Suryanarayan Cherukuvada

Nitrofurantoin–p-aminobenzoic acid cocrystal: Hydration stability and dissolution rate studies

Nitrofurantoin (NF) drug is known to transform to a hydrate form in aqueous medium. The hydration stability and dissolution rate of a few cocrystals of NF were compared with that of its stable β polymorph and hydrate form II. Hydrogen bonding and molecular packing in the novel cocrystal structures were analyzed. Pharmaceutical cocrystals of NF with p-aminobenzoic acid (PABA) and urea showed superior physicochemical properties compared with the known L-arginine salt hydrate. All the solid-state adducts were characterized by single-crystal X-ray diffraction, X-ray powder diffraction, differential scanning calorimetry, and thermogravimetric analysis. NF-PABA cocrystal was found to be superior among the compounds studied in terms of minimal transformation to NF hydrate and comparable dissolution rate to the reference drug.

Fast dissolving eutectic compositions of two anti-tubercular drugs

Co-crystallization of anti-tubercular drugs pyrazinamide (PZA) and isoniazid (INH) with each other and with dicarboxylic acid coformers was studied. Grinding of the two drugs to make a co-crystal resulted instead in a 1:1 binary eutectic, PZA–INH, and addition of succinic acid (SA) and fumaric acid (FA) to the binary drugs gave a 1:1:1 ternary eutectic composition, PZA–SA–INH and PZA–FA–INH, respectively. The 1:0.5 binary drug–diacid adducts, PZA–SA, PZA–FA, INH–SA and INH–FA, are co-crystal structures by single crystal X-ray diffraction. The ternary eutectics PZA–diacid–INH were identified as composed of the co-crystals PZA–(diacid)0.5 and INH–diacid(0.5) rather than the pure components. All new crystalline multi-component phases were characterized by powder X-ray diffraction, differential scanning calorimetry, infrared, and solid-state NMR. Solubility and dissolution experiments on the novel phases showed that their intrinsic dissolution rates are in the order, PZA–SA–INH > INH > PZA–INH > PZA–FA–INH > PZA. Thus pyrazinamide–isoniazid two-drug combination becomes a fast dissolving ternary eutectic phase with succinic acid.

Polymorphism in an API ionic liquid: ethambutol dibenzoate trimorphs

Three polymorphs of the dibenzoate salt of the anti-tubercular drug ethambutol (EDB) were crystallized as ionic liquids (m.p. < 100 °C) and characterized by diffraction (PXRD), thermal (DSC) and spectroscopy (IR, Raman, ss-NMR) techniques. Their stability relationships were established by DSC and VT-PXRD: EDB form 1 is the most stable, followed by form 3, and form 2 is the least stable at room temperature (25 °C); form 3 is the most stable, then form 1, and form 2 is the least stable at high temperature (90 °C).

High solubility crystalline hydrates of Na and K furosemide salts

Novel sodium and potassium salts of the poorly soluble loop diuretic drug furosemide were prepared with the intent of improving drug solubility and bioavailability. Furo–Na salt was obtained as a trihydrate upon crystallization from aqueous NaOH solution, and furo–K salt crystallized as a monohydrate from KOH solution. Both salt hydrates were characterized by X-ray diffraction, DSC, TGA, and IR spectroscopy. An exothermic phase transition at 165 °C in the DSC heating curve of the furo–Na salt indicates the likelihood of polymorphism in its anhydrate phase. Based on solubility studies, furo–Na–trihydrate and furo–K–monohydrate in pH 7 phosphate buffer medium exhibited significantly higher aqueous solubilities of 41 mg mL−1 and 106 mg mL−1 compared to the free drug (0.01 mg mL−1). The physical stability of these fast dissolving salts under accelerated ICH conditions of 40 °C and 75% RH was modest, with furo–Na salt being stable for 2 weeks and furo–K salt for 1 week.

