Page 1 of 45 Molecular Pharmaceutics 1 2 3 4 5 6 7 Investigating the Influence of Polymers on 8 9 10 11 12 Supersaturated Flufenamic Acid Cocrystal Solutions 13 14 15 16 1 1 2 2 1 17 Minshan Guo , Ke Wang , Noel Hamill , Keith Lorimer and Mingzhong Li * 18 19 20 1School of pharmacy, De Montfort University, Leicester, UK 21 22 23 2Almac Science, Seagoe Industrial Estate, Craigavon, UK 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 ACS Paragon Plus Environment 1 Molecular Pharmaceutics Page 2 of 45 1 2 3 4 5 6 7 Table of contents graphic 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 ACS Paragon Plus Environment 2 Page 3 of 45 Molecular Pharmaceutics 1 2 3 Abstract 4 5 6 7 The development of enabling formulations is a key stage when demonstrating the effectiveness 8 9 10 of pharmaceutical cocrystals to maximize the oral bioavailability for poorly water soluble drugs. 11 12 Inhibition of drug crystallization from a supersaturated cocrystal solution through a fundamental 13 14 understanding of the nucleation and crystal growth is important. In this study, the influence of 15 16 17 the three polymers of polyethylene glycol (PEG), polyvinylpyrrolidone (PVP) and a copolymer 18 19 of N-vinly-2-pyrrodidone (60%) and vinyl acetate (40%) (PVP-VA) on the flufenamic acid 20 21 22 (FFA) crystallization from three different supersaturated solutions of the pure FFA and two 23 24 cocrystals of FFA-NIC CO and FFA-TP CO has been investigated by measuring nucleation 25 26 induction times and desupersaturation rates in the presence and absence of seed crystals. It was 27 28 29 found that the competition of intermolecular hydrogen bonding among drug/coformer, 30 31 drug/polymer and coformer/polymer was a key factor responsible for maintaining 32 33 supersaturation through nucleation inhibition and crystal growth modification in a cocrystal 34 35 36 solution. The supersaturated cocrystal solutions with predissolved PEG demonstrated more 37 38 effective stabilization in comparison to the pure FFA in the presence of the same polymer. In 39 40 contrast, neither of the two cocrystal solutions, in the presence of PVP or PVP-VA, exhibited a 41 42 43 better performance than the pure FFA with the same predissolved polymer. The study suggests 44 45 that the selection of a polymeric excipient in a cocrystal formulation should not be solely 46 47 48 dependent on the interplay of the parent drug and polymer without considering the coformer 49 50 effects. 51 52 53 54 KeyWords: Cocrystal; polymers; Flufenamic Acid; crystal growth; nucleation; supersaturation. 55 56 57 58 59 60 ACS Paragon Plus Environment 3 Molecular Pharmaceutics Page 4 of 45 1 2 3 4 Introduction 5 Development of supersaturating drug delivery systems to enhance oral bioavailability of poorly 6 7 1 8 water soluble drugs has been of interest for many decades . In these systems, two essential steps 9 10 need to be considered: the drug in a high energy form, e.g. amorphous forms, crystalline salts or 11 12 cocrystals, should dissolve rapidly to generate a high concentration above the saturation 13 14 15 solubility and then this supersaturated solution must be maintained for a reasonable period to 16 17 allow for significant absorption and eventually sufficient bioavailability. This has been referred 18 19 to as a “spring and parachute” approach 2. As a supersaturated drug solution is 20 21 22 thermodynamically unstable and has the tendency to return to the equilibrium state through drug 23 24 crystallization, extensive work has been carried out to delay the drug crystallization by inclusion 25 26 of different excipients as effective crystallization inhibitors in formulations 3. For example, 27 28 29 significant progress has been made in amorphous solid dispersion formations by using polymeric 30 31 crystallization inhibitors to maintain the solid drug in an amorphous state and also maintain the 32 33 4, 5 34 drug supersaturation after dissolution . It has been found that inhibition of the drug 35 36 crystallization is a result of the polymers interfering in the nucleation and/or crystal growth 37 38 stages of the more stable phase, through physical or chemical interactions between the drug and 39 40 41 polymer excipients, such as; solution viscosity enhancement, non-specific hydrophobic drug- 42 43 polymer interactions and specific drug-polymer intermolecular interactions through hydrogen 44 45 bonding 6-12. 46 47 48 Compared with amorphous solid forms, the crystalline forms of the drug substances are 49 50 generally preferred in a formulation because of their thermodynamic stability and purity. 