Novel Co-crystals and Eutectics of Febuxostat: Characterization, Mechanism of Formation, and Improved Dissolution.

Co-crystallization studies were undertaken to improve the solubility of a highly water-insoluble drug febuxostat (FXT), used in the treatment of gout and hyperuricemia. The selection of co-crystal former (CCF) molecules such as 1-hydroxy 2-naphthoic acid (1H-2NPH), 4-hydroxy benzoic acid (4-HBA), salicylic acid (SAC), 5-nitro isophthalic acid (5-NPH), isonicotinamide (ISNCT), and picolinamide (PICO) was based on the presence of complementary functional groups capable of forming hydrogen bond and the ΔpKa difference between FXT and CCF. A liquid-assisted grinding (LAG) method was successfully employed for the rapid screening of various pharmaceutical adducts. These adducts were characterized based on their unique thermal (differential scanning calorimetry) and spectroscopic (Fourier transform infrared and Raman spectroscopy) profiles. Binary phase diagrams (BPD) were plotted to establish a relationship between the thermal events and adduct formed. Powder X-ray diffraction (PXRD) studies were carried out to confirm the formation of eutectic/co-crystal. Thermogravimetric analysis (TGA) was also performed for the novel co-crystals obtained. The propensity for strong homo-synthons over weak hetero-synthons and strong hetero-synthons over weak homo-synthons during supramolecular growth resulted in the formation of eutectics and co-crystals respectively. FXT:1H-2NPH (1), FXT:4-HBA (1), FXT:SAC (1, 2), and FXT:5-NPH (2-1) gave rise to pure eutectic systems, while FXT:ISNCT (2-1) and FXT:PICO (1) gave rise to novel co-crystals with characteristic DSC heating curves and PXRD pattern. Additionally, the impact of microenvironmental pH and microspeciation profile on the improved dissolution profile of the co-crystals was discussed. Graphical Abstract.

The Role of Cocrystallization-Mediated Altered Crystallographic Properties on the Tabletability of Rivaroxaban and Malonic Acid.

The present work aims to understand the crystallographic basis of the mechanical behavior of rivaroxaban-malonic acid cocrystal (RIV-MAL Co) in comparison to its parent constituents, i.e., rivaroxaban (RIV) and malonic acid (MAL). The mechanical behavior was evaluated at the bulk level by performing "out of die" bulk compaction and at the particle level by nanoindentation. The tabletability order for the three solids was MAL < RIV < RIV-MAL Co. MAL demonstrated "lower" tabletability because of its lower plasticity, despite it having reasonably good bonding strength (BS). The absence of a slip plane and "intermediate" BS contributed to this behavior. The "intermediate" tabletability of RIV was primarily attributed to the differential surface topologies of the slip planes. The presence of a primary slip plane (0 1 1) with flat-layered topology can favor the plastic deformation of RIV, whereas the corrugated topology of secondary slip planes (1 0 ) could adversely affect the plasticity. In addition, the higher elastic recovery of RIV crystal also contributed to its tabletability. The significantly "higher" tabletability of RIV-MAL Co among the three molecular solids was the result of its higher plasticity and BS. Flat-layered topology slip across the (0 0 1) plane, the higher degree of intermolecular interactions, and the larger separation between adjacent crystallographic layers contributed to improved mechanical behavior of RIV-MAL Co. Interestingly, a particle level deformation parameter H/E (i.e., ratio of mechanical hardness H to elastic modulus E) was found to inversely correlate with a bulk level deformation parameter σ0 (i.e., tensile strength at zero porosity). The present study highlighted the role of cocrystal crystallographic properties in improving the tabletability of materials.

Molecular Basis of Water Sorption Behavior of Rivaroxaban-Malonic Acid Cocrystal.

The present study aims to investigate the molecular basis of water sorption behavior of rivaroxaban-malonic acid cocrystal (RIV-MAL). It was hypothesized, that the amount of water sorbed by a crystalline solid is governed by the surface molecular environment of different crystal facets and their relative abundance to crystal surface. Water sorption behavior was measured using a dynamic vapor sorption analyzer. The surface molecular environment of different crystal facets and their relative contribution were determined using single crystal structure evaluation and face indexation analysis, respectively. The surface area-normalized water sorption for rivaroxaban (RIV), malonic acid (MAL), and RIV-MAL at 90% RH/25 °C was 0.28, 92.6, and 11.1% w/w, respectively. The crystal surface of MAL had a larger contribution (58.7%) of hydrophilic (Hphi) functional groups and showed the "highest" water sorption (92.6% w/w). On the contrary, RIV had a larger surface contribution (65.2%) of hydrophobic (Hpho) functional groups, and the smaller contribution (34.8%) of Hphi+Hpho groups exhibited the "lowest" water sorption (0.28% w/w). The "intermediate" water sorption (11.1% w/w) by RIV-MAL, as compared to RIV, was ascribed to the increased surface contribution of Hphi+Hpho groups (from 34.8 to 42.1%) and reduced hydrophobic surface contribution (from 65.2 to 57.9%). However, the significantly higher water gained (∼39-fold) by the cocrystal as compared to RIV, despite the nominal change in the surface contributions, was further attributed to the relatively stronger hydrogen bonding interactions between the surface-exposed carboxyl groups and water molecules. The study highlights that the amount of water sorbed by the cocrystal is governed by the surface molecular environment and additionally by the strength of hydrogen bonding. This investigation has implications on designing materials with a desired moisture-sorption property.

