@article {42631, title = {Crystal engineering of a zwitterionic drug to neutral cocrystals: a general solution for floxacins}, journal = {Chemical Communications}, volume = {52}, year = {2016}, month = {SEP}, pages = {12610-12613}, abstract = {

The transformation of zwitterionic Sparfloxacin (SPX) to the neutral form is achieved by cocrystallization. Neutral forms of drugs are important for higher membrane permeability, while zwitterions are more soluble in water. The twin advantages of higher solubility/dissolution rate and good stability of neutral SPX are achieved in a molecular cocrystal compared to its zwitterionic SPX hydrate. The amine-phenol supra-molecular synthon drives cocrystal formation, with the paraben ester acting as a "proton migrator{\textquoteright}{\textquoteright} for the ionic to neutral transformation.

}, doi = {10.1039/c6cc06627e}, author = {Gunnam, Anilkumar and Suresh, Kuthuru and Ganduri, Ramesh and Nangia, Ashwini} } @article {45765, title = {Polymorphism, isostructurality and physicochemical properties of glibenclamide salts}, journal = {CrystEngComm}, volume = {19}, year = {2017}, month = {FEB }, pages = {918-929}, type = {Article}, abstract = {

Novel salts of glibenclamide (GBA), namely glibenclamide-sodium (GBA-Na), glibenclamide-potassium (GBA-K) and glibenclamide-ammonium (GBA-NH4) were crystallized under different conditions to obtain their polymorphs, and their aqueous solubility and hydration stability studies are reported. The GBA-Na salt is dimorphic (forms I and II)and also exists as hydrate GBA-Na-H2O (form III). The GBA-K salt exists in anhydrous and hydrate forms (GBA-K, forms I and II). Crystal structure analysis of GBA-Na forms I and II showed differences in geometry of the central metal atom and ligand orientation. This kind of polymorphism of sulfonyl urea salts appears to be novel in the Cambridge Structural Database (CSD). The iso-structurality of GBA-Na form I with GBA-NH4 and GBA-K form I salts is discussed. The potassium salts of GBA exhibited higher solubility compared to pure GBA. Specifically GBA-K salt forms I and II showed higher solubility by 77 fold in the water and 33 fold in phosphate buffer (pH 7) compared to the other salts. Dynamic vapor sorption (DVS) showed reversible water sorption without hysteresis for all salts, except for GBA-K form II which transformed to form I after a sorption and desorption cycle as confirmed by PXRD.