Polymorphism in metformin embonate salt – recurrence of dimeric and tetrameric guanidinium–carboxylate synthons

In this manuscript, we discuss two novel polymorphic crystal structures of metformin–embonate, a drug widely known for its use in anti-diabetic treatments. Form I crystallizes in the monoclinic P21/c space group and form II in the triclinic P space group. Both polymorphs contain 2 : 1 stoichiometry of metformin and embonic acid. Proton transfer results in a guanidinium carboxylate ion pair which has well aligned donor and acceptor groups for effective hydrogen bonding. Two types of guanidinium–carboxylate variations are observed in the polymorphs. The first is the dimer motif, R22 (8), and the second is the tetramer motif, R24 (16). In addition, there is a self complementary N–H⋯N dimer motif, R22 (8), between the two guanidinium groups. It is interesting to note that both polymorphs contain these three synthons but the arrangement of the synthons differs between them. Predominantly, these are packing polymorphs. The highly recurring nature or robustness of the synthons is likely to arise from the structural complementary nature of the interacting groups and due to the charge assistance in the ion pair. The subtle hydrogen bonding differences in the polymorphs are corroborated with infrared and Raman spectroscopic observations. The polymorph stability relationships are established through DSC, a slurry method, equilibrium solubility and IDR measurements. The results indicate that the polymorphs have an enantiotropic relationship – form I is the high temperature stable form and form II is the room temperature stable form. Form II, the more stable form at RT, has lower solubility and lower dissolution rates compared to form I. The guanidine–carboxylate dimer synthon is estimated to be highly robust in the CSD synthon analysis (72.3% in the presence of competing groups and 96.3% in their absence), which can be reliably explored for crystal engineering applications.

Adaptability of aripiprazole towards forming isostructural hydrogen bonding networks in multi-component salts: a rare case of strong O–H⋯O− ↔ weak C–H⋯O mimicry

Aripiprazole is complexed with benzoic acid (I), 2,4-dihydroxybenzoic acid (II), 2,5-dihydroxybenzoic acid (III), hydrochloric acid (IV) and salicylic acid (V). The resulting salts are characterized by single crystal X-ray diffraction, powder X-ray diffraction, infrared spectroscopy, differential scanning calorimetry, and thermogravimetric analysis. Two salts from the Cambridge Structural Database (aripiprazole nitrate and perchlorate) are included for structural comparison. Interestingly, aripiprazole forms two types of isostructural crystals with the modulation of its conformation and hydrogen bond synthons. Salts with aromatic acids engage in three-dimensional isostructural helical networks and the inorganic acid salts form two-dimensional layered networks. Remarkably, the helices mediated by strong charge assisted O–H⋯O− interactions are mimicked by weaker neutral C–H⋯O interactions in aromatic salts of aripiprazole. Our results suggest the isostructurality may be more common in multi-component systems. The salts are stable and can be potential alternatives for suitable formulation of aripiprazole.

Blonanserin HCl salt and its monohydrate

X-Ray crystal structure of the hydrochloride salt of an antipsychotic drug blonanserin (BLN) and characterization of a high temperature polymorph are reported. The crystal structure of BLN HCl monohydrate was determined. All new solid-state forms are characterized by X-ray diffraction, thermal microscopy, ss-NMR, and FT-IR spectroscopy. BLN HCl transformed to its monohydrate form during solubility measurement. The solubility of BLN and BLN HCl monohydrate in 60% EtOH–water is 1.6 g L−1 and 119.2 g L−1 respectively.

