ABSTRACT
Famotidine (FMT) an anti-ulcer drug, recently being repurposed in COVID-19 treatment, suffers from poor aqueous solubility and restricted bioavailability (<40%). To conquer the limitations endured by this potent anti-ulcer agent, two novel 1:1 cocrystals of FMT, namely Famotidine-Sorbic Acid (FSOR) and Famotidine-Syringic Acid (FSY), were synthesized using the liquid-assisted grinding method and evaluated. Distinct DSC thermograms and PXRD patterns advocate the existence of a new crystalline form. The unique organization of the hydrogen-bonded network, in the prepared cocrystals, is inferred by variation in characteristic vibrational frequencies in FT-IR spectroscopic analysis and supported by crystal structure determination. FSOR cocrystallize in orthorhombic PNCB and FSY in triclinic P 1 crystal system. Further, a significant amplification in the solubility (9 to 5-fold) and dissolution (8 to 5-fold) of FMT in cocrystalline form, with simultaneous augmentation in peak plasma concentration (2 to 1.5-fold higher) and relative bioavailability (approx. 200% to 135%). This is associated with the remarkable increment in their anti-ulcer and anti-oxidant potential. Thus, the study illustrates that cocrystallization as a worthy approach in the efficient delivery of neutral compounds suffering from inadequate solubility crisis.
Subject(s)
Anti-Ulcer Agents , Biological Products , COVID-19 Drug Treatment , Antioxidants , Crystallization/methods , Famotidine , Humans , Hydrogen , Pharmaceutical Preparations , Solubility , Sorbic Acid , Spectroscopy, Fourier Transform InfraredABSTRACT
PURPOSE: Rebamipide (REB) a potent anti-ulcer agent, has not been exploited to its full potential, owing to it extremely poor solubility, leading to highly diminutive bioavailability (<10%). The purpose is to carry out its solid-state modification. METHOD: Cocrystallisation was done with three GRAS coformers namely citric acid (CA), 3,4-dihydroxybenzoic acid (DHBA) and oxalic acid (OXA) employing the liquid-assisted grinding method. Cocrystal formation was based upon amide-carboxyl and amide-hydroxyl supramolecular synthons. Characterization of novel cocrystals i.e. RCA, RDHBA and ROXA was carried out by DSC, PXRD and additionally by FT-IR spectroscopy. Chemical structures have been determined utilizing the PXRD pattern by Material Studio®. Furthermore, cocrystals were subjected to solubility and intrinsic dissolution rate (IDR) evaluation. Also, pharmacodynamic and pharmacokinetic studies were performed and compared with pure rebamipide. RESULT: The appearances of a single sharp melting endotherm in DSC, along with novel characteristic peaks in PXRD infer the existence of a new crystalline form. Shifting in characteristic vibrations in FT-IR spectroscopy supports the establishment of distinct hydrogen-bonded networks. Structural determination revealed that RCA crystallizes in 'Bb2b' space groups whereas RDHBA in 'P1' and ROXA crystallize out in the 'P-1' space group. All the cocrystals exhibited superior apparent solubility and almost 7-13 folds increase in IDR. Furthermore, 1.6-2.5 folds enhancement in relative bioavailability and remarkable amplification in anti-ulcer, anti-inflammatory and the antioxidant potential of these cocrystals were observed. CONCLUSION: The study ascertains the advantages of cocrystallization, with RCA showing greatest potential and suggests a viable alternative approach for improved formulation of rebamipide.
Subject(s)
Alanine/analogs & derivatives , Biological Products/chemistry , Chemical Engineering , Edema/drug therapy , Quinolones/chemistry , Stomach Ulcer/drug therapy , Alanine/administration & dosage , Alanine/chemistry , Alanine/pharmacokinetics , Animals , Biological Availability , Biological Products/pharmacokinetics , Carrageenan/administration & dosage , Carrageenan/immunology , Chemistry, Pharmaceutical/methods , Crystallization , Disease Models, Animal , Drug Compounding/methods , Edema/chemically induced , Edema/immunology , Humans , Hydrogen Bonding , Indomethacin , Male , Powder Diffraction , Quinolones/administration & dosage , Quinolones/pharmacokinetics , Rats , Spectroscopy, Fourier Transform Infrared , Stomach Ulcer/chemically inducedABSTRACT
The effectiveness of Diacerein as an anti-osteoarthritis drug is limited due to its acutely poor aqueous solubility and bioavailability. The present study demonstrates cocrystallization as a successful technique to improve the biopharmaceutical parameters of diacerein. Three cocrystals of diacerein were prepared by an eco-friendly technique with three suitable coformers namely isonicotinamide, nicotinamide, and theophylline. The formation of a new solid phase was inferred from the DSC thermograms and powder diffraction pattern and was supported by FTIR. The crystal structures of the cocrystals determined from the PXRD pattern using Material Studio software. Detailed analysis showed the formation of supramolecular hetero-synthons of complementary functional groups of the coformers with the carbonyl and carboxyl groups of diacerein. The structural conformation of the cocrystalline state was also provided by the shifts in the ssNMR pattern of the cocrystals. The three new cocrystals were found to have a relatively high solubility and intrinsic dissolution rate which showed remarkable improvement in anti-arthritic activity as compared to diacerein. Thus, proving cocrystallization to be a potential solution to the solubility limited bioavailability problems of diacerein.
