Influence of the microwave technology on solid dispersions of mefenamic acid and flufenamic acid

RESEARCH ARTICLE Influence of the microwave technology on solid dispersions of mefenamic acid and flufenamic acid Sultan Alshehri1*, Faiyaz Shakeel1, Mohamed Ibrahim1, Ehab Elzayat1, Mohammad Altamimi1, Gamal Shazly1,2, Kazi Mohsin1, Musaed Alkholief1, Bader Alsulays3, Abdullah Alshetaili3, Abdulaziz Alshahrani1, Bander Almalki1, Fars Alanazi1 1 Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia, 2 Department of Pharmaceutics, Faculty of Pharmacy, Assiut University, Assiut, Egypt, 3 Department of Pharmaceutics, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj, Saudi Arabia * a1111111111 a1111111111 a1111111111 a1111111111 a1111111111 OPEN ACCESS Citation: Alshehri S, Shakeel F, Ibrahim M, Elzayat E, Altamimi M, Shazly G, et al. (2017) Influence of the microwave technology on solid dispersions of mefenamic acid and flufenamic acid. PLoS ONE 12 (7): e0182011. https://doi.org/10.1371/journal. pone.0182011 Editor: Etsuro Ito, Waseda University, JAPAN Received: June 16, 2017 Accepted: July 11, 2017 Published: July 31, 2017 Copyright: © 2017 Alshehri et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Abstract The present studies were undertaken to develop solvent-free solid dispersions (SDs) for poorly soluble anti-inflammatory drugs mefenamic acid (MA) and flufenamic acid (FFA) in order to enhance their in vitro dissolution rate and in vivo anti-inflammatory effects. The SDs of MA and FFA were prepared using microwaves irradiation (MW) technique. Different carriers such as Pluronic F127® (PL), Eudragit EPO® (EPO), polyethylene glycol 4000 (PEG 4000) and Gelucire 50/13 (GLU) were used for the preparation of SDs. Prepared MW irradiated SDs were characterized physicochemically using differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), Fourier transform infra-red (FT-IR) spectroscopy, powder X-ray diffraction (PXRD) and scanning electron microscopy (SEM). The physicochemical characteristics and drug release profile of SDs were compared with pure drugs. The results of DSC, TGA, FT-IR, PXRD and SEM showed that SDs were successfully prepared. In vitro dissolution rate of MA and FFA was remarkably enhanced by SDs in comparison with pure MA and FFA. The SDs of MA and FFA prepared using PEG 400 showed higher drug release profile in comparison with those prepared using PL, EPO or GLU. The dissolution efficiency for MA-PEG SD and FFA-PEG SD was obtained as 61.40 and 59.18%, respectively. Optimized SDs were also evaluated for in vivo anti-inflammatory effects in male Wistar rats. The results showed significant % inhibition by MA-PEG (87.74% after 4 h) and FFA-PEG SDs (81.76% after 4 h) in comparison with pure MA (68.09% after 4 h) and pure FFA (55.27% after 4 h) (P<0.05). These results suggested that MW irradiated SDs of MA and FFA could be successfully used for the enhancement of in vitro dissolution rate and in vivo therapeutic efficacy of both drugs. Data Availability Statement: All the data are within the paper. Funding: This work was supported by Deanship of Scientific Research, King Saud University. Competing interests: The authors have declared that no competing interests exist. PLOS ONE | https://doi.org/10.1371/journal.pone.0182011 July 31, 2017 1 / 18 Influence of the microwave technology on solid dispersions Introduction Solubility of drug molecules affects the in vitro dissolution rate and consequently in vivo absorption and bioavailability of the drugs. Thus, the drug solubility plays an important role in the therapeutic achievement of a drug. Moreover, the preferred drug concentration in systemic circulation and the pharmacological response depend on the drug solubility [1, 2]. The number of limitations such as need of high doses, increase administration frequencies and increase side effects may result from poorly soluble drugs [3]. The majority of the recently formulated drugs exhibit low bioavailability due to their poor aqueous solubility and dissolution rate [4]. The dissolution rate of poorly soluble drugs in the gastrointestinal (GI) fluids is the rate-limiting step for the absorption of drugs in systemic circulation. Thus, the solubility and dissolution rate of such drugs must be enhanced in order to enhance their bioavailability [5]. Improving the solubility of poorly soluble drugs leads to enhancement in the dissolution rate and drug release and consequently drug bioavailability [6]. Different techniques have been investigated in order to improve the solubility of poorly soluble drugs e.g. solubilization in surfactant system [7, 8], complexation [8], micronization [1], drug derivatization [9], solid dispersion [1–6], cosolvent technique [10], nanoparticles [11], nanoemulsions/self-nanoemulsifying drug delivery systems [12–14] and co-crystal technology etc. [15]. Microwave (MW) irradiation is relatively a novel method used for solubility and bioavailability enhancement of thermo-stable and drying materials [16, 17]. MW equipment depends on the use of the electromagnetic waves between the radio and infrared frequencies over the range of 0.3–300 GHz. These waves migrate within the materials, causing oscillation of the molecules and finally generating heat [18]. MW technique is different in comparison with conventional heating in which the surface of the material heats first and then the heat moves inward. In MW technique, the heat is generated inside the material and then passes to the entire volume with the constant heating rate [19]. MWs have the ability to penetrate any material leading to heat production everywhere in the material at the same time. This is due to the absorption of MW energy by the dipolar moment of the molecules converting it into the heat. There are several advantages of MW technology in comparison with other techniques such as energy saving, non-contact heating, quick start-up and stopping, low operating cost, portability of equipment and processes, the ability to treat waste in-situ, rapid volumetric heating and no overheating at the surface [20]. MW energy converts the crystalline form of the drug to the amorphous forms and hence improves drug dissolution rate which could results in enhanced drug bioavailability [16]. Mefenamic acid (MA) and flufenamic acid (FFA) are non-steroidal anti-inflammatory drugs (NSAIDs) that are N-phenylanthranilic acid derivatives [21]. The molecular structures of MA and FFA are presented in Fig 1. These NSAIDs are potent analgesic, antipyretic and anti-inflammatory drugs which are being applied in the treatment of rheumatoid arthritis, osteoarthritis and other painful musculosketal conditions [21–23]. They have the capacity to inhibit cyclooxygenase and may antagonize the certain effects of prostaglandins [24]. They belong to clas (...truncated)