Molecular salts of urocanic acid and L-histidine

Urocanic acid (UA), an intermediate of L-Histidine (LH) catabolism, is a natural sunscreen and photoprotectant against UV-B induced DNA damage. UA exists as a hydrated zwitterion in the crystalline state, unlike its precursor L-Histidine which is an anhydrate, and interestingly, no multi-component crystal forms of UA are reported. In our endeavour to understand the subtle factors that govern the co-crystallization behavior of structurally related molecules, UA and LH have been selected for extensive co-crystallization studies with hydroxybenzoic acids. It is noteworthy that UA prefers to form anhydrous molecular salts while LH results in salts which are hydrated! Based on the single crystal structural analysis it has been clearly illustrated that the presence of an additional amine group in LH which anticipates an auxiliary hydrogen bond for a stable supramolecular assembly, a moiety like water which hydrates the compound would be preferred. In this context, the role of ortho-hydroxy group and symmetrically substituted hydroxy groups in the formation and/or non-formation (in certain cases) of UA and LH molecular salts is analysed. In addition, we also report the first ever guest-free (anhydrous form) structure of native UA and studied its hydration/dehydration property. The formation of anhydrous salts in hydrated UA and hydrated salts in anhydrous LH have been explored. [1] Mohammad, T. et al. (1999). Photochemistry and Photobiology. 69, 115-135. [2] Cambridge Structural Database (2016). Cambridge Crystallographic Data Centre, version. 5.37, ConQuest, 1.18, http://www.ccdc.cam.ac.uk/. [3] Ganduri, R. et al. (2017). CrystEngComm. 19, 1123-1132.

Solid-form screening of antiepileptic drug retigabine

Epilepsy is a common neurological disorder observed in an estimated prevalence of 1% of the world’s population. The therapeutic strategy in treating epilepsy involves reducing neuronal excitability. Retigabine (RTG) has been developed as an orally active, neuronal potassium channel opener and with its low solubility and high permeability is identified as a class II drug under the Biopharmaceutics Classification System (BCS) as a water insoluble drug. Hence, enhancing the aqueous solubility is crucial for the dosage to be minimized thus enhancing both clinical (reducing side effects) and commercial aspects. We have approached this issue in terms of polymorphism, cocrystallization adducts including salts, cocrystals and eutectics of RTG. Retigabine exists in three polymorphic forms, two are determined from single crystal X-ray diffraction studies, The third form is less stable and readily converts to the most stable form A. Further, thermal and seeding experiments are performed to determine the stability order among the three polymorphs. Co-cocrystallization of RTG results in a nitrate salt, cocrystal of hydroxy substituted benzoic acids, a eutectic with benzoic acid and the structural aspects of these water soluble adducts have been analysed.

Multi-component adducts of benzoic acid–fluorobenzoic acid combinations

Cocrystals and solid solutions are different yet related crystalline multi-component adducts known to modulate the physicochemical properties of various chemical substances, thus finding applications in pharmaceutical and materials science. Solid solutions are more candid to design than cocrystals as it is well-established that a solid solution is formed by substitutional incorporation of a substance in the crystal lattice of another substance based on the isomorphous and/or isostructural relationships. Thus, a solid solution retains homomeric interactions and adopts the crystal structure of one of the parent substances. In contrast, a cocrystal can manifest for a combination wherein heteromeric interactions outweigh homomeric interactions of individual components. Since the heteromeric interactions are structure-directing, a cocrystal has unique crystal packing and can be readily characterized by X-ray diffraction techniques. Cocrystallization behaviour among various benzoic acid–fluorobenzoic acid combinations is explored to evaluate the propensity of preferred adduct in these combinations. It is reported that benzoic acid-4-fluorobenzoic acid combination forms a solid solutions whereas benzoic acid-pentafluorobenzoic acid combination forms a cocrystal. In the background of these extremes, a systematic cocrystallization study has been undertaken to determine the effect of number of fluorine atoms in the metamorphosis of homomeric interactions to heteromeric ones for combinations containing di-, triand tetra-fluorobenzoic acids. The gradation from solid solution (BA–monofluoro BA) to cocrystal (BA–pentafluoro BA) with eutectic phases in certain diand trifluorobenzoic acid combinations is discussed. The study involves crystal structure determination, powder diffraction and thermal analysis and thus allows for deriving general guidelines to generate desired crystal forms by fine tuning heteroand homomeric interactions.