}, issn = {1466-8033}, doi = {10.1039/c6ce02295b}, author = {Suresh, Kuthuru and Khandavilli, U. B. Rao and Gunnam, Anilkumar and Nangia, Ashwini} } @article {44444, title = {Curcumin: pharmaceutical solids as a platform to improve solubility and bioavailability}, journal = {Crystengcomm}, volume = {20}, year = {2018}, month = {JUN}, pages = {3277-3296}, abstract = {Curcumin (CUR) is the prime curcuminoid in the Indian dietary spice turmeric, Curcuma longa, a plant of the Zingiberaceae family. CUR has promising and diverse therapeutic benefits, such as antioxidant, anti-inflammatory, antitumor, anti-hyperglycemic, antimalarial, antibacterial, and antiviral activity, including anti-Alzheimer{\textquoteright}s disease. However, CUR is yet to reach the status of a therapeutic drug candidate mainly because a standard solid dosage of curcumin suffers from poor oral bioavailability (0.05 g mL(-1), less than 1\%). The reasons behind its low bioavailability include poor solubility (<8 g mL(-1) in water), low permeability and absorption, and rapid metabolism (short elimination half-life of <2 h). A successful CUR therapy requires an appropriate formulation system that will enhance the bioavailability and offer greater therapeutic efficacy. This review covers a comprehensive description of the CUR pharmaceutical solids, such as polymorphs, cocrystals, eutectics, and coamorphous solid-state forms with aim to determine ways to improve its physicochemical properties, including dissolution rate, solubility, physicochemical stability, mechanical strength, compressibility for tablet formation, and oral bioavailability. The cumulative publications in the past decade have forecast a bright future for development of an oral drug formulation of curcumin.}, doi = {10.1039/c8ce00469b}, author = {Suresh, Kuthuru and Nangia, Ashwini} } @article {44445, title = {Curcumin-artemisinin coamorphous solid: Xenograft model preclinical study}, journal = {Pharmaceutics}, volume = {10}, year = {2018}, month = {MAR}, pages = {Article Number: 7}, abstract = {Curcumin is a natural compound present in Indian spice turmeric. It has diverse pharmacological action but low oral solubility and bioavailability continue to limit its use as a drug. With the aim of improving the bioavailability of Curcumin (CUR), we evaluated Curcumin-Pyrogallol (CUR-PYR) cocrystal and Curcumin-Artemisinin (CUR-ART) coamorphous solid. Both of these solid forms exhibited superior dissolution and pharmacokinetic behavior compared to pure CUR, which is practically insoluble in water. CUR-ART coamorphous solid showed two fold higher bioavailability than CUR-PYR cocrystal (at 200 mg/kg oral dose). Moreover, in simulated gastric and intestinal fluids (SGF and SIF), CUR-ART is stable up to 3 and 12 h, respectively. In addition, CUR-PYR and CUR-ART showed no adverse effects in toxicology studies (10 times higher dose at 2000 mg/kg). CUR-ART showed higher therapeutic effect and inhibited approximately 62\% of tumor growth at 100 mg/kg oral dosage of CUR in xenograft models, which is equal to the positive control drug, doxorubicin (2 mg/kg) by i.v. administration.}, doi = {10.3390/pharmaceutics10010007}, author = {Mannava, M. K. Chaitanya and Suresh, Kuthuru and Bommaka, Manish Kumar and Konga, Durga Bhavani and Nangia, Ashwini} } @article {45448, title = {Entacapone: improving aqueous solubility, diffusion permeability, and cocrystal stability with theophylline}, journal = {Crystal Growth \& Design}, volume = {18}, year = {2018}, month = {OCT}, pages = {6061-6069}, type = {Article}, abstract = {Cocrystallization is a well-established technique to improve the solubility, bioavailability, and stability of active pharmaceutical ingredients (APIs) but permeability and diffusion rate control via cocrystals is relatively less well studied, and the exact role of coformers in influencing the diffusion rate of drug cocrystals is still not fully understood. The aqueous solubility and permeability diffusion of Entacapone, ETP, a Biopharmaceutical Classification System (BCS) Class IV drug of low solubility and low permeability, with Generally Regarded as Safe (GRAS) coformers has been studied. Fixed stoichiometry cocrystals of ETP with acetamide (ACT, 1:1), nicotinamide (NAM, 1:1), isonicotinamide (INAM, 1:1), pyrazinamide (PYZ, 1:1), and isoniazid (INZ), 1:1) were prepared by solvent-assisted grinding. Theophylline (THP) resulted in a cocrystal hydrate (ETP-THP-FIYD 1:1:1). The cocrystals were structurally characterized by single crystal and powder X-ray diffraction, DSC and TGA thermal measurements, and IR and NMR spectroscopy. Solubility and dissolution rate showed that there is a correlation between cocrystal stability and solubility governed by the heteromeric N-H center dot center dot center dot O, O-H center dot center dot center dot N, and O-H center dot center dot center dot O hydrogen bonds and conformational changes of ETP in cocrystal structures. ETP-THP-HYD and ETP-PYZ exhibit faster dissolution rate and high solubility and they are stable in phosphate buffer medium compared to the other cocrystals which dissociate partially during solubility experiments. Diffusion rates in a Franz cell showed that the stable and high solubility ETP-THP-HYD cocrystal has good permeability. Given that stability, solubility, and permeability are in general inversely correlated, the entacapone-theophylline hydrate cocrystal is a unique example of the thermodynamically stable cocrystal exhibiting high solubility and high permeability.}, issn = {1528-7483}, doi = {10.1021/acs.cgd.8b00921}, author = {Bommaka, Manish Kumar and Mannava, M. K. Chaitanya and Suresh, Kuthuru and Gunnam, Anilkumar and Nangia, Ashwini} } @article {44390, title = {Salts and salt cocrystals of the antibacterial drug pefloxacin}, journal = {Crystal Growth \& Design}, volume = {18}, year = {2018}, month = {MAY}, pages = {2824-2835}, abstract = {Pefloxacin (PEF) is an amphoteric, antibacterial drug which exists as a neutral molecule in the crystal structure stabilized by C-H center dot center dot center dot O and C-H center dot center dot center dot F interactions. The design of multicomponent solids using crystal engineering was undertaken in a cocrystal/salt screen of PEF with generally recognized as safe (GRAS) dicarboxylic acids to improve the solubility and phase stability of the drug. Ten multicomponent forms, namely, five salts, two salt hydrates, and three salt cocrystals, were prepared by liquid-assisted grinding followed by crystallization. In some cases, salt and salt cocrystals were obtained concomitantly during solution evaporative crystallization. Single crystal X-ray diffraction showed that the structures are stabilized by N+-H center dot center dot center dot O-, O-H center dot center dot center dot O, C-H center dot center dot center dot O, C-H center dot center dot center dot F, and pi-pi stacking interactions. The bulk phase purity of multicomponent forms was characterized by powder X-ray diffraction, spectroscopy, and thermal techniques. The salt/salt cocrystal forms exhibit a faster dissolution rate and higher solubility compared to pure PEF in pH 1.2 (acidic, like gastric environment) and pH 7 phosphate buffer media (neutral, like intestinal passage). Specifically the PEF+-SA(-) salt (SA = succinic acid) showed remarkably high solubility, dissolution rate, and stability compared to the other multicomponent forms and PEF neutral form. The drug formulation compatible pefloxacin succinate is a promising soluble and stable PEF salt.}, doi = {10.1021/acs.cgd.7b01600}, author = {Gunnam, Anilkumar and Suresh, Kuthuru and Nangia, Ashwini} } @article {46141, title = {Role of hydrogen bonding in cocrystals and coamorphous solids: indapamide as a case study}, journal = {Crystengcomm}, volume = {21}, year = {2019}, month = {APR }, pages = {2043-2048}, type = {Article}, abstract = {