51 52 Pharmaceutical cocrystals have therefore attracted significant attention over the last decade due 53 54 55 to their ability to modulate the physicochemical properties of a drug compound to overcome any 56 57 solubility limited bioavailability problem 13-16. Similar to the amorphous solid forms, those 58 59 60 ACS Paragon Plus Environment 4 Page 5 of 45 Molecular Pharmaceutics 1 2 3 cocrystals with improved solubility and dissolution rates become thermodynamically unstable 4 5 6 once dissolved due to supersaturation of the drug . This results in precipitation of stable solid 7 8 phases of the parent drugs and reduction of the solubility advantage of the cocrystal 17-19. In order 9 10 to achieve the full potential of cocrystals, rational strategies are required that identify the 11 12 20- 13 appropriate crystallization inhibitors of polymers and/or surfactants in cocrystal formulations 14 15 25. In comparison with the amorphous solid dispersion systems, in which the supersaturated 16 17 18 solution behavior is determined by the ternary drug/polymer/solvent interaction, the complexity 19 20 of a cocrystal supersaturated solution increases considerably due to inclusion of an additional 21 22 component of a coformer. This can interfere with the drug molecule, polymeric excipients, 23 24 25 and/or solvent, resulting in alteration of the inhibition ability of the polymers on the drug. It is 26 27 not surprising that inclusions of excipients of polymers and surfactants in the indomethacin or 28 29 carbamazepine cocrystal formulations have not shown effectiveness in capturing the enhanced 30 31 21, 24 32 solubility advantage . Although research has demonstrated that a combination of a cocrystal 33 34 of celecoxib-nicotinamide or danazol-vanillin with both a polymer and surfactant can provide an 35 36 37 enhanced dissolution rate and a high oral bioavailability, there is no mechanistic understanding 38 22, 23 39 of how these additives interact with the drug molecules in solution . Therefore, it is of huge 40 41 importance to investigate the role of polymeric excipients as potential crystallization inhibitors 42 43 44 for rational design of cocrystal formulation systems. 45 46 In this work, for the first time, a systematic investigation was conducted to explore the impact 47 48 of different polymeric additives in cocrystal formulations to elucidate the molecular mechanism 49 50 51 of polymer/drug/coformer interactions that affect the kinetics of nucleation and growth of the 52 53 parent drug. In the study, Flufenamic acid form I (FFA I) was selected as a parent model drug 54 55 along with two coformers of Nicotinamide (NIC) and Theophylline (TP). This was due to their 56 57 58 59 60 ACS Paragon Plus Environment 5 Molecular Pharmaceutics Page 6 of 45 1 2 3 ability to form FFA-NIC cocrystals (FFA-NIC CO) and FFA-TP cocrystals (FFA-TP CO), both 4 5 26, 27 6 of which display different physicochemical properties . FFA, a nonsteroidal anti- 7 8 inflammatory drug (NSAID), has the problem of low bioavailability after oral administration due 9 10 to its low solubility 26-28. Among its nine reported polymorphs, FFA I (white color) and FFA III 11 12 29 13 (yellow color) have been used in the commercial solid dosage forms . Three chemically diverse 14 15 polymers including polyethylene glycol (PEG), polyvinylpyrrolidone (PVP) and copolymer of 16 17 18 vinyl pyrrolidone/vinyl acetate (PVP-VA) were selected because they have been widely used as 19 3, 30, 31 20 crystallization inhibitors in other supersaturating drug delivery systems . Among these 21 22 polymers, PEG is the most hydrophilic, containing a high percentage of hydrogen donors 32. In 23 24 25 comparison to PVP, more hydrophobic PVP-VA, containing 40% acetate side chains, was used 26 27 to investigate the specific intermolecular interaction with the drug and/or coformers. The 28 29 solubility parameter was calculated for comparison of the hydrophobicity of the model drug, 30 31 32 coformers and polymers. Chemical structures of the model drug, coformers and monomer units 33 34 of the polymers are shown in Table 1. 35 36 37 Equilibrium solubility tests were first carried out to evaluate the potential role of polymers in 38 39 changing the apparent FFA solubility in solution. A solvent shift method was then used to 40 41 generate an initial FFA supersaturation condition to study crystallization kinetics of both 42 43 33 44 nucleation and growth . Induction time determined by polarized light microscopy was used to 45 46 quantify the drug nucleation from a supersaturated solution in the absence and presence of 47 48 different pre-dissolved polymers. The impact of different polymers on growth was characterized 49 50 51 by measuring desupersaturation curves in the presence of the seeds of the pure FFA I crystals.