Effects of polyvinylpyrrolidone and poly (ethylene glycol) on preparation of ibuprofen pharmaceutical cocrystal

In this study, we investigated the effects of polymers on the pharmaceutical cocrystal formation process. Ibuprofen (IBU) was selected as the active pharmaceutical ingredient (API), nicotinamide (NIC) and saccharin (SAC) as the cocrystal coformer (CCF), ethanol/water as the solvent, polyvinylpyrrolidone (PVP) and poly (ethylene glycol) (PEG) as the representative polymers. We prepared IBU-NIC and IBU-SAC cocrystals in ethanol-water cosolvent in the absence or presence of polymers.

Cocrystal screening products were characterized by FTIR, DSC, PXRD, and HPLC. The results showed that the mixture of IBU and IBU-NIC cocrystal can be prepared in ethanol-water cosolvent without polymers. The addition of PVP facilitates the formation of pure IBU-NIC cocrystal; however, no cocrystal was formed in PEG solutions. SAC could not cocrystallize with IBU in the ethanol-water solvent in the absence of polymers. Neither PVP nor PEG could facilitate the formation of the IBU-SAC cocrystal.

Introduction

A pharmaceutical cocrystal is composed of one active pharmaceutical ingredient (API) and one coformer. As a new class of solid drugs, a pharmaceutical cocrystal can improve the physicochemical properties of poorly water-soluble drugs (Aakeröy and Salmon, 2005; Shiraki et al., 2008; Qiao et al., 2011). Ibuprofen (IBU), with the chemical name (R/S)-2-(4-isobutylphenyl) propanoic acid (Figure 1), is a non-steroidal anti-inflammatory drug (NSAID) that is widely used for its anti-inflammatory, analgesic, and antipyretic properties in treating inflammation, pain, and fever(Chow et al., 2012). However, as a class II drug under the Biopharmaceutical Classification System (BCS), IBU shows high permeability but poor aqueous solubility which limits its bioavailability.

To improve the solubility of IBU, the pharmaceutical cocrystal method was applied to prepare IBU cocrystals. The most studied IBU cocrystal was made with coformer nicotinamide (NIC, Figure 1) at a molar ratio of 1:1. Researchers have successfully synthesized IBU-NIC cocrystals using the solution method (Berry et al., 2008). However, the pure IBU-NIC cocrystal product cannot be easily obtained in single kinds of pure solvent because the two cocrystal components have nonequivalent solubility in the same solvent, which may result in the crystallization of a single reactant or a mixture of individual reactant and cocrystal (Qiao et al., 2011; Chow et al., 2012). Several approaches have been investigated to solve this problem, such as the reaction cocrystallization (RC) approach or using cosolvents (Rager and Hilfiker, 2010; Sun et al., 2015). The RC method is more difficult to operate and the solvent species and the volume ratio need to be identified and optimized by performing many experiments.

Surfactants or polymers can impart thermodynamic stability to cocrystals, and hence inhibit solution-mediated phase transformation (SMPT) of cocrystals. SMPT is caused by a rapid dissociation of the cocrystal to API and coformer in solution, and consequently, the precipitation of a single API solid is caused by supersaturation (Huang and Rodríguez-Hornedo, 2011; Li et al., 2013; Alhalaweh et al., 2014; Guo et al., 2016). Thus, cocrystal preparation via the solution method and cocrystal dissolution can be considered to be two directions of the complex process of API and coformer. Since polymers can impart stability to cocrystals during their dissolution by maintaining supersaturation of the cocrystal components, the polymer might have a positive role in cocrystal preparation. The addition of a proper polymer can help to obtain an equivalent concentration of two components, which is helpful for cocrystal formation with a 1:1 molecular ratio.

In this study, the effects of polymers on cocrystal formation were investigated. Polyvinylpyrrolidone and poly(ethylene glycol) (molecular structures shown in Figure 1) were selected as representative polymers. IBU was selected as the API; the IBU-NIC cocrystal formation process in solution was further investigated in the presence of polymers. Saccharin (SAC, Figure 1) is widely used in pharmaceutical cocrystal research; several pharmaceutical cocrystals have been developed using SAC as the coformer (Basavoju et al., 2008; Alhalaweh et al., 2012; Lee et al., 2015; Qiu and Li, 2015). SAC and NIC have similar structures, which contain an amide group and an aromatic ring; thus, it was also selected as the coformer in this study for cocrystallization with IBU.

SAC can cocrystallize with IBU through the wet grinding method (Hashib et al., 2015); however, there is no reference regarding the successful formation of the IBU-SAC cocrystal through the solution method. In this study, we prepared IBU-NIC and IBU-SAC cocrystals in ethanol-water cosolvent in the absence or presence of polymers. The cocrystal screening products were characterized by FTIR, DSC, and PXRD. The solubility of the successfully prepared pure cocrystal products was determined by HPLC and compared to pure API. The effects of polymers on the IBU cocrystal formation process have been discussed.

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Materials

Ibuprofen (IBU, ≥98% purity) was obtained from Jianglai Reagent Co., Ltd. (Shanghai, China) and dried for 12 h at 40 °C before use. Nicotinamide (NIC, ≥99% purity) and saccharin (SAC, ≥98% purity) were obtained from Aladdin Industrial Co. (Shanghai, China) and used as received. Polyvinylpyrrolidone K30 (PVP), poly (ethylene glycol) (PEG, Mn = 1 kDa and PDI = 1.07), methanol (99.9% purity), and potassium dihydrogen phosphate (KH₂PO₄, ≥98% purity) were purchased from Tianjin Guangfu Fine Chemical Research Institute (Tianjin, China) and used as received. Ethanol from Yongda Chemical Reagent Co., Ltd. (Tianjin, China) was of analytical grade and used as received. Potassium bromide (KBr, ≥99% purity) purchased from Yongda Chemical Reagent Co., Ltd. (Tianjin, China) was dried for 24 h at 50 °C and finely ground immediately before use.

Xintong YangYang ChenNing Qiao, Effects of polyvinylpyrrolidone and poly (ethylene glycol) on preparation of ibuprofen pharmaceutical cocrystal, https://doi.org/10.1590/s2175-97902022e18768

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