media [7]. Still, it is not clear how the inclusion of the buffered system into the SD is related with drug crystallinity. Dissolution enhancement of a basic drug with hydrophilic polymers by using a mixed solvent of 1 N hydrochloric acid and methanol in a SD of the salt form was studied. However, no information of pH modifiers was described [8]. One disadvantage of the SD method and modulation of pH M is the limited solubilization capacity, especially with a high drug-loaded system. Furthermore, no detailed attempt has been made to under- stand the modulating mechanism of pH modifiers in SD systems or how these potential changes of drug crystallinity and pH M control are correlated with enhanced dissolution of poorly water-soluble drugs. Telmisartan (TEL) was selected as a model drug. Therapy with this drug offers a good quality of life for hypertensive patients due to the minimal side effects [9]. TEL is manufactured and supplied in the free acid form and is characterized by a very poor solubility, resulting in low bioavailability [10]. According to the chemical structure of TEL, the TEL is readily ionizable and subsequently the solubility is also pH-dependent. The aim of this study was to investigate the effect of incorporating alkalizers into PEG 6000 based SDs on the dissolution rate of TEL. The alkalizers MgO, NaOH, KOH, Na 2 CO 3 , NaHCO 3 , bentonite, Na 2 HPO 4 , Journal of Controlled Release 129 (2008) 59–65 ⁎ Corresponding author. Tel.: +82 33 250 6919; fax: +82 33 242 3654. E-mail address: bjl@kangwon.ac.kr (B.-J. Lee). 0168-3659/$ – see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.jconrel.2008.04.001 Contents lists available at ScienceDirect Journal of Controlled Release journal homepage: www.elsevier.com/locate/jconrel