Influence of Drug-Polymer Interactions on Dissolution of Thermodynamically Highly Unstable Cocrystal.

Solubility advantage of thermodynamically highly unstable cocrystals, which undergo solution-mediated phase transformation (SMPT) in less than 1 min, does not translate to enhanced dissolution. The present study was aimed to understand the impact of polymeric additives on dissolution of thermodynamically highly unstable cocrystal with specific emphasis on influence of drug-polymer interactions. Exemestane-maleic acid was selected as a model cocrystal with SMPT time of <30 s and eutectic constant ( Keu) of 75475. Hydroxypropylcellulose (HPC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), and polyvinylpyrrolidone (PVP) were selected as polymers for a dissolution study based on measurement of induction time using precipitation study. In the presence of 0.2% w/v of HPC, the cocrystal showed significantly higher drug release (∼3-fold) as compared with the cocrystal in the absence of predissolved polymers. Differential dissolution profiles of the cocrystal were observed with each polymer and the order of increasing dissolution rate was found to be HPC ≈ HPMCAS > PVP. The molecular basis of the differential dissolution performance was investigated using infrared spectroscopy, solution-state nuclear magnetic resonance spectroscopy, and nuclear Overhauser effect spectroscopy (NOESY). The polymers with stronger interactions with drug in the cocrystal (HPMCAS and HPC) displayed higher dissolution rate as compared with that of no intermolecular interaction (PVP). The study also highlighted that, despite no influence of the polymers on the cocrystal SMPT, dissolution enhancement was achieved. This was attributed to small-sized drug crystals (1-3 µm) generated from the supersaturation-mediated crystallization and improved solvation due to drug-polymer interactions. These findings have implications on development of drug products using thermodynamically unstable cocrystals.

Codelivery of benzoyl peroxide & adapalene using modified liposomal gel for improved acne therapy.

AIM: Current study investigates therapeutic efficacy and tolerability of benzoyl peroxide (BPO)- and adapalene (AD)-loaded modified liposomal gel (BPO-AD-mLipo gel) for improved acne therapy. MATERIALS & METHOD: BPO-AD-mLipo were optimized and loaded in Carbopol gel. Both BPO-AD-mLipo and BPO-AD-mLipo-gel were extensively characterized for different quality attributes. Ex vivo dermal bioavailability, dermal distribution, in vivo anti-acne efficacy and skin irritation studies were performed and compared with marketed formulation (Epiduo®, Galderma Laboratories LP, TX, USA). RESULTS: BPO-AD-mLipo illustrated size 256.4 ± 9.3 nm with polydispersity index âˆ¼ 0.2. Significantly enhanced dermal bioavailability (AD-2.1, 5.4; BPO-3.0, 7.83-fold) and reduction in skin irritation and papule density in animal model were observed with BPO-AD-mLipo-gel as compared with free drugs and Epiduo, respectively. CONCLUSION: BPO-AD-mLipo gel provides effective and safer alternative approach for codelivery of anti-acne drugs.

Challenges in Translational Development of Pharmaceutical Cocrystals.

The last 2 decades have witnessed increased research in the area of cocrystals resulting in deeper scientific understanding, increase in intellectual property landscape, and evolution in the regulatory environment. Pharmaceutical cocrystals have received significant attention as a new solid form on account of their ability to modulate poor physicochemical properties of drug molecules. However, pharmaceutical development of cocrystals could be challenging, thus limiting their translation into viable drug products. In the present commentary, the role of cocrystals in the modulation of material properties and challenges involved in the pharmaceutical development of cocrystals have been discussed. The major hurdles encountered in the development of cocrystals such as safety of coformers, unpredictable performance during dissolution and solubility in different media, difficulties in establishing in vitro-in vivo correlation, and polymorphism have been extensively discussed. The influence of selecting appropriate formulation and process design on these challenges has been discussed. Finally, a brief outline of cocrystals that are undergoing clinical development has also been presented.