The stronger sulfonamide-pyridine (SO2NH2 center dot center dot center dot N-Py) and sulfonamide-carboxamide (SO2NH2 center dot center dot center dot O = C-NH) hydrogen bonds direct the formation of cocrystals, while the weaker sulfonamide-amine (SO2NH2 center dot center dot center dot N-H) hydrogen bond results in coamorphous products. IDP-PIP and IDP-ARG coamorphous solids exhibit remarkable stability under accelerated conditions.

}, issn = {1466-8033}, doi = {10.1039/c8ce01075g}, author = {Allu, Suryanarayana and Suresh, Kuthuru and Bolla, Geetha and Mannava, M. K. Chaitanya and Nangia, Ashwini} } @article {47684, title = {Entacapone polymorphs: crystal structures, dissolution, permeability, and stability}, journal = {Crystal Growth \& Design}, volume = {21}, year = {2021}, month = {OCT }, pages = {5573-5585}, type = {Article}, abstract = {Entacapone (ETP) is a catechol-O-methyltransferase (COMT) drug used to treat Parkinson{\textquoteright}s disease. ETP is available in the marketplace under the brand name Comtan since 2010, and ETP form-I was first reported in a patent published in 2001. However, analysis of its Xray crystal structures and stability relationship of ETP polymorphs and their dissolution and permeability profile have not yet been reported. We crystallized two new conformational polymorphs of ETP from a water and acetone mixture and studied the structural origin of polymorphism and their phase transformations, stability, equilibrium solubility, dissolution, and permeability properties. The ETP molecule adopts different conformations in the polymorphic structures with slight changes in carbonyl and nitrile group orientations. Thermal analysis suggests that form-III and form-IV are enantiotropically related to form-I, which is the thermodynamically stable form at ambient conditions. In contrast, form-II is monotropically related to form-I. Equilibrium solubility, dissolution, and permeability studies show that form-II persists in the slurry medium and dissolves faster with a high flux rate compared to the stable form-I in phosphate buffer solution at 37 +/- 0.5 degrees C.}, issn = {1528-7483}, doi = {10.1021/acs.cgd.1c00381}, author = {Bommaka, Manish Kumar and Mannava, M. K. Chaitanya and Rai, Sunil K. and Suresh, Kuthuru and Nangia, Ashwini K.} }