Improvement in physicochemical properties of ezetimibe using a crystal engineering technique Snehal P. Mulye, Samina A. Jamadar, Poonam S. Karekar, Yogesh V. Pore ⁎, Shashikant C. Dhawale Department of Pharmaceutical Chemistry, Government College of Pharmacy, Karad, Maharashtra, 415 124, India abstract article info Article history: Received 5 February 2011 Received in revised form 16 November 2011 Accepted 11 February 2012 Available online 21 February 2012 Keywords: Ezetimibe Benzoic acid Salicylic acid Crystal engineering Dissolution Physicochemical properties In an attempt to improve the physicochemical properties of poorly aqueous soluble ezetimibe, its pharmaceutical co-crystals were successfully engineered with different crystal forming agents; benzoic acid and salicylic acid in equimolar ratios by solution crystallization technique. The physicochemical properties of pure ezetimibe and corresponding co-crystals were accessed in terms of phase solubility studies, melting point, flowability, drug content uniformity, saturation solubility and dissolution studies. Fourier transformation infrared spectroscopy (FTIR), X-ray powder diffractometry (XRPD) and scanning electron microscopy (SEM) techniques were employed to investigate the hydrogen bonding interaction, crystallinity and surface morphological characteris- tics of prepared co-crystals respectively. The results indicated a marked improvement in flow properties and saturation solubility of co-crystals (p b 0.001). Further, in case of dissolution experiments, both the co-crystals showed a significant enhancement (DE 5 and DE 20 , p b 0.001) in the dissolution profiles as compared to pure ezetimibe. It could be concluded that substantial manipulation of physicochemical properties of ezetimibe could be possible with benzoic acid and salicylic acid using crystal engineering technique. © 2012 Elsevier B.V. All rights reserved. 1. Introduction Crystal engineering of active pharmaceutical ingredients (APIs) has become a subject of considerable interest for formulation experts in recent years. The crystalline form of API is generally being preferred in a pharmaceutical industry for delivery because of the inherent and ther- modynamic stability of crystalline API [1–3]. However, crystalline API can exist in different polymorphic forms causing inadequate solubility and dissolution characteristics resulting in limited oral bioavailability, especially for poorly water-soluble compounds [4,5]. Various strategies have been adopted to improve the aqueous solubility of poorly water- soluble APIs including micronization to produce increased surface area for dissolution [6], use of lipidic systems for lipophilic drugs [7], use of salt forms and surfactants [8,9], solubilization of drugs in co-solvents [10], inclusion complexation with cyclodextrins [11] and solid disper- sion [12–14]. Recently crystal engineering technique to produce phar- maceutical co-crystals has been widely exploited for improving the physicochemical properties of APIs [15–19]. A pharmaceutical co-crystal is a single crystalline complex incorpo- rating an API and the other a co-crystal former (may be an excipient or another drug) bound together in the crystal lattice through noncovalent interactions (primarily hydrogen bonding) [20–22]. It is an alternative approach to manipulate physical and technical properties of drugs such as solubility, dissolution rate, stability, and compressibility and to improve overall performance of APIs without affecting their pharmaco- logical properties [23–25]. The key benefits associated with co-crystals are stability, theoretical capability of all types of drug molecules (including weakly ionizable and non-ionizable) to form co-crystals and the existence of numerous potential counter-molecules, including food additives, preservatives, pharmaceutical excipients as well as other APIs, for co-crystal synthesis [5,20,21]. Considering these advantages, it was thought worthwhile to exploit this technique for the manipulation of physicochemical properties of poorly water-soluble ezetimibe in this article. Further, as numbers of carboxylic acids have been demonstrated to act as crystal forming agents [26,27,15,21], benzoic acid and salicylic acid have been attempted for this purpose. Ezetimibe (Fig. 1), selected in the present work is chemically 1-(4- fluorophenyl)-3(R)-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4(S)-(4- hydroxyphenyl)-2-azetidinone belonging to the lipid lowering agents category. It inhibits the intestinal absorption of cholesterol [28]. Ezeti- mibe is a white crystalline powder having poor aqueous solubility characteristics [29] which leads to its limited dissolution resulting in poor bioavailability (35–65%). The dissolution is a rate limiting step for the absorption of poorly water-soluble drugs [30,31] and hence drugs showing limited dissolution give poor therapeutic outcome as a result of poor oral bioavailability. Improving the aqueous solubility/dissolution can overcome this problem. Several papers have reported the improve- ment in solubility/dissolution properties of ezetimibe by complexation with cyclodextrin [32], solid dispersion [33] and preparing liquid–solid compacts [34]. Powder Technology 222 (2012) 131–138 ⁎ Corresponding author. Tel.: + 91 09890237303, + 91 02164 274133; fax: + 91 02164 271196. E-mail address: dryogeshpore@rediffmail.com (Y.V. Pore). 0032-5910/$ – see front matter © 2012 Elsevier B.V. All rights reserved. doi:10.1016/j.powtec.2012.02.020 Contents lists available at SciVerse ScienceDirect Powder Technology journal homepage: www.elsevier.com/locate/powtec