Extended release of flurbiprofen from tromethamine-buffered HPMC hydrophilic matrix tablets

The continued popularity into the 21st century of extended release matrices based on hydroxypropyl methylcellulose (HPMC) can be attributed to (i) the effectiveness of hydrophilic matrix technology, (ii) the high acceptability of the polymer, (iii) the ease of dosage form manufacture and (iv) a knowledge base that spans many decades (Huber et al. 1966; Alderman 1984; Melia 1991; Li et al. 2005; Timmins et al. 2016).

However, a potential drawback is the potential for poor drug bioavailability. This can arise from changes in drug ionization and subsequent solubility as the dosage form traverses the differing pH environments of the gastrointestinal tract (Badawy & Hussain 2007; McConnell et al. 2008). In a hydrophilic matrix, changes in drug solubility can fundamentally change drug pharmacokinetics through a change in drug release mechanisms, for example from diffusion to erosion-dominated release when the pH conditions reduce drug solubility (Timmins et al. 1997; Siepmann & Peppas 2001; Pygall et al. 2009; Pygall et al. 2010). This potential limitation of hydrophilic matrix formulations may be mitigated by utilizing buffering excipients to modify the microenvironmental pH within the dosage form (Gabr 1992; Espinoza 2000; Streubel et al. 2000; Nie et al. 2004; Kranz et al. 2005; Varma et al. 2005; Siepe et al. 2006; Tatavarti & Hoag 2006; Pygall et al. 2009; Bassi & Kaur 2010; Pygall et al. 2010; Nicholson et al. 2012).

The primary aim of the buffer addition is to maintain the pharmaceutical active in an ionized state throughout the gel layer and hence facilitate diffusion-based drug liberation, irrespective of the pH environment presented external to the dosage form. There are several literature examples in which the release of weakly basic drugs has been improved by the incorporation of organic acids, or acid group-substituted polymers (Gabr 1992; Timmins et al. 1997; Streubel et al. 2000; Varma et al. 2005; Siepe et al. 2006; Nicholson et al. 2012). However, there are fewer reports of potential pH-dependent drug release mitigation strategies for hydrophilic matrices containing acidic drugs (Fuder et al. 1997; Rao et al. 2003; Riis et al. 2007; Pygall et al. 2009; Pygall et al. 2010).

To overcome the observed pH-dependent dissolution of commercially available extended release formulations of divalproex sodium, the excipient Fujicalin (a proprietary form of processed dibasic calcium phosphate anhydrous) was added as a non-polymeric potential alkalizing agent. It was shown to have some capacity for affecting the pH when added to 0.1 N hydrochloric acid, but its weak buffering effect meant it was of limited utility in providing pH-independent drug release of the compound studied. Alternate approaches using aminoalkyl methacrylate copolymers were more successful (Rao et al. 2003). A previous study from our group has shown how tromethamine [tris(hydroxylmethyl) aminomethane, THAM, TRIS and trometamol] can be used as successful buffering agent for a weak acid drug, felbinac (Pygall et al. 2010). In HPMC hydrophilic matrices, incorporated excipients and drugs can modify drug release kinetics by influencing the hydration behavior of the polymer (Maderuelo et al. 2011). For example, an excipient that retards the rate of polymer swelling and the formation of the gel layer can result in more extensive penetration of liquid into the matrix core and hence a shorter extended release (Bajwa et al. 2006; Pygall et al. 2009; Williams et al. 2009).

Incompatibilities between HPMC and other ingredients are not uncommon and a previous study has illustrated how high levels of trisodium citrate can markedly accelerate drug release by suppressing gel layer development (Pygall et al. 2009) This is consistent with the known effects of multivalent salts (Mitchell et al. 1990; Khan et al. 2013) which disrupt the molecular hydration sheath of the polymer, promote hydrophobic interactions and thereby retard polymer swelling and gel layer formation (Bajwa et al. 2006). There is also evidence that certain drugs can influence the hydration of HPMC and similar cellulose ether polymers. These effects can be detected by their (i) raising or (ii) lowering of the HPMC sol: gel transition temperature of HPMC and have been attributed respectively, to the (i) solubilization of methoxyl regions and (ii) Hofmeister-like disruption of the polymer hydration sheath (Liu et al. 2008).

Examples of drugs exhibiting these effects include tetracycline (Mitchell et al. 1990), propranolol (Mitchell et al. 1991), diclofenac (Rajabi-Siahboomi et al. 1993), ibuprofen (Ridell et al. 1999) and nicotinamide (Hino & Ford 2001). There has also been an additional study that has explored the impact of substituted phenols, modeling the key moieties of several drug molecules, on HPMC phase behavior (Banks et al. 2014). Several of these interacting drugs are weak acids and it is of interest to understand how adding a buffering agent to the matrix will influence the release properties of a matrix where the drug can influence gel layer formation. Increasing drug solubility within the hydrated matrix would facilitate pH-independent diffusion-based release, but increasing the drug concentration in the gel layer might result in significant effects on the polymer hydration and so compromise the extended release properties of the matrix.

A comparison of tromethamine with sodium citrate as internal buffering agents for HPMC (4000 cps) 2208 and 2910 matrices containing felbinac, a weak acid drug which exhibits pH-dependent solubility showed how drug release, in both pH 1.2 and 7.5 media, was accelerated by both buffers. It was confirmed that felbinac had no significant influence on polymer hydration, so observed effects on polymer hydration were due to the buffer employed. Tromethamine-buffered matrices provided extended, diffusionbased release kinetics, without loss of matrix integrity, including at high matrix buffer content (Pygall et al. 2010). Drug release kinetics appeared to be independent of media pH. In contrast to trisodium citrate, tromethamine did not depress the solgel transition temperature or suppress HPMC particle swelling, and had minimal effects on gel layer formation. Measurements of internal gel layer pH showed that both buffers produced a rapid alkalization of the gel layer which was progressively lost. However, tromethamine provided a higher internal pH and a greater longevity of pH modification. Based on these findings, tromethamine offers a useful buffering option for weak acid drugs in HPMC-based matrix systems.

Materials

Hypromellose USP 2910 4000 cps (Methocel E4M HPMC CR premium EP) and Hypromellose USP 2208 4000 cps (Methocel K4M HPMC CR premium EP) were kind gifts from Colorcon Ltd (Orpington, Kent, UK). Flurbiprofen and tromethamine were obtained from Sigma-Aldrich (Poole, Dorset) and were 98.5% pure. Compression grade dextrose was a gift from Cerestar (Manchester, UK). Magnesium stearate was obtained from BDH Laboratory Supplies (Dorset, UK). Water used for solution preparation was Maxima HPLC grade (USF Elga, Buckinghamshire, UK) with a maximum conductance of 18 MX cm.

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Samuel Pygall, Sarah Kujawinski, Peter Timmins & Colin Melia (2018) Extended release of flurbiprofen from tromethamine-buffered HPMC hydrophilic matrix tablets, Pharmaceutical Development and Technology, 23:9, 874-881,
https://doi.org/10.1080/10837450.2017